The Scientific Observer Issue 32

Half-Synthetic Yeast Engineered for the First Time How Body-on-a-Chip Is Transforming Research ISSUE 32, NOVEMBER 2023 Biology NATURE'S TOOLS, REDESIGNED 2 CONTENT FROM THE NEWSROOM 04 ARTICLE Half-Synthetic Yeast Engineered for the First Time 06 Molly Campbell RESEARCH SPOTLIGHT Implanting Microdevices Into Brain Tumors To Determine the Best Treatment 09 Suhanee Mitragotri ARTICLE Addressing the Question of Nutritional Equivalence in Future Foods 11 Karen Steward FEATURE ARTICLE Synthetic Biology: Nature's Tools, Redesigned 15 Kerry Taylor-Smith ARTICLE How Body-on-a-Chip Tech Is Transforming Research 20 Kate Robinson & Lucy Lawrence ARTICLE The Latest Frontiers in Agricultural Science 24 Molly Campbell 06 20 15 FEATURE Synthetic Biology: Nature's Tools, Redesigned Kerry Taylor-Smith AnnaMaria Vasco, iStock 3 Kate Robinson Kate Robinson is an Assistant Editor at Technology Networks. EDITORS’ NOTE CONTRIBUTORS Have an idea for a story? If you would like to contribute to The Scientific Observer, please feel free to email our friendly editorial team. Kerry Taylor-Smith Kerry Taylor-Smith is a Science Writer who covers everything from climate change and the environment to health and wellness, to material science, astronomy and space. Karen Steward, PhD Karen is a Senior Science Specialist for Technology Networks. Lucy Lawrence Lucy is a Senior Digital Content Producer at Technology Networks. Molly Campbell Molly is a Senior Science Writer at Technology Networks. Suhanee Mitragotri Suhanee is a student at Harvard University, majoring in neuroscience with a minor in global health and health policy. Dear Readers, Welcome to issue 32 of The Scientific Observer, the monthly magazine brought to you by Technology Networks. From the Technology Networks newsroom, we bring you a curation of the most interesting research stories from the last month. Did you know that female chimpanzees can experience menopause? Or that your favorite music might help to sooth the experience of pain? From alarming pesticide research in Sri Lanka to a world-first virology discovery at the University of Pittsburgh, this issue’s news highlights aren’t to be missed. The intersection of science and agriculture will be critical for addressing our planet’s growing population and the effects of climate change. Synthetic biology – a field that fuses biology and engineering – will undoubtedly play a profound role, offering innovative solutions to enhance crop resilience, increase yields and minimize the environmental footprint of agriculture. In this month’s feature article, Kerry Taylor-Smith explores how nature’s tools – when redesigned – can support humanity’s efforts to combat some of our biggest global issues. Also in issue 32, Molly Campbell reports on a recent announcement from The Synthetic Yeast Genome Project 2.0. The project – which aims to synthesize an entirely synthetic yeast genome – is now halfway to achieving its goal after engineering yeast that has an over half synthetic genome. The milestone brings us one step closer to harnessing synthetic genomes for a multitude of purposes, such as the production of medicines or biofuels. This, and much more, in issue 32 of The Scientific Observer. The Technology Networks Editorial Team 4 From the Newsroom FROM THE NEWSROOM In a first-of-its-kind discovery, scientists visualize a satellite virus latching onto a helper virus. JOURNAL: Journal of the International Society of Microbial Ecology Viruses Can Latch Onto One Another MOLLY CAMPBELL Your favorite music might be good for more than a workout soundtrack or late-night listening session, suggests a new study. The research suggests that individuals’ most-loved music could reduce feelings of pain compared to relaxing stock music. JOURNAL: Frontiers in Pain Research Pain-Busting Ballads: Researchers Identify Music That Best Soothes Pain RUAIRI J MACKENZIE Female chimpanzees in the wild can experience menopause and survival past their reproductive years in a similar way to humans, reveals a new study that could help researchers to understand why menopause and post-fertile survival occur in nature as well as its evolution in humans. JOURNAL: Science Wild Chimpanzees Can Experience Menopause Similar to Humans SARAH WHELAN 5 FROM THE NEWSROOM 5 Want to learn more? Check out the Technology Networks newsroom. A new study suggests that the active ingredient in Roundup – the world’s most popular herbicide – may play a role in the epidemic levels of chronic kidney disease seen in rural Sri Lanka. JOURNAL: Environmental Science and Technology Letters Popular Herbicide Ingredient Linked to Chronic Kidney Disease Epidemic in Sri Lanka ALEX BEADLE In a new paper, researchers say they have found “definitive” archeological evidence that seaweeds and other freshwater plants were eaten in Europe from the Mesolithic period to the early Middle Ages. JOURNAL: Nature Communications Ancient Europeans Regularly Ate Seaweed LEO BEAR-MCGUINNESS 6 SCIENTISTS ENGINEER A STRAIN OF YEAST THAT HAS AN OVER HALF SYNTHETIC GENOME. T he Synthetic Yeast Genome Project 2.0 (Sc2.0) is a global project working to synthesize the entire yeast genome. In a collection of papers spanning Cell, Molecular Cell and Cell Genomics, the project declares a major milestone: it has created a yeast strain comprising over 50% synthetic DNA. GENERATING SYNTHETIC GENOMES Synthetic genomes are created by designing and assembling DNA sequences that are then inserted into an organism’s cells, effectively allowing researchers to “customize” the organism with certain characteristics. It’s an area of research within synthetic biology that utilizes recent advances in molecular biology, genetic engineering and gene synthesis. “Writing a genome is in many ways a test of how well you understand its function and its evolved natural ‘design’, says Dr. Jef Boeke, a synthetic biologist at New York University (NYU) Langone Health and the leader of Sc2.0. The first efforts to generate synthetic genomes largely focused on viruses or bacteria. In 2010, scientists from the J. Craig Venter Institute synthesized the first synthetic bacHalf-Synthetic Yeast Engineered for the First Time MOLLY CAMPBELL iStock terial genome Mycoplasma mycoides JCVI-syn1.0. Boeke and colleagues have been working hard on Sc2.0 for at least 18 years, as synthesizing a yeast genome is more technologically challenging than a bacterial genome. “It’s substantially bigger. It’s more repetitive than bacterial genomes, and it’s made up of many individual chromosomes, whereas most bacteria have only one,” Boeke explains. It’s a challenge that is worthwhile in Boeke’s mind, considering that humans are more closely related to yeast than bacteria, making yeast a better model for understanding how human cells work. YEAST’S DESIGNER GENOME The half-synthetic yeast has a “designer” genome that is based on Saccharomyces cerevisiae (S. cerevisiae), commonly referred to as baker’s or brewer’s yeast. Boeke and colleagues wanted to create a strain that could help them understand how the model organism functions and how it could be improved. It was therefore important that the synthetic yeast was highly modified. Non-coding and repetitive elements of DNA were removed and a diversity generator called Synthetic Chromosome Recombination and Modification by LoxP-mediated Evolution, or the “SCRaMbLE” system, was added. Boeke and colleagues also created a new chromosome, which does not exist in nature. Genes encoding transfer R NA (tR NA) are often associated with regulatory elements that can lead to stability issues when integrated into a synthetic chromosome. The researchers decided to remove these genes and created a tRNA “neochromosome”. “The tR NA neochromosome is not modeled on an existing natural chromosome but was literally designed piece by piece, on a computer, and the pieces came from at least 5 different species of microorganisms,” says Boeke. “The fact that it can function, by producing tR NAs like a natural genome does, is pretty amazing. It is also designed to avoid ‘head-on collisions’ between R NA polymerase and DNA polymerase which can lead to DNA breaks and other challenges for the cell.” STRAIN GENERATED THAT IS OVER 50% SYNTHETIC S. cerevisiae’s genome is organized into 16 chromosomes, with each team in the consortium responsible for producing one synthetic chromosome