Monthly Archives: May 2020

The relationship between the coronavirus and human genetics is murky.

When some people become infected with the coronavirus, they only develop mild or undetectable cases of COVID-19. Others suffer severe symptoms, fighting to breathe on a ventilator for weeks, if they survive at all.

Despite a concerted global scientific effort, doctors still lack a clear picture of why this is.

Could genetic differences explain the differences we see in symptoms and severity of COVID-19?

To test this, we used computer models to analyze known genetic variation within the human immune system. The results of our modeling suggest that there are in fact differences in peoples DNA that could influence their ability to respond to a SARS-CoV-2 infection.

When a virus infects human cells, the body reacts by turning on what are essentially anti-virus alarm systems. These alarms identify viral invaders and tell the immune system to send cytotoxic T cells a type of white blood cell to destroy the infected cells and hopefully slow the infection.

But not all alarm systems are created equal. People have different versions of the same genes called alleles and some of these alleles are more sensitive to certain viruses or pathogens than others.

A model of an HLA protein (green and yellow) bound to a piece of a virus (orange and blue) in this case, influenza. Prot reimage via Wikimedia Commons, CC BY-SA

To test whether different alleles of this alarm system could explain some of the range in immune responses to SARS-CoV-2, we first retrieved a list of all the proteins that make up the coronavirus from an online database.

We then took that list and used existing computer algorithms to predict how well different versions of the anti-viral alarm system detected these coronavirus proteins.

The part of the alarm system that we tested is called the human leukocyte antigen system, or HLA. Each person has multiple alleles of the genes that make up their HLA type. Each allele codes for a different HLA protein. These proteins are the sensors of the alarm system and find intruders by binding to various peptides chains of amino acids that make up parts of the coronavirus that are foreign to the body.

Once an HLA protein binds to a virus or piece of a virus, it transports the intruder to the cell surface. This marks the cell as infected and from there the immune system will kill the cell.

In general, the more peptides of a virus that a persons HLAs can detect, the stronger the immune response. Think of it like a more sensitive sensor of the alarm system.

The section of DNA that codes for HLAs is on the sixth chromosome. Pdeitiker at English Wikipedia / Wikipedia, CC BY

The results of our modeling predict that some HLA types bind to a large number of the SARS-CoV-2 peptides while others bind to very few. That is to say, some sensors may be better tailored to SARS-CoV-2 than others. If true, the specific HLA alleles a person has would likely be a factor in how effective their immune response is to COVID-19.

Because our study only used a computer model to make these predictions, we decided to test the results using clinical information from the 2002-2004 SARS outbreak.

We found similarities in how effective alleles were at identifying SARS and SARS-CoV-2. If an HLA allele appeared to be bad at recognizing SARS-CoV-2, it was also bad at recognizing SARS. Our analysis predicted that one allele, called B46:01, is particularly bad with regards to both SARS-CoV-2 and SARS-CoV. Sure enough, previous studies showed that people with this allele tended to have more severe SARS infections and higher viral loads than people with other versions of the HLA gene.

Based on our study, we think variation in HLA genes is part of the explanation for the huge differences in infection severity in many COVID-19 patients. These differences in the HLA genes are probably not the only genetic factor that affects severity of COVID-19, but they may be a significant piece of the puzzle. It is important to further study how HLA types can clinically affect COVID-19 severity and to test these predictions using real cases. Understanding how variation in HLA types may affect the clinical course of COVID-19 could help identify individuals at higher risk from the disease.

To the best of our knowledge, this is the first study to evaluate the relationship between viral proteins across a wide range of HLA alleles. Currently, we know very little about the relationship between many other viruses and HLA type. In theory, we could repeat this analysis to better understand the genetic risks of many viruses that currently or could potentially infect humans.

Written by Austin Nguyen, PhD Candidate in Computational Biology and Biomedical Engineering at Oregon Health & Science University, Abhinav Nellore, Assistant Professor of Biomedical Engineering & Surgery at Oregon Health & Science University, and Reid Thompson, Assistant Professor of Radiation Medicine at Oregon Health & Science University.

Originally published on The Conversation.

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Whether the Coronavirus Puts You in the Hospital Could Depend on Your Genes And Were Unraveling Which Ones Matter - SciTechDaily

Westport, CT, May 05, 2020 (GLOBE NEWSWIRE) -- BioSig Technologies, Inc. (NASDAQ: BSGM) (BioSig or the Company) today appointed Mr. Dennis Purcell to the Board of Directors of its majority-owned subsidiary ViralClear Pharmaceuticals, Inc.

