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Tag: Genetics

  • Artificial Intelligence Catalyzes Gene Activation Research and Uncovers Rare DNA Sequences

    Artificial Intelligence Catalyzes Gene Activation Research and Uncovers Rare DNA Sequences

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    BYLINE: Mario Aguilera

    Newswise — Artificial intelligence has exploded across our news feeds, with ChatGPT and related AI technologies becoming the focus of broad public scrutiny. Beyond popular chatbots, biologists are finding ways to leverage AI to probe the core functions of our genes.

    Previously, University of California San Diego researchers who investigate DNA sequences that switch genes on used artificial intelligence to identify an enigmatic puzzle piece tied to gene activation, a fundamental process involved in growth, development and disease. Using machine learning, a type of artificial intelligence, School of Biological Sciences Professor James T. Kadonaga and his colleagues discovered the downstream core promoter region (DPR), a “gateway” DNA activation code that’s involved in the operation of up to a third of our genes.

    Building from this discovery, Kadonaga and researchers Long Vo ngoc and Torrey E. Rhyne have now used machine learning to identify “synthetic extreme” DNA sequences with specifically designed functions in gene activation. Publishing in the journal Genes & Development, the researchers tested millions of different DNA sequences through machine learning (AI) by comparing the DPR gene activation element in humans versus fruit flies (Drosophila). By using AI, they were able to find rare, custom-tailored DPR sequences that are active in humans but not fruit flies and vice versa. More generally, this approach could now be used to identify synthetic DNA sequences with activities that could be useful in biotechnology and medicine.

    “In the future, this strategy could be used to identify synthetic extreme DNA sequences with practical and useful applications. Instead of comparing humans (condition X) versus fruit flies (condition Y) we could test the ability of drug A (condition X) but not drug B (condition Y) to activate a gene,” said Kadonaga, a distinguished professor in the Department of Molecular Biology. “This method could also be used to find custom-tailored DNA sequences that activate a gene in tissue 1 (condition X) but not in tissue 2 (condition Y). There are countless practical applications of this AI-based approach. The synthetic extreme DNA sequences might be very rare, perhaps one-in-a-million—if they exist they could be found by using AI.”

    Machine learning is a branch of AI in which computer systems continually improve and learn based on data and experience. In the new research, Kadonaga, Vo ngoc (a former UC San Diego postdoctoral researcher now at Velia Therapeutics) and Rhyne (a staff research associate) used a method known as support vector regression to “train” machine learning models with 200,000 established DNA sequences based on data from real-world laboratory experiments. These were the targets presented as examples for the machine learning system. They then “fed” 50 million test DNA sequences into the machine learning systems for humans and fruit flies and asked them to compare the sequences and identify unique sequences within the two enormous data sets.

    While the machine learning systems showed that human and fruit fly sequences largely overlapped, the researchers focused on the core question of whether the AI models could identify rare instances where gene activation is highly active in humans but not in fruit flies. The answer was a resounding “yes.” The machine learning models succeeded in identifying human-specific (and fruit fly-specific) DNA sequences. Importantly, the AI-predicted functions of the extreme sequences were verified in Kadonaga’s laboratory by using conventional (wet lab) testing methods.

    “Before embarking on this work, we didn’t know if the AI models were ‘intelligent’ enough to predict the activities of 50 million sequences, particularly outlier ‘extreme’ sequences with unusual activities. So, it’s very impressive and quite remarkable that the AI models could predict the activities of the rare one-in-a-million extreme sequences,” said Kadonaga, who added that it would be essentially impossible to conduct the comparable 100 million wet lab experiments that the machine learning technology analyzed since each wet lab experiment would take nearly three weeks to complete.

    The rare sequences identified by the machine learning system serve as a successful demonstration and set the stage for other uses of machine learning and other AI technologies in biology.

    “In everyday life, people are finding new applications for AI tools such as ChatGPT. Here, we’ve demonstrated the use of AI for the design of customized DNA elements in gene activation. This method should have practical applications in biotechnology and biomedical research,” said Kadonaga. “More broadly, biologists are probably at the very beginning of tapping into the power of AI technology.”

    Funding from the National Institutes of Health (R35 GM118060) supported the research.

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    University of California San Diego

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  • Genetically Edited Eggs: Allergen-Free and Safe

    Genetically Edited Eggs: Allergen-Free and Safe

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    Newswise — Researchers have developed a chicken egg that may be safe for people with egg white allergies. Chicken egg allergies are one of the most common allergies in children. Though most children outgrow this allergy by age 16, some will still have an egg allergy into adulthood. Egg white allergies can cause a variety of symptoms, including vomiting, stomach cramps, breathing problems, hives, and swelling and some people with egg white allergies are unable to receive certain flu vaccines.

    Using genome editing technology, researchers have produced an egg without the protein that causes egg white allergies. This protein, called ovomucoid, accounts for approximately 11% of all the protein in egg whites.

    Research detailing the food safety profile of this modified egg, called the OVM-knockout, was detailed in a paper published in Food and Chemical Toxicology in April 2023.

    “To use OVM-knockout chicken eggs as food, it is important to evaluate its safety as food. In this study, we examined the presence or absence of mutant protein expression, vector sequence insertion, and off-target effects in chickens knocked out with OVM by platinum transcription activator-like effector nucleases (TALENs),” said Ryo Ezaki, an assistant professor at the Graduate School of Integrated Sciences for Life at Hiroshima University in Hiroshima, Japan. TALENs are restriction enzymes that recognize specific DNA sequences and break or cut them.

    In order to develop the OVM-knockout eggs, researchers needed to detect and eliminate the ovomucoid protein in the egg whites. TALENs were engineered to target a piece of RNA called exon 1, which codes for specific proteins. The eggs produced from this technique were then tested to ensure there was no ovomucoid protein, mutant ovomucoid protein, or other off-target effects. The eggs had the desired frameshift mutation, which is a mutation created by inserting or deleting nucleotide bases in a gene, and none of them expressed mature ovomucoid proteins. Anti-ovomucoid and anti-mutant ovomucoid antibodies were used to detect any traces of the protein, but there was no evidence of ovomucoid in the eggs. This means that mutant ovomucoids could not create new allergens. This is an important step in determining the safety profile of the eggs.

    Other gene editing tools, such as CRISPR, tend to have off-target mutagenesis effects. This means that new mutations are prompted by the gene editing process. However, whole genome sequencing of the altered egg whites showed mutations, which were possibly off-target effects, were not localized to the protein-coding regions.

    “The eggs laid by homozygous OVM-knockout hens showed no evident abnormalities. The albumen contained neither the mature OVM nor the OVM-truncated variant,” said Ezaki. “The potential TALEN-induced off-target effects in OVM-knockout chickens were localized in the intergenic and intron regions. Plasmid vectors used for genome editing were only transiently present and did not integrate into the genome of edited chickens. These results indicate the importance of safety evaluations and reveal that the eggs laid by this OVM knockout chicken solve the allergy problem in food and vaccines.”

    Looking ahead, researchers will continue to verify the safety profile of the OVM-knockout eggs. Because some people are highly allergic to this specific protein, even small amounts of ovomucoid can cause a reaction. Researchers will need to perform additional immunological and clinical studies to determine the safety of the OVM-knockout eggs. At this time, researchers have determined that OVM-knockout eggs are less allergenic than standard eggs and can be safely used in heat-processed foods that patients with egg allergies can eat. “The next phase of research will be to evaluate the physical properties and processing suitability of OVM-knockout eggs, and to confirm their efficacy through clinical trials,” said Ezaki. “We will continue to conduct further research toward the practical application of allergy-reduced eggs.”

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    Other contributors include Tetsushi Sakuma, Mei Matsuzaki, Takashi Yamamoto, and Hiroyuki Horiuchi of the Graduate School of Integrated Sciences for Life at Hiroshima University and Daisuke Kodama, Ryou Sasahara, and Taichi Shiraogawa from the R&D Division of the Institute of Technology Solution at Kewpie Corporation in Tokyo Japan.

    The Japan Society for the Promotion of Science KAKENHI (19H03107, 19K22286) and JST COI Grant Number JPMJPF 2010 supported this research.

    About Hiroshima University

    Since its foundation in 1949, Hiroshima University has striven to become one of the most prominent and comprehensive universities in Japan for the promotion and development of scholarship and education. Consisting of 12 schools for undergraduate level and 5 graduate schools, ranging from natural sciences to humanities and social sciences, the university has grown into one of the most distinguished comprehensive research universities in Japan. English website: https://www.hiroshima-u.ac.jp/en

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  • Researchers track antimicrobial resistance in E. coli isolated from swine

    Researchers track antimicrobial resistance in E. coli isolated from swine

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    BYLINE: Ananya Sen

    Newswise — The spread of drug-resistant microbes has become a global health concern that threatens our ability to treat infections. The widespread use of antimicrobials in livestock, such as swine farms, exacerbates this problem. Therefore, we need surveillance systems to monitor these microbes to support the public health authorities. To this end, researchers at the University of Illinois Urbana-Champaign have tracked the antimicrobial resistance of Escherichia coli isolated from swine.

    Antimicrobials are essential for preventing and treating infections in humans and animals. According to the US Food and Drug Administration, 70% of all antibiotic sales in the US are used for livestock production. However, microbes change over time to combat these chemicals, eventually becoming resistant. As a result, infections become harder to treat. Concerningly, these resistant organisms can spread from farm animals to humans, creating a bigger health crisis.

    The researchers focused on E. coli since these bacteria are ubiquitous in the intestinal tract of humans and pigs, and they are good indicators to test whether meat and meat products have been contaminated. E. coli can also acquire and transfer resistance genes to other bacteria in the intestinal tract, making them ideal for monitoring programs of livestock and humans.

    “It is important to monitor the emergence of antimicrobial-resistant bacteria in the swine industry because in 2022 the US was the third largest producer and consumer of swine meat and products, after the European Union and China,” said Hamid Reza Sodagari, a postdoctoral research associate in the Varga lab. “Although it is a big problem, to the best of our knowledge this paper is the first surveillance study in the US that looks at antimicrobial resistance in E. coli from swine at slaughter.”

    The study used publicly available surveillance data of cecal samples, which were collected from the intestine after slaughter. The researchers focused on market swine and sows in the US between 2013 and 2019, and used the data compiled by the United States Department of Agriculture Food Safety Inspection Service under the National Antimicrobial Resistance Monitoring System for Enteric Bacteria program.