at a time. “Sc2.0 started small and grew to be a project involving researchers in four continents and nine countries,” says Boeke. The teams independently assembled each chromosome to produce 16 strains, each of which comprised 15 native chromosomes and one synthetic chromosome. The next challenge was finding a way to pull all of the synthetic chromosomes together. The researchers developed a new method called chromosome substitution to bring the synthetic chromosomes together in a single strain. “We combined two methods to do this: transfer of the synthetic chromosome to a recipient strain by doing a special kind of genetic cross. In this cross, a single chromosome moves from one nucleus to the other – a process called ‘chromoduction’,” explains Boeke. “This leads to a cell with one extra synthetic chromosome. At this point, the resident natural chromosome corresponding to it can be destabilized by forcing R NA polymerase to traverse its centromere, a process that greatly destabilizes it. Et voila! A cell with a synthetic chromosome swapped in place of a native chromosome.” By integrating seven of the synthetic chromosomes, Sc2.0 has succeeded in generating a strain that is over 50% synthetic. The synthetic yeast strain was found to possess genetic defects, or “bugs”, such as genetic interactions between genes located on the synthetic chromosomes. Such issues had been anticipated, so Boeke and colleagues were prepared to map the bugs and find a fix. “The defects can result from R NA Scanning electron micrographs of the syn6.5 strain of yeast which has ~31% synthetic DNA and displays normal morphology and budding behavior. 7 Cell/Zhao et al 8 iStock not folding up as it should,” says Boeke. “Once mapped, bugs can be easily corrected by removing the changed bases and restoring the native sequence. This has already been done for every bug.” A MAJOR MILESTONE The collection of papers marks a milestone in genomics and synthetic biology, but the real fun will begin once the rest of the synthetic chromosomes are integrated. “That’s when we’re really going to be able to start shuffling that deck and producing yeast that can do things that we’ve never seen before,” says Boeke. Synthetic genomes designed for the production of medicines or biofuels might well become a reality in the near future – the foundations are being laid, after all. Boeke is often asked, “which genome is next”? His team at NYU Langone Health is currently working on “The Dark Matter Project”, which seeks to understand what new information lies in the non-protein-coding portion of the mammalian genome. ⚫ Dr. Jef Boeke was speaking to Molly Campbell, Senior Science Writer for Technology Networks. References 1. Zhao Y, Coelho C, Hughes A, et al. Debugging and consolidating multiple synthetic chromosomes reveals combinatorial genetic interactions. Cell. 2023. doi: 10.1016/j. cell.2023.09.025 2. Schindler D, Walker R, Jiang S, et al., Design, construction, and functional characterization of a tR NA neochromosome in yeast. Cell. 2023. doi: 10.1016/j.cell.2023.10.015 3. Shen Y, Gao F, Wang Y, et al. Dissecting aneuploidy phenotypes by constructing Sc2.0 chromosome VII and SCRaMbLEing synthetic disomic yeast. Cell Genomics. 2023. doi: 10.1016/j.xgen.2023.100364 4. McCulloch L, Sambasivam V, Hughes A, et al. Consequences of a telomerase-related fitness defect and chromosome substitution technology in yeast synIX strains. Cell Genomics. 2023. doi: 10.1016/j.xgen.2023.100419 WANT TO LEARN MORE ABOUT SYNTHETIC BIOLOGY? Visit the Technology Networks synthetic biology topic hub, where you can access educational resources, events, news and products related to synthetic biology. 9 iStock Implanting Microdevices Into Brain Tumors To Determine the Best Treatment Suhanee Mitragotri RESEARCH SPOTLIGHT Malignant brain tumors account for one to two percent of all types of cancers in adults and remain one of the hardest types of cancer to treat. A multi-institutional study published in Science Translational Medicine, led by Dr. Pierpaolo Peruzzi at Brigham and Women’s Hospital, demonstrates the potential for using intratumoral microdevices (IMDs) to test various cancer drugs on the tumor before implementing systemic treatment. iStock 9 Research Spotlight 10 iStock THE CHALLENGE OF HETEROGENEITY IN BRAIN TUMORS Gliomas, one of the most aggressive forms of brain tumors in humans, have been researched heavily over the past decades and various genes have been implicated in this cancer, including EGFR, PDGFRA, and TP53. Therapies have been developed to target these genes and inhibit cancer growth and proliferation. While these therapies have been successful in preclinical models, many of them have shown variable success in clinical testing, largely because every glioma has a distinct genetic makeup and developing therapies that can target mutant genes in all patients is extremely difficult. Therefore, it has become evident that cancer treatments for patients would be most effective if they are created based on the specific genetic profile of the tumor at hand. Inspired by this era of personalized medicine, Peruzzi et al. developed tiny biocompatible IMDs that can be inserted into the tumor at the time of surgery and release small doses of different drugs at distinct points in the surrounding tissue over the course of two hours. Afterwards, the tissue can be analyzed to measure the impact of each individual drug on the cancer’s growth and proliferation. ASSESSING SAFETY AND EFFICACY OF MICRODEVICES IN DELIVERING DRUGS Six patients diagnosed with brain tumors were enrolled in the study (50% female, 50% male). The median age of the participants was 76 years, with a range between 27 and 86 years of age. All patients were already scheduled to undergo tumor resection surgery during which each had two IMDs implanted at the tumor site, giving a total of implanted 12 IMDs. The researchers delivered nine drugs through the IMDs, specifically temozolomide, doxorubicin, lapatinib, lomustine, irinotecan, carboplatin, osimertinib, abemaciclib and everolimus. They measured the safety of the IMDs in all patients and analyzed the feasibility of conducting molecular analysis on the tissue after surgery. They assessed DNA damage (via pH2AX expression) and apoptosis (via CC3 expression) in the tissue surrounding the IMD, as well as measuring how distance from the implantation site impacted the degree of drug effect. The key findings of the paper were: • The IMD implantation resulted in no adverse events or significant changes in surgical outcomes or cost, and 11 out of the 12 implantations resulted in tissue specimens that could be successfully processed in molecular analysis. • The greatest degree of DNA damage in the surrounding tissue was found in patient 3, where 65.8% of the cells were impacted, and the lowest amount was found in patient 5, where 9.8% of the cells were impacted. • Apoptosis induction was generally low (< 5%), except in patient 3, where it was measured in 13.1% of the cells. • The greatest DNA damage was found in tissue near the IMD site and was found to decrease with lower doses. • Changes in gene transcription on a drug-to-drug basis correlated with the pathways each drug targeted, confirming that the drugs worked as expected. ANALYZING TISSUE FROM THE IMD SITE TO DETERMINE DRUG EFFICACY Dr. Peruzzi and his team have demonstrated the potential that IMDs have in quickly assessing the best treatment for a specific patient’s brain tumor. The implementation of IMDs was safe in all patients and did not impact the outcomes of surgical procedures or increase surgical costs significantly. By measuring the amount of DNA damage and apoptosis in the tissue surrounding the IMD, the researchers were able to assess the impact that each drug had on cancer progression, as each drug was released in a distinct location within the tissue. A variable range of DNA damage was seen from patient to patient, which could be due to the heterogeneity of tumors. Furthermore, DNA damage appeared to be concentrated at the IMD site, indicating that the delivery of treatment was localized. While this study displays the promise that IMDs could have in the treatment of brain tumors, there are limitations to the work. Firstly, since the IMD implantation was conducted in patients who were already undergoing scheduled surgery, the IMD could only be inside the tumor