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Article Contents

Introduction, human enhancement, genetic engineering, conclusions.

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Human enhancement: Genetic engineering and evolution

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Mara Almeida, Rui Diogo, Human enhancement: Genetic engineering and evolution, Evolution, Medicine, and Public Health , Volume 2019, Issue 1, 2019, Pages 183–189, https://doi.org/10.1093/emph/eoz026

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Genetic engineering opens new possibilities for biomedical enhancement requiring ethical, societal and practical considerations to evaluate its implications for human biology, human evolution and our natural environment. In this Commentary, we consider human enhancement, and in particular, we explore genetic enhancement in an evolutionary context. In summarizing key open questions, we highlight the importance of acknowledging multiple effects (pleiotropy) and complex epigenetic interactions among genotype, phenotype and ecology, and the need to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). We also propose that a practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations. Overall, we suggest that it is essential for ethical, philosophical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

Lay Summary: This Commentary explores genetic enhancement in an evolutionary context. We highlight the multiple effects associated with germline heritable genetic intervention, the need to consider the unit of impact to human populations and their natural environment, and propose that a practicable distinction between ‘therapy’ and ‘enhancement’ is needed.

There are countless examples where technology has contributed to ameliorate the lives of people by improving their inherent or acquired capabilities. For example, over time, there have been biomedical interventions attempting to restore functions that are deficient, such as vision, hearing or mobility. If we consider human vision, substantial advances started from the time spectacles were developed (possibly in the 13th century), continuing in the last few years, with researchers implanting artificial retinas to give blind patients partial sight [ 1–3 ]. Recently, scientists have also successfully linked the brain of a paralysed man to a computer chip, which helped restore partial movement of limbs previously non-responsive [ 4 , 5 ]. In addition, synthetic blood substitutes have been created, which could be used in human patients in the future [ 6–8 ].

The progress being made by technology in a restorative and therapeutic context could in theory be applied in other contexts to treat non-pathological conditions. Many of the technologies and pharmaceutical products developed in a medical context to treat patients are already being used by humans to ‘enhance’ some aspect of their bodies, for example drugs to boost brain power, nutritional supplements, brain stimulating technologies to control mood or growth hormones for children of short stature. Assistive technology for disabled people, reproductive medicine and pharmacology, beside their therapeutic and restorative use, have a greater potential for human ‘enhancement’ than currently thought. There are also dual outcomes as some therapies can have effects that amount to an enhancement as for example, the artificial legs used by the South African sprinter Oscar Pistorius providing him with a competitive advantage.

This commentary will provide general ethical considerations on human enhancement, and within the several forms of so-called human biomedical enhancement, it will focus on genetic engineering, particularly on germline (heritable) genetic interventions and on the insights evolutionary biology can provide in rationalizing its likely impact. These insights are a subject often limited in discussions on genetic engineering and human enhancement in general, and its links to ethical, philosophical and policy discussions, in particular [ 9 ]. The rapid advances in genetic technology make this debate very topical. Moreover, genes are thought to play a very substantial role in biological evolution and development of the human species, thus making this a topic requiring due consideration. With this commentary, we explore how concepts based in evolutionary biology could contribute to better assess the implications of human germline modifications, assuming they were widely employed. We conclude our brief analysis by summarizing key issues requiring resolution and potential approaches to progress them. Overall, the aim is to contribute to the debate on human genetic enhancement by looking not only at the future, as it is so often done, but also at our evolutionary past.

The noun ‘enhancement’ comes from the verb ‘enhance’, meaning ‘to increase or improve’. The verb enhance can be traced back to the vulgar Latin inaltiare and late Latin inaltare (‘raise, exalt’), from ‘ altare ’ (‘make high’) and altus (‘high’), literally ‘grown tall’. For centuries human enhancement has populated our imagination outlined by stories ranging from the myths of supernormal strengths and eternal life to the superpowers illustrated by the 20th century comic books superheroes. The desire of overcoming normal human capacities and the transformation to an almost ‘perfect’ form has been part of the history of civilization, extending from arts and religion to philosophy. The goal of improving the human condition and health has always been a driver for innovation and biomedical developments.

In the broadest sense, the process of human enhancement can be considered as an improvement of the ‘limitations’ of a ‘natural version’ of the human species with respect to a specific reference in time, and to different environments, which can vary depending on factors such as, for example, climate change. The limitations of the human condition can be physical and/or mental/cognitive (e.g. vision, strength or memory). This poses relevant questions of what a real or perceived human limitation is in the environment and times in which we are living and how it can be shifted over time considering social norms and cultural values of modern societies. Besides, the impact that overcoming these limitations will have on us humans, and the environment, should also be considered. For example, if we boost the immune system of specific people, this may contribute to the development/evolution of more resistant viruses and bacteria or/and lead to new viruses and bacteria to emerge. In environmental terms, enhancing the longevity of humans could contribute to a massive increase in global population, creating additional pressures on ecosystems already under human pressure.

Two decades ago, the practices of human enhancement have been described as ‘biomedical interventions that are used to improve human form or functioning beyond what is necessary to restore or sustain health’ [ 10 ]. The range of these practices has now increased with technological development, and they are ‘any kind of genetic, biomedical, or pharmaceutical intervention aimed at improving human dispositions, capacities, or well-being, even if there is no pathology to be treated’ [ 11 ]. Practices of human enhancement could be visualized as upgrading a ‘system’, where interventions take place for a better performance of the original system. This is far from being a hypothetical situation. The rapid progress within the fields of nanotechnology, biotechnology, information technology and cognitive science has brought back discussions about the evolutionary trajectory of the human species by the promise of new applications which could provide abilities beyond current ones [ 12 , 13 ]. If such a possibility was consciously embraced and actively pursued, technology could be expected to have a revolutionary interference with human life, not just helping humans in achieving general health and capabilities commensurate with our current ones but helping to overcome human limitations far beyond of what is currently possible for human beings. The emergence of new technologies has provided a broader range of potential human interventions and the possibility of transitioning from external changes to our bodies (e.g. external prosthesis) to internal ones, especially when considering genetic manipulation, whose changes can be permanent and transmissible.

The advocates of a far-reaching human enhancement have been referred to as ‘transhumanists’. In their vision, so far, humans have largely worked to control and shape their exterior environments (niche construction) but with new technologies (e.g. biotechnology, information technology and nanotechnology) they will soon be able to control and fundamentally change their own bodies. Supporters of these technologies agree with the possibility of a more radical interference in human life by using technology to overcome human limitations [ 14–16 ], that could allow us to live longer, healthier and even happier lives [ 17 ]. On the other side, and against this position, are the so-called ‘bioconservatives’, arguing for the conservation and protection of some kind of ‘human essence’, with the argument that it exists something intrinsically valuable in human life that should be preserved [ 18 , 19 ].

There is an ongoing debate between transhumanists [ 20–22 ] and bioconservatives [ 18 , 19 , 23 ] on the ethical issues regarding the use of technologies in humans. The focus of this commentary is not centred on this debate, particularly because the discussion of these extreme, divergent positions is already very prominent in the public debate. In fact, it is interesting to notice that the ‘moderate’ discourses around this topic are much less known. In a more moderate view, perhaps one of the crucial questions to consider, independently of the moral views on human enhancement, is whether human enhancement (especially if considering germline heritable genetic interventions) is a necessary development, and represents an appropriate use of time, funding and resources compared to other pressing societal issues. It is crucial to build space for these more moderate, and perhaps less polarized voices, allowing the consideration of other positions and visions beyond those being more strongly projected so far.

Ethical and societal discussions on what constitutes human enhancement will be fundamental to support the development of policy frameworks and regulations on new technological developments. When considering the ethical implications of human enhancement that technology will be available to offer now and in the future, it could be useful to group the different kinds of human enhancements in the phenotypic and genetic categories: (i) strictly phenotypic intervention (e.g. ranging from infrared vision spectacles to exoskeletons and bionic limbs); (ii) somatic, non-heritable genetic intervention (e.g. editing of muscle cells for stronger muscles) and (iii) germline, heritable genetic intervention (e.g. editing of the C–C chemokine receptor type 5 (CCR5) gene in the Chinese baby twins, discussed later on). These categories of enhancement raise different considerations and concerns and currently present different levels of acceptance by our society. The degree of ethical, societal and environmental impacts is likely to be more limited for phenotypic interventions (i) but higher for genetic interventions (ii and iii), especially for the ones which are transmissible to future generations (iii).

The rapid advances in technology seen in the last decades, have raised the possibility of ‘radical enhancement’, defined by Nicholas Agar, ‘as the improvement of human attributes and abilities to levels that greatly exceed what is currently possible for human beings’ [ 24 ]. Genetic engineering offers the possibility of such an enhancement by providing humans a profound control over their own biology. Among other technologies, genetic engineering comprises genome editing (also called gene editing), a group of technologies with the ability to directly modify an organism’s DNA through a targeted intervention in the genome (e.g. insertion, deletion or replacement of specific genetic material) [ 25 ]. Genome editing is considered to achieve much greater precision than pre-existing forms of genetic engineering. It has been argued to be a revolutionary tool due to its efficiency, reducing cost and time. This technology is considered to have many applications for human health, in both preventing and tackling disease. Much of the ethical debate associated with this technology concerns the possible application of genome editing in the human germline, i.e. the genome that can be transmitted to following generations, be it from gametes, a fertilized egg or from first embryo divisions [ 26–28 ]. There has been concern as well as enthusiasm on the potential of the technology to modify human germline genome to provide us with traits considered positive or useful (e.g. muscle strength, memory and intelligence) in the current and future environments.

Genetic engineering: therapy or enhancement and predictability of outcomes

To explore some of the possible implications of heritable interventions we will take as an example the editing (more specifically ‘deletion’ using CRISPR genome editing technology) of several base pairs of the CCR5 gene. Such intervention was practised in 2018 in two non-identical twin girls born in China. Loss of function mutations of the CCR5 had been previously shown to provide resistance to HIV. Therefore, the gene deletion would be expected to protect the twin baby girls from risk of transmission of HIV which could have occurred from their father (HIV-positive). However, the father had the infection kept under control and the titre of HIV virus was undetectable, which means that risk of transmission of HIV infection to the babies was negligible [ 29 ].

From an ethical ground, based on current acceptable practices, this case has been widely criticized by the scientific community beside being considered by many a case of human enhancement intervention rather than therapy [ 29 , 30 ]. One of the questions this example helps illustrate is that the ethical boundary between a therapy that ‘corrects’ a disorder by restoring performance to a ‘normal’ scope, and an intervention that ‘enhances’ human ability outside the accepted ‘normal’ scope, is not always easy to draw. For the sake of argument, it could be assumed that therapy involves attempts to restore a certain condition of health, normality or sanity of the ‘natural’ condition of a specific individual. If we take this approach, the question is how health, normality and sanity, as well as natural per se, are defined, as the meaning of these concepts shift over time to accommodate social norms and cultural values of modern societies. It could be said that the difficulty of developing a conceptual distinction between therapy and enhancement has always been present. However, the potential significance of such distinction is only now, with the acceleration and impact of technological developments, becoming more evident.

Beyond ethical questions, a major problem of this intervention is that we do not (yet?) know exactly the totality of the effects that the artificial mutation of the CCR5 may have, at both the genetic and phenotypic levels. This is because we now know that, contrary to the idea of ‘one gene-one trait’ accepted some decades ago, a gene—or its absence—can affect numerous traits, many of them being apparently unrelated (a phenomenon also known as pleiotropy). That is, due to constrained developmental interactions, mechanisms and genetic networks, a change in a single gene can result in a cascade of multiple effects [ 31 ]. In the case of CCR5, we currently know that the mutation offers protection against HIV infection, and also seems to increase the risk of severe or fatal reactions to some infectious diseases, such as the influenza virus [ 32 ]. It has also been observed that among people with multiple sclerosis, the ones with CCR5 mutation are twice as likely to die early than are people without the mutation [ 33 ]. Some studies have also shown that defective CCR5 can have a positive effect in cognition to enhance learning and memory in mice [ 34 ]. However, it’s not clear if this effect would be translated into humans. The example serves to illustrate that, even if human enhancement with gene editing methods was considered ethically sound, assessing the totality of its implications on solid grounds may be difficult to achieve.

Genetic engineering and human evolution: large-scale impacts

Beyond providing the opportunity of enhancing human capabilities in specific individuals, intervening in the germline is likely to have an impact on the evolutionary processes of the human species raising questions on the scale and type of impacts. In fact, the use of large-scale genetic engineering might exponentially increase the force of ‘niche construction’ in human evolution, and therefore raise ethical and practical questions never faced by our species before. It has been argued that natural selection is a mechanism of lesser importance in the case of current human evolution, as compared to other organisms, because of advances in medicine and healthcare [ 35 ]. According to such a view, among many others advances, natural selection has been conditioned by our ‘niche-construction’ ability to improve healthcare and access to clean water and food, thus changing the landscape of pressures that humans have been facing for survival. An underlying assumption or position of the current debate is that, within our human species, the force of natural selection became minimized and that we are somehow at the ‘end-point’ of our evolution [ 36 ]. If this premise holds true, one could argue that evolution is no longer a force in human history and hence that any human enhancement would not be substituting itself to human evolution as a key driver for future changes.

However, it is useful to remember that, as defined by Darwin in his book ‘On the Origin of the Species’, natural selection is a process in which organisms that happen to be ‘better’ adapted to a certain environment tend to have higher survival and/or reproductive rates than other organisms [ 37 ]. When comparing human evolution to human genetic enhancement, an acceptable position could be to consider ethically sound those interventions that could be replicated naturally by evolution, as in the case of the CCR5 gene. Even if this approach was taken, however, it is important to bear in mind that human evolution acts on human traits sometimes increasing and sometimes decreasing our biological fitness, in a constant evolutionary trade-off and in a contingent and/or neutral—in the sense of not ‘progressive’—process. In other worlds, differently from genetic human enhancement, natural selection does not ‘ aim ’ at improving human traits [ 38 ]. Human evolution and the so-called genetic human enhancement would seem therefore to involve different underlying processes, raising several questions regarding the implications and risks of the latter.

But using genetic engineering to treat humans has been proposed far beyond the therapeutic case or to introduce genetic modifications known to already occur in nature. In particular, when looking into the views expressed on the balance between human evolution and genetic engineering, some argue that it may be appropriate to use genetic interventions to go beyond what natural selection has contributed to our species when it comes to eradicate vulnerabilities [ 17 ]. Furthermore, when considering the environmental, ecological and social issues of contemporary times, some suggest that genetic technologies could be crucial tools to contribute to human survival and well-being [ 20–22 ]. The possible need to ‘engineer’ human traits to ensure our survival could include the ability to allow our species to adapt rapidly to the rate of environmental change caused by human activity, for which Darwinian evolution may be too slow [ 39 ]. Or, for instance, to support long-distance space travel by engineering resistance to radiation and osteoporosis, along with other conditions which would be highly advantageous in space [ 40 ].

When considering the ethical and societal merits of these propositions, it is useful to consider how proto-forms of enhancement has been approached by past human societies. In particular, it can be argued that humans have already employed—as part of our domestication/‘selective breeding’ of other animals—techniques of indirect manipulation of genomes on a relatively large scale over many millennia, albeit not on humans. The large-scale selective breeding of plants and animals over prehistoric and historic periods could be claimed to have already shaped some of our natural environment. Selective breeding has been used to obtain specific characteristics considered useful at a given time in plants and animals. Therefore, their evolutionary processes have been altered with the aim to produce lineages with advantageous traits, which contributed to the evolution of different domesticated species. However, differently from genetic engineering, domestication possesses inherent limitations in its ability to produce major transformations in the created lineages, in contrast with the many open possibilities provided by genetic engineering.

When considering the impact of genetic engineering on human evolution, one of questions to be considered concerns the effects, if any, that genetic technology could have on the genetic pool of the human population and any implication on its resilience to unforeseen circumstances. This underlines a relevant question associated with the difference between ‘health’ and biological fitness. For example, a certain group of animals can be more ‘healthy’—as domesticated dogs—but be less biologically ‘fit’ according to Darwin’s definition. Specifically, if such group of animals are less genetically diverse than their ancestors, they could be less ‘adaptable’ to environmental changes. Assuming that, the human germline modification is undertaken at a global scale, this could be expected to have an effect, on the distribution of genetically heritable traits on the human population over time. Considering that gene and trait distributions have been changing under the processes of evolution for billions of years, the impact on evolution will need to be assessed by analysing which genetic alterations have been eventually associated with specific changes within the recent evolutionary history of humans. On this front, a key study has analysed the implications of genetic engineering on the evolutionary biology of human populations, including the possibility of reducing human genetic diversity, for instance creating a ‘biological monoculture’ [ 41 ]. The study argued that genetic engineering will have an insignificant impact on human diversity, while it would likely safeguard the capacity of human populations to deal with disease and new environmental challenges and therefore, ensure the health and longevity of our species [ 41 ]. If the findings of this study were considered consistent with other knowledge and encompassing, the impact of human genetic enhancements on the human genetic pool and associated impacts could be considered secondary aspects. However, data available from studies on domestication strongly suggests that domestication of both animals and plans might lead to not only decreased genetic diversity per se, but even affect patterns of variation in gene expression throughout the genome and generally decreased gene expression diversity across species [ 42–44 ]. Given that, according to recent studies within the field of biological anthropology recent human evolution has been in fact a process of ‘self-domestication’ [ 45 ], one could argue that studies on domestication could contribute to understanding the impacts of genetic engineering.

Beyond such considerations, it is useful to reflect on the fact that human genetic enhancement could occur on different geographical scales, regardless of the specific environment and geological periods in which humans are living and much more rapidly than in the case of evolution, in which changes are very slow. If this was to occur routinely and on a large scale, the implications of the resulting radical and abrupt changes may be difficult to predict and its impacts difficult to manage. This is currently highlighted by results of epigenetics studies, and also of the microbiome and of the effects of pollutants in the environment and their cumulative effect on the development of human and non-human organisms alike. Increasingly new evidence indicates a greater interdependence between humans and their environments (including other microorganisms), indicating that modifying the environment can have direct and unpredictable consequences on humans as well. This highlight the need of a ‘systems level’ approach. An approach in which the ‘bounded body’ of the individual human as a basic unit of biological or social action would need to be questioned in favour of a more encompassing and holistic unit. In fact, within biology, there is a new field, Systems Biology, which stresses the need to understand the role that pleiotropy, and thus networks at multiple levels—e.g. genetic, cellular, among individuals and among different taxa—play within biological systems and their evolution [ 46 ]. Currently, much still needs to be understood about gene function, its role in human biological systems and the interaction between genes and external factors such as environment, diet and so on. In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of human evolution enable us to better understand the implications of genetic interventions.

New forms of human enhancement are increasingly coming to play due to technological development. If phenotypic and somatic interventions for human enhancement pose already significant ethical and societal challenges, germline heritable genetic intervention, require much broader and complex considerations at the level of the individual, society and human species as a whole. Germline interventions associated with modern technologies are capable of much more rapid, large-scale impacts and seem capable of radically altering the balance of humans with the environment. We know now that beside the role genes play on biological evolution and development, genetic interventions can induce multiple effects (pleiotropy) and complex epigenetics interactions among genotype, phenotype and ecology of a certain environment. As a result of the rapidity and scale with which such impact could be realized, it is essential for ethical and societal debates, as well as underlying scientific studies, to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). An important practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations, although a distinct line between the two may be difficult to draw.

In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of humans and other organisms, including domesticated ones, enable us to better understand the implications of genetic interventions. In particular, effective regulation of genetic engineering may need to be based on a deep knowledge of the exact links between phenotype and genotype, as well the interaction of the human species with the environment and vice versa .

For a broader and consistent debate, it will be essential for technological, philosophical, ethical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) of Portugal [CFCUL/FIL/00678/2019 to M.A.].

Conflict of interest : None declared.

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Harvard researchers, others share their views on key issues in the field

Medicine is at a turning point, on the cusp of major change as disruptive technologies such as gene, RNA, and cell therapies enable scientists to approach diseases in new ways. The swiftness of this change is being driven by innovations such as CRISPR gene editing , which makes it possible to correct errors in DNA with relative ease.

Progress in this field has been so rapid that the dialogue around potential ethical, societal, and safety issues is scrambling to catch up.

This disconnect was brought into stark relief at the Second International Summit on Human Genome Editing , held in Hong Kong in November, when exciting updates about emerging therapies were eclipsed by a disturbing announcement. He Jiankui, a Chinese researcher, claimed that he had edited the genes of two human embryos, and that they had been brought to term.

There was immediate outcry from scientists across the world, and He was subjected to intense social pressure, including the removal of his affiliations, for having allegedly disregarded ethical norms and his patients’ safety.

Yet as I. Glenn Cohen, faculty director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, has said, gene editing comes in many varieties, with many consequences. Any deep ethical discussion needs to take into account those distinctions.

Human genome editing: somatic vs. germline

The germline editing He claimed to have carried out is quite different from the somatic gene therapies that are currently changing the frontiers of medicine. While somatic gene editing affects only the patient being treated (and only some of his or her cells), germline editing affects all cells in an organism, including eggs and sperm, and so is passed on to future generations. The possible consequences of that are difficult to predict.

Somatic gene therapies involve modifying a patient’s DNA to treat or cure a disease caused by a genetic mutation. In one clinical trial, for example, scientists take blood stem cells from a patient, use CRISPR techniques to correct the genetic mutation causing them to produce defective blood cells, then infuse the “corrected” cells back into the patient, where they produce healthy hemoglobin. The treatment changes the patient’s blood cells, but not his or her sperm or eggs.

Germline human genome editing, on the other hand, alters the genome of a human embryo at its earliest stages. This may affect every cell, which means it has an impact not only on the person who may result, but possibly on his or her descendants. There are, therefore, substantial restrictions on its use.

Germline editing in a dish can help researchers figure out what the health benefits could be, and how to reduce risks. Those include targeting the wrong gene; off-target impacts, in which editing a gene might fix one problem but cause another; and mosaicism, in which only some copies of the gene are altered. For these and other reasons, the scientific community approaches germline editing with caution, and the U.S. and many other countries have substantial policy and regulatory restrictions on using germline human genome editing in people.

But many scientific leaders are asking: When the benefits are believed to outweigh the risks, and dangers can be avoided, should science consider moving forward with germline genome editing to improve human health? If the answer is yes, how can researchers do so responsibly?

CRISPR pioneer Feng Zhang of the Broad Institute of Harvard and MIT responded immediately to He’s November announcement by calling for a moratorium on implanting edited embryos in humans. Later, at a public event on “Altering the Human Genome” at the Belfer Center at Harvard Kennedy School (HKS), he explained why he felt it was important to wait:

“The moratorium is a pause. Society needs to figure out if we all want to do this, if this is good for society, and that takes time. If we do, we need to have guidelines first so that the people who do this work can proceed in a responsible way, with the right oversight and quality controls.”

Professors at the University’s schools of medicine, law, business, and government saw He’s announcement as a turning point in the discussion about heritable gene therapies and shared their perspectives on the future of this technology with the Gazette.

Here are their thoughts, issue by issue:

Aside from the safety risks, human genome editing poses some hefty ethical questions. For families who have watched their children suffer from devastating genetic diseases, the technology offers the hope of editing cruel mutations out of the gene pool. For those living in poverty, it is yet another way for the privileged to vault ahead. One open question is where to draw the line between disease treatment and enhancement, and how to enforce it, considering differing attitudes toward conditions such as deafness.

Robert Truog , director of the Center for Bioethics at Harvard Medical School (HMS), provided context:

“This question is not as new as it seems. Evolution progresses by random mutations in the genome, which dwarf what can be done artificially with CRISPR. These random mutations often cause serious problems, and people are born with serious defects. In addition, we have been manipulating our environment in so many ways and exposing ourselves to a lot of chemicals that cause unknown changes to our genome. If we are concerned about making precise interventions to cure disease, we should also be interested in that.

“To me, the conversation around Dr. He is not about the fundamental merits of germline gene editing, which in the long run will almost certainly be highly beneficial. Instead, it’s about the oversight of science. The concern is that with technologies that are relatively easy to use, like CRISPR, how does the scientific community regulate itself? If there’s a silver lining to this cloud, I think it is that the scientific community did pull together to be critical of this work, and took the responsibility seriously to use the tools available to them to regulate themselves.”

When asked what the implications of He’s announcement are for the emerging field of precision medicine, Richard Hamermesh, faculty co-chair of the Harvard Business School/Kraft Precision Medicine Accelerator, said:

“Before we start working on embryos, we have a long way to go, and civilization has to think long and hard about it. There’s no question that gene editing technologies are potentially transformative and are the ultimate precision medicine. If you could precisely correct or delete genes that are causing problems — mutating or aberrant genes — that is the ultimate in precision. It would be so transformative for people with diseases caused by a single gene mutation, like sickle cell anemia and cystic fibrosis. Developing safe, effective ways to use gene editing to treat people with serious diseases with no known cures has so much potential to relieve suffering that it is hard to see how anyone could be against it.

“There is also commercial potential and that will drive it forward. A lot of companies are getting venture funding for interesting gene therapies, but they’re all going after tough medical conditions where there is an unmet need — [where] nothing is working — and they’re trying to find gene therapies to cure those diseases. Why should we stop trying to find cures?

“But anything where you’re going to be changing human embryos, it’s going to take a long time for us to figure out what is appropriate and what isn’t. That has to be done with great care in terms of ethics.”

George Q. Daley  is dean of HMS, the Caroline Shields Walker Professor of Medicine, and a leader in stem cell science and cancer biology. As a spokesperson for the organizing committee of the Second International Summit on Human Genome Editing, he responded swiftly to He’s announcement in Hong Kong. Echoing those remarks, he said:

“It’s time to formulate what a clinical path to translation might look like so that we can talk about it. That does not mean that we’re ready to go into the clinic — we are not. We need to specify what the hurdles would be if one were to move forward responsibly and ethically. If you can’t surmount those hurdles, you don’t move forward.

“There are stark distinctions between editing genes in an embryo to prevent a baby from being born with sickle cell anemia and editing genes to alter the appearance or intelligence of future generations. There is a whole spectrum of considerations to be debated. The prospect includes an ultimate decision that we not go forward, that we decide that the benefits do not outweigh the costs.”

Asked how to prevent experiments like He’s while preserving academic freedom, Daley replied:

“For the past 15 years, I have been involved in efforts to establish international standards of professional conduct for stem cell research and its clinical translation, knowing full well that there could be — and has been — a growing number of independent practitioners directly marketing unproven interventions to vulnerable patients through the internet. We advocated so strongly for professional standards in an attempt to ward off the risks of an unregulated industry. Though imperfect, our efforts to encourage a common set of professional practices have been influential.

“You can’t control rogue scientists in any field. But with strongly defined guidelines for responsible professional conduct in place, such ethical violations like those of Dr. He should remain a backwater, because most practitioners will adhere to generally accepted norms. Scientists have a responsibility to come together to articulate professional standards and live by them. One has to raise the bar very high to define what the standards of safety and efficacy are, and what kind of oversight and independent judgment would be required for any approval.

“We have called for an ongoing international forum on human genome editing, and that could take many shapes. We’ve suggested that the national academies of more countries come together — the National Academy of Sciences in the U.S. and the Royal Society in the U.K. are very active here — because these are the groups most likely to have the expertise to convene these kinds of discussions and keep them going.”

Cohen , speaking to the legal consequences of germline human genome editing, said:

“I think we should slow down in our reaction to this case. It is not clear that the U.S. needs to react to Dr. He’s announcement with regulation. The FDA [Food and Drug Administration] already has a strong policy on germline gene editing in place. A rider in the Consolidated Appropriations Act of 2016 — since renewed — would have blocked the very same clinical application of human germline editing He announced, had it been attempted in the U.S.

“The scientific community has responded in the way I’d have liked it to. There is a difference between ‘governance’ and ‘self-governance.’ Where government uses law, the scientific community uses peer review, public censure, promotions, university affiliations, and funding to regulate themselves. In China, in Dr. He’s case, you have someone who’s (allegedly) broken national law and scientific conventions. That doesn’t mean you should halt research being done by everyone who’s law-abiding.

“Public policy or ethical discussion that’s divorced from how science is progressing is problematic. You need to bring everyone together to have robust discussions. I’m optimistic that this is happening, and has happened. It’s very hard to deal with a transnational problem with national legislation, but it would be great to reach international consensus on this subject. These efforts might not succeed, but ultimately they are worth pursuing.”

Professor Kevin Eggan of Harvard’s Department of Stem Cell and Regenerative Biology said, “The question we should focus on is: Will this be safe and help the health of a child? Can we demonstrate that we can fix a mutation that will cause a terrible health problem, accurately and without the risk of harming their potential child? If the answer is yes, then I believe germline human genome editing is likely to gain acceptance in time.

“There could be situations where it could help a couple, but the risks of something going wrong are real. But at this point, it would be impossible to make a risk-benefit calculation in a responsible manner for that couple. Before we could ever move toward the clinic, the scientific community must come to a consensus on how to measure success, and how to measure off-target effects in animal models.

“Even as recently as this past spring and fall, the results of animal studies using CRISPR — the same techniques Dr. He claimed to have used — generated a lot of confusion. There is disagreement about both the quality of the data and how to interpret it. Until we can come to agreement about what the results of animal experiments mean, how could we possibly move forward with people?

“As happened in England with mitochondrial replacement therapy, we should be able to come to both a scientific and a societal consensus of when and how this approach should be used. That’s missing.”