    “Federal agencies often don’t have the manpower to carry out such long-term and detailed analyses. Alternatively, for most researchers such studies are challenging because usually they track samples on a smaller scale. In this paper, however, we were able to look at more than 3,000 samples across several years,” said Csaba Varga, an assistant professor of epidemiology at the University of Illinois College of Veterinary Medicine and a faculty member in the “Infection Genomics for One Health” research theme within the campus’s Carl R. Woese Institute for Genomic Biology.

    Using different statistical methods, the researchers found that since 2013, the number of antimicrobials to which E. coli is resistant has either remained steady or increased over the years. In particular, the resistance to ceftriaxone, an important antimicrobial drug in both human and veterinary medicine, increased from 0.8% in 2013 to 7.7% in 2019. Even though these numbers are not high compared to the resistance to other antimicrobials, the increasing trend is concerning.

    “We don’t know why there is an increasing trend. It may be caused by mobile genetic elements, which can transfer antimicrobial resistance from one bacterium to another. We need to do further research at the molecular level to understand the reason for the increase,” Sodagari said.

    “We are not blaming anyone for this problem. Our study is meant to show that there is an issue and that surveillance systems are very important to show the changes in resistance,” Varga said. “By gathering this data, we hope that the public health authorities will be able to develop mitigation strategies.”

    The study “Evaluating Antimicrobial Resistance Trends in Commensal Escherichia coli Isolated from Cecal Samples of Swine at Slaughter in the United States, 2013-2019” was published in Microorganisms and can be found at 10.3390/microorganisms11041033.

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    University of Illinois Urbana-Champaign

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  • Perfect Timing: Insights into Floral Development’s Clock

    Perfect Timing: Insights into Floral Development’s Clock

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    Newswise — Ikoma, Japan – The intricate process of flower development has long fascinated scientists seeking to unravel the mysteries behind nature’s precision timing. In a study published in the journal Plant Cell, a research team led by Nara Institute of Science and Technology (NAIST), Japan has shed light on the inner workings of floral meristem termination and stamen development, uncovering a unique mechanism driven by the interplay of genetic and epigenetic factors.

    Flowers owe their intricate structures to delicate stem cell differentiation, a process by which founder cells develop into specialized cells in floral meristems. However, the precise moment at which stem cells cease self-renewal and transform into their form remains largely unknown. Driven by a desire to decipher this critical temporal transition, the researchers turned their attention to AGAMOUS (AG), a pivotal MADS domain transcription factor governing floral meristem termination.

    Through meticulous investigations in the model plant Arabidopsis thaliana, the team discovered that AG serves as a master conductor, orchestrating gene expression through a process known as cell cycle-coupled H3K27me3 dilution. This remarkable phenomenon involves the dilution of a histone modification called H3K27me3 along specific gene sequences, effectively kickstarting gene activation. The scientists identified several key genes directly regulated by AG at various time points of this cycle.

    The study revealed a genetic network tightly controlled by AG, with genes such as KNUCKLES (KNU), AT HOOK MOTIF NUCLEAR LOCALIZED PROTEIN18 (AHL18), and PLATZ10 emerging as critical players. “By unraveling the inner workings of this regulatory circuit, we gained unprecedented insight into the intricate timing mechanisms that drive proper floral meristem termination and stamen development,” says first author Margaret Anne Pelayo.

    To unlock the secrets of this remarkable system, the researchers devised a mathematical model capable of predicting gene expression timing with astonishing accuracy. By modifying the length of H3K27me3-marked regions within the genes, they successfully demonstrated that gene activation could be delayed or reduced, confirming the influence of this epigenetic timer. The team’s findings offer a novel perspective on how nature controls the gene expression during flower development.

    Furthermore, their study identified AHL18 as a stamen-specific gene with a profound impact on stamen growth and development. Misexpression of AHL18 led to intriguing developmental defects, highlighting the gene’s vital role in ensuring proper stamen elongation and maturation. Additionally, the team discovered that AHL18 selectively binds to genes crucial for stamen growth, uncovering a new layer of regulatory complexity in flower development.

    Nobutoshi Yamaguchi, senior author of the study, opined that this research not only deepens our understanding of the mechanisms underpinning floral development but also presents a potential tool for fine tuning gene expression patterns. Manipulating the delicate balance of epigenetic modifications opens up exciting possibilities for controlling plant reproduction in a flexible and reversible manner, ultimately benefiting our food supply and agricultural practices.

    This study paves the way for further exploration of epigenetic approaches to regulate gene expression with exquisite precision. By unraveling nature’s perfect clock, scientists may one day unlock new strategies for enhancing crop productivity and bolstering plant resilience, and contribute to food security despite environmental challenges.

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    About Nara Institute of Science and Technology (NAIST)

    Established in 1991, Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Known as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become tomorrow’s leaders in science and technology.

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  • New algorithm can predict diabetic kidney disease

    New algorithm can predict diabetic kidney disease

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    Newswise — LA JOLLA, CALIF. – May 15, 2023 – Researchers from Sanford Burnham Prebys and the Chinese University of Hong Kong have developed a computational approach to predict whether a person with type 2 diabetes will develop kidney disease, a frequent and dangerous complication of diabetes. Their results, published in Nature Communications, could help doctors prevent or better manage kidney disease in people with type 2 diabetes.

    “This study provides a glimpse into the powerful future of predictive diagnostics,” says co-senior author Kevin Yip, Ph.D., a professor and director of Bioinformatics at Sanford Burnham Prebys. “Our team has demonstrated that by combining clinical data with cutting-edge technology, it’s possible to develop computational models to help clinicians optimize the treatment of type 2 diabetes to prevent kidney disease.”

    Diabetes is the leading cause of kidney failure worldwide. In the United States, 44% of cases of end-stage kidney disease and dialysis are due to diabetes. In Asia, this number is 50%.

    “There has been significant progress developing treatments for kidney disease in people with diabetes,” says co-senior author Ronald Ma, MB BChir, FRCP, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong. “However, it can be difficult to assess an individual patient’s risk for developing kidney disease based on clinical factors alone, so determining who is at greatest risk of developing diabetic kidney disease is an important clinical need.”

    The new algorithm depends on measurements of a process called DNA methylation, which occurs when subtle changes accumulate in our DNA. DNA methylation can encode important information about which genes are being turned on and off, and it can be easily measured through blood tests.

    “Our computational model can use methylation markers from a blood sample to predict both current kidney function and how the kidneys will function years in the future, which means it could be easily implemented alongside current methods for evaluating a patient’s risk for kidney disease,” says Yip.

    The researchers developed their model using detailed data from more than 1,200 patients with type 2 diabetes in the Hong Kong Diabetes Register. They also tested their model on a separate group of 326 Native Americans with type 2 diabetes, which helped ensure that their approach could predict kidney disease in different populations.

    “This study highlights the unique strength of the Hong Kong Diabetes Register and its huge potential to fuel further discoveries to improve our understanding of diabetes and its complications,” says study co-author Juliana Chan, M.D., FRCP, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong, who established the Hong Kong Diabetes Register more than two decades ago.

    “The Hong Kong Diabetes Register is a scientific treasure,” adds first author Kelly Yichen Li, Ph.D., a postdoctoral scientist at Sanford Burnham Prebys. “They follow up with patients for many years, which gives us a full picture of how human health can change over decades in people with diabetes.”

    The researchers are currently working to further refine their model. They are also expanding the application of their approach to look at other questions about human health and disease—such as determining why some people with cancer don’t respond well to certain treatments.

    “The science is still evolving, but we are working on incorporating additional information into our model to further empower precision medicine in diabetes,” adds Ma.

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    Additional authors on the study include Claudia Ha Ting Tam, Cadmon King Poo Lim, Wing Yee So, Chuiguo Huang, Guozhi Jiang, Mai Shi, Hueng Man Lee, Hui-yao Lan and Cheuk-Chun Szeto, Chinese University of Hong Kong; Hongbo Liu, Katalin Susztak, University of Pennsylvania; Samantha Day, Robert L. Hanson and Robert G. Nelson, National Institute of Diabetes and Digestive and Kidney Diseases.

    The study was supported by grants from The Hong Kong Research Grants Council Theme-based Research Scheme (T12-402/13N) and Research Impact Fund (R4012-18), with additional support from the Research Grants Council (C4015-20E, C4045-18W, C4057-18E, C7044-19G, 14107420 and 14203119), National Institutes of Health (P30 CA030199-41, U54 AG079758-01, R21 AG075483-01S1, R01 DK087635, DK076077 and DK105821) and support from the Croucher Foundation and the Chinese University of Hong Kong.

    The study’s DOI is 10.1038/s41467-023-37837-7

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

    About the Faculty of Medicine, The Chinese University of Hong Kong (CU Medicine)

    CU Medicine was set up to meet the needs of society by providing graduates with the professional development and knowledge that equips them to be caring and competent medical practitioners. As a young medical school established in 1981, the Faculty ranks top 3 in Asia and 32nd globally in the QS World University Rankings by Subject 2023.

    We have a team of over 1,200 full-time teaching and research staff from 19 departments/schools covering the entire range of research and clinical disciplines. We encourage collaborative working between scientists and clinicians across disciplines and specialties, and remain at the forefront of the translational medicine revolution. Our Faculty members excel in tackling challenging health problems, making a memorable impact on patients’ lives and the wider society.

    CU Medicine has won an internationally renowned research reputation for its encouraging environment for the effective pursuit of world-class research as well as remarkable contributions from team members.

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  • Gene editing, new DNA repair methods found

    Gene editing, new DNA repair methods found

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    Newswise — (Santa Barbara, Calif.) — Gene editing is a powerful method for both research and therapy. Since the advent of the Nobel Prize-winning CRISPR/Cas9 technology, a quick and accurate tool for genome editing discovered in 2012, scientists have been working to explore its capabilities and boost its performance. 

    Researchers in UC Santa Barbara biologist Chris Richardson’s lab have added to that growing toolbox, with a method that increases the efficiency of CRISPR/Cas9 editing without the use of viral material to deliver the genetic template used to edit the target genetic sequence. According to their new paper published in the journal Nature Biotechnology, their method stimulates homology-directed repair (a step in the gene editing process) by approximately threefold “without increasing mutation frequencies or altering end-joining repair outcomes.”

    “We’ve found a chemical modification that improves non-viral gene editing and also discovered an intriguing new type of DNA repair,” Richardson said.

