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Biotechnology Research Paper Topics

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This collection of biotechnology research paper topics provides the list of 10 potential topics for research papers and overviews the history of biotechnology.

Biotechnology

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Get 10% off with 24start discount code, 1. animal breeding: genetic methods.

Modern animal breeding relies on scientific methods to control production of domesticated animals, both livestock and pets, which exhibit desired physical and behavioral traits. Genetic technology aids animal breeders to attain nutritional, medical, recreational, and fashion standards demanded by consumers for animal products including meat, milk, eggs, leather, wool, and pharmaceuticals. Animals are also genetically designed to meet labor and sporting requirements for speed and endurance, conformation and beauty ideals to win show competitions, and intelligence levels to perform obediently at tasks such as herding, hunting, and tracking. By the late twentieth century, genetics and mathematical models were appropriated to identify the potential of immature animals. DNA markers indicate how young animals will mature, saving breeders money by not investing in animals lacking genetic promise. Scientists also successfully transplanted sperm-producing stem cells with the goal of restoring fertility to barren breeding animals. At the National Animal Disease Center in Ames, Iowa, researchers created a gene-based test, which uses a cloned gene of the organism that causes Johne’s disease in cattle in order to detect that disease to avert epidemics. Researchers also began mapping the dog genome and developing molecular techniques to evaluate canine chromosomes in the Quantitative Trait Loci (QTL). Bioinformatics incorporates computers to analyze genetic material. Some tests were developed to diagnose many of several hundred genetic canine diseases including hip dysplasia and progressive retinal atrophy (PRA). A few breed organizations modified standards to discourage breeding of genetically flawed animals and promote heterozygosity.

2. Antibacterial Chemotherapy

In the early years of the twentieth century, the search for agents that would be effective against internal infections proceeded along two main routes. The first was a search for naturally occurring substances that were effective against microorganisms (antibiosis). The second was a search for chemicals that would have the same effect (chemotherapy). Despite the success of penicillin in the 1940s, the major early advances in the treatment of infection occurred not through antibiosis but through chemotherapy. The principle behind chemotherapy was that there was a relationship between chemical structure and pharmacological action. The founder of this concept was Paul Erhlich (1854–1915). An early success came in 1905 when atoxyl (an organic arsenic compound) was shown to destroy trypanosomes, the microbes that caused sleeping sickness. Unfortunately, atoxyl also damaged the optic nerve. Subsequently, Erhlich and his co-workers synthesized and tested hundreds of related arsenic compounds. Ehrlich was a co-recipient (with Ilya Ilyich Mechnikov) of the Nobel Prize in medicine in 1908 for his work on immunity. Success in discovering a range of effective antibacterial drugs had three important consequences: it brought a range of important diseases under control for the first time; it provided a tremendous stimulus to research workers and opened up new avenues of research; and in the resulting commercial optimism, it led to heavy postwar investment in the pharmaceutical industry. The therapeutic revolution had begun.

3. Artificial Insemination and in Vitro Fertilization

Artificial insemination (AI) involves the extraction and collection of semen together with techniques for depositing semen in the uterus in order to achieve successful fertilization and pregnancy. Throughout the twentieth century, the approach has offered animal breeders the advantage of being able to utilize the best available breeding stock and at the correct time within the female reproductive cycle, but without the limitations of having the animals in the same location. AI has been applied most intensively within the dairy and beef cattle industries and to a lesser extent horse breeding and numerous other domesticated species.

Many of the techniques involved in artificial insemination would lay the foundation for in vitro fertilization (IVF) in the latter half of the twentieth century. IVF refers to the group of technologies that allow fertilization to take place outside the body involving the retrieval of ova or eggs from the female and sperm from the male, which are then combined in artificial, or ‘‘test tube,’’ conditions leading to fertilization. The fertilized eggs then continue to develop for several days ‘‘in culture’’ until being transferred to the female recipient to continue developing within the uterus.

4. Biopolymers

Biopolymers are natural polymers, long-chained molecules (macromolecules) consisting mostly of a repeated composition of building blocks or monomers that are formed and utilized by living organisms. Each group of biopolymers is composed of different building blocks, for example chains of sugar molecules form starch (a polysaccharide), chains of amino acids form proteins and peptides, and chains of nucleic acid form DNA and RNA (polynucleotides). Biopolymers can form gels, fibers, coatings, and films depending on the specific polymer, and serve a variety of critical functions for cells and organisms. Proteins including collagens, keratins, silks, tubulins, and actin usually form structural composites or scaffolding, or protective materials in biological systems (e.g., spider silk). Polysaccharides function in molecular recognition at cell membrane surfaces, form capsular barrier layers around cells, act as emulsifiers and adhesives, and serve as skeletal or architectural materials in plants. In many cases these polymers occur in combination with proteins to form novel composite structures such as invertebrate exoskeletons or microbial cell walls, or with lignin in the case of plant cell walls.

The use of the word ‘‘cloning’’ is fraught with confusion and inconsistency, and it is important at the outset of this discussion to offer definitional clarification. For instance, in the 1997 article by Ian Wilmut and colleagues announcing the birth of the first cloned adult vertebrate (a ewe, Dolly the sheep) from somatic cell nuclear transfer, the word clone or cloning was never used, and yet the announcement raised considerable disquiet about the prospect of cloned human beings. In a desire to avoid potentially negative forms of language, many prefer to substitute ‘‘cell expansion techniques’’ or ‘‘therapeutic cloning’’ for cloning. Cloning has been known for centuries as a horticultural propagation method: for example, plants multiplied by grafting, budding, or cuttings do not differ genetically from the original plant. The term clone entered more common usage as a result of a speech in 1963 by J.B.S. Haldane based on his paper, ‘‘Biological possibilities for the human species of the next ten-thousand years.’’ Notwithstanding these notes of caution, we can refer to a number of processes as cloning. At the close of the twentieth century, such techniques had not yet progressed to the ability to bring a cloned human to full development; however, the ability to clone cells from an adult human has potential to treat diseases. International policymaking in the late 1990s sought to distinguish between the different end uses for somatic cell nuclear transfer resulting in the widespread adoption of the distinction between ‘‘reproductive’’ and ‘‘therapeutic’’ cloning. The function of the distinction has been to permit the use (in some countries) of the technique to generate potentially beneficial therapeutic applications from embryonic stem cell technology whilst prohibiting its use in human reproduction. In therapeutic applications, nuclear transfer from a patient’s cells into an enucleated ovum is used to create genetically identical embryos that would be grown in vitro but not be allowed to continue developing to become a human being. The resulting cloned embryos could be used as a source from which to produce stem cells that can then be induced to specialize into the specific type of tissue required by the patient (such as skin for burns victims, brain neuron cells for Parkinson’s disease sufferers, or pancreatic cells for diabetics). The rationale is that because the original nuclear material is derived from a patient’s adult tissue, the risks of rejection of such cells by the immune system are reduced.

6. Gene Therapy

In 1971, Australian Nobel laureate Sir F. MacFarlane Burnet thought that gene therapy (introducing genes into body tissue, usually to treat an inherited genetic disorder) looked more and more like a case of the emperor’s new clothes. Ethical issues aside, he believed that practical considerations forestalled possibilities for any beneficial gene strategy, then or probably ever. Bluntly, he wrote: ‘‘little further advance can be expected from laboratory science in the handling of ‘intrinsic’ types of disability and disease.’’ Joshua Lederberg and Edward Tatum, 1958 Nobel laureates, theorized in the 1960s that genes might be altered or replaced using viral vectors to treat human diseases. Stanfield Rogers, working from the Oak Ridge National Laboratory in 1970, had tried but failed to cure argininemia (a genetic disorder of the urea cycle that causes neurological damage in the form of mental retardation, seizures, and eventually death) in two German girls using Swope papilloma virus. Martin Cline at the University of California in Los Angeles, made the second failed attempt a decade later. He tried to correct the bone marrow cells of two beta-thalassemia patients, one in Israel and the other in Italy. What Cline’s failure revealed, however, was that many researchers who condemned his trial as unethical were by then working toward similar goals and targeting different diseases with various delivery methods. While Burnet’s pessimism finally proved to be wrong, progress in gene therapy was much slower than antibiotic or anticancer chemotherapy developments over the same period of time. While gene therapy had limited success, it nevertheless remained an active area for research, particularly because the Human Genome Project, begun in 1990, had resulted in a ‘‘rough draft’’ of all human genes by 2001, and was completed in 2003. Gene mapping created the means for analyzing the expression patterns of hundreds of genes involved in biological pathways and for identifying single nucleotide polymorphisms (SNPs) that have diagnostic and therapeutic potential for treating specific diseases in individuals. In the future, gene therapies may prove effective at protecting patients from adverse drug reactions or changing the biochemical nature of a person’s disease. They may also target blood vessel formation in order to prevent heart disease or blindness due to macular degeneration or diabetic retinopathy. One of the oldest ideas for use of gene therapy is to produce anticancer vaccines. One method involves inserting a granulocyte-macrophage colony-stimulating factor gene into prostate tumor cells removed in surgery. The cells then are irradiated to prevent any further cancer and injected back into the same patient to initiate an immune response against any remaining metastases. Whether or not such developments become a major treatment modality, no one now believes, as MacFarland Burnet did in 1970, that gene therapy science has reached an end in its potential to advance health.

7. Genetic Engineering

The term ‘‘genetic engineering’’ describes molecular biology techniques that allow geneticists to analyze and manipulate deoxyribonucleic acid (DNA). At the close of the twentieth century, genetic engineering promised to revolutionize many industries, including microbial biotechnology, agriculture, and medicine. It also sparked controversy over potential health and ecological hazards due to the unprecedented ability to bypass traditional biological reproduction.

For centuries, if not millennia, techniques have been employed to alter the genetic characteristics of animals and plants to enhance specifically desired traits. In a great many cases, breeds with which we are most familiar bear little resemblance to the wild varieties from which they are derived. Canine breeds, for instance, have been selectively tailored to changing esthetic tastes over many years, altering their appearance, behavior and temperament. Many of the species used in farming reflect long-term alterations to enhance meat, milk, and fleece yields. Likewise, in the case of agricultural varieties, hybridization and selective breeding have resulted in crops that are adapted to specific production conditions and regional demands. Genetic engineering differs from these traditional methods of plant and animal breeding in some very important respects. First, genes from one organism can be extracted and recombined with those of another (using recombinant DNA, or rDNA, technology) without either organism having to be of the same species. Second, removing the requirement for species reproductive compatibility, new genetic combinations can be produced in a much more highly accelerated way than before. Since the development of the first rDNA organism by Stanley Cohen and Herbert Boyer in 1973, a number of techniques have been found to produce highly novel products derived from transgenic plants and animals.

At the same time, there has been an ongoing and ferocious political debate over the environmental and health risks to humans of genetically altered species. The rise of genetic engineering may be characterized by developments during the last three decades of the twentieth century.

8. Genetic Screening and Testing

The menu of genetic screening and testing technologies now available in most developed countries increased rapidly in the closing years of the twentieth century. These technologies emerged within the context of rapidly changing social and legal contexts with regard to the medicalization of pregnancy and birth and the legalization of abortion. The earliest genetic screening tests detected inborn errors of metabolism and sex-linked disorders. Technological innovations in genomic mapping and DNA sequencing, together with an explosion in research on the genetic basis of disease which culminated in the Human Genome Project (HGP), led to a range of genetic screening and testing for diseases traditionally recognized as genetic in origin and for susceptibility to more common diseases such as certain types of familial cancer, cardiac conditions, and neurological disorders among others. Tests were also useful for forensic, or nonmedical, purposes. Genetic screening techniques are now available in conjunction with in vitro fertilization and other types of reproductive technologies, allowing the screening of fertilized embryos for certain genetic mutations before selection for implantation. At present selection is purely on disease grounds and selection for other traits (e.g., for eye or hair color, intelligence, height) cannot yet be done, though there are concerns for eugenics and ‘‘designer babies.’’ Screening is available for an increasing number of metabolic diseases through tandem mass spectrometry, which uses less blood per test, allows testing for many conditions simultaneously, and has a very low false-positive rate as compared to conventional Guthrie testing. Finally, genetic technologies are being used in the judicial domain for determination of paternity, often associated with child support claims, and for forensic purposes in cases where DNA material is available for testing.

9. Plant Breeding: Genetic Methods

The cultivation of plants is the world’s oldest biotechnology. We have continually tried to produce improved varieties while increasing yield, features to aid cultivation and harvesting, disease, and pest resistance, or crop qualities such as longer postharvest storage life and improved taste or nutritional value. Early changes resulted from random crosspollination, rudimentary grafting, or spontaneous genetic change. For centuries, man kept the seed from the plants with improved characteristics to plant the following season’s crop. The pioneering work of Gregor Mendel and his development of the basic laws of heredity showed for other first time that some of the processes of heredity could be altered by experimental means. The genetic analysis of bacterial (prokaryote) genes and techniques for analysis of the higher (eukaryotic) organisms such as plants developed in parallel streams, but the rediscovery of Mendel’s work in 1900 fueled a burst of activity on understanding the role of genes in inheritance. The knowledge that genes are linked along the chromosome thereby allowed mapping of genes (transduction analysis, conjugation analysis, and transformation analysis). The power of genetics to produce a desirable plant was established, and it was appreciated that controlled breeding (test crosses and back crosses) and careful analysis of the progeny could distinguish traits that were dominant or recessive, and establish pure breeding lines. Traditional horticultural techniques of artificial self-pollination and cross-pollination were also used to produce hybrids. In the 1930s the Russian Nikolai Vavilov recognized the value of genetic diversity in domesticated crop plants and their wild relatives to crop improvement, and collected seeds from the wild to study total genetic diversity and use these in breeding programs. The impact of scientific crop breeding was established by the ‘‘Green revolution’’ of the 1960s, when new wheat varieties with higher yields were developed by careful crop breeding. ‘‘Mutation breeding’’— inducing mutations by exposing seeds to x-rays or chemicals such as sodium azide, accelerated after World War II. It was also discovered that plant cells and tissues grown in tissue culture would mutate rapidly. In the 1970s, haploid breeding, which involves producing plants from two identical sets of chromosomes, was extensively used to create new cultivars. In the twenty-first century, haploid breeding could speed up plant breeding by shortening the breeding cycle.

10. Tissue Culturing

The technique of tissue or cell culture, which relates to the growth of tissue or cells within a laboratory setting, underlies a phenomenal proportion of biomedical research. Though it has roots in the late nineteenth century, when numerous scientists tried to grow samples in alien environments, cell culture is credited as truly beginning with the first concrete evidence of successful growth in vitro, demonstrated by Johns Hopkins University embryologist Ross Harrison in 1907. Harrison took sections of spinal cord from a frog embryo, placed them on a glass cover slip and bathed the tissue in a nutrient media. The results of the experiment were startling—for the first time scientists visualized actual nerve growth as it would happen in a living organism—and many other scientists across the U.S. and Europe took up culture techniques. Rather unwittingly, for he was merely trying to settle a professional dispute regarding the origin of nerve fibers, Harrison fashioned a research tool that has since been designated by many as the greatest advance in medical science since the invention of the microscope.

From the 1980s, cell culture has once again been brought to the forefront of cancer research in the isolation and identification of numerous cancer causing oncogenes. In addition, cell culturing continues to play a crucial role in fields such as cytology, embryology, radiology, and molecular genetics. In the future, its relevance to direct clinical treatment might be further increased by the growth in culture of stem cells and tissue replacement therapies that can be tailored for a particular individual. Indeed, as cell culture approaches its centenary, it appears that its importance to scientific, medical, and commercial research the world over will only increase in the twenty-first century.

History of Biotechnology

Biotechnology grew out of the technology of fermentation, which was called zymotechnology. This was different from the ancient craft of brewing because of its thought-out relationships to science. These were most famously conceptualized by the Prussian chemist Georg Ernst Stahl (1659–1734) in his 1697 treatise Zymotechnia Fundamentalis, in which he introduced the term zymotechnology. Carl Balling, long-serving professor in Prague, the world center of brewing, drew on the work of Stahl when he published his Bericht uber die Fortschritte der zymotechnische Wissenschaften und Gewerbe (Account of the Progress of the Zymotechnic Sciences and Arts) in the mid-nineteenth century. He used the idea of zymotechnics to compete with his German contemporary Justus Liebig for whom chemistry was the underpinning of all processes.

By the end of the nineteenth century, there were attempts to develop a new scientific study of fermentation. It was an aspect of the ‘‘second’’ Industrial Revolution during the period from 1870 to 1914. The emergence of the chemical industry is widely taken as emblematic of the formal research and development taking place at the time. The development of microbiological industries is another example. For the first time, Louis Pasteur’s germ theory made it possible to provide convincing explanations of brewing and other fermentation processes.

Pasteur had published on brewing in the wake of France’s humiliation in the Franco–Prussian war (1870–1871) to assert his country’s superiority in an industry traditionally associated with Germany. Yet the science and technology of fermentation had a wide range of applications including the manufacture of foods (cheese, yogurt, wine, vinegar, and tea), of commodities (tobacco and leather), and of chemicals (lactic acid, citric acid, and the enzyme takaminase). The concept of zymotechnology associated principally with the brewing of beer began to appear too limited to its principal exponents. At the time, Denmark was the world leader in creating high-value agricultural produce. Cooperative farms pioneered intensive pig fattening as well as the mass production of bacon, butter, and beer. It was here that the systems of science and technology were integrated and reintegrated, conceptualized and reconceptualized.

The Dane Emil Christian Hansen discovered that infection from wild yeasts was responsible for numerous failed brews. His contemporary Alfred Jørgensen, a Copenhagen consultant closely associated with the Tuborg brewery, published a widely used textbook on zymotechnology. Microorganisms and Fermentation first appeared in Danish 1889 and would be translated, reedited, and reissued for the next 60 years.

The scarcity of resources on both sides during World War I brought together science and technology, further development of zymotechnology, and formulation of the concept of biotechnology. Impending and then actual war accelerated the use of fermentation technologies to make strategic materials. In Britain a variant of a process to ferment starch to make butadiene for synthetic rubber production was adapted to make acetone needed in the manufacture of explosives. The process was technically important as the first industrial sterile fermentation and was strategically important for munitions supplies. The developer, chemist Chaim Weizmann, later became well known as the first president of Israel in 1949.