According to Catherine Racowsky, professor of obstetrics, gynecology and reproductive biology at Brigham and Women’s Hospital, constraints on the use of embryos in federally funded research pose barriers to studying the risks and benefits of germline editing in humans. She added:

“Until the work is done, carefully and with tight oversight, to understand any off-target effects of replacing or removing a particular gene, it is inappropriate to apply the technology in the clinical field. My understanding of Dr. He’s case is that there wasn’t a known condition in these embryos, and by editing the genes involved with HIV infection, he could also have increased the risks of susceptibility to influenza and West Nile viruses.

“We need a sound oversight framework, and it needs to be established globally. This is a technology that holds enormous promise, and it is likely to be applied to the embryo, but it should only be applied for clinical purposes after the right work has been done. That means we must have consensus on what applications are acceptable, that we have appropriate regulatory oversight, and, perhaps most importantly, that it is safe. The only way we’re going to be able to determine that these standards are met is to proceed cautiously, with reassessments of the societal and health benefits and the risks.”

Asked about public dialogue around germline human genome editing, George Church , Robert Winthrop Professor of Genetics at HMS, said:

“With in vitro  fertilization (IVF), ‘test tube babies’ was an intentionally scary term. But after Louise Brown, the first IVF baby, was born healthy 40 years ago, attitudes changed radically. Ethics flipped 180 degrees, from it being a horrifying idea to being unacceptable to prevent parents from having children by this new method. If these edited twins are proven healthy, very different discussions will arise. For example, is a rate of 900,000 deaths from HIV infection per year a greater risk than West Nile virus, or influenza? How effective is each vaccine?”

Science, technology, and society

Sheila Jasanoff , founding director of the Science, Technology, and Society program at HKS, has been calling for a “global observatory” on gene editing, an international network of scholars and organizations dedicated to promoting exchange across disciplinary and cultural divides. She said:

“The notion that the only thing we should care about is the risk to individuals is very American. So far, the debate has been fixated on potential physical harm to individuals, and not anything else. This is not a formulation shared with other countries in the world, including practically all of Europe. Considerations of risk have equally to do with societal risk. That includes the notion of the family, and what it means to have a ‘designer baby.’

“These were not diseased babies Dr. He was trying to cure. The motivation for the intervention was that they live in a country with a high stigma attached to HIV/AIDS, and the father had it and agreed to the intervention because he wanted to keep his children from contracting AIDS. AIDS shaming is a fact of life in China, and now it won’t be applied to these children. So, are we going to decide that it’s OK to edit as-yet-to-be children to cater to this particular idea of a society?

“It’s been said that ‘the genie is out of the bottle’ with germline human genome editing. I just don’t think that’s true. After all, we have succeeded in keeping ‘nuclear’ inside the bottle. Humanity doesn’t lack the will, intelligence, or creativity to come up with ways for using technology for good and not ill.

“We don’t require students to learn the moral dimensions of science and technology, and that has to change. I think we face similar challenges in robotics, artificial intelligence, and all kinds of frontier fields that have the potential to change not just individuals but the entirety of what it means to be a human being.

“Science has this huge advantage over most professional thought in that it has a universal language. Scientists can hop from lab to lab internationally in a way that lawyers cannot because laws are written in many languages and don’t translate easily. It takes a very long time for people to understand each other across these boundaries. A foundational concept for human dignity? It would not be the same thing between cultures.

“I would like to see a ‘global observatory’ that goes beyond gene editing and addresses emerging technologies more broadly.”

To learn more:

Technology and Public Purpose project, Belfer Center for Science and International Affairs, Harvard Kennedy School of Government, https://www.belfercenter.org/tapp/person

Concluding statement from the Second International Summit on Human Genome Editing. http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b

A global observatory for gene editing: Sheila Jasanoff and J. Benjamin Hurlbut call for an international network of scholars and organizations to support a new kind of conversation. https://www.nature.com/articles/d41586-018-03270-w

Building Capacity for a Global Genome Editing Observatory: Institutional Design. http://europepmc.org/abstract/MED/29891181

Glenn Cohen’s blog: How Scott Gottlieb is Wrong on the Gene Edited Baby Debacle. http://blog.petrieflom.law.harvard.edu/2018/11/29/how-scott-gottlieb-is-wrong-on-the-gene-edited-baby-debacle/

Gene-Editing: Interpretation of Current Law and Legal Policy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651701/

Forum: Harvard T.H. Chan School of Public Health event on the promises and challenges of gene editing, May 2017: https://theforum.sph.harvard.edu/events/gene-editing/

Petrie-Flom Center Annual Conference: Consuming Genetics: Ethical and Legal Considerations of New Technologies: http://petrieflom.law.harvard.edu/events/details/2019-petrie-flom-center-annual-conference

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• Published: 20 April 2022

Beyond safety: mapping the ethical debate on heritable genome editing interventions

• Mara Almeida   ORCID: orcid.org/0000-0002-0435-6296 1 &
• Robert Ranisch   ORCID: orcid.org/0000-0002-1676-1694 2 , 3  

Humanities and Social Sciences Communications volume  9 , Article number:  139 ( 2022 ) Cite this article

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Genetic engineering has provided humans the ability to transform organisms by direct manipulation of genomes within a broad range of applications including agriculture (e.g., GM crops), and the pharmaceutical industry (e.g., insulin production). Developments within the last 10 years have produced new tools for genome editing (e.g., CRISPR/Cas9) that can achieve much greater precision than previous forms of genetic engineering. Moreover, these tools could offer the potential for interventions on humans and for both clinical and non-clinical purposes, resulting in a broad scope of applicability. However, their promising abilities and potential uses (including their applicability in humans for either somatic or heritable genome editing interventions) greatly increase their potential societal impacts and, as such, have brought an urgency to ethical and regulatory discussions about the application of such technology in our society. In this article, we explore different arguments (pragmatic, sociopolitical and categorical) that have been made in support of or in opposition to the new technologies of genome editing and their impact on the debate of the permissibility or otherwise of human heritable genome editing interventions in the future. For this purpose, reference is made to discussions on genetic engineering that have taken place in the field of bioethics since the 1980s. Our analysis shows that the dominance of categorical arguments has been reversed in favour of pragmatic arguments such as safety concerns. However, when it comes to involving the public in ethical discourse, we consider it crucial widening the debate beyond such pragmatic considerations. In this article, we explore some of the key categorical as well sociopolitical considerations raised by the potential uses of heritable genome editing interventions, as these considerations underline many of the societal concerns and values crucial for public engagement. We also highlight how pragmatic considerations, despite their increasing importance in the work of recent authoritative sources, are unlikely to be the result of progress on outstanding categorical issues, but rather reflect the limited progress on these aspects and/or pressures in regulating the use of the technology.

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Introduction.

The ability to alter a sequence of genetic material was initially developed in microorganisms during the 1970s and 1980s (for an overview: Walters et al., 2021 ). Since then, technological advances have allowed researchers to alter DNA in different organisms by introducing a new gene or by modifying the sequence of bases in the genome. The manipulation of the genome of living organisms (typically plants) continues a course that science embraced more than 40 years ago, and may ultimately allow, if not deliberately curtailed by societal decisions, the possibility of manipulating and controlling genetic material of other living species, including humans.

Genetic engineering can be used in a diverse range of contexts, including research (e.g., to build model organisms), pharmacology (e.g., for insulin production) and agriculture (e.g., to improve crop resistance to environmental pressures such as diseases, or to increase yield). Beyond these applications, modern genetic engineering techniques such as genome editing technologies have the potential to be an innovative tool in clinical interventions but also outside the clinical realm. In the clinical context, genome editing techniques are expected to help in both disease prevention and in treatment (Porteus, 2019 ; Zhang, 2019 ). Nevertheless, genome editing technology raises several questions, including the implications of its use for human germline cells or embryos, since the technology’s use could facilitate heritable genome editing interventions (Lea and Niakan, 2019 ). This possible use has fuelled a heated debate and fierce opposition, as illustrated by the moratoriums proposed by researchers and international institutions on the use of the technology (Lander et al., 2019 ; Baltimore et al., 2015 ; Lanphier et al., 2015 ). Heritable human germline modifications are currently prohibited under various legislations (Baylis et al., 2020 ; Ledford, 2015 ; Isasi et al., 2016 ; König, 2017 ) and surveys show public concerns about such applications, especially without clear medical justification (e.g., Gaskell et al., 2017 ; Jedwab et al., 2020 ; Scheufele et al., 2017 ; Blendon et al., 2016 ).

To analyse some implications of allowing heritable genome editing interventions in humans, it is relevant to explore underlying values and associated ethical considerations. Building on previous work by other authors (e.g., Coller, 2019 ; de Wert et al., 2018 ; van Dijke et al., 2018 ; Mulvihill et al., 2017 ; Ishii, 2015 ), this article aims to provide context to the debates taking place and critically analyse some of the major pragmatic, categorical and sociopolitical considerations raised to date in relation to human heritable genome editing. Specifically, we explore some key categorical and sociopolitical considerations to underline some of the possible barriers to societal acceptance, key outstanding questions requiring consideration, and possible implications at the individual and collective level. In doing so, we hope to highlight the predominance of pragmatic arguments in the scientific debate regarding the permissible use of heritable genome editing interventions compared to categorical arguments relevant to broader societal debate.

Human genome editing: a brief history of CRISPR/Cas9

Human genome editing is an all-encompassing term for technologies that are aimed at making specific changes to the human genome. In humans, these technologies can be used in embryos or germline cells as well as somatic cells (Box 1 ). Concerning human embryos or germline cells, the intervention could introduce heritable changes to the human genome (Lea and Niakan, 2019 ; Vassena et al., 2016 ; Wolf et al., 2019 ). In contrast, an intervention in somatic cells is not intended to result in changes to the genome of subsequent generations. It is worth noting that intergenerational effects occur only when the modified cells are used to establish a pregnancy which is carried to term. Thus, a distinction has been made between germline genome editing (GGE), which may only affect in vitro embryos in research activity, and heritable genome editing (HGE), which is used in reproductive medicine (e.g., Baylis et al., 2020 ). HGE could be used to prevent the transmission of serious genetic disease; however, other applications could be imagined, e.g., creating genetic resistance or even augmenting human functions.

In the last decade, prominent technical advances in genome engineering methods have taken place, including the zinc-finger nucleases (ZFNs) and TAL effector nucleases (TALENs), making human genome modification a tangible possibility (Gaj et al., 2013 ; Li et al., 2020 ; Gupta and Musunuru, 2014 ). In 2012, a study showed that the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), combined with an enzyme called Cas9, could be used as a genome‐editing tool in human cell culture (Jinek et al., 2012 ). In 2013, the use of CRISPR/Cas9 in mammalian cells was described, demonstrating the application of this tool in the genome of living human cells (Cong et al., 2013 ). In 2014, CRISPR/Cas9 germline modifications were first used in non-human primates, resulting in the birth of gene-edited cynomolgus monkeys (Niu et al., 2014 ). This was followed in 2015 by the first-ever public reported case of genome modification in non-viable human embryos (tripronuclear zygotes) (Liang et al., 2015 ). This study has caused broad concerns in the scientific community (Bosley et al., 2015 ) with leading journals rejecting publication for ethical reasons. Five years after these initial experiments were conducted, more than 10 papers have been published reporting the use of genome editing tools on human preimplantation embryos (for an overview: Niemiec and Howard, 2020 ).

Compared to counterpart genome technologies (e.g., ZFNs and TALENs), CRISPR/Cas9 is considered by many a revolutionary tool due to its efficiency and reduced cost. More specifically, CRISPR/Cas9 seems to provide the possibility of a more targeted and effective intervention in the genome involving the insertion, deletion, or replacement of genetic material (Dance, 2015 ). The potential applicability of CRISPR/Cas9 technique is considered immense, since it can be used on all type of organisms, from bacteria to plants, non-human cells, and human cells (Barrangou and Horvath, 2017 ; Hsu et al., 2014 ; Doudna and Charpentier, 2014 ; Zhang, 2019 ).

Box 1 Difference associated with germline cells and somatic cells.

For the purposes of the analysis presented in this article, one of the main differences is the heritability of genes associated with either type of cell. Germline cells include spermatozoa, oocytes, and their progenitors (e.g., embryonic cells in early development), which can give rise to a new baby carrying a genetic heritage coming from the parents. Thus, germline are those cells in an organism which are involved in the transfer of genetic information from one generation to the next. Somatic cells, conversely, constitute many of the tissues that form the body of living organisms, and do not pass on genetic traits to their progeny.

Germline interventions: the international debate

As a reaction to the 2015 study with CRISPR/Cas9, several commentaries by scientists were published regarding the future use of the technology (e.g., Bosley et al., 2015 ; Lanphier et al., 2015 ; Baltimore et al., 2015 ). Many of them focused on germline applications, due to the possibility of permanent, heritable changes to the human genome and its implications for both individuals and future generations. These commentaries included position statements calling for great caution in the use of genome editing techniques for heritable interventions in humans and suggested a voluntary moratorium on clinical germline applications of CRISPR/Cas9, at least until a broad societal understanding and consensus on their use could be reached (Brokowski, 2018 ; Baltimore et al., 2015 ; Lander, 2015 ). Such calls for a temporary ban were often seen as reminiscent of the “Asilomar ban” on recombinant DNA technology in the mid-1970s (Guttinger, 2017 ). Other commentaries asked for research to be discouraged or halted all together (Lanphier et al., 2015 ). More firmly, the United States (US) National Institutes of Health (NIH) released a statement indicating that the NIH would not fund research using genome editing technologies on human embryos (Collins, 2015 ).

In December 2015, the first International Summit on Human Gene Editing took place, hosted by the US National Academy of Sciences, the US National Academy of Medicine, the UK Royal Society, and the Chinese Academy of Sciences (NASEM). The organizing committee issued a statement about appropriate uses of the technology that included the following: “It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application” (NASEM, 2015 ).

Following this meeting, initiatives from different national bodies were organized to promote debate on the ethical issues raised by the new genome editing technologies and to work towards a common framework governing the development and permissibility of their use in humans. This included an ethical review published in 2016 by the Nuffield Council on Bioethics, addressing conceptual and descriptive questions concerning genome editing, and considering key ethical questions arising from the use of the technology in both human health and other contexts (Nuffield Council on Bioethics, 2016 ). In 2017, a committee on human genome editing set up by the US National Academy of Sciences (NAS) and the National Academy of Medicine (NAM) carried out a so-called consensus study “Human Genome Editing: Science, Ethics, and Governance” (NASEM, 2017 ). This study put forward a series of recommendations on policies and procedures to govern human applications of genome editing. Specifically, the study concluded that HGE could be justified under specific conditions: “In some situations, heritable genome editing would provide the only or the most acceptable option for parents who desire to have genetically related children while minimizing the risk of serious disease or disability in a prospective child” (NASEM, 2017 ). The report stimulated much public debate and was met with support and opposition since it was seen as moving forward on the permissibility of germline editing in the clinical context (Ranisch and Ehni, 2020 ; Hyun and Osborn, 2017 ).

Following the report in 2016, the Nuffield Council on Bioethics published a second report in 2018. Similar to the NASEM 2017 report, this report emphasizes the value of procreative freedom and stresses that in some cases HGE might be the only option for couples to conceive genetically related, healthy offspring. In this document, the Nuffield Council on Bioethics maintains that there are no categorical reasons to prohibit HGE. However, it highlights three kinds of interests that should be recognized when discussing prospective HGE. They are related to individuals directly affected by HGE (parents or children), other parts of society, and future generations of humanity. In this context, two ethical principles are highlighted as important to guide future evaluations of the HGE use in specific interventions: “(...) to influence the characteristics of future generations could be ethically acceptable, provided if, and only if, two principles are satisfied: first, that such interventions are intended to secure, and are consistent with, the welfare of a person who may be born as a consequence, and second, that any such interventions would uphold principles of social justice and solidarity (…)” (Nuffield Council on Bioethics, 2018 ). This report was met with criticism for (implicitly) advocating genetic heritable interventions might be acceptable even beyond the boundaries of therapeutic uses. This is particularly controversial and goes well beyond the position previously reached by the NASEM report (which limited permissible uses of genome editing at preventing the transmission of genetic variants associated to diseases) (Drabiak, 2020 ). On the other hand, others have welcomed the report and, within it, the identification of explicit guiding ethical principles helpful in moving forward the debate on HGE (Gyngell et al., 2019 ).

As a follow-up to the 2015 conference, a second International Summit on Human Gene Editing was scheduled for November 2018 in Hong Kong (National Academies of Sciences, Engineering, and Medicine, 2019 ). The event, convened by the Hong Kong Academy of Sciences, the UK Royal Society, the US National Academy of Sciences and the US National Academy of Medicine, was supposed to focus on the prospects of HGE. Just before the Summit began, news broke that He Jiankui, a Chinese researcher and invited speaker at the Summit, created the world’s first genetically edited babies resulting from the use of CRISPR/Cas9 in embryos (Regalado, 2018 ; Lovell-Badge, 2019 ). Although an independent investigation of the case is still pending, his experiments have now been reviewed in detail by some scholars (e.g., Greely, 2019 , 2021 ; Kirksey, 2020 ; Davies, 2020 ; Musunuru, 2019 ). These experiments were globally criticized, since they did not follow suitable safety procedures or ethical guidelines (Wang and Yang, 2019 ; Lovell-Badge, 2019 ; Krimsky, 2019 ), nor considered the recommendations previously put forward by international reports (NASEM, 2017 ; Nuffield Council on Bioethics, 2018 ) and legal frameworks (Araki and Ishii, 2014 ; Isasi et al., 2016 ). Different reactions were triggered, including another call by scientists for a global moratorium on clinical human genome editing, to allow time for international discussions to take place on its appropriate uses (Lander et al., 2019 ) or an outright ban on the technology (Botkin, 2019 ). There were also calls for a measured analysis of the possible clinical applications of human genome editing, without the imposition of a moratorium (Daley et al., 2019 ; Dzau et al., 2018 ).

Most countries currently have legal frameworks to ban or severely restrict the use of heritable genome editing technologies (Araki and Ishii, 2014 ; Isasi et al., 2016 ; Baylis et al., 2020 ). However, since He’s experiment, the possibility that researchers might still attempt (with some likelihood of success) to use the technology in human embryos, became a growing concern, particularly since some scientists have already announced their interest in further clinical experiments (Cyranoski, 2019 ). For many, He’s experiments highlighted the ongoing risks associated with the use of modern genome editing technology without proper safety protocols and regulatory frameworks at an international level (Ranisch et al., 2020 ). This has triggered the need to develop clear and strict regulations to be implemented if these tools are to be used in the future. This incident also led to the formation of several working groups, including the establishment of an international commission on the Clinical Use of Human Germline Genome Editing set up by the US National Academy of Medicine, the US National Academy of Sciences, and the UK’s Royal Society. In 2020, the commission published a comprehensive report on HGE, proposing a translational pathway from research to clinical use (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020 ). Likewise, a global expert Advisory Committee was established by the World Health Organization (WHO) with the goal of developing recommendations on governance mechanisms for human genome editing. Although the committee insisted in an interim recommendation that “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline genome editing” (WHO, 2019 ), it did not express fundamental concerns on the possibility that some forms of HGE will one day become a reality. In 2021, the WHO’s Advisory Committee issued some publications, including a “Framework for governance” report and a “Recommendations” report (WHO, 2021 ). Building on a set of procedural and substantive values and principles, the “Framework for Governance” report discusses a variety of tools and institutions necessary for developing appropriate national, transnational, and international governance and oversight mechanisms for HGE. Specifically, the report considers the full spectrum of possible applications of human genome editing (including epigenetic editing and human enhancement) and addresses specific challenges associated with current, possible and speculative scenarios. These range from somatic gene therapy for the prevention of serious hereditary diseases to potentially more controversial applications reminiscent of the He Jiankui case (e.g., the use of HGE in reproductive medicine outside regulatory controls and oversight mechanisms). Additionally, the “Recommendations” report proposes among other things whistleblowing mechanisms to report illegal or unethical research. It also highlights the need for a global human genome editing registry, that should also cover basic and preclinical research on different applications of genetic manipulation, including HGE. The report also emphasises the need of making possible benefits of human genome editing widely accessible.

The idea of a human genome editing registry has also been supported by the European Group on Ethics in Science and New Technologies (EGE), an advisory board to the President of the European Commission. After an initial statement on genome editing published in 2016, still calling for a moratorium on editing of human embryos (EGE, 2016 ), the EGE published a comprehensive Opinion in 2021 (EGE, 2021 ). Although the focus of this report is on the moral issues surrounding genome editing in animals and plants, HGE is also discussed. Similar to the WHO Advisory Committee, the EGE recommends for HGE not to be introduced prematurely into clinical application and that measures should be taken to prevent HGE’s use for human enhancement.

Overall, when reviewing reports and initiatives produced since 2015, common themes and trajectories can be identified. A key development is the observation that the acceptance of the fundamental permissibility of such interventions appears to be increasing. This constitutes an important change from previous positions, reflecting the fact that human germline interventions have long been considered a ‘red line’ or at least viewed with deep scepticism (Ranisch and Ehni, 2020 ). In particular, while there is agreement that it would be premature to bring HGE into a clinical context, key concerns expressed by authoritative international bodies and committees are now associated with acceptable uses of the technology, rather than its use per se. Consideration is now being given to the conditions and objectives under which germline interventions could be permissible, instead of addressing the fundamental question of whether HGE may be performed at all. The question of permissibility is often linked to the stage of technological development. These developments are remarkable, since the key ethical aspects of genome editing are now frequently confined to questions of safety or cost–benefit ratios, rather than categorical considerations.

Another common issue can also be found in recent reports: the question of involving society in the debate. There is consensus on the fact that the legitimacy and governance of HGE should not be left solely to scientists and other experts but should involve society more broadly. Since germline interventions could profoundly change the human condition, the need for a broad and inclusive public debate is frequently emphasized (Iltis et al., 2021 ; Scheufele et al., 2021 ). The most striking expression of the need for public engagement and a “broad societal consensus” can be found in the final statement by the 2015 International Summit on Human Gene Editing organizing committee, as previously quoted (NASEM, 2015 ). Furthermore, the EGE and others also stresses the need for an inclusive societal debate before HGE can be considered permissible.

The pleas for public engagement are, however, not free of tension. For example, the NASEM’s 2017 report was criticised for supporting HGE bypassing the commitment for the broad societal consensus (Baylis, 2017 ). Regarding HGE, some argue that only a “small but vocal group of scientists and bioethicists now endorse moving forward” (Andorno et al., 2020 ). Serious efforts to engage the public on the permissibility and uses of HGE have yet to be made. This issue not only lacks elaboration on approaches to how successful public participation can occur, but also how stop short of presenting views on how to translate the public’s views into ethical considerations and policy (Baylis, 2019 ).

Potential uses of heritable genome editing technology

HGE is expected to allow a range of critical interventions: (i) preventing the transmission of genetic variants associated with severe genetic conditions (mostly single gene disorders); (ii) reducing the risk of common diseases (mostly polygenic diseases), with the promise of improving human health; and (iii) enhancing human capabilities far beyond what is currently possible for human beings, thereby overcoming human limitations. The identification of different classes of potential interventions has shifted the debate to the applications considered morally permissible beyond the acceptable use of HGE (Dzau et al., 2018 ). Specifically, there are differences in the limits of applicability suggested by some of the key cornerstone publications discussed above. For example, the NASEM ( 2017 ) report suggests limiting the use of HGE to the transmission of genetic variants linked to severe conditions, although in a very regulated context. In a very similar way, the 2020 report from the International Commission on the Clinical Use of Human Germline Genome Editing suggests that the initial clinical use of HGE should be limited to the prevention of serious monogenic diseases. By contrast, the 2018 Nuffield Council on Bioethics Report does not seem to limit the uses of genome editing to specific applications, though suggests that applications should be aligned with fundamental guiding ethical principles and need to have followed public debate (Savulescu et al., 2015 ). The same report also discusses far-reaching and speculative uses of HGE that might achieve “other outcomes of positive value” (Nuffield Council on Bioethics, 2018 ). Some of these more speculative scenarios include “built-in genetic resistance or immunity to endemic disease”; “tolerance for adverse environmental conditions” and “supersenses or superabilities” (Nuffield Council on Bioethics, 2018 , p. 47).

There have been different views on the value of HGE technology. Some consider that HGE should be permissible in the context of therapeutic applications, since it can provide the opportunity to treat and cure diseases (Gyngell et al., 2017 ). For example, intervention in severe genetic disorders is considered as therapeutic and hence morally permissible, or even obligatory. Others consider HGE to be more like a public health measure, which could be used to reduce the prevalence of a disease (Schaefer, 2020 ). However, others maintain that reproductive uses of HGE are not therapeutic because there is no individual in a current state of disease which needs to be treated, rather a prospective individual to be born with a specific set of negative prospective traits (Rulli, 2019 ).

Below, HGE is discussed in the context of reproductive uses and conditions of clinical advantage over existent reproductive technologies. The HGE applications are explored regarding their potential for modifying one or more disease-related genes relevant to the clinical context. Other uses associated with enhancement of physical and mental characteristics, which are considered non-clinical (although the distinction is sometimes blurred), are also discussed.

Single gene disorders

An obvious application of HGE interventions is to prevent the inheritance of genetic variants known to be associated with a serious disease or condition. Its potential use for this purpose could be typically envisaged through assisted reproduction, i.e., as a process to provide reproductive options to couples or individuals at risk of transmitting genetic conditions to their offspring. Critics of this approach often argue that other assisted reproductive technologies (ARTs) and preimplantation screening technologies e.g., preimplantation genetic diagnosis (PGD), not involving the introduction of genetic modifications to germline cells, are already available for preventing the transmission of severe genetic conditions (Lander, 2015 ; Lanphier et al., 2015 ). These existent technologies aim to support prospective parents in conceiving genetically related children without the condition that affect them. In particular, PGD involves the creation of several embryos by in vitro fertilization (IVF) treatment that will be tested for genetic anomalies before being transferred to the uterine cavity (Sermon et al., 2004 ). In Europe, there is a range in the regulation of the PGD technology with most countries having restrictions of some sorts (Soini, 2007 ). The eligibility criteria for the use of PGD also vary across countries, depending on the range of heritable genetic diseases for which it can be used (Bayefsky, 2016 ).

When considering its effectiveness, PGD presents specific limitations, which include the rare cases in which either both prospective parents are homozygous carriers of a recessive genetic disease, or one of the parents is homozygous for a dominant genetic disease (Ranisch, 2020 ). In these cases, all embryos produced by the prospective parents will be affected by the genetic defect, and therefore it will not be possible to select an unaffected embryo after PGD. Currently, beyond adoption of course, the options available for these prospective parents include the use of a third-party egg or sperm donors.

Overall, given the rarity of cases in which it is not applicable, PGD is thought to provide a reliable option to most prospective parents for preventing severe genetic diseases to be transmitted to their offspring, except in very specific cases. HGE interventions have been suggested to be an alternative method to avoid single gene disorders in the rare cases in which selection techniques such as PGD cannot be used (Ranisch, 2020 ). It has also been proposed to use tools such as CRISPR/Cas9 to edit morphologically suitable but genetically affected embryos, and thus increase the number of embryos available for transfer (de Wert et al., 2018 ; Steffann et al., 2018 ). Moreover, HGE interventions are considered by some as a suitable alternative to PGD, even when the use of PGD could be possible. One argument in this respect is that, although not leading to the manifestation of the disease, the selected embryos can still be carriers of it. In this respect, differently from PGD, HGE interventions can be used to eliminate unwanted, potential future consequences of genetic diseases (i.e., by eliminating the critical mutation carried out in the selected embryo), with the advantage of reducing the risks of further propagation of the disease in subsequent future generations (Gyngell et al., 2017 ).

Overall, HGE interventions are thought to offer a benefit over PGD in some situations by providing a broader range of possible interventions, as well as by providing a larger number of suitable embryos. The latter effect is usually important in the cases where unaffected embryos are small in number, making PGD ineffective (Steffann et al., 2018 ). Whether these cases provide a reasonable ground to justify research and development on the clinical use of HGE remain potentially contentious. Some authors have suggested that the number of cases in which PGD cannot be effectively used to prevent transmission of genetic disorders is so marginal that clinical application of HGE could hardly be justified (Mertes and Pennings, 2015 ). Particularly when analyzing economic considerations (i.e., the allocation of already scarce resources towards clinical research involving expensive techniques with limited applicability) and additional risks associated with direct interventions. In either case of HGE being used as an alternative or a complementary tool to PGD, PGD will most likely still be used to identify those embryos that would manifest the disease and would hence require subsequent HGE.

The PGD technique, however, is not itself free of criticism and possible moral advantages of HGE over PGD have also been explored (Hammerstein et al., 2019 ; Ranisch, 2020 ). PGD remains ethically controversial since, identifying an unaffected embryo from the remaining embryos (which will not be used and ultimately discarded) amounts to the selection of ‘healthy’ embryos rather than ‘curing’ embryos affected by the genetic conditions. On the other hand, given a safe and effective application of the technology, the use of HGE is considered by many morally permissible to prevent the transmission of genetic variants known to be associated with serious illness or disability (de Miguel Beriain, 2020 ). One question that remains is whether HGE and PGD have a differing or equal moral permissibility or, at least, comparable. On issues including human dignity and autonomy, it was argued that HGE and PGD interventions can be considered as equally morally acceptable (Hammerstein et al., 2019 ). This equal moral status was, however, only valid if HGE is used under the conditions of existent gene variants in the human gene pool and to promote the child health’s best interest in the context of severe genetic diseases (Hammerstein et al., 2019 ). Because of selection and ‘therapy’, moral assessments resulted in HGE interventions being considered to some extent preferable to PGD, once safety is carefully assessed (Gyngell et al., 2017 ; Cavaliere, 2018 ). Specifically, PGD’s aim is selective and not ‘therapeutic’, which could be said to contradict the aims of traditional medicine (MacKellar and Bechtel, 2014 ). In contrast to PGD’s selectivity, HGE interventions are seen as ‘pre-emptively therapeutic’, and therefore closer to therapy than PGD (Cavaliere, 2018 ). However, it is also argued that HGE does not have curative aims, and thus it is not a therapeutic application, as there is no patient involved in the procedure to be cured (Rulli, 2019 ). On balance, there appears to be no consensus on which of the approaches, HGE and PGD, is morally a better strategy to prevent the transmission of single gene disorders, with a vast amount of literature expressing diverse positions when considering different scenarios (Delaney, 2011 ; Gyngell et al., 2017 ; Cavaliere, 2018 ; Ranisch, 2020 ; Rehmann-Sutter, 2018 ; Sparrow, 2021 ).