Mr. Purcell brings to ViralClear a wealth of life science and investment experience. Mr. Purcell is the Founder of Aisling Capital LLC and previously served as Senior Managing Partner. Prior to Aisling Capital, Mr. Purcell served as Managing Director of the Life Sciences Investment Banking Group at Chase H&Q (formerly Hambrecht & Quist, H&Q). Aisling Capital (formerly Perseus-Soros Bio-pharmaceutical Fund), formed in 2001, is a leading venture capital fund that has invested over $2 billion in emerging biopharmaceutical companies globally which has helped the industry to mature and become the main source of new innovative drugs and devices being used to treat diseases today. While at H&Q, Mr. Purcell was directly involved with over two hundred completed transactions and supervised over $10 billion of financing and advisory assignments in the Life Sciences industry. Prior to joining H&Q, Mr. Purcell was a Managing Director in the Healthcare Group at PaineWebber, Inc.

Mr. Purcell is a frequent commentator on the industry and has been honored in the Biotech Hall of Fame by Genetic Engineering News, named to the Biotechnology All-Stars list by Forbes ASAP, honored as one of the top 50 Irish-American businessmen and cited as one of the top 100 contributors to the biotechnology industry.

Mr. Purcell serves on numerous healthcare company boards. He currently sits on the Boards of Real Endpoints, Summus Global, Inc., BioScience Managers Pty Ltd., and Ichnos Sciences. He also serves as a member of the Board of: the Editorial Advisory Board at Life Science Leader Magazine; the Executive Committee at NYBIO Association; the University of Delaware Investment Visiting Committee as well as the Biopharmaceutical Innovation Board at the University of Delaware; the Foundation of the Alliance for Regenerative Medicine; and the Healthcare sector of the New York City Investment Fund. He is also an Executive in Residence at Columbia University.

Mr. Purcell received his M.B.A. from Harvard Business School and his B.S. in Accounting from the University of Delaware.Mr. Purcell is the latest high-profile addition to the Companys Board and will serve alongside former Chief Medical Officer of Celgene Jerome Zeldis, M.D., Ph.D, Nick Spring, CEO of ViralClear and a former senior executive at Merck & Co. and Anthony Zook, former senior executive at Astra Zeneca, Plc.

ViralClear assembled a team with a highly impressive collective skillset to address a very pressing public health issue. I look forward to joining the management and my fellow Board members as the Company seeks to translate the strong in vitro findings into clinically meaningful results, commented Mr. Purcell.

We are thrilled to welcome Dennis at this important time in our Companys development, and look forward to his contributions, added Jerome Zeldis, M.D., Ph.D, Executive Chair of ViralClear Pharmaceuticals, Inc.

The Company recently announced that Mayo Clinic is set to become a study site for a planned Merimepodib Phase II clinical trial for the treatment of COVID-19, once permitted by the FDA. The study will be a randomized, placebo-controlled trial. Data from the Phase II trial is expected within three months from its commencement.

Dennis is a fantastic addition to ViralClear Board. His extensive knowledge of the biotech industry and his directorship expertise will be highly valuable to the Company as it reaches inflection points in its development, stated Kenneth L. Londoner, Chairman and CEO of BioSig Technologies, Inc. and Director of ViralClear Pharmaceuticals, Inc.

About merimepodibAnti-viral candidate merimepodib (MMPD) targets RNA-dependant polymerases. The molecule has shown activity against a broad spectrum of RNA viruses and has demonstrated satisfactory safety data from over 300 patients treated for hepatitis C. Recently, the Company published first pre-clinical data generated under contract with Galveston National Laboratory at The University of Texas Medical Branch. The Company recently submitted two manuscripts titledThe IMPDH inhibitor merimepodib provided in combination with the adenosine analogue remdesivir reduces SARS-CoV-2 replication to undetectable levels in vitro and The IMPDH inhibitor merimepodib suppresses SARS-COV-2 replications. The manuscripts were authored by Natalya Bukreyeva, Emily K. Mantlo, Rachel A. Sattler, Cheng Huang, John T. Manning, Slobodan Paessler, DVM, Ph.D of the UTMB Galveston National Laboratory and Jerome Zeldis, M.D., Ph.D of ViralClear. In-vitro studies referenced in the manuscript demonstrated that merimepodib decreased viral production by over 98%.

