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35-Year Mystery of Retrons Solved—Unusual Molecules Combining RNA and DNA Strands Are Part of Bacterial Defense Mechanism Against Phage; Similarities Noted to “Guard” Mechanism Used by Plants

Peculiar hybrid structures called retrons (image at left; see graphic summary at end) that are half RNA, half single-strand DNA are found in many species of bacteria. Since their discovery around 35 years ago, researchers have learned how to use retrons for producing single strands of DNA in the lab, but no one knew what their function was in the bacteria, despite much research into the matter. In a paper published online on November 5, 2020 in Cell, a Weizmann Institute of Science (Israel) team reports on solving the long-standing mystery. The article is titled “Bacterial Retrons Function in Anti-Phage Defense.” Retrons are immune system "guards" that ensure the survival of the bacterial colony when it is infected by viruses. In addition to uncovering a new strategy used by bacteria to protect themselves against viral infection--one that is surprisingly similar to that employed by plant immune systems--the research revealed many new retrons that may, in the future, add to the genome-editing toolkit. The study, conducted in the Microbial Genomics lab (https://www.weizmann.ac.il/molgen/Sorek/) of Weizman Professor Rotem Sorek of the Institute's Molecular Genetics Department, was led by Adi Millman, Dr. Aude Bernheim, and Avigail Stokar-Avihail in Professor Sorek’s lab. Professor Sorek and his team did not set out to solve the retron mystery; they were seeking new elements of the bacterial immune system, specifically elements that help bacteria to fend off viral infection. Their search was made easier by their recent finding that bacteria's immune system genes tend to cluster together in the genome within so-called “defense islands.” When the researchers uncovered the unique signature of a retron within a bacterial defense island, the team decided to investigate further.

Researchers Develop Phenome-Risk Classification Machine Learning Algorithm to Identify Patients Who Are at High Risk for Developmental Stuttering; Results Presented at ASHG 2020 Virtual Annual Meeting (October 27-30)

On Day 3 (Thursday, October 29) of the American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (https://www.ashg.org/meetings/2020meeting/), one of the most interesting presentations was on the subject of developmental stuttering. Douglas M. Shaw (a graduate student in the Vanderbilt Genetics institute, Vanderbilt University) gave talk entitled “Applying a Phenome Risk Classifying Model to Identify Undiagnosed Developmental Stuttering Cases in a Biobank for Genome Wide Association Analysis.” In the abstract to his talk, Shaw described “developmental stuttering” as a speech disorder characterized by a disturbance in fluency and speech pattern, with an adult prevalence of 1-3% in the US. Despite twin-based studies showing ~50% heritability, the genetic etiology of stuttering is still largely unknown. No population-based genome wide association analysis (GWAS) has yielded variants that reach genome-wide significance, Shaw and colleagues wrote. Shaw noted that within Vanderbilt’s Electronic Health Record-linked biorepository (BioVU), only 142 cases of stuttering have diagnostic ICD9/10 (ICD9-307.0, ICD10-F98.5, ICD9-315.35, ICD10-F80.81, ICD10-R47.82) codes out of 92,762 genotyped samples, suggesting a large portion of people who stutter are not well-captured within the EHR. To address this case acquisition issue and provide a large enough sample set to power a GWAS, Shaw and colleagues developed a phenome-risk classification machine learning algorithm to identify patients who are at high risk for developmental stuttering.