    Find, Cut and Paste

    The CRISPR/Cas9 method works by capitalizing on a defense technique employed by bacteria against viral attackers. To do this, the bacteria snip a piece of the invading virus’s genetic material, and incorporate it into their own in order to recognize it later. Should the bacteria get reinfected, they can target the now-familiar genetic sequences for destruction.

    In gene editing, this process uses the enzyme Cas9 as molecular “scissors” to snip sequences it recognizes, guided by the CRISPR system. This cut is also an opportunity to replace the severed genes with similar (homologous) but improved ones, utilizing the cell’s natural repair mechanisms. If successful, the cell should have modified expressions and functions thereafter.

    To deliver the repair template DNA to the nucleus of the cell where its genetic material lives, oftentimes viruses are used. While they are effective, the researchers say, viral workflows “are expensive, difficult to scale and potentially toxic to cells.”

    Nonviral templates are potentially less expensive and more scalable, although researchers still must overcome efficiency and toxicity barriers. In their study, the Richardson Lab found that introducing interstrand crosslinks into the workflow increased homology directed repair dramatically.

    “Every workflow that we have put this approach into has worked better by roughly threefold,” Richardson said.

    Interstrand crosslinks are lesions that keep the double strands of a DNA helix tethered to each other, making them unable to replicate. Cancer chemotherapies use this mechanism to interrupt tumor growth and kill cancer cells. Added to a homology directed repair template, however, these crosslinks were found to stimulate the cell’s natural repair mechanisms and increase the likelihood of editing success.

    “Basically, what we’ve done is taken this template DNA and damaged it,” Richardson said. “We’ve in fact damaged it in the most severe way I can think of. And the cell doesn’t say, ‘Hey this is junk; let me throw it away.’ What the cell actually says is, ‘Hey this looks great; let me stick it into my genome.’” The result is a highly efficient and minimally error-prone nonviral system of gene editing.

    Their discovery, like many breakthroughs in science, was actually something of a happy accident. While working to purify proteins to study DNA repair, graduate student researcher and lead author Hannah Ghasemi noted unanticipated changes to the outcomes of their experiments.

    “We were introducing these chemical modifications to the DNA templates in order to be able to pull them out of the cells and see what proteins were bound to them, and I was just checking to see if this modification had somehow affected the editing in any capacity,” she said. “I was expecting to either see no change or that it actually might have negatively affected the editing.”

    What she found instead was a positive effect, up to three times the editing activity of the uncrosslinked controls. Furthermore, the team found that even with the increase in edits — and therefore the chances for errors — there was no increase in mutation frequency. They are still investigating the specific mechanisms leading to this result, but they have ideas.

    “What we think happens is that the cell detects and tries to repair the damaged DNA that we’ve added this crosslink to,” Richardson said. “And in doing so, it delays the cell past a checkpoint where it would normally stop this recombination process. And so by prolonging the amount of time that it takes the cell to do this recombination, it makes it more likely that the edits will go to completion.” Studying this new process could also lead to a better understanding about how cells detect editing reagents and how they “decide” to accept them or not, he said.

    This method will find the most use in ex-vivo gene editing applications, according to the team, that is, in the realm of disease research and preclinical work.

    “We can more effectively knock down genes and insert things into genomes to study systems outside of the human body in a lab setting,” Ghasemi said. This development allows them to more efficiently build disease models and test hypotheses about how diseases work, which could lead to better clinical and therapeutic approaches.

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  • What is a species? | CNN

    What is a species? | CNN

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    CNN
     — 

    A frog that looks like it’s made of tempered chocolate. A rainbow-colored fish that dwells in the ocean’s “twilight zone.” A hairy sloth with a coconut-shaped head.

    These are just a few of the hundreds of newfound species that scientists described in 2022. The animals join a growing list of more than 1.25 million species that have been scientifically described and cataloged since the 18th century.

    But what defines an organism as a species that’s new to science? And what exactly is a species, for that matter?

    Biologists have wrestled with the concept for about as long as the field of biology has existed. Renowned naturalist Charles Darwin wrote in 1859: “No one definition has as yet satisfied all naturalists; yet every naturalist knows vaguely what he means when he speaks of a species.”

    Fast-forward to the present, and the debate hasn’t changed much. “There are many definitions, and none of them applies broadly to all life on the planet,” said Bruno de Medeiros, assistant curator of insects at the Field Museum in Chicago.

    And yet, recognizing and distinguishing between species is vital — and not only for biologists. It’s also necessary for cultivating the food we eat, treating diseases caused by different pathogens, and conserving endangered animals, plants and habitats.

    The concept is also a critical part of understanding our own evolutionary history and defining our relationship to all life on the planet.

    Teeming with life, Earth is covered with organisms of all shapes and sizes. Some are too small to see without a microscope. Others may tower hundreds of feet tall. Myriad life forms may gestate in a womb or sprout in soil, hatch from an egg or germinate in a corpse. They could be scaly, chitinous, furry or feathered; perhaps they are leafy, dotted with cilia or slick with slime. They might roam for thousands of miles or spend their lifetimes rooted in one spot.

    Scientists make sense of all this biological diversity by classifying organisms based on shared ancestry and features such as physical appearance, internal structures and reproduction. A universal, hierarchical classification system was proposed in 1753 by Swedish biologist Carl Linnaeus, and it’s still generally followed today. This branch of science is known as taxonomy.

    The broadest categories for all life on Earth are the domains. There are three domains — Bacteria, Archaea and Eukaryota — and they organize life based on cellular structure. Eukaryotes have cells that typically contain a single nucleus housing DNA: All multicellular life — animals, plants and fungi — as well as some types of unicellular life, are eukaryotes. Bacteria and Archaea are single-celled microorganisms that don’t have a nucleus, and they are evolutionarily distinct from one another.

    The next category is kingdoms. In each kingdom, there are subcategories: phylum, class, order, family, genus and species. With each subcategory, the criteria for grouping organisms become progressively more specific and selective.

    For example, humans are animals. That means we’re eukaryotes in the Animalia kingdom. Our phylum is Chordata, which includes any animal with a spinal cord. We are part of the class Mammalia. Within mammals, we are primates, sharing ancestry with apes, monkeys and lemurs. Our branch of the primate family tree is Hominidae, which includes our closest relatives: the great apes, such as gorillas, chimpanzees and bonobos.

    Finally, we arrive at our genus and species — and our scientific name — Homo sapiens. We are the only surviving lineage in the Homo genus. Neanderthals (Homo neanderthalensis), our last remaining relatives in the Homo group, went extinct about 40,000 years ago.

    Theoretically, “a species is a set of populations or one population of organisms that shares a common evolutionary history and reproduces with one another but not outside that group,” according to Nancy Simmons, curator-in-charge of mammalogy at the American Museum of Natural History in New York City.

    Myotis nimbaensis is a species of bat discovered in 2021 that's named for West Africa's Nimba Range, the mountain chain where it is found.

    If an animal population in a certain locale looks more or less the same, behaves the same, and mates and generates fertile offspring only with each other, “usually, we call this a species,” de Madeiros added.

    But color, markings and even size can vary widely within a species; this is true for many species of spiders. Not all life reproduces sexually, so that criteria isn’t universal for defining a species, either. And in some organisms that sexually reproduce, closely related species may interbreed and produce fertile offspring. Coydogs, for example, are fertile hybrids of coyotes (Canis latrans) and dogs (Canis familiaris). Humans and Neanderthals interbred, and portions of Neanderthal DNA linger in the human genome, in people of non-African descent.

    It can take millions of years for new species to evolve; often, what biologists are observing is evolution in progress. Closely related species can differ from each other a lot or a little — anatomically and genetically — depending on environmental circumstances and when they diverged from a shared ancestor.

    In the best-case scenarios for describing new species, there are many data sources, Simmons explained. A candidate typically differs physically from its close relatives, with different measurements, different morphology (anatomical structures), or different colors or patterns.

    “But then ideally we’d have other lines of evidence too — different genetic code or some sort of DNA variation,” Simmons told CNN. Behavior can also distinguish between species. In bats, for example, echolocation calls are often species-specific.

    All these criteria — anatomy, genetics, behavior and location — enabled Simmons and her colleagues to describe a newfound orange-and-black bat species, Myotis nimbaensis, in 2021.

    In recent decades, genetic data has transformed classification. Genomic analysis can reveal species-defining differences in near-identical organisms, as de Madeiros discovered while analyzing DNA sequences for palm flower weevils — a type of beetle with an elongated snout — that he had collected in Brazil in 2013 and 2014.

    Weevils of the genus Anchylorhynchus mate on flowers in palm trees in Brazil. Genomic analysis showed two nearly identical weevil species belonging to this genus living alongside one another.

    Initially, he thought there was a mistake in the data. “I had identical beetles that were clearly very distantly related species,” he said. But when he reexamined the insects, which belonged to the genus Anchylorhynchus, he noticed subtle differences in concave depressions in the males’ undersides. These indentations help the males fit snugly on top of females while mating, and likely are important for helping beetles identify and mate with females from the correct species, de Madeiros said.

    In many ways, genetic data has made it easier for scientists to tell species apart — but it has also raised its own set of issues, particularly when closely related organisms that look alike and exhibit similar behavior are also very similar genetically.

    “We get into questions of how much of a percentage of a difference in the genetic code do you have to have to be a distinct species — and people disagree on that, too,” Simmons said. “So, even when we have genetic data, you don’t find complete agreement about how to interpret it.”

    However difficult it might be to define a species, scientists won’t be running out of new discoveries anytime soon. By some estimates, Earth is home to approximately 8.7 million species — about 6.5 million living on land and 2.2 million in the oceans, which means that roughly 86% of land species and 91% of marine species are yet to be found and described.

    “We have a great challenge ahead to keep describing this diversity — how it evolves and how it will continue existing on our planet,” de Madeiros said.

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  • Van Andel Institute, Washington University School of Medicine in St. Louis to lead genome center under $140M NIH initiative

    Van Andel Institute, Washington University School of Medicine in St. Louis to lead genome center under $140M NIH initiative

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    Newswise — GRAND RAPIDS, Mich. (May 11, 2023) — Van Andel Institute’s Hui Shen, Ph.D., and Washington University School of Medicine in St. Louis’s Ting Wang, Ph.D., will co-lead a collaborative project supported by the Somatic Mosaicism across Human Tissues (SMaHT) Network, a new $140 million National Institutes of Health-led effort to better understand the genetic differences between individual cells and tissues in the body.