About BioSig TechnologiesBioSig Technologies is a medical technology company commercializing a proprietary biomedical signal processing platform designed to improve signal fidelity and uncover the full range of ECG and intra-cardiac signals (www.biosig.com).

The Companys first product, PURE EP(tm) System is a computerized system intended for acquiring, digitizing, amplifying, filtering, measuring and calculating, displaying, recording and storing of electrocardiographic and intracardiac signals for patients undergoing electrophysiology (EP) procedures in an EP laboratory.

About ViralClearBioSigs subsidiary ViralClear Pharmaceuticals, Inc., is seeking to develop a novel pharmaceutical to treat COVID-19. Merimepodib is intended to be an orally administered, broad-spectrum anti-viral agent that has demonstrated strong activity against COVID-19 in cell cultures in laboratory testing. The product candidate has completed Phase I and three Phase II trials in other indications.

Forward-looking Statements This press release contains forward-looking statements. Such statements may be preceded by the words intends, may, will, plans, expects, anticipates, projects, predicts, estimates, aims, believes, hopes, potential or similar words. Forward- looking statements are not guarantees of future performance, are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Companys control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the geographic, social and economic impact of COVID-19 on our ability to conduct our business and raise capital in the future when needed, (ii) our inability to manufacture our products and product candidates on a commercial scale on our own, or in collaboration with third parties; (iii) difficulties in obtaining financing on commercially reasonable terms; (iv) changes in the size and nature of our competition; (v) loss of one or more key executives or scientists; and (vi) difficulties in securing regulatory approval to market our products and product candidates. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Companys filings with the Securities and Exchange Commission (SEC), including the Companys Annual Report on Form 10-K and its Quarterly Reports on Form 10-Q. Investors and security holders are urged to read these documents free of charge on the SECs website at http://www.sec.gov. The Company assumes no obligation to publicly update or revise its forward-looking statements as a result of new information, future events or otherwise.

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Biotech and Investment Veteran Dennis Purcell Joins the Board of ViralClear Pharmaceuticals, a majority-owned subsidiary of BioSig Technologies, Inc....

University of Waterloo biology professor Kathleen Hill co-led a team of researchers whove identified an underlying genomic signature for 29 different COVID-19 sequences. They did this using a new graphics-based software classification tool powered by machine learning. When sequencing the genome of a virus like COVID-19, the classification software makes use of a decision tree method to run through the best possible choices and achieve a 100 percent accurate outcome within minutes.

This is a 3D map of researchers' machine learning classification tool. (a) 3,273 viral sequences from the researchers first test, representing 11 viral families and realm Riboviria; (b) 2,779 viral sequences from the second test, classifying 12 viral families of realm Riboviria; and (c) 208 Coronaviridae sequences classified into genera. (Image courtesy of PLOS.)

Researchers wrote a paper about their findings called Machine learning using intrinsic genomic signatures for rapid classification of novel pathogens: COVID-19 case study. According to the paper, The proposed method combines supervised machine learning with digital signal processing (MLDSP) for genome analyses, augmented by a decision tree approach to the machine learning component, and a Spearmans rank correlation coefficient analysis for result validation. These tools are used to analyze a large dataset of over 5000 unique viral genomic sequences, totaling 61.8 million bp, including the 29 COVID-19 virus sequences available on January 27, 2020.

The teams results confirm the currently accepted hypothesis that COVID-19 (SARS-CoV-2) originated from bats, and their results classified it as Sarbecovirus within Betacoronavirus. The findings suggest that their machine learning approach is a reliable, scalable and quick option for taxonomic classification of novel viruses. This means that the tool can be used to better serve real-time worldwide reaction and strategy to combat novel viruses in the future.

Mobilizing medical personnel to react as quickly as possible is invaluable in the fight against a global pandemic and will also be incredibly useful in helping develop correct treatments to outbreaks of novel viruses, including the rapid development of vaccines.

Bottom Line

The research is encouraging for future outbreaks, but what it means for the treatment and rapid development of vaccines for the COVID-19 outbreak remains unclear. New studies are showing the efficacy of Remdesivir in treating patients infected with COVID-19, and two vaccinations from Oxford and Germany that seem to be making rapid progress are set to begin human trials in the coming months. Lets hope for the best.