In Germany scarce oil-based lubricants were replaced by glycerol made by fermentation. Animal feed was derived from yeast grown with the aid of the new synthetic ammonia in another wartime development that inspired the coining of the word biotechnology. Hungary was the agricultural base of the Austro–Hungarian empire and aspired to Danish levels of efficiency. The economist Karl Ereky (1878–1952) planned to go further and build the largest industrial pig-processing factory. He envisioned a site that would fatten 50,000 swine at a time while railroad cars of sugar beet arrived and fat, hides, and meat departed. In this forerunner of the Soviet collective farm, peasants (in any case now falling prey to the temptations of urban society) would be completely superseded by the industrialization of the biological process in large factory-like animal processing units. Ereky went further in his ruminations over the meaning of his innovation. He suggested that it presaged an industrial revolution that would follow the transformation of chemical technology. In his book entitled Biotechnologie, he linked specific technical injunctions to wide-ranging philosophy. Ereky was neither isolated nor obscure. He had been trained in the mainstream of reflection on the meaning of the applied sciences in Hungary, which would be remarkably productive across the sciences. After World War I, Ereky served as Hungary’s minister of food in the short-lived right wing regime that succeeded the fall of the communist government of Bela Kun.

Nonetheless it was not through Ereky’s direct action that his ideas seem to have spread. Rather, his book was reviewed by the influential Paul Lindner, head of botany at the Institut fu¨ r Ga¨ rungsgewerbe in Berlin, who suggested that microorganisms could also be seen as biotechnological machines. This concept was already found in the production of yeast and in Weizmann’s work with strategic materials, which was widely publicized at that very time. It was with this meaning that the word ‘‘Biotechnologie’’ entered German dictionaries in the 1920s.

Biotechnology represented more than the manipulation of existing organisms. From the beginning it was concerned with their improvement as well, and this meant the enhancement of all living creatures. Most dramatically this would include humanity itself; more mundanely it would include plants and animals of agricultural importance. The enhancement of people was called eugenics by the Victorian polymath and cousin of Charles Darwin, Francis Galton. Two strains of eugenics emerged: negative eugenics associated with weeding out the weak and positive eugenics associated with enhancing strength. In the early twentieth century, many eugenics proponents believed that the weak could be made strong. People had after all progressed beyond their biological limits by means of technology.

Jean-Jacques Virey, a follower of the French naturalist Jean-Baptiste de Monet de Lamarck, had coined the term ‘‘biotechnie’’ in 1828 to describe man’s ability to make technology do the work of biology, but it was not till a century later that the term entered widespread use. The Scottish biologist and town planner Patrick Geddes made biotechnics popular in the English-speaking world. Geddes, too, sought to link life and technology. Before World War I he had characterized the technological evolution of mankind as a move from the paleotechnic era of coal and iron to the neotechnic era of chemicals, electricity, and steel. After the war, he detected a new era based on biology—the biotechnic era. Through his friend, writer Lewis Mumford, Geddes would have great influence. Mumford’s book Technics and Civilization, itself a founding volume of the modern historiography of technology, promoted his vision of the Geddesian evolution.

A younger generation of English experimental biologists with a special interest in genetics, including J. B. S. Haldane, Julian Huxley, and Lancelot Hogben, also promoted a concept of biotechnology in the period between the world wars. Because they wrote popular works, they were among Britain’s best-known scientists. Haldane wrote about biological invention in his far-seeing work Daedalus. Huxley looked forward to a blend of social and eugenics-based biological engineering. Hogben, following Geddes, was more interested in engineering plants through breeding. He tied the progressivism of biology to the advance of socialism.

The improvement of the human race, genetic manipulation of bacteria, and the development of fermentation technology were brought together by the development of penicillin during World War II. This drug was successfully extracted from the juice exuded by a strain of the Penicillium fungus. Although discovered by accident and then developed further for purely scientific reasons, the scarce and unstable ‘‘antibiotic’’ called penicillin was transformed during World War II into a powerful and widely used drug. Large networks of academic and government laboratories and pharmaceutical manufacturers in Britain and the U.S. were coordinated by agencies of the two governments. An unanticipated combination of genetics, biochemistry, chemistry, and chemical engineering skills had been required. When the natural mold was bombarded with high-frequency radiation, far more productive mutants were produced, and subsequently all the medicine was made using the product of these man-made cells. By the 1950s penicillin was cheap to produce and globally available.

The new technology of cultivating and processing large quantities of microorganisms led to calls for a new scientific discipline. Biochemical engineering was one term, and applied microbiology another. The Swedish biologist, Carl-Goran Heden, possibly influenced by German precedents, favored the term ‘‘Biotechnologi’’ and persuaded his friend Elmer Gaden to relabel his new journal Biotechnology and Biochemical Engineering. From 1962 major international conferences were held under the banner of the Global Impact of Applied Microbiology. During the 1960s food based on single-cell protein grown in fermenters on oil or glucose seemed, to visionary engineers and microbiologists and to major companies, to offer an immediate solution to world hunger. Tropical countries rich in biomass that could be used as raw material for fermentation were also the world’s poorest. Alcohol could be manufactured by fermenting such starch or sugar rich crops as sugar cane and corn. Brazil introduced a national program of replacing oil-based petrol with alcohol in the 1970s.

It was not, however, just the developing countries that hoped to benefit. The Soviet Union developed fermentation-based protein as a major source of animal feed through the 1980s. In the U.S. it seemed that oil from surplus corn would solve the problem of low farm prices aggravated by the country’s boycott of the USSR in1979, and the term ‘‘gasohol‘‘ came into currency. Above all, the decline of established industries made the discovery of a new wealth maker an urgent priority for Western governments. Policy makers in both Germany and Japan during the 1970s were driven by a sense of the inadequacy of the last generation of technologies. These were apparently maturing, and the succession was far from clear. Even if electronics or space travel offered routes to the bright industrial future, these fields seemed to be dominated by the U.S. Seeing incipient crisis, the Green, or environmental, movement promoted a technology that would depend on renewable resources and on low-energy processes that would produce biodegradable products, recycle waste, and address problems of the health and nutrition of the world.

In 1973 the German government, seeking a new and ‘‘greener’’ industrial policy, commissioned a report entitled Biotechnologie that identified ways in which biological processing was key to modern developments in technology. Even though the report was published at the time that recombinant DNA (deoxyribonucleic acid) was becoming possible, it did not refer to this new technique and instead focused on the use and combination of existing technologies to make novel products.

Nonetheless the hitherto esoteric science of molecular biology was making considerable progress, although its practice in the early 1970s was rather distant from the world of industrial production. The phrase ‘‘genetic engineering’’ entered common parlance in the 1960s to describe human genetic modification. Medicine, however, put a premium on the use of proteins that were difficult to extract from people: insulin for diabetics and interferon for cancer sufferers. During the early 1970s what had been science fiction became fact as the use of DNA synthesis, restriction enzymes, and plasmids were integrated. In 1973 Stanley Cohen and Herbert Boyer successfully transferred a section of DNA from one E. coli bacterium to another. A few prophets such as Joshua Lederberg and Walter Gilbert argued that the new biological techniques of recombinant DNA might be ideal for making synthetic versions of expensive proteins such as insulin and interferon through their expression in bacterial cells. Small companies, such as Cetus and Genentech in California and Biogen in Cambridge, Massachusetts, were established to develop the techniques. In many cases discoveries made by small ‘‘boutique’’ companies were developed for the market by large, more established, pharmaceutical organizations.

Many governments were impressed by these advances in molecular genetics, which seemed to make biotechnology a potential counterpart to information technology in a third industrial revolution. These inspired hopes of industrial production of proteins identical to those produced in the human body that could be used to treat genetic diseases. There was also hope that industrially useful materials such as alcohol, plastics (biopolymers), or ready-colored fibers might be made in plants, and thus the attractions of a potentially new agricultural era might be as great as the implications for medicine. At a time of concern over low agricultural prices, such hopes were doubly welcome. Indeed, the agricultural benefits sometimes overshadowed the medical implications.

The mechanism for the transfer of enthusiasm from engineering fermenters to engineering genes was the New York Stock Exchange. At the end of the 1970s, new tax laws encouraged already adventurous U.S. investors to put money into small companies whose stock value might grow faster than their profits. The brokerage firm E. F. Hutton saw the potential for the new molecular biology companies such as Biogen and Cetus. Stock market interest in companies promising to make new biological entities was spurred by the 1980 decision of the U.S. Supreme Court to permit the patenting of a new organism. The patent was awarded to the Exxon researcher Ananda Chakrabarty for an organism that metabolized hydrocarbon waste. This event signaled the commercial potential of biotechnology to business and governments around the world. By the early 1980s there were widespread hopes that the protein interferon, made with some novel organism, would provide a cure for cancer. The development of monoclonal antibody technology that grew out of the work of Georges J. F. Kohler and Cesar Milstein in Cambridge (co-recipients with Niels K. Jerne of the Nobel Prize in medicine in 1986) seemed to offer new prospects for precise attacks on particular cells.

The fear of excessive regulatory controls encouraged business and scientific leaders to express optimistic projections about the potential of biotechnology. The early days of biotechnology were fired by hopes of medical products and high-value pharmaceuticals. Human insulin and interferon were early products, and a second generation included the anti-blood clotting agent tPA and the antianemia drug erythropoietin. Biotechnology was also used to help identify potential new drugs that might be made chemically, or synthetically.

At the same time agricultural products were also being developed. Three early products that each raised substantial problems were bacteria which inhibited the formation of frost on the leaves of strawberry plants (ice-minus bacteria), genetically modified plants including tomatoes and rapeseed, and the hormone bovine somatrotropin (BST) produced in genetically modified bacteria and administered to cattle in the U.S. to increase milk yields. By 1999 half the soy beans and one third of the corn grown in the U.S. were modified. Although the global spread of such products would arouse the best known concern at the end of the century, the use of the ice-minus bacteria— the first authorized release of a genetically engineered organism into the environment—had previously raised anxiety in the U.S. in the 1980s.

In 1997 Dolly the sheep was cloned from an adult mother in the Roslin agricultural research institute outside Edinburgh, Scotland. This work was inspired by the need to find a way of reproducing sheep engineered to express human proteins in their milk. However, the public interest was not so much in the cloning of sheep that had just been achieved as in the cloning of people, which had not. As in the Middle Ages when deformed creatures had been seen as monsters and portents of natural disasters, Dolly was similarly seen as monster and as a portent of human cloning.

The name Frankenstein, recalled from the story written by Mary Shelley at the beginning of the nineteenth century and from the movies of the 1930s, was once again familiar at the end of the twentieth century. Shelley had written in the shadow of Stahl’s theories. The continued appeal of this book embodies the continuity of the fears of artificial life and the anxiety over hubris. To this has been linked a more mundane suspicion of the blending of commerce and the exploitation of life. Discussion of biotechnology at the end of the twentieth century was therefore colored by questions of whose assurances of good intent and reassurance of safety could be trusted.

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research paper in biotechnology

ORIGINAL RESEARCH article

Effect of novel polyethylene insert configurations on boneimplant micromotion and contact stresses in total ankle replacement prostheses: a finite element analysis provisionally accepted.

  • 1 Zhangjiagang Fifth People's Hospital, China
  • 2 Dongying People’s Hospital, China
  • 3 Jingxian Hospital, China
  • 4 Affiliated Hospital of Zunyi Medical University, China
  • 5 First Affiliated Hospital, School of Medicine, Zhejiang University, China

The final, formatted version of the article will be published soon.

Artificial ankle replacement (TAR) has been in existence for decades. TAR has preserved the function of the affected limb for osteoarthritis patients and has become an alternative to ankle arthrodesis. However, TAR has the disadvantage of a high revision rate, which has caused certain obstacles to the promotion of this technology.Considering that the main cause of TAR failure is prosthesis loosening, in order to prolong the TAR survival rate, the reduction of prosthesis micromotion becomes the focus of scholars. In our research this time, we followed the design idea of elastic optimization and developed 3 new inserts. In the new inserts, flexible materials are embedded in ordinary UHMWPE materials, which increases the elasticity of the inserts and can absorb more kinetic energy can reduce the bone-implant interface micromotion and joint surface contact stress, which provides a valuable reference for the development of a new generation of artificial ankle prosthesis. I hope this paper is suitable for Frontiers in Bioengineering and Biotechnology.We deeply appreciate your consideration of our manuscript, and we look forward to receiving comments from the reviewers. If you have any queries, please don't hesitate to contact me at the address below.

Keywords: Total ankle replacement, artificial ankle, insert, elasticity improvement, Finite Element Analysis

Received: 17 Jan 2024; Accepted: 01 Apr 2024.

Copyright: © 2024 Xu, Gong, Hu, Bian, Jin and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Zhi Xu, Zhangjiagang Fifth People's Hospital, Zhangjiagang, China

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Nano-biotechnology, an applicable approach for sustainable future

Nikta shahcheraghi.

1 Department of Engineering, University of Science and Culture, Tehran, Iran

Hasti Golchin

2 Faculty of Biological Sciences, Kharazmi University, No.43.South Moffateh Ave., 15719-14911 Tehran, Iran

Zahra Sadri

Yasaman tabari.

3 Faculty of Sciences and Advanced Technologies, Science and Culture University, 1461968151 Tehran, Iran

Forough Borhanifar

Shadi makani.

Nanotechnology is one of the most emerging fields of research within recent decades and is based upon the exploitation of nano-sized materials (e.g., nanoparticles, nanotubes, nanomembranes, nanowires, nanofibers and so on) in various operational fields. Nanomaterials have multiple advantages, including high stability, target selectivity, and plasticity. Diverse biotic (e.g., Capsid of viruses and algae) and abiotic (e.g., Carbon, silver, gold and etc.) materials can be utilized in the synthesis process of nanomaterials. “Nanobiotechnology” is the combination of nanotechnology and biotechnology disciplines. Nano-based approaches are developed to improve the traditional biotechnological methods and overcome their limitations, such as the side effects caused by conventional therapies. Several studies have reported that nanobiotechnology has remarkably enhanced the efficiency of various techniques, including drug delivery, water and soil remediation, and enzymatic processes. In this review, techniques that benefit the most from nano-biotechnological approaches, are categorized into four major fields: medical, industrial, agricultural, and environmental.

Introduction

The development process of a sustainable future generally consists of methods that ensure the satisfaction of future needs, while fulfills the current generation’s requirements (Raghav et al. 2020 ). To obtain a proper overview of upcoming demands in the future, it is important to anticipate future stressors (e.g., climate change) (Iwaniec et al. 2020 ). Since nanotechnology is applicable in various majors, it is expected that nano-based techniques will take a key role in a sustainable future (Raghav et al. 2020 ), along with making substantial impacts on the universal economic situation due to their wide range of applications in variant industries (Adam and Youssef 2019 ). The unification of diverse fields in science, Inspired by the oneness of nature, is one of the most noticeable subject matters now in the early twenty-first century. Merging four massively operational fields of science has received great attention in recent decades: nanotechnology, biotechnology, information technology, and cognitive sciences (NBIC), which are known as “convergent technologies” (Roco and Bainbridge 2013 ). Non-renewable sources don’t seem efficient for providing large amounts of energy required in various industrial technologies. Convergent technologies are considered as a remedy for this issue. For instance, several nano-based technologies, which consume biological-renewable energy sources, have been introduced (Zhironkin et al. 2019 ). The unification of material on nanoscale makes the mentioned combination of multiple technologies possible. Hence, nanotechnology plays a critical role in NBIC advancement (Roco and Bainbridge 2013 ). According to the definition set by National Nanotechnology Initiatives in 1999, Nanotechnology is an advanced area of research that allows for the production of a wide class of materials in the nanoscale range (less than 100 nm) to make use of size-and structure-dependent properties and phenomena (Luo et al. 2020 ). Although “nano” is defined as that which is less than 100 nm in size, the use of this definition in the biomedical field is less strict and instead may encompass particles up to 1000 nm in size (Landowski et al. 2020 ). Nanotechnology has a wide range of applications, including Agricultural usages (Ndlovu et al. 2020 ), biofuel production (Zahed et al. 2021a ), cancer Immunotherapy (Goracci et al. 2020 ), carbon capture (Zahed et al. 2021b ) and biomarker detection like nanobiochips, nanoelectrodes, or nanobiosensors (Bayda et al. 2020 ). Nanomaterials (NMs) are chemical substances or materials that are manufactured and used at a very small scale, i.e., 1–100 nm in at least one dimension. NMs are categorized according to their dimensionality, morphology, state, and chemical composition (Saleh 2020 ). NMs can be used for rapid extraction of RNA of the novel coronavirus (Kailasa et al. 2021 ). Expanding nanoscience through various branches can eventually enhance the intelligence and capability of individuals, solve various social issues, cure numerous diseases, and generally improve the quality of mankind's life in the long term (Roco and Bainbridge 2013 ). Deploying nanotechnology into biotechnology will help the commercialization process of nano-based techniques and make them more practical in the industry (Maine et al. 2014 ). The idea of developing interdisciplinary research (IDR) (Jang et al. 2018 ) in science presents a promising landscape of the future, in which human intelligence has reached such high levels that the term “superhuman” would be more proper for humankind. According to the Israeli philosopher Harari, with the appearance of a highly technologically advanced society, only individuals with great intelligence and technological advancements can survive through natural selection in society. He states that superhumans will be produced by society eventually, considering the logic of social Darwinism, and this will be a remarkable phenomenon of the twenty-first century (Mantatov et al. 2019 ). One massive application of nanobiotechnology is enhancing the efficiency of various therapies (Table ​ (Table1). 1 ). The application of nanobiotechnology in delivering chemical drugs or gene modifying agents to their target cells will increase the efficiency of the treatments and reduce the side effects remarkably. Within the previous two decades, RNA-based therapeutic methods, including messenger RNA (mRNA), microRNA, and small interfering RNA (siRNA), have been supremely developed. These therapeutic approaches are expected to be operative in the treatment and prevention of various diseases, such as cancers, genetic disorders, diabetes, inflammatory diseases, and neurodegenerative diseases (Lin et al. 2020 ). In the case of cancers, conventional therapies (surgery, chemotherapy, and irradiation) may cause severe side effects to patients, plus they are often inefficient for disease treatment (Hager et al. 2020 ). Loading anti-cancer drugs into nanomaterials provides a nano-based drug delivery system that detracts the side effects. Platinum (Pt) compounds are one of the most common anti-cancer drugs since 1978. Pt drugs directly aim at the DNA of the targeted cells, thus covering up the defects of the malformed DNA repair mechanisms in cancerous cells. Encapsulating Pt drugs into liposomes constructs a nano-based drug delivery system for treating cancers (Rottenberg et al. 2021 ). Gold nanoparticles (AuNPs) are advantageous options for cancer treatment and diagnosis. AuNPs are created in the size range between 1 and 150 nm and in various shapes, including nanorods (AuNRs), nanocages, nanostars, and nanoshells (AuNSs). AuNPs consist of high rates of biocapability and exhibit controlled patterns of medicine release in the drug delivery process. AuNPs consist of conduction electrons on their surfaces which get excited by certain wavelengths of light. This feature enables AuNPs to adsorb light and produce heat that is fatal to cells. Destroying the cancerous cells with the heat released under irradiation is called photothermal therapy (PTT) or photodynamic therapy (PDT) (D’Acunto et al. 2021 ).

