Monthly Archives: June 2020

On March 16, a single tweet mobilized an army of over 700 geneticists from 36 countries to battle a tiny virus by trying to understand the role human genetics plays in why some people have no reaction to COVID-19, and others get very sick and die. Goal: aggregate genetic and clinical information on individuals affected by COVID-19, tweeted Andrea Gemma, a geneticist at the Institute for Molecular Medicine in Helsinki, Finland. Just a few weeks later the COVID-19 Host Genetics Initiative was up and running and is now identifying human genes associated with COVID and its symptomsnothing definitive yet, although the possibility of breakthroughs has been substantially improved by the combined DNA-discovery firepower of over 150 labs and biobanks that store and analyze millions of human genomes.

Nor is this pandemic display of raw scientific muscle and intensity of focus unique right now. Pandemic-bound researchers around the world are combining forces for possibly the largest scientific hive-mind effort in history thats converging on a single conundrum. It also arrives as a slew of technologies developed over the past generation are coming online and being applied to the COVID puzzleeverything from CRISPR gene editing and faster and cheaper genetic sequencing to social media and the integration of artificial intelligence and machine learning in bioresearch and health IT.

COVID-19 has ravaged bioscience just like it has cut a destructive and sometimes deadly swath through much of what we used to call normal. Yet even as labs have shuttered, experiments have halted, and droves of scientists and technicians have been laid offand research and clinical attention has been diverted from any disease thats non-COVIDis it possible that some scientific silver linings may emerge out of this tragic Year of the Pandemic?

Could we see a near-future surge of scientific advancement, what Stanford bio-informaticist Carlos Bustamante likened to what happened when we went to the moon? You had all this spillover technology that gave us, say, the Internet, he said. Or is it possible that somewhere, somehow, a new respect for science and evidence will emerge out of COVID-19? Theres kind of a reward system now for people to pay attention to facts, said George Church, Professor of Genetics at Harvard Medical School, rather than just making stuff up. And that reward is in terms of fewer relatives and friends and colleagues dying.

As the world is teetering and we struggle to absorb a daily barrage of less than sanguine newsnot only about COVID but also in politics, racial relations, and the economy NEO.LIFE asked prominent bioscientists and big thinkers if there might be glimmers of hope that will emerge when the all clear is finally declared.

Im seeing an intensity of purpose like Ive never seen before, said Eric Topol, director and founder of the Scripps Research Translational Institute. Putting this great big brain trust in science on such a seemingly insurmountable problem will change how we do things going forward.

We are seeing biologists working with statisticians, public health experts collaborating with logistics experts, added Katharina Voltz, founder and CEO of OccamzRazor. With the coronavirus, you need the experts on SARS, on spike proteins, on pulmonary diseases, to all come together and collaborate on a shared canvas.

Were asking questions we never asked about, say, the flu, added Carlos Bustamante, attributing this to the rise of the hive mind. For instance, were learning about COVID at a molecular phenotyping detail like weve not done for any other infectious disease. (Molecular refers mostly to genetics, and phenotype to observable traits in a human or other organism.) Its been amazing for this disease how weve accepted that different people respond differently to this infection. That is not true of almost any other large-scale infection we talk about.

We can take heart that for the first time in history we have the computing power to actually make sense of all of this complexity as artificial intelligence and machine learning in biology is moving from hype to reality. One of the trends that were seeing now is the application of machine learning to dissect and extract patterns from a deluge of genomic, proteomic, metabolic data, said Katharina Voltz. We can perform many experiments in silicoon the computerand only run the most important crucial parts of the experimental method in the lab, as a confirmation of our theoretical models.

Machine learning is going to transform how we think in biology, agreed Wayne Koff, CEO, Human Vaccines Project. Its going to generate hypotheses. We will be able to better focus on smaller groups of peoplethe vulnerable groups, the diseased, the elderly, the poor, the newborns, those living in the developing world.