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Researchers Develop New Classification Tool to Find COVID-19 Genetic Signature - ENGINEERING.com

There are four animals that have become relevant in the context of the coronavirus disease (Covid-19). This column is about them.

It was only in 2013, after a decade of looking for the source of the Sars-CoV (or Sars-CoV-1) virus that causes the Severe Acute Respiratory Syndrome, that scientists found the natural host of the virus, horseshoe bats specifically, horseshoe bats in a cave outside a large city in Chinas Yunnan province. Somehow, the virus had made the jump from the bats, to civets in Guangdong, and from them to humans (the Chinese eat civet meat and the first people to be infected were wildlife traders from Guangdong). A fascinating article in Scientific American in March narrated this quest as part of its profile of Shi Zhengli, a virologist in Wuhan. Scientists say the bats may well be the natural host of the virus that causes the coronavirus disease too.

Horseshoe bats, then, are the first animals of relevance in the context of Covid-19. That shouldnt surprise anyone. Research has established that bats are hosts to more zoonoses (pathogens that can cross over to humans, causing an infection) than any other species.

Sometimes, the transmission happens directly. Sometimes, it happens through another animal. In the case of Sars, it was the masked palm civet that was the intermediary. In the case of the Middle East Respiratory Syndrome, or Mers, it was a species of camel. In the case of Covid-19, scientists believe the intermediary was the pangolin specifically, the Malayan Pangolin. India has a species of pangolin too, the Indian Pangolin. Pangolins are widely used in Chinese medicine, so its easy to see how Sars-CoV-2 could have jumped from bats to pangolins to humans.

The pangolin, then is the second animal of relevance in the context of Covid-19, which, as of Thursday, has infected 3.8 million people, and killed 265,000 (of the 3.8 million, 1.3 million have recovered).

The global scale of the pandemic, which has no cure right now, has meant everyone knows the significance of ChAdOx1 nCoV-19. This is the vaccine being developed at the University of Oxford. The vaccine hopes to tackle Covid-19 by injecting a weakened adenovirus into which genetic material from Sars-CoV-2 has been inserted something that should generate an immune response. The adenovirus the scientists at Oxford are using is one that causes cold in chimpanzees, which explains the name of the vaccine (Ch for chimpanzee and Ad for adenovirus). We humans share 99% of our DNA with chimpanzees and bonobos (another ape, and one that belongs to the same genus as chimpanzees).

Chimpanzees are the third animal of relevance in the context of Covid-19, especially given that ChAdOx1 nCoV-19 remains our best bet yet. There are expectations that it will be available this year itself, and Indias Serum Institute has already started making it taking a bet that an ongoing clinical trial will work.

But chimpanzees arent the only potential saviours of the human race. Over the past two days, there has been a lot of focus on llamas, the ungulates with pretty eyelashes. It turns out that they have antibodies that can tackle Covid-19 (the findings of a study on this were published earlier this week on the respected journal, Cell). It also turns out that the antibodies produced by llamas can be merged with antibodies produced by other species, including humans. Indeed, research has shown that all other members of the family llamas belong to, camelidae, produce antibodies with the same property they are stable at higher temperatures, and lend themselves to genetic engineering because of their small size.

The llama, then, is the fourth animal of relevance in the context of the pandemic. And if llamas hold the answer to the virus, they will become as famous as the horses that helped humankind in the fight against diphtheria -- but thats another story.

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Covid-19: What you need to know today - Hindustan Times

This article originally appeared on The Conversation. You can read it here.

Scientists are constantly revealing newly discovered benefits of exercise. In experiments over the past 10 years, my research has found that exercise can help with a respiratory problem known as ARDS.

ARDS is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs that prevents oxygen from reaching the organs. It has been reported in many COVID-19 patients.

I am an exercise physiologist with training in medicine. More than 30 years ago, I gave up my career in general surgery in China and came to the U.S. to pursue a basic research career in molecular exercise physiology, as I was intrigued by the superb health benefits of regular exercise.

Most recently I've been thinking about the potential impact of regular exercise in preventing this deadly complication of COVID-19. I have not done any experiments specifically around COVID-19, but my work with mice may inform other researchers exploring ways to protect people that suffer from ARDS.