Medical applications of nanobiotechnology

On the other hand, RNA-based therapies can regulate the expression of immune-relevant genes, therefore increasing anti-tumor immune responses directly. Several nanomaterials have been introduced that can deliver nucleic acid therapeutics to tumors and immune cells (Lin et al. 2020 ). There are biomimetic strategies for providing a co-delivery system that is capable of supporting both chemical and RNA-based therapies (Liu et al. 2019 ). Considering RNAs as therapeutic agents or drug targets requires precise knowledge about the 3D structure of specific RNAs. There are reliable algorithms for pronging the second structure of RNAs, but the tertiary architecture which determines the RNA’s functions is quite challenging to anticipate. Bioinformatics provides several methods for predicting the tertiary structures of RNAs such as Vfold, iFoldRNA, 3DRNA, and RNAComposer. They all face particular hurdles, but it should be noted that the field of computational RNA structure anticipation, has a bright future (Biesiada et al. 2016 ). RNA-based vaccines are quite impressive immunotherapeutic tools in cancer therapies. However, the in vivo delivery of synthesized mRNAs could face some obstacles. Encrusting mRNAs with a lipid-polyethylene glycol (lipid-PEG) shell increases the mRNA delivery rate up to 95% more than the conventional nanoparticle-free mRNA vaccines (Islam et al. 2021 ).

In RNA-based nano-techniques, utilizing large-sized RNAs faces several difficulties. Wang et al. have reported an interesting method of using gold nanoparticles (enriched by expanded genetic alphabet transcriptions) to increase the effectiveness of detecting the large natural or artificially synthesized RNAs through an RNA nano-based labeling technique. These techniques are highly dependent on the conjugation between nanoparticles and RNAs (Wang et al. 2020 ). Since gene sequencing is of great importance, multiple biotechnology-based diagnostic tools, including quantitative PCR, DNA barcoding, next-generation sequencing, and imaging techniques are commonly currently used. These methods are considered economically advantageous, along with providing a reliable diagnosis. Incorporating nano-based sensors with mentioned tools increases the sensitivity and spatiotemporal resolution, which are two fundamental features of the gene sequencing process (Kumar et al. 2020 ). Designing nano-based devices for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) has been promoted recently. Nanomaterials such as gold nanoparticles, magnetic nanoparticles, and graphene (G) significantly increase the accuracy and decrease the required time and costs. Hence, render beneficial tools for viral detection more effective compared to the traditional techniques. Nanoparticles are specified via anti-bodies to identify particular antigens on the surface of the virus. Suspected samples from the patient, air, and surface can get examined by nano-based serological or molecular diagnosis methods (Abdelhamid and Badr 2021 ).

Nanomaterials can be utilized in the form of membranes. Chemically or physically synthesized nanomembranes remarkably advance the conventional water purification techniques (Lohrasebi and Koslowski 2019 ; Kim et al. 2020 ). Incorporating nanomembranes with bioreactors is the basis of the membrane bioreactor (MBR) technique, which is exploited in wastewater reclamation (Ma et al. 2018 ). Eliminating pollutant components from the environment is one of the main purposes of nanobiotechnology (Table ​ (Table2). 2 ). In the agricultural fields, nano-bio technologically modified pesticides and fertilizers notably prevent crop loss. Nano-based bioremediation processes have been developed to reduce soil pollutions and are expected to improve both environmental and agricultural approaches (Usman et al. 2020 ). Several studies are expanding the idea of producing nano plants that show better biological performances (e.g., photosynthesis) compared to natural plants (Marchiol 2018 ) (Table ​ (Table3). 3 ). Enzymes empowered by nanomaterials have rendered higher recovery and productivity rates and thus are potentially able to act spotless in different industrial techniques (Adeel et al. 2018 ; Zhang et al. 2021 ) (Table ​ (Table4 4 ).

Environmental applications of nanobiotechnology

Agricultural applications of nanobiotechnology

Industrial applications of nanobiotechnology

The objective of this study is to review the applications of nanoscience in enhancing the efficiency of biotechnological methods (Fig.  1 ).

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Diverse Applications of Nanobiotechnology: multiple techniques, including Drug delivery-based therapies, remediating processes, and industrial nano-bio catalysts benefit from nano-scaled particles

Application of nano-based materials for drug delivery, therapeutic and diagnostic processes

One recently promoted technique in the gene therapy field is the application of the CRISPR/Cas9 systems, which has been indicated to be highly effective in the treatment of monogenic disorders, non-monogenic disorders, and infectious diseases. Emerging studies have suggested that nanocarriers, which are created from Polymer polyethyleneimine (PEI), are more efficient in delivering CRISPR/Cas9 systems to targeted cells compared to the viral carriers (Deng et al. 2019 ). Gene mutation-related diseases such as cancers and human immunodeficiency viruses are potentially treated by DNA-based vaccines. This type of vaccine enhances disease symptoms by delivering specific gene sequences-which are embedded in plasmids- to targeted cells. Despite having clinical utilization, DNA vaccines face limitations in delivering their genetic cargos to the target cells. Designing efficient nano-delivery systems will eliminate such deficiencies PEI (Lim et al. 2020 ). Virus-like nanoparticles (Jeevanandam et al. 2019 ) seem to form applicable nanocarriers for this purpose (Fig.  2 ).

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Encapsulating therapeutic agents within nanoparticles: embedding medicine or gene-modifying agents into the nanoparticles remarkably enhances the therapeutic efficiency along with diminishing potential side effects

Nanomaterials used in cancer diagnosis can be mainly divided into contrasting agents (magnetic, iron oxide and gold nanoparticles) and fluorescent agents (quantum dots). Some nanocarriers have inherent optical properties (such as carbon nanotubes, gold and magnetic nanoparticles) that can be converted into high energy to cells for destruction and can serve as nanotheranostics (Barani et al. 2021 ).

Nanomaterials used in smart drug delivery-based cancer therapies are categorized as organic and inorganic materials. Micelles, vesicles, multilamellar liposomes, and solid lipid nanoparticles are some examples of self-assembled organic nanomaterials. Other organic materials are not capable of self-assembling and need to be synthesized, such as nanotubes and dendrimers. Gold nanoparticles, quantum dots, mesoporous silica nanoparticles, and superparamagnetic iron oxide nanoparticles (SPIONs) are classified as inorganic nanomaterials (Lombardo et al. 2019 ). SPIONs are vastly utilized in therapeutic approaches, including cancer therapy, radiation therapy, and tissue engineering. SPIONs are synthesized through different physical, chemical, and biological methods. Bacteria and plants are the biomaterials upon which the biological method is based (Samrot et al. 2020 ). Nanoparticles containing both organic and inorganic materials (hybrid nanoparticles) have been indicated to be highly efficient, as well (Lombardo et al. 2019 ). Embedding targeting ligands (e.g., antibodies, peptides, aptamers, and small molecules) on the surface of nanoparticles assures the delivery of medicines to specific sites in the body, such as tumor tissues. The mentioned process is called: “targeted drug delivery system” (Doroudian et al. 2021 ). There are two types of targeting delivery: passive targeting and active targeting. In the passive form, the high aggregations of medicines at the tumor sites are related to the nano-scaled size of the nanocarriers. The tight junctions between epithelial cells of the vessel tissues prevent the nanoparticles from exiting the vessel. The cancerous cells loosen the tight junctions of the adjacent vessels. Therefore, nanocarriers can pass through the vessel and get into the tumor site. The targeting ligands incorporated with nanoparticles are not responsible for the passive targeting action. The binding between the targeting ligands and the particular receptors on the cancerous cells-which are exclusively found on the surface of the tumor cells- causes a more precise drug delivery, which is known as active targeting (Doroudian et al. 2019 ). Although drug-loaded nanoparticles efficiently carry the medicines to target cites, according to the in-vivo studies, these nanoparticles might not be quite biodegradable. Hence using such nanoparticles could lead to toxicities and side effects. It is worth mentioning that Zhou et al. have developed biodegradable nanoparticles using poly (aspartic acid) (PASP) microtube, a thin Fe intermediate layer, and a core of Zn (Zhou et al. 2019 ).

Nano-based drug delivery systems provide highly promising prospects for treating neurodegenerative disorders. It is reasonable to assume that treating neurological diseases by conventional drug delivery systems is extremely challenging due to the presence of the blood–brain barrier (BBB). The blood–brain barrier prevents the entrance of therapeutical agents to the central nervous system (CNS), therefore, making the conventional therapies inadequate. The blood–brain barrier provides a stable environment for the CNS and regulates the cell-to-cell interactions, which take place in the CNS. The dysfunction of the blood–brain barrier leads to severe neurodegenerative disorders (e.g., Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)). The blood–brain barrier is responsible for the proper functioning of the CNS, so naturally, it has a super-sensitive permeability. This feature of the blood–brain barrier is highly related to the tight junctions between the barrier’s cells. Only 1–4 percent of most CNS medicines succeed in passing the blood–brain barrier. Nanoparticles are more likely to pass the barrier because of their nano-scaled size. Encapsulating drugs in nanoparticles can significantly increase the drug transmission rate through the blood–brain barrier (Furtado et al. 2018 ). For instance, graphene, metals, carbon-nanotubes, and metal-oxides are the nanomaterials that can get exploited in the treatment procedure of patients with Alzheimer’s disease (AD). AD is caused by different genetic and environmental cues. Chemical and electrical malformations are observed in the brain of an AD patient. Acrine and physostigmine, which are conventional medicines for AD, have been proved to stimuli severe effects on the gastrointestinal tract and nervous system. Therefore, attention is drawn to nano-based therapies (Nawaz et al. 2021 ). Marcos-Contreras et al. have proposed that the augmentation of VCAM-1 ligands to the drug-loaded nanocarriers can significantly improve the cerebral accumulation rate of nanoparticles in inflamed brains (Marcos-Contreras et al. 2020 ) (Fig.  3 ).

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Nano-based drug delivery in the therapies of neurodegenerative disorders: blood–brain barrier (BBB) is a noticeable obstacle for conventional medicines; however, drugs encapsulated within nanoparticles efficiently penetrate through the BBB and reach the central nervous system (CNS)

Although nano-based medications of neurodegenerative disorders seem spotless theoretically, the internal environment of the body puts out several obstacles on the path of the medicine nano-delivering. For instance, lipid nanoparticles (LNPs) may safely carry their therapeutic cargos to the targeted cells, but if the drug needs to reach the cytoplasm, lipid nanoparticles are not capable of efficiently crossing the cell membrane. Small interfering RNAs (siRNAs) are delivered to hepatocytes via lipid nanoparticles, but only 2% of them accomplish reaching to the cytoplasm. It should be mentioned that big data and computational methods can help scientists to predict the in-vivo challenges of nano-drug delivery to design proper techniques to overcome them (Paunovska et al. 2019 ). Besides, bioinformatics provides tools for measuring the interaction rate between exploited nanomaterials and drug targets (Nawaz et al. 2021 ). Designing efficient nanomaterials is fundamental for nanotechnological approaches. Carbon nanotubes (CNTs) and graphene-based nanomaterials have been vastly utilized in nanotechnology during the last two decades (Kinloch et al. 2018 ). As a case in point, Single-walled carbon nanotubes (SWCNTs) are considered as excellent options for designing nano-based biomedical approaches, including but not limited to drug delivery systems. The most noticeable features of SWCNTs are their great photophysical properties (Farrera et al. 2017 ). Even though Carbon nanotubes (CNTs) and graphene-based nanomaterials have unique qualities such as high flexibility, they face some challenges in their load transfer capability, dispersion, and viscosity. Hence, creating more applicable and eco-friendly nanomaterials has drawn intense attention (Kinloch et al. 2018 ). AlNadhari et al. have introduced algae as a green and eco-friendly source of materials that can be used in nanoparticles. Algae-based nanoparticles in the biomedical field consist of therapeutical characteristics, such as antibacterial, anti-fungal, and anti-cancer features (AlNadhari et al. 2021 ). Milk-derived proteins such as β-lactoglobulin (β-LG), lactoferrin (LF), and the caseins (CN) are other biological alternatives for synthesizing nanocarriers. Anti-cancer medicines have been embedded into protein-based nanocarriers and successfully deteriorated cancerous tumors (Tavakoli et al. 2021 ). Azarakhsh et al. have demonstrated specific binding sites for the anti-cancer drug, Oxali-palladium (OX) and iron nanoparticles (NP) on the Beta-Casein (β-CN). Hence, the Beta-Casein can perform as an efficient carrier for both agents (Azarakhsh et al. 2021 ). One common strategy in designing nanocarriers for cancer therapies is to create nanoparticles that can detect the vitamin or growth factor receptors on target cells. Cancerous cells usually over-express the receptors for such nutrients so that they can keep their high proliferation rate (Peer et al. 2020 ). Reprogramming the nutrient signaling and micropinocytosis of the cancer cells seriously affects the efficacy of Nano-particulate albumin-bound paclitaxel (nab-paclitaxel, nab-PTX); which is one of the most commonly prescribed nanomedicines (Li et al. 2021 ).

Antimicrobial peptides (AMPs) are short-chain, often cationic, peptides possessing several attributes which make them attractive alternatives to conventional antibiotics with s a low likelihood of resistance developing in target organisms (Meikle et al. 2021 ). Conjugation and functionalization of nanoparticles with potentially active antimicrobial peptides has added advantages that widen their applications in the field of drug discovery as well as a delivery system, including imaging and diagnostics (Mohid and Bhunia 2021 ).

Silver nanoparticles coated with zinc oxide (Ag@ZnO), can stimulate proliferation and migration of human keratinocytes, HaCaT, with increased expression of Ki67 and vinculin at the leading edge of wounds. Interestingly, Ag@ZnO stimulates keratinocytes to produce the antimicrobial peptides hBD2 and RNase7, promoting antibacterial activity against both extracellular and intracellular Staphylococcus aureus isolated from wounds (Majhi et al. 2021 ).

Wound dressing is an important action against an injury. In recent years, nanotechnology has been combined with wound dressing techniques, and there are several new materials and techniques available for this action. The nanoparticles’ dimensions make them suitable for penetrating into the wound. Thus, bioactive agents and drugs can be released locally (De Luca et al. 2021 ). Numerous synthetic and natural materials have been applied for wound healing; Hyaluronic Acid, as an illustration, is one of the most-used materials (Ahire and Dicks 2016 ).

In 2017 Polyethylene Oxide (PEO)-hyaluronic acid (HA) nanofibers as an inhibitor of Listeria monocytogenes infection (Ahire et al. 2017a ). Gauze is a traditional wound dressing used to protect dermal wounds from bacterial infection. In a study in 2021, an antibacterial gauze was prepared by the combined use of antimicrobial peptides and AgNPs. The prepared antibacterial gauze showed excellent antibacterial activity against E.coli, S. enteritidis, S. aureus , and B. cereus and also exhibited good biocompatibility (Chen et al. 2021a , b ). In 2014, Ahire and Dicks introduced 2,3-Dihydroxybenzoic Acid-Containing Nanofiber as a suitable nanomaterial for wound dressing as it prevents Pseudomonas aeruginosa infection (Ahire and Dicks 2014 ). To inhibit the growth of this microorganism, Copper-Containing Anti-Biofilm Nanofiber Scaffolds can be used too. Copper-containing nanoparticles have the potential of inhibiting Escherichia coli growth either (Ahire et al. 2016 ). Surfactin-loaded nanofibers are also a great candidate to be used in wound dressings or in the coating of prosthetic devices to prevent biofilm formation and secondary infections (Ahire et al. 2017b ). In addition to nano-therapies, nano-diagnostic agents- metal nanoparticles- have been indicated to be highly applicable in the detection of viruses, including covid-19 (Fouad 2021 ). Several biotic [e.g., algae (AlNadhari et al. 2021 ) and viral capsid (Jeevanandam et al. 2019 )] and abiotic [e.g., gold, silver, graphene oxide, and zin oxide (Fouad 2021 )] nanomaterials have been reported to be applicable in biomedical processes. The combination of biotic and abiotic sources provides efficient nanomaterials as well. For example, the highly effective graphene-starch nanocomposites, are resulted from embedding graphene-based nanomaterials into the starch biopolymers (Mishra and Manral 2021 ). The delivery of therapeutics via nanoemulsions (NE) has shown striking results. Sánchez-Rubio et al. have successfully defeated deficiencies of vitamin E (e.g., hydrophobicity and low stability) by creating nanoemulsions comprising vitamin E. the sperm samples derived from the red deer’s epididymal tissue was treated with the mentioned nanoemulsions and the sperms’ viability and resistance against oxidative stress, was increased (Sánchez-Rubio et al., 2020 ). Jeong et al. have reported another growth-promoting method that elevates the maturation process of cultured cells. The mentioned technique aims to develop an extremely operational and cost-effective bioreactor that enables in-vitro maturation of heart tissue. Next-generation stage-top incubator (STI) containing nano grooves patterned PDMS diaphragm (NGPPD) was designed to boost cell maturation and myogenic differentiation. The surface of NGPPD was covered with a slim layer of gold (Au) (Jeong et al. 2021 ). Microfluidic systems are proven to have applications in biological analysis, tissue engineering, etc. Embedding nanolitre volumes into micro-sized fluidic channels is the basis of the aforementioned technique (Valencia et al. 2020 ).