Computers and the Internet are also lifelines for all of us personally needing to stay connected, and as biomedicine tries to navigate a world of shelter-in-place and social distancing. Weve just dragged the country through half a decade of telemedicine in three months, said Carlos Bustamante. Are we going to now give that all up and go back to having to wait in the doctors office with everybody else coughing to see a doctor?

I think this pandemic will be a big moment for biology, said synthetic biologist Pamela Silver, professor of Biochemistry and Systems Biology at Harvard Medical School. Biologys going to fix the COVID problem, but it can also fix a ton of other problems, tooproblems like the environment, food, and other diseases. And the only way were going to get there is with engineering biologymanipulating and improving the biological mechanisms.

One way to accomplish this is what Silver and other synthetic biologists call plug and playthe creation of basic biological components for research and for developing treatments and preventatives like vaccines that have been synthesized in a lab, ready to be deployed, say, when the next virus arrives. Im thinking that as we learn how to manipulate viruses and create methods for booting up responses faster it becomes a kind of plug-and-play system that is nimble, said Silver, and this goes not just for vaccines. It goes for everything, anything. You have a new disease, or any kind of therapeutic, and youre better prepared.

Eric Topol, however, frets about the neglect or lack of emphasis on non COVID-19 diseases. This is a concern and will continue to be for the near future. Katharina Volz added that once this crisis is over, we need to hyper-focus on other diseases, too. You really have to put this same urgency that we have for COVID now and apply it to other diseases that may have a potentially bigger economic and personal impact than COVID, she said, Alzheimers and Parkinsons and many others.

Weve just dragged the country through half a decade of telemedicine in three months.

Scientists also worry about the leadership vacuum they see in the world. I hope, as we go forward, we will get better leadership, said Eric Topol. Weve seen how science can contribute where it was given true authority, so I think thats going to be another path forwardI hopealthough in the U.S. we have horrible tensions between politics and science that shouldnt exist.

No one really knows what biomedicine will look like when this is over. But it is comforting to know that something positive may come out of COVID. As Carlos Bustamante said: I want everything I do to be drafted behind COVID. Im thinking of the mother of all cycling teams. [Cycling teams assign one cyclist to ride first in line so the others can draft behind them, which makes it easier for them to pedal]. And youre drafting behind COVID, and then once youve reached the finish line, you can take that energy and hopefully channel it into other disease areas that can be cured.

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After the MadnessPandemic Silver Linings in Bioscience - NEO.LIFE

The Genome Aggregation Database (gnomAD) Consortium has released seven papers leveraging its database to study genetic variants and their potential for guiding discovery of safer drugs.

The Genome Aggregation Database (gnomAD) Consortium has announced the release of the first seven papers based on discoveries from their database of more than 125,000 exomes and 15,000 whole genomes from populations around the world.

Since 2012 the consortium, originally the Exome Aggregation Consortium (ExAC), has expanded upon the work of the 1000 Genomes Project and other similar efforts to catalogue human genetic variation. From the initial release of whole exome data in October 2014, the database has grown to include genomes and exomes from more than 25,000 people of East and South Asian descent, nearly 18,000 of Latino descent and 12,000 of African or African-American descent, known as the gnomAD v2.1.1 dataset.

According to the consortium, more than 100 scientists and groups internationally have provided data and/or analytical effort to the consortium.

The studies cover several areas, including:

These studies represent the first significant wave of discovery to come out of the gnomAD Consortium, said Daniel MacArthur, scientific lead of the gnomAD project, a senior author on six of the studies, an institute member in the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard, and director of Centre for Population Genomics at the Garvan Institute of Medical Research and Murdoch Childrens Research Institute in Australia. The power of this database comes from its sheer size and population diversity, which we were able to reach thanks to the generosity of the investigators who contributed data to it, and of the research participants in those contributing studies.

Two of the seven papers demonstrate the utility of the large genomic datasets for learning about rare or understudied types of genetic variants.