    Somatic mosaicism occurs when DNA, which houses the genetic code, accumulates slight changes throughout a person’s lifetime.

    Some variations may impede cells’ ability to function. Somatic mosaicism is a key contributor to cancer, but its role in other diseases is not well understood.

    SMaHT aims to identify and catalog these somatic variants in different individuals and enable new research into development, aging and a host of disorders.

    Together, Van Andel Institute and Washington University will serve as one of five SMaHT-supported Genome Characterization Centers, which will conduct leading-edge genomic analysis for the network.

    Wang will serve as the project’s director; Shen will serve as co-director. The project is supported by a $15 million grant from the NIH Common Fund as part of SMaHT.

    “We all carry such genetic mosaicism in our bodies, but the extent and implications of these variations remain unclear. Establishing an accurate picture of its role in the body is a massive undertaking that only can be achieved through collaboration,” Shen said. “I am thrilled to partner with Dr. Wang and the SMaHT Network, and look forward to contributing to a fuller understanding of this important and yet very much uncharted aspect of our cells.”

    In total, the NIH Common Fund issued 22 awards to establish the SMaHT Network. The project is akin to other large-scale NIH-supported projects such as the Human Genome Project, a 13-year endeavor that resulted in the first full blueprint of the human genome. 

    Shen is an internationally recognized expert in bioinformatics and epigenetics, the study of changes to DNA that do not alter the DNA sequence itself. She was a long-time member of The Cancer Genome Atlas (TCGA), an NIH-led collaborative effort to molecularly map 33 different cancer types. TCGA ended in 2018 with the publication of its Pan-Cancer Atlas, a comprehensive resource for scientists seeking to understand how and why cancer develops. Shen is a current member of the National Cancer Institute’s Genome Data Analysis Network (GDAN), a successor to TCGA that develops new tools to assist in the analysis of data.

    Research reported in this publication is supported by the NIH Common Fund under award no. UM1DA058219. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

     

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    ABOUT VAN ANDEL INSTITUTE Van Andel Institute (VAI) is committed to improving the health and enhancing the lives of current and future generations through cutting-edge biomedical research and innovative educational offerings. Established in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to more than 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to foster discovery. The Institute’s scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators develop inquiry-based approaches for K-12 education to help students and teachers prepare the next generation of problem-solvers, while our Graduate School offers a rigorous, research-intensive Ph.D. program in molecular and cellular biology. Learn more at vai.org.

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    Van Andel Institute

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  • First microbiome-targeting drug using CRISPR created by scientists

    First microbiome-targeting drug using CRISPR created by scientists

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    Newswise — Many people have experienced infections from E. coli, which are primarily seen as inconvenient and unpleasant. For some patients, like those with blood cancer, however, there is a risk that the bacteria will travel into the bloodstream. In those cases, an E. coli infection is too often fatal. The mortality rate is 15-20%.

    The predominant cure for such infections is the use of antibiotics that have detrimental effects on the patient’s microbiome, which play a key part in our physical and emotional well-being, and other side effects. Furthermore, growing problems with antibiotic resistance render such treatments less effective in treating infections.

    An international team of scientists has now engineered the first published CRISPR-based candidate (see fact box) for a drug that targets E. coli directly and leaves the microbiome intact. A new paper in Nature Biotechnology titled ‘Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice’ describes the development of the drug candidate to a stage where it is ready for tests on humans.

    Through extensive use of synthetic biology, the team designed four bacterial viruses that use CRISPR technology to kill the unwanted bacteria precisely.

    “We believe that a narrow spectrum drug with these properties could be very useful to cancer patients, among others, who often get serious infections that are difficult to treat with current antibiotics,” says Morten Otto Alexander Sommer, a professor at DTU Biosustain, Co-founder of SNIPR Biome, and lead author of the paper.

    The work was carried out in collaboration with JAFRAL (Slovenia), JMI Laboratories (US), and Division of Infectuous Diseases at Weill Cornell Medicine (US).

    Engineering phages to target E. coli

    The team, primarily based at SNIPR Biome, screened a library of 162 naturally occurring phages (viruses that kill specific bacteria; see fact box). They found that eight of these phages showed promise in targeting E. coli. They then engineered the phages through gene editing to improve their ability to target E. coli.

    A cocktail of four of these phages, which they named SNIPR001, very effectively targeted bacteria in biofilms and reduced the number of E. coli in a manner that surpassed that of  naturally occurring phages. Further, they showed that the cocktail of phages was tolerated well in the gut of mice and mini pigs while reducing the emergence of E. coli. SNIPR001 is now in clinical development and has been granted a Fast-Track designation (expedited review) by the US Food and Drug Administration.

    FACT BOX: An overview of the SNIPR001 creation process:

    1. Naturally occurring phages are screened against a panel of E. coli strains.
    2. Phages with broad activity against E. coli are tail fibre engineered and/or armed with CRISPR–Cas systems containing sequences specific to E. coli, creating CAPs (Cas-armed phages).
    3. These CAPs are tested for host range, in vivo efficacy, and CMC specifications.

    SNIPR001 comprises four complementary CAPs and is a new precision antibiotic that selectively targets E.coli to prevent bacteremia in haematological cancer patients at risk of neutropenia (low levels of white blood cells).

    Blood cancer patients are first in line

    The reason this new development is exciting for blood cancer patients has to do with side effects stemming from their chemotherapy treatment. It causes the patient’s bone marrow to produce fewer blood cells and inflammation of the intestines. The latter increases the intestines’ permeability allowing bacteria from the gut to travel into the bloodstream. This combination of side effects leaves the patient vulnerable to infections from bacteria like E. coli. In such cases, the

    Today, patients at risk (i.e., with low levels of white blood cells) receive antibiotic treatments ahead of their chemotherapy, but in some cases, E. coli shows very high resistance to commonly used antibiotics. Also, the antibiotics themselves have several side effects that in some cases reduce the effect of the cancer treatments.

    “We need a wider variety of options available to treat these patients, preferably ones where we can specifically target the bacteria responsible to avoid side effects and that do not add to the problem of antibiotic resistance,” says Morten Otto Alexander Sommer.

    In recent years, researchers have been looking back towards using phages to treat infections because of the increase in antibiotic resistance. Before antibiotics were broadly available, phages were widely used and studied in countries that were then part of the Soviet Union. Still, there are few clinical trials, and the results haven’t been convincing, according to the paper.

    “Through emerging technologies like CRISPR, the use of phages in treating infections has become a viable pathway. As our results show, there is potential for enhancing naturally occurring phages through genetic engineering. It is my hope that this approach may also serve as a blueprint for new antimicrobials targeting resistant pathogens,” says Morten Otto Alexander Sommer.

    FACT BOX: CRISPR, phages, and phage therapy

    CRISPR technology is a way for scientists to edit DNA sequences in cells. It’s based on a defence mechanism bacteria naturally use to protect themselves. CRISPR technology uses a molecule called Cas9, which works like a pair of scissors to cut DNA at a specific spot.

    After the cut, the DNA can be fixed, or a new piece can be added. Scientists can use this tool to create genetically modified organisms, find new ways to treat genetic diseases, and learn more about how genes work.

    Phages are tiny viruses that can kill specific bacteria. They’re everywhere on Earth and help regulate bacterial populations and nutrient cycling. They infect and kill bacteria, and when the bacteria die, they release nutrients into the environment.

    Scientists use phages to treat bacterial infections, which is called phage therapy. They identify and isolate phages that can kill a specific bacterial strain and use them to fight infections caused by that strain.

    Phage therapy has some advantages to antibiotics, like targeting specific bacteria without side effects and potentially reducing antibiotic resistance.

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    Technical University of Denmark (DTU)

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  • Archaea Diversity Drops in Warming Climate

    Archaea Diversity Drops in Warming Climate

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    Newswise — Led by Jizhong Zhou, Ph.D., the director of the Institute for Environmental Genomics at the University of Oklahoma, an international research team conducted a long term experiment that found that climate warming reduced the diversity of and significantly altered the community structure of soil archaea. Their findings are published in the journal Nature Climate Change.

    At the microbiological level, life can be described as belonging to one of three kingdoms – how species are described in relation to one another. Eukarya contains complex organisms like animals and plants and microorganisms such as fungi. The other two categories, bacteria and archaea, are comprised only of microorganisms. Archaea are prevalent in a range of environments, from some of the most hostile like volcanoes and permafrost. However, archaea are also common in the human microbiome and as an important part of soil ecology.

    “As temperature is a major driver of biological processes, climate warming will impact various ecological communities,” Zhou said. “Based on long-term time-series data, our previous studies revealed that experimental warming leads to the divergent succession of soil bacterial and fungal communities, accelerates microbial temporal scaling, reduces the biodiversity of soil bacteria, fungi and protists, but increases bacterial network complexity and stability. However, how climate warming affects the temporal succession of the archaeal community remains elusive. Archaea are ubiquitously present in soil and are vital to soil functions, e.g., nitrification and methanogenesis.”

    Using a long-term multifactor experimental field site at OU’s Kessler Atmospheric and Ecological Field Station, the researchers showed that experimental warming of a tallgrass prairie ecosystem significantly altered the community structure of soil archaea and reduced their taxonomic and phylogenetic diversity. In contrast to the researchers’ previous observations in bacteria and fungi, their finds show that climate warming leads to convergent succession of the soil archaeal community, suggesting archaeal community structures would become more predictable in a warmer world.

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    About the Project

    The article, “Experimental Warming Leads to Convergent Succession of Grassland Archaeal Community” published May 3, 2023 in Nature Climate Change. DOI no. 10.1038/s41558-023-01664-x. Zhou, who is also a George Lynn Cross Research Professor of Microbiology in the Dodge Family College of Arts and Sciences, is the corresponding author. The first author is Ya Zhang, Institute for Environmental Genomics and Department of Microbiology and Plant Biology at OU. 

    About the University of Oklahoma Office of the Vice President for Research and Partnerships 

    The University of Oklahoma is a leading research university classified by the Carnegie Foundation in the highest tier of research universities in the nation. Faculty, staff and students at OU are tackling global challenges and accelerating the delivery of practical solutions that impact society in direct and tangible ways through research and creative activities. OU researchers expand foundational knowledge while moving beyond traditional academic boundaries, collaborating across disciplines and globally with other research institutions as well as decision makers and practitioners from industry, government and civil society to create and apply solutions for a better world. Find out more at ou.edu/research.