Polygenetic conditions

HGE is also argued to have the potential to be used in other disorders which have a polygenic disposition and operate in combination with environmental influences (Gyngell et al., 2017 , 2019 ). Many common diseases, which result from the involvement of several genes and environmental factors, fall into this category. Examples of common diseases of this type includes diabetes, coronary artery disease and different types of cancers, for which many of the genes involved were identified by studies of genome wide association (e.g., Wheeler and Barroso, 2011 ; Peden and Farral, 2011 ). These diseases affect the lives of millions of people globally, severely impacting health and often leading to death. Furthermore, these diseases have a considerable burden on national health systems. Currently, many of these diseases are controlled through pharmaceutical products, although making healthier life choices about diet and exercise can also contribute to preventing and managing some of them. Despite the interest, the use of PGD in polygenic conditions would hardly be feasible, due to the number of embryos needed to select the preferred genotype and available polygenic predictors (Karavani et al., 2019 ; Shulman and Bostrom, 2014 ).

In theory, HGE could be a potentially useful tool to target different genes and decrease the susceptibility to multifactorial conditions in current and future generations. The application of HGE to polygenic conditions is often argued by noting that the range of applicability of the technique (well beyond single gene disorders) would justify and outweigh the cost needed to develop it. However, to do so, a more profound knowledge of genetic interactions, of the role of genes and environmental factors in diverse processes would be needed to be able to modify such interconnected systems with limited risk to the individual (Lander, 2015 ). Besides, it is now understood that, depending on the genetic background, individuals will have different risks of developing polygenetic diseases (risk-associated variants), but hardly any certainty of it. In other words, although at the population level there would most likely be an incidence of the disease, it is not possible to be certain of the manifestation of the disease in any specific individual. As a result, the benefits of targeting a group of genes associated to a disease in a specific individual would have to be assessed in respect to the probability of incidence of the disease. The risk-benefit ratio for HGE is considerably increased for polygenic conditions compared to monogenic disorders. Additionally, the risks of adverse effects, e.g., off-target effects, increases with the number of genes targeted for editing. The latter effects make the potential benefits of HGE in polygenic diseases more uncertain than in single gene disorders.

Genetic enhancement

A widespread concern regarding the use of HGE is that such interventions could be used not only to prevent serious diseases, but also to enhance desirable genetic traits. Currently, our knowledge on how to genetically translate information into specific phenotypes is very limited and some argue that it might never be technically feasible to achieve comprehensive genetic enhancements using current gene editing technologies (Janssens, 2016 ; Ranisch, 2021 ). Similar to many diseases, in which different genetic and other factors are involved, many of the desirable traits to be targeted by any enhancement will most likely be the result of a combination of several different genes influenced by environment and context. Moreover, the implications for future generations of widespread genetic interventions in the human population and its potential impact on our evolutionary path are difficult to assess (Almeida and Diogo, 2019 ). Nevertheless, others argue that genetic enhancement through HGE could be possible in the near future (de Araujo, 2017 ).

There has been much discussion regarding the meaning of the terms and the conceptual or normative difference between ‘therapy’ and ‘enhancement’ (for an early discussion: Juengst, 1997 ; Parens, 1998 ). There are mainly three different meanings of ‘enhancement’ used in the literature. First, ‘enhancement’ is sometimes used to refer to measures that go beyond therapy or prevention of diseases, i.e., that transcend goals of medicine. Second, ‘enhancement’ is used to refer to measures that equip a human with traits or capacities that they typically do not possess. In both cases, the term points to equally controversial and contrasting concepts: on the one hand, those of ‘health’, ‘disease’ or ‘therapy’, and on the other, those of ‘normality’ or ‘naturalness’. Third, ‘enhancement’ is sometimes also used as an umbrella-term describing all measures that have a positive effect on a person’s well-being. According to this definition, the cure, or prevention of a disease is then also not opposed to an enhancement. Here again, this use refers to the controversial concept of ‘well-being’ or a ‘good life’.

It is beyond the scope of this article to provide a detailed review of the complex debate about enhancement (for an overview: Juengst and Moseley, 2019 ). However, three important remarks can be made: first, although drawing a clear line between ‘enhancement’ and ‘therapy’ (or ‘normality’, etc.) will always be controversial, some cases can be clearly seen as human enhancement. This could include modifications to augment human cognition, like having a greater memory, or increasing muscle mass to increase strength, which are not considered essential for human health (de Araujo, 2017 ).

Second, it is far from clear whether a plausible account of human enhancement would, in fact, be an objectivist account. While authors suggest that there is some objectivity regarding the conditions that constitute a serious disease (Habermas, 2003 ), the same might not be true for what constitutes an improvement of human functioning. It may rather turn out that an enhancement for some might be seen as a dis-enhancement for others. Furthermore, the use of the HGE for enhancement purposes can be considered at both an individual and a collective level (Gyngell and Douglas, 2015 ; Almeida and Diogo, 2019 ), with a range of ethical and biological implications. If HGE is to be used for human enhancement, this use will be in constant dependence on what we perceive as ‘normal’ functioning or as ‘health’. Therefore, factors such as cultural and societal norms will have an impact on where such boundaries are drawn (Almeida and Diogo, 2019 ).

Third, it should be noted that from an ethical perspective the conceptual question of what enhancement is, and what distinguishes it from therapy, is less important than whether this distinction is ethically significant in the first place. In this context, it was pointed out that liberal positions in bioethics often doubt that the distinction between therapy and enhancement could play a meaningful role in determining the limits of HGE (Agar, 1998 ). The consideration of genetic intervention for improving or adding traits considered positive by individuals have raised extreme positions. Some welcome the possibility to ameliorate the human condition, whilst others consider it an alarming attempt to erase aspects of our common human ‘nature’. More specifically, some authors consider HGE a positive step towards allowing humans the opportunity to obtain beneficial traits that otherwise would not be achievable through human reproduction, thus providing a more radical interference in human life to overcome human limitations (de Araujo, 2017 ; Sorgner, 2018 ). The advocates of this position are referred to as ‘bioliberals’ or ‘transhumanists’ (Ranisch and Sorgner, 2014 ), and its opponents are referred to as ‘bioconservatives’ (Fukuyama, 2002 ; Leon, 2003 ; Sandel, 2007 ). Transhumanism supports the possibility of humans taking control of their biology and interfering in their evolution with the use of technology. Bioconservatism defends the preservation and protection of ‘human essence’ and expresses strong concerns about the impact of advanced technologies on the human condition (Ranisch and Sorgner, 2014 ).

For the general public, HGE used in a clinical context seems to be less contentious compared when used as a possible human enhancement tool. Specifically, some surveys indicate that the general-public typically exhibits a reduced support for the use of genome editing interventions for enhancement purposes compared to therapeutic purposes (Gaskell et al., 2017 ; Scheufele et al., 2017 ). In contrast, many technologies and pharmaceutical products developed in the medical context to treat patients are already being used by individuals to ‘enhance’ some aspect of their bodies. Some examples include drugs to boost brain power, nutritional supplements, and brain-stimulating technologies to control mood, even though their efficiency and safety is not clear. This could suggest that views on enhancement may vary depending on the context and on what is perceived as an enhancement by individuals. It may be informative to carry out detailed population studies to explore whether real ethical boundaries and concerns exist, or whether these are purely the result of the way information is processed and perceived.

Heritable genome editing: Mapping the ethical debate

Even though genome editing methods have only been developed in the last decade, the normative implication of interventions into the human germline have been discussed since the second half of the 20th century (Walters et al., 2021 ). Some even argue that, virtually, all the ethical issues raised by genetic engineering were already being debated at that time (Paul, 2005 ). This includes questions about the distinction between somatic and germline interventions, as well as between therapy and enhancement (e.g., Anderson, 1985 ). Nevertheless, as it has been widely noted, it is difficult to draw clear lines between these two categories (e.g., McGee, 2020 ; Juengst, 1997 ), and alternative frameworks have been proposed, particularly in the context of HGE (Cwik, 2020 ). Other questions include the normative status of human nature (e.g., Ramsey, 1970 ), the impossibility of consent from future generations (e.g., Lappe, 1991 ), possible slippery slopes towards eugenics (e.g., Howard and Rifkin, 1977 ), or implications for justice and equality (e.g., Resnik, 1994 ).

When discussing the ethics of HGE, roughly three types of considerations can be distinguished: (i) pragmatic, (ii) sociopolitical, and iii) categorical (Richter and Bacchetta, 1998 ; cf. Carter, 2002 ). Pragmatic considerations focus on medical or technological aspects of HGE, such as the safety or efficacy of interventions, risk–benefit ratio, possible alternatives or the feasibility of responsible translational research. Such considerations largely depend on the state of science and are thus always provisional. For example, if high-risk technologies one day evolve into safe and reliable technologies, some former pragmatic considerations may become obsolete. Sociopolitical aspects, on the other hand, are concerned with the possible societal impact of technologies, e.g., how they can promote or reduce inequalities, support or undermine power asymmetries, strengthen, or threaten democracy. Similar to pragmatic considerations, sociopolitical reasons depend on specific contexts and empirical factors. However, these are in a certain sense ‘outside’ the technology—even though technologies and social realities often have a symbiotic relationship. While sociopolitical considerations can generate strong reasons against (or in favour of) implementing certain technologies, most often these concerns could be mitigated by policies or good governance. Categorical considerations are different and more akin to deontic reasons. They emphasise categorical barriers to conduct certain deeds. It could be argued, for instance, that the integrity of the human genome or the impossibility to obtain consent from future generation simply rule out certain options to modify human nature. Such categorical considerations may persist despite technological advances or changing sociopolitical conditions.

Comparing the bioethical literature on genetic engineering from the last century with the ongoing discussions shows a remarkable shift in the ethical deliberation. In the past, scholars from the field of medical ethics, as well as policy reports, used to focus on possible categorical boundaries for germline interventions and on possible sociopolitical consequences of such scenarios. For instance, the influential 1982 report “Splicing Life” from the US President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioural Research prominently discussed concerns about ‘playing God’ against the prospects of genetically engineering human beings, as well as possible adverse consequences of such interventions. Although this study addresses potential harms, pragmatic arguments played only a minor role, possibly due to the technical limitations at the time.

With the upcoming availability of effective genome editing techniques, the focus on the moral perspective seems to have been reversed. Increasingly, the analysis of the permissibility of germline interventions is confined to questions of safety and efficacy. This is demonstrated by the 2020 consensus study report produced by an international commission convened by the US National Academy of Medicine, the US National Academy of Sciences, and the UK’s Royal Society, which aimed at defining a translational pathway for HGE. Although the report recognizes that HGE interventions does not only raise pragmatic questions, ethical aspects were not explicitly addressed (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020 ).

Similarly, in 2019, a report on germline interventions published by the German Ethics Council (an advisory body to the German government and parliament) emphasizes that the “previous categorical rejection of germline interventions” could not be maintained (Deutscher Ethikrat, 2019 , p. 5). The German Ethics Council continues to address ethical values and societal consequences of HGE. However, technical progress and the development of CRISPR/Cas9 tools seem to have changed the moral compass in the discussion about germline interventions.

For a comprehensive analysis of HGE to focus primarily on pragmatic arguments such as safety or efficacy would be inadequate. In recent years, developments in the field of genome editing have occurred at an incredibly fast pace. At the same time, there are still many uncertainties about the efficacy of the various gene editing methods and unexpected effects in embryo editing persist (Ledford, 2015 ). Social and political implication also remain largely unknown. To date, it has been virtually impossible to estimate how deliberate interventions into the human germline could shape future societies and to conduct a complete analysis of the safety aspects of germline interventions.

Moreover, as the EGE notes, we should be cautious not to limit the complex process of ethical decision-making to pragmatic aspects such as safety. The “‘safe enough’ narrative purports that it is enough for a given level of safety to be reached in order for a technology to be rolled out unhindered, and limits reflections on ethics and governance to considerations about safety” (EGE, 2021 , p. 20). Consequently, the EGE has highlighted the need to engage with value-laden concepts such as ‘humanness’, ‘naturalness’ or ‘human diversity’ when determining the conditions under which HGE could be justified. Even if a technology has a high level of safety, its application may still contradict ethical values or lead to undesirable societal consequences. Efficacy does not guarantee compatibility with well-established ethical values or cultural norms.

While concepts such as ‘safety’ or ‘risk’ are often defined in scientific terms, this does not take away the decision of what is ethically desirable given the technical possibilities. As Hurlbut and colleagues put it in the context of genome editing: “Limiting early deliberation to narrowly technical constructions of risk permits science to define the harms and benefits of interest, leaving little opportunity for publics to deliberate on which imaginations need widening, and which patterns of winning and losing must be brought into view” (Hurlbut et al., 2015 ). Therefore, if public engagement is to be taken seriously, cultural norms and values of those affected by technologies must also be considered (Klingler et al., 2022 ). This, however, means broadening the narrow focus on pragmatic reasons and allowing categorical as well as sociopolitical concerns in the discourse. Given the current attention on pragmatic reasons in current debates on HGE, it is therefore beneficial to revisit the categorical and sociopolitical concerns that remain unresolved. The following sections provide an overview of relevant considerations that can arise in the context of HGE and that underline many of the societal concerns and values crucial for public engagement.

Human genome ‘integrity’

Heritability seems to be one of the foremost considerations regarding germline genome editing, as it raises relevant questions on a ‘natural’ human genome and its role in ‘human nature’ (Bayertz, 2003 ). This follows an ongoing philosophical debate on ‘human nature’, at least as defined by the human genome. This has ensued a long debate on the value of the human genome and normative implications associated with its modification (e.g., Habermas, 2003 ). Although a comprehensive discussion of these topics goes beyond the scope of this paper, the human genome is viewed by many as playing an important role in defining ‘human nature’ and providing a basis for the unity of the human species (for discussion: Primc, 2019 ). Considering the implications for the individual and the collective, some affirm the right of all humans to inherit an unmodified human genome. For some authors, germline modification is considered unethical, e.g., a “line that should not be crossed” (Collins, 2015 ) or a “crime against humanity” (Annas et al., 2002 ).

The Universal Declaration on the Human Genome and Human Rights (UDHGHR) states that “the human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity” (Article 1, UNESCO, 1997 ). The human genome is viewed as our uniquely human collective ‘heritage’ that needs to be preserved and protected. Critics of heritable genetic interventions argue that germline manipulation would disrupt this natural heritage and therefore would threaten human rights and human equality (Annas, 2005 ). Heritable human genome editing creates changes that can be heritable to future generations. For many, this can represent a threat to the unity and identity of the human species, as these modifications could have an impact on the human’s gene pool. Any alterations would then affect the evolutionary trajectory of the human species and, thus, its unity and identity.

However, the view of the human genome as a common heritage is confronted with observations of the intrinsic dynamism of the genome (Scally, 2016 ). Preservation of the human genome, at least in its current form, would imply that the genome is static. However, the human genome is dynamic and, at least in specific periods of environmental pressure, must have naturally undergone change, as illustrated by human evolution (Fu and Akey, 2013 ). The genome of any individual includes mutations that have occurred naturally. Most of them seem to be neither beneficial nor detrimental to the ability of an individual to live or to his/her health. Others can be detrimental and limiting to their wellbeing. It has been shown that, on average, each human genome has 60 new mutations compared to their parents (Conrad et al., 2011 ). At the human population level, a human genome can have in average 4.1–5 million variants compared to the ‘reference’ genome (Li and Sadler, 1991 ; Genomes Project C, 2015 ). The reference genome itself is thus a statistical entity, representing the statistic distribution of the probability of different gene variants in the whole genome. Human genomic variation is at the basis of the differences in the various physical traits present in humans (e.g., eye colour, height, etc.), as well as specific genetic diseases. Thus, the human population is comprised of genomes with a pattern of variants and not of ‘one’ human genome that needs to be preserved (Venter et al. 2001 ). The human genome has naturally been undergoing changes throughout human history. An essentialist view of nature seems to be the basis for calling for the preservation of genome integrity. However, in many ways, this view is intrinsically challenged by the interpretation portrayed by evolutionary biology of our genetic history already more than a century ago. Nevertheless, despite the dynamic state of the human genome, this in itself cannot justify the possibility of modifying the human genome. It is also worth considering that the integrity of the human genome could also be perceived in a ‘symbolic’ rather than biological literal meaning. Such an interpretation would not require a literally static genome over time, but instead suggest a boundary between ‘naturally’ occurring variation and ‘artificially’ induced change. This is rather a version of the ‘natural’/unnatural argument, rather than an argument for a literally unchanged genetic sequence.

The modification of the human genome raises complex questions about the characterization of the human species genome and if there should be limits on interfering with it. The options to modify the human genome could range from modifying only the genes that are part of the human gene pool (e.g., those genes involved in severe genetic diseases such as Huntington’s disease) to adding new variants to the human genome. Regarding variants which are part of the common range of variation found in the human population (although it is not possible to know all the existent variations), the question becomes whether HGE could also be used in any of them (e.g., even the ones providing some form of enhancement) or only in disease-associated variants and thus be restricted to the prevention of severe genetic diseases. In both cases, the integrity of the human genome is expected to be maintained with no disruption to human lineage. However, it could be argued that this type of modification is defending a somewhat conservative human nature argument, since it is considering that a particular genetic make-up is ‘safe’ or would not involve any relevant trade-offs. In contrast, a different conclusion could be drawn on the integrity of the human genome when introducing genotypical and phenotypical traits that do not lie within the common range of variation found in the population (Cwik, 2020 ). In all cases, since the implications of the technology are intergenerational and consequently, it will be important to carry out an assessment of the risks that we, as a species, are willing to take when dealing with disease and promoting health. For this, we will need to explore societal views, values and cultural norms associated with the human genome, as well as possibly existing perceptions of technology tampering with ‘nature’. To support such an assessment, it would be useful to draw on a firm concept of human nature and the values it implies, beyond what is implied by genetic aspects.

Human dignity

In several of the legally binding and non-binding documents addressing human rights in the biomedical field, human dignity is one of the key values emphasized. There are concerns that heritable genome interventions might conflict with the value of human dignity (Calo, 2012 ; Melillo, 2017 ). The concerns are considered in the context of preserving the human genome (Nordberg et al. 2020 ). More specifically, the recommendation on Genetic Engineering by the Council of Europe (1982) states that “ the rights to life and to human dignity protected by Articles 2 and 3 of the European Convention on Human Rights imply the right to inherit a genetic pattern which has not been artificially changed” (Assembly, 1982 ). This is supported by the Oviedo Convention on Human Rights and Biomedicine (1997), where Article 13 prohibits any genetic intervention with the aim of introducing a modification in the genome of any descendants. The Convention is the only international legally binding instrument that covers human germline modifications among the countries which have ratified it (Council of Europe, 1997 ). However, there have been some authors disputing the continued ban proposed by the Oviedo Convention (Nordberg et al. 2020 ). Such authors have focused on the improvements of safety and efficacy of the technology in contrast to authors focusing on its value for human dignity (Baylis and Ikemoto, 2017 ; Sykora and Caplan, 2017 ). The latter authors seem to highlight the concept of human dignity to challenge heritable interventions to the human genome.

But a question in debate has been to demonstrate how ‘human dignity’, described in such norms, relates to heritable genome interventions. The concept of the human genome as common genetic heritage, distinguishing humans from other species seems one of the main principles implied by such norms. In this view, the human genome determines who belongs to the human species and who does not, and thus confers an individual the dignity of being a human by association. This creates an inherent and strong link between the concept of human genome and the concept of human dignity and its associated legal rights (Annas, 2005 ). It could be argued that a genetic modification to an individual may make it difficult for him/her to be recognized as a human being and therefore, preservation of the human genome being important for human dignity to be maintained. This simple approach, or at least interpretation, however, ignores the fact that the human genome is not a fixed or immutable entity, as exemplified by human evolution (as discussed in the previous section). As a result, the view that HGE interventions are inherently inadmissible based on the need to preserve human dignity is contested (Beriain, 2018 ; Raposo, 2019 ). More broadly, the idea that biological traits are the basis for equality and dignity, supporting the need for the human genome to be preserved, is often challenged (Fenton, 2008 ).

It is argued that to fully assess the impact of the HGE interventions on human dignity, it will be necessary to have a better understanding of the concept of human dignity in the first place (Häyry, 2003 ; Cutas, 2005 ). For some, however, human dignity is a value that underlies questions of equality and justice. Thus, the dignity-based arguments could uncover relevant questions in the discussion of ethical implications on modifying the human genome (Segers and Mertes, 2020 ). In the Nuffield Council on Bioethics Report (2018) principles of social justice and solidarity, as well as welfare, are used to guide the debate on managing HGE interventions. Similarly, the concept of human dignity could, therefore, provide the platform upon which consideration of specific values could be discussed, broaden the debate on HGE to values shared by society.

Right of the child: informed consent

In many modern societies, every individual, including children, have the rights to autonomy and self-determination. Therefore, each person is entitled to decide for themselves in decisions relating to their body. These rights are important for protecting the physical integrity of a person. When assessing the implication of allowing individuals to take (informed) decisions relative to the use of heritable genetic interventions on someone else’s body, it is useful to reflect on the maturity of existing medical practices and, more broadly, on the additional complexities associated with the heritability of any such intervention.

In modern health-care systems, informed consent provides the opportunity for an individual to exercise autonomy and make an informed decision about a medical procedure, based on their understanding of the benefits and risks of such procedure. Informed consent is thus a fundamental principle in medical (research) ethics when dealing with human subjects (Beauchamp and Childress, 2019 ).

Heritable genome interventions present an ethical constraint on the impossibility of future generations of providing consent to an intervention on their genome (Smolenski, 2015 ). In other words, future generations cannot be involved in a decision which could limit their autonomy, since medical or health-related decisions affecting them are placed on the present generation (and, in the case of a child to be born, more specifically, on his/her parents). However, many other actions taken by parents of young children also intentionally influence the lives of those children and have been doing so for millennia (Ranisch, 2017 ). Although these actions may not involve altering their genes, many of such actions can have a long-lasting impact on a child’s life (e.g., education and diet). However, it could be argued that they do not have the irreversible effect that HGE will have in the child and future generations. In cases where parents act to expand the life choices of their children by eliminating disease (e.g., severe genetic diseases), this would normally be thought to outweigh any possible restriction on autonomy. In these cases, if assuming HGE benefits will outweigh risks regarding safety and efficacy, the use of HGE could be expected to contribute to the autonomy of the child, as him/her would be able in the future to have a better life, not constrained by the limitations of the disease. As a result, even if it is accepted that these technologies may in one way reduce the autonomy of future generations, some believe that this will often be outweighed by other effects increasing autonomy (Gyngell et al., 2017 ). In other words, it is reasonable to suppose that, when taken by parents based on good information and understanding of risks and impacts, the limitation in the autonomy of unborn children associated with heritable genetic interventions would be compensated by the beneficial effects of increasing their autonomy when born (Gyngell et al., 2017 ).

It has often been emphasized that possible genetic interventions must not curtail the future possibilities of offspring to live their lives according to their own idea of a good life. This view originated in the liberal tradition and is associated with the “right to an open future”, defended by Joel Feinberg ( 1992 ). That is an anticipatory autonomy right that parents can violate, even though the offspring could exercise it only in the future. Feinberg has discussed the right to an open future in the context of religious education. However, various authors have applied this argument to the question of permissible and desirable genetic interventions (Buchanan et al., 2000 ; Glover, 2006 ; Agar, 1998 ). Accordingly, germline modifications or selection would have to allow the offspring to have a self-determined choice of life plans. It would therefore be necessary to provide offspring with genetic endowments that represent the so-called all-purpose goods. These goods are “useful and valuable in carrying out nearly any plan of life or set of aims that humans typically have” (Buchanan et al., 2000 , p. 167). While this claim is certainly appealing, in reality it will be difficult to identify phenotypes that will only broaden and do not narrow the spectrum of life plans. Take, for example, body size: a physique favourable for a basketball player would at the same time be less favourable in successfully riding horses as a professional jockey and vice versa. Increasing some opportunities often means reducing other ones.

The arguments of informed consent and open future need to be explored outside the realm of severe genetic diseases by considering other scenarios (including scenarios of genetic enhancement). Hereby, the effects of the interventions on the autonomy of future generations can be assessed more comprehensively. As for enhancement, decisions outside the realm of health can be more controversial, as the traits that parents see fit to generate enhancement may inadvertently condition a child’s choices in the future in an undesirable way.

If HGE is to be used, questions on how the consent and information should be provided to parents to fully equip them to decide in the best interests of the child will need to be assessed (Evitt et al., 2015 ). This is evident if considering the informed consent used in the study conducted by He Jiankui. One of the many criticisms of the study was the inadequacy of the informed consent process provided to the parents, which did not meet regulatory or ethical standards (Krimsky, 2019 ; Kirksey, 2020 ). This raises questions on how best to achieve ethical and regulatory compliance regarding informed consent in applications of HGE (Jonlin, 2020 ).

Discrimination of people with disabilities

For many years, there has been an effort to develop selective reproduction technologies to prevent genetic diseases or conditions leading to severe disabilities. These forms of reproductive genetic disease prevention are based on effectively filtering and eradicating embryos or foetuses affected by genetic diseases. There are divergent views regarding the use of these technologies. For example, the disability rights movement argues that the use of technologies such as prenatal testing (PNT) and PGD discriminates against people living with a disability (Scully, 2008 ; Asch and Barlevy, 2012 ). The key arguments presented supporting this view are: (i) the limited value of a genetic trait in respect to the life of an embryo (Parens and Asch, 2000 ) and (ii) the ‘expressivist’ argument (Buchanan, 1996 ; Shakespeare, 2006 ). The first argument is based on the critique that a disabling trait is viewed as being more significant than the life of an embryo/foetus. This argument was initially used in the context of prenatal testing and selective termination, and has also been applied in the context of new technologies like PGD (Parens and Asch, 2000 ). The second, the ‘expressivist’ argument, argues that the use of these technologies expresses negative or discriminatory views on the disabling conditions they are targeting and subsequently on the people living with these conditions (Asch and Wasserman, 2015 ). The expressivist argument, however, has been challenged by stressing the importance of differentiating between the disability itself and the people living with disability (Savulescu, 2001 ). The technology’s use is aimed at reducing the incidence of disability, and it does not have a position of value on the people that have a specific condition.

When applying the same arguments to the use of HGE in comparison with other forms of preventing heritable genetic diseases, some important considerations can be made. Regarding the first argument, in contrast to selective reproduction technologies, HGE may allow the removal of the disabled trait with the aim of ensuring survival of the affected embryo. However, most likely, PGD would be used before and after the editing of the embryos to help the identification of the ones requiring intervention and verifying the efficiency of the genetic intervention (de Miguel Beriain, 2018 ; Ranisch, 2020 ). Similarly, the expressivist argument continues to be challenged if the application of human HGE is envisaged in the context of severe genetic diseases (e.g., Tay-Sachs and Huntington’s disease). It has been argued that the choice to live without a specific genotype neither implies discriminating people living with a respective condition nor considering the life of people living with the disease not worth living or less valuable (Savulescu, 2001 ). In other words, the expressivist argument is not a valid or a sufficiently strong ethical argument for prospective parents not to have the option to have a future child without a genetic disease.

It is worth noting that the debate on the use of reproduction technologies for the prevention of genetic diseases is not at all new, and that modern HGE techniques only serve to highlight ethical concerns that have been expressed for a long time. In the case of preventing genetic diseases, the application of both arguments to HGE intervention could be considered not to provide sufficiently strong ethical arguments to limit the use of the technology in the future. However, it is worth exploring whether scientific innovations like HGE are either ameliorating or reinvigorating ethical concerns expressed so far, for example in creating a future that respects or devalues disability as a part of the human condition. Perhaps even more importantly, given their potential spectrum of possible intervention and efficacy, it is important to reflect on whether the broad use of HGE could have an impact on concepts of disability and ‘normality’ as a whole distorting an already unclear ethical line between clinical and non-clinical interventions. Moreover, research work exploring the relationship between disability and identity indicated that personhood with disability can be an important component to people’s identity and interaction with the world. In the case of heritable human genome editing, it is not yet known how this technology will impact the notions of identity and personhood in people who had their germline genome modified (Boardman and Hale, 2018 ). For further progress on these issues public engagement might be important to gather different views and perceptions on the issue.

Justice and equality

Beside the limits of applicability, another common ethical concern associated with the use of genome editing technologies, as with many new technologies, is the question of accessibility (Baumann, 2016 ). Due to the large investments that will need to be made for continuing development of the technology, there is a (perceived) risk of it becoming an expensive technology that only a few wealthy individuals in any population (and/or only citizens in comparatively rich countries) can access. In addition, there is concern that patenting of genome editing technologies will delay widespread access or lead to unequal distribution of corresponding benefits (Feeney et al., 2018 ). This may, consequently, contribute to further increases in existing disparities, since individuals or countries with the means of accessing better health treatments may have economic advantages (Bosley et al., 2015 ). This could enhance inequality at different levels, depending on the limits of applicability of the technology. Taken to its extreme, the use of the technology could allow germline editing to create and distinguish classes of individuals that could be defined by the quality of their manipulated genome.