for around two hours, which may not have been enough time to observe changes in markers for apoptosis. Furthermore, the study consisted of a small population size, and larger clinical studies will need to be conducted to confirm the predictive capability of IMDs. THE NEED FOR LARGER AND LONGER CLINICAL STUDIES Brain tumors remain one of the hardest cancers to treat, largely due to their heterogeneity, but Peruzzi et al. have developed a viable technology that can provide physicians with information as to what treatments are the most effective for a given patient’s tumor. Larger clinical studies that build upon this research should consider ways to leave the IMD in the tumor for longer periods of time, to maximize the effect that these drugs can have on the surrounding tissue and provide doctors with more accurate information regarding their efficacy. In an era of personalized medicine, IMDs could hold the key for the future of cancer treatment and clinical care. ⚫ RESEARCH SPOTLIGHT 10 11 iStock ALTERNATIVE PROTEINS CAN BE A SUSTAINABLE SUBSTITUTE FOR MEAT BUT CONSUMERS SHOULD BE AWARE OF NUTRITIONAL VARIABILITY T here is no denying that our food supply chain is a system under stress with our ever-expanding population, compounded by a changing climate that’s squeezing producers to maximize production under increasingly challenging circumstances. And then there’s the environmental impact that agriculture itself is having, with livestock rearing fingered as a significant contributor, feeding back into a cyclical problem. It is therefore no wonder that the research into and appetite for alternative protein sources has exploded in the last few years. Multiple avenues are being explored, some more novel and ambitious than others, including microbial fermentation, cellular agriculture, mycoproteins, insects, algae and plant-based proteins. While the likes of cellular agriculture are still providing the consumer with animal cells and the nutritional value they convey, the same cannot necessarily be said for their plant-based counterparts. THE LABELING ILLUSION Look at most food packaging and it will provide you with a breakdown of the nutritional values of that product. However, how many of us really understand what we are being shown or what’s being hidden? While nutritional breakdowns may give us an idea of the number of grams of saturated fat something contains or its calorific value, we are only seeing part of the picture. Labels generally state the protein content grouped together as a single entity, but proteins are made up of amino acids, the composition of which can vary greatly from protein to protein. This fact is vitally important when we consider our dietary needs. While our bodies are able to synthesize some amino acids, others must be ingested in the food we eat, hence it is important that we include protein sources rich in these missing “essential amino acids” in our diet. But looking at most packaging, it is Addressing the Question of Nutritional Equivalence in Future Foods KAREN STEWARD 12 iStock not possible to tell whether the amino acids obtained from a plant-based burger, for example, are equivalent to those we could obtain from eating its meat-based counterpart. The amino acid make-up is not the only aspect that may vary either. Digestibility, a factor impacted by how the building blocks of molecules are put together in those foods, can have a great impact on what we can or cannot obtain from it. The presence of so called “antinutrients”, such as phytic acid, present in some legumes used as a popular meat substitute, can also reduce the bioavailability of nutrients and compounds present. So, what may superficially appear “the same”, has the potential to mask important differences in nutritional values. A 2019 consumer survey conducted by the International Food Information Council highlighted how presenting nutritional information in this way can impact consumer attitudes and opinions towards foods that will inevitably influence their food choices. ARE PLANT-BASED FOODS NUTRITIONALLY EQUIVALENT TO ANIMAL PRODUCTS? In short, the answer to this question is no. However, that’s not to say meat = good, plants = bad, there are wins and losses on both sides. A 2021 study by Dr. Stephan van Vliet and colleagues at Duke University School of Medicine, published in Science Reports, highlighted some of these discrepancies at the metabolic level. The team used untargeted metabolomics to explore the metabolite profiles of grass-fed ground beef and a popular plant-based alternative that had been matched for serving size and fat content. While the nutritional labeling on the products appeared very similar, their analyses revealed around a 90% difference in metabolite profile between the foods that spanned the nutrient classes, including amino acids, fatty acids, vitamins and phenols. Teasing these results apart showed that 22 metabolites were found exclusively in the beef and a further 51 were in greater quantities in the beef than the plant-based alternative. However, 31 metabolites were found exclusively in the plant-based alternative and a further 67 were in greater quantities than in the beef product. While the beef provided compounds such as glucosamine, which benefits connective tissues and blood vessels, and antioxidants including squalene that the plant-based product lacked, the plant-based alternative provided vitamin C and phenolic antioxidants among other beneficial molecules that were absent in the beef. The study gives us a taste of just how different these apparently similar foods are and the problem with routinely tracking (around 150 in the case of many databases) and reporting (around 13 in the case of most nutritional information labels) only a fraction of the nutritional components and/or grouping them together. This also highlights that studies based on label or categorization information rather than more comprehensive analytical data may miss important shortcomings and benefits of both animal products and their alternatives. The authors concluded from their results that, on this basis, the products shouldn’t be viewed as interchangeable but instead as complementary to one another from a nutritional standpoint. They write, “The complexity of the whole food matrix—as indicated here by our metabolomics findings—highlights that attempting to mimic food sources using single constituents such as isolated proteins, vitamins and minerals is challenging and arguably underestimates the complexity of the food source it is meant to mimic.” This echoes evidence from other groups that protein sources are not metabolically or nutritionally equivalent, with De Marchi and colleagues finding 21-fold less methionine—an essential amino acid for humans—in plant-based compared to beef burgers. They concluded that complete and unbiased nutritional information on such products is necessary so that consumers can adjust their diet accordingly to continue to meet their nutritional needs. Since then, further studies have gone on to add to this body of evidence, look for alternative sources that do deliver high-quality protein and ways to bridge the gap. A NEED FOR GUIDANCE A number of studies have also highlighted nutritional disparities of animal, traditional plant-based and novel plant-based foods that may be visible on nutritional labels but to which many of us may pay little attention based 13 on our preconceptions about plantbased alternatives compared to their animal-based counterparts. In a bid to enhance the sensory appeal of novel alternative proteins over some traditional plant-based substitutes, some products have turned to the addition of salt, sugar and fat and are themselves classed as ultra-processed foods. A 2021 study from Tso and Forde found that while a diet of traditional plant-based substitutes met daily requirements for calcium, potassium, magnesium, phosphorus, zinc, iron and Vitamin B12 and was lower in saturated fat, sodium and sugar than the reference omnivorous diet, diets based on novel plant-based substitutes failed to meet daily requirements for calcium, potassium, magnesium, zinc and Vitamin B12 and exceeded the reference diet for saturated fat, sodium and sugar. A 2022 study from researchers at the University of Göttingen highlighted the differences in nutritional values for both meat and cheese against their plant-based alternatives