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    University of Oklahoma

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  • Honey Bee Brains: A Look at Evolution

    Honey Bee Brains: A Look at Evolution

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    Newswise — Researchers have proposed a new model for the evolution of higher brain functions and behaviors in the Hymenoptera order of insects. The team compared the Kenyon cells, a type of neuronal cell, in the mushroom bodies (a part of the insect brain involved in learning, memory and sensory integration) of “primitive” sawflies and sophisticated honey bees. They found that three diverse, specialized Kenyon cell subtypes in honey bee brains appear to have evolved from a single, multifunctional Kenyon cell-subtype ancestor. In the future, this research could help us better understand the evolution of some of our own higher brain functions and behaviors.

    Are you “busy as a bee,” a “social butterfly” or a “fly on the wall”? There are many ways we compare our behavior to that of insects, and as it turns out there may be more to it than just fun idioms. Studying insects could help us understand not only how their behavior has evolved, but also the behavior of highly evolved animals, including ourselves. Mammalian brains are big and complex, so it is difficult to identify which behaviors and neural and genetic changes have co-developed over time. By comparison, insect brains are much smaller and simpler, making them useful models for study.

    “In 2017, we reported that the complexity of Kenyon cell (KC) subtypes in mushroom bodies in insect brains increases with the behavioral diversification in Hymenoptera (a large and varied order of insects)” explained Professor Takeo Kubo from the Graduate School of Science at the University of Tokyo and co-author of the current study. “In other words, the more KC subtypes an insect has, the more complex its brain and the behaviors it may exhibit. But we didn’t know how these different subtypes evolved. That was the stimulus for this new study.”

    The team from the University of Tokyo and Japan’s National Agriculture and Food Research Organization (NARO) chose two Hymenoptera species as representatives for different behaviors: the solitary turnip sawfly (which has a single KC subtype) and the sophisticated, social honey bee (which has three KC subtypes). As the sawfly has a more “primitive” brain, it is thought to contain some ancestral properties of the honey bee brain. To uncover the potential evolutionary pathways between them, the researchers used transcriptome analysis to identify the gene expression profiles (the genetic activity) of the various KC subtypes and speculate their functions.

    “I was surprised that each of the three KC subtypes in the honey bee showed comparable similarity to the single KC type in the sawfly,” said Assistant Professor Hiroki Kohno, co-author from the Graduate School of Science.  “Based on our initial comparative analysis of several genes, we had previously supposed that additional KC subtypes had been added one by one. However, they appear to have been separated from a multifunctional ancestral type, through functional segregation and specialization.” As the number of KC subtypes increased, each subtype almost equally inherited some distinct properties from an ancestral KC. These then modified in different ways, resulting in their varied present-day functions.

    The researchers wanted a specific behavioral example of how ancestral KC functions are present in both the sawfly and the honey bee. So, they trained sawflies to engage in a common honey bee behavior test, where they learn to associate an odor stimulus with a reward. Although challenging at first, the team was eventually able to engage the sawflies in the memory task. The researchers then manipulated a gene called CaMKII in sawfly larvae, which in honey bees is associated with forming long-term memory, a KC function. When the larvae became adults, their long-term memory was impaired, indicating that the gene plays a similar role in both sawflies and honey bees. Although CaMKII was expressed (i.e., was active) across the entire single KC subtype in sawflies, in honey bees, it was preferentially expressed in only one KC subtype. This suggests that the role of CaMKII in long-term memory was passed down to the specific KC subtype in the honey bee.

    Despite differences in the size and complexity of insect and mammalian brains, there are commonalities in terms of function and the basic architecture of the nervous system. That is why the model proposed in this study for the evolution and diversification of KC subtypes may help towards better understanding the evolution of our own behavior. Next, the team is interested in studying KC types acquired in parallel with social behaviors, such as the honey bee’s “waggle dance.”

    “We would like to clarify whether the model presented here is applicable to the evolution of other behaviors,” said Takayoshi Kuwabara, doctoral student and lead author from the Graduate School of Science. “There are many mysteries about the neural basis that controls social behavior, whether in insects, animals or humans. How it has evolved still remains largely unknown. I believe that this study is a pioneering work in this field.”

    —–

    Paper Title:

    Takayoshi Kuwabara, Hiroki Kohno, Masatsugu Hatakeyama, Takeo Kubo. Evolutionary dynamics of mushroom body Kenyon cell types in hymenopteran brains from multi-functional type to functionally specialized types. Science Advances. DOI: 10.1126/sciadv.add4201

    Funding:

    This research was supported by Grant-in-Aid for Scientific Research (B) 20H03300 (TKubo) and Grant-in-Aid for JSPS Fellows 21J20847 (TKuwabara).

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    University of Tokyo

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  • The Association of Biomolecular Resource Facilities 2023 Annual Meeting, May 7-10, Boston

    The Association of Biomolecular Resource Facilities 2023 Annual Meeting, May 7-10, Boston

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    Newswise — May 5, 2023 (Lexington, KY) – The Association of Biomolecular Resource Facilities (ABRF) 2023 Annual Meeting will be held May 7-10 at the Sheraton Boston Hotel.  This year’s meeting focuses on Driving Collaborative Science, and features dozens of sessions on timely topics on the latest technology and strategies for shared research resources. With close to 1000 attendees from more than 200 leading academic research institutions and commercial manufacturers attending, the ABRF 2023 Annual Meeting will be the largest event for shared research resources, or Core, facilities.

    Among the notable sessions at the 2023 ABRF Annual Meeting are:

    ABRF Award for Outstanding Contributions to Biomolecular Technologies  – presented to Dr. Chris Enke and Richard Yost for the development of the triple quadrupole mass spectrometer and the tremendous impact triple quads have made for a wide range of biomedical research applications.

    ABRF Diversity Equity and Inclusion Award – presented to Dr. Tshaka Cunningham with Polaris Genomics and Future Kings, a regional nonprofit which serves boys and girls of color from economically challenged communities through a unique, year-long afterschool educational program that guides young men and women in grades 6-12 from underserved communities to explore exciting career opportunities in science, technology, engineering, and mathematics (STEM). Their targeted focus is on cybersecurity, computer game design, biomedical sciences, and engineering.

    Keynote speakers: Beth Cimini, Ph.D., Senior Group Leader, Broad Institute will present Making More from Your Microscopy:  Advances in High-Content Image Analysis

    Ed Boyden, Ph.D., HHMI and MIT,  will close the meeting with an engaging presentation on Optical Tools for Analyzing and Controlling Biological Systems.

    Along with these key sessions, the ABRF Annual Meeting will include dozens of workshops on current developments in specific technology areas, including Genomics, Imaging, Mass Spectrometry, Flow Cytometry, and Proteomics, as well as best practices for Core Facilities Management and Leadership.  Attendees will also engage with over 70 biotechnology manufacturers and systems developers to view the latest advances in research instrumentation and tools to support their ground-breaking work. Visit the meeting web site for the latest information or contact ABRF to learn more.

     

    About the Association of Biomolecular Resource Facilities

    The Association of Biomolecular Resource Facilities is a unique membership association comprising over 2000 members working within or in the support of resource and research biotechnology laboratories. Our members represent over 400 laboratories and administrative offices in government, academia, research, industry and commercial settings. ABRF promotes education and career advancement for scientists, core administrators, and staff through conferences, a quarterly journal, publication of research group studies and conference scholarships. The society also sponsors multi-center research studies designed to help members incorporate new biotechnologies into their laboratories.

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    Federation of American Societies for Experimental Biology (FASEB)

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  • High School Students Learn the Basics of Base Editing to Cure “GFP-itis”

    High School Students Learn the Basics of Base Editing to Cure “GFP-itis”

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    Newswise — Genome editing is used to modify the genes of living organisms to elicit certain traits, such as climate-resilient crops or treating human disease at the genetic level. It has become increasingly popular in agriculture, medicine and basic science research over the past decade, and will continue to be relevant and utilized well into the future. Given this prevalence, researchers at the University of California San Diego have started an outreach program that introduces genome-editing technologies to high school students.

    Assistant Professor of Chemistry and Biochemistry Alexis Komor, and Ph.D. candidates Mallory Evanoff and Carlos Vasquez, designed the Genome Editing Technologies Program as a way to educate students on base-editing technologies, expose them to scientists from diverse backgrounds and invite questions about college, professional development, and the everyday life of a graduate student or faculty member within academia. The program is detailed in April 20 issue of The CRISPR Journal.

    Base editors enable scientists to introduce point mutations at targeted sites in the genome of living cells with high efficiency and precision and, thus, have the therapeutic potential to treat thousands of human genetic disorders. Proof-of-concept studies have already demonstrated this technology’s potential in cell therapies and in treating progeria, sickle cell disease and liver diseases.

    “As we were testing out some of these tools, we asked ourselves, how do we make base editors accessible to high schoolers? How do we make this process really visible?” said Evanoff.

    Komor’s team generated a base-editing reporter system using E. coli bacteria. In this system, base-editing activity results in the expression of green fluorescent protein (GFP). The team installed a mutation in the bacterium’s GFP gene to remove its fluorescence. To emphasize the connection to genetic diseases, this phenotype is called “GFP-itis,” and students are tasked with “curing” the bacteria. Using base-editing technology, students correct the mutation back to wild-type, resulting in bacterial cells that fluoresce green.

    The program happens over three days, creating a more meaningful partnership with the school and building a better foundation of trust with the students. “We wanted the students to get to know us better and feel comfortable asking questions about a career in STEM,” said Komor. “A popular question is simply, ‘How do I get into undergraduate research?’ One of the students in the first school we visited, Sage Creek High School, is actually an undergraduate researcher in our lab now.”

    That student is Preety Iyer, a first-year human biology major, who recalled Komor’s visit to her high school as “an amazing opportunity to get hands-on experience with gene-editing technology. It seemed like an intangible concept to me when I was learning about it in my biology classes. Being walked through the entire process and being able to do it myself strengthened my understanding of DNA and gene editing.” 

    Iyer plans to become a doctor working with patients who have rare genetic disorders, and she’s excited to gain more valuable hands-on experience in Komor’s lab: “I’ve been able to use equipment and practice techniques, like flow cytometry and plasmid preparation, that other students don’t get to use until later in their academic careers.” 