Application of nanoparticles on bioreactors as contributory agents

Since wastewater reclamation is a universal challenge and plays a major role in providing clean water for many people across the world, various techniques have been developed for this purpose. Among them, the application of membrane bioreactors (MBRs) in water purification has attracted great attention recently. In the MBR technique, the conventional activated sludge (CAS) process is incorporated with a filtration process provided by a physicochemical membrane (Ma et al. 2018 ). It has been shown that treating the mentioned membrane with nanoparticles in different types of MBR techniques can significantly improve the efficiency of the process (Abass and Zhang 2020 ; Jiang et al. 2019 ). The pharmaceutical industry produces one of the most pollutant wastewaters; which contains various amounts of organic compounds, including benzene, polynuclear aromatic hydrocarbons (PAHs), and heterocyclic, etc. these compounds have high Chemical Oxygen Demand (COD) and low degradability; which makes conventional biological treatments inefficient for treating them. However, applying O 3 , O 3 /Fe 2+ , O 3 /nZVI (nano zerovalent iron) processes in wastewater purgation has made noticeable signs of progress. Nano catalytic ozonation process (O 3 /nZVI) in a semi-batch reactor has the highest effect on advancing degradation amongst all (Malik et al. 2019 ). An experiment conducted in southern Tehran succeeded in removing the Methyl Tertio Butyl Ether (MTBE) and benzene from groundwater, using Fenton’s chemical oxidation with stabilized nano zerovalent iron particles (S-NZVI) as a catalyst. The removal efficiency of MTBE and benzene were increased to 90% and 96%, respectively, by reducing the pH of the reaction environment down to 3.2. Acidification of the environment decreased iron consumption as well (Beryani et al. 2017 ).

Nano-bioremediation

One green and cost-effective approach for treating the pollutant soils to reduce their toxicity is applying living organisms (bacteria, fungi, plants, etc.) through a process named: “bioremediation.” Integrating bioremediation with nanoparticles increases the efficiency of the process (Usman et al. 2020 ). The technology of nano-remediation is a sustainable method to reduce the contaminants of the soil by various means (Yue et al. 2021 ; Sajjadi et al. 2021 ; Lian et al. 2021 ). As an example, the reduction of Cr (VI) levels using this technology is known to be worthwhile in many aspects (Azeez et al. 2020 ; He et al. 2020 ). Chemically active nanoparticles can trigger the dechlorination/dehalogenation process in organic pollutants and neutralize them, consequently. Even the toughest pollutants are targeted in this nano-bio-based remediation method. The time needed for the purgation of highly contaminated soils will be minimized by virtue of the mentioned technique (Usman et al. 2020 ). Iron oxide nanoparticles (NP) and Fe 3 O 4 /biochar nanocomposites are vastly exploited in the synthesis of nanoparticles of nano-bioremediation (Patra Shahi et al. 2021 ). It is worth noting that nano zerovalent iron (nZVI) is an effective technology in the case of remediation that has been applied broadly in recent years due to high levels of reactivity for contaminants (Luo et al. 2021 ; Visentin et al. 2020 ; Ken and Sinha 2020 ; Hou et al. 2019 ; Zhu et al. 2019 ).

The bioremediation process can be used in water purification as well. Separating solid components from liquid waste is a necessary stage in the water remediation process. The fresh market waste may contain infectious components, which can seriously harm humans and plants. Hence, it is important to develop methods to collect, separate, and treat these adverse agents. Solid wastes in the wastewater contain high amounts of carbohydrates and proteins, and they provide matrices for the colonization of infectious organisms. Altogether, the presence of solid wastes improves the growth rate of pathogenic organisms. After solid matters got collected, they should be stored and treated immediately. The treatment process must not be delayed because the enriched environment of the solid wastes can easily get corrupted. One way to treat them is through triggering the fermentation and composting processes. Adding effective microorganisms (EM), such as lactic acid/phototropic bacteria and yeast, accelerates the conventional fermentation and composting processes used for the solid waste treatment (Al-Gheethi et al. 2020 ). Costa et al. have sequenced the whole genome of the strain Streptomyces sp. Z38, and detected growth-promoting, heavy metal-eliminating, and anti-microbial features within specific biosynthetic genes. Streptomyces sp. Z38 seems to be a suitable agent for bioremediation due to its ability to decompose heavy metals such as Cr (VI) and Cd (II). Costa et al. have supplemented the bioactive water (BW) extracted from Streptomyces sp. Z38 with AgNO 3 additives and produced silver nanoparticles (AgNPs) that are capable of performing the bioremediation process (Costa et al. 2020 ). There are other effective nanomaterials exploited to reduce many pollutants from soil and wastewater. For instance, utilization of nano-manganese oxide to eliminate ZnII/CoII from water (Mahmoud et al. 2020 ), application of nano-semiconductors on water and their Photocatalytic effectiveness (Oliveira et al. 2021 ), nano-scaled Iron (II) sulfide exploited to reduce hexavalent chromium from soil (Tan et al. 2020 ), production of nanocomposite for eliminating viruses (Al-Attabi et al. 2019 ), and successful application of nano biosurfactants which cause no toxicity for the environment (Debnath et al. 2021 ). Nano-bioremediation as an emergent approach causes some concerns and benefits at the same time. It is possible that nanomaterials exploited in this method would be a threat to the organism populations that exist naturally in water bodies. On the other hand, new living organisms would be introduced through bioremediation. The mentioned two scenarios can potentially put the anthropogenic features of ecosystems in danger (Weijie et al. 2020 ). Concerning this problem, however, scientists are trying to apply new methods to remove nanoparticles from marine ecosystems via other technologies (Ebrahimbabaie et al. 2020 ).

Designing nano-based water purification techniques, to overcome the problem of lack of clean water, across the world

Waterborne diseases that cause almost 10–20 million deaths annually are considered crucial health-related issues. According to the World Health Organization and environmental protection agencies, the pollution level of several water bodies has long crossed the defined limitations. Thus, developing methods for purging water from adverse components is of great concern (Sahu et al. 2021 ). The water purification process profits extremely from nanobiotechnology. Nanoparticles are extremely efficient in eliminating pollutants (e.g., dye components) due to their nano-scaled size and increased surface areas. In the case of dye removal, magnetic nanoparticles have been proved to be proper candidates (Lohrasebi and Koslowski 2019 ). Nanoadsorbents such as silica gel, activated alumina, clays, limestone, chitosan, activated carbon, and zeolite are cost-effective and profitable options for eliminating the contaminating agents during water purification process (Ali et al. 2020 ).

Copper and copper compounds are potent biocides and have been utilized as a disinfectant for centuries due to their anti-microbial properties. It becomes more functional in its nano form and exhibits outstanding synergist, anti-fungal, and anti-bacterial effects (Bashir et al. 2021 ).

Copper nanoparticles have the potential of combination with other materials like Polyacrylonitrile (PAN) nanofibres and Polyethylene Terephthalate Filters to act more beneficial (Ahire and Neveling 2018 ; Nguyen et al. 2021 ).

Metallic nanomaterials, carbon-based nanomaterials, nanocomposites, and dendrimers are four major types of nanomaterials that can be applied in wastewater purgation (Murshid et al. 2021 ). Graphene-based nano-channels, which are inspired by aquaporin channels, have been utilized as water filters and are expected to enhance the water permeability and the salt rejection rate. It is worth noting that the efficiency of these filters can be affected by various factors. For example, it has been indicated that increasing the charges on the channel will decrease the water flow through the channel but, on the other hand, increase the ion rejection rate (Lohrasebi and Koslowski 2019 ). Carbon nanotubes (CNTs) have rendered noticeable results in eliminating the water contaminants, as well (Kutara et al. 2016 ).

The biosafety of water purification via finger-sized unit (FSU) has been certified by cellular and animal tests. In one study, Li et al. loaded 3D printed finger-sized units with prepared wheat straw (WS). To prepare WS for mentioned technique, the carbonized wheat straw (CWS) was adjusted with nano-scaled zinc oxide during an in-situ surface-modification process (CWS/ZnO). The resulted FSU was able to reduce bacteria, organic dyes, and heavy metal ions; therefore, elevating the purification efficiency. Since WS is one of the major agricultural wastes worldwide, applying it in water purification will not only cost very low but will reduce the air pollution which is caused by burning WS in many countries. The WS has a hallow, flexible, and electrical conductor structure. These features make WS a great candidate for enhancing water purification performance (Li et al. 2019 ).

For designing a nano-based filtering membrane, nanoparticles don’t always have to be chemically synthesized or externally applied on the membrane. An emerging study has suggested a top-down approach that uses biomass to provide a functional membrane for the purification of the emulsions. This method can be used massively in cleaning oily waters resulting from industrial or domestic activities. The biomass used in the mentioned technique is wood tissue. The lignin and hemicellulose fractions are removed sectionally, and therefore, a highly porous, flexible, and durable membrane is provided. Since the lignin is removed and there is no hydrophobia left, the resulting wood membrane consists of outstanding water-absorbing and anti-oil properties. The wood-nanotechnology-based membrane shows significant efficiency due to its numerous advantages, including being green, economical, easy to produce, durable, and having selective wettability (Kim et al. 2020 ).

Rezaei et al. have synthesized a flower-shaped ZnO/GO/Fe 3 O 4 ternary nanocomposite through the co-precipitation method, which is considered a rather fast and easy synthesis approach. The mentioned nanocomposite improves the ZnO degradation through a performance with an efficiency that is more than two times greater than the efficiency of the methods using ZnO particles alone. Hence, the ZnO/GO/Fe 3 O 4 ternary nanocomposite seems to be an economical and time-saving approach for wastewater remediation (Rezaei et al. 2021 ).

It is worth noting that the vast uses of nanoparticles in different industrial products increase the risk of the inevitable release of nanoparticles into the environment, and therefore cause some concerns about the potential damages of nanobiotechnology. The urban wastewater seems to be highly exposed to industrial nanoparticles. The high concentrations of nanoparticles in the urban wastewater contaminate the sewage sludge, consequently. Wastewater treatment plants (WWTPs) are currently exploited to remove nanoparticles from wastewater and sewage sludge (Wang and Chen 2016 ). Nanoparticles synthesized and utilized in the industry can end up in marine ecosystems. Nanoparticles are developed from various chemical components such as carbon, silver, gold, and copper, which are potentially hazardous to live organisms. Since nanoparticles are extremely small in size, likely, they will easily enter the bodies of aquatic animals. It has been demonstrated that the accumulation of nanoparticles in the animal’s body can cause severe morphological and behavioral deformities. Genetic materials of cells may undergo various changes as well (Gökçe 2021 ).

FeO ion, which is known as Nanoscale zerovalent iron particles (nZVI), is massively used in the synthesis of nanoparticles applied in wastewater nano-based treatments. Bensaida et al. have shown that combining nZVI with another metal (Cu) enhances the growth of the microbial populations in the wastewater treated with this nZVI\Cu bimetallic nanoparticles (Bensaida et al. 2021 ).

Exploiting nanobiotechnology-based methods in food industry

Nanotechnology-based pharmaceuticals were developed primarily, but wide applications of nanoscience in food and agricultural industries have been introduced as well (Sahani and Sharma 2020 ). Utilizing nanoscience in any stage of the food production process-either cultivation, production, post-harvest processing, or packaging—seems to be lucrative. The application of nano-based methods in the food industry has various advantages, but the most arguable of them would be its impact on shelf life augmentation and spoilage prevention (Bhuyan et al. 2019 ). Since Oxygen is known as an important cause of food spoilage in the food industry, scientists have developed the technology of advanced coatings based on nanotechnology to prevent Oxygen from spoiling the product (Rovera et al. 2020 ). Multiple nanoparticles have the potential to deliver nutritional or antimicrobial components into food materials (Bhuyan et al. 2019 ). It has been reported that nanotechnology is a good option to deliver pesticides and nutrients successfully into the soil and improve the strength and tolerance of products in different stressful situations and reduce the probable contaminations (Ali et al. 2021 ). Among different nanoparticles such as silver, titanium dioxide, and zinc oxide, nanoliposomes are found to be small and have a large surface area which makes them more adhesive to biological tissues- therefore more bioavailable in comparison to others. Nanoliposomes are suitable candidates for creating a delivery system during food preparation. Food provided with the help of nanotechnology is called “Nano food” (Bhuyan et al. 2019 ). Nano foods can perform as therapeutic options. It is interesting to mention a recent study that has proposed exploiting nanoemulsions to convey needed nutrients to gastrectomy patients. These types of patients usually suffer from conditions like anorexia, energy deficit, and malnutrition, which can be treated by efficient nutrition delivery provided by nano food (Razavi et al. 2020 ). As mentioned earlier, in the food preparation process, antimicrobial components can be delivered along with nutritional components via a nano-based delivery system. Polyphenols are great examples of substantial antioxidant and antimicrobial agents in the food industry. Nevertheless, polyphenols have some limitations, including instability, low solubility, inefficient bioavailability, and being drastically susceptible to being degraded. There are several factors that reinforce degradation: Oxygen, light, pH, and interactions between polyphenols and other components in food. Polyphenol-loaded nanoparticles relatively overcome the mentioned obstacles due to their capacity to protect phenolic compounds against degrading processes (Milinčić et al. 2019 ). As a renewable and biodegradable source, starch is a useful polymer that has been applied in different fields such as the pharmaceutical and food industries. Nano-size starch is an advanced material with new abilities in the matter of hydrophobicity and stability (Wang and Zhang 2020 ). In the field of the food industry, there are also many other new methods based on nanotechnology, for instance, designing natural proteins as nano-architectures to deliver nutraceuticals (Tang 2021 ), new strategies for packaging food products by exploitation of the knowledge of nano-biotechnology, and nanomaterials (Reshmy et al. 2021 ; Jogee et al. 2021 ; Tiwari et al. 2021 ), utilization of the nano-delivery techniques to overcome the problems of consuming bioactive ingredients (Hosseini et al. 2021 ; Ozogul et al. 2021 ), producing nanoparticles in the shape of powder using the nanospray driers (Jafari et al. 2021 ), detection of food contaminants by nano-Ag combinations (Yao et al. 2021 ), and even the application of nano-engineering in the field of the beverage industry (Saari and Chua 2020 ).

Nano-bio catalysts; an attempt to remove the barriers of enzymatic bioprocesses in the biotechnology industry

Organic enzymes, which are normally found in nature, have large applications in the biotechnology industry. Since organic enzymes are green and eco-friendly, they are usually preferred to commercially synthesized enzymes. Pectinase is considered to be extremely useful for manufacturing purposes. Pectinase application in industrial bioprocesses covers a large range from clarification of juice/ wine and tea/coffee fermentation to wastewater and industrial waste remediation. All enzymes- regardless of being organic or chemically synthesized- consist of limitations that make their usage challenging. Three major disadvantages of enzymes are inefficient recoverability, operational stability, and recyclability (Zhang et al. 2021 ). Functional nanomaterial-based bio-carriers render a proper environment for the enzymatic immobilization process, therefore facilitating recovery and recycling of enzymes and enhancing the efficiency of bioprocesses in the long run. Accordingly, designing nano-based carriers with these features has been attracted great attention. To achieve this aim, Graphene- immobilized nano-bio-catalysts have been proved to be greatly useful due to the Graphene’s characteristics: electrical, optical, thermal, and mechanical high potency (Adeel et al. 2018 ; Zhang et al. 2021 ).

Nanomaterial-based nanocatalysts are useful in optimizing the biodiesel production process. This ability is related to the features of nano-scaled materials, including crystallisability, high adsorption and storage potential, having catalytic activities, and great stability and durability. Various materials can be used to create nanoparticles for this mean; some examples are metal oxide (calcium, magnesium oxide, and strontium oxide), Magnetic material, and Carbon. Carbon-based nanomaterials consist of multiple types, such as carbon nanotubes, carbon nanofibers, graphene oxide, and biochar.

All examples mentioned above have been proved to be highly effective in increasing the efficiency of the biodiesel synthesizing process and reducing the time and cost required for operating the process without utilizing nanotechnology (Nizami and Rehan 2018 ).

Replacing non-renewable energy sources with renewable ones is a great step in guaranteeing a sustainable future. Various devices, including solar and fuel cells, have been developed for this purpose. Conventional fuel cells are made from metal reactants instead of fossil fuels. They provide an electron circulation, transfer electrons from the substrate to specific electrodes, and eventually produce sustainable energy. The metals used as catalysts in fuel cells (e.g., hydrogen, methane, and methanol) are usually expensive and non-durable. On the other hand, biofuel cells use cost-effective bio-catalysts (e.g., microbes and enzymes) instead of metal catalysts. Despite the mentioned advantages, biofuel cells have one major limitation: the low rate of electron transfer between substrate and electrodes, which is significantly enhanced by supplementing biofuel cells with nanomaterials. Nanomaterials are able to assemble the substrate (e.g., enzymes) with the electrodes. In other words, using them in the structure of electrodes, the electron absorption of electrodes improves- related to the high surface area rate of nanomaterials- therefore, a direct transition of electrons between enzymes and electrodes develops. Silver nanoparticles-Graphene oxide (Ag-GO), Graphite, Carbon-nanotube forest (CNTF), Carbon nanotube (CNT), and Nitrogen-doped hollow nanospheres with large pores (pNHCSs) are the nanomaterials applied in nano- biofuel cells. Respectively, Glucose oxidase (GO x ), Glucose oxidase and Laccase, Fructose dehydrogenase & laccase, Glucose oxidase and laccase, and NADH dehydrogenase form the enzymatic system of each nanomaterial (Sharma et al. 2021 ).