using nutritional scoring and analytical chemistry-based techniques to evaluate vitamin and mineral content. The work highlighted that fat, saturated fatty acids and salt in particular varied considerably between the samples tested. While some of these differences may be visible on nutritional labels, the authors suggested that because of these types of differences, “consumers need guidance on how to compose a balanced plant-based diet.” This message is reinforced by a UK study highlighting the high level of salt in five out of six plant-based meat alternatives tested, with three quarters not meeting UK salt intake guidelines. In Canada, legislation has been introduced this year stipulating criteria for the protein content, protein quality and minimum content of a range of vitamins and minerals permitted in meat alternatives to try and help address some of these concerns. FILLING THE GAP Redressing nutritional inequities, both present and absent from nutritional labels, between alternative protein sources and the animal products they are seeking to emulate is understandably an active area for future foods research. Enhancing the micronutrient profile while reducing reliance on nutritionally sensitive components such as salt and sugar are of particular interest. Fortification is one method by which missing components may be added to meat alternatives. Vitamin B12 is a good example, being important to health but typically absent or only present in unavailable forms in plants. However, adding individual components without the complex matrix in which they are found in the original meat product may mean that synergistic benefits gained from meat consumption will still be impaired. Genes may be engineered in that enhance the capabilities of plants or cells to produce these missing nutrients. This approach has been utilized successfully to enhance the nutritional value of bovine cells used to produce cell-cultured meat. However, in this particular case, the scientists sought to provide added nutritional benefits that would not normally be present in the original meat product rather than add back in something that was missing. Even if a nutrient is present in both the meat and alternate protein source on analysis, that does not necessarily mean that its bioavailability is the same in both foodstuffs. Take iron for example. In meat, iron is present in heme, which has greater bioavailability than the non-heme form found in plants such as legumes that provide popular meat alternatives. To address this, scientists have developed a novel plant-based alternate protein source in which the iron is present in the heme form thanks to a soy leghemoglobin protein preparation derived from Pichia pastoris yeast. However, while encouraging, this is far from standard practice in foods we are likely to find on supermarket shelves. FOOD FOR THOUGHT While recent innovation in the alternative protein source space has seen great improvements in organoleptic properties such as texture, taste and appearance, it would appear that there is still much to be done to address nutritional inequalities. The general message seems to be that alternative protein sources, especially those derived from plants, can provide a more sustainable alternative to animal products but currently there is a significant degree of nutritional variability within the field. Consequently, it is important that consumers do not see many of these products as a straight swap or consider only the protein quantity of the product, with a more flexitarian approach to their consumption advised by some. At risk groups such as children, pregnant women and the elderly need to be particularly careful and improvements in regulation and legislation standards could help to safeguard shoppers. ⚫ It is important that consumers do not see many of these products as a straight swap or consider only the protein quantity of the product. It’s simple, just choose the groups and click the bubble. Our Facebook groups allow you to keep up to date with the latest news and research and share content with like-minded professionals. With three diverse groups there is something for everyone. Hi. How are you? Have you seen our Facebook groups? Thanks! I’ll come join the conversation. Come join the Neuroscience, News and Research Group here. Discover the Analytical Science Network Group here. Explore The Science Explorer Group here. No I haven’t. Could you tell me more? Sounds great! How do I join? Biology NATURE'S TOOLS, REDESIGNED KERRY TAYLOR-SMITH AnnaMaria Vasco 16 iStock Credit Line S ynthetic biology is a multidisciplinary field that remodels organisms for useful purposes by engineering them to have novel abilities, often drawing inspiration from nature to build molecular components that don’t exist in the natural world. It uses living organisms to solve problems by breaking them down into individual components and applies engineering principles to coordinate changes to R NA, DNA and proteins to form biological systems with novel functions. These systems can be designed based on known biology, or from scratch, to carry out a certain task. “I like a simple definition, that contrasts analytic biology, the study of living systems that already exist in nature, with synthetic biology, which makes new or modified living systems that do not exist in nature,” says Dr. Jamie A Davies, professor of experimental anatomy at the University of Edinburgh. “This links nicely with the dichotomy between analytical chemistry, the study of what already is, and synthetic chemistry, which makes something new.” Synthetic biology has several useful applications, in conservation for example, to restore biodiversity and confer disease and stress resistance, in bioremediation to clean pollutants from the air and water, in manufacturing, agriculture and farming and in biofuels. In medicine, synthetic biology is helping scientists to better understand diseases and treatment. It can be used to produce drugs and new vaccines, improve monitoring and diagnosis and alter human cells with properties designed to help patients. Research is also turning its attention to building new tissues. SYNTHETIC BIOLOGY AND THERAPEUTICS Nature is an important source of bioactive products, and therefore often a source of new therapeutics; over the last 30 years most anticancer, anti-infective and anti-bacterial drugs originated from natural sources, like plants, fungi or bacteria, and their derivatives. But developing a new therapeutic is time-consuming, expensive and challenging; it can take 10 to 15 years from target identification to approval, and cost as much as $2.9 billion per drug, with only 1 in 5,000 targets making it to market. Synthetic biology can aid the design of new therapeutics in two broad ways, says Davies: “One is epitomized by CAR T cells used to treat cancer: engineering human cells to have new properties that are useful, for example, the ability to mount a ferocious attack on a patient's tumor, and put them back into the body to do that job.” CAR T, or Chimeric Antigen Receptors T-Cell Therapy, is a highly complex and innovative type of immunotherapy that harnesses a patient’s own immune system to target cancer cells. T cells or lymphocytes are harvested from the patient’s blood and genetically engineered in the lab to recognize and bind to specific proteins, or antigens, on the surface of cancer cells, before eradicating them. These therapies initially focused on acute lymphoblastic leukemia (ALL), the most common cancer in children, but have the ability to eradicate very 16 iStock 17 advanced leukemias and lymphomas, and can keep cancer at bay for several years after infusion. The second way that synthetic biology can aid drug discovery, says Davies, is engineering cells to perform the physiological role of another, for example, non-pancreatic cells to make insulin in response to blood sugar. This application is currently experimental and not yet used in humans. “People with type 1 diabetes destroy natural pancreatic cells because of an autoimmune problem, but do not destroy other cells, like skin cells, so engineering these other cells to do the insulin job would cure diabetes,” he says. Scientists at the J. Craig Venter Institute have engineered bacterial cells that naturally live deep within the skin to function like insulin cells, which entered preclinical testing in 2021. “A