Study Uncovers Subset of COVID-19 Patients Who Recover Quickly and Sustain Antibodies; Results Published in Cell

One of the pressing questions about COVID-19 remains: How long does immunity last? One key indicator of immunity is the presence of virus-specific antibodies. Previous studies have provided conflicting accounts about whether people who have recovered from infection can sustain potentially-protective antibodies or not. A new study led by investigators from Brigham and Women's Hospital in Boston examined blood samples and cells from patients who had recovered from mild to moderate COVID-19 and found that while antibodies against the virus declined in most individuals after disease resolution, a subset of patients sustained anti-virus antibody production several months following infection. These antibody "sustainers" had a shorter course of symptoms, suggesting that some individuals who recover from COVID-19 faster may be mounting a more effective and durable immune response to the virus. Results are published in Cell. The article is titled "Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production.” "We've found a subset of individuals that heal quickly while sustaining virus-specific antibody levels after COVID-19," said Duane Wesemann, MD, PhD, an Immunologist and Associate Physician in the Brigham Division of Allergy and Clinical Immunology and an Associate Professor at Harvard Medical School. "The kind of immune response we're seeing in these individuals is a bit like investing in an insurance policy--it's the immune system's way of adding a potential layer of protection against future encounters with the virus." The Wesemann lab studies the entire set of antibodies a host's immune system produces and how these antibodies learn to recognize pathogens. In the spring of 2020, the team turned its attention to the COVID-19 pandemic and the immune response of people who become infected.

National Human Genome Research Institute (NHGRI) Publishes New Vision for Human Genomics--NHGRI's 2020 Strategic Vision Describes Opportunities in Human Genomics for Improving Human Health—Vision Published in Nature

On October 28, 2020, The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH¬) published its “Strategic Vision for Improving Human Health at the Forefront of Genomics” (https://www.nature.com/articles/s41586-020-2817-4) online in the journal Nature. This vision describes the most compelling research priorities and opportunities in human genomics for the coming decade, signaling a new era in genomics for the Institute and the field. “We crafted our new strategic vision at an important inflection point in human genomics," said Eric Green, MD, PhD, NHGRI Director. "Genomics is now prevalent across the research landscape, and so NHGRI focused its strategic attention on the most cutting-edge aspects of the field. Our criteria for inclusion was that future advances must be widely beneficial and have the greatest impact on understanding genome biology and facilitating the implementation of genomic medicine." Genomics is now prevalent across the research landscape, and so NHGRI focused its strategic attention on the most cutting-edge aspects

Regeneron's Antibody Cocktail Inmazeb® Is First FDA-Approved Treatment for Ebola (Zaire Ebolavirus); Novel Anti-Viral Antibody Medicine Developed Using Same “Rapid Response” Technologies As Regeneron’s Investigational COVID-19 Antibody Combination

On October 14, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced that the U.S. Food and Drug Administration (FDA) had approved Inmazeb® (atoltivimab, maftivimab, and odesivimab-ebgn) for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including newborns of mothers who have tested positive for the infection. “We are incredibly proud that the FDA has approved Inmazeb, which is also known as REGN-EB3. This is the first time the FDA has approved a treatment specifically for Ebola, which has caused a number of deadly outbreaks,” said George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer of Regeneron. “Decades of investment in our VelociSuite® rapid response technologies, the dedication of world-class scientists, and the courageous contributions of healthcare providers and patients, together with remarkable cooperation between leading international health organizations and governments, have led to this important moment. As we apply the same sophisticated technologies and manufacturing capabilities against COVID-19, we hope this will be one of many demonstrations of how the power of science can be successfully deployed against dangerous infectious diseases.” As part of an agreement announced (https://investor.regeneron.com/news-releases/news-release-details/barda-...) in July 2020 (https://investor.regeneron.com/news-releases/news-release-details/barda-...), Regeneron will deliver an established number of Inmazeb treatment doses over the course of six years to the Biomedical Advanced Research and Development Authority (BARDA), as part of the U.S. Department of Health and Human Services’ (HHS) goal of building national preparedness for public health emergencies.