The concern that the possibility of germline interventions in humans could entrench or even increase inequalities has accompanied the discussion about ethics of genetic interventions from the very beginning until today (e.g. Resnik, 1994 ). In ‘Remaking Eden’ Lee Silver envisioned a divided future society, consisting of a genetically enhanced class, the “genRich”, and a genetic underclass, the “naturals” (Silver, 1997 ). Françoise Baylis recently echoed such concerns regarding future HGE interventions, namely that “unequal access to genome-editing technologies will both accentuate the vagaries of the natural lottery and introduce an unjust genetic divide that mirrors the current unjust economic and social divide between rich and poor individuals” (Baylis, 2019 , p. 67). At the same time, the possibility to genetically intervene in the ‘natural lottery’ has also been associated with the hope of countering natural inequalities and increase equality of opportunities. Robert Sinsheimer may be among the first to envision such a ‘new’ individualistic type of ‘eugenics’ that “would permit in principle the conversion of all of the unfit to the highest genetic level” (Sinsheimer, 1969 , p. 13). More recently, in the book ‘From chance to choice: Genetics and justice’ (2000) it is argued that “equality of opportunity will sometimes require genetic interventions and that the required interventions may not always be limited to the cure or prevention of disease” (Buchanan et al., 2000 , p. 102). When discussing issues related to justice and equality, it will be important to involve a broad spectrum of stakeholders to better evaluate the economic effects of the commercialization of the technology.

Conclusions

With ongoing technological developments and progress with guiding and regulating its acceptable use, the possibility of HGE interventions in the human genome is closer than ever to becoming a reality. The range of HGE applicability can go from preventing the transmission of genetic variants associated with severe genetic conditions (mostly single gene disorders but also, to a lesser extent, polygenic diseases) to genetic enhancements. The permissibility of HGE has often been considered on the basis of possible uses, with therapeutic uses generally considered more acceptable than non-therapeutic ones (including human enhancement). When compared with other technologies with similar therapeutic uses (e.g., PGD) already in use, HGE presents similarities and differences. However, from an ethical acceptability perspective, there is currently no consensus on whether HGE is more or less acceptable than PGD.

An important conclusion of this study is that, along with the technological development of genome germline editing techniques, a shift in the focus of analyses on its applicability has been observed. More specifically, the emphasis on pragmatic considerations seems to have increased substantially compared with the previous emphasis on categorical and sociopolitical arguments. Many of the most recent publications from authoritative advisory committees and institutions discuss the permissibility of HGE interventions primarily on the basis of pragmatic arguments, in which safety and efficacy are the main focus. Since germline interventions could profoundly change the human condition, the need for a broad and inclusive public debate on this topic has also been frequently emphasized. However, limited consideration has been given to approaches to carry out such action effectively, and on how to consider their outcomes in relevant policies and regulations.

It is currently not entirely clear whether: (i) the pragmatic position championed by such authoritative sources builds on the premise that the ethical debate has reached sufficient maturity to allow a turning point; (ii) the lack of progress has somewhat hampered further consideration of issues still considered controversial; (iii) regulatory pressure is somewhat de facto pushing forward the introduction of such technologies despite critical, unresolved ethical issues. Based on the analysis presented in this paper, a combination of the latter factors (ii and iii) seems more likely. In engaging the public in societal debates on the acceptability of such technologies, unresolved questions are likely to re-emerge. Specifically, it is possible that categorical and sociopolitical considerations will gain renewed focus during public engagement. In other words, when involving the public in discussions on HGE, it is possible that cultural values and norms, not only questions of safety and efficacy, will re-emerge as crucial to the acceptance of the technology (What is meant by natural? What is understood by humanity? etc.).

HGE interventions put into question specific biological and moral views of individuals, including views on the value of the human genome, on human dignity, on informed consent, on disability and on societal equality and justice. The range of ethical issues affected by the introduction of such technology, often still characterised by non-convergent, and at times conflicting, positions, illustrate the importance of further consideration of these issues in future studies and public engagement activities. As a result, society’s moral uncertainties will need to be assessed further to support the regulation of HGE technologies and form a well-informed and holistic view on how they can serve society’s common goals and values.

Data availability

This statement is not applicable.

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Acknowledgements

This work was supported by Fundação para Ciência e a Tecnologia (FCT) of Portugal [UIDP/00678/2020 to M.A]. We thank Dr. Michael Morrison for his comments and Dr. Gustav Preller for his proofreading of this manuscript.

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Almeida, M., Ranisch, R. Beyond safety: mapping the ethical debate on heritable genome editing interventions. Humanit Soc Sci Commun 9 , 139 (2022). https://doi.org/10.1057/s41599-022-01147-y

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12.4: Genetic Engineering - Risks, Benefits, and Perceptions

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Learning Objectives

• Summarize the mechanisms, risks, and potential benefits of gene therapy
• Identify ethical issues involving gene therapy and the regulatory agencies that provide oversight for clinical trials
• Compare somatic-cell and germ-line gene therapy

Many types of genetic engineering have yielded clear benefits with few apparent risks. Few would question, for example, the value of our now abundant supply of human insulin produced by genetically engineered bacteria. However, many emerging applications of genetic engineering are much more controversial, often because their potential benefits are pitted against significant risks, real or perceived. This is certainly the case for gene therapy, a clinical application of genetic engineering that may one day provide a cure for many diseases but is still largely an experimental approach to treatment.

Mechanisms and Risks of Gene Therapy

Human diseases that result from genetic mutations are often difficult to treat with drugs or other traditional forms of therapy because the signs and symptoms of disease result from abnormalities in a patient’s genome. For example, a patient may have a genetic mutation that prevents the expression of a specific protein required for the normal function of a particular cell type. This is the case in patients with Severe Combined Immunodeficiency (SCID), a genetic disease that impairs the function of certain white blood cells essential to the immune system.

Gene therapy attempts to correct genetic abnormalities by introducing a nonmutated, functional gene into the patient’s genome. The nonmutated gene encodes a functional protein that the patient would otherwise be unable to produce. Viral vectors such as adenovirus are sometimes used to introduce the functional gene; part of the viral genome is removed and replaced with the desired gene (Figure \(\PageIndex{1}\)). More advanced forms of gene therapy attempt to correct the mutation at the original site in the genome, such as is the case with treatment of SCID.

So far, gene therapies have proven relatively ineffective, with the possible exceptions of treatments for cystic fibrosisand adenosine deaminase deficiency, a type of SCID. Other trials have shown the clear hazards of attempting genetic manipulation in complex multicellular organisms like humans. In some patients, the use of an adenovirus vector can trigger an unanticipated inflammatory response from the immune system, which may lead to organ failure. Moreover, because viruses can often target multiple cell types, the virus vector may infect cells not targeted for the therapy, damaging these other cells and possibly leading to illnesses such as cancer. Another potential risk is that the modified virus could revert to being infectious and cause disease in the patient. Lastly, there is a risk that the inserted gene could unintentionally inactivate another important gene in the patient’s genome, disrupting normal cell cycling and possibly leading to tumor formation and cancer. Because gene therapy involves so many risks, candidates for gene therapy need to be fully informed of these risks before providing informed consent to undergo the therapy.

Gene Therapy Gone Wrong

The risks of gene therapy were realized in the 1999 case of Jesse Gelsinger, an 18-year-old patient who received gene therapy as part of a clinical trial at the University of Pennsylvania. Jesse received gene therapy for a condition called ornithine transcarbamylase (OTC) deficiency, which leads to ammonia accumulation in the blood due to deficient ammonia processing. Four days after the treatment, Jesse died after a massive immune response to the adenovirus vector. 1

Until that point, researchers had not really considered an immune response to the vector to be a legitimate risk, but on investigation, it appears that the researchers had some evidence suggesting that this was a possible outcome. Prior to Jesse’s treatment, several other human patients had suffered side effects of the treatment, and three monkeys used in a trial had died as a result of inflammation and clotting disorders. Despite this information, it appears that neither Jesse nor his family were made aware of these outcomes when they consented to the therapy. Jesse’s death was the first patient death due to a gene therapy treatment and resulted in the immediate halting of the clinical trial in which he was involved, the subsequent halting of all other gene therapy trials at the University of Pennsylvania, and the investigation of all other gene therapy trials in the United States. As a result, the regulation and oversight of gene therapy overall was reexamined, resulting in new regulatory protocols that are still in place today.

Exercise \(\PageIndex{1}\)

• Explain how gene therapy works in theory.
• Identify some risks of gene therapy.

Oversight of Gene Therapy

Presently, there is significant oversight of gene therapy clinical trials. At the federal level, three agencies regulate gene therapy in parallel: the Food and Drug Administration (FDA), the Office of Human Research Protection (OHRP), and the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH). Along with several local agencies, these federal agencies interact with the institutional review board to ensure that protocols are in place to protect patient safety during clinical trials. Compliance with these protocols is enforced mostly on the local level in cooperation with the federal agencies. Gene therapies are currently under the most extensive federal and local review compared to other types of therapies, which are more typically only under the review of the FDA. Some researchers believe that these extensive regulations actually inhibit progress in gene therapy research. In 2013, the Institute of Medicine (now the National Academy of Medicine) called upon the NIH to relax its review of gene therapy trials in most cases. 2 However, ensuring patient safety continues to be of utmost concern.

Ethical Concerns

Beyond the health risks of gene therapy, the ability to genetically modify humans poses a number of ethical issues related to the limits of such “therapy.” While current research is focused on gene therapy for genetic diseases, scientists might one day apply these methods to manipulate other genetic traits not perceived as desirable. This raises questions such as:

Exercise \(\PageIndex{2}\)

• Which genetic traits are worthy of being “corrected”?
• Should gene therapy be used for cosmetic reasons or to enhance human abilities?
• Should genetic manipulation be used to impart desirable traits to the unborn?
• Is everyone entitled to gene therapy, or could the cost of gene therapy create new forms of social inequality?
• Who should be responsible for regulating and policing inappropriate use of gene therapies?

The ability to alter reproductive cells using gene therapy could also generate new ethical dilemmas. To date, the various types of gene therapies have been targeted to somatic cells, the non-reproductive cells within the body. Because somatic cell traits are not inherited, any genetic changes accomplished by somatic-cell gene therapy would not be passed on to offspring. However, should scientists successfully introduce new genes to germ cells (eggs or sperm), the resulting traits could be passed on to offspring. This approach, called germ-line gene therapy, could potentially be used to combat heritable diseases, but it could also lead to unintended consequences for future generations. Moreover, there is the question of informed consent, because those impacted by germ-line gene therapy are unborn and therefore unable to choose whether they receive the therapy. For these reasons, the U.S. government does not currently fund research projects investigating germ-line gene therapies in humans.

Risky Gene Therapies

While there are currently no gene therapies on the market in the United States, many are in the pipeline and it is likely that some will eventually be approved. With recent advances in gene therapies targeting p53, a gene whose somatic cell mutations have been implicated in over 50% of human cancers, 3 cancer treatments through gene therapies could become much more widespread once they reach the commercial market.

Bringing any new therapy to market poses ethical questions that pit the expected benefits against the risks. How quickly should new therapies be brought to the market? How can we ensure that new therapies have been sufficiently tested for safety and effectiveness before they are marketed to the public? The process by which new therapies are developed and approved complicates such questions, as those involved in the approval process are often under significant pressure to get a new therapy approved even in the face of significant risks.

To receive FDA approval for a new therapy, researchers must collect significant laboratory data from animal trials and submit an Investigational New Drug (IND) application to the FDA’s Center for Drug Evaluation and Research (CDER). Following a 30-day waiting period during which the FDA reviews the IND, clinical trials involving human subjects may begin. If the FDA perceives a problem prior to or during the clinical trial, the FDA can order a “clinical hold” until any problems are addressed. During clinical trials, researchers collect and analyze data on the therapy’s effectiveness and safety, including any side effects observed. Once the therapy meets FDA standards for effectiveness and safety, the developers can submit a New Drug Application (NDA) that details how the therapy will be manufactured, packaged, monitored, and administered.

Because new gene therapies are frequently the result of many years (even decades) of laboratory and clinical research, they require a significant financial investment. By the time a therapy has reached the clinical trials stage, the financial stakes are high for pharmaceutical companies and their shareholders. This creates potential conflicts of interest that can sometimes affect the objective judgment of researchers, their funders, and even trial participants. The Jesse Gelsinger case (see Case in Point: Gene Therapy Gone Wrong ) is a classic example. Faced with a life-threatening disease and no reasonable treatments available, it is easy to see why a patient might be eager to participate in a clinical trial no matter the risks. It is also easy to see how a researcher might view the short-term risks for a small group of study participants as a small price to pay for the potential benefits of a game-changing new treatment.

Gelsinger’s death led to increased scrutiny of gene therapy, and subsequent negative outcomes of gene therapy have resulted in the temporary halting of clinical trials pending further investigation. For example, when children in France treated with gene therapy for SCID began to develop leukemia several years after treatment, the FDA temporarily stopped clinical trials of similar types of gene therapy occurring in the United States. 4 Cases like these highlight the need for researchers and health professionals not only to value human well-being and patients’ rights over profitability, but also to maintain scientific objectivity when evaluating the risks and benefits of new therapies.

Exercise \(\PageIndex{3}\)

• Why is gene therapy research so tightly regulated?
• What is the main ethical concern associated with germ-line gene therapy?

Key Concepts and Summary

• While gene therapy shows great promise for the treatment of genetic diseases, there are also significant risks involved.
• There is considerable federal and local regulation of the development of gene therapies by pharmaceutical companies for use in humans.
• Before gene therapy use can increase dramatically, there are many ethical issues that need to be addressed by the medical and research communities, politicians, and society at large.
• 1 Barbara Sibbald. “Death but One Unintended Consequence of Gene-Therapy Trial.” Canadian Medical Association Journal 164 no. 11 (2001): 1612–1612.
• 2 Kerry Grens. “Report: Ease Gene Therapy Reviews.” The Scientist , December 9, 2013. http://www.the-scientist.com/?articl...erapy-Reviews/ . Accessed May 27, 2016.
• 3 Zhen Wang and Yi Sun. “Targeting p53 for Novel Anticancer Therapy.” Translational Oncology 3 , no. 1 (2010): 1–12.
• 4 Erika Check. “Gene Therapy: A Tragic Setback.” Nature 420 no. 6912 (2002): 116–118.

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Most Americans Accept Genetic Engineering of Animals That Benefits Human Health, but Many Oppose Other Uses

Public concerns about animal biotechnology focus on risks to animals, humans and the ecosystem.

As Americans consider the possible uses of genetic engineering in animals, their reactions are neither uniformly accepting nor resistant; instead, public reactions vary depending on the mechanism and intended purpose of the technology, particularly the extent to which it would bring health benefits to humans.

Presented with five different scenarios of animal genetic engineering that are currently available, in development or considered possible in the future, Americans provide majority support only for the two that have clear potential to pre-empt or ameliorate human illness.

The survey’s most widely accepted use of genetic intervention of animals involves mosquitoes. Seven-in-ten Americans (70%) believe that genetically engineering mosquitoes to prevent their reproduction and therefore the spread of some mosquito-borne diseases would be an appropriate use of technology, while about three-in-ten (29%) see the use of genetic engineering for this purpose as taking technology too far.

And a 57% majority considers it appropriate to genetically engineer animals to grow organs or tissues that could be used for humans needing a transplant.

But other uses of animal biotechnology are less acceptable to the public, including the creation of more nutritious meat for human consumption (43% say this is appropriate) or restoring an extinct animal species from a closely related species (32% say this is appropriate). And one application that is already commercially available is largely met with resistance: Just 21% of Americans consider it an appropriate use of technology to genetically engineer aquarium fish to glow using a fluorescence gene, while 77% say this is taking technology too far.

These are some of the findings from a new Pew Research Center survey, conducted April 23-May 6 among a nationally representative sample of 2,537 U.S. adults that looks at public views about genetic engineering of animals – a term that encompasses a range of biotechnologies that can add, delete or change an animal’s existing genetic material and thereby introduce new traits or characteristics.

Although most Americans are largely in agreement that using genetic engineering in mosquitoes to prevent the spread of mosquito-borne illnesses is appropriate, views about other uses of genetic engineering of animals considered in the survey differ by gender, levels of science knowledge and religiosity. Men are more accepting of these uses of technology than women, those with high science knowledge are more accepting than those with medium or low science knowledge and those low in religious commitment are more accepting than those with medium or high levels of religious commitment.

For example, about two-thirds of men (65%) see genetic engineering of animals to grow human organs or tissues for transplants as appropriate, compared with about half of women (49%). Also, Americans with high science knowledge (72%) are more inclined than those with medium (55%) or low (47%) science knowledge to say this would be appropriate. And a larger share of those with low religious commitment (68%) than medium (54%) or high (48%) religious commitment consider genetic engineering of animals to grow human organs or tissues for transplants to be appropriate.

Emerging developments in animal biotechnology raise new social, ethical and policy issues for society, including the potential impact on animal welfare .

The survey finds that the 52% of Americans who in general oppose the use of animals in scientific research are, perhaps not surprisingly, also more inclined to consider specific uses of genetic engineering of animals to be taking technology too far.

There are large differences between these groups when it comes to using animal biotechnology for humans needing an organ or tissue transplant and the idea of using such technology to produce more nutritious meat.

Reasoning behind public qualms over animal biotechnology

To better understand people’s beliefs about genetic engineering of animals, the survey asked a subset of respondents to explain, in their own words, the main reason behind their view that genetic engineering in each of these circumstances would be taking technology too far.

A common refrain in these responses raised the possibility of unknown risks for animals, humans or the ecosystem. Some saw these technologies as humankind inappropriately interfering with the natural world or raised general concerns about unknown risks.

About three-in-ten of those who said genetic engineering of mosquitoes would be taking technology too far explained that humankind would be disrupting nature (23%) or interfering with God’s plan (8%).

One respondent put it this way:

“Nature is a balance and every time man interferes with it, it doesn’t turn out well.”

Some 24% of those with objections to the idea of reducing the fertility of mosquitoes through genetic engineering in order to reduce mosquito-borne illnesses raised concerns about the possible impact on the ecosystem.

Such responses include:

“I do not think we know enough about the effects of removing a whole class of insects from the environment. What would be the effects on those animal and plants ‘up the chain’?”

“Mosquitoes are part of a complex ecosystem and food chain. By preventing their reproduction, we risk disrupting the entire ecosystem.”

Objections to the idea of using animal biotechnology to grow organs or tissues for transplant in humans focused on beliefs about using animals for human benefit (21%) and potential risks for human health from creating human organs from animals (16%).

For example:

“In manufacturing organs, the existence of these animals would be miserable … in order to cultivate such organs the animals would need to be in a lab setting and would more than likely never see the light of day. I can’t ethically say that I would agree with such a practice.”

“When you mix human and nonhuman genetics I believe that will cause extreme problems down the road.”

“Animal organs are not made for humans even though some animal and human organs may be very similar. Who knows what side effects this could cause? Even human-to-human organ transplants often reject, so I can only imagine the bad side effects that an animal-to-human transplant would cause. Keep things simple and the way nature intended.”

Genetic engineering could produce more nutritious meat by altering animal proteins. Those who think this is taking technology too far raised a number of different concerns. Some cited general concerns about as-yet-unknown risks (20% of those asked), while a similar share (19%) saw this as messing with nature or God’s plan in a way that goes beyond what humans should do.

“Should we as human beings change the course of nature’s ‘natural selection’ and potentially introduce unintended serious consequences? ”

About one-in-ten (12%) objected to the idea on the grounds that people should rely less on meat in their diet or that any genetic engineering in foods is a likely health risk.

One example of these concerns:

“Meat is nutritious as it is. There is no need to try to increase nutrition. Rather we should be decreasing human reliance on meat as a foodstuff.”

Those who objected to the idea of bringing back extinct species often raised concerns about unintended harm to the ecosystem. Roughly two-in-ten (18%) of those asked explained their views by saying there is a reason that these animals are currently extinct, with some saying these animals would be unlikely to survive if brought back, and another 12% of this group raised potential risks to other species and the ecosystem from bringing an extinct animal into a different world.

Others discussed these ideas in terms of God’s plan and human interference with the natural world (23%).

A few examples:

“God is the creator of all living things, not mankind. Extinction is part of evolution of the universe.”

“Nature has selected species to become extinct over millions and millions of years. We have no right to bring animals back and play God.”

And 14% said they regard bringing back an extinct species as taking technology too far because they do not see a need or purpose to this, especially as it does not seem to bring any benefit to humans, or that resources should be focused elsewhere.

A sampling of these concerns:

“For what purpose would it be done? Is there a benefit to humanity other than having a rare zoo specimen? Would the extinct species cease to become extinct through natural reproduction – if not that, the whole effort is without merit.”

“I don’t see the purpose of bringing any animal back. Would it provide a better way of life for humans?”

Objections to the idea of changing the appearance of aquarium fish using genetic engineering to make the fish glow often focused on the lack of apparent need or benefit to either humans or animals.

About half (48%) of those who say engineering a glowing fish takes technology too far said they do not see the purpose for humans or society, questioned its necessity or considered it frivolous or a waste of resources.

Some examples:

“It’s frivolous. Technology should be used to help people, animals and the environment, not put on a glow show.”

“Why? If you only do something because you can is not a good reason. If any genetic engineering is allowed it will get out of hand. It would be a fine line that I am sure we would cross.”

“It seems a frivolous thing to do, much like someone getting plastic surgery to remove wrinkles or other signs of aging. The person’s life is not extended by a ‘better’ appearance. The aquarium fish also do not benefit from their changed appearance.”

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Synthetic epigenetics-assisted microbial chassis engineering

Affiliations.

• 1 State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China.
• 2 State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China.
• 3 State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China. Electronic address: [email protected].
• PMID: 37400289
• DOI: 10.1016/j.tim.2023.06.001

Microbial chassis engineering is the milestone of efficient biotechnological applications. However, microbial chassis cell engineering is adversely affected by (i) regulatory tool orthogonality, (ii) host metabolic fitness, and (iii) cell population heterogeneity. Herein, we explore how synthetic epigenetics can potentially address these limitations and offer insights into prospects in this field.

Keywords: epigenetics; genetic circuits; genetic engineering; microbial chassis engineering.

Copyright © 2023 Elsevier Ltd. All rights reserved.

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• Biotechnology
• Metabolic Engineering*
• Synthetic Biology*

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May 6, 2024

Purdue-USDA team develops fast-track process for genetic improvement of plant traits

Rajeev Ranjan, a postdoctoral researcher in horticulture and landscape architecture, analyzes genetically modified Arabidopsis seeds that have higher oil content to confirm that other agronomically important traits, including seed size and seed per fruit, are not negatively affected. (Purdue Agricultural Communications/Tom Campbell)

WEST LAFAYETTE, Ind. — Researchers interested in improving a given trait in plants can now identify the genes that regulate the trait’s expression without doing any experiments.

Purdue University’s Kranthi Varala and 10 co-authors published the details of the new web-based regulatory gene discovery tool in the April 23 issue of Proceedings of the National Academy of Sciences. Varala has a patent pending on the results that relates to economically important seed oil biosynthesis.

The Purdue-USDA team sought to build a resource that learns, from large amounts of publicly available data, to quickly identify what special genes called transcription factors regulate the expression of a given trait in various plant species.

“Every study focuses on a handful of them,” said Varala, assistant professor of horticulture and landscape architecture . “Our premise was that if we can put all of it into a single analysis, then we can use this data to build something global.”

Arabidopsis served as the PNAS study’s model plant, “but this approach has nothing specific to Arabidopsis,” Varala said. “The approach is general enough that you could start with a corn dataset. You could do it with rice, with tomato, whatever crop you’re working on as long as you have thousands of gene expression measurements that people have done. And there are over a dozen species now where we have tens of thousands of gene-expression studies.”

To prove the system works, the team focused on a genetic pathway that regulates how plants make and store oil in their seeds. The team picked that trait because of its importance in food and biofuel production, and because more than 300 of the genes involved are already known. 

By genetically manipulating a plant’s transcription factors, researchers can increase or decrease the amount of oil produced in its seeds.

Like other researchers, Varala has pursued many projects over the years where his goal was to identify the genes and regulators involved in solving one problem. This meant conducting careful, time-consuming experiments. But the data generated fell short of providing all the answers he sought. He compared it to working an equation knowing only three of the 10 factors involved.

“You can’t solve the equation,” he said. Likewise, Varala often wanted to ask more questions than the data could answer. That motivated him to build a framework that uses all possible data to ask those questions without having to do all the relevant experiments to obtain a list of candidates that then need genetic validation. 

“I’m trying to short-circuit the initial data collection phase,” Varala said, so that scientists can focus on conducting the genetic validations. But to do so, his team had to begin with a dataset based on 18,000 individual studies.

Varala and his team analyzed this massive dataset using the Bell and the now-retired Brown supercomputers at Purdue’s Rosen Center for Advanced Computing . The team built a machine-learning framework to speed the process for others.

It would be impossible for one person to do this manually. A team could do it, but that would introduce biases in how group members process the data. The machine-learning classifier operates without bias.

The novelty of the approach is that instead of pulling data related to all organs, it focuses on organ-specific datasets. Independent gene networks regulate these organs — leaves, roots, shoots, flowers and seeds.

“Instead of using all organs, we said, within the seed experiments that people have done over the years, can we use all the data to learn something that’s happening in the seed and not necessarily the root or the leaf or the flower? That improved our approach a lot,” Varala said.

The team used a computational method called the inference approach to predict what transcription factors were going to regulate the seed oil biosynthesis process in Arabidopsis.  

“The ones we know help us validate that our approach is working correctly. The ones that we don’t know are good candidates for finding out new biology,” Varala said. “This purely computational approach knows nothing about seeds or oil or anything like that. We gave it a list of genes and it was able to rediscover the known ones without knowing any biological context.”

The lead author, Rajeev Ranjan, a postdoctoral researcher in the Department of Horticulture and Landscape Architecture at Purdue, took the other 12 of the top 20 and asked if those predictions are true. “We were able to generate mutant lines for 11 of those 12. Five of those 11 do change the seed oil content,” he said. “Further, we also showed that overexpression of one factor increases seed oil up to 12%.” 

The eight known regulatory genes, added to the eight new ones, showed that the inference approach accurately identified 13 of the top 20 candidates. The strength of the approach is that working only from a list of genes, it can predict with high accuracy which ones will regulate a trait of interest.

“It took a long time to do because it’s a long, complicated process, and there was no guarantee that it would work,” said Varala of the four-year project. “Nothing on this scale had been attempted before.”

Varala has disclosed the innovation to the Purdue Innovates Office of Technology Commercialization, which has applied for a patent to protect his intellectual property.

This research was supported by the U.S. Department of Energy Office of Science.

About Purdue University

Purdue University is a public research institution demonstrating excellence at scale. Ranked among top 10 public universities and with two colleges in the top four in the United States, Purdue discovers and disseminates knowledge with a quality and at a scale second to none. More than 105,000 students study at Purdue across modalities and locations, including nearly 50,000 in person on the West Lafayette campus. Committed to affordability and accessibility, Purdue’s main campus has frozen tuition 13 years in a row. See how Purdue never stops in the persistent pursuit of the next giant leap — including its first comprehensive urban campus in Indianapolis, the new Mitchell E. Daniels, Jr. School of Business, and Purdue Computes — at https://www.purdue.edu/president/strategic-initiatives .

Writer: Steve Koppes 

Media contact: Maureen Manier, [email protected]

Source: Kranthi Varala, [email protected]

Agricultural Communications: 765-494-8415;

Maureen Manier, Department Head, [email protected]

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NSF Issues MIE’s Jinglei Ping Prestigious CAREER Award to Develop Novel Method for Detecting Genetic Materials

The amplification-free electronic detection of genetic materials holds significant promise for advancing the point-of-care diagnostics of numerous diseases. The problem, however, is that current, state-of-the-art, all-electrical methods struggle to achieve high sensitivity and rapid detection simultaneously. To solve this vital problem, the National Science Foundation (NSF) has issued a five-year, $550,000 CAREER Award to Assistant Professor Jinglei Ping of the UMass Amherst Mechanical and Industrial Engineering Department. Ping’s NSF research will develop a trailblazing method for detecting genetic materials such as DNA and RNA by cleverly combining high sensitivity with speed to overcome the shortcomings of existing techniques. See  NSF Award Search: Award # 2338857 - CAREER: Highly Rapid and Sensitive Nanomechanoelectrical Detection of Nucleic Acids .

As Ping explains, “The project will lead to compact, quick, accurate, and user-friendly devices for genetic-material detection. These devices operate by measuring the electrical responses of multiple genetic materials when they vibrate in an external electric field.” 

According to Ping, “Such innovation holds the potential to revolutionize bioengineering, enabling more-efficient testing of genetic materials, especially in [geographical] regions without advanced laboratory facilities. Consequently, it promises to enhance pandemic management and global healthcare.”

One goal of Ping’s proposed research is to boost both the sensitivity and time efficiency of nucleic-acid detection by two orders of magnitude. 

Ping says that his research project is highly innovative because it departs from the status quo of electrical, nucleic-acid sensors, which directly convert the occurrence of probe-target, nucleic-acid hybridization into electrical response. Instead, Ping aims to harness a new pathway he has already developed for nano-mechano-electrical “transduction,” or the conversion of mechanical vibration into electrochemical signals. 

Technically, the expected outcomes of this project are twofold. First, Ping and his team will achieve a comprehensive understanding of the nano-mechano-electrical transduction principle for maximizing the multiplexity, selectivity, and sensitivity in nucleic-acid detection.