Metal–organic frameworks (MOFs); highly advantageous materials

Porous materials are known to be highly advantageous due to their high absorption and surface areas. Zeolites, activated carbons, and silicas are examples of this family, but the most eminent member among them are Metal–organic frameworks (MOFs). MOFs have features that make them unique for several applications. For example, MOFs show a high absorption rate, which is caused by their high surface areas. Another property of MOFs is their possession of several adjustable microporous channels, which makes it easy to produce different and changeable functional sites through them. The latest feature brings MOFs the shape and size selectivity. By controlling the starting materials and reaction parameters, it is possible to determine the morphology of MOFs (Kinik et al. 2020 ; Jun et al. 2020 ) into various shapes, including granule, pellet, thin-film, gel, foam, paper sheet, monolith, and hollow structures (Kinik et al. 2020 ).

There are two types of MOFs: (1) neutral MOFs and (2) ionic MOFs. Ionic MOFs are able to be used directly in anion purgation processes. For example, one approach for reducing the pollutant anions from the environment is synthesizing a cationic framework along with extra-framework anions. The synthesis of mentioned frameworks occurs by utilizing neutral nitrogen donors. The extra-framework anions will exchange with pollutant anions through an Ion exchange process called: “Anion trapping”.

Anions are extremely abundant in nature. One of the most pollutant and hazardous anions is phosphates. These toxic anions are highly used in pesticides. Other examples of toxic anions, which are considerably frequent in industrial wastes, are the bulky anions. These are the dye molecules exploited in industry. Various diseases like cancers, lung/kidney dysfunction, and brain diseases, including Alzheimer’s, are caused by dangerous anions like those mentioned above. Hence, creating methods that are able to recognize and delete the perilous anions from the environment is one of the most appreciated scientific approaches. MOFs have been proved to be functional for this mean (Desai et al. 2019 ).

Since MOFs have considerable surface areas and modifiable structure—different open metal sites and other functional groups can be introduced into their frameworks—they are suitable options for numerous applications which are generally related to detection and storage. In the case of storage, they exhibit acceptable physical adsorption for CO 2 (one of the major causes of global warming), H 2 (a clean energy source), and Methane (CH 4 ). The ability to adsorb variant components makes MOFs proper for water purification applications. Several toxic and harmful components which are responsible for water contamination, including organic pollutants (like dyes and oils) and heavy metal ions, can be detected, adsorbed, and removed by MOFs. Introducing different chemical groups into MOFs creates different internal interactions, which enable MOFs to detect target molecules functionally. Therefore, they can be used in active centers of catalysts, photocatalysts, and biosensors (Kinik et al. 2020 ).

MOFs-based nanozymes

Nanozymes are classified into two types: (1) natural enzymes that are incorporated with nanomaterials and (2) nanomaterials that exhibit inherent enzymatic features. Exploiting MOFs as nanomaterials in nanozyme structures will produce an emergent form of nanozymes, called: “MOF-based nanozymes”; which have multiple advantages over conventional forms. MOFs provide more catalytic sites, simplify the entrance of small substrate molecules -due to their porous structure-, enhance the substrate exclusivity, and altogether improve the catalytic function of enzymes. MOF-based nanozymes are effective in designing biosensors, biocatalysis, and biomedical imaging techniques. A recent promising application of them is in cancer therapy which reduces side effects significantly (Ding et al. 2020 ).

Agricultural usages of nanobiotechnology

Applying nanobiotechnology in agriculture to improve the agricultural production rate has been of great importance recently. Achieving this purpose will solve several problems related to the universal hunger dilemma. Several nanofertilizers, nano pesticides, and nano-bio sensors have been created, which are able to increase crop value and decrease crop loss caused by agricultural pests (Usman et al. 2020 ). Conventional chemical pesticides and fertilizers can be deteriorative for soil composition and fertility. This happens because chemical residues can target many molecules other than the ones that have been defined as their main targets (Chhipa 2019 ). Besides, pesticides can have ruinous impacts on the microorganisms that naturally exist in the environment and are required for the crop’s growth (Nehra et al. 2021 ). Utilizing nanoparticles can considerably reduce such unwanted events due to the high exclusivity of these particles. Silver, zinc, iron, titanium, phosphorus, molybdenum, and polymer are suitable materials to be used in the structure of agricultural nanoparticles (Chhipa 2019 ). Nanoparticles containing nutrients, fertilizers, and pesticides, can be sprayed externally to the plant. The folium will adsorb the nanoparticles and send them to the soil (Chugh et al. 2021 ).

Another application of nanobiotechnology in diminishing the damages of some traditional pesticides is designing nano-bio sensors that can efficiently detect toxic pesticides. Dichlorvos is one of these toxic pesticides that accumulate in the air, soil, water, and crops; and therefore causes neural, genetical, respirational, and muscular disorders. Dichlorvos-sensitive Nano-biosensors comprise immobilized enzymes embedded in nanomaterials. Acetylcholinesterase (AChE), tyrosinase enzymes, and some others are options for the enzymatic part of the nanodevice. For the nano- matrix section, both organic (carbon, graphene, chitosan, and onion membrane) and inorganic (silver, gold, silica, and Titania) options are available (Mishra et al. 2021 ). Nanomaterials can enhance the remediation process of contaminated soils through distinct abiotic and biotic directions, including the nano-bioremediation process (Usman et al. 2020 ).

Other than improving the functions of existed plants, the possibility of introducing engineered plants with better performances has been discussed recently. The term “plant nano bionics” refers to a pioneering idea of involving nanoparticles in living plants to make their intrinsic functions adjustable. The landscape of this idea is designing engineered artificial photosynthetic systems, enhancing the growth rate of this new type of plant, and many other novel applications which are expected to grow extremely in the years ahead (Marchiol 2018 ).

It is necessary to mention that inorganic nanoparticles that may be found in consumer products, may alter the gut composition and could lead to various gut-related diseases. Thus, there have to be some limitations in nanoparticle agricultural usages (Gangadoo et al. 2021 ; Ghebretatios et al. 2021 ).

Using nanoparticles in cosmetic products

Nowadays, due to special and distinctive physicochemical characteristics, nanomaterials are being vastly used in different industries. Recent studies are focused on applying nano-based technologies to improve the quality of cosmetic products. Nanostructures are about to deliver active ingredients to the skin. For this reason, it is more suitable to use lipid particles that are better adaptable to dermal absorption. The high stability of the combination of nanomaterials and lipid particles with cosmetic components indicates high efficiency. However, the probable risks of this method should not be ignored (Benrabah et al. 2020 ; Khezri et al. 2018 ). Producing nanoparticles using plants (Phyto-metal nano-based particles) is another advantageous method to decrease the toxicity of nanomaterials and their hazardous effects on the body. For this reason, this material is suitable for dermal uses and cosmetic applications (Paiva-Santos et al. 2021 ). Chitosan nanoparticles with better penetrability (Ta et al. 2021 ; Sakulwech et al. 2018 ), Gold and silver nanoparticles with a higher ability to reduce microbial contaminants (Séby 2021 ), Titanium dioxide (TiO 2 ) nanoparticles deposited with yttrium oxide (Y 2 O 3 ) with better attenuation of ultraviolet radiation and less cytotoxicity (Borrás et al. 2020 ), nanoparticles with high uptake of oily components (de Azevedo Stavale et al. 2019 ) are other examples of the efficient application of nanotechnology in the field of cosmetic products.

Since nanoparticles are small in size, they exhibit perfect penetrability through the skin. Hence, using nanoparticles in cosmetic productions improves the supplementation of skin, hair, or teeth with active cosmetic ingredients (APIs). It is important to note that utilizing nanoparticles for several applications, as an emerging field of science, causes various concerns about being toxic or harmful for the body or the environment. The cosmetic industry’s products are commonly designed for skin, hair, nail, teeth, and therefore, are directly related to the health of the human body. Thus, it is reasonable to assume that there are even more concerns about using nanoparticles in this industry compared to others (Santos et al. 2019 ).

In addition to these cases, nanotechnology can be useful for the detection of harmful components in cosmetic ingredients. Therefore the application of methods like covered iron oxide nanoparticles with silver for detection of mercury contamination in cosmetics (Chen et al. 2021a , b ), Quantitative assessment of the Triamcinolone acetonide (TCA) (which is a hazardous component in high doses) using nanoparticles with luminescence property (Zhang et al. 2019a ), And detection of harmful N-nitrosamines with the utilization of magnetic nanoparticles (Miralles et al. 2019 ) are worth mentioning.

Oil industry benefits from multiple types of nanomaterials

Nanomaterials can play a major role in the advancement of the oil industry. Almost every form of nanomaterial—discussed in previous sections—has been exhibited to have numerous applications in the oil industry. Nanomaterial can be effectively exploited in various processes of this industry, including oil exploration/production and recovering the oilfield. Nanofluids (synthesized from nanomaterials) optimize the oil production process. Nanocatalysts have applications in petrochemical processes along with operating an efficient oil purgation function. Several applications of this technology are mentioned below.

There are nanomembranes designed to provide a proper matrix for separating water and oil from gas. They eventually purify the gas and delete redundant components from wastewater (Saleh 2018 ). Metal workings such as machining and stamping industry require some types of lubricants and coolants, which are mostly oil products. There has been produced an oil-based cutting fluid made up of Al 2 O 3 nanoparticles to decrease the friction force between the object and snipping tool (Subhedar et al. 2021 ). Encapsulation of extracted essential oil from hyssop in a nano-complex improves the antioxidant and antifungal efficiency of the oil (Hadidi et al. 2021 ). The application of nano-silica in the procedure of oil cementing enhances the resistance of the cement (Goyal et al. 2021 ; Thakkar et al. 2020 ). In the process of oil recovery, there is a high energy loss that imposes damages to the injection system and lowers the heat level. To keep the rate of temperature in a higher range and decrease the energy loss, scientists have applied nano-thermal insulators that are more economical (Afra et al. 2021 ; Zhao et al. 2021 ; Zhou et al. 2020 ). Gas and oil products can be cleaned from H 2 S by applying nanomaterials (Agarwal and Sudharsan 2021 ). Utilizing starch nano coatings (Wang et al. 2021 ), Lignin and nano-silica (Gong et al. 2021 ), Lotus leaf coated with nano-SiO 2 (Yang et al. 2021 ), and nano zeolite membrane are new methods for the separation of oil and water due to their high hydrophobic property (Anis et al. 2021 ). Nanotechnology can be used to improve the quality of engine oil, which results in the better stability and lubricity power as well as a reduced rate of released carbon mono oxide (Tonk 2021 ; Saidi et al. 2021 ; Thirugnanam et al. 2021 ; Ardebili et al. 2020 ). Advanced nanoemulsions show high stability and benefits for the oil industry due to the larger surface and the ability to wet (Kumar et al. 2021 ). Encapsulation of essential oils in nanostructures indicates a better performance as a pesticide due to better maintenance of the oil (Campolo et al. 2020 ). Producing an oil-in-water emulsion by applying protein nanoparticles can protect unstable and active ingredients and benefit the medicine and food industry (Xu et al. 2020 ).

Combining diverse fields of science in a manner that they overcome each other’s deficiencies indicates promising results. Within the last decades, biotechnology has made a lot of progress. Merging nanotechnology with biotechnological methods enables scientists to design less time taking, more economical, and more efficient techniques. This Nano-biotechnological approach influences multiple therapeutic, agricultural, environmental, and industrial methods. For instance, the effectiveness of the emergent crisper/cas9 systems increases noticeably by applying the nano-scaled additives at the process.

In this review, we investigated the current advancements and limitations of biotechnology, along with the nano-based alternatives rendered by nanotechnology. It seems highly probable that biotechnology will accomplish even more improvements in the future, and its incorporation with nanotechnology gets humankind one step closer to a sustainable future. Besides, the nano-based techniques are less costly compared to the conventional ones. Thus, with nano-biotechnology promoting, a revolution in the economic situation of the world is not implausible.

Author contributions

All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript.

Declarations

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Contributor Information

Nikta Shahcheraghi, Email: [email protected] .

Hasti Golchin, Email: moc.liamg@87nihclogitsah .

Zahra Sadri, Email: moc.liamg@6707irdasarhaz .

Yasaman Tabari, Email: [email protected] .

Forough Borhanifar, Email: [email protected] .

Shadi Makani, Email: [email protected] .

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  • Published: 27 March 2024

The complex polyploid genome architecture of sugarcane

  • A. L. Healey   ORCID: orcid.org/0000-0002-3088-6856 1 ,
  • O. Garsmeur 2 , 3 ,
  • J. T. Lovell   ORCID: orcid.org/0000-0002-8938-1166 1 , 4 ,
  • S. Shengquiang   ORCID: orcid.org/0000-0002-4336-8994 4 ,
  • A. Sreedasyam   ORCID: orcid.org/0000-0001-7336-7012 1 ,
  • J. Jenkins   ORCID: orcid.org/0000-0002-7943-3997 1 ,
  • C. B. Plott   ORCID: orcid.org/0000-0002-0109-5174 1 ,
  • N. Piperidis   ORCID: orcid.org/0000-0002-7880-7870 5 ,
  • N. Pompidor 2 , 3 ,
  • V. Llaca   ORCID: orcid.org/0000-0003-4822-2924 6 ,
  • C. J. Metcalfe   ORCID: orcid.org/0000-0001-9375-3332 7 ,
  • J. Doležel   ORCID: orcid.org/0000-0002-6263-0492 8 ,
  • P. Cápal 8 ,
  • J. W. Carlson 4 ,
  • J. Y. Hoarau   ORCID: orcid.org/0000-0001-9734-4165 2 , 3 , 9 ,
  • C. Hervouet   ORCID: orcid.org/0009-0000-5225-7244 2 , 3 ,
  • C. Zini 2 , 3 ,
  • A. Dievart   ORCID: orcid.org/0000-0001-9460-4638 2 , 3 ,
  • A. Lipzen 4 ,
  • M. Williams 1 ,
  • L. B. Boston 1 ,
  • J. Webber 1 ,
  • K. Keymanesh 4 ,
  • S. Tejomurthula 4 ,
  • S. Rajasekar 10 ,
  • R. Suchecki   ORCID: orcid.org/0000-0003-4992-9497 11 ,
  • A. Furtado   ORCID: orcid.org/0000-0001-6130-9026 12 ,
  • P. Parakkal 6 ,
  • B. A. Simmons   ORCID: orcid.org/0000-0002-1332-1810 12 , 13 ,
  • K. Barry   ORCID: orcid.org/0000-0002-8999-6785 4 ,
  • R. J. Henry   ORCID: orcid.org/0000-0002-4060-0292 12 , 14 ,
  • J. Grimwood   ORCID: orcid.org/0000-0002-8356-8325 1 ,
  • K. S. Aitken   ORCID: orcid.org/0000-0003-4372-0721 7 ,
  • J. Schmutz   ORCID: orcid.org/0000-0001-8062-9172 1 , 4 &
  • A. D’Hont   ORCID: orcid.org/0000-0002-5318-921X 2 , 3  

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  • Agriculture
  • Genome evolution
  • Genome informatics
  • Plant genetics
  • Polyploidy in plants

Sugarcane, the world’s most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide 1 . While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued 2 . The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species ( Saccharum officinarum ) and the wild species ( Saccharum spontaneum ). In contrast to the existing single haplotype (‘monoploid’) representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.

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Sugarcane domestication began approximately 10,000 years ago with the first ‘sweet’ cultivars ( Saccharum officinarum ) derived from Saccharum robustum 3 . Modern day cultivars, however, are all derived from a few interspecific hybridizations performed by breeders a century ago between ‘sweet’ octoploid S. officinarum and the ‘wild’ polyploid Saccharum spontaneum . Sugarcane interspecific hybridization has provided major breakthroughs in disease resistance and adaptation to otherwise stressful environmental conditions. However, early generation hybrids also had much lower sugar yield, owing to the large wild genomic contribution. To re-establish high sugar yield, breeders backcrossed hybrids to S. officinarum 4 . This process was accelerated by the unreduced (‘2 n ’) transmission of S. officinarum chromosomes in the first two generations so backcrossed (BC1) cultivars contained 11% more domesticated sequence than would be expected by typical ( n  +  n ) inheritance patterns.

While interspecific hybridization and backcrossing represent crucial steps for modern sugarcane breeding, they produced cultivars with extraordinarily complex genomes. In addition to variable progenitor subgenome dosage (due to unreduced ‘2 n ’ gamete transmission), hybrid sugarcane meiotic recombination and chromosome pairing is variable within and among progenitor subgenomes. Chromosome pairing is mainly bivalent (although meiotic abnormalities can occur) 5 , 6 , 7 but with differential pairing affinity between chromosomes, leading to a continuum of polysomic inheritance (with random association between homologues) and disomic inheritance (with systematic association between a pair of homologues) 8 , 9 , 10 . Recombination between progenitor subgenomes can also generate ‘interspecific recombinant’ chromosomes that contain both ‘wild’ and ‘sweet’ ancestry. As a result, chromosomes may be highly heterozygous, translocated, inherited purely from progenitor genomes, aneuploid, interspecific recombinant or entirely identical-by-descent to another chromosome. These processes result in a diverse and complex hybrid sugarcane genome.

The road to a representative genome

The complexity of hybrid sugarcane genomes and pedigrees is exemplified by the development of the ‘R570’ cultivar, which was generated by breeders on Reunion island in 1980 (ref. 11 ) (Fig. 1a,b ). Similar to other modern cultivars, R570 has a genome size (2 C) of approximately 10 billion bases (‘gigabases’ (Gb)), a ploidy of approximately 12 x and 2 n  ≈ 114 chromosomes, several of which have recombined between progenitor species’ genomes 12 , 13 (Fig. 1c,d ); however, aneuploidy is common and the number of copies of each chromosome varies within and among cultivars. R570 was chosen as a model by the sugarcane community to study modern genome architecture and durable resistance to brown rust ( Puccinia melanocephala ), once a major disease in the tropics and subtropics 14 , 15 . Despite development of numerous R570 genetic resources (for example, cytogenetics, genetic maps, BAC clone libraries, ‘monoploid’ assembly 16 ) and other attempts to assemble other cultivars 17 , 18 , modern sugarcane cultivars still lack a high-quality polyploid reference genome.

figure 1

a , An image of field-grown R570 (approximately 4 m in height). b , Estimated recorded pedigree of the R570 in a . Standardized contributions of progenitor genomes (red,  S. spontaneum  ( Ss ), ‘wild‘ sugarcane; blue, ‘sweet’ S. officinarum ( So )) are indicated by the proportional size of the pie diagrams, relative to expectations of n  +  n inheritance. Cultivar names for each cross of the pedigree are provided in single quotes. ‘*’ indicates ‘2 n ’ chromosome transmission in the first two generations, and ‘+’ denotes an F 1 hybrid. Although the exact pedigree of cultivars ‘R331’ and ‘Co213’ is unknown, they are estimated to be a BC2F2 and BC2:BC1 F 1 , respectively. IBD, identical by descent. c , Chromosome preparation of R570 after in situ hybridization, with S. spontaneum -specific probes shown in red. d , Karyotype diagram of R570 mirroring the colours in b .