Regeneron's Ongoing COVID-19 Phase 2/3 Outpatient Trial Prospectively Demonstrates REGN-COV2 Antibody Cocktail Significantly Reduced Virus Levels & Reduced Need for Further Medical Attention

On October 28, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced positive, prospective results from an ongoing Phase 2/3 seamless trial in the COVID-19 outpatient setting showing its investigational antibody cocktail, REGN-COV2, met the primary and key secondary endpoints. REGN-COV2 significantly reduced viral load and patient medical visits (hospitalizations, emergency room, urgent care visits, and/or physician office/telemedicine visits). "The first job of an antiviral therapeutic drug is to lower the viral load, and our initial data in 275 patients strongly suggested that the REGN-COV2 antibody cocktail could lower viral load and thereby potentially improve clinical outcomes. Today's analysis, involving more than 500 additional patients, prospectively confirms that REGN-COV2 can indeed significantly reduce viral load and further shows that these viral reductions are associated with a significant decrease in the need for further medical attention," said George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer of Regeneron. "We continue to see the strongest effects in patients who are most at risk for poor outcomes due to high viral load, ineffective antibody immune response at baseline, or pre-existing risk factors. Regeneron has shared these results with the U.S. Food and Drug Administration as part of its review of our Emergency Use Authorization submission, and we continue to focus on completing our ongoing trials evaluating REGN-COV2 for the treatment and prevention of COVID-19."

Genome-Wide Analysis ID’s Genetic Effects on Reproductive Success & Ongoing Natural Selection at FADS Locus; FADS1/2 Allele Represents Perhaps Only Example of Genetic Variant with Evidence of Both Ancient & Ongoing Selection, Scientists Say at ASHG 2020

An international team of researchers who identified genetic variants associated with reproductive success say their findings could highlight mechanisms underlying fertility and infertility. In addition, their analyses detected genetic alleles under present-day selection, providing an insight into the nature of ongoing natural selection in humans. Iain Mathieson, PhD, a population geneticist at the University of Pennsylvania, presented the results of the study at the American Society of Human Genetics 2020 Virtual Meeting. The title of his presentation was “Genome-Wide Analysis Identifies Genetic Effects on Reproductive Success and Ongoing Natural Selection at the FADS Locus,” and was delivered in the ASHG’s Thursday morning session “Natural Selection on Polygenic Traits and Omics.” “This study is of interest in relation to our findings on reproductive biology and potential links to infertility,” says co-author of the study Melinda Mills, PhD, Director of the Leverhulme Centre for Demographic Science at the University of Oxford (UK). “But it also empirically tests one of the most gripping and fundamental questions asked by scientists across many disciplines and decades: Is there evidence of ongoing natural selection in humans and, if so, what is it and how does it operate?” The new study builds upon previous research on the genetic bases of reproductive behavior (timing and number of children) and reproductive development to identify individual genetic determinants of number of children ever born or childlessness. The researchers performed genome-wide association studies (GWAS) in up to 785,604 individuals of European ancestry and identified 43 genetic loci associated with either number of children ever born or childlessness.

First Results of COVID-19 Host Genetics Initiative (HGI) Study Announced at ASHG 2020 Virtual Annual Meeting (October 27-30)

The COVID-19 pandemic is a global health crisis. Insights into why some people develop more severe symptoms than others and how to better treat the disease are desperately needed. The COVID-19 Host Genetics Initiative (https://www.covid19hg.org/) was created to study the relationship between variation in the human genome and SARS-CoV-2 infection. This is an ongoing, international, collaborative effort to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. Andrea Ganna, PhD, EMBL-group leader at the Institute for Molecular Medicine Finland and an instructor at Harvard Medical School and Massachusetts General Hospital, presented the results of the Initiative’s first genome-wide association studies and follow-up analyses at the American Society of Human Genetics 2020 Virtual Meeting. The COVID-19 Host Genetics Initiative (HGI) was formed in March 2020 as a way to bring together the international human genetics community to generate, share, and analyze data related to COVID-19 infection and outcomes. The decentralized Initiative has three main goals: (1) to provide an environment to foster resource-sharing to facilitate COVID-19 host genetics research; (2) to organize analytical activities across studies to identify genetic determinants of COVID-19 susceptibility, severity, and outcomes; and (3) to provide a platform to share results, as well as individual-level data, from such studies. By June 2020, the HGI included 190 studies from 46 countries and more than 1,100 researchers. “Our biggest accomplishment so far is bringing this community together,” says Dr. Ganna. “One of our strengths is the inclusion of researchers from countries that are underrepresented in large genetic consortia, such as Qatar and Brazil.” Collaboration is essential for battling a global pandemic, says Dr. Ganna.