nd you can extend this idea to many similar diseases,” Davies says. The other broad way is using engineered metabolic pathways to produce difficult-to-make drugs, notes Davies: “The real example in current use is engineering production of the antimalarial drug artemisinin into yeast cells, by 'borrowing' genes from plants to build up a new metabolic pathway in the yeast. A nd this idea could be extended to all sorts of other molecules.” The main source of artemisinin is extracted from Artemisia annua; however, its artemisinin content is only 0.1–1% – nowhere near enough to meet global demand. The chemical synthesis of artemisinin is complicated, expensive and offers a low yield, so the ability to produce artemisinin in vivo using synthetic biology is attractive. Researchers have explored the option of synthesizing artemisinin using Escherichia coli (E. coli) and Saccharomyces cerevisiae (S. cerevisiae) as chassis cells – a cellular host or recipient of engineered biological systems in synthetic biology – and yeast as the cell factory, thus transferring the production of artemisinin from plant to yeast. Synthetic biology is highly and rapidly adaptable, making it ideal to respond to urgent needs like vaccines. An approach focusing on large-scale nucleic acid manipulation was successfully used to create a COVID-19 vaccine, while genomic codon deoptimization is used to create injectable and nasal vaccines against the f lu and respiratory syncytial virus. Other vaccines are based on introducing DNA and R NA components encoding viruses into human cells. These cells produce viral antigenic peptides in a repetition of the natural infectious process to induce immunity. SYNTHETIC BIOLOGY AND DIAGNOSTICS Synthetic biology also has a role to play in diagnosing disease; systems can be introduced into cells to sense biological signals and chemical substances within the cell, and even respond to stimuli. Davies says synthetic biology’s role here is to engineer cells or proteins to be sensitive and accurate sensors of markers of disease: “This might include a simple test, a drop of blood or urine, or even a patch on the skin, to report all the time to a reader that can talk to a mobile phone and let doctors monitor how someone is doing. These sensors offer the promise 18 iStock to be combinatorial too – to measure many things at once.” Techniques based on gene circuit construction and rapid, iterative prototyping have enabled the development of devices, ranging from whole-cell living assays to engineered cell-free nucleic acid sensors and amalgams in between, which have been applied to non-communicable diseases such as cancer and coronary artery disease, and communicable diseases. One area of active research is paper-based toehold switch R NA sensors. RNA toehold switch sensors are robust molecular switches that can detect R NA molecules in a sequence-specific way, and when combined with a paper-based cellfree molecular diagnostic platform, are capable of detecting Ebola, Zika virus, COVID-19 and other respiratory diseases. Another is the use of CR ISPR-Cas technology as a rapid molecular diagnostics tool for nucleic acids and detection of pathogens. The technique enables researchers to target specific stretches of genetic code and to edit DNA at precise locations. Each disease-causing virus or microbial pathogen has a characteristic sequence of nucleic acids. CR ISPR-Cas technology can recognize and snip this specific nucleic acid sequence in a sample, meaning it can be used as a diagnostic biomarker. Screening based on CRISPR-Cas can be helpful in searching for biomarkers that identify populations sensitive to a certain cancer treatments, for example. SYNTHETIC BIOLOGY AND AGRICULTURE CR ISPR isn’t just limited to medical applications; it also has a role to play in farming and agriculture, where it is an effective technique for manipulating a number of crops, including maize, wheat and apples. Genetic editing can be used to introduce desirable qualities into plants in a faster, controlled and specific way. It allows scientists to make very precise changes to the plant’s DNA to confer traits, such as immunity or resistance against a certain pests or pathogens, to change how the plant grows or to change the soil microbiome to help improve crop yield and quality. “Synthetic biology approaches, like genetic editing, can help improve food security, increase the yield and the resilience of crops in the face of climate change,” says Professor Alistair McCormick, chair of plant engineering biology at the University of Edinburgh. “The population is expected to reach 10 billion by 2050, and we need to improve all of these to feed the growing population.” Genetic editing gives us the ability to grow the same crops on the same amount of land, but with a better yield, says McCormick, citing the recent example of knocking out the gene KRN2 in rice and maize, which led to 8 and 10% increases in grain yields, using thanks to gene editing. The technique also allows scientists to alter the characteristics of staple crops like rice, which have been modified to produce beta carotene, a nutrient typically associated with preventing vitamin A deficiency , and to develop a type of wheat less likely to produce acrylamide, a potentially carcinogenic compound, during cooking or baking. This Synthetic biology is helping scientists to better understand diseases and treatments. 19 wheat has recently been subject to its first ever field trial and showed a significant reduction of acrylamide when the f lour is baked. Synthetic biology can also be used to produce healthier or specifically designed food ingredients, like high-value proteins, lipids and vitamins. Food production by microbes is considered a promising alternative that could allow food to be produced quickly in an environmentally friendly way. However, such techniques will not be enough to meet the growing demand for food, McCormick adds – increasing crop productivity is essential for global food security. His work focuses on photosynthesis and how it can be manipulated to produce novel products or improve plant productivity. McCormick’s group aims to improve photosynthetic CO2 assimilation by engineering algae to increase photoassimilation rates and therefore productivity. He notes that growing algae and heterotrophic species together is a “hot new research topic”. If these species can be grown together, then CO2 could be captured, converted into sugar and then used by the cell media. Researchers at the University of Michigan recently created a strain of cyanobacteria that can export up to 85% of the carbon it fixes as sucrose. Their approach, they say, “is promising as a potential alternative to land-based crops for sugar production, as this level of productivity could exceed sugar output from sugarcane or corn if it could be scaled up.” Another “hot topic” is that of engineered probiotics designed to improve health by increasing the specificity of probiotic microbes or improving the antimicrobial activity of the probiotic against pathogenic infections of the gastrointestinal tract. Synthetic biology approaches have been used to engineer the probiotic bacteria, Lactobacillus johnsonii (L. johnsonii) to be effective against Clostridium perfringens (C. perfringens) a bacteria that causes food poisoning. SYNTHETIC BIOLOGY’S IMPACT, NOW AND IN THE FUTURE Davies says synthetic biology's greatest current strength is that it allows scientists to test their understanding: “In the same way that you can test your understanding of aerodynamics by making simple paper planes, we can test our understanding of complex biology by making simple things that work according to the principles we have derived, and we can see if they really work.” “A nd when they don't, that tells us we have not really understood things at all and need to go back and do better analytic science,” he adds. Davies believes tools like CA R T will continue to grow and will have greater impact, as will non-medical applications, like organisms engineered to clean up water, which are important for health. “But most of this is still very expensive and experimental, and I think it will be a while before we see real impacts,” he says. “For now, the impacts are in research itself.” McCormick believes synthetic biology will evolve into engineering biology – a move already being championed by