    So far, the Genome Editing Technologies Program has visited three local high schools. The schools have had well-developed science classes and much of the equipment needed to run the experiment. The majority of students had also heard of or learned about genome engineering before. Now that Komor’s team has run the program a few times and solicited feedback from students, they hope to expand to schools without such robust science programming. 

    “My high school background in science wasn’t strong in large part because of the lack of mentorship,” said Vasquez. “It’s important to us to reach students who may not have even considered a career in STEM or medicine. To look in their eyes and instill confidence, to show we believe in them — having someone like that when I was in high school would have made a world of difference.”

    The make the experiment as accessible as possible, the team has simplified the base-editing experiment and provides all the necessary equipment. Accessibility also means making the program available to other institutions that may want to implement something similar. Interested scientists or instructors can order plasmid materials from AddGene, a worldwide nonprofit plasmid repository. These plasmids are the DNA needed to make the GFP-itis cells, as well the plasmids needed to as “cure” GFP-itis.

    The goal of the program is not only to make base editing accessible to high school students, but also to encourage critical thinking and reflect on base editing in social and cultural contexts. Komor’s team asked students to think about the difference between a disease and a trait and to consider the implications of germline genome editing, in which edits are inherited by all future descendants of the edited individual, regardless of whether those descendants consent to the procedure.

    “The ethical discussion is what hits a home run with the students,” said Vasquez. “They’ll be responsible for future gene-editing policies. It’s interesting to see them thinking about the ethical side of science.”

    “We’ve had some really good discussions about what is a disease and what is a trait,” stated Evanoff. “If we have the ability to make genetic-disease corrections, who will be able to afford those treatments? Where does the equitability lie in this technology? We don’t have the answers to that. I say to students, ‘That’s going to be your job to figure out!’”

    This research was supported by the National Science Foundation (MCB-2048207), the National Institute of General Medical Sciences (T32 GM007240-41), the National Institute of Health (T32 GM112584), the Howard Hughes Medical Institute (GT13672 and the Gilliam Fellowship Program) and the National Academies of Sciences, Engineering, and Medicine Ford Foundation Predoctoral Fellowship Program.

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    University of California San Diego

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  • Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

    Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

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    Newswise — PHILADELPHIA— A new approach to the genetic engineering of cells promises significant improvements in speed, efficiency, and reduction in cellular toxicity compared to current methods. The approach could also power the development of advanced cell therapies for cancers and other diseases, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

    In the study, which appeared this week in Nature Biotechnology, researchers found that protein fragments used by some viruses to help them get into cells could also be used to get CRISPR-Cas gene editing molecules into cells and their DNA-containing nuclei with extraordinarily high efficiency and low cellular toxicity.

    The scientists expect the new technique to be particularly useful for modifying T cells and other cells from a patient’s own body to make cell therapies. One such application could be CAR T (chimeric antigen receptor T cell) therapy, which uses specially modified immune cells from a patient to treat cancer. The T cells—a type of white blood cell—are removed from the patient and reprogrammed to find and attack cancer cells when reintroduced to the bloodstream.  

    The first FDA-approved CAR T therapy was developed at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States. The therapies have revolutionized the treatment of certain B cell leukemias, lymphomas, and other blood cancers, putting many patients who otherwise had little hope into long-term remission.

    “This new approach—building on Penn Medicine’s history of cell and gene therapy innovation—has the potential to be a major enabling technology for engineered cellular therapies,” said co-senior author E. John Wherry, PhD, Richard and Barbara Schiffrin President’s Distinguished Professor and chair of Systems Pharmacology & Translational Therapeutics at Penn Medicine.

    CRISPR-Cas molecules are derived from ancient bacterial antiviral defenses, and are designed to precisely remove DNA at desired locations in a cell’s genome. Some CRISPR-Cas-based systems combine the deletion of old DNA with the insertion of new DNA for versatile genome editing. This approach can be used to replace faulty genes with corrected ones or delete or modify genes to enhance cellular function. Some systems can also add genes that confer new properties to CAR T cells such as the ability to recognize tumors or withstand the harsh tumor microenvironment that normally exhausts T cells.

    Although CRISPR-Cas systems are already widely used as standard laboratory tools for molecular biology, their use in modifying patients’ cells to make cell-based therapies has been limited—in part because CRISPR-Cas molecules can be hard to get into cells and then into cells’ DNA-containing nuclei.

    “Current methods of getting CRISPR-Cas systems into cells, which include the use of carrier viruses and electric pulses, are inefficient for cells taken directly from patients (called primary cells). These methods also typically kill many of the cells they are used on, and can even cause broad unwanted changes in gene activity,” said co-senior author Shelley L. Berger, PhD, the Daniel S. Och University Professor in Cell and Developmental Biology and Genetics and director of the Penn Epigenetics Institute.

    In the study, researchers explored the use of small, virus-derived protein fragments, called peptides, to pilot CRISPR-Cas molecules more efficiently through the outer membranes of primary human cells and into their nuclei. Notably, researchers found that a fused combination of two modified peptides—one found in HIV and one in influenza viruses—could be mixed with CRISPR-Cas molecules to get them into primary human or mouse cells and their nuclei with efficiencies of up to nearly 100 percent, depending on the cell type—with almost no toxicity or gene-expression changes.

    The team demonstrated the approach, which they call PAGE (peptide-assisted genome editing), for several types of envisioned cell therapy including CAR T cell therapies.

    In addition to its potential use in cell and gene therapies, the authors note the PAGE approach could see wide application in basic scientific research. The inefficiency of standard CRISPR-Cas cell penetration methods has meant that gene-editing to create mouse models of diseases typically requires a multi-step, time-consuming process of generating transgenic mice—to introduce the gene-editing machinery into their DNA. By contrast, PAGE with its high efficiency and low toxicity might enable rapid, efficient, and straightforward gene editing in ordinary lab mice.

    “The simplicity and power of the peptide-assist concept suggests that it could potentially be adapted in the future for the delivery into primary cells of other genome-editing proteins, or even protein-based drugs,” said co-senior author Junwei Shi, PhD, an assistant professor of Cancer Biology and member of the Penn Epigenetics Institute and Abramson Family Cancer Research Institute.

    The study was a collaboration that included the laboratories of Penn co-author Rahul Kohli, MD, PhD, an associate professor of Infectious Diseases and Biochemistry and Biophysics, and co-author Gerd Blobel, MD, PhD, the Frank E. Weise III Professor of Pediatrics and co-director of the Epigenetics institute.

    This study was supported by the National Institute of Health (R01-HL119479, R01-GM138908, AI105343, AI082630, AI108545, AI155577, AI149680, U19AI082630, R35-CA263922, R01-CA258904), the Parker Institute for Cancer Immunotherapy, and institutional funds from University of Pennsylvania.

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    Perelman School of Medicine at the University of Pennsylvania

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  • 240 Mammal Genomes Reveal Human Disease Risks

    240 Mammal Genomes Reveal Human Disease Risks

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    Newswise — Why is it that certain mammals have an exceptional sense of smell, some hibernate, and yet others, including humans, are predisposed to disease? A major international research project, jointly led by Uppsala University, Sweden and the Broad Institute, USA, has surveyed and analysed the genomes of 240 different mammals. The results, now published in 11 articles in the journal Science, show how the genomes of humans and other mammals have developed over the course of evolution. The research shows which regions have important functions in mammals, which genetic changes have led to specific characteristics in different species and which mutations can cause disease.

    “In combination, the 11 articles we are now publishing in Science provide an enormous amount of information about the function and development of mammalian genomes,” says Kerstin Lindblad-Toh, Professor of Comparative Genomics at Uppsala University and one of two leaders of the international consortium of researchers. “Moreover, we have produced data that can be used for studies of evolution and medical research for many years to come.”

    In a large international project jointly led by Uppsala University and the Broad Institute, more than 30 research teams have together surveyed and analysed the genomes of 240 mammal species. The results, now published in 11 articles in the journal Science, show how the genomes of humans and other mammals have developed in the course of evolution.

    The human genome contains approximately 20,000 genes that constitute the code for manufacturing all the proteins in the body. The genome also contains instructions that direct where, when and how much of the proteins are produced. These parts of the genome, which are called regulatory elements, are much more difficult to identify than the parts that give rise to proteins. However, studying a great many mammals’ genomes makes it possible to figure out which parts of the genome are functionally important.

    The hypothesis shared by the researchers behind the publications in Science has been that if a position in the genome has been preserved throughout 100 million years of evolution, it likely serves a function in all mammals. For the first time, they have been able to test this hypothesis on a large scale. By making a detailed survey and systematic comparison of the genomes of 240 mammals, the researchers have identified regions of the human genome with previously uncharacterised function. These regions are likely regulatory elements and are significant for the correct functioning of the genome. Mutations in these can play an important role in the origin of diseases or in the distinctive features of mammal species.

    The researchers identified more than three million important regulatory elements in the human genome, about half of which were previously unknown. They were also able to ascertain that at least 10 per cent of the genome is functional, ten times as much as the approximately one per cent that codes for proteins.

    The 240 different mammals in the study vary widely in their characteristics, such as the acuteness of their sense of smell or the size of their brain. The researchers were able to find regions in the genomes that lead to some species having a superior sense of smell or to certain species hibernating.

    “It’s exciting to now have a picture of which mutations have steered the development of specific traits in these widely divergent mammals,” says Matthew Christmas, researcher and co-first author of one of the articles focusing on the function of the genome and how it affects distinctive features in different species.

    One of the studies shows that mammals had begun to change and diverge ven before the Earth was hit by the asteroid that killed the dinosaurs, approximately 65 million years ago.

    “Our results can also provide important information about whether mammals are at risk of extinction, depending on how much variation they have in their genome. This is information that can lay the foundation for understanding how to manage a species to help it survive,” says Professor Lindblad-Toh.

    The new knowledge also helps researchers understand how diseases arise, by linking the positions in the genome conserved by evolution to known conditions. This can be done for all species and will also be usable with reference to human diseases.

    “Our analyses of 240 mammals give us a better insight into the regulatory signals in the genome. We calibrated our results on positions that are known to contribute to disease, and then could use these to suggest additional positions which could be prioritised for neurological traits, such as schizophrenia or immune conditions including asthma or eczema,” says Jennifer Meadows, researcher and co-first author of the second article, which focuses on how the project’s data can contribute to knowledge about diseases.