Genetics & COVID-19 Pandemic Are Focus of Special Session at ASHG 2020 Virtual Annual Meeting (October 27-30); On Wednesday, Six Researchers Reported Recent Data on Susceptibility and Severity in “Late-Breaking COVID-19 Research Update” Session

With the COVID-19 pandemic still raging worldwide, members of the American Society of Human Genetics (ASHG) are working to understand how the virus spreads and infects people, why there is so much variability in susceptibility and severity, and where to look for potential therapeutics. On Wednesday, October 28, six researchers presented recent results of several studies relevant to the current pandemic at the ASHG 2020 Virtual Annual Meeting (October 27-30). So far, this meeting has attracted over 6,000 registrants from more than 80 countries around the world. Approximately 1,000 of these registrants tuned in for this special timely session titled “Late-Breaking COVID-19 Research Update.” COVID-19 symptoms vary widely, ranging from asymptomatic in some patients to fatal in others. Elucidating the role of human genetic variation could result in a better understanding of susceptibility to infection, as well as of differences in patient presentation and outcomes. Three studies addressed human genetics and COVID-19 susceptibility and severity. In the first, Jack Kosmicki, Regeneron Genetics Center, and colleagues presented the results of the largest trans-ancestry exome sequencing study of COVID-19 to date. In a replication of previous findings, the researchers identified the 3p21.31 locus and suggested it contributes to variability in severity. The group failed to replicate an association between COVID-19 and the ABO locus, suggesting that the previous finding may have been a false positive. Beyond previously reported associations, Kosmicki and colleagues also identified three novel loci and three genes associated with COVID-19.

Boehringer Ingelheim Begins Phase 2 Clinical Trial of Targeted Therapy to Help People with Severe Respiratory Illness from COVID-19

On October 28, 2020, Boehringer Ingelheim announced the initiation of a Phase 2 clinical trial of BI 764198, an inhibitor of TRPC6, a receptor-operated cation channel. This potent and selective inhibitor of TRPC6 may alleviate the damage to the lung and decrease the risk or severity of acute respiratory complications in patients hospitalized for COVID-19. The aim of therapy with BI 764198 is to reduce the need for ventilator support, to improve patient recovery rate, and ultimately to save lives. Boehringer Ingelheim is committed to fighting COVID-19 and contributing, with its expertise and resources, to the development of new therapeutic options for patients suffering from the virus’ severe complications. “COVID-19 can cause serious lung complications, such as viral pneumonia, and, in severe cases, can lead to acute respiratory distress syndrome (ARDS) and lung failure,” said Lorraine B. Ware (https://medicine.vumc.org/person/lorraine-b-ware-md), MD, Ralph and Lulu Oven Endowed Chair and Professor of Medicine, and Pathology, Microbiology and Immunology, Vanderbilt University Medical Center. “Patients hospitalized with ARDS due to COVID-19 are often unable to breathe on their own and may require life support from a mechanical ventilator to help supply oxygen to the body. While we hope that future vaccines will help reduce cases of severe COVID-19, there remains an unmet need to address respiratory complications in infected patients, and provide healthcare professionals an effective alternative to mechanical ventilation that can potentially reduce the treatment burden within the hospital setting.” Approximately 15% of patients infected with SARS-CoV-2 develop severe disease and up to 30% of severely ill patients may require medical care in an intensive care unit (ICU).

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