UK R I. He says it will become more inclusive of branches like bioengineering and increase its remit to chemistry, physics and material science. The biggest impact, in his opinion, will be “in high value products, in pharma and in vaccines”. “A nd it will make a big difference in agriculture to ensure we get as much as we can out of what we have. It may not solve the problem, but it will certainly help ease it,” he concludes. ⚫ iStock 20 iStock P rofessor Donald Ingber, founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, is responsible for the development of human organ chips. These organ chip systems provide researchers with a window into inter-organ physiology and the body’s response to drugs, without the need for animal testing. These chips can be applied to drug development, disease modeling and personalized medicine. Technology Networks invited Ingber to an Ask Me Anything session to answer your questions about this incredible technology. Lucy Lawrence (LL): What is a body-on-a-chip system? Donald Ingber (DI): So, we call them organs-on-chips or organ chips, and if you link them together, you can get a body-on-a-chip. The organ chips that we first developed were small devices the size of a computer memory stick. They are optically clear and made out of a f lexible polymer silicone rubber. They have two hollow tiny channels less than a millimeter wide that run parallel on top of each other and are separated by a porous membrane. We can put different cell or tissue types on either side [of the membrane] to create tissue-tissue interfaces, which is why we call it an organ-on-a-chip rather than a tissue-on-a-chip. We are able to stretch and relax the membrane and attached tissues How Body-on-a-Chip Tech Is Transforming Research KATE ROBINSON & LUCY LAWRENCE 21 Technology Networks, adapted from Organs-on-Chips: Furthering Our Understanding of Disease laterally, so we can mimic breathing motions if we have air above. If we have f luids on both sides, we can mimic peristalsis or deformation in any tissue. We've been able to mimic physiology and disease states, drug actions and toxin actions with incredible fidelity. If you flow medium through the vascular channel line by endothelial cells, through the chip, you could take the effluent and put it into the inflow part of the next chip, to create a bodyon-a-chip. This allows you to look at multi-organ coupling. LL: What sparked your interest in body-on-a-chip technology and organ-on-a-chip technology? DI: When I was an undergraduate student, I had insight that mechanical forces might be as important for cell shape as chemicals and genes, and that led me on a path to experimental testing. Eventually, I convinced people that it was true by developing ways to control cell shape via distortion or stretching. In our first paper published in 1994, we adapted computer microchip manufacturing techniques to gain control over features at the same nanometer/ micrometer scale at which cells live. We also created a technique to control how far cells can spread by making islands coated with extracellular matrix the size of cells. That's how we got into microchips and cell biology. We then started making hollow channels that are called microf luidics and then we began culturing cells in those channels. LL: What are the challenges or limitations that you've come across while developing and using your body- and organ-ona-chip systems? DI: With organ-on-a-chip, the biggest limitation we faced were bubbles. The tubes are very small, so, if you get bubbles in them by connecting and disconnecting tubes, this can cause the cells to die. In efforts to commercialize organ-on-chip systems, “click and play” approaches are being developed that don’t have connectors. This has made the technology much more robust, and has helped enormously. Cell sourcing is always a challenge, whatever in vitro model you use, we find that organoids and primary adult cells have been the best over induced pluripotent stem cells because they retain epigenetic signatures and disease states. R ight now, the chips are relatively low throughput, but incredibly high content. Whole body-on-chips have additional problems, as you now have to use multiple cell types for culturing and you have to time them so that they can be put on the chips, differentiated and all aligned so the chips can be coupled together. But developing noninvasive readouts, whether we use electrodes, oxygen sensors or f luorescent reporters, are challenges that you would face in any culture system. A nother challenge is the amount of data generated, similar to an animal model, and for people used to 96- well plates with quick assays, it's very different. Figure 1: A three-layer microfluidic chip model with cells grown on a porous membrane. "We can put different cell or tissue types on either side [of the membrane] to create tissuetissue interfaces, which is why we call it an organ-on-a-chip rather than a tissue-on-a-chip," says Ingber. 22 LL: Can organ chips be used to study microbial infectious diseases? DI: Absolutely. Not only can we study pathogens, but we can also study healthy microbiome versus diseased microbiome. Another major advantage of microfluidic organ chips as opposed to microphysiological systems is the ability to keep a complex microbiome in direct contact with live human cells for multiple days. If you took an organoid and put microbes on it, you would have about 16 to 24 hours before they die. So, we've used diluted stool samples from patients in the lumen of our intestine chips. If the microbiome is healthy, they remain intact for five days. If it’s unhealthy, you will see blunting of the villi, compromised barriers and inflammatory cytokines. We recently published a paper on a vagina chip with healthy microbiome versus disease, and we're using the chip with the Gates Foundation to test live biotherapeutic products. These products for bacterial vaginosis are moving to clinical trials in South Africa and the United States in the next few months, and we can see these actually suppress inflammation on these chips. In terms of pathogens, we've done viral infection and bacterial infection of intestine chips. We use metabolomics and can figure out which metabolites mediate the microbiome. In this case, we were looking at human microbiome protecting against enterohemorrhagic E. coli versus mouse microbiome, because humans and mice have totally different sensitivity. LL: Could your replica models be linked to an artificial intelligence (AI) environment for studying and testing? DI: We have papers in preprint and in development where we used machine learning and A I approaches. In these studies, we started with transcriptomic data from patients to see which genes across the whole transcriptome would need to be “f lipped” to make faulty genes healthy. We then looked through all the available transcriptomic data on the web for every known drug, and then the AI machine learning computational tool prioritizes which [drugs] are most likely to reverse the state. These can then be explored more using in vitro models, including organ chips, to get transcriptomic data on human models. The interesting thing about the computer tool is that it also analyzes known gene networks and known gene drug networks, and you can identify drug targets and then not only repurpose existing drugs, which we've done and moved to clinical trials, but actually identify new targets and identify new drugs. We also do it the other way around, by which we use a molecular dynamics simulation for drug molecular design, and then we integrate machine learning and A I, in this process. We use organ chips coupled with it to generate human data. ⚫ Professor Donald Ingber was speaking to Lucy Lawrence, Senior Digital Content Producer for Technology Networks. Editing by Kate Robinson. Prof. Ingber’s groundbreaking research has transformed the landscape of biomedical science and opened new avenues in drug discovery, disease modeling and personalized medicine. 