A genome such as R570 poses many technical assembly and genome representation challenges, as R570 has all the complexities of both outbred and inbred genomes. Given variable pairing affinities among R570 chromosomes, it could potentially be biologically appropriate to follow the standard outbred genome representation where an assembly is built for each meiotic homologue. However, given its backcrossed pedigree, 2 n  +  n chromosome transmission and double maternal/paternal grandparent ‘POJ2878’ (Fig. 1b ), we expect a majority of the genome to be inbred, with on average 12.5% of sequences exactly duplicated. Normally, identical sequences in inbred genomes are represented as a single collapsed haplotype (for example, the CHM13 human cell line 19 ) or computationally duplicated in each haplotype (for example, tetraploid potato genome 20 ). In the case of R570, it is impossible to confidently place exactly duplicated sequences due to variable copy number and complex patterns of recombination between progenitor subgenomes. Therefore, we opted for a standard partial-inbred genome assembly for R570, where the ‘primary’ assembly is a complete representation of unique haplotypes in R570 whereas the ‘alternate’ represents nearly identical, additional haplotypes. While ‘alternate’ here does not have the same meaning as compared to organisms with strict disomic pairing, we structured the R570 genome in a similar manner to improve utility for the community.

In a typical genome, a highly contiguous assembly could be organized (‘scaffolded’) into chromosomes solely by Hi-C or optical mapping; however, both of these technologies require short unique sequence anchors, which are rare in the R570 genome. Therefore scaffolding required a custom pipeline that leveraged multiple lines of evidence, including PacBio HiFi circular consensus sequencing, Bionano Direct Label and Stain optical mapping, genetic linkage mapping, synteny, single-chromosome sorted sequencing and Hi-C. We combined these diverse resources through a custom pipeline (Extended Data Fig. 1a, Supplementary Data, Supplementary Figs. 1 – 11 and Supplementary Table 1 ) to construct a 5.04 Gb (12.6 Mb contig N50; average 12 contigs per chromosome) primary assembly (Fig. 2a,b , Extended Data Fig. 1b and Supplementary Fig. 12 ) that encompasses roughly half of the 10 Gb of sequence and 114 chromosomes ( Methods ) expected from R570 flow cytometry estimation 13 . The 3.7 Gb of additional sequence represented in the ‘alternate’ assembly are nearly identical to, but not necessarily meiotic pairs of, the corresponding primary chromosomes. For example: Chr6E_alt (20.4 Mb) is 99.34% similar to Chr6E (50.1 Mb; Extended Data Fig. 1c ), and HiFi reads cannot be mapped uniquely to 39.7% of the alternate assembly (Supplementary Table 2 ). In addition to this highly similar sequence, R570 has an expected approximately 12.5% inbreeding coefficient due to a shared grandparent (POJ2878; Fig. 1b ). Thus, we expect approximately 1.25 Gb of genome to be absent in the alternate assembly and collapsed to a single representation in the primary. Our 8.72 Gb combined primary and alternate assembly very closely aligns with this expectation.

figure 2

a , Schematic representation of the primary genome assembly. Although R570 has approximately 12 chromosome copies per homolog, backcrossing and 2 n  +  n chromosome transmission have led to near-identical haplotypes that are collapsed (represented as colour shades) in the genome assembly. b , One-to-one ortholog genes among chromosomes 1–10 of Sorghum bicolor (v.3.1.1) and primary chromosomes of R570. Each region is coloured based on progenitor contribution within R570. c , GENESPACE-generated synteny map among (bottom to top) Sorghum bicolor (v.3.1), S. spontaneum (genotype AP85-441), R570 primary and R570 monoploid genome assemblies. Horizontal segments indicate chromosomes; colours (red–purple) indicate the orthologous Sorghum bicolor chromosomes (1–10) and ‘braids’ represent syntenic blocks between each pair of genomes. x- axis positions are scaled by gene-rank order.

Source Data

The high-quality (0.1% gaps; long terminal repeat (LTR) assembly index (LAI) 21 : 22.82) primary assembly captures a full representation of the diversity present in R570 and will serve as the basis for genome-enabled biotechnology in sugarcane. As is the case with typical outbred diploid genomes, duplicate copies between haplotypes can complicate or bias analyses—usually one haplotype is used as the reference for mapping. Thus, here we focus on the primary assembly for efforts central to candidate gene discovery, such as gene expression and variant detection. To support these efforts, we used gene homology and RNA sequencing (RNA-seq) transcript evidence to describe the full suite of protein coding sequences and annotate genes in the primary R570 assembly. The primary annotation is highly complete (BUSCO = 99.8% total, 99.3% duplicate completeness) 22 with 194,593 coding sequences (and 105,138 alternative spliced transcripts). In contrast to previous monoploid assemblies, which contained a single representation of each ancestral chromosome, synteny-aware gene families (built with GENESPACE 23 ) were present in six ( n  = 40,752) copies in the primary genome (6.78 mean syntenic block coverage with Sorghum bicolor ( S. bicolor ); Fig. 2c , Table 1 and Supplementary Table 3 ), which reflects half of the expected 12 x ploidy and matches the expected copy number in the primary assembly. This within-genome variation is now available to breeders, but was obscured with current monoploid (single-copy) methods. Combined, the primary and alternate assemblies provide by far the most complete genomic sequences available for cultivated sugarcane.

The architecture of the R570 genome

Knowledge of the global genome architecture of modern sugarcane cultivars is currently derived mainly from molecular cytogenetics 12 , 13 , 24 , 25 , genetic mapping 8 , 16 , 26 and haplotype sequence comparisons 27 , 28 , 29 , 30 . Our chromosome-scale R570 assembly provides the first fine-grain description of the genome architecture of modern sugarcane cultivars, a foundation to describe the patterns of genomic evolution and diversity within a neo-polyploid hybrid, a crucial resource for burgeoning sugarcane molecular breeding efforts. Perhaps the most critical element of interspecific sugarcane breeding is the maintenance and enrichment of S. spontaneum progenitor sequence, conferring disease resistance and environmental adaptation 25 . The progenitor species of R570 are highly diverged (approximately 1.6 million years; Supplementary Table 4 and Supplementary Fig. 13 ), which enabled extraction of 27 bp species specific repeats used to assign progenitor blocks in the genome ( Supplementary Data ). Consistent with previous cytogenetic estimates 12 , 13 , we found that 3.66 Gb (73%) and 1.37 Gb (27%) of the R570 primary genome assembly (5.04 Gb) is derived from S. officinarum and S. spontaneum , respectively (Supplementary Tables 5 and 6 ). Separate evolutionary trajectories have also produced distinct ploidy levels and basic chromosome numbers between progenitors ( S. officinarum, 2 n  = 8 x , basic chromosome number x  = 10; S. spontaneum, 2 n  = 4 − 16 x  = typical basic chromosome number x  = 8). The basic chromosome set ( x  = 10) of S. officinarum is directly syntenic to the ten chromosomes of S. bicolor , its most well-studied annotated diploid relative. In contrast, the basic chromosome set ( x  = 8, but can vary) of S. spontaneum is a result of six chromosomes being rearranged into four 13 , 16 , 31 , 32 , each of which are observed in the R570 primary assembly (Chr5_9A, Chr 6_9A, Chr 7_10A and Chr 8_10A; Fig. 2b ).

Despite rearrangements in S. spontaneum , most of the progenitor chromosomes within R570 are syntenic and share sequence homology, facilitating interspecific recombination. Indeed, cytogenetic experiments among multiple sugarcane hybrid cultivars indicate that homologous pairing and recombination between chromosomes from different progenitors is likely common 12 , 25 . In the R570 primary assembly, we observed 13 interspecific recombinant chromosomes among seven of ten basic chromosomes (Fig. 2b ). The assembly also confirmed a cytogenetic predicted chromosome resulting from a translocation between S. spontaneum chromosome 5 and S. officinarum chromosome 8 (Fig. 2b ) which is so far found only in R570 and no other modern cultivar 13 . Homoeologous introgressions, which can be enriched in breeding targets, have been observed in other systems, both in traditional breeding (for example, oat 33 ) and synthetic polyploids (for example, Brassica 34 and wheat 35 ). R570 recombinant chromosomes contain diversity within progenitor genomes that is not easily purged through inbreeding, likely providing additive genetic variance accessible to breeders in advanced-generation intercrosses.

Breeding practices such as backcrossing, ‘2 n ’ chromosome transmission and small breeding population sizes, have resulted in high DNA sequence redundancy and exact duplicates, particularly those derived from S. officinarum . For example, the cultivar ‘POJ2878’ has been used in many breeding programs worldwide and is both a maternal and paternal grandparent of R570 (Fig. 1b ). To catalogue the genomic structure of copy number variation and molecular sequence variation within R570, we used highly accurate PacBio HiFi reads (median length 17 kb), to find roughly half the genome (50.4%) is identical-by-descent where haplotypes are collapsed among multiple copies (2–4 x ) (Supplementary Table 7 , Supplementary Fig. 14 and Extended Data Fig. 1d ). The remainder of the genome (49.6%) contains enough sequence variation (heterozygosity) to enable single, unique alignments of PacBio reads that distinguish separate haplotypes. Each of basic chromosomes of R570 are covered by one to four S. spontaneum haplotypes (Fig. 2b ) most of which (86%) is heterozygous, single-copy sequence. In contrast, only 48% of the S. officinarum portion is heterozygous, while the majority is collapsed among multiple haplotypes. Indeed, 87% of the duplicated sequence among the primary and alternate assemblies (39.7%; previously discussed; Supplementary Table 2 ) is derived from S. officinarum . Since breeding for increased sugar content and other traits rely on additive contributions of gene dosage, these perfectly duplicated regions represent potential targets for copy-number aware genotyping and molecular breeding efforts. However, exploring the genomic contribution of the domesticated progenitor is difficult as genotyping inbred haplotypes require restrictively large numbers of progeny to screen (for example, triplex marker segregation in S1 = 143:1 (ref. 36 )). The most common genetic marker used for sugarcane breeding (simplex, segregation in S1 = 3:1 (ref. 37 ); Supplementary Data ) is significantly biased toward the S. spontaneum regions of the genome (45% of markers; Fisher exact test: ×3.25 enrichment, P  < 0.0001), and is found almost exclusively in heterozygous haplotypes (98%) (Extended Data Fig. 1e ). While this bias towards heterozygous regions renders the majority of the genome invisible to traditional genetic mapping, the R570 assembly will allow easier exploration of quantitative trait loci (QTLs) through cataloguing of haplotype structure and progenitor contribution within the genome.

Exploration of targets for breeding

Many crucial traits for sugarcane improvement are polymorphic in the progenitor species and dosage dependent in hybrid breeding programs. For example, brown rust resistance (see below) appears to be derived from a single-copy locus within the genome, while high sugar content requires additive contributions of gene copies from S. officinarum . To accelerate similar breeding efforts and develop marker assisted selection strategies, we documented copy number and protein sequence variation between and within R570 progenitor subgenomes within the primary assembly and annotation (Table 1 , Fig. 2c and Supplementary Table 3 ). Using progenitor block classification, we were able to assign 68% of gene models ( n  = 132,618) to S. officinarum and 31% to S. spontaneum ( n  = 61,197). Inspection of homeologs among progenitors found 87% of gene copies derived from S. officinarum and 95% derived from S. spontaneum contained non-synonymous variation (Supplementary Table 8 ), but it is important to note that many of these genes are located in regions where haplotypes are collapsed ( n  = 58,038; 87% S. officinarum assigned; Supplementary Table 9 ), and thus some gene models are likely under-represented. Peptide polymorphism largely mirrored the % identical homeolog analyses, where S. officinarum homeologs had an average pairwise identity (PID) of 86% while S. spontaneum homeologs had significantly more variation (mean PID = 83%; Mann–Whitney U  = 3.5 × 10 8 , P  < 0.0001). The investigation of genes impacted by structural variants, which may prevent recombination and subsequent generation of desirable allelic combinations is also significantly biased towards S. officinarum portions of the genome ( n  = 5,090; 94% of impacted genes; Fisher’s exact test, odds ratio: 9.03, P  < 0.0001; Supplementary Table 10 ). A survey of unique material (genes with no orthology in the other progenitor; n  = 32,544) found ×1.2 more genes derived from S. officinarum than expected (Fisher’s exact test, odds ratio: 1.24, P  < 0.0001); although investigation of the largest novel gene family contributed from the S. spontaneum found a nine gene tandem duplication of leucine rich repeat genes on Chr7_10A. Furthermore, annotation of resistance gene analogues (RGAs) 38 throughout the genome (Supplementary Table 11 ) showed significant enrichment for S. spontaneum derived motifs (Fisher’s exact test, odd’s ratio 2.14, P  < 0.0001), particularly on homologous regions of chromosomes 3, 6 and 7 (×4.81, ×3.35 and ×4.11 enrichment, respectively, P  < 0.0001; Supplementary Table 12 ).

Hybrid and backcrossing breeding programs often introduce large swaths of linked maladaptive alleles that reduce crop yield in early generations. In modern sugarcane cultivars, interspecific hybridization not only introduced disease resistance alleles from S. spontaneum , but also alleles that reduced the high-sucrose (‘brix’) content in the domesticated S. officinarum . Previous studies suggested that discrete loci disproportionately explained sugar content variation 39 , 40 , 41 , but some of these experiments were performed in different genetic backgrounds, with only the monoploid assembly or S. bicolor available for candidate gene discovery, offering a collapsed view of allelic variation that exists in the R570 genome. Using comparative genomics between S. bicolor BTx623 (short stature, early maturing, cereal genotype) and rio (‘sweet sorghum’; tall, late maturing, high soluble sugar content), we explored sugar transport genes underlying the rio ‘sweet’ phenotype of high concentrations of soluble sugars within its stem 42 , a phenotype also of interest by sugarcane breeders. Of the candidates described in ref. 42 , 43 S. bicolor BTx623 genes were contained as single placement anchors within R570 syntenic orthogroups, with 505 syntenic orthologs among other genomes ( Sorghum ‘rio’: R570 monoploid: S. spontaneum (genotype AP85-441): R570; syntenic orthologs per genome = 39:37:130:299; mean gene copies per homologue per genome = 1:1:3:7).

Percent PID among the S. bicolor homologue and syntenic orthologs found sugar transport genes are highly conserved ( Sorghum ‘rio’: R570 monoploid: S. spontaneum (genotype AP85-441): R570; median PIDs per genome = 100%:91%:94%:94%) (for example, SUT4-Sobic.008G193300, Extended Data Fig. 2a ), although some R570 alleles contain frameshift mutations that are likely to impair function (for example, SoffiXsponR570.05Bg071800-L744A-Sobic.002G075800-Glycoside hydrolase ortholog, S. officinarum allele, Extended Data Fig. 2b ) or possess highly variable alleles with regions where individual homeologs can be distinguished (for example, Sobic.005G082100-cell wall pectinesterase; Extended Data Fig. 2c ). Annotation of the R570, paired with information of gene dosage, allelic variation and progenitor contribution will enable the sugarcane community to better comprehend germplasm resources at their disposal, for both R570 and other hybrid cultivars.

Apart from high sugar production, a defining characteristic of modern sugarcane cultivars is biotic disease resistance. One of the most important diseases that affects all sugarcane growing regions around the world is brown rust, caused by the fungus, Puccinia melanocephala . Once a major pathogen of sugarcane that caused yield losses of up to 50%, breeders have successfully mitigated P. melancocephala -derived losses by selecting for disease resistance. A major locus ( Bru1 ) that confers durable resistance to this disease (Fig. 3a ) was identified in cultivar R570 (refs. 43 , 44 ). To uncover the causative allele underlying Bru1 , previous studies used an extensive map-based cloning approach that screened approximately 2,400 self-pollinated R570 progeny, constraining Bru1 to a set of BAC sequences that spanned approximately 209 kb (refs. 27 , 44 ) ( Methods ). Although the region contained 13 gene models (Fig. 3b and Supplementary Table 13 ), it also contained an unsized gap and large haplotype insertion, both of which prevent further fine-scale mapping and exhaustive candidate gene discovery 27 , 44 . Nonetheless, the fixed insertion haplotype enabled the design of Bru1 diagnostic PCR markers. These have been effectively used in modern cultivar breeding programs worldwide, demonstrating that the single-dose Bru1 locus has been the major source of effective (or ‘durable’) brown rust resistance for decades across multiple environments 14 .

figure 3

a , Brown rust disease resistance in R570. Top panel shows selfed R570 offspring with the Bru1 locus, while the bottom panel shows offspring lacking Bru1 . b , Gap-filled haplotype assembly identifies a TKP as candidate causal genes for Bru1 durable brown rust resistance. Blue pentagons represent curated gene models and grey pentagons are large transposable elements. Bru1 TKP7 and TKP8 candidate genes are indicated in red with their location on Chr. 3D.