Secondly, the team will achieve rapid, high-sensitivity, nucleic-acid detection by integrating nano-mechano-electrical transduction with microscale transversal “electrophoresis,” the term used to describe the motion of particles in  a gel  or fluid within a relatively uniform electric field. 

Ping expects these outcomes “to generate significant positive impact on bioengineering advancement and rapid, accurate, point-of-care, nucleic-acid testing.”

Ping heads the  Ping Lab | Nano/Bio Interfaces & Applications , whose goal, he says, “is to determine the fundamental principles governing applications of nanomaterials and nanomaterial-based device structures in biotechnology, healthcare, environmental monitoring, and so on.” (April 2024)

Jinglei Ping

Biosensing devices and systems based on two-dimensional (2D) materials and translation of 2D materials into applications in point-of-care diagnostics.

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National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on Agriculture and Natural Resources; Committee on Genetically Engineered Crops: Past Experience and Future Prospects. Genetically Engineered Crops: Experiences and Prospects. Washington (DC): National Academies Press (US); 2016 May 17.

Genetically Engineered Crops: Experiences and Prospects.

• Hardcopy Version at National Academies Press

5 Human Health Effects of Genetically Engineered Crops

In this chapter, the committee examines the evidence that substantiates or negates specific hypotheses and claims about the health risks and benefits associated with foods derived from genetically engineered (GE) crops. There are many reviews and official statements about the safety of foods from GE crops (for example, see Box 5-1 ), but to conduct a fresh examination of the evidence, the committee read through a large number of articles with original data so that the rigor of the evidence could be assessed.

Sample of Statements About the Safety of Genetically Engineered Crops and Food Derived from Genetically Engineered Crops.

Some of the evidence available to the committee came from documents that were part of the U.S. regulatory process for GE crops conducted by the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). Other evidence came from studies published by regulatory agencies in other countries or by companies, nongovernmental organizations (NGOs), and academic institutions. The committee also sought evidence from the public and from the speakers at its public meetings and webinars. 1

The committee thinks that it is important to make clear that there are limits to what can be known about the health effects of any food, whether non-GE or GE. If the question asked is “Is it likely that eating this food today will make me sick tomorrow?” researchers have methods of getting quantitative answers. However, if the question is “Is it likely that eating this food for many years will make me live one or a few years less than if I never eat it?” the answer will be much less definitive. Researchers can provide probabilistic predictions that are based on the available information about the chemical composition of the food, epidemiological data, genetic variability across populations, and studies conducted with animals, but absolute answers are rarely available. Furthermore, most current toxicity studies are based on testing individual chemicals rather than chemical mixtures or whole foods because testing of the diverse mixtures of chemicals experienced by humans is so challenging ( Feron and Groten, 2002 ; NRC, 2007 ; Boobis et al., 2008 ; Hernández et al., 2013 ).

With regard to the issue of uncertainty, it is useful to note that many of the favorable institutional statements about safety of foods from GE crops in Box 5-1 contain caveats, for example: “no overt consequences,” “no effects on human health have been shown,” “are not per se more risky,” and “are not likely to present risks for human health.” Scientific research can answer many questions, but absolute safety of eating specific foods and the safety of other human activities is uncertain.

The review in this chapter begins with an examination of what is known about the safety of foods from non-GE plants and how they are used as counterparts to those from GE crops in food-safety testing. U.S. food-safety regulatory testing for GE products and GE food-safety studies conducted outside the agency structure are then assessed. A variety of hypothesized health risks posed by and benefits of GE crops are examined, and the chapter concludes with a short discussion of the challenges that society will face in assessing the safety of GE foods that are likely to be developed with emerging genetic-engineering technologies.

• COMPARING GENETICALLY ENGINEERED CROPS WITH THEIR COUNTERPARTS

An oft-cited risk of GE crops is that the genetic-engineering process could cause “unnatural” changes in a plant's own naturally occurring proteins or metabolic pathways and result in the unexpected production of toxins or allergens in food ( Fagan et al., 2014 ). Because analysis of risks of the product of the introduced transgene itself is required during risk assessment, the argument for unpredicted toxic chemicals in GE foods is based on the assumption that a plant's endogenous metabolism is more likely to be disrupted through introduction of new genetic elements via genetic engineering than via conventional breeding or normal environmental stresses on the plant. The review below begins by discussing natural chemical constituents of plants in the context of food safety to provide a background on what the natural plant toxins are and how they vary in non-GE plants. The review then goes on to explain the premise used by regulatory agencies to compare GE crops with their non-GE counterparts.

Endogenous Toxins in Plants

Most chemicals of primary metabolism (for example, those involved in the formation of carbohydrates, proteins, fats, and nucleic acids) are shared between animals and plants and are therefore unlikely to be toxic. Perceived risks associated with alterations of plant compounds arise mainly from alterations of plant-specific molecules, popularly known as plant natural products and technically named secondary metabolites. Collectively, there are more than 200,000 secondary metabolites in the plant kingdom ( Springob and Kutchan, 2009 ). Crop species vary in the number of secondary metabolites that they produce. For example, potato ( Solanum tuberosum ) is known for its high diversity of secondary metabolites and can have more than 20 sesquiterpenes (a single group of related compounds), some of which are thought to confer resistance to diseases ( Kuc, 1982 ). The concentrations of these secondary metabolites within some tissues in a particular plant species may vary from high—for example, chlorogenic acids alone make up about 12 percent of the dry matter of green coffee beans ( Ferruzzi, 2010 )—to trace amounts (many minor saponins in legumes) and may be associated with particular stages of plant development (some found only in seeds) or may increase in response to external stimuli, such as pathogen or herbivore attack, drought, or altered mineral nutrition ( Small, 1996 ; Pecetti et al., 2006 ; Nakabayashi et al., 2014 ). Many secondary metabolites function as protective agents, for example, by absorbing damaging ultraviolet radiation ( Treutter, 2006 ), acting as antinutrients ( Small, 1996 ), or killing or halting insects and pathogens that damage crops ( Dixon, 2001 ). Plant secondary metabolites that protect against pathogen attack have been classified as either phytoanticipins (if they exist in a preformed state in a plant before exposure to a pathogen) or phytoalexins (if their synthesis and accumulation are triggered by pathogen attack) ( VanEtten et al., 1994 ; Ahuja et al., 2012 ). The toxic properties of some plant compounds are understood, but most of these compounds have not been studied. Some secondary metabolites and other products (such as proteins and peptides) in commonly consumed plant materials can be toxic to humans when consumed in large amounts, and examples are listed below:

• Steroidal glycoalkaloids in green potato skin, which can cause gastrointestinal discomfort or, more severely, vomiting and diarrhea.
• Oxalic acid in rhubarb, which can cause symptoms ranging from breathing difficulty to coma.
• Gossypol in cottonseed oil and cake, which can cause respiratory distress, anorexia, impairment of reproductive systems, and interference with immune function in monogastric animals.
• Nonprotein amino acid canavanine in alfalfa sprouts, which can be neurotoxic.
• Hemolytic triterpene saponins in many legume species, which can increase the permeability of red blood cell membranes.
• Cyanogenic glycosides in almonds and cassava, which can cause cyanide poisoning.
• Phototoxic psoralens in celery, which are activated by ultraviolet sunlight and can cause dermatitis and sunburn and increase the risk of skin cancer.

Friedman (2006) provided information that demonstrated that some glycoalkaloids in potato can have both harmful and beneficial effects. The Food and Agriculture Organization has recognized that foods often contain naturally occurring food toxins or antinutrients but that at naturally occurring concentrations in common diets they can be safely consumed by humans ( Novak and Haslberger, 2000 ; OECD, 2000 ). The health risks associated with some secondary metabolites in common foodstuffs are generally well understood, and the plants are either harvested at times when the concentrations of the compounds are low, the tissues with the highest concentrations of toxins are discarded, or, as in the case of cassava ( Manihot esculenta ), the food is prepared with special methods to remove the toxic compounds. In other cases, food preparation may be the cause of the presence of a toxic compound (for example, the formation of the probable carcinogen acrylamide when potatoes are fried at high temperatures or when bread is toasted). Plant breeders have generally screened for toxins that are typical of the plant group from which a crop was domesticated and have excluded plants that have high concentrations of the compounds.

Unintended changes in the concentrations of secondary metabolites can result from conventional breeding ( Sinden and Webb, 1972 ; Hellenas et al., 1995 ). In some cases, conventionally bred varieties have been taken off the market because of unusually high concentrations of a toxic compound, as in the case of a Swedish potato variety that was banned from sale in the 1980s because of high concentrations of glycoalkaloids ( Hellenas et al., 1995 ).

Rather than being a cause of worry, many secondary metabolites are perceived as having potential health benefits for humans and are consumed in increasingly large quantities ( Murthy et al., 2015 ). Examples include the isoflavone phytoestrogens found in a number of leguminous plants, such as soybean ( Glycine max ) and clover ( Trifolium spp.), which have been ascribed beneficial activities, including chemoprevention of breast and prostate cancers, cardiovascular disease, and post-menopausal ailments ( Dixon, 2004 ; Patisaul and Jefferson, 2010 ). Also, various perceived antioxidants, such as anthocyanins ( Martin et al., 2013 ), and some saponins may have anticancer activity ( Joshi et al., 2002 ). There is, however, disagreement as to whether many of the compounds are beneficial or toxic at the concentrations consumed in herbal medicines or dietary supplements (see, for example, Patisaul and Jefferson, 2010 ).

FINDING: Crop plants naturally produce an array of chemicals that protect against herbivores and pathogens. Some of these chemicals can be toxic to humans when consumed in large amounts.

Substantial Equivalence of Genetically Engineered and Non–Genetically Engineered Crops

A major question addressed in the regulation of GE crops is whether the concentrations of the toxic secondary metabolites are affected by genetic engineering. In addition to the plant toxins, nutrients, introduced genes, and proteins and their metabolic products in specific GE crops are assessed with a comparative approach that is generally encompassed by the concept of substantial equivalence.

The concept of substantial equivalence has a long history in safety testing of GE foods. The term and concept were “borrowed from the [U.S. FDA's] definition of a class of new medical devices that do not differ materially from their predecessors, and thus, do not raise new regulatory concerns” ( Miller, 1999:1042 ). No simple definition of substantial equivalence is found in the regulatory literature on GE foods. In 1993, the Organisation for Economic Co-operation and Development (OECD) explained that the “concept of substantial equivalence embodies the idea that existing organisms used as food, or as a source of food, can be used as the basis for comparison when assessing the safety of human consumption of a food or food component that has been modified or is new” ( OECD, 1993:14 ).

The Codex Alimentarius Commission's Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants is careful to state that “the concept of substantial equivalence is a key step in the safety assessment process. However, it is not a safety assessment in itself; rather it represents the starting point which is used to structure the safety assessment of a new food relative to its conventional counterpart” ( CAC, 2003:2 ). The Codex guideline also makes clear that a safety assessment of a new food based on the concept of substantial equivalence “does not imply absolute safety of the new product; rather, it focuses on assessing the safety of any identified differences so that the safety of the new product can be considered relative to its conventional counterpart” ( CAC, 2003:2 ). The OECD (2006) came to a similar conclusion. Conflict among stakeholders often comes into play during the determination of what constitutes evidence of differences from substantial equivalence sufficient to justify a detailed food-safety assessment.

The Codex Alimentarius Commission concluded that the concept of substantial equivalence “aids in the identification of potential safety and nutritional issues and is considered the most appropriate strategy to date for safety assessment of foods derived from recombinant-DNA plants” ( CAC, 2003:2 ). Despite some criticism of the substantial-equivalence concept itself (for example, Millstone et al., 1999 ) and operational problems (for example, Novak and Haslberger, 2000 ), it remains the cornerstone for GE food-safety assessment by regulatory agencies. The present committee examined its use in practice and its empirical limitations.

The precautionary principle, which is described in more detail in Chapter 9 (see Box 9-2 ) is a deliberative principle related to the regulation of health, safety, and the environment and typically involves taking measures to avoid uncertain risks. The precautionary principle has been interpreted in a number of ways, but it is not necessarily incompatible with use of the concept of substantial equivalence. In the case of foods, including GE foods, it can be reasonably argued that even a small adverse chronic effect should be guarded against, given that billions of people could be consuming the foods. However, the degree of precaution taken in the face of uncertainty is a policy decision that varies among countries and according to the specific uncertainty being considered. For example, many European countries and the European Union (EU) as a whole generally take a more precautionary approach with GE foods and climate change whereas the United States has historically taken a more precautionary approach with tobacco products and ozone depletion ( Wiener et al., 2011 ). The reader is directed to Chapter 9 for further discussion of how different regulatory frameworks address uncertainty in the safety of GE foods.

Some differences between a GE food and its non-GE counterpart are intentional and identifiable (for example, the presence of a Bt toxin in maize kernels) or are due to practices directly associated with the use of the GE crops (for example, increased use of glyphosate). Some of the risks posed by the intended changes can be anticipated on the basis of the physiological and biochemical characteristics of the engineered change. There are often established protocols for assessing such risks, especially when a change involves exposure to a known toxin. However, other risks have been hypothesized for GE crops because previous uses of a trait (for example, Bt as an insecticidal spray) did not have consumption of the GE plant products as the route of exposure. New routes of exposure could result in unanticipated effects.

In contrast with such intended differences, some potential differences between GE crops and their non-GE counterparts are unintentional and can be difficult to anticipate and discern ( NRC, 2004 ). Two general sources of unintended differences could affect food safety:

• Unintended effects of the targeted genetic changes on other characteristics of the food (for example, the intended presence of or increase in one compound in plant cells could result in changes in plant metabolism that affect the abundance of other compounds).
• Unintended effects associated with the genetic-engineering process (for example, DNA changes resulting from plant tissue culture).

Much of the concern voiced by some citizens and scientists about the safety of GE foods is focused on potential risks posed by unintended differences. Some of the biochemical and animal testing done by or for government agencies is aimed at assessing the toxicity of such unintended differences, but what is adequate and appropriate testing for assessing specific toxicities is often difficult to determine. In some cases, the unintended effects are somewhat predictable or can be determined; in such cases, tests can be designed. In other cases, the change or risk could be something that has not even been considered, so the only effective testing is of the whole food itself. As discussed in Chapter 6 , there is a tradeoff between costs of such testing and societal benefits of reduction in risks.

The approach of comparing new varieties to existing varieties is just as applicable to crops developed by conventional plant breeding as it is to GE crops (see Chapter 9 ). The discussion above on endogenous toxins (see section “Endogenous Toxins in Plants”) shows that such crops pose some risks. The 2000 National Research Council report Genetically Modified Pest-Protected Plants found that “there appears to be no strict dichotomy between the risks to health and the environment that might be posed by conventional and transgenic pest-protected plants” ( NRC, 2000:4 ). Similarly, the 2004 National Research Council report Safety of Genetically Engineered Foods found that all forms of conventional breeding and genetic engineering may have unintended effects and that the probability of unintended effects of genetic engineering falls within the range of unintended effects of diverse conventional-breeding methods. The 2002 National Research Council report Environmental Effects of Transgenic Plants found that “the transgenic process presents no new categories of risk compared to conventional methods of crop improvement but that specific traits introduced by both approaches can pose unique risks” ( NRC, 2002:5 ). That finding remains valid with respect to food safety and supports the conclusion that novel varieties derived from conventional-breeding methods could be assessed with the substantial-equivalence concept.

FINDING: The concept of substantial equivalence can aid in the identification of potential safety and nutritional issues related to intended and unintended changes in GE crops and conventionally bred crops.

FINDING: Conventional breeding and genetic engineering can cause unintended changes in the presence and concentrations of secondary metabolites.

• OVERVIEW OF U.S. REGULATORY TESTING OF RISKS TO HUMAN HEALTH

Although the committee agrees that crops developed through conventional breeding could result in food-safety risks, its statement of task focuses on GE crops. Furthermore, there have been claims and counterclaims about the relative safety of GE crops and their associated technologies compared with conventionally bred crops and their associated technologies. Therefore, the remainder of this chapter examines possible risks and benefits associated with GE crops and assesses the methods used to test them in and beyond government regulatory systems.

Whether testing is done for regulatory purposes or beyond the regulatory realm, it typically involves three categories of testing: acute or chronic animal toxicity tests, chemical compositional analysis, and allergenicity testing or prediction. Although the precision, transparency, specific procedures, and interpretation of results vary among countries, criticisms about the adequacy of testing are not so much country-specific as they are method- and category-specific. For example, there may be arguments about whether a 90-day whole-food animal test is more appropriate than a 28-day test, but the bigger issue is about whether whole-food testing is appropriate. The committee uses a description of the U.S. testing methods as an example, but it mostly examines the criticism of food-safety testing more broadly.

The structure of the U.S. regulatory process for GE crops based on the Coordinated Framework for the Regulation of Biotechnology is briefly reviewed in Chapter 3 and is examined in more detail in Chapter 9 . The focus in this chapter is on the testing itself. The present section provides insight into U.S. procedures by describing the risk-testing methods used for two examples of traits in commercialized GE crops: Bt toxins and crop resistance to the herbicides glyphosate and 2,4-D.

Regulatory Testing of Crops Containing Bt Toxins

EPA considers plant-produced Bt toxins to be “plant-incorporated protectants,” a class of products generally defined as “a pesticidal substance that is intended to be produced and used in a living plant, or in the produce thereof, and the genetic material necessary for the production of that pesticidal substance” (40 CFR §174.3). EPA specifically exempts plant-incorporated protectants whose genetic material codes for a pesticidal substance that is derived from plants that are sexually compatible. Bt toxin genes are not exempted because they come from bacteria (see Chapter 9 for regulatory details).

For Bt toxins produced by GE crops, EPA took into consideration that there was already toxicity testing of Bt toxins in microbial pesticides and that the toxins were proteins that, if toxic, typically show almost immediate toxicity at low doses ( EPA, 2001a ; also see Box 5-2 ). The pesticidal safety tests mostly involved acute toxicity testing in mice and digestibility studies in simulated gastric fluids because one characteristic of food allergens is that they are not rapidly digested by such fluids.

Cry1F Testing by the U.S. Environmental Protection Agency.

Box 5-2 provides a verbatim example of the procedures used for testing as reported in EPA fact sheets for the Cry1F Bt toxin so that readers can see what is involved in the testing. The actual research is not typically done by EPA itself. The registrant is usually responsible for testing. Results of the tests of Cry1F show no clinical signs of any toxicity even when Cry1F protein was fed at 576 mg/kg body weight, which would be the equivalent of about ¼ cup of pure Cry1F for a 90.7-kilogram (200-pound) person. Another part of the testing described in Box 5-2 is allergenicity testing. Concerns about the EPA testing methods are discussed in sections below on each category of testing.

Regulatory Testing of Crops Resistant to Glyphosate and 2,4-D and of the New Uses of the Herbicides Themselves

The regulatory actions taken for herbicide-resistant (HR) crops are different from regulatory actions taken to assess Bt crops. With Bt crops, regulatory actions are related to the crop itself. With HR crops, there are regulatory processes for the plant itself and separate regulatory processes for the new kind of exposure that can accompany spraying of a herbicide on a crop or on a growth stage of a crop that has never been sprayed prior to availability of the GE variety.

EPA governs the registration of herbicides such as glyphosate and 2,4-D. Both glyphosate and 2,4-D were registered well before the commercialization of GE crops. However, EPA has authority to re-examine herbicides if their uses or exposure characteristics change.

A good example of such re-examination was the 2014 EPA registration of the Dow AgroSciences Enlist Duo® herbicide, which contains both glyphosate and 2,4-D for use on GE maize ( Zea mays ) and soybean. Because the glyphosate component of Enlist Duo had already been in use on GE maize and soybean, EPA did not conduct further testing of glyphosate alone. However, 2,4-D was registered previously only for applications to maize up to 20 centimeters tall and for preplant applications to soybean. The proposed use of 2,4-D on GE crops was expected to change use patterns and exposure and thereby triggered a safety assessment of the new use 2,4-D. Additionally, EPA compared the toxicity of the formulation that contained both herbicides to the toxicity of the individual herbicides and concluded the formulation did not show greater toxicity or risk compared to either herbicide alone.

In the human health risk assessment portion of the EPA Enlist Duo registration document, the following tests and results with 2,4-D were considered ( EPA, 2014a ):

• An acute dietary test in rats that found a lowest observed-adverse-effect level (LOAEL) of 225 mg/kg (about 1 ounce per 200-pound person).
• A chronic-dietary-endpoint, extended one-generation reproduction toxicity study in rats that found a LOAEL of 46.7 mg/kg-day in females and higher in males.
• Inhalation tests involving data from a 28-day inhalation toxicity study in rats that found a LOAEL of 0.05 mg/L-day.
• Dermal tests that showed no dermal or systemic toxicity after repeated applications to rabbits at the limit dose of 1000 mg/kg-day.
• Reviews of epidemiological and animal studies, which did not support a linkage between human cancer and 2,4-D exposure.

Analysis of the results of those tests and agronomic and environmental assessments resulted in the product's registration.

EPA received over 400,000 comments in response to the initial proposal to register the new use of 2,4-D. Some of the concerns submitted to EPA were similar to ones some members of the public expressed in public comments to the committee, including questions about whether EPA had considered toxicity of only the active ingredient or of the formulated herbicide and whether it had tested for synergistic effects of 2,4-D and glyphosate. EPA (2014b:7) responded that

acute oral, dermal, and inhalation data, skin and eye irritation data, and skin sensitization data are available for the 2,4-D choline salt and glyphosate formulation for comparison with the 2,4-D parent compound and glyphosate parent compound data, and these test results show similar profiles. The mixture does not show a greater toxicity compared to either parent compound alone. Although no longer duration toxicity studies are available, toxic effects would not be expected as the maximum allowed 2,4-D exposure is at least 100-fold below levels where toxicity to individual chemicals might occur, and exposure to people is far below even that level.

The committee did not have access to the actual data from the registrant. 2

EPA does not regulate the commercialization of the GE herbicide-resistant crops themselves. That is the role of USDA's Animal and Plant Health Inspection Service (APHIS) under the Plant Protection Act. Under its statutory authority, APHIS controls and prevents the spread of plant pests (see Box 3-5 ). On the basis of a plant-pest risk assessment (USDA–APHIS, 2014a), APHIS concluded that Enlist™ GE herbicide-resistant maize and soybean engineered to be treated with the Enlist Duo herbicide (containing glyphosate and 2,4-D) were unlikely to become plant pests and deregulated them on September 18, 2014 (USDA–APHIS, 2014b). In its document on the decision to deregulate Enlist GE herbicide-resistant maize and soybean (USDA–APHIS, 2014a:ii), APHIS states a general policy that “if APHIS concludes that the GE organism is unlikely to pose a plant pest risk, APHIS must then issue a regulatory determination of nonregulated status, since the agency does not have regulatory authority to regulate organisms that are not plant pests. When a determination of nonregulated status has been issued, the GE organism may be introduced into the environment without APHIS' regulatory oversight.”

FDA did not identify any safety or regulatory issues in its consultation with Dow AgroSciences on the Enlist maize and soybean varieties ( FDA, 2013 ). FDA also explained the basis of Dow's conclusion that Enlist soybean is not “materially different in composition” from other soybean varieties ( FDA, 2013 ):

Dow reports the results of compositional analysis for 62 components in soybean grain, including crude protein, crude fat, ash, moisture, carbohydrates, [acid detergent fiber] ADF, [neutral detergent fiber] NDF, total dietary fiber (TDF), lectin, phytic acid, raffinose, stachyose, trypsin inhibitor, soy isoflavones (i.e., total daidzein, total genistein, total glycitein), minerals, amino acids, fatty acids, and vitamins. No statistically significant differences in the overall treatment effect and the paired contrasts between each of the DAS-44406-6 soybean treatment groups and the control were observed for 29 of the components. A statistically significant difference in the overall treatment effect was observed for 16 components (crude protein, carbohydrates (by difference), NDF, calcium, potassium, cystine, palmitic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, folic acid, γ-tocopherol, total tocopherol, lectin, and trypsin inhibitor). However, differences between the control and the DAS-44406-6 treatment groups were small in magnitude. Differences between DAS-44406-6 soybean and the control were considered not biologically relevant because the mean values were either within the ranges generated using the reference lines, consistent with the ranges of values in the published literature, or both.

FINDING: U.S. regulatory assessment of GE herbicide-resistant crops is conducted by USDA, and by FDA when the crop can be consumed, while the herbicides are assessed by EPA when there are new potential exposures.

FINDING: When mixtures of herbicides are used on a new GE crop, EPA assesses the interaction of the mixture as compared to the individual herbicidal compounds.

Technical Assessment of Human Health Risks Posed by Genetically Engineered Crops

As explained in Chapter 2 , the development and use of GE crops is governed by more than national and regional regulatory standards. In the cases of the GE crops commercially available in the United States and some other countries in 2015, inputs from many public and private institutions regarding their specific concerns have influenced the type and extent of GE crop food-safety tests conducted by companies, agencies, and other researchers. Many stakeholders have criticized the testing used by U.S. and other national regulatory agencies for lacking rigor (for example, Hilbeck et al., 2015 ). Researchers in companies, NGOs, and universities have sometimes conducted more extensive safety tests than are required by national agencies or have reanalyzed existing data, as described below. All testing as of 2015 fell into three categories: animal testing, compositional analysis, and allergenicity testing and prediction.

Animal Testing

Short-term and long-term rodent testing with compounds and whole foods.

One common criticism of the animal testing conducted by or for regulatory agencies in the United States and elsewhere is related to its short duration (for example, Séralini et al., 2014 ; Smith, 2014 ). Indeed, there is a range in the duration and doses within the test protocols used by regulatory agencies that depends in part on the product. Doses for subchronic and chronic toxicity studies are such that the lowest dose (exposure level), which is many times higher than expected for human exposure, is set to ensure that it does not elicit acute adverse effects that would interfere with examining the potential chronic-effect endpoints. As can be seen in the discussion above, EPA conducted an extended one-generation reproduction toxicity study in male and female rats in its assessment of 2,4-D, and it relied on previous long-term studies for the assessment of cancer risk associated with it. For assessment of the Bt toxin Cry1F and for the bacterially derived proteins in 2,4-D-resistant maize and soybean, company testing submitted to EPA, FDA, and USDA relied on acute toxicity testing. In all the cases above, the experiments were conducted by adding large amounts of a single test chemical to an animal's diet. Tests with high concentrations of a chemical are typical of EPA testing protocols for pesticides.

What is different between GE crop evaluation and that of general agricultural chemicals is the use of “whole food” tests. These tests are aimed at assessing potential hazards due to the combined intentional and unintentional changes that might have been caused by the genetic engineering of the crop. In such tests, it is not possible to use concentrations higher than what is in the crop itself because potential unintended effects are not typically known. Thus, it is impossible for a researcher to know what compounds should be increased in concentration in a fabricated diet, and the only way to assess such unintended effects is to feed the actual GE crop to test animals. For testing GE maize, soybean, and rice ( Oryza sativa ), 3 flour from kernels or seed is added to an animal's diet and constitutes between about 10–60 percent of the diet. The high percentages can be used because the crop products are nutritious for the animal. In the case of whole foods that are not typically part of a rodent's diet, whether GE or non-GE, it is impossible to achieve very high concentrations of the test food because it would cause nutritional imbalance. The whole-food tests done for regulatory agencies are generally conducted for 28 or 90 days with rats, but some researchers have run tests for multiple generations.

The utility of the whole-food tests has been questioned by a number of government agencies and by industry and academic researchers (for example, Ricroch et al., 2014 ), and they are not an automatic part of the regulatory requirements of most countries that have specific GE food-testing requirements ( CAC, 2008 ; Bartholomaeus et al., 2013 ). However, in its 2010 report A Decade of EU-Funded GMO Research (2001–2010) , the European Directorate-General for Research and Innovation concluded that “the data from a well-designed 90-day rodent feeding study, together with data covering the gene insert, the compositional analysis, and the toxicity of the novel gene product, form the optimal basis for a comparative assessment of the safety of [genetically engineered] food and its conventional counterpart in the pre-market situation” ( EC, 2010a:157 ). The European Food Safety Authority (EFSA) developed principles and guidance for establishing protocols for 90-day whole-food studies in rodents at the European Commission's request ( EFSA, 2011b ), and 90-day, whole-food studies were made mandatory by the European Commission ( EC, 2013 ). Most studies reported in the peer-reviewed literature have concluded that there was a lack of adverse effects of biological or toxicological significance (see, for example, Knudsen and Poulsen, 2007 ; MacKenzie et al., 2007 ; He et al., 2008 , 2009 ; Onose et al., 2008 ; Liu et al., 2012 ), even though some of the studies found statistically significant differences between the GE and non-GE comparator in toxicity.

The criticisms of whole-food tests come from two perspectives. One perspective is that whole-food studies cannot provide useful tests of food safety because they are not sensitive enough to detect differences (see, for example, Bartholomaeus et al., 2013 ; Kuiper et al., 2013 ; Ricroch et al., 2013a , 2014 ) and that animal testing is not needed because other types of required testing ensure safety ( Bartholomaeus et al., 2013 ; Ricroch et al., 2014 ). Ricroch et al. (2014) pointed to the costs of the 90-day tests, which they reported as being €250,000 (in 2013 money). The second perspective is that whole-food tests could be useful, but there is concern about their design and conduct or about the parties who conduct them (the companies commercializing the GE crops). That perspective is evident in Séralini et al. (2007) , Domingo and Bordonaba (2011) , Hilbeck et al. (2015) , and Krimsky (2015) . Boxes 5-3 and 5-4 describe some of the specific procedures and practices involved in doing these tests.

Common Procedures for Rodent Toxicity Studies for Safety Evaluation.

Laboratory Practices for Consistency among Studies.