A cause of death for 3%-17% of patients infected with SARS-CoV-2 is ARDS. COVID-19 patients with this dismal clinical complication have a mortality rate of greater than 50%.

Specifically, ARDS can occur when viral infection of the cells in the lungs activates the immune system and attracts white blood cells to travel through the bloodstream to the lung tissue to fight off the viral infection.

However, when too many white blood cells appear in the lung tissue at once, it can cause lung tissue damage. This is because they produce too much of damaging molecules called free radicals which break proteins, the cell membrane and DNA.

As a consequence, the blood vessels in the lung become leaky, causing accumulation of the fluid in the lung tissue, and the air sacs of the lung fill up with fluid. This prevents those same air sacs, called alveoli, from filling with air, blocking oxygen in the air from getting into the blood. Patients die of oxygen deprivation.

The cells that line our blood vessels are flat-shaped endothelial cells. One early step in this complicated ARDS disease process is the lining of the blood vessel becomes sticky to white blood cells by making sticky proteins on the cell surface, a phenomenon called endothelial cell activation.

This triggers a vicious cycle; the greater endothelial cell activation, the more free radicals the white blood cells release. This in turn destroys the endothelial cells, making the blood vessel leak more and damages lung tissue.

More than 10 years ago, I started to study the protective role of exercise-induced antioxidant enzymes against loss of muscle size. My research has shown that endurance exercise promotes production of an antioxidant called extracellular superoxide dismutase (EcSOD) that breaks down the free radical superoxide outside of the cells.

EcSOD is the only antioxidant enzyme that is secreted into the blood that reaches other vital organs and binds to the endothelial cells and other cells through a unique binding structure of the enzyme. This makes EcSOD unlike any supplemental antioxidant pill or food rich in antioxidants that we may consume. An oral antioxidant, once absorbed into the blood, does not target a given organ to provide protection, while EcSOD sticks to specific organs.

When I first saw the evidence of increased EcSOD in skeletal muscle by aerobic exercise training, I was inspired to do an experiment in which I tested whether just increasing the amount of this enzyme through genetic engineering, instead of naturally through exercise, would provide protection from various diseases in which free radicals are known to play important roles, such as muscle atrophy and heart failure.

I engineered a mouse that produced more EcSOD in skeletal muscle than would the typical mouse to mimic the effects of aerobic exercise training. We obtained clear evidence that these mice were protected from muscle atrophy and diabetes-induced heart failure.

I then artificially triggered ARDS in mice by injecting mice with a chemical produced by bacteria that are known to cause this condition. To my pleasant surprise, genetically engineered mice with higher concentrations of EcSOD in their blood were far more likely to survive the severe ARDS and multiple organ failure compared with a dismal mortality in the typical mice. This mimics the situation in intensive care where more than 80% of the patients die when they suffer from the failure of multiple organs, including ARDS.

I then confirmed that indeed it was the EcSOD in the genetically engineered mice that provided the protection. When I performed an experiment in which a genetically engineered mouse shared blood with a normal mouse following a surgical procedure called parabiosis, or I took blood from a mouse with high EcSOD and transfused it into a normal mouse suffering from ARDS, the normal mouse had reduced severity of ARDS and clinical blood markers of multiple organ failure. Using various biochemical and imaging technologies, we saw the evidence of reduced endothelial cell activation and reduced protein, cell membrane and DNA damage caused by free radicals in the lung tissue.

These studies have provided proof-of-principle evidence that delivery of the EcSOD gene or protein to elevate the amount of EcSOD in the blood and vital organs may be an effective intervention for protection of the lungs and other vital organs against damages caused by ARDS and multiple organ failure.

My findings in mice may inspire other researchers to come up with innovative ways to prevent and treat the deadly complication of COVID-19.

For example, future studies may identify the exercise type, intensity and duration to optimally increase EcSOD levels in the lungs and other vital organs in humans to build up the defense against deadly complications of COVID-19 or other disease conditions. Of course, the findings may inspire research to foster pharmacological, protein and or gene therapies to treat COVID-19 patients with ARDS.

The EcSOD antioxidant story is just one of many about the health benefits of exercise. I believe we can learn from exercise to develop effective therapies to treat ARDS caused by COVID-19 and other disease conditions.

Zhen Yan is Professor of Cardiovascular Medicine, University of Virginia

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Exercise may help reduce the risk of deadly COVID-19 complication - GOOD Magazine