    The genome of healthy and sick people is compared to understand which mutations lead to disease. This produces a picture of the region in the genome that may be important, but does not yield an exact knowledge of which mutation causes the disease.

    “A large proportion of the mutations that lead to common diseases, like diabetes or obsessive-compulsive disorder, lie outside the genes and have to do with gene regulation. Our studies make it easier to identify the mutations that lead to disease and to understand what goes wrong,” says Lindblad-Toh.

    The researchers also studied the cancer medulloblastoma, which is the most common type of malignant brain tumour in children. Although modern treatments have improved the prognosis, not all children can be cured. Moreover, those that survive often experience lifelong side-effects from the aggressive treatment.

    “In patients with medulloblastoma, we found many new mutations in evolutionarily conserved positions. We hope that analysis of these mutations will lay the ground for new diagnostics and therapies,” says Karin Forsberg-Nilsson, Professor of Stem Cell Research at Uppsala University, who led the cancer part of the study.

    This work was supported in part by the National Institutes of Health (US), the Swedish Research Council (SWE), the Knut and Alice Wallenberg Foundation (SWE), and the National Science Foundation (US).

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    Uppsala University

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  • Genetic code of hornets sequenced to understand their successful invasion

    Genetic code of hornets sequenced to understand their successful invasion

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    Newswise — The genomes of two hornet species, the European hornet and the Asian hornet (or yellow-legged hornet) have been sequenced for the first time by a team led by UCL (University College London) scientists.

    By comparing these decoded genomes with that of the giant northern hornet, which has recently been sequenced by another team, the researchers have revealed clues suggesting why hornets have been so successful as invasive species across the globe.

    Hornets are the largest of the social wasps; they play important ecological roles as top predators of other insects. In their native regions, they are natural pest controllers, helping regulate the populations of insects such as flies, beetles, caterpillars and other types of wasps. These services are critical for healthy, functional ecosystems, as well as for agriculture.

    But hornets also tend to be very successful as invasive species. They can become established in areas they are not native to and cause potentially huge ecological and economic damage by hunting important pollinators, such as honeybees, wild bees and hoverflies.

    To better understand how these species have so successfully expanded their ranges, the international team of scientists investigated the genomes of three types of hornets.

    A genome sequence is the set of instructions – a genetic code – that makes a species. Comparing the genomes of different species can give insights into their biology – their behaviour, evolution, and how they interact with the environment.

    The researchers have newly sequenced the genomes of the native European hornet, Vespa crabro – an important top predator, which is protected in parts of Europe – and the invasive yellow-legged Asian hornet Vespa velutina, which has become established through much of Europe over the last 20 years threatening native ecosystems, and has occasionally been sighted in the UK. They compared these with the genome of the giant northern hornet, Vespa mandarinia – a species known for its role as pest controller, pollinator and food provider in its native Asian range, but is a recent arrival in North America, where it may threaten native fauna.

    By analysing differences between the three related species, the researchers were able to identify genes that have been rapidly evolving since the species differentiated themselves from other wasps and from one another, and found some noteworthy genes that are rapidly evolving, particularly relating to communication and olfaction (smell).

    The study’s first author, Dr Emeline Favreau (UCL Centre for Biodiversity & Environment), said: “We were excited to find evidence of rapid genome evolution in these hornet genomes, compared to other social insects. Lots of genes have been duplicated or mutated; these included genes that are likely to be involved in communication and in sensing the environment.”

    Genome evolution allows organisms to adapt to their environment and make the most of their surroundings by developing new behaviours and physiology.

    Co-author Dr Alessandro Cini, who began the work at UCL before moving to the University of Pisa, said: “These findings are exciting, as they may help explain why hornets have been so successful in establishing new populations in non-native regions.

    “Hornets are carried to different parts of the world accidentally by humans. All that is needed is a small number of mated queens to be transported, hidden in cargo perhaps. The genomes suggest that hornets have lots of genes involved in detecting and responding to chemical cues – these may make them especially good at adapting to hunt different types of prey in non-native regions.”

    Senior author Professor Seirian Sumner (UCL Centre for Biodiversity & Environment) said: “These hornet genomes are just the beginning. The genomes of more than 3,000 insect species have now been sequenced by efforts around the world, but wasps are under-represented among these.

    “Genomes tell us about aspects of the ecology and evolution that other methods cannot. Evolution has equipped these insects with an incredible genetic toolbox with which to exploit their environment and hunt their prey.”

    Armed with these new genomes, the scientists hope to help improve the management of hornet populations, both for their ecosystem services as pest controllers in native zones, and as ecological threats in regions where they are invasive.

    The study involved researchers in the UK, Italy, Spain, Israel, France, New Zealand, and Austria, and was primarily funded by the Natural Environment Research Council.

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    University College London

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  • Supreme Court clears way for Texas death row inmate Rodney Reed to try to use DNA to prove innocence | CNN Politics

    Supreme Court clears way for Texas death row inmate Rodney Reed to try to use DNA to prove innocence | CNN Politics

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    CNN
     — 

    The Supreme Court cleared the way on Wednesday for Texas death row inmate Rodney Reed to seek post-conviction DNA evidence to try to prove his innocence.

    Reed claims an all-White jury wrongly convicted him of killing of Stacey Stites, a 19-year-old White woman, in Texas in 1998.

    Texas had argued that he had waited too long to bring his challenge to the state’s DNA procedures in federal court, but the Supreme Court disagreed. Now, he can go to a federal court to make his claim.

    The ruling was 6-3. Justice Brett Kavanaugh delivered the opinion of the court and was joined by Chief Justice John Roberts and Justices Sonia Sotomayor, Elena Kagan, Amy Coney Barrett and Ketanji Brown Jackson.

    Since Reed’s conviction, Texas courts had rejected his various appeals. Celebrities such as Kim Kardashian and Rihanna have expressed support, signing a petition asking the state to halt his eventual execution.

    The case puts a new focus on the testing of DNA crime-scene evidence and when an inmate can make a claim to access the technology in a plea of innocence. To date, 375 people in the United States have been exonerated by DNA testing, including 21 who served time on death row, according to the Innocence Project, a group that represents Reed and other clients seeking post-conviction DNA testing to prove their innocence.

    Kavanaugh, in his opinion Wednesday, said that the court agreed to hear the case because federal appeals courts have disagreed about when inmates can make such claims without running afoul of the statute of limitations. Kavanaugh said Reed could make the claim after the Texas Court of Criminal Appeals ultimately denied his request for rehearing, rejecting an earlier date set out by the appeals court.

    “Significant systemic benefits ensue from starting the statute of limitations clock when the state litigation in DNA testing cases like Reed’s has concluded,” Kavanaugh said.

    He noted that if any problems with a defendant’s right to due process “lurk in the DNA testing law” the case can proceed through the appellate process, which could ultimately render a federal lawsuit unnecessary.

    Justices Clarence Thomas, Samuel Alito and Neil Gorsuch dissented.

    Alito, joined by Gorsuch in his dissent, said Reed should have acted more quickly to bring his appeal. “Instead,” Alito wrote, “he waited until an execution date was set.”

    Alito charged Reed with making the “basic mistake of missing a statute of limitations.”

    Reed has been on death row for the murder of Stites.

    A passerby found Stites’ body near a shirt and a torn piece of belt. Investigators targeted Reed because his sperm was found inside her. Reed acknowledged the two were having an affair, but says that her fiancé, a local police officer named Jimmy Fennell, was the last to see her alive.

    Reed claims that over the last two decades he has discovered a “considerable body of evidence” demonstrating his innocence. Reed claims that the DNA testing would point to Fennell as the murder suspect. Fennell was later jailed for sexually assaulting a woman in his custody and Reed claims that numerous witnesses said he had threatened to strangle Stites with a belt if he ever caught her cheating on him. Reed seeks to test the belt found at the scene that was used to strangle Stites.

    The Texas law at issue allows a convicted person to obtain post-conviction DNA testing of biological material if the court finds that certain conditions are met. Reed was denied. He came to the Supreme Court in 2018 and was denied again. Now he is challenging the constitutionality of the Texas law arguing that the denial of the DNA testing violates his due process rights. 

    But the 5th US Circuit Court of Appeals held that he waited too long to bring the claim. “An injury accrues when a plaintiff first becomes aware, or should have become aware, that his right had been violated.” The court said that he became aware of that in 2014 and that his current claim is “time barred.” 

    Reed’s lawyers argued that he could only bring the claim once the state appeals court had ruled, at the end of state court litigation. In court, Parker Rider-Longmaid said that the “clock doesn’t start ticking” until state court proceedings come to an end. He said Texas’ reading of the law would mean that other procedures in the appellate process are “irrelevant.”

    This story has been updated with additional developments.

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  • New test could help identify type 2 diabetes risk

    New test could help identify type 2 diabetes risk

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    Newswise — Analysing changes to DNA in the blood can improve the ability to predict a person’s risk of developing type 2 diabetes within a decade.

    Scientists looked at the influence of these changes – known as DNA methylation – alongside other risk factors in almost 15,000 people to predict the likelihood of developing the condition years in advance of any symptoms developing.

    The findings could lead to preventative measures being put in place earlier, reducing the economic and health burden caused by type 2 diabetes.

    Methylation is a chemical process in the body in which a small molecule called a methyl group is added to DNA.

    Current risk prediction tools for type 2 diabetes use information such as age, sex, BMI and family history of the disease.

    Researchers from the University of Edinburgh found that the inclusion of DNA methylation data alongside these risk factors provided a more accurate prediction.

    The scientists used their results to estimate the predictive performance using a hypothetical screening scenario of 10,000 people, where one in three individuals develop type 2 diabetes over a 10-year period.

    The model that used DNA methylation correctly classed an extra 449 individuals compared with traditional risk factors alone.

    The addition or removal of these methyl groups can affect how some molecules act in the body. These methylation patterns can help to track ageing processes and development of disease.

    Data came from 14,613 volunteers in the Generation Scotland study – a large study designed to help scientists investigate the causes of disease, understand the country’s healthcare priorities, and inform future medical treatments and health policies.

    The team also repeated the analyses in 1,451 individuals from a study based in Germany to ensure their findings could be replicated in people from different backgrounds.

    Type 2 diabetes is a serious condition where the insulin a pancreas makes cannot work properly, or a pancreas cannot make enough insulin. This can lead to high blood sugar levels and, in turn, a range of health issues such as heart diseases and stroke, nerve damage and foot problems.