23 iStock hough tells me, believed that speech was something that began as a purely social instrument for communication between people that over the course of development became gradually internalized. This process of internalizing, Fernyhough says, gives us “tools for thinking” that benefit our development. AN EVOLUTIONARY BENEFIT TO INNER SPEECH? Not all aspects of our inner speech give obvious advantages to our behavior. Anyone who has anxiously spent hours internally processing worried thoughts about an exam, only to have no time to actually study for it, might wonder why such unhelpful examples of inner speech were not chopped out at an earlier point in evolution. Surely an early human would have been much “fitter” to their environment if they just threw a spear straight into a mammoth without ruminating on how they were going to extract the spear later, and whether this particular mammoth was going to be as delicious as the one they had caught last winter? Jonny Smallwood, a professor in the Department of Psychology at the University of York, has made the study of one particularly aimless form of rumination, daydreaming, his own research niche. “Things like daydreaming, even though they might seem “purposeless” must be having some kind of quite important role in how we guide our lives,” says Smallwood. But what is that role? Smallwood’s studies have looked at how people from different countries and cultures daydream. All his participants had one thing in common – they tended to think about the future. Smallwood reckons that this common finding hints at why internal states like daydreaming and inner speech have become so widespread. “One of the ways that the internal representation system can be selected for is because you can prepare for an interaction with another person and you can think about the kind of things that they might be happy or unhappy for you to say. Then, when you get into that circumstance, you’re less likely to say the wrong thing, which might make the interaction smoother,” says Smallwood. NO SUCH THING AS A UNIVERSAL BEHAVIOR Internal processes like inner speech and daydreaming might give us an evolutionary advantage. But the most interesting thing about these processes isn’t their function, but their prevalence. Fernyhough has noted that inner speech, despite perhaps seeming to many people like the most innate behavior of all, is not ubiquitous. “You certainly find that private speech in children is pretty universal. You don’t find many kids who are developing in a typical way that don’t use private speech. But when it comes to adults, I came across people who clearly just weren’t doing much inner speech,” says Fernyhough. These internally silent volunteers instead commonly relied on imagery in their day-to-day thoughts, with pictures replacing words as their thinking tool of choice. “To my mind it says it’s something that a lot of humans do because it’s handy. But it’s by no means an essential component of consciousness,” says Fernyhough. “We find different ways to get to the same outcome and I think that’s one of the marvels of psychology.” Variation in how we think isn’t limited to whether we use words or images. Sometimes, the very nature of our thinking can become disrupted. Fernyhough became acutely aware of this when he shared his developmental psychology findings with psychiatrist colleagues, who took his comments about inner speech to be referring to auditory hallucinations, or “hearing voices”. These hallucinations are most commonly linked in popular culture to the mental health disorder schizophrenia. In reality, schizophrenia is a complex disorder, and auditory hallucinations are just part of an often varied range of symptoms. The idea that hearing voices is unique to schizophrenia is also misleading, suggests Fernyhough. “The experience of hearing voices is involved in all sorts of different psychiatric diagnoses, everything from post-traumatic stress disorder (PTSD) to eating disorders. It is also experienced by quite a small but significant number of people who are not mentally ill who hear voices quite regularly, but don’t seek help for them because they’re not troubled by them.” HEARING THE VOICE Is there a fundamental difference between inner speech and auditory hallucinations? This question has been the target of a project Fernyhough is helping run at Durham, funded by the Wellcome Trust, called Hearing the Voice. The study is still ongoing, but some early conclusions are that the difference between these internal states is very simple. “The idea is that when somebody hears a voice, what they’re actually doing is some inner speech, but for some reason, they don’t recognize that they themselves made that bit of language in their heads,” says Fernyhough. “It’s experienced as coming from somewhere else or from someone else.” What complicates this idea are the many types of both inner speech and auditory hallucinations. Fernyhough thinks that his theory will apply to some types of both experiences, but not all. Some hallucinations have acoustic properties, as if the speaker is in the room with you. Sometimes the voice has an accent or a timbre or a pitch. “It’s very hard to pin down what it is that makes some people have an experience that feels alien, that is distressing, especially when some people have what seems to be the same experience, but don’t find it distressing,” Variation in how we think isn’t limited to whether we use words or images. Sometimes, the very nature of our thinking can become disrupted. Disseminate Your Research With Us We know how important it is to disseminate your findings when working in research, but also what a challenge it can be to find opportunities beyond the conference hall. We want to address this! Technology Networks is spearheading a project to help researchers raise the profile of their work to a wider audience and increase coverage of the fantastic research papers out there that may not get the media attention they deserve. There is a lot of great research output and a very engaged audience that wants to hear about it, so share your work with us! Find Out More 24 iStock T he Enabling Nutrient Symbioses in Agriculture (ENSA) project seeks to develop cereals that carry the same ability as legumes have, to biologically fix nitrogen by harnessing interactions with soil microbes. By reducing the need for nitrogen fertilizer, the project could have a profound impact on sustainability in agriculture. In this interview for Technology Networks, Professor Giles Oldroyd, director of the Crop Science Centre at the University of Cambridge and leader of ENSA, discusses the project’s research mission and the landscape of food and agriculture more generally, including the recent passing of The Genetic Technology (Precision Breeding Act) in the UK. Molly Campbell (MC): Your research mission is to eradicate the need for inorganic fertilisers in agriculture through the use of beneficial microbial associations. How are you working to achieve this? Giles Oldroyd (GO): The ENSA project aims to deliver environmentally sustainable crop innovations that boost the yields and livelihoods of smallholder farmers around the world. Rather than intensifying the use of chemical inputs, such as inorganic fertilizers that are both environmentally harmful and inaccessible to many small-scale farmers, ENSA’s work aims to maximize the beneficial microbial associations between plants, soil fungi and bacteria. We are working to develop crops that make better use of the nutrients already present in the air and the soil, using many of the processes that plants themselves have evolved over millions of years. In particular, our work is focused on interactions with nitrogen-fixing bacteria and with beneficial fungi that expand the surface of the root and help capture of nitrates, phosphates and water to support plant production. For the former, we are aiming to expand the nitrogen-fixation ability – currently only present in legumes – The Latest Frontiers in Agricultural Science MOLLY CAMPBELL 25 into cereal crops, while also improving the efficiency of nitrogen-fixation in legume crops like soybeans and cowpeas. Likewise, for interactions with beneficial fungi, we are aiming to optimize the performance of arbuscular mycorrhizal associations in crops to facilitate phosphate, nitrate, water and micronutrient capture. MC: In your opinion, what are the latest innovations in food and agriculture research? GO: Our work has uncovered that many of the genes essential for the interaction with nitrogen-fixing bacteria are also essential for the association with arbuscular mycorrhizal fungi. This means a core genetic framework for establishing N-fixation exists within crops such as cassava and cereals, to