The committee heard from invited speakers ( Entine, 2014 ; Jaffe, 2014 ) and members of the public who provided comments at meetings and it received a number of written public comments highlighting the work of one research group ( Séralini et al., 2012 , 2014 ) that has conducted a number of whole-food studies of GE herbicide-resistant and insect-resistant crops and of direct consumption of glyphosate. Some comments made to the committee pointed to the publications of that research group as evidence that GE crops and foods derived from GE crops were deleterious to human health; other comments questioned the robustness and accuracy of the research. The committee also heard from the lead researcher himself at one of its meetings ( Séralini, 2014 ). Because of the attention garnered by this specific research group, the committee examined the primary research paper from the group and many articles related to it ( Box 5-5 ).

Controversial Results of an Animal Feeding Study of Genetically Engineered Crops and Glyphosate.

A general question that remains for all whole-food studies using animals is, How many animals, tested for how long, are needed to assess food safety when a whole food is tested? That question is related to the question of how large an effect the tested food would have to have on the animal for it to be detected with the experiment. The statistical procedure called power analysis can answer the first question, but the committee did not find such analyses in articles related to GE crop whole-food studies. The EFSA scientific committee ( EFSA, 2011b ) provided general guidance on power analysis. Figure 5-2 , from the EFSA report, shows the relationship between the number of experimental units (cages with two animals) per treatment group and the power of an experiment in standard-deviation units. Standard deviations quantify how much the measurement of a trait or effect varies among animals that have been given the same diet. The report concluded that, if researchers follow OECD Test No. 408 of 10 males and 10 females per treatment ( OECD, 1998a ), a test should be able to detect a difference equal to about 1 standard deviation (with 90-percent confidence) unless the food has a different effect on males and females, in which case, the smallest difference that could be detected would be about 1.5 standard deviations from the experimental mean.

General statistical information on the number of experimental units needed per treatment group as a function of standardized effect size for 80-percent and 90-percent power and 5-percent significance level using a two-sided t test. SOURCE: EFSA (2011b). (more...)

Because the relationship is quite abstract for the nonstatistician, the committee examined the size of the standard deviations in a number of whole-food safety articles. It found that the sizes of the standard deviations compared with the mean value of a measured trait depended heavily on the trait being measured and on the specific research article. For example, in the Hammond et al. (2004) study, the average white blood cell count for the four treatments, each with 9 or 10 female Sprague-Dawley rats, is 6.84 10 3 /µl, and the average standard deviation is 1.89 10 3 /µl. On the basis of rough calculations, this test would have the power to discern statistically whether the GE food caused an increase in white blood cell count of about 35 percent with about 90-percent confidence. If the male white blood cell count effects and standard deviations were similar to those in females, the test could have found about a 25-percent increase.

OECD (1998a) made general recommendations, such as those used in Hammond et al. (2004) , for the number of units (cages with two animals) per treatment. Following these guidelines leads to the assumption that less than a 25-percent change in the white blood cell count was not biologically relevant. The EU Standing Committee on the Food Chain and Animal Health adopted the mandatory use of 90-day whole-food testing of GE crops, and its protocols generally follow OECD guidelines for the testing of chemicals ( EC, 2013 ).

EFSA also published a document ( EFSA, 2011c ) that focused specifically on the questions, What is statistical significance? and What is biological relevance? The accessibly written document makes clear that the two are very different and that it is important to decide how large a difference is biologically relevant before designing an experiment to test a null hypothesis of no difference. The problem in most whole-food animal studies is in determining how large a biological difference is relevant. Most of the statistically significant differences observed in the literature on the animal-testing data were around a 10- to 30-percent change, but the authors do not give detailed explanations of why they conclude that a statistically significant difference is not biologically relevant. A general statement is sometimes made that the difference is within the range for the species, but because the range of values for the species typically come from multiple laboratories, such a statement is not useful unless the laboratories, instrumentation, and health of the animals were known to be comparable.

Clearly, the European Commission relied on both expert judgment and citizen concerns in making its assessment of biological relevance of the effects of GE foods in requiring 90-day testing. It is reasonable to ask what balance of the two is the basis for this judgment. As pointed out by the 2002 National Research Council report, “risk analysis of transgenic plants must continue to fulfill two distinct roles: (1) technical support for regulatory decision making and (2) establishment and maintenance of regulatory legitimacy” ( NRC, 2002:6 ). Fulfilling the two roles can lead to different country-specific and region-specific decisions. This issue is discussed further in Chapter 9 .

One specific criticism of the 90-day whole-food studies revolves around an EU-funded project conducted by Poulsen et al. (2007) in which rice was genetically engineered to produce the kidney bean lectin, agglutinin E-form, which is known to have toxic properties. In a 90-day test, rats were fed diets of 60-percent rice with the lectin gene or 60-percent rice without the lectin gene. The researchers concluded that they did not find any meaningful differences between the two treatments. However, in a treatment in which the diets were spiked with 0.1-percent recombinant lectin (a high dose), biological effects including significant differences in weight of small intestines, stomach, and pancreas and in plasma biochemistry were found. Poulsen et al. included results from a preceding 28-day feeding study and compositional analyses of the rice diets. The criticism involves the question, If a whole-food study with a known toxin does not demonstrate effects, how can the test be considered useful? ( Bartholomaeus et al., 2013 ). If a whole-food study with an animal finds statistically significant effects, there is obviously a need for further safety testing, but when there is a negative result, there is uncertainty as to whether there is an adverse effect on health. In the specific case of lectin gene in rice, one could argue that the statistical power of the whole-food test was insufficient or that, when the toxin is in the structure of the food, it is no longer toxic so the food is safe.

Other Long-Term Studies with Rodents

In addition to the work of Séralini et al. (2012 , 2014 ), there have been other long-term rodent studies, some of which included multiple generations. Magana-Gomez and de la Barca (2009) , Domingo and Bordonaba (2011) , Snell et al. (2012) , and Ricroch et al. (2013b) reviewed the studies. Some found no statistically significant differences, but quite a few found statistically significant differences that the authors generally did not consider biologically relevant, typically without providing data on what was the normal range. In the multigeneration studies, the sire and dam are dosed via the diet before conception, and the parent generation and pups are dosed via the diet throughout the duration of the study to determine multiple generational outcomes, including growth, behavior, and phenotypic characteristics. Some studies have looked at three or four generations. For example, Kiliç and Akay (2008) conducted a three-generation rat study in which 20 percent of the diet was Bt maize or a non- Bt maize that otherwise was genetically similar. All generations of female and male rats were fed the assigned diets, and the third-generation offspring that were fed the diets were sacrificed after 3.5 months for analysis. The authors found statistical differences in kidney and liver weights and long kidney glomerular diameter between the GE and non-GE treatments but considered them not biologically relevant. Similarly, statistically significant differences were observed in amounts of globulin and total protein between the two groups. There was no presentation of standards used for judging what would be a biologically relevant difference or for what the normal range was in the measurements.

The standard deviations in measurements of the traits (that is, effects) of individual animals in a treatment in the long-term studies were similar to those of studies of shorter duration. Therefore, the power of the tests to detect statistically significant differences was in the range of 10–30 percent. The committee could not find justification for considering this statistical power sufficient. It can be argued that the number of replicates (number of units of two animals per treatment) in the studies should be substantially increased, but one argument against an increase in numbers is related to the ethics of subjecting more animals to testing ( EC, 2010b ). One could also argue that it is unethical to conduct an underpowered study. However, most if not all of the rodent studies are based on widely accepted safety evaluation protocols with fixed numbers of animals per treatment. Cultural values regarding precaution for human safety and those regarding the number of animals subjected to testing are in conflict in this case. As pointed out by Snell et al. (2012) , a close examination of the long-term and multigenerational studies reveals that some have problems with experimental design, the most common being that the GE and non-GE sources were not isogenic and were grown in different locations (or unknown locations). Those problems in design make it difficult to determine whether differences are due to the genetic-engineering process or GE trait or to other sources of variation in the nutritional quality of the crops.

In cases in which testing produces equivocal results or tests are found to lack rigor, follow-up experimentation with trusted research protocols, personnel, and publication outlets is needed to decrease uncertainty and increase the legitimacy of regulatory decisions. There is a precedent of such follow-up studies in the literature on GE crop environmental effects that could serve as a general model for follow-up food-safety testing (see Chapter 4 section “Genetically Engineered Crops, Milkweed, and Monarch Butterflies”). The USDA Biotechnology Risk Assessment Research Grants Program has enabled this approach in a few cases.

Beyond Rodent Studies

Mice and rats are typically used in toxicity studies because of their general physiological similarities to humans and their small size, but some farm animals are considered to be better models of human physiology than rodents. The best example is the pig, which is considered to be better than rodents as a model, especially with respect to nutritional evaluations ( Miller and Ullrey, 1987 ; Patterson et al., 2008 ; Litten-Brown et al., 2010 ). Porcine insulin has been used for decades to control blood sugar in patients who have childhood-onset diabetes mellitus (type I diabetes). Pig heart valves are used for human mitral valve replacement, and pig skin has been investigated as a possible donor tissue. The pig is monogastric as is the human, and its gastrointestinal tract absorbs and metabolizes nutrients (lipids and micronutrients) in the same manner as in humans.

Reviews of studies with animals fed GE foods have included studies using both rodents and farm animals ( Bartholomaeus et al., 2013 ; DeFrancesco, 2013 ; Ricroch et al., 2013a , b , 2014 ; Swiatkiewicz et al., 2014 ; Van Eenennaam and Young, 2014 ). Those animal studies have taken advantage of the fact that maize and soybean are major components of the diets of many farm animals. Some of the reported studies that used farm animals have designs similar to those of rodent studies and have variation in duration and replicates similar to that of the rodent experiments. Some of the tests were run for 28 days (for example, Brouk et al., 2011 ; Singhal et al., 2011 ), others for a long term ( Steinke et al., 2010 ) or in multiple generations ( Trabalza-Marinucci et al., 2008 ; Buzoianu et al., 2013b ).

The experiments with pigs are especially relevant. Most of them were conducted in one prolific laboratory ( Walsh et al., 2011 , 2012a , b , 2013 ; Buzoianu et al., 2012a , b , c , d , 2013a , b ). The studies range from examination of short-term growth of piglets to multigenerational studies of sows and piglets, with mixed designs having either generation or both exposed to Bt maize and non- Bt maize. Characteristics measured included food consumption and growth, assessment of organ size and health, immunological markers, and microbial communities. The authors of the studies generally concluded that Bt maize does not affect health of the pigs, but they reported a number of statistically significant differences between Bt maize treatment and control maize treatment. In one experiment ( Walsh et al., 2012a ), the weaned piglets that were fed Bt maize had lower feed-conversion efficiency during days 14–30 (P > 0.007) but no significant effect over the full span of the experiment. In another experiment ( Buzoianu et al., 2013b ), there was lower efficiency in the Bt treatment during days 71–100 (P > 0.01) but again no effect over the full span of the experiment.

In those experiments with pigs and experiments with other farm animals and rodents, there was apparently one source of the GE food and one source of the non-GE food per study, and it is generally not clear that the food sources were isogenic or grown in the same location. That makes it difficult to determine whether any statistical differences found were due to the engineered trait or to the batches of food used, which in at least some experiments varied in nutrient content and may have differed in bioactive compounds (produced in response to plant stressors), which may have a profound effect on outcomes of nutritional studies. Another issue is that many statistical tests were performed in most studies. That could result in accumulation of false-positive results ( Panchin and Tuzhikov, 2016 ). Although this is not a situation in which a stringent correction for doing multiple tests is called for ( Dunn, 1961 ), there is reason to be cautious in interpretation of statistical significance of individual results because multiple tests can lead to artifactual positive results. The issue of multiple test results is common in many fields, and one approach used in genetics is to use the initial tests for hypothesis generation with follow-up experiments that test an a priori hypothesis (for example, Belknap et al., 1996 ). If a straightforward application of Bonferonni correction is used, each animal study that measures multiple outcomes, whether for GE crops or any other potential toxicant, could require over 1,000 animals to obtain reasonable statistical power ( Dunn, 1961 ).

In addition to the literature on controlled experiments with livestock, Van Eenennaam and Young (2014) reviewed the history of livestock health and feed-conversion ratios as the U.S. livestock industry shifted from non-GE to GE feed. Producers of cattle, milk cows, pigs, chickens, and other livestock are concerned about the efficiency of conversion of animal feed into animal biomass because it affects profit margins. The data examined start as early as 1983 and run through 2011. Therefore, livestock diets shifted from all non-GE feed to mostly GE feed within the duration of the study. Van Eenennaam and Young found that, if anything, the health and feed-conversion efficiencies of livestock had increased since the introduction of GE crops but that the increase was a steady rise, most likely because of more efficient practices not associated with use of GE feed. In the studies that they reviewed, the number of animals examined was large (thousands). Of course, most livestock are slaughtered at a young age, so that data cannot address the issue of longevity directly. However, given the general relationship between general health and longevity, the data are useful.

FINDING: The current animal-testing protocols based on OECD guidelines for the testing of chemicals use small samples and have limited statistical power; therefore, they may not detect existing differences between GE and non-GE crops or may produce statistically significant results that are not biologically meaningful.

FINDING: In addition to experimental data, long-term data on the health and feed-conversion efficiency of livestock that span a period before and after introduction of GE crops show no adverse effects on these measures associated with introduction of GE feed. Such data test for correlations that are relevant to assessment of human health effects, but they do not examine cause and effect.

RECOMMENDATION: Before an animal test is conducted, it is important to justify the size of a difference between treatments in each measurement that will be considered biologically relevant.

RECOMMENDATION: A power analysis for each characteristic based on standard deviations in treatments in previous tests with the animal species should be done whenever possible to increase the probability of detecting differences that would be considered biologically relevant.

RECOMMENDATION: In cases in which early published studies produced equivocal results regarding health effects of a GE crop, followup experimentation using trusted research protocols, personnel, and publication outlets should be used to decrease uncertainty and increase the legitimacy of regulatory decisions.

RECOMMENDATION: Public funding in the United States should be provided for independent follow-up studies when equivocal results are found in reasonably designed initial or preliminary experimental tests.

Compositional Analysis

Compositional analysis of genetically engineered crops.

As part of the regulatory process of establishing substantial equivalence, GE crop developers submit data comparing the nutrient and chemical composition of their GE plant with a similar (isoline) variety of the crop. In the United States, submitting such data to FDA is voluntary, although as of 2015 this seems to always be done by developers. Developers and regulators compare key components of the GE variety with published reference guides that list the concentrations and variabilities of nutrients, antinutrients, and toxicants that occur in crops already in the food supply. 4 The section “Regulatory Testing of Crops with Resistance to Glyphosate and 2,4-D and the New Uses of the Herbicides Themselves” earlier in this chapter gives an example of the types of nutrients and chemicals that are generally measured. In the specific case of the soybean resistant to 2,4-D and glyphosate, measurements of 62 components in the soybean were submitted by Dow AgroSciences. There were statistically significant differences between the GE and comparison varieties in 16 of the 62. The differences were considered to be small and within the range of published values for other soybean varieties. They were therefore “considered not biologically relevant.” In compositional analysis, as in some of the whole-food animal testing, it is difficult to know how much of the variance and range in values for the components is due to the crop variety, the growing conditions, and the specific laboratory experimental equipment. In the United States, regulatory agencies require that the comparison be between the GE crop and its isogenic conventionally bred counterpart grown in side-by-side plots. In those cases, it is hard to attribute differences to anything but the genetic-engineering process.

FINDING: Statistically significant differences in nutrient and chemical composition have been found between GE and non-GE plants by using traditional methods of compositional analysis, but the differences have been considered to fall within the range of naturally occurring variation found in currently available non-GE crops.

Composition of Processed Genetically Engineered Foods

General compositional analysis and the specific content of the introduced proteins are typically conducted on raw products, such as maize kernels or soybean seed. However, much of the human consumption of these products occurs after substantial exposure to heat or other processing. If in processing of foods the amounts of GE proteins substantially increase, consumers are potentially exposed to a risk that is different from that anticipated from testing the raw material. In the production of oil, for example, the goal is to separate the oil from other compounds in the raw crop, such as proteins and carbohydrates. Crude oils can contain plant proteins ( Martín-Hernández et al., 2008 ), but in highly purified oils even sophisticated approaches have failed to find any nondegraded proteins ( Hidalgo and Zamora, 2006 ; Martín-Hernández et al., 2008 ). Those results are reflected in the fact that people who are allergic to soybean are not affected by purified oils ( Bush et al., 1985 ; Verhoeckx et al., 2015 ).

A few studies have searched for a means of finding DNA in plant-derived oils to identify the origin of the oil as GE or non-GE for labeling purposes ( Costa et al., 2010a , b ) or to identify the origin of olive oil ( Muzzalupo et al., 2015 ). It is possible to detect DNA, but the amounts are typically diminished in purified oils to 1 percent or less of the original content. Similarly, Oguchi et al. (2009) were not able to find any DNA in purified beet sugar. Some countries exempt products from labeling if GE protein or DNA is not detectable. For example, in Japan, where foods with GE ingredients typically require labeling, oil, soy sauce, and beet sugar are excluded because of degradation of GE proteins and DNA ( Oguchi et al., 2009 ). Australia and New Zealand have similar exemptions from labeling for such highly refined foods as sugars and oils ( FSANZ, 2013 ).

The detection of GE protein and DNA in other processed foods depends on the type of processing. For example, the amount of the Bt protein Cry1Ab detected by immunoassay in tortillas depends on cooking time ( de Luis et al., 2009 ). The detected amount of Cry9C protein remaining in samples of corn bread, muffins, and polenta was about 13, 5, and 3 percent of the amount in the whole-grain maize ( Diaz et al., 2002 ). For Cry1Ab in rice, Wang et al. (2015) found that baking was more effective in lowering the detection using polyclonal antibodies of the Cry1Ab protein than microwaving, but 20 minutes of baking at 180°C left almost 40 percent of the protein intact. Heat denaturation of proteins can lower antibody binding to epitopes and cause lower detection of GE proteins.

FINDING: The amount of GE protein and DNA in food ingredients can depend on the specific type of processing; some foods contain no detectable protein and little DNA. In a few countries that have manda tory labeling of GE foods, that is taken into account, and food without detectable GE DNA or GE protein is not labeled.

Newer Methods for Assessing Substantial Equivalence

As explained in Chapter 2 , governance of GE crops includes regulatory governance. Although not required to by governing bodies, companies and academic researchers have moved beyond the typical measurements of food composition to newer technologies that involve transcriptomics, proteomics, and metabolomics. The new methods provide a broad, nontargeted assessment of thousands of plant characteristics, including the concentrations of most of the messenger RNAs, proteins, and small molecules in a plant or food. These methods are more likely to detect changes in a GE crop than the current regulatory approaches. If a GE crop has been changed only as intended, any changes observed in these -omics measurements theoretically should be predictable in a given environment. The science behind the methods, including the current limitations of their interpretation, is discussed in Chapter 7 . The discussion here focuses on how the methods have already been applied in the assessment of risk of health effects of currently commercialized GE crops.

Ricroch et al. (2011) reviewed -omics data from 44 studies of crops and detailed studies of the model plant Arabidopsis thaliana . Of those studies, 17 used transcriptomics, 12 used proteomics, and 26 used metabolomic methods. Ricroch (2013) updated the number of studies to 60. The committee found that many more studies had been done since those reviews were published, and many of them have used multiple -omics approaches. The sophistication of the studies has increased ( Ibáñez et al., 2015 ) and is likely to increase further. As recommended in Chapter 7 , there is a need to develop further and share databases that contain detailed -omics data ( Fukushima et al., 2014 ; Simó et al., 2014 ).

In some studies of GE plants in which simple marker genes were added, there were almost no changes in the transcriptome ( El Ouakfaoui and Miki, 2005 ), but use of other -omics methods has revealed changes ( Ren et al., 2009 ). For example, in a comparison of glyphosate-resistant soybean and non-GE soybean, García-Villalba et al. (2008) found that three free amino acids, an amino acid precursor, and flavonoid-derived secondary metabolites (liquiritigenin, naringenin, and taxifolin) had greater amounts in the GE soybean and 4-hydroxy-l-threonine was present in the non-GE soybean, but not in the GE variety. They hypothesized that the change in the flavonoids may have been because the modified EPSPS enzyme (a key enzyme of the shikimate pathway leading to aromatic amino acids) introduced to achieve glyphosate resistance could have different enzymatic properties that influenced the amounts of aromatic amino acids. The committee was not aware of such a hypothesis before this metabolomic study. (A concern was expressed in a comment submitted to the committee that the EPSPS transgene would cause endocrine disruption. The committee found no evidence to suggest that the changes found by García-Villalba et al. would have such an effect.)

On the basis of previous experimentation, it is predicted that, when a gene for a nonenzymatic protein (such as a Bt toxin gene) is added to a plant, there will be very few changes in the plant's metabolism ( Herman and Price, 2013 ). However, when a gene has been added specifically to alter one metabolic pathway of a plant, a number of predicted and unpredicted changes have been found. For example, Shepherd et al. (2015) found that, when they downregulated enzymes (that is, decreased expression or activity) involved in the production of either of two toxic glycoalkaloids (alpha-chaconine and alpha-solanine) in a GE potato with RNA-interfering transgenes that regulated synthesis of one toxic glycoalkaloid, the other compound usually increased. When they downregulated production of both compounds, beta-sitosterol and fucosterol increased. Neither of these compounds has the degree of toxicity associated with alpha-chaconine and alpha-solanine. Other compounds also differed from controls in concentration, but some of the changes may have been due to products generated during the tissue-culture process used in these experiments and not to the transgenes.

Many of the studies have found differences between the GE plants and the isogenic conventionally bred counterparts, but for many components there is more variation among the diverse conventionally bred varieties than between the GE and non-GE lines ( Ricroch et al., 2011 , Ricroch, 2013 ). Furthermore, the environmental conditions and the stage of the fruit or seed affect the finding. Chapter 7 addresses the future utility of the -omics approaches in assessing the biological effects of genetic engineering.

FINDING: In most cases examined, the differences found in comparisons of transcriptomes, proteomes, and metabolomes in GE and non-GE plants have been small relative to the naturally occurring variation found in conventionally bred crop varieties due to genetics and environment.

FINDING: If an unexpected change in composition beyond the natural range of variation in conventionally bred crop varieties were present in a GE crop, -omics approaches would be more likely to find the difference than current methods.

FINDING: Differences in composition found by using -omics methods do not, on their own, indicate a safety problem.

Food Allergenicity Testing and Prediction

Allergenicity is a widespread adverse effect of foods, several plants, tree and grass pollens, industrial chemicals, cosmetics, and drugs. Self-reporting of lifetime allergic responses to each of the most common food allergens (milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish) ranges from 1 to 6 percent of the population ( Nwaru et al., 2014 ). Allergies are induced in a two-step process: sensitization from an initial exposure to a foreign protein or peptide followed by elicitation of the allergic response on a second exposure to the same or similar agent. Sensitization and elicitation are generally mediated by immunoglobulins, primarily IgE, and the responses may range from minor palatal or skin itching and rhinitis to severe bronchial spasms and wheezing, anaphylaxis, and death. In addition to IgE responses to food allergens, IgA has been identified as an inducible immune mediator primarily in the gastrointestinal mucosa in response to foods, foreign proteins, pathogenic microorganisms, and toxins. The role of IgA in classical allergy has been investigated ( Macpherson et al., 2008 ).

Assessment of the potential allergenicity of a food or food product from a GE crop is a special case of food-toxicity testing and is based on two scenarios: transfer of any protein from a plant known to have food-allergy properties and transfer of a protein that could be a de novo allergen. Predictive animal testing for allergens in foods (GE and non-GE) is not sufficient for allergy assessment ( Wal, 2015 ). Research efforts are ongoing to discover or develop an animal model that predicts sensitization to allergy ( Ladics and Selgrade, 2009 ), but so far none has proved predictive ( Goodman, 2015 ). Therefore, researchers have relied on multiple indirect methods for predicting whether an allergic response could be caused by a protein that is either added to a food by genetic engineering or appears in the food as an unintended effect of genetic engineering. Endogenous protein concentrations with known allergic properties also have to be monitored because it is possible that their concentration could increase due to genetic engineering.

A flow diagram of the interactive approach to allergen testing recommended by the Codex Alimentarius Commission ( CAC, 2009 ) and EFSA (2010 , 2011a ) is presented in Figure 5-3 ( Wal, 2015 ); Box 5-2 describes the EPA testing of the Bt toxin Cry1F that generally follows this approach. The logic behind the approach starts with the fact that any gene for a protein that comes from a plant that is known to cause food allergies has a higher likelihood of causing allergenicity than any gene from a plant that does not cause an allergic response. If the introduced protein is similar to a protein already known to be an allergen, it becomes suspect and should be tested in people who have an allergy to the related protein. Finally, if a protein fits none of the above characteristics but is not digested by simulated gastric fluid, it could be a novel food allergen. The latter factor comes from research demonstrating that some, but not all, proteins already known to be food allergens are resistant to digestion by gut fluid.

Flow chart summarizing the weight-of-evidence approach for assessment of allergenicity of a newly expressed protein in genetically engineered (GE) organisms. SOURCE: CAC (2009) and EFSA (2010, 2011a) in Wal (2015). NOTE: This approach starts with questions (more...)

There is one case in which that approach was used and a GE crop with allergenicity issues was detected early and prevented from being commercialized, and a second case in which a GE crop was withdrawn from the market based on the possibly that it included a food allergen. In the first case, research was conducted on a soybean line genetically engineered to produce a Brazil nut ( Bertholletia excelsa ) protein, which was a known allergen. Sera from patients allergic to Brazil nut protein were available and tested positive for activity against the GE soybean protein. Because the segregation from the human food supply of GE soybean with that protein could not be guaranteed, the project was halted ( Nordlee et al., 1996 ). The soybean variety was never commercialized.

In the second case, EPA allowed a Bt maize variety developed by Aventis CropScience with a potential for allergenicity (due to decreased digestion of the protein Cry9c in simulated gastric fluid) to be sold as cattle feed under the name StarLink™; because of the potential for allergenicity, the variety was not approved for direct human consumption. However, the Bt protein was found in human food, so the maize variety was removed from all markets. After that incident, EPA no longer distinguished between Bt proteins in human food versus in animal feed ( EPA, 2001b ). Bt crop varieties are approved in the United States for all markets or none.

The interactive approach for testing should work for GE crops when the testing is for a transgene that is expressed by the plant as a protein that does not affect its metabolism (for example, Bt toxins). The testing does not cover endogenous allergens whose concentrations have been increased by unintended effects of genetic engineering. In 2013, the European Commission set a requirement for assessing endogenous allergens in GE crops ( EC, 2013 ). A number of articles since then have supported the approach ( Fernandez et al., 2013 ) or have found it unnecessary and impractical ( Goodman et al., 2013 ; Graf et al., 2014 ). Soybean is an example of a crop that has endogenous allergens. A paper on endogenous soybean allergens concluded that there is enough knowledge of only some soybean allergens for proper testing ( Ladics et al., 2014 ). As emphasized by Wal (2015) , there is considerable variation among conventionally bred varieties in the concentrations of endogenous allergens, especially when they are grown under different conditions. Therefore, the existing variation must be taken into consideration in assessing a GE variety. Of course, the issue is not only the magnitude of variation but the potential change in the overall exposure of the global human population to the allergen.

One example of an existing potential allergen of concern is gamma-zein, one of the storage proteins produced in the maize kernel that is a comparably hard-to-digest protein ( Lee and Hamaker, 2006 ). Concern was expressed to the committee that GE maize may have higher amounts of gamma-zein, which could be allergenic ( Smith, 2014 ). Krishnan et al. (2010) found that young pigs consuming maize generate antibodies against gamma-zein. That observation and the fact that the protein withstands pepsin digestion suggest that gamma-zein could be an allergen. In a comparison of the Bt maize line MON810 with non- Bt maize, known maize allergens, including the 27-kDa and 50-kDa gamma-zein proteins, were not found to be in significantly different amounts ( Fonseca et al., 2012 ). On the other hand, conventionally bred Quality Protein Maize is reported to have a 2 to 3 fold higher concentration of the 27-kDa gamma-zein protein ( Wu et al., 2010 ). There is one patent for decreasing gamma-zein through genetic engineering. 5

There can be a connection between immune response and allergenicity. One well-cited study brought up in the public comment period was that by Finamore et al. (2008) , who assessed the effect of Bt maize ingestion on the mouse gut and peripheral immune system. They found that Bt maize produced small but statistically significant changes in percentage of T and B cells and of CD4+, CD8+, γδT, and αβT subpopulations at gut and peripheral sites and alterations of serum cytokines in weanlings fed for 30 days and in aged mice. However, there was no significant response in weaning mice that were fed for 90 days, which they related to further maturation of the immune system. They concluded that there was no evidence that the Bt toxin in maize caused substantial immune dysfunction. Similarly, Walsh et al. (2012a) did not find immune function changes in a long-term pig feeding study (80 or 110 days) on Bt MON810 maize compared with non-GE maize. Overall, no changes of concern regarding Bt maize feeding and altered immune response have been found.

At a public meeting that the committee held on health effects of GE foods, a question was raised about whether current testing for allergenicity is insufficient because some people do not have acidic conditions in their stomachs. Regarding that issue, digestibility of the proteins is assessed with simulated gastric fluid (0.32 percent pepsin, pH 1.2, 37°C), under the premise that an undigested protein may lead to the absorption of a novel allergenic fragment ( Astwood et al., 1996 ; Herman et al., 2006 ). Stomach fluid is typically acidic, with a pH of 1.5–3.5, which is the range at which pepsin (the digestive enzyme of the stomach) is active, and the volume of stomach fluid is 20–200 mL (about 1–3 ounces). Simulated gastric fluid was developed to represent human gastric conditions in the stomach and is used in bioavailability studies of drugs and foods ( U.S. Pharmacopeia, 2000 ).