    More than 4.9 million people live with diabetes in the UK, with 90 per cent of those with type 2.

    The study is published in the journal Nature Aging: https://www.nature.com/articles/s43587-023-00391-4. Researchers from the University of Edinburgh were supported by experts at the University of Helsinki, the German Research Center for Environmental Health (GmbH) and the German Center for Diabetes Research (DZD).

    Yipeng Cheng, a PhD student from the University of Edinburgh’s Centre for Genomic and Experimental Medicine, said: “It is promising that our findings were observed in the Scottish and German studies with both showing an improvement in prediction above and beyond commonly used risk factors. Delaying onset is important as diabetes is a risk factor for other common diseases, including dementias.”

    The study’s principal investigator, Professor Riccardo Marioni, also from the University of Edinburgh’s Centre for Genomic and Experimental Medicine, said: “Similar approaches could be taken for other common diseases to generate broad health predictors from a single blood or saliva sample. We are incredibly grateful for our study volunteers who make this research possible – the more people that join our study, the more precisely we can identify signals that will help delay or reduce the onset of diseases as we age.”

    Generation Scotland is currently recruiting volunteers and has recently opened to young people aged between 12 and 15 for the first time. Anyone who lives in Scotland can sign up online at www.generationscotland.org

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    University of Edinburgh

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  • Blind dating in bacteria evolution

    Blind dating in bacteria evolution

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    Newswise — Proteins are the key players for virtually all molecular processes within the cell. To fulfil their diverse functions, they have to interact with other proteins. Such protein-protein interactions are mediated by highly complementary surfaces, which typically involve many amino acids that are positioned precisely to produce a tight, specific fit between two proteins. However, comparatively little is known about how such interactions are created during evolution.

    Classical evolutionary theory suggests that any new biological feature involving many components (like the amino acids that enable an interaction between proteins) evolves in a stepwise manner. According to this concept, each tiny functional improvement is driven by the power of natural selection because there is some benefit associated with the feature. However, whether protein-protein interactions also always follow this trajectory was not entirely known.

    Using a highly interdisciplinary approach, an international team led by Max Planck researcher Georg Hochberg from the Terrestrial Microbiology in Marburg have now shed new light on this question. Their study provides definitive evidence that highly complementary and biologically relevant protein-protein interactions can evolve entirely by chance.

    Proteins cooperate in a photoprotection system

    The research team made their discovery in a biochemical system that microbes use to adapt to stressful light conditions. Cyanobacteria use sunlight to produce their own food through photosynthesis. Since much light damages the cell, cyanobacteria have evolved a mechanism known as photoprotection: if light intensities become dangerously high, a light intensity sensor named Orange Carotenoid Protein (OCP) changes its shape. In this activated form, OCP protects the cell by converting excess light energy into harmless heat. In order to return into its original state, some OCPs depend on a second protein: The Fluorescence Recovery Protein (FRP) binds to activated OCP1 and strongly accelerates its recovery.

    ‘Our question was: Is it possible that the surfaces that allow these two proteins to form a complex evolved entirely by accident, rather than through direct natural selection?’ says Georg Hochberg. ‘The difficulty is that the end result of both processes looks the same, so we usually cannot tell why the amino acids required for some interaction evolved – through natural selection for the interaction or by chance. To tell them apart, we would need a time machine to witness the exact moment in history these mutations occurred, ’Georg Hochberg explains.

    Luckily, recent breakthroughs in molecular and computational biology has equipped Georg Hochberg and his team with a laboratory kind of time machine: ancestral sequence reconstruction. In addition, the light protection system of cyanobacteria, which is under study in the group of Thomas Friedrich from Technische Universität Berlin since many years, is ideal for studying the evolutionary encounter of two protein components. Early cyanobacteria acquired the FRP proteins from a proteobacterium by horizontal gene transfer. The latter had no photosynthetic capacity itself and did not possess the OCP protein.

    To work out how the interaction between OCP1 and FRP evolved, graduate student Niklas Steube inferred the sequences of ancient OCPs and FRPs that existed billions of years ago in the past, and then resurrected these in the laboratory. After translation of the amino acid sequences into DNA he produced them using E. coli bacterial cells in order to be able to study their molecular properties.

    A fortunate coincidence

    The Berlin team then tested whether ancient molecules could form an interaction. This way the scientists could retrace how both protein partners got to know each other. ‘Surprisingly, the FRP from the proteobacteria already matched the ancestral OCP of the cyanobacteria, before gene transfer had even taken place. The mutual compatibility of FRP and OCP has thus evolved completely independently of each other in different species, says Thomas Friedrich. This allowed the team to prove that their ability to interact must have been a happy accident: selection could not plausibly have shaped the two proteins’ surfaces to enable an interaction if they had never met each other. This finally proved that such interactions can evolve entirely without direct selective pressure.

    ‘This may seem like an extraordinary coincidence,’ Niklas Steube says. ‘Imagine an alien spaceship landed on earth and we found that it contained plug-shaped objects that perfectly fit into human-made sockets. But despite the perceived improbability, such coincidences could be relatively common. But in fact, proteins often encounter a large number of new potential interaction partners when localisation or expression patterns change within the cell, or when new proteins enter the cell through horizontal gene transfer.’ Georg Hochberg adds, ‘Even if only a small fraction of such encounters ends up being productive, fortuitous compatibility may be the basis of a significant fraction of all interactions we see inside cells today. Thus, as in human partnerships, a good evolutionary match could be the result of a chance meeting of two already compatible partners.’

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    Max Planck Society (Max-Planck-Gesellschaft)

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  • tRNA biomarkers for cancer diagnosis and prognosis enabled by new method

    tRNA biomarkers for cancer diagnosis and prognosis enabled by new method

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    Newswise — Ribonucleic acid (RNA) molecules are present in all living cells, with different types of RNA having different jobs. For example, messenger RNA is copied from DNA and carries instructions on how to make a protein. Transfer RNA (tRNA) links the mRNA sequence with its corresponding amino acid, ensuring that proteins are stitched together correctly as instructed by DNA. 

    Cells naturally modify RNA molecules in order to enhance their stability, structure and function. When this modification process goes wrong, it can have important consequences for human health and disease. In the case of tRNA, incorrect or missing modifications produce faulty or incomplete proteins, with the dysregulation of tRNA modifications being linked to various human diseases, including neurodegenerative diseases, metabolic diseases, and cancer. 

    tRNAs are “information-rich” molecules with huge potential for the diagnosis and prognosis of diseases, but so far haven’t been exploited for such purpose due to the lack of methods that can capture this information in a quantitative and cost-efficient manner. For example, some types of cancers are difficult to diagnose because their symptoms are non-specific and can be confused with other conditions. At the same time, certain tRNA modification profiles are only known to exist in specific cancer types and can serve as highly-specific biomarkers. 

    Being able to isolate tRNA molecules from blood samples and quantify their modifications can help diagnose cancers without the use of imaging tests or invasive biopsies. Furthermore, the type of tRNA modifications can change depending on the state of the disease, providing valuable information about the prognosis of the condition. 

    Current methods for measuring tRNA molecules typically involve techniques such as next-generation sequencing or mass spectrometry, however, these methods have limited use for diagnostic purposes because they are either unable to detect modifications, or they cannot identify at which location of the tRNA they are occurring at.  

    Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have addressed this challenge by developing a new method that can measure both the abundance and modification of tRNA molecules in a single step. The method is called Nano-tRNAseq and is first described today in the journal Nature Biotechnology. 

    Nano-tRNAseq is based on nanopore sequencing, a technology that can directly sequence individual RNA molecules by passing them through a small pore. Each of the nucleotides that compose an RNA molecule has a slightly different size and shape, with a corresponding change in the electrical current that occurs as each nucleotide passes through the pore. Computer programs detect changes in the current to identify the sequence of the RNA molecules, including any modifications. As a proof of concept, the researchers used Nano-tRNAseq to accurately measure tRNA abundances and modifications in samples taken from yeast cells exposed to different environmental conditions. 

    The method has significant advantages over conventional techniques. “For the first time, we can study both tRNA abundance and tRNA modification profiles simultaneously. As a bonus, the method is rapid, cost-effective, high-throughput, and has single-molecule resolution. Previously, we relied on two separate methods that, together, are less informative, and it would take weeks and cost thousands of euros to obtain results. Nano-tRNAseq is a fraction of the cost, and we can have results within a couple of days, and in the near future, within a few hours” says Morghan Lucas, PhD candidate at the Centre for Genomic Regulation and first author of the study.  

    The rapid data analysis enabled by the method is critical for clinical decision-making. Another advantage is that the nanopore sequencing machines required for the technique are small, lightweight and can be powered by a laptop or portable battery, making them easy to transport to remote locations and enable use in the field or the clinic. 

    The researchers note there are still some limitations to the new method, such as the inability to predict which tRNA modification is dysregulated in a given sample unless the precise modifications found in that tRNA have been previously identified using other experimental methods. “While tRNA modification profiles of lower eukaryotic species, such as yeast, are well characterized, this is not the case for humans. By using Nano-tRNAseq in parallel with other methods, we can describe the modification profiles of the complete set of human tRNAs and, in the future, use Nano-tRNAseq to identify which changes in tRNAs are associated with a given human disease,” adds Morghan Lucas. 

    The method was developed by Dr. Eva Novoa’s research group at the Centre for Genomic Regulation (CRG). Dr. Novoa plans on using the technology to further her research efforts funded by the Spanish Association Against Cancer (AECC). 

    “tRNA molecules can be cleaved into small but stable RNA fragments which circulate in blood plasma. These molecules are typically altered in cancer patients, and are hugely information-rich for diagnostic and prognostic purposes. Nano-tRNAseq is a proof-of-concept technology that paves the way for the development of a simple, cost-effective and highly-precise method that can quantify these molecules in a non-invasive manner. Our aim is to further develop this technology and combine it with artificial intelligence tools to determine the malignancy of a biological sample in less than 3 hours, and at a cost of no more than 50 euros per sample” says Dr. Eva Novoa, senior author of the study and researcher at the Centre for Genomic Regulation. 

    The study was funded by the Spanish Ministry of Economy, Industry, and Competitiveness and a European Research Council Starting Grant. Collaborators include the Institute for Research in Biomedicine (IRB) in Barcelona and the CNRS-Université de Lorraine in Nancy, France. 

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    Center for Genomic Regulation

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