In contrast to previous resources, our R570 genome assembly spans the entirety of the Bru1 target region (chromosome 3D: 5944326–6253115 bp). Crucially, this includes a complete approximately 100 kb stretch of contiguous sequence across the previously unsized gap region 44 . Filling this previously unsized gap and demonstrating that it did not include additional candidate genes was an essential step before investing in the analysis of all candidate genes in the region. Manual curation of the gap-filled region confirmed the 13 gene models, whose functions were assessed, searching for genes involved in disease resistance mechanisms, with two genes standing out as top candidates ( Methods ). Curated genes 7 and 8 (gene IDs, SoffiXsponR570.03Dg024200 and SoffiXsponR570.03Dg024300) share homology (both classified as RLK-PELLE-DSLV kinases 45 ), are located within the bounds of the haplotype-specific insertion (Fig. 3b ), and are each single copy in the R570 genome. While gene 7 (SoffiXsponR570.03Dg024200) contains all 12 functional kinase subdomains, gene 8 (SoffiXsponR570.03Dg024300) contains only domains I through VII and is likely a pseudokinase. These two genes represent a tandem kinase-pseudokinase (TKP), similar to barley stem rust (RPG1 (ref. 46 )) and yellow rust resistance Yr15 (ref. 47 ). The current model of molecular action for TKP resistance suggests the pseudokinase acts as a decoy for fungal pathogen effectors 48 , while the functional kinase generates a signal cascade, innervating the plant effector-triggered immune response. Due to their variation and novelty, TKPs (and other variants (for example, tandem kinase-kinases and so on)) are difficult to find using only sequence homology. Their structure has been predicted across the plant domain of life, but only five examples have been functionally validated in monocots, all of which conferred resistance to fungal pathogens 49 . Combined, these results support this tandem kinase-pseudokinase (TKP7 and TKP8) as the causal gene for Bru1 brown rust resistance and will permit future biotechnological improvement of sugarcane for brown rust.

Conclusions

The polyploid genome assembly and annotation of sugarcane cultivar R570 is an essential stepping stone in the emerging genomic revolution for sugarcane. This work reveals the genomic effects of breeding practices that transformed sugarcane into sugar/biomass production factories, a remarkable feat by breeders considering the complexity of the genome and the revelation that much of the ‘sweet’ domesticated alleles contributed from S. officinarum are identical and thus are largely inaccessible to QTL mapping efforts. Further, the persistence of the S. spontaneum progenitor genomic contribution, despite multiple rounds of backcrossing to S. officinarum and 2 n  +  n chromosome transmission, is highlighted by the enrichment of both RGA motifs and unique gene family contributions from the wild progenitor species. The ability to separate, resolve and investigate individual haplotypes and chromosomes within R570 enables a much greater understanding of the fine-grain architecture of this very complex genome and will lead to substantial improvements in the genetic understanding of agronomic traits through exploration of allelic variation, copy number and gene presence/absence variation 2 .

One of the most important, yet complex, questions underlying agronomic trait discovery in sugarcane is epistatic interaction among alleles. Desirable traits such as sucrose transport and accumulation are complex enough in diploid plants, let alone in highly polyploid sugarcane with approximately 12 x copies of each chromosome. Annotation and pan-genome synteny networks in R570, paired with new differential expression analyses enabled by this work, will help reveal the complicated regulation of transcription factors and multiple, identical target sequences within sugarcane. Furthermore, demonstrating that while half the genome is identical/collapsed among haplotypes, the remaining sequence is heterozygous and is over-represented by S. spontaneum will help improve the construction and design of genetic markers that do not rely solely on segregation for QTL mapping. While interspecific hybrid sugarcane represents one of the most complex plant genomes ever sequenced, it is likely by no-means the most complex genome that kingdom Plantae can offer. The strategies outlined here that combine multiple sequencing technologies and techniques are broadly applicable and can be applied to complex plant genomes sequenced in the future. Description of the Bru1 disease resistance locus and discovery of strong candidate genes corresponding to a tandem kinase-pseudokinase will allow targeted validation experiments. Its putative molecular function supports that tandem kinase resistance mechanisms are durable and capable of protecting globally distributed crops across many environments. This work represents the culmination of a decades-long global collaboration by sugarcane breeders and researchers to develop genomic resources for R570 to better understand one of the most valuable crops in the world, the modern sugarcane hybrid cultivar.

Genome sequencing

Illumina libraries.

Illumina libraries for this manuscript were sequenced on a combination of Illumina X10, HiSeq and NovaSeq platforms. HipMer assembly and selfed progeny (Extended Data Fig. 1a ): sequencing libraries were constructed using an Illumina TruSeq DNA PCR-free library kit using standard protocols. Libraries were sequenced on an Illumina X10 instrument using paired ends and a read length of 150 base pairs.

Single flow-sorted chromosome libraries

Sequencing libraries were constructed using an Illumina TruSeq DNA Nano library kit using standard protocols. Libraries were sequenced on either the Illumina HiSeq2500 or NovaSeq 6000 instrument using paired ends and a read length of 150 base pairs.

Remaining Illumina libraries

Illumina Tight Insert Fragment, 400 bp–2 ug of DNA was sheared to 400 bp using the Covaris LE220 and size selected using the Pippin (Sage Science). The fragments were treated with end-repair, A-tailing and ligation of Illumina compatible adaptors (IDT) using the KAPA-Illumina library creation kit (KAPA Biosystems). The prepared libraries were quantified using KAPA Biosystems’ next-generation sequencing library qPCR kit (Roche) and run on a Roche LightCycler 480 real-time PCR instrument. The quantified libraries were then prepared for sequencing on the Illumina HiSeq sequencing platform using a TruSeq Rapid paired-end cluster kit, v.2, with the HiSeq 2500 sequencer instrument to generate a clustered flowcell for sequencing. Sequencing of the flowcell was performed on the Illumina HiSeq 2500 sequencer using HiSeq Rapid SBS sequencing kits, v.2, following a 2 × 250 indexed run recipe.

PacBio libraries

Continuous long-read PacBio sequencing primer was then annealed to the SMRTbell template library and sequencing polymerase was bound to them using a Sequel Binding kit v.2.1. The prepared SMRTbell template libraries were then sequenced on a Pacific Biosystem Sequel sequencer using v.3 sequencing primer, 1 M v.2 single-molecule real-time cells and v.2.1 sequencing chemistry with 1 × 600 sequencing video run times. PacBio HiFi sequencing was performed using circular consensus sequencing (CCS) mode on a PacBio Sequel II instrument. High molecular weight DNA was either needle-sheared or sheared using a Diagenode Megaruptor 3 instrument. Libraries were constructed using SMRTbell Template Prep Kit v.2.0 and tightly sized on a SAGE ELF instrument (1–18 kb). Sequencing was performed using a 30 h video time with 2 h pre-extension and the resulting raw data was processed using the CCS4 algorithm.

RNA-seq libraries

Illumina RNA-Seq with poly(A) selection plate-based RNA sample preparation was performed on the PerkinElmer Sciclone NGS robotic liquid handling system using Illumina’s TruSeq Stranded mRNA HT sample prep kit using poly(A) selection of mRNA following the protocol outlined by Illumina in their user guide: https://support.illumina.com/sequencing/sequencing_kits/truseq-stranded-mrna.html , and with the following conditions: total RNA starting material was 1 ug per sample and eight cycles of PCR were used for library amplification. The prepared libraries were quantified using KAPA Biosystems’ next-generation sequencing library qPCR kit and run on a Roche LightCycler 480 real-time PCR instrument. Sequencing of the flowcell was performed on the Illumina NovaSeq sequencer using NovaSeq XP v.1 reagent kits and an S4 flowcell, following a 2 × 150 bp indexed run recipe.

Chromosome in situ hybridization

Chromosome mitotic metaphase preparations and fluorescence in situ hybridization were performed as described in ref. 13 . The S. spontaneum retro-transposon specific oligo probe was designed by Arbor Biosciences using their proprietary software based on the retro-transposon sequences as described in ref. 50 . Probes were either labelled with fluorochromes ATTO 488 or ATTO 550.

Single flow-sorted chromosome preparation

Stems of adult plants were cut into single-bud segments, cleaned and soaked in 0.5% carbendazim solution for 24 h, placed in a plastic tray, covered with wet perlite and incubated at 32 °C in the dark, until the roots were approximately 1.5 cm long. For cell-cycle synchronization and accumulation of metaphases, the segments were washed in ddH 2 O, then transferred to a plastic tray filled with 150 ml 0.1 × Hoagland solution containing 3 mmol l −1 hydroxyurea and incubated at 25 or 32 °C for 18 h in the dark. After a 2 h recovery treatment, the roots were immersed in 2.5 µmo l −1 amiprophos-methyl solution and incubated for 3 h at 25 or 32 °C. Suspensions of intact chromosomes were prepared by mechanical homogenization of root tips fixed with 3% formaldehyde and 0.5% Triton X-100, and stained with 4′,6-Diamidino-2-phenylindole dihydrochloride (DAPI) 51 . The instrument used for flow sorting was a FACSAria II SORP flow cytometer (BD Biosciences) and Beckman Coulter MoFlo AstriosEQ cell sorter (Beckman Coulter). The software used was FACSDiva v.6.1.3 (BD Biosciences) and Summit v.6.2.2 (Beckman Coulter). For chromosome sorting, initial gating was set on dotplots DAPI-A versus FSC-A and the final sorting gate was set on DAPI-A versus DAPI-W dotplots to exclude chromosome doublets (Supplementary Fig. 15 ). The identity of flow-sorted fractions was determined by fluorescence microscopy of chromosomes sorted onto microscope slides 51 . The analysis revealed that chromosomes could be separated into a few size fractions and while the sorted populations were 100% pure chromosomes, it was not possible to sort individual sugarcane chromosomes. To overcome this problem and prepare samples of chromosome-specific DNA for sequencing, single copies of chromosomes were sorted and their DNA amplified 52 . This strategy for preparing sugarcane chromosomes for flow cytometry was first described in ref. 51 and is a modification of the protocol described in ref. 53 .

Optical map construction

Ultra-high molecular weight (uHMW) DNA was isolated from agarose-embedded nuclei as previously described in ref. 54 with some modifications. Approximately 2 g of young, healthy R570 leaves were collected and fast-frozen in a 50 ml conical tube, ground in a mortar with liquid nitrogen and briefly incubated in Bionano homogenization buffer (HB+; Bionano Plant DNA isolation Kit; Bionano Genomics). Cell debris was filtered out by sequentially passing the homogenate through 100 µm and 40 µm cell strainers. Nuclei in suspension were pelleted by centrifugation at 2,000 g at 8 °C for 20 min, resuspended in 3 ml homogenization buffer HB+ and subjected to discontinuous density gradient centrifugation as described in the Plant Tissue DNA Isolation Base Protocol (Revision D; Bionano Genomics). The nuclei-enriched interphase layer was recovered, pelleted and embedded in low-melting-point agarose using a 90-µl CHEFgel electrophoresis plug mould (Bio-Rad). The resulting plug was incubated twice, for a total of 12 h at 50 °C, in Bionano Lysis buffer supplemented with 1.6 mg ml −1 Puregene Proteinase K, washed four times in Bionano Wash Buffer and five times in TE buffer. The uHMW nDNA was recovered by melting and digesting the plug with agarase at 43 °C, followed by drop dialysis. In total, approximately 9 µg uHMW DNA was recovered at a concentration of 136 ng µl −1 and used for subsequent genome mapping processes.

Genome mapping was performed using the Bionano Genomics Direct Label and Stain chemistry in a Bionano Saphyr instrument, using the method described in ref. 55 , with a few modifications. Approximately 800 ng of uHMW DNA was used per reaction and a total of eight flow cells were loaded to collect molecules with a total combined length of 3,499,160 Mbp. A subset of 1,650,737 molecules with a minimum length of 450 kb, and N50 of 547 kb were selected for assembly. The final total combined length of the filtered subset was 1,097,878,758 bp, with estimated effective coverage of assembly of ×101.2.

Genome assembly was performed using the Bionano Genomics Access software platform (Bionano Tools v.1.3.8041.8044; Bionano Solve v.3.3_10252018), running the pipeline v.7981 and RefAligner v.7989. Two separated assemblies were performed using the optArguments_nonhaplotype_noES_BG_DLE1_saphyr.xml parameters. The initial assembly was performed without complex multi-path region (CMPR) cuts and produced 570 maps with a N50 length of 36.444 Mbp and total map length of 7,654.039 Mbp. One additional assembly was performed using the CMPR cut option, which introduces map cuts at potential duplications to reduce potential homeolog and phase switching. CMPR-cut-enabled assembly generated 1,512 maps with N50 length of 9.546 Mbp and total map length of 9,282.351 Mbp.

PacBio HiFi Bionano hybrid scaffolds were generated using the Bionano Genomics Access software (Tools v.1.3) and the DLE-1 configuration file hybridScaffold_DLE1_config.xml using auto-conflict resolution. In total, the genome was captured in 122 hybrid scaffolds (Scaffold N50 = 78.823 and maximum scaffold size of 131.769 Mbp. The total scaffold length was 5,074 Mbp, with 4.9 Mbp of sequence remaining un-scaffolded.

Genome assembly overview

Complete representation of all sequences in the 10 Gb genome of R570 was impossible without artificially duplicating collapsed sequences, of which there are many. To scaffold the contigs into chromosomes, we applied five complementary techniques ( Supplementary Data ). First, we used the Bionano optical map to initially order contigs into long-range scaffolds. Second, scaffolds were clustered into homeologous groups based on 237 linkage groups constructed from approximately 1.8 million simplex markers that were assayed from 96 self-pollinated progeny. Third, additional clustering was performed using genetic markers derived from single flow-sorted chromosome libraries sequenced from R570 (refs. 52 , 53 ). After making initial joins, both simplex and single-chromosome genetic markers were re-aligned putative chromosomes to investigate misjoins, which were broken and corrected. Fourth, we resolved overlapping scaffolds by checking for redundant collinear sets of Sorghum bicolor gene models mapped against the contigs using pblat 56 with default parameters. Finally, we manually evaluated chromatin linkages from 558 Gb (approximately ×56) Hi-C data to manually verify joins made between scaffolds during chromosome construction (Extended Data Fig. 1a ). The highly contiguous primary assembly (5.04 Gb, 12.6 Mb contig N50; 67 chromosomes) also includes optical scaffolds (‘os’; n  = 20) and unanchored scaffolds ( n  = 56). The primary assembly contains 0.1% gaps with an LTR assembly index 21 (LAI; measure of intact LTR elements) of 22.82, indicating the assembly is high quality and complete. Where possible, the alternate assembly (3.73 Gb, 2.1 Mb contig N50; comprised of nearly identical haplotypes in the primary assembly; discussed in  Supplementary Data ), was physically anchored to the most similar chromosome in the primary assembly based on best unique alignments using minimap2 (v.2.20-r1061) 57 . Contigs and scaffolds that did not have a single best unique alignment were left unanchored. It should be noted that this sequence similarity-based grouping does not suggest that contigs on alternative scaffolds with the same name (for example, Chr6E and Chr6E_alt) necessarily come from the same biological haplotype. Thus, we provide the alternate scaffolds to represent the complete population of sequences in R570, and not as a source for global comparisons against the primary or other reference genomes.

Collapsed haplotypes

To determine which regions of the genome were perfectly identical and collapsed into a single haplotype (in contrast to the alternate assembly that contains nearly identical haplotypes, which could be distinguished by the assembler but most often not by unique HiFi read placements), PacBio HiFi reads were re-aligned back to the assembly using minimap2 (ref. 57 ) (parameters: -M 0 --secondary=no --hard-mask-level -t 30 -x asm5). Read coverage (script: combinePAFsAndCount.R) was calculated using script: relative to the median depth (37) per 10 kb window, ignoring repetitive regions where the median coverage was greater than five (greater than ×185 raw coverage). Depth classifications (×0–4) were calculated from the median coverage ranges (×0 (0–0.25), ×1 (0.25–1.4), ×2 (1.4–2.3), ×3 (2.3–3.5), ×4 (3.5–5.0)), based on histogram peaks. Depth classifications per 10 kb window were converted to their run-length equivalent using the script: convertCountsToRLEs.R. To ensure accurate representation of haplotypes, NucFreq 54 was used to analyse regions where haplotypes were collapsed (×2–4 depth regions; approximately 1.2 Gb of primary genome sequence). In summary, HiFi reads were aligned to the combined primary and alternate assembly using pbmm2 (v.1.1.0; parameters: --log-level DEBUG --preset SUBREAD --min-length 5,000 --sort). Samtools 58 was then used to merge individual bam files (from each HiFi sequencing run) and exclude unmapped reads and supplementary alignments. (samtools view -F 2308). The NucFreq output coverage bed (obed) file was converted to run-length equivalents (script: RLEruns.R), where alternate base calls were greater than 20% of the combined coverage. To ensure adequate coverage for analysis, regions with outlier depth ranges beyond the 10th and 90th percentiles were excluded. Additionally, repetitive regions of the genome (95% repetitive, masked with a 24mer and 10 kb regions where greater than 90% of bases were annotated as retrotransposons (from LAI analysis) were also excluded using BEDtools 59 subtract. Of the approximately 1.2 Gb considered, approximately 4.8 Mb of sequence (0.4% of considered regions; 0.1% of bases within constructed primary chromosomes) appear to contain non-identically collapsed haplotypes, mainly driven by high depth collapsed regions (×2–3 depth regions = 0.3% of bases; ×4 depth regions = 1.5% of bases).

Genome annotation

Gene models were annotated using our PERTRAN pipeline (described in detail in ref. 60 using approximately 3.7 B pairs of 2 × 150 stranded paired-end Illumina RNA-seq and 31 M PacBio Iso-Seq CCSs reads. In short, PERTRAN conducts genome-guided transcriptome short read assembly via GSNAP (v.2013-09-30) 61 and builds splice alignment graphs after alignment validation, realignment and correction. The resulting approximately 1.5 M putative full-length transcripts were corrected and collapsed by genome-guided correction pipeline, which aligns CCS reads to the genome with GMAP 61 with intron correction for small indels in splice junctions if any and clusters alignments when all introns are the same or 95% overlap for single exon. Subsequently 1,763,610 transcript assemblies were constructed using PASA (v.2.0.2) 62 from RNA-seq transcript assemblies above. Homology support was provided by alignments to 17 publicly available genomes and Swiss-Prot proteomes. Gene models were predicted by homology-based predictors, FGENESH+ (v.3.1.0) 63 , FGENESH_EST (similar to FGENESH+, but using expressed sequence tags (ESTs) to compute splice site and intron input instead of protein/translated open reading frames (ORFs) and EXONERATE (v.2.4.0) 64 , PASA assembly ORFs (in-house homology constrained ORF finder) and from AUGUSTUS (v.3.1.0) 65 trained by the high confidence PASA assembly ORFs and with intron hints from short read alignments. We improved these preliminary annotations by comparing sequences and gene quality between R570 subgenomes by aligning high-quality gene models between subgenomes and forming gene models from intragenomic alignments. We compared scores between these intragenomic homology-based models and the PASA assemblies; higher-scoring homology supported models that were not contradicted by transcriptome evidence were retained to replace existing partial copy. The selected gene models were subject to Pfam analysis and gene models with greater than 30% Pfam TE domains were removed. We also removed (1) incomplete, (2) low-homology-supported without full transcriptome support and (3) short single exon (less than 300 BP CDS) without protein domain nor transcript support gene models. Repetitive sequences were defined using de novo by RepeatModeler (v.open1.0.11) 66 and known repeat sequences in RepBase.