support arbuscular mycorrhizal associations. At the same time, our work has also discovered that our target cereal crops have inherited processes involved in forming symbiosis with arbuscular mycorrhizal fungi, which appears to be the evolutionarily-earliest beneficial microbial association in plants. This means the symbiosis signaling present in cereals shares many similarities with the signaling pathway for recognition of nitrogen-fixing rhizobia in legumes. Moving forward, our goal is to re-network these pre-existing processes in cereal crops, rather than creating new ones from scratch. If successful, these approaches would not only revolutionize small-holder farmer production but would also deliver sustainable and secure food production systems for high-income countries. Other research opportunities that I feel are very likely to have significant impact in food production are around the attempts to enhance photosynthetic efficiency, driving up the effectiveness of carbon capture and the utilization of knowledge from mechanisms of plant immunity that are creating opportunities to drive resilience to pathogens. And of course, existing technologies – including Bt – that are already very effective at controlling insect pests. These traits have significant potential to stack together, alongside our work in ENSA, which could be revolutionizing with regards to sustainable productivity. MC: The Genetic Technology (Precision Breeding) Act was passed in the UK earlier this year. Can you describe what this means for researchers and commercial companies developing gene-edited products? GO: The Genetic Technology (Precision Breeding) Act has come at a time of rising challenges to food systems and food production, both globally and in the UK itself. As background context to the passage of the Act, the UK imports around half the food it consumes from more than 180 countries, many of which face rising temperatures, more frequent droughts, degraded soils and new pest threats. As the impact of climate change accelerates and creates new strains on food production, farmers at home and overseas can no longer afford to rely on and wait for hardier crops produced by conventional breeding alone, which is unlikely to keep up with the rapidly changing challenges of new growing conditions. iStock NITROGEN FIXATION Nitrogen fixation is a biological process where atmospheric nitrogen is converted into ammonia by microorganisms such as bacteria and archaea. Nitrogen-fixing bacteria can live freely in soil or within legumes, where they produce ammonia that helps the plant to grow. ARBUSCULAR MYCORRHIZAL ASSOCIATIONS The most common type of symbiotic relationship in plants and microbes, mycorrhizal associations help to improve plant stress resistance, nutrition, soil structure and fertility. BT TECHNOLOGY The bacterium Bacillus thuringiensis possesses genes that encode the production of toxins. These genes, when incorporated into transgenic crops, help to promote pest resistance. Bt corn, for example, has been approved for cultivation and commercialization in some countries across the world. 26 Having secured passage in March 2023, the Act opens up new possibilities for science and innovation that could transform the pace of agricultural research and development, to the benefit of the entire global crop science sector. The law, first and foremost, allows for the commercial development of gene-edited food in England, accelerating what might otherwise be possible through natural processes and conventional breeding over a longer timeframe. This means researchers can cut down the time it takes to supply farmers with more resilient or higher yielding crop varieties, which could be the difference between failed harvests and food shortages or food security and continuous supply. Likewise, the Act also clears the way for a more diverse plant science sector in the UK by mainstreaming genetic technologies in a way that encourages more research among public sector institutes and start-ups. Finally, the Act also stands to generate new varieties, products and technologies that can be adapted and used by other parts of the world, including developing countries where agriculture is a primary economic driver yet faces greater threats from the more pressing impact of climate change. The act does not change the position on genetically modified crops, which, in the UK, like the EU, holds a very restrictive position on release of GM foods. While there are many important traits that can be delivered in food crops through gene editing, there remain some traits, such as the transfer of nitrogen-fixation, that require genetic modification. Hence, while I very much welcome to advances brought to bear by the precision breeding bill, I believe we still need to consider how we facilitate delivery of some of the transformative traits that only genetic modification will allow. MC: Can you discuss the importance of creating sustainable agricultural practices, why it can be challenging and how we can do better on this front? GO: The input-heavy processes currently used by farmers, particularly in high-income countries, are unsustainable and expensive. The Green Revolution use of inorganic fertilizers promoted higher yields, but at a significant cost to the environment. However, in many low-income countries, fertilizers continue to be inaccessible for the vast majority of small-scale farmers, and agricultural yields remain low as a result. For instance, the synthetic N fertilizer supply chain was responsible for estimated emissions of 1.13 GtCO2e (gigatonnes of carbon dioxide equivalent) in 2018 alone, representing 10.6% of agricultural emissions and 2.1% of global greenhouse gas emissions. The use of inorganic fertilizers also contributes to eutrophication and biodiversity declines. At the same time, most smallholders in sub-Saharan Africa lack the resources to buy inorganic fertilizers. For example, average nitrogen application rates are 25 kg/ha in sub-Saharan Africa, compared to 100 kg/ha in the USA (on average). As a result, most smallholder farmers are often working with very nutrient depleted soils, resulting in limited yields. Average maize productivity in sub-Saharan Africa is two tonnes/ha, as compared to nine tonnes/ha in the USA. iStock 27 iStock There is therefore an urgent need to reach similar yield gains as those achieved from the Green Revolution, but without the need for environmentally damaging and economically unsustainable inorganic fertilisers. MC: What should the key priorities be for food and agricultural researchers in the near future? GO: During my research career I have observed a revolution in our understanding of how plants function. This has been underpinned by technological advances in genetics and genomics. We are in a radically different position in our understanding of biological systems than we were when I first started working in a laboratory 30 years ago. We have the opportunity to apply this deep knowledge for the advancement of our food production systems, creating more productive and far more sustainable crops, in forms that should be readily available to even the world’s poorest farmers. While it is important to continue to deepen our understanding of how plants function, I believe it is equally as important to ensure we apply this knowledge to the betterment of society, in this case, to more productive, more sustainable and more equitable food production systems. Too often these more strategic approaches come secondary to discovery science. I argue the two should go hand in hand and I personally find it hugely motivating to think that I could contribute to delivering impact. We face phenomenal challenges over the following decades, we need plant science now more than ever, but we also need plant scientists to apply their passion and intelligence to delivering future-proofed food production. ⚫ Professor Giles Oldroyd was speaking to Molly Campbell, Senior Science Writer at Technology Networks. “Genetically modified organisms refer to crops where DNA that does not originate from that species remains in the final product. This is distinct from gene-edited crops, where tools such as CRISPR or TALENs modify the existing genome in the plant, without the need for new genetic material remaining in the final product,” says Oldroyd. 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