In general, if the pH of the stomach is greater than 5, pepsin will not be active, and less breakdown of large proteins will take place. Hence, the usefulness of simulated gastric fluid in the case of a less acidic (higher pH) stomach is questionable, whether used for non-GE foods or GE foods. Untersmayr and Jensen-Jarolim (2008:1301) concluded that “alterations in the gastric milieu are frequently experienced during a lifetime either physiologically in the very young and the elderly or as a result of gastrointestinal pathologies. Additionally, acid-suppression medications are frequently used for treatment of dyspeptic disorders.” Trikha et al. (2013) used a group of 4,724 children (under 18 years old) who had received a diagnosis of gastroesophageal reflux disease (GERD) and who were treated with gastric acid-suppressive medication and matched with 4,724 children who had GERD but were not so treated. Those treated with acid-reducing medicine were more than 1.5 times as likely to have a diagnosis of food allergy as those who were not so treated. The difference between the two GERD groups was statistically significant (hazard ratio, 1.68; 95-percent confidence interval, 1.15–2.46).

The National Research Council report Safety of Genetically Engineered Foods pointed out that there were important limitations in allergenicity predictions that could be done before commercialization ( NRC, 2004 ). Since that report was published, there have been improvements in the allergen database, and research has been funded to improve precommercialization prediction. However, as the committee heard from an invited speaker, “no new methods have been demonstrated to predict sensitization and allergy in the absence of proven exposure” ( Goodman, 2015 ). Before commercialization, the general population will probably not have been exposed to an allergen similar enough to an allergen in a GE plant to cause cross-reactivity, so it would be useful to use the precommercialization tests only as a rough predictor. To ensure that allergens did not remain in the food system, the Safety of Genetically Engineered Foods report called for a two-step process of precommercialization testing and post-commercialization testing. Even though progress has been made on allergenicity prediction since that report was published in 2004, the committee found that post-commercialization testing would be useful in ensuring that no new allergens are introduced. There have been no steps toward post-commercialization testing since 2004. The committee recognized that such testing would be logistically challenging, as described in a scientific report to EFSA ( ADAS, 2015 ). Post-commercialization surveillance of such specific agents as drugs and medical devices is difficult, but there is generally a well-defined endpoint to look for in patients. In the case of food, the detection of an allergic response to a particular protein would be confounded by multiple exposures in the diet. However, several region-wide human populations have been exposed to GE foods for many years whereas others have not; this could enable an a priori hypothesis to be tested that populations that have been exposed to foods from specific GE crops will not show a higher rate of allergic response to such foods.

FINDING: For crops with endogenous allergens, knowing the range of allergen concentrations in a broad set of crop varieties grown in a variety of environments is helpful, but it is most important to know whether adding a GE crop to the food supply will change the general exposure of humans to the allergens.

FINDING: Because testing for allergenicity before commercialization could miss allergens to which the population had not previously been exposed, post-commercialization allergen testing would be useful in ensuring that consumers are not exposed to allergens, but such testing would be difficult to conduct.

FINDING: There is a substantial population of persons who have higher than usual stomach pH, so tests of digestibility of proteins in simulated acidic gastric fluid may not be relevant to this population.

• GENETICALLY ENGINEERED CROPS AND OCCURRENCE OF DISEASES AND CHRONIC CONDITIONS

The overall results of short-term and long-term animal studies with rodents and other animals and other data on GE-food nutrient and secondary compound composition convinces many (for example, Bartholomaeus et al., 2013 ; Ricroch et al., 2013a , b ; Van Eenennaam and Young, 2014 ) but not all involved researchers (for example, Dona and Arvanitoyannis, 2009 ; Domingo and Bordonaba, 2011 ; Hilbeck et al., 2015 ; also see DeFrancesco, 2013 ) that currently marketed GE foods are as safe as foods from conventionally bred crops. The committee received comments from an invited speaker ( Smith, 2014 ) and from the public regarding the possible relationship between increases in the incidence of specific chronic diseases and the introduction of GE foods into human diets. Appendix F includes a representative list of the comments about GE food safety that were sent to the committee through the study's website. The comments mentioned concerns about such chronic diseases as cancers, diabetes, and Parkinson's; possible organ-specific injuries (liver and kidney toxicity); and such disorders as autism and allergies. Smith (2003:39) made the claim that “diabetes rose by 33 percent from 1990 to 1998, lymphatic cancers are up, and many other illnesses are on the rise. Is there a connection to [genetically modified] foods? We have no way of knowing because no one has looked for one.”

As part of the committee's effort to respond to its task to “assess the evidence for purported negative effects of GE crops and their accompanying technologies,” it used available peer-reviewed data and government reports to assess whether any health problems may have increased in frequency in association with commercialization of GE crops or were expected to do so on the basis of the results of toxicity studies. The committee presents additional biochemical data from animal experiments but relies mostly on epidemiological studies that used time-series data. The epidemiological data for some specific health problems are generally robust over time (for example, cancers) but are less reliable for others. The committee presents the available data knowing that they include a number of sources of bias, including changes over time in survey methods and in the tools for detection of specific chronic diseases. As imperfect as the data may be, they are in some cases the only information available beyond animal experiments for formulating or testing hypotheses about possible connections between a GE food and a specific disease. The committee points out that the lack of rigorous data on incidence of disease is not only a problem for assessing effects of GE foods on health. More rigorous data on time, location, and sociocultural trends in disease would enable better assessment of potential health problems caused by environmental factors and other products from new technologies.

Cancer Incidence

A review of the American Cancer Society's database indicates that mortality from cancers in the United States and Canada has continued to decrease or stabilized in all categories except cancers of the lung and bronchus attributable to smoking. The decreases in mortality are due in part to early detection and improved treatment, so mortality data can mask the rate at which cancers occur. For that reason, the committee sought data on cancer incidence rather than cancer mortality. Figures 5-4 and 5-5 show changes in cancer incidence in U.S. women and men, respectively, from 1975 to 2011 ( NCI, 2014 ). If GE foods were causing a substantial number of specific cancers, the incidence of those cancers would be expected to show a change in slope in the time source after 1996, when GE traits were first available in commercial varieties of soybean and maize. The figures show that some cancers have increased and others decreased, but there is no obvious change in the patterns since GE crops were introduced into the U.S. food system. Figures 5-6 and 5-7 show cancer incidence in women and men in the United Kingdom, where GE foods are not generally being consumed. For the specific types of cancers that are reported in both the United States and the United Kingdom, there is no obvious difference in the patterns that could be attributed to the increase in consumption of GE foods in the United States. (The absolute numbers cannot be compared because of differences in methodology.)

Trends in cancer incidence in women in the United States, 1975–2011. SOURCE: NCI (2014). NOTE: Age-adjusted to the 2000 U.S. standard population and adjusted for delays in reporting. Dashed line at 1996 indicates year GE soybean and maize were (more...)

Trends in cancer incidence in men in the United States, 1975–2011. SOURCE: NCI (2014). NOTE: Age-adjusted to the 2000 U.S. standard population and adjusted for delays in reporting. Dashed line at 1996 indicates year GE soybean and maize were first (more...)

Cancer incidence in women in the United Kingdom, 1975–2011. DATA SOURCE: Cancer Research UK. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics. Accessed October 30, 2015. NOTE: Dashed line at 1996 indicates year (more...)

Cancer incidence in men in the United Kingdom, 1975–2011. DATA SOURCE: Cancer Research UK. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics. Accessed October 30, 2015. NOTE: Dashed line at 1996 indicates year (more...)

Forouzanfar et al. (2011) published data on breast and cervical cancer incidence worldwide from 1980 to 2010. As can be seen in Figure 5-8 , the global incidence of those two cancers has increased. An examination of the plots for North America (high income) (Canada and the United States), where GE foods are eaten, compared with the plots for western Europe, where GE foods generally are not eaten, shows similar increases in incidence of breast cancer and no increase in cervical cancer. The data do not support the hypothesis that GE-food consumption has substantially increased breast and cervical cancer. (The data for North America [high income] and western Europe are different from those in the studies above on the incidence of cancer in the United States and the United Kingdom.)

Global incidence of breast (A) and cervical (B) cancer. SOURCE: Forouzanfar et al. (2011). NOTE: North America (high income): Canada, United States; Western Europe: Andorra, Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, (more...)

Taken together, Figure 5 through Figure 8 do not support the hypothesis that GE foods have resulted in a substantial increase in the incidence of cancer. However, they do not establish that there is no relationship between cancer and GE foods because there can be a delay in the onset of cancer that would obscure a trend, and one could hypothesize that something else has occurred with GE foods in the United States that has lowered cancer incidence and thus obscured a relationship. The committee had limited evidence on which to make its judgments, but the evidence does not support claims that the incidence of cancers has increased because of consumption of GE foods.

There is ongoing debate about potential carcinogenicity of glyphosate in humans. Assessment of glyphosate is relevant to the committee's report because it is the principal herbicide used on HR crops (Livingston, et al. 2015), and it has been shown that there are higher residues of glyphosate in HR soybean treated with glyphosate than in non-GE soybean ( Duke et al., 2003 ; Bøhn et al., 2014 ). Box 5-5 provides details about a study by Séralini et al. (2012 , 2014 ) that concluded that glyphosate causes tumors in rats. The committee found that this study was not conclusive and used incorrect statistical analysis. The most detailed epidemiological study that tested for a relationship between cancer and glyphosate as well as other agricultural chemicals found “no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate” ( Mink et al., 2012:440 ; also see section below “Health Effects of Farmer Exposure to Insecticides and Herbicides”).

In 1985, EPA classified glyphosate as Group C (possibly carcinogenic to humans) on the basis of tumor formation in mice. However, in 1991, after reassessment of the mouse data, EPA changed the classification to Group E (evidence of noncarcinogenicity in humans) and in 2013 reaffirmed that “based on the lack of evidence of carcinogenicity in two adequate rodent carcinogenicity studies, glyphosate is not expected to pose a cancer risk to humans” ( EPA, 2013:25399 ).

In 2015, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) issued a monograph on glyphosate as part of its volume on some organophosphate insecticides and herbicides ( IARC, 2015 ). In the monograph, IARC classified glyphosate in Group 2A (probably carcinogenic to humans). A summary and reasons for the classification were published in Lancet Oncology ( Guyton et al., 2015 ).

The 2015 IARC Working Group found that, although there is “ limited evidence in humans for the carcinogenicity of glyphosate,” there is “ sufficient evidence in experimental animals for the carcinogenicity of glyphosate” ( IARC, 2015:78 ). Furthermore, IARC noted that there is mechanistic support in that glyphosate induces oxidative stress, which could cause DNA damage, and some epidemiological data that support the classification.

EFSA (2015) evaluated glyphosate after the IARC report was released and concluded that glyphosate is unlikely to pose a carcinogenic risk to humans. Canada's health agency concluded that “the level of human exposure, which determines the actual risk, was not taken into account by WHO (IARC)” ( Health Canada, 2015 ). The Canadian agency found that current food and dermal exposure to glyphosate even by those who work directly with glyphosate is not a health concern as long as it is used as directed on product labels ( Health Canada, 2015 ). EPA (2015) found that glyphosate does not interact with estrogen, androgen, or thyroid systems.

A comment to the committee expressed concern that glyphosate breaks down to formaldehyde, which was classified as a known human carcinogen by IARC (2006) . However, this hypothesis was not supported; Franz et al. (1997) used radiolabeled glyphosate and failed to show formation of formaldehyde in the normal environmental degradation of glyphosate.

FINDING: The incidence of a variety of cancer types in the United States has changed over time, but the changes do not appear to be associated with the switch to consumption of GE foods. Furthermore, patterns of change in cancer incidence in the United States are generally similar to those in the United Kingdom and Europe, where diets contain much lower amounts of food derived from GE crops. The data do not support the assertion that cancer rates have increased because of consumption of products of GE crops.

FINDING: There is significant disagreement among expert committees on the potential harm that could be caused by the use of glyphosate on GE crops and in other applications. In determining the risk from glyphosate and formulations that include glyphosate, analyses must take into account both marginal exposure and potential harm.

Kidney Disease

It has been hypothesized that kidney disease may have increased because GE proteins reached the kidney. The committee examined epidemiological data to determine whether there was a correlation between the consumption of GE foods and the prevalence of chronic kidney disease (CKD).

The total prevalence of all stages of CKD in the United States increased 2 percent from about 12 percent in 1988–1994 to 14 percent in 1999–2004, but the total prevalence has not increased significantly since then. Figure 5-9 presents prevalence data on the five progressively more serious, recognized stages of CKD ( USRDS, 2014 ). The greatest percent increase is seen in Stage 3, and based on the study ( USRDS, 2014 ), a large amount of the increase occurred in people with comorbidity of cardiovascular disease. Prevalence of CKD increases substantially with age ( Coresh et al., 2003 ), so the aging of the U.S. population may contribute to the overall increase ( U.S. Census Bureau, 2014 ), as does the increase in diabetes and hypertension ( Coresh et al., 2007 ).

Prevalence of chronic kidney disease by stage among National Health and Nutrition Examination Survey (NHANES) participants, 1988–2012. SOURCE: NHANES 1988–1994, 1999–2004, and 2005–2012; participants 20 years old and older; (more...)

FINDING: The available data on prevalence of chronic kidney disease in the United States show a 2 percent increase from 1988 to 2004, but the increase does not appear to be attributable to consumption of GE foods.

Obesity in humans is a complex condition associated with several genetic and environmental factors—including geography, ethnicity, socioeconomic status, lack of exercise, availability of fresh fruits and vegetables, and less nutritional meals ( Thayer et al., 2012 )—and an altered functioning microbiome ( Turnbaugh et al., 2009 ).

Studies of various species examined body-weight gain when animals were fed a GE crop, a non-GE isogenic comparator, or a non-GE, nonisogenic control. The authors concluded that there were no biologically relevant differences in body-weight gain regardless of the length of the studies ( Rhee et al. 2005 ; Hammond et al., 2006 ; Arjó et al., 2012 ; Buzoianu et al., 2012b ; Ricroch et al., 2013a , b ; Halle and Flachowsky, 2014 ; Nicolia et al. 2014) .

Human population studies have shown that obesity has become more prevalent in the United States (for example, Fryar et al., 2014 ). An (2015) provided a graphic of the change in U.S. adults (sorted by education level) from 1984 to 2013 ( Figure 5-10 ). As can be seen in the figure, the percentage of obese U.S. adults increased until about 2009, at which time it appears to level off. Because there is no increase in the slope after commercialization of GE crops, these data do not support the hypothesis that GE crops have increased obesity. These time-series data do not prove that there is no association, but if one is present, it is not strong.

FIGURE 5-10

Annual trend for adjusted prevalence of obesity in U.S. adults by education level, 1984–2013. SOURCE: An (2015). NOTE: Prevalence of obesity was adjusted to account for gender, age group, and race or ethnicity. Dashed line at 1996 indicates year (more...)

Those statistics on obesity coincide with those on the incidence of type II diabetes in the United States ( Abraham et al., 2015 ) and therefore do not support a relationship between GE crops and type II diabetes.

FINDING: The committee found no published evidence to support the hypothesis that the consumption of GE foods has caused higher U.S. rates of obesity or type II diabetes.

Gastrointestinal Tract Diseases

Although the gastrointestinal tract has evolved to digest dietary proteins in the stomach and small intestine effectively for absorption and use of amino acids, it is normal for some full proteins or their fragments to cross the gut barrier through a paracellular route (between cells) or damaged mucosa and for the immune system, which has a high presence at the interface of the gut wall and the internal circulation, to respond accordingly. It is also not unusual, given the high sensitivity of today's analytical equipment, for proteins or fragments to be detected in minute amounts in different body fluids. Detection methods are not specific to transgene-produced proteins but can find any dietary protein or fragment that is able to pass from the gastrointestinal tract into the bloodstream and tissues. The presence of a dietary protein or its fragment in the bloodstream or in tissues is not unusual or a cause for health concerns.

About 60–70 percent of the body's immune system is in the gastrointestinal tract's gut-associated lymphoid tissue, which has an interface with the gut luminal contents, including toxins, allergens, and the associated microbiota. For GE crops, a public concern has been that the immune system is compromised through ingested transgenic proteins. That possibility has been investigated in animal studies that examined immune system bio-markers and epithelial cell integrity (see section “Beyond Rodent Studies” above and Walsh et al., 2011 ).

It was suggested to the committee in presentations and public comments that fragments of transgenes may have some special properties that would result in human diseases if they were absorbed into the body through the digestive tract. The mechanism by which such genes or proteins would affect the body is not clear, although Smith (2013) hypothesized that consuming GE foods increased gut permeability.

FINDING: The committee could find no published evidence supporting the hypothesis that GE foods generate unique gene or protein fragments that would affect the body.

Celiac Disease

Celiac disease is an autoimmune disorder that affects about 1 percent of the population of western countries. It is triggered in susceptible people by consumption of gluten-containing cereal grains ( Fasano et al., 2003 ; Catassi et al., 2010 ). Symptoms of celiac disease are the result of an immune reaction that causes marked gastrointestinal inflammation in persons susceptible to gliadin, a component of gluten protein found in wheat, rye ( Secale cereale ), and barley ( Hordeum vulgare ) ( Green and Cellier, 2007 ). In addition to exposure to gluten, the etiology of celiac disease is multifactorial and includes genetic predisposition, microbial infection of the gastrointestinal tract, antibiotic exposure, and gastrointestinal erosion ( Riddle et al., 2012 ). Diagnosis is based on detection of serum concentrations (serotypes) of IgA tissue transglutaminase and endomysial antibody IgA, the relief of symptoms upon gluten avoidance, and tissue biopsy. The genetic changes related to the serotyped IgAs are found in about 30 percent of the Caucasian population, but susceptibility to celiac disease is found in only 1 percent of this population ( Riddle et al., 2012 ).

The committee was able to find data on the incidence of celiac disease in the United Kingdom ( West et al., 2014 ; Figure 5-11 ) and a detailed study conducted by the Mayo Clinic in one county in Minnesota ( Murray et al., 2003 ; Ludvigsson et al., 2013 ). In the Minnesota and UK studies, there is a clear pattern of increase in celiac-disease incidence (or at least its detection or the extent of self-reports) that started before 1996 ( Catassi et al., 2010 ), when U.S. citizens began to consume more GE foods and the use of glyphosate increased in the United States but not in the United Kingdom. The increases are similar in magnitude to that found in U.S. military personnel, in whom prevalence increased from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008 ( Riddle et al., 2012 ). The authors cautioned that most cases of celiac disease are undiagnosed. Some of the observed increase may be related to improvements in diagnostic criteria, greater awareness of the disease in physicians and patients, better blood tests, and increases in the number of biopsies. However, recent observations point to an increase in incidence beyond those factors (J. A. Murray, Mayo Clinic, personal communication, February 1, 2016).

FIGURE 5-11

Three-year rolling average incidence of celiac disease in 1990–2011, by age group, in the United Kingdom. SOURCE: West et al., 2014. NOTE: Dashed line at 1996 indicates year genetically engineered soybean and maize were first grown in the United (more...)

On the basis of data collected in the 2009–2010 National Health and Nutrition Examination Survey, Rubio-Tapia et al. (2012) reported a prevalence of celiac disease of 0.71 percent with 1.01 percent in non-Hispanic whites in a sample of 7,798 subjects. It should be noted that there has not been any commercial production of GE wheat, rye, or barley in the world. The committee found no evidence that the introduction of GE foods affected the incidence or prevalence of celiac disease worldwide.

FINDING: Celiac-disease detection began increasing in the United States before the introduction of GE crops and the increased use of glyphosate. It appears to have increased similarly in the United Kingdom, where GE foods are not typically consumed and glyphosate use did not increase. The data are not robust, but they do not show a major difference in the rate of increase in incidence of celiac disease between the two countries.

Food Allergies

Speakers and some members of the public suggested that the prevalence of food allergies has increased because of GE crops. The committee examined records on the prevalence of food allergies in the United States over time. As is clear from Figure 5-12 and Jackson et al. (2013) , the prevalence of food allergies in the United States is rising. For a rough comparator, the committee examined data on hospital admissions for food allergies in the United Kingdom over time ( Figure 5-13 ). UK citizens eat far less food derived from GE crops. The data ( Gupta et al., 2007 ) suggest that food allergies are increasing in the United Kingdom at about the same rate as in the United States (but the types of measurement are different).

FIGURE 5-12

Percentage of children 0–17 years old in the United States with a reported allergic condition in the preceding 12 months, 1997–2011. a Significantly increasing linear trend for food and skin allergy from 1997–1999 to 2009–2011. (more...)

FIGURE 5-13

Trends in hospital admission rates for anaphylaxis related to food allergy by age in the United Kingdom during 1990–2004. SOURCE: Gupta et al. (2007). NOTES: ICD = International Classification of Diseases. Green = ages 0–14 years; blue (more...)

FINDING: The committee did not find a relationship between consumption of GE foods and the increase in prevalence of food allergies.

Autism Spectrum Disorder

Autism is often described by such symptoms as difficulty in communicating, forming personal relationships, and using language and abstract concepts. According to the American Psychiatric Association (2013) , autism spectrum disorder (ASD) encompasses the previous diagnoses of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified, and childhood disintegrative disorder. Accurate diagnosis of ASD can be difficult, but efforts to identify children with ASD have increased in the United States over the last three decades ( CDC, 2014 ).

In the 2010 Centers for Disease Control and Prevention (CDC) survey of ASD in 11 regions of the United States ( CDC, 2014 ), the overall prevalence in children 8 years old was about 1 in 68 (1.47 percent), but there was wide variation among regions and sociocultural groupings of children. The CDC report stated that “the extent to which this variation might be attributable to diagnostic practices, under-recognition of ASD symptoms in some racial/ethnic groups, socioeconomic disparities in access to services, and regional differences in clinical or school-based practices that might influence the findings in this report is unclear” ( CDC, 2014:1 ). The degree to which the increase in ASD prevalence since 1990 is due to improved diagnosis is also unclear.

Before 1990, few children in the United States or the United Kingdom had diagnoses of ASD ( Taylor et al., 2013 ), but the prevalence has increased dramatically in both countries. Researchers in the United States and United Kingdom wrote a report that examined prevalence of ASD in the United Kingdom over time and compared it with that in the United States ( Taylor et al., 2013 ). They concluded that “a continuous simultaneous extraordinary rise in the number of children diagnosed as autistic began in both countries in the early 1990s and lasted for a decade. The distribution of first time diagnosis according to age and gender was the same. These similarities between countries as well as within different locations in each country point to a common etiology for this extraordinary medical case” ( Taylor et al., 2013:5 ). There is a higher prevalence in the United States, but it is difficult to evaluate whether it is because of differences in efforts in and approaches to diagnosis and in sociocultural factors that seem to influence prevalence. The overall similarities in prevalence of ASD in the United Kingdom, where GE foods are rarely eaten, and in the United States, where GE foods are commonly eaten, suggest that the major rise in ASD is not associated with consumption of GE foods.

FINDING: The similarity in patterns of increase in autism spectrum disorder in children in the United States, where GE foods are commonly eaten, and the United Kingdom, where GE foods are rarely eaten, does not support the hypothesis of a link between eating GE foods and prevalence of autism spectrum disorder.

• OTHER HUMAN HEALTH CONCERNS RELATED TO GENETICALLY ENGINEERED CROPS

The committee heard from some members of the public and some invited speakers that ailments of gastrointestinal origin could be caused by GE crops or their associated technologies or by foods derived from GE crops. The committee investigated the evidence available for that hypothesis.

Gastrointestinal Tract Microbiota

The committee received comments from the public that foods derived from GE crops could change the gut microbiota in an adverse way. Three scenarios can be considered as related to the potential effects of GE crops on the gut microbiota: the effect of the transgene product (for example, Bt toxin), unintended alteration of profiles of GE plant secondary metabolites, and herbicide (and adjuvant) residue (for example, glyphosate) and its metabolites in HR crops.

Research on the human gut microbiota (the community of microorganisms that live in the digestive tract) is rapidly evolving with recent reports ( Dethlefsen and Relman, 2011 ; David et al., 2014 ) that suggest that microbiota perturbations occur fairly quickly owing to dietary components or antibiotic treatment. Microbiota composition and state are now well recognized to be linked to noncommunicable chronic diseases and other health problems, so factors that cause either beneficial or adverse changes in the microbiota are of interest to researchers and clinicians. However, the science has not reached the point of understanding how specific changes in microbiota composition affect health and what represents a “healthy” microbiota. The effect of different dietary patterns (for example, high-fat versus high-carbohydrate diets) on the gut microbiota has been linked to metabolic syndrome ( Ley, 2010 ; Zhang et al., 2015 ).

As discussed above, most proteins, including those in GE and conventionally bred crops, are at least partially digested in the stomach by the action of pepsin that is maintained by the acidic pH of the stomach in most people. Further digestion and absorption are a function of the small intestine, where amino acids and dipeptides and tripeptides are absorbed. Therefore, an effect of a dietary protein on the microbiota, whether from GE or non-GE foods, is unlikely. However, there is some evidence that Bt proteins can be toxic to microorganisms ( Yudina et al., 2007 ), and some nondegraded Bt protein is found within the lumen of the gut but not in the general circulation of pigs ( Walsh et al., 2011 ). Buzoianu et al. (2012c , 2013a ) studied the effect of Bt maize feeding on microbiota composition in pigs. In their 2012 study, 110-day feeding of Bt maize (variety MON810) and of isogenic non-GE maize diets led to no differences in cultured Enterobacteriaceae, Lactobacillus , and total anaerobes from the gut; 16S rRNA sequencing showed no differences in bacterial taxa, except the genus Holdemania with which no health effects are associated ( Buzoianu et al., 2012c ). In the follow-up study in which intestinal content of sows and their offspring were examined with 16S rRNA gene sequencing, the only observed difference for major bacterial phyla was that Proteobacteria were less abundant in sows fed Bt maize before farrowing and in offspring at weaning compared with the controls ( Buzoainu et al., 2013a ). Fecal Firmicutes were more abundant in offspring fed GE maize. There were other inconsistent differences in mostly low-abundance microorganisms. On the basis of the overall results from their studies, the authors concluded that none of the changes seen in the animals was expected to have biologically relevant health effects on the animals.

Relatively few studies have examined the influence of plant secondary metabolites from any crop on the gut microbiota. The review of Valdés et al. (2015) highlighted investigations on polyphenol-rich foods—such as red wine, tea, cocoa, and blueberries—on the microbiota. Effects were considered minor. As discussed above (see the section “Endogenous Toxins in Plants”), current commercialized GE crops do not have distinctly different secondary metabolite profiles that would lead one to think that they would affect the gut microbiota.

No studies have shown that there are perturbations of the gut microbiota of animals fed foods derived from GE crops that are of concern. However, the committee concluded that this topic has not been adequately explored. It will be important to conduct research that leads to an understanding of whether GE foods or GE foods coupled with other chemicals have biologically relevant effects on the gut microbiota.

FINDING: On the basis of available evidence, the committee determined that the small perturbations found in the gut microbiota of animals fed foods derived from GE crops are not expected to cause health problems. A better understanding of this subject is likely as the methods for identifying and quantifying gut microorganisms mature.

Horizontal Gene Transfer to Gut Microorganisms or Animal Somatic Cells

Horizontal (or lateral) gene transfer is “the stable transfer of genetic material from one organism to another without reproduction or human intervention” ( Keese, 2008:123 ). Since GE crops were commercialized, concern has been voiced by some scientists and some members of the public that foreign DNA introduced into plants through genetic-engineering technologies might, after ingestion, be transferred to the human gut microbiota and directly or indirectly (that is, from bacteria) into human somatic cells. Although most of the concern regarding horizontal gene transfer has been focused on antibiotic-resistance genes used as markers of the transgenic event, other transgenes, such as those with Bt toxins, have also been of concern.

A prerequisite for horizontal gene transfer is that the recombinant DNA must survive the adverse conditions of both food processing and passage through the gastrointestinal tract. Netherwood et al. (2004) showed in patients with a surgically implanted exiting tube placed at the end of the small intestine (an ileostomy) that a small amount of the GE soybean transgene EPSPS passed through the upper gastrointestinal tract to the point of the distal ileum; in subjects without an ileostomy, no transgene was recovered from their feces. In their review on stability and degradation of DNA from foods in the gastrointestinal tract, Rizzi et al. (2012) noted that recombinant plant DNA fragments were detected in the gastrointestinal tracts of nonruminant animals but not detected in blood or other tissues, although some nonrecombinant plant DNA could be found. The authors concluded that some natural plant DNA fragments persist in the lumen of the gastrointestinal tract and in the bloodstream of animals and humans.

For an event to be considered horizontal gene transfer, DNA must be in the form of a functional (rather than fragmented) gene, enter into bacterial or somatic cells, and be incorporated into the genome with an appropriate promoter, and it must not adversely affect the competitiveness of the cells; otherwise, the effect would be short-lived.

Plant DNA has not been demonstrated to be incorporated into animal cells; however, it has been shown to be transferred in prokaryotes (bacteria). Indeed, molecular geneticists had to find genetic-engineering approaches for getting DNA to be taken into eukaryote cells and incorporated into a genome. The report A Decade of EU-Funded GMO Research (2001–2010) ( EC, 2010a ) described a study that shows that rumen ciliates (a type of microorganism) exposed to Bt 176 maize for 2 or 3 years did not incorporate the Bt 176 transgene. There are no reproducible examples of horizontal gene transfer of recombinant plant DNA into the human gastrointestinal microbiota or into human somatic cells. Three independent reviews of the literature on the topic ( van den Eede et al., 2004 ; Keese, 2008 ; Brigulla and Wackernagel, 2010 ) concluded that new gene acquisition by the gut bacteria through horizontal gene transfer would be rare and does not pose a health risk.