Comparative genomics

Syntenic orthologs among the R570 primary annotation, S. bicolor (v.3.1) 67 , S. spontaneum (genotype AP85-441) 32 , Setaria viridis (v.2.1) 68 and the R570 monoploid path 16 were inferred via GENESPACE (v.0.9.4) 23 pipeline using default parameters (analysis script: genespaceCommands.R). In brief, GENESPACE compares protein similarity scores into syntenic blocks using MCScanX 69 and uses Orthofinder (v.2.5.4) 70 to search for orthologs/paralogs within synteny constrained blocks. Syntenic blocks were used to query pairwise peptide differences among progenitor alleles, determine divergence among progenitor orthologs using S. bicolor syntenic anchors and search for progenitor specific orthogroups (scripts, PID_calc.R; GENESPACE_orthogroupParsing.R; Jupyter Notebook: r570_orthogroupProgenitorAnalysis_forSupp.ipynb).

Structural variants

To identify the large structural rearrangements (inversions, translocations and inverted translocations) and local variations (insertions and deletions), each homeologous chromosome group (B, C, D, E, F, G) was aligned to chromosome A using minimap2 (v.2.20-r1061) 57 with parameter setting ‘-ax asm5 -eqx’. The resulting alignments were used to identify structural variations with SyRI (v.1.6) 71 and annotation gff3 was used to obtain genes affected by variations between homeologous chromosomes.

Orthogroup diversity

Calculation of mean pairwise differences among progenitor specific homeologs was performed by first extracting all pairwise combinations of progenitor assigned alleles within orthogroups that were anchored by an S. bicolor ortholog. Among these, 25,000 peptide pairs per progenitor were randomly selected and pairwise aligned using R package Biostrings (v.2.70.2) 72 . Pairwise identity calculation was based on matches/alignment length (PID2; script PID_calc.R). Multiple sequence alignments among syntenic orthogroups for sugar transport gene candidates were performed using MAFFT (v.7.487) 73 and were visualized using ggmsa 74 (script MSAalignmentPlots.R). Fold scores for each peptide were calculated using ESMfold (v.2.0.1) 75 .

Resistance gene analogues

RGAs were annotated on scaffolds larger than 10 megabases with NLR-Annotator (v.2) 38 using default parameters. The 4,116 predicted RGAs (Supplementary Table 11 ) were assigned to progenitors by intersecting the location of each motif with progenitor assignment blocks (Supplementary Table 6 ).

Progenitor divergence

To determine the neutral substitution rate between S. officinarum and S. spontaneum , 45,000 random ortholog pairs were extracted from all pairwise combinations of progenitor assigned alleles ( n  = 193,815) within S. bicolor anchored orthogroups. Peptide sequence pairs were aligned using MAFFT (v.7.487) 73 and converted into coding sequence (CDS) using pal2nal (v.13) 76 . Pairwise synonymous mutation rates (Ks) among sequences were calculated using seqinr (v.4.2-16) 77 , finding a single synonymous (ks) mutation peak at 0.012 (Supplementary Fig. 13 ). Assuming a neutral nuclear mutation rate of 0.383 × 10 −8  to 0.386 × 10 −8 (ref. 78 ), S. officinarum and S. spontaneum diverged approximately 1.55–1.56 million years ago.

Bru1 genetic and physical maps

We developed a map-based cloning approach adapted to the high polyploid context of sugarcane to target the durable major rust resistance gene Bru1 . Haplotype-specific chromosome walking was performed through fine genetic mapping exploiting 2,383 individuals from self-progenies of R570 and physical mapping exploiting two BAC libraries 44 , 79 . The high-resolution genetic map of the targeted region included flanking markers for Bru1 (at 0.14 and 0.28 cM), 13 co-segregating markers and the partial BAC physical map of the target haplotype included two gaps 44 ; Fig. 3b . To complete the physical map of the target Bru1 haplotype, we constructed a new BAC library (using enzyme BamHI) using a mix of DNA from four brown-rust-resistant individuals from the R570 S1 population. The BAC library contained 119,040 clones with an average insert size of 130 kb and covered 3.2-fold the target haplotype and 1.6-fold the total genome.

BAC-ends and BAC subclones from the four BACs (CIR009O20, 022M06, CIR012E03 and 164H22) surrounding the two remaining gaps (‘left’ and ‘right’) in the physical map of the Bru1 haplotype were isolated and used for chromosome walking (as described in ref. 44 ). Two BACs (CIRB251D13 (150 kb) and CIRB286F09 (130 kb)) were identified and sequenced to fill the right gap. Five BACs (CIRB009N07 (100 kb), CIRB114G05 (100 kb), CIRB127D08 (125 kb), CIRB210D07 (105 kb) and CIRB236L05 (150 kb)) reduced the size of the left gap by 35 kb, but an unsized gap remained. The R570 genome assembly spanned the entirety of the Bru1 target haplotype region with one contig, closing the left gap (99,750 bp) enabling all candidate genes in the region to be investigated (Fig. 3b ).

Bru1 candidate genes

The target gap-filled haplotype that represented 0.42 cM and 309 kb was manually annotated, predicting a total of 13 genes (Fig. 3b and Supplementary Table 13 ). Nine of these genes were also present on all or some of the hom(e)ologous BACs/haplotypes in the R570 genome 27 . Three of the curated genes were present only in the insertion specific to the Bru1 haplotype. Other whole-genome annotated genes (SoffiXsponR570.03Dg024000; SoffiXsponR570.03Dg024100; SoffiXsponR570.03Dg024600; SoffiXsponR570.03Dg024700) in the region were short, mono-exonic peptides that either contained no protein domains or appeared to be annotated transposable elements, and thus were not supported in the curated candidate gene list (Supplementary Table 13 ). Among the 13 predicted genes, we searched genes that presented high homology with genes already shown to be involved in resistance mechanisms. We identify five such genes, four genes encoding serine/threonine kinases (genes 1, 5, 7 and 8) and one gene encoding an endoglucanase (gene 13). Annotation of these genes was refined manually through phylogenetic analysis that included genes with high homology from other plants present in databases and search of conserved functional protein domains.

Gene 13, which encodes an endoglucanase, comprised 3 exons and two introns with a genomic size of 1.8 kb for a predicted transcript of 1.5 kb. Sequence alignment and phylogenetic analyses performed with beta-1-4 endoglucanase and beta-1-3 endoglucanase from monocots and dicots showed that gene 13 belongs to the beta-1-4 endoglucanase. This gene presents high homology (greater than 60%) with beta-1-4 endoglucanase from other plants and has the highest homology (88% of identity, 100% coverage) with the orthologous Miscanthus gene (CAD6248271.1). Beta-1-4 endoglucanases are involved in cell development 80 in particular on elongation of the cell wall 81 but have not been reported as involved in disease resistance. This suggested that this gene is not a good candidate for being Bru1 .

Gene 1 is composed of eight exons and seven introns. Its genomic size is 4.3 kb and the CDS size is 882 bp. The protein encoded by the gene has 96.5 % identity (100% coverage) with a kinase involved in cell division control in Sorghum (XP_002451427.1) and therefore, it did not appear to be a good candidate.

Gene 5 is composed of six exons and five introns. Its genomic size was 1.1 kb and the predicted CDS size 534 bp. Alignment of its amino acid sequence with Interpro conserved protein domain database showed that only part of the protein (exons 4 to 6) has homology with subdomains VIb to XI of the serine/threonine kinases. This serine/threonine kinase was thus not complete, lacking some of the functional subdomains and appeared to be a pseudogene. Therefore, it did not appear to be a good candidate.

Gene 7 is composed of six exons and five introns, and gene 8 has four exons and three introns. Both present homology with receptor-like kinases. Annotation of conserved protein domains showed that gene 7 has all the 12 subdomains of kinases and thus could encode a functional protein, while gene 8 encompasses only part of these sub domains (I to VII) and could correspond to a pseudokinase. The classification with the ITAK database ( http://itak.feilab.net/cgi-bin/itak/index.cgi ) revealed they both belong to the RLK-PELLE-DSLV family 45 , the same family to which belong the barley stem rust resistance gene ( RPG1 (ref. 46 )) and the wheat yellow rust resistance gene ( Yr15 (ref. 47 )) shown to be a tandem kinase-pseudokinase (TKP). In addition, the third intron of gene 7 has a very large size of approximately 11 kb, including a large TE, a particular structure shared with RPG1 and Yr15 TKPs. Bru1 , like RPG1 and Yr15 , is among the relatively rare resistance genes that confer durable fungal resistance. This tandem kinase-pseudokinase (TKP7 and TKP8) is therefore a solid candidate for Bru1 .

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

Additional work to support the findings of this manuscript can be found in the Supplementary Data section. Sequencing libraries (Illumina DNA/RNA and PacBio continuous long read/HiFi) are publicly available within the sequence read archive (SRA). BioProjects and individual accession numbers are provided in Supplementary Table 14 . Genome assembly and annotation for the primary assembly is freely available at Phytozome ( https://phytozome-next.jgi.doe.gov/ ). This Whole Genome Shotgun project has been deposited at DDBJ/ENA/GenBank under the accession JAQSUU000000000 . The version described in this paper is JAQSUU010000000 . Publicly available genomes used for comparative genomics can be downloaded here: Setaria viridis (v.2.1; https://phytozome-next.jgi.doe.gov/info/Sviridis_v2_1 ), Sorghum bicolor (v.3.1; https://phytozome-next.jgi.doe.gov/info/Sbicolor_v3_1_1 ), R570 monoploid tiling path ( http://sugarcane-genome.cirad.fr ) and Saccharum spontaneum ( http://www.life.illinois.edu/ming/downloads/Spontaneum_genome/ ). Raw data used for analysis in this paper are freely available on figshare ( https://doi.org/10.6084/m9.figshare.22138004 ).  Source data are provided with this paper.

Code availability

Scripts and data files used for analysis in this paper are freely available on figshare ( https://doi.org/10.6084/m9.figshare.22138004 ) and on GitHub ( https://github.com/a-healey/r570scripts ).

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Acknowledgements

The work (proposal: https://doi.org/10.46936/10.25585/60001084 and https://doi.org/10.46936/10.25585/60001194 ) conducted by the USA Department of Energy (DOE) Joint Genome Institute ( https://ror.org/04xm1d337 ), a DOE Office of Science User Facility and the DOE Joint BioEnergy Institute, are supported by the Office of Science of the USA Department of Energy operated under Contract No. DE-AC02-05CH11231 with Lawrence Berkeley National Laboratory. The work conducted at CIRAD was supported by the International Consortium for Sugarcane Biotechnology. The work at the Institute of Experimental Botany (IEB) was supported by the ERDF project “Plants as a Tool for Sustainable Global Development” No. CZ.02.1.01/0.0/0.0/16_019/0000827. We thank M. Tsai of HudsonAlpha for uploading libraries to the Short Read Archive of NCBI and D. Flowers for the ESMfold scores of sugar transport genes.

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Genome Sequencing Center, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

A. L. Healey, J. T. Lovell, A. Sreedasyam, J. Jenkins, C. B. Plott, M. Williams, L. B. Boston, J. Webber, J. Grimwood & J. Schmutz

CIRAD, UMR AGAP Institut, Montpellier, France

O. Garsmeur, N. Pompidor, J. Y. Hoarau, C. Hervouet, C. Zini, A. Dievart & A. D’Hont

UMR AGAP Institut, Univ Montpellier, CIRAD, INRAE, Institut Agro, Montpellier, France

Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

J. T. Lovell, S. Shengquiang, J. W. Carlson, A. Lipzen, K. Keymanesh, S. Tejomurthula, K. Barry & J. Schmutz

Sugar Research Australia, Te Kowai, Queensland, Australia

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ERCANE, Sainte-Clotilde, La Réunion, France

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Arizona Genomics Institute, University of Arizona, Tucson, AZ, USA

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CSIRO Agriculture and Food, Urrbrae, South Australia, Australia

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Queensland Alliance for Agriculture and Food Innovation, University of Queensland, Brisbane, Queensland, Australia

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Contributions

C.M., J.D., P.C., S.R., M.W., C.H., L.B.B., J.W., P.P. and J.G. performed the DNA extraction, library preparation and sequencing. A.L.H., O.G., J.T.L., S.S., J.J., C.B.P., V.L. and J.C. performed the genome assembly and annotation. The analysis was conducted by A.L.H., O.G., J.T.L., V.L., N.P., N.H., J.Y.H., C.Z., A.F., A.D., R.S., J.S., K.A. and A.D.H. A.L.H., O.G., J.T.L., A.S., V.L., J.S., K.A. and A.D.H. wrote the manuscript. A.L.H., G.M., B.S., K.B., R.J.H., J.G., J.S., K.A. and A.D.H. contributed to the conception, project management and resource contribution.

Corresponding authors

Correspondence to A. L. Healey , J. Schmutz or A. D’Hont .

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Nature thanks Elizabeth Cooper and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended data fig. 1 r570 genome assembly overview and analysis..

A) Simplified genome assembly pipeline for sugarcane R570. The pipeline combines multiple sequencing technologies (HiFi contigs, optical map, genetic map, single chromosome libraries, Hi-C, Sorghum synteny), leveraging the strengths of each for phasing homeologous chromosomes, while using manual inspection and iterative steps to overcome each technology’s weaknesses. See ‘ Supplemental Data ’ for a full explanation and rationale for each step. B) Hi-C read heatmap for R570. Chromosomes are clustered based on homology, with Hi-C reads (~ 56X coverage) aligned to the finalized version of the assembly. C) Alignment of primary and alternate chromosomes. During genome construction and finalization, near perfect duplicate contigs were discovered when constructing chromosomes, which were binned into an alternate assembly to improve the utility of the genome (see  Supplemental Data ). When possible these contigs were ordered and oriented into chromosomes based on their closest, unique alignment in the primary assembly. For example, Chromosome 6E and its anchored alternate were aligned using nucmer (v4.0; -l 100 --maxmatch -b 400). Dots represents a 1-1 alignment between the two sequences that is greater than 15 kilobases in length. Each point is coloured based on alignment percent identity. D) Haplotype collapse summary for R570. To quantify regions of haplotype collapse within the R570 genome, PacBio HiFi reads were aligned to the assembly, using read depth to determine haplotype copy number. 0X unique coverage regions represent genomic blocks where reads could not uniquely map between the primary and alternate assembly. Counted bases represent genome sequences where depth could be reliably calculated (0-4X). Represented bases account for collapsed bases in the assembly (example 1 Mb of 3X coverage = 3 Mb represented sequence). E) Simplex marker densities in the sugarcane R570 genome. Simplex markers (80 bp) from the R570 genetic map (obtained by testing 3:1 segregation pattern in 96 genotyped S1 progeny) were searched in the R570 genome assembly, retaining only exact, single copy match locations. Position densities were then visualized by calculating the percent number of matched bases per 10 kb sliding window (1 kb step length). Lines underneath each chromosome correspond to progenitor and haplotype collapse block assignments.

Extended Data Fig. 2 Sugar accumulation candidate gene alignments.

A) Alignment of syntenic orthologs for SUT4 (Sobic.008G193300). B) Alignment of syntenic orthologs for SIP2 (Sobic.002G075800). C) Alignment of syntenic orthologs for PME (Sobic.005G082100). Top section for each panel shows the full length of the alignment, while the bottom section displays a zoomed in region (outlined in a pink dotted outline) to show specific differences among species and alleles. Prog- progenitor assignment of R570 alleles. Each ortholog position was intersected with progenitor assignments to assign origin to each peptide. %PID- Percent pairwise identity (number of matches/alignment length * 100) for each syntenic ortholog relative to the S. bicolor (BTx623). Copy number (CN)- PacBio HiFi read depths (representing collapsed identical haplotypes) ranges were intersected with gene position to provide an indication of additional collapsed alleles (eg. copy number = 2; one represented allele + one identical collapsed allele). Fold score (FS)- syntenic orthologs (except for monoploid annotated peptides) were folded using ESMfold and scored for quality. Score provided is the percent of high-quality amino acids present in the peptide sequence.

Supplementary information

Supplementary information.

This file contains Supplementary text and data, Table 1, Figs. 1–15 and References.

Reporting Summary

Supplementary table 2.

Haplotype depth summary across the genome assembly.

Supplementary Table 3

Syntenic orthogroups among S.bicolor , S. spontaneum , R570 monoploid path, R570 primary assembly.

Supplementary Table 4

Synonymous (Ks) peak among orthologs between S. officinarum and S. spontaneum .

Supplementary Table 5

Progenitor base assignment summary.

Supplementary Table 6

Progenitor assigned blocks base in genome.

Supplementary Table 7

Haplotype windowed depth blocks across the genome.

Supplementary Table 8

Allelic diversity among progenitors within orthogroups.

Supplementary Table 9

Intersection of genes and haplotype depth.

Supplementary Table 10

List of genes impacted by structural variants.

Supplementary Table 11

Resistance gene analogue motif locations.

Supplementary Table 12

Resistance gene analogue enrichment values.

Supplementary Table 13

Bru1 curated candidate genes and function.

Supplementary Table 14

SRA Bioproject information.

Source data

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Healey, A.L., Garsmeur, O., Lovell, J.T. et al. The complex polyploid genome architecture of sugarcane. Nature (2024). https://doi.org/10.1038/s41586-024-07231-4

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