FINDING: On the basis of its understanding of the process required for horizontal gene transfer from plants to animals and data on GE organisms, the committee concludes that horizontal gene transfer from GE crops or conventionally bred crops to humans does not pose a substantial health risk.

Transfer of Transgenic Material Across the Gut Barrier into Animal Organs

Conflicting reports exist regarding the question of intact transgenes and transgenic proteins from foods crossing the gut barrier. Spisák et al. (2013) published results that indicate that complete genes in foods can pass into human blood. That is plausible, but Lusk (2014) examined the approach used by Spisák et al. and found it more likely that the findings were due to contaminants. Lusk emphasized the need for negative controls in such studies. Placental transfer of foreign DNA into mice was found by Schubbert et al. (1998) by detection in the mouse fetus, but a later report from the same laboratory ( Hohlweg and Doerfler, 2001 ) did not find the transfer in an eight-generation study.

Studies with dairy cows and goats did not find transgenes or GE proteins in milk, although chloroplast DNA fragments were detected in milk ( Phipps et al., 2003 ; Nemeth et al., 2004 ; Calsamiglia, et al., 2007; Rizzi et al., 2008 ; Guertler et al., 2009 , Einspanier, 2013 ; Furgał-Dierżuk et al., 2015 ). That makes it clear that there is no apparent potential for trangenes or transgenic proteins to be present in dairy products. However, these animals are ruminants, and their digestive systems are different from that of humans.

Walsh et al. (2012a) studied the fate of a Bt gene and protein in pigs that have digestive systems that are more similar to that of humans. They found no evidence of the gene or protein in any organs or blood after 110 days of feeding on Bt maize, but they did find them in the digestive contents of the stomach, cecum, and colon. Fragments of Cry1Ab transgene (as well as other common maize gene fragments) but not the intact Bt gene were found in blood, liver, spleen, and kidney of pigs raised on Bt maize ( Mazza et al., 2005 ).

FINDING: Experiments have found that Cry1Ab fragments but not intact Bt genes can pass into organs and that these fragments present concerns no different than other genes that are in commonly consumed non-GE foods and that pass into organs as fragments.

FINDING: There is no evidence that Bt transgenes or proteins have been found in the milk of ruminants. Therefore, the committee finds that there should be no exposure to Bt transgenes or proteins from consuming dairy products.

OVERALL FINDING ON PURPORTED ADVERSE EFFECTS ON HUMAN HEALTH OF FOODS DERIVED FROM GE CROPS: On the basis of detailed examination of comparisons of currently commercialized GE and non-GE foods in compositional analysis, acute and chronic animal-toxicity tests, long-term data on health of livestock fed GE foods, and human epidemiological data, the committee found no differences that implicate a higher risk to human health from GE foods than from their non-GE counterparts.

• ASSESSMENT OF HUMAN HEALTH BENEFITS FROM GENETICALLY ENGINEERED CROPS

There are now a number of examples of crops, either commercialized or in the pipeline toward commercialization, that have GE traits that could improve human health. Improvement of human health can be the sole motivation for development of a specific crop trait, or it can be the secondary effect of a crop trait that is developed primarily for another reason. For example, the genetic engineering of rice to have higher beta-carotene has the specific goal of reducing vitamin A deficiency. GE maize that produces Bt toxins is engineered to decrease insect-pest damage, but a secondary effect could be a decrease in contamination of maize kernels by fungi that produce mycotoxins, such as fumonisins, that at high concentrations could impair human health. Beyond the direct effects of the crops on improvement of human health, there is also a potential indirect benefit associated with a decline in the exposure of insecticide applicators and their families to some insecticides because some GE plants decrease the need for insecticidal control.

Foods with Additional Nutrients or Other Healthful Qualities

Improved micronutrient content.

According to WHO, some 250 million preschool children are vitamin A–deficient. Each year, 250,000–500,000 vitamin A–deficient children become blind, and half of them die within 12 months of losing their sight. 6 Unlike children in wealthier societies, those children have diets that are restricted mostly to poor sources of nutrients, such as rice ( Hefferon, 2015 ). Overall improvement of the diets of the children and their parents is a goal that has not been reached; measures that improve the nutritional quality of their food sources are desirable although not optimal, as a diverse, healthy diet would be.

Crop breeders have used conventional breeding to improve the concentrations of beta-carotene in maize ( Gannon et al., 2014 ; Lividini and Fiedler, 2015 ), cassava, banana and plantain ( Musa spp.) ( Saltzman et al., 2013 ), and sweet potato ( Ipomoea batatas ) ( Hotz et al., 2012a , b ). There is some loss of beta-carotene during storage and cooking, but bioavailability is still good ( Sanahuja et al., 2013 ; De Moura et al., 2015 ). The most rigorous assessments of the effects of those high–beta-carotene varieties were conducted with orange-fleshed sweet potato (high in beta-carotene) in farming areas of Mozambique and Uganda. In both countries, there was increased beta-carotene intake. In Uganda, there was a positive relationship between consumption of high–beta-carotene sweet potato and positive vitamin A status ( Hotz et al., 2012a ). A more recent study in Mozambique found a decrease in diarrhea prevalence associated with consumption of the high–beta-carotene sweet potato ( Jones and DeBrauw, 2015 ).

No reported experiments have tested any crop with high–beta-carotene for unintended effects. There has been concern about the potential for too high a concentration of beta-carotene in crops because of the hypervitaminosis A syndrome that can be caused by direct intake of too much vitamin A, but that is not a problem when the source is beta-carotene ( Gannon et al., 2014 ).

Golden Rice, which was produced through genetic engineering to increase beta-carotene content, is one of the most recognized examples of the use of genetic-engineering technology to improve a crop's nutritional value. It is based on the understanding that rice possesses the entire machinery to synthesize beta-carotene in leaves but not in the grain. The breakthrough in the development of Golden Rice was the finding that only two genes are required to synthesize beta-carotene in the endosperm of the rice grain ( Ye et al., 2000 ). The first version of Golden Rice had a beta-carotene content of 6 µg/g. To raise the content to a point where it could alleviate vitamin A deficiency without consumption of very large amounts of rice, a second version of Golden Rice was produced by transforming the plant with the psy gene from maize. The carotene content was thereby raised above 30 µg/g ( Paine et al., 2005 ). Varieties that yield well, have good taste and cooking qualities, and cause no adverse health effects from unintended changes in the rice could have highly important health effects ( Demont and Stein, 2013 ; Birol et al., 2015 ). There have been claims that Golden Rice was ready for public release for well over a decade ( Hefferon, 2015 ), but this is not the case.

There is a publication on a field test of the first version of Golden Rice ( Datta et al., 2007 ), but the committee could not find information on the newer, higher–beta-carotene Golden Rice in the peer-reviewed literature. Therefore, it contacted the International Rice Research Institute (IRRI) Golden Rice project coordinator, Violeta Villegas, for an update on the status of the project. In discussions with Dr. Villegas (IRRI, personal communication, 2015), it was clear that the project is progressing with a new lead transgenic event, GR2-E, because of difficulties with the previous lead event, GR2-R. The GR2-E event has been backcrossed into varieties that have been requested by several countries including the Philippines, Bangladesh, and Indonesia. As of March 2016, Golden Rice GR2-E in PSBRc82 and BRRI dhan20 genetic backgrounds was being grown in confined field tests in the Philippines and Bangladesh, respectively. Both Golden Rice varieties underwent preliminary assessment inside the greenhouse prior to planting in confined field tests. If performance is good, the varieties will be moved to open field-testing on multiple locations. Once a food regulatory approval is received in one of the participating countries, IRRI will supply the rice with the GR2-E event to an independent third party to assess its efficacy at alleviating vitamin A deficiency.

Past issues with persons and organizations opposed to Golden Rice for a myriad of reasons may have affected IRRI's work on the rice, but the overall project status 7 points out that development of Golden Rice varieties that meet the needs of farmers and consumers and that are in full compliance with the regulatory systems of the partnering countries remains the primary objective. IRRI's summary statement on its Golden Rice project was that “Golden Rice will only be made available broadly to farmers and consumers if it is successfully developed into rice varieties suitable for Asia, approved by national regulators, and shown to improve vitamin A status in community conditions. If Golden Rice is found to be safe and efficacious, a sustainable delivery program will ensure that Golden Rice is acceptable and accessible to those most in need.” 8

Increasing concentrations of beta-carotene is only one goal of conventional crop breeding and genetic engineering. Projects for increasing iron and zinc in crops as different as wheat, pearl millet ( Pennisetum glaucum ), and lentil ( Lens culinaris ) are at varied stages of development ( Saltzman et al., 2013 ).

FINDING: Experimental results with non-GE crop varieties that have increased concentrations of micronutrients demonstrate that both GE and non-GE crops with these traits could have favorable effects on the health of millions of people, and projects aimed at providing these crops are at various stages of completion and testing.

Altering Oil Composition

Substantial efforts have been made to increase the oxidative stability of soybean oil, a major cooking oil all over the world, as a means of avoiding trans-fats generated through the hydrogenation process and enhancing omega-3 fatty acid content of the oil for use in both food and feed applications. Soybean oil is composed principally of five fatty acids: palmitic acid (16:0, carbon number:double bond number), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), and linolenic acid (18:3) in approximate percentages of 10, 4, 18, 55, and 13. High content of unsaturated fats creates a disadvantage in industrial processing because they are susceptible to oxidation and trans-fat generation during hydrogenation, whereas oils with a high percentage of oleic acid (about 80 percent) require less processing and offer another route to decrease concentrations of trans-fats in food products. High-oleic acid-containing soybean was produced by downregulating expression of the fatty acid desaturating enzymes FAD2-1A and -1B to decrease the concentration of trans-fats in soybean ( EFSA, 2013 ). In 2015, high-oleic acid soybean was commercially available in North America and was produced on a small area in the United States for specialty-product contracts (C. Hazel, DuPont Pioneer, personal communication, December 14, 2015).

Canola ( Brassica napus ), known in Europe as rapeseed, is the major oilseed crop in Canada. Canola was developed through conventional breeding at the University of Manitoba, Canada, by Downey and Stefansson in the early 1970s and had a good nutritional profile—58-percent oleic acid and 36-percent polyunsaturated fatty acids—in addition to low erucic acid and a moderate concentration of saturated fatty acid (6 percent). Because of demand for saturated functional oils for the trans - fat–free market, high-lauric acid GE canola was created in 1995 through an “ Agrobacterium mediated transformation in which the transfer-DNA (T-DNA) contained the gene encoding the enzyme 12:0 ACP thioesterase ( bay TE ) from the California Bay tree ( Umbellularia californica ). In addition, the T-DNA contained sequences that encoded the enzyme neomycin phosphotransferase II (NPTII). The expression of NPTII activity was used as a selectable trait to screen transformed plants for the presence of the bay TE gene. No other translatable DNA sequences were incorporated into the plant genome” ( Health Canada, 1999:1 ). The presence of lauric acid (12:0) in the oil allows it to be used as a replacement for other types of oils with lauric acid (for example, coconut and palm kernel oil) in such products as “confectionery coatings and fillings, margarines, spreads, shortenings, and commercial frying oils. It has also been used as a substitute for cocoa butter, lard, beef fats, palm oil, and partially or fully hydrogenated soybean, maize, cottonseed, peanut, safflower, and sunflower oils” ( Health Canada, 1999:2 ). However, low yield and comparably poor agronomic traits have removed high-lauric acid canola from the commercial market. The long-term use of crops with altered oil content is uncertain.

FINDING: Crops with altered oil composition might improve human health, but this will depend on the specific alterations, how the crops yield, and how the products of the crops are used.

Genetically Engineered Foods with Lower Concentrations of Toxins

Acrylamide is produced in starchy foods when they are cooked at high temperatures. Processing of potatoes for French fries and potato chips generates acrylamide. Toasting bread also produces acrylamide. That is viewed as a problem because the U.S. National Toxicology Program (2014) concluded that acrylamide “is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals” and causes neurological damage at high exposure. Acrylamide is produced from a chemical reaction between asparagine and a reducing sugar, so decreasing the concentration of either is expected to decrease acrylamide. A potato line was genetically engineered to have low amounts of free asparagine and in early tests had as little as 5 percent of the acrylamide compared with non-GE potatoes when cooked at high temperatures ( Rommens et al., 2008 ).

In 2014, USDA deregulated a low-acrylamide potato produced by Simplot Plant Sciences (USDA–APHIS, 2014c) on the basis of nonplant pest status. The company also provided information to FDA. No problems were found by FDA with respect to the company's assessment of composition or safety ( FDA, 2015 ). It should be noted that for many people reduced acrylamide in potatoes is expected to lower overall acrylamide intake substantially, but many foods contain acrylamide ( FDA, 2000b , revised 2006). An FDA survey of commonly consumed foods showed French fries at seven McDonald's locations had an average acrylamide concentration of 288 parts per billion (ppb), whereas Gerber Finger Foods Biter Biscuits had 130 ppb and Wheatena Toasted Wheat Cereal had 1,057 ppb, which is much more than from fast-food French fries ( FDA, 2002 , revised 2006). 9 Any toasted bread is expected to be high in acrylamide. Therefore, how much low-acrylamide potato decreases total exposure depends on individual diets. Furthermore, EPA has established limits for exposure to acrylamide, and current actual exposures are generally below the limits.

Although the low-acrylamide potato is the only GE crop with a lower food-toxin concentration that has been deregulated in the United States, other GE crops with lower natural toxin concentrations are in the pipeline. Potatoes and other crops in the “deadly nightshade” family (Solanaceae, which includes tomato and eggplant) produce glycoalkaloids, some of which have human toxicity, as described above (see the section “Endogenous Toxins in Plants” in this chapter). Langkilde et al. (2012) conducted a compositional and toxicological analysis of the potatoes with lower solanine and higher chaconine. The study used Syrian golden hamsters instead of rats because the hamsters are very sensitive to the glycoalkaloids. There were some statistically significant differences, but they were considered not of biological relevance. At this point, the evidence is not sufficient to conclude that a low-glycoalkaloid potato would be healthier for humans.

Highly toxic chemicals (aflatoxins and fumonisins) are produced by Fusarium and Aspergillis fungi on the kernels of maize ( Bowers et al., 2014 ). Aflatoxins are considered by the U.S. National Toxicology Program (2014) to be “human carcinogens based on sufficient evidence of carcinogenicity from studies in humans.” They are also associated with many other illnesses and considered a global health problem ( Wild and Gong, 2010 ). Fumonisins cause a number of physiological disorders and are considered possibly carcinogenic to humans ( IARC, 2002 ). Several investigators have reported a substantial decrease in fumonisins in Bt maize compared with conventionally bred varieties ( Munkvold and Desjardins, 1997 ; Bowers et al., 2014 ). However, there is no clear association between Bt maize and aflatoxin concentrations ( Wiatrak et al., 2005 ; Abbas et al., 2007 ; Bowen et al., 2014 ).

Research continues on how to use genetic engineering to develop varieties of maize and peanut ( Arachis hypogaea ) that inhibit aflatoxin production, but a GE solution has so far been elusive ( Bhatnagar-Mathur et al., 2015 ). A reduction in aflatoxin in both maize and peanut would have substantial health benefits in some developing countries ( Williams et al., 2004 ; Wild and Gong, 2010 ).

FINDING: It is possible that GE crops that would result in improved health by lowering exposure of humans to plant-produced toxins in foods could be developed, but there is insufficient information to assess the possibility. However, GE plants that indirectly or directly reduce fungal-toxin production and intake would offer substantial benefits to some of the world's poorest populations, which have the highest dietary intake of food-associated fungal toxins.

Health Effects of Farmer Exposure to Insecticides and Herbicides

Chapter 4 presents data that demonstrate substantially lower use of insecticides in some Bt crops than in conventionally bred crops. There is a logical expectation that a decrease in the number of insecticide applications would lead to lower farm-worker exposure and therefore lower health burden, especially in countries where acute poisonings due to applicator exposure are common. Racovita et al. (2015) reviewed five studies of Bt cotton in China, India, Pakistan, and South Africa that ranged from one to four growing seasons. All reported a decline in the number of insecticide applications to Bt versus non- Bt cotton. In a study in China by Huang et al. (2002) , Bt cotton was treated with insecticides 6.6 times and non- Bt cotton was treated 19.8 times during the growing season. The frequency of Bt and non- Bt cotton farmers reporting poisonings were 5 percent and 22 percent, respectively in 1999, 7 percent and 29 percent in 2000, 8 percent and 12 percent in 2001. Kouser and Qaim (2011) found fewer overall insecticide treatments in a study conducted in India: 1.5 treatments of Bt cotton and 2.2 treatments of non- Bt cotton. In this study, the farmers who used Bt cotton reported 0.19 poisonings per season while those with conventionally bred cotton reported 1.6 poisonings. Bennett et al. (2006) studied the same types of farmers in South Africa. Bt cotton was not yet widely available in the beginning of the experiment, but eventually some farmers adopted Bt cotton and decreased spraying. The study looked at overall poisonings according to hospital records over time; there were 20 poisonings in the year before common availability of Bt cotton and four in a later year, when there was 60 percent adoption of Bt cotton.

The findings of those and other studies (for example, Huang et al., 2005 ; Dev and Rao, 2007 ; Kouser and Qaim, 2013 ) are in line with an expectation of a decrease in poisonings when Bt cotton is grown instead of non- Bt cotton. However, Racovita et al. (2015:15) , who carefully assessed each of the studies, found many shortcomings that led them to conclude that “the link between [genetically modified] crop cultivation and a reduction in number of pesticide poisonings should be considered as still circumstantial.” The shortcomings include the fact that the number of poisonings is based on farmer recall of incidents sometimes more than a year after the field season or, in the Bennett et al. (2006) study, simply based on hospital cases. Another issue was that there may have been differences in risk–avoidance behavior between farmers who did and did not plant Bt cotton. Finally, the studies focused on farmers, not farm workers, who do not control farm operations. Racovita et al. (2015) called for more rigorous studies that would address the shortcomings of previous studies, given the politicized nature of the use of Bt crops.

Farm-worker exposure to insecticides and herbicides is lower in the United States and some other developed countries than is the case for farm workers on resource-poor farms. However, there is substantial exposure, and any effects seen in the United States would be of global concern. Prospective cohort studies of health are the high benchmark of epidemiology studies, and the Agricultural Health Study (AHS) funded by the U.S. National Institute of Environmental Health Sciences used this approach to evaluate private and commercial applicators in Iowa and North Carolina. The landmark study resulted in two peer-reviewed articles on glyphosate exposure and cancer incidence ( De Roos et al., 2005 ; Mink et al., 2012 ) and one on glyphosate exposure and non-cancer health outcomes ( Mink et al., 2011 ). De Roos et al. (2005:49) concluded that “glyphosate exposure was not associated with cancer incidence overall or with most cancer subtypes we studied.” The data suggested a weak association with multiple myeloma on the basis of a small number of cases, but that association was not found in a follow-up study ( DeRoos et al., 2005 ; Mink et al., 2012 ). Mink et al. (2012:440) reported on the continuation of the AHS cohort study and found “no consistent pattern of positive associations indicating a causal relationship between total cancer (in adults or children) or any site-specific cancer and exposure to glyphosate.” Mink et al. (2011) reviewed noncancer health outcomes that included respiratory conditions, diabetes, myocardial infarction, reproductive and developmental outcomes, rheumatoid arthritis, thyroid disease, and Parkinson's disease. They reviewed cohort, case–control, and cross-sectional studies within the AHS study and found “no evidence of a consistent pattern of positive associations indicating a causal relationship between any disease and exposure to glyphosate” ( Mink et al., 2011:172 ).

FINDING: There is evidence that use of Bt cotton in developing countries is associated with reduced insecticide poisonings. However, there is a need for more rigorous survey data addressing the shortcomings of existing studies.

FINDING: A major government-sponsored prospective study of farm-worker health in the United States does not show any significant increases in cancer or other health problems that are due to use of glyphosate.

• ASSESSMENT OF FOOD SAFETY OF CROPS TRANSFORMED THROUGH EMERGING GENETIC-ENGINEERING TECHNOLOGIES

Increased Precision and Complexity of Genetic-Engineering Alterations

At the time that the committee wrote its report, major commercialized GE crops had been engineered by using Agrobacterium tumefaciens mediated or gene gun-mediated transformation, both of which result in semirandom insertion of the transgene into the genome. Variation in expression of the transgene was routinely observed because of the specific genomic characteristics of the insertion sites. Because of that variation, there was a need to screen large numbers of transgenic plants to identify the optimal transgenic individual. Regulations in the United States require approval of each transformation event regardless of whether the transgene itself was previously approved for release in that crop. That is at least in part because of the potential for unintended effects of each insertion.

Precision genome-editing technologies now permit insertion of single or multiple genes into one targeted location in the genome and thereby eliminate variation that is due to position effects (see Chapter 7 ). Such precision is expected to decrease unintended effects of gene insertion, although it will not eliminate the effects of somaclonal variation (discussed in Chapter 7 ).

Consider, for example, the engineering of completely new metabolic pathways into a plant for nutritional enhancement. The simplest example would be a set of two genes, such as has been used to create Golden Rice to deliver precursors of vitamin A. A more complex example would be engineering of fish oils (very long-chain unsaturated fatty acids) to improve the health profile of plant oils; depending on the target species, this process has required introduction of at least of three and at most nine transgenes ( Abbadi et al., 2004 ; Wu et al., 2005 ; Ruiz-Lopez et al., 2014 ). If each of those transgenes is integrated into the genome on a different chromosome on the basis of separate insertion events, it will require a number of generations of crosses to put them all together in one plant. If, instead, all the transgenes could be targeted at the same site on a chromosome either simultaneously or one after another, they would not segregate from each other as they were moved into elite varieties. From a food-safety perspective, engineering transgenes into a single target locus also ensures that expression of the whole pathway is preserved so that the correct end product accumulates. Emerging genetic-engineering technologies currently enable insertion of a few genes in one construct, but in the future that number may increase dramatically.

In the future, the scale of genetic-engineering alterations may go much further than just manipulating oil profiles. The committee heard from speakers about projects aimed at changing the entire photosynthetic pathway of the rice plant ( Weber, 2014 ) to create an entirely novel crop ( Zhu et al., 2010 ; Ruan et al., 2012 ). The committee also heard from researchers interested in developing cereal crops with nitrogen fixation. Those projects are discussed further in Chapter 8 . Although the precision of future genetic-engineering alterations should decrease unintended effects of the process of engineering, the complexity of the changes in a plant may leave it not substantially equivalent to its non-GE counterpart.

It is also important to note that crops that use RNA interference (RNAi) were coming on the market when the committee was writing its report. EPA convened a science advisory panel to evaluate hazards that might arise from use of this genetic-engineering approach. The panel concluded that “dietary RNA is extensively degraded in the mammalian digestive system by a combination of ribonucleases (RNases) and acids that are likely to ensure that all structural forms of RNA are degraded throughout the digestive process. There is no convincing evidence that ingested [double-stranded] RNA is absorbed from the mammalian gut in a form that causes physiologically relevant adverse effects” ( EPA, 2014c:14 ). When the committee was writing its report, deployment of dietary RNAi was a new technology. EPA's panel made a number of recommendations, including investigating factors that may affect absorption and effects of dietary double-stranded RNAs and investigating the stability of double-stranded RNA in people who manifest diseases.

FINDING: The precision of emerging genetic-engineering technologies should decrease some sources of unintended changes in the plants, thus simplifying food-safety testing. However, engineering involving major changes in metabolic pathways or insertion of multiple resistance genes will complicate the determination of food safety because changes in metabolic pathways are known to have unexpected effects on plant metabolites.

Increased Diversity of Crops To Be Engineered

The most far-ranging effects of emerging genetic-engineering technologies may be the diversity of crops that will be engineered and commercialized. Commercial GE crops at the time the committee conducted its review were mainly high-production commodity crops (maize, soybean, and cotton) engineered with trans-kingdom genes, but the applications of emerging genetic-engineering technologies are much broader: these technologies can be easily applied to any plant species that can be regenerated from tissue culture. Furthermore, the emerging technologies described in Chapter 7 can focus on any gene in which an altered nucleotide sequence results in a desired trait.

As a consequence, the committee expects a sizable increase in the number of food-producing crop species that are genetically altered. Examples of new target crops include forages (grasses and legumes), beans, pulses, a wide array of vegetables, herbs, and spices, and plants grown for flavor compounds. New traits will probably include fiber content (either increased to add more fiber or decreased to improve digestibility), altered oil profiles, decreased concentrations of antinutrients, increased or more consistent concentrations of such phytochemicals as antioxidants (for example, flavonoids) and phytoestrogens (for example, isoflavones or lignans), and increased mineral concentrations. Some of these are considered further in Chapter 8 .

From a food-safety perspective, the increase in crops and traits presents a number of challenges. First is the need to develop better and more detailed baseline data on the general chemical composition and probably the transcriptomic profiles of currently marketed conventionally bred varieties of the crops (see Chapter 7 ). Perhaps more problematic will be designing whole-food animal-testing regimens if the food from the crop cannot be used as a major component of the test animals' diet. Maize, rice, soybean, and other grains can be added to diets at up to 30 percent without adverse effects on animal health. That is unlikely to be the case with new spices or some vegetables. It would be beneficial if new, publicly acceptable approaches for testing could be developed that do not require animal testing ( NRC, 2007 ; Liebsch et al., 2011 ; Marx-Stoelting et al., 2015 ). Chapter 9 addresses the potential need to move to an entirely product-based approach to regulation and testing based on the novelty of a new crop or food.

FINDING: Some future GE crops will be designed to be substantially different from current crops and may not be as amenable to animal testing as currently marketed GE crops.

RECOMMENDATION: There is an urgent need for publicly funded research on novel molecular approaches for testing future products of genetic engineering so that accurate testing methods will be available when the new products are ready for commercialization.

• CONCLUSIONS

The committee's objective in this chapter was to examine the evidence that supports or negates specific hypotheses and claims about the risks and benefits associated with foods derived from GE crops. As acknowledged at the beginning of the chapter, understanding the health effects of any food, whether non-GE or GE, can be difficult. The properties of most plant secondary metabolites are not understood, and isolating the effects of diet on animals, including humans, is challenging. Although there are well-developed methods for assessing potential allergenicity of novel foods, these methods could miss some allergens. However, the research that has been conducted in studies with animals and on chemical composition of GE foods reveals no differences that would implicate a higher risk to human health from eating GE foods than from eating their non-GE counterparts. Long-term epidemiological studies have not directly addressed GE food consumption, but available time-series epidemiological data do not show any disease or chronic conditions in populations that correlate with consumption of GE foods. The committee could not find persuasive evidence of adverse health effects directly attributable to consumption of GE foods.

New methods to measure food composition that involve transcriptomics, proteomics, and metabolomics provide a broad, nontargeted assessment of thousands of plant RNAs, proteins, and compounds. When the methods have been used, the differences found in comparisons of GE with non-GE plants have been small relative to the naturally occurring variation found in conventionally bred crop varieties. Differences that are detected by using -omics methods do not on their own indicate a safety problem.

There is some evidence that GE insect-resistant crops have had benefits to human health by reducing insecticide poisonings and decreasing exposure to fumonisins. Several crops had been developed or were in development with GE traits designed to benefit human health; however, when the committee was writing its report, commercialized crops with health benefits had been only recently introduced and were not widely grown, so the committee could not evaluate whether they had had their intended effects.

New crops developed with the use of emerging genetic-engineering technologies were in the process of being commercialized. The precision associated with the technologies should decrease some sources of unintended changes that occur when plants are genetically engineered and thus simplify food-safety testing. However, engineering involving major changes in metabolic pathways or insertion of multiple resistance genes will complicate the determination of food safety because changes in metabolic pathways are known to have unexpected effects on plant metabolites. Therefore, publicly funded research on novel approaches for testing future products of genetic engineering is needed so that accurate testing methods will be available when the new products are ready for commercialization.

The committee has compiled publicly available information on funding sources and first-author affiliation for the references cited in this chapter; the information is available at https://www ​.nationalacademies ​.org/ge-crops .

In November 2015, EPA took steps to withdraw the product's registration in light of new information that indicated there could be synergistic effects of the two herbicides, which could possibly result in greater toxicity to nontarget plants ( Taylor, 2015 ). A court ruling in January 2016 allowed the herbicide to remain on the market while EPA considered other administrative actions ( Callahan, 2016 ).

GE rice was not commercialized in 2015, but GE varieties in development have been tested.

OECD develops consensus documents that provide reference values for existing food crops ( OECD, 2015 ). These are publicly available online at http://www ​.oecd.org/science ​/biotrack/consensusdocumentsfortheworkonthesafetyofnovelfoodsandfeedsplants.htm (accessed May 9, 2016). The International Life Science Institute (ILSI) also maintains a crop composition database at www ​.cropcomposition.org (accessed May 9, 2016). ILSI reports that in 2013 the database contained more than 843,000 data points representing 3,150 compositional components.

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What is the status of the Golden Rice project coordinated by IRRI? Available at http://irri ​.org/golden-rice ​/faqs/what-is-the-status-of-the-golden-rice-project-coordinated-by-irri . Accessed October 30, 2015.

Acrylamide concentrations reported by FDA were for individual purchased food products and were not adjusted for unit-to-unit variation.

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• Cite this Page National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on Agriculture and Natural Resources; Committee on Genetically Engineered Crops: Past Experience and Future Prospects. Genetically Engineered Crops: Experiences and Prospects. Washington (DC): National Academies Press (US); 2016 May 17. 5, Human Health Effects of Genetically Engineered Crops.
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