One such study, the flagship paper published in Nature, led by MacArthur and Konrad Karczewski, first author of the paper and a computational biologist at the Broad Institute and Massachusetts General Hospitals (MGHs) Analytic and Translational Genetics Unit, maps loss-of-function (LoF) variants.

LoFs are genetic changes that are thought to completely disrupt the function of protein-coding genes.

By comparing the number of variants in each gene across the more than 443,000 LoF variants the team identified in the gnomAD dataset, the authors were also able to classify all protein-coding genes according to how tolerant they are to disruptive mutations. The classification system pinpoints genes that are more likely to be involved in severe diseases such as intellectual disability.

The gnomAD catalog gives us our best look so far at the spectrum of genes sensitivity to variation and provides a resource to support gene discovery in common and rare disease, Karczewski explained.

In their paper, also published in Nature, graduate student Ryan Collins, Broad associated scientist Harrison Brand, institute member Michael Talkowski and colleagues used gnomAD to explore structural variants.

Structural variants include duplications, deletions, inversions and other changes involving larger DNA segments (generally >50-100 bases long). Their study presents gnomAD-SV, a catalogue of more than 433,000 structural variants identified within nearly 15,000 of the gnomAD genomes, that represents most of the major known classes of structural variation.

Structural variants are notoriously challenging to identify within whole genome data, and have not previously been surveyed at this scale, noted Talkowski, who is also a faculty member in the Center for Genomic Medicine at MGH. But they alter more individual bases in the genome than any other form of variation, and are well established drivers of human evolution and disease.

The authors were surprised to find that >25 percent of all rare LoF variants in the average individual genome are actually structural variants and that many people carry what should be deleterious or harmful structural alterations, without the expected phenotypes or clinical outcomes. They also highlighted that genes were just as sensitive to duplications as they were deletions.

We learned a great deal by building this catalogue in gnomAD, but weve clearly only scratched the surface of understanding the influence of genome structure on biology and disease, Talkowski said.

Two of the studies describe how the diverse, population-scale data could be used by researchers to pick drug targets.

One of these studies was based on musings by Broad associated scientist Eric Minikel, about whether genes with naturally-occurring predicted LoF variants could be used to assess the safety of targeting those genes with drugs. He suggested that if a gene is naturally deactivated without harmful effects, then it could possibly be safe to inhibit with a drug.

Minikel, MacArthur and golleagues leveraged the gnomAD dataset to explore this question, the results and their suggestions for how insights about LoF variants can be incorporated into the drug development process were published in Nature Medicine.

The collaborators on the study used the data on LoF variants to study the potential safety liabilities of reducing the expression of a gene called LRRK2. This gene is associated with risk of developing Parkinsons disease and so is a desirable target for intervention strategies.

The team predicted from the data that drugs able to reduce LRRK2 protein levels or partially block the genes activity are unlikely to have severe side effects.

Weve cataloged large amounts of gene-disrupting variation in gnomAD, MacArthur said. And with these two studies weve shown how you can then leverage those variants to illuminate and assess potential drug targets.

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First studies of human genetic variation released by gnomAD Consortium - Drug Target Review

Love it or hate it, rocket is popular all over the world. Also known as arugula, roquette and rucola, its known for its pungent and peppery flavours. It might look like an unassuming leafy vegetable, but the reasons for its taste, health benefits and whether we like it all comes down to genetics.

Rocket actually encompasses several species, all of them part of the same family as broccoli, cabbage, kale, mustard and watercress the Brassicales. Its distinctive aroma and flavours are created by chemical compounds produced by its leaves, called isothiocyanates. Some of these compounds can be eye-wateringly hot, whereas others can have a radishy flavour or none at all.

In the wild, isothiocyanates are thought to help defend plants from herbivores and disease, and also help it tolerate environmental stress. But for humans, eating isothiocyanates confers health benefits. Studies have shown them to have anti-cancer properties, and anti-neurodegenerative effects against diseases such as Alzheimers.

For this reason, plants containing isothiocyanates interest scientists particularly those with little taste and flavour. One such compound is sulforaphane, which is found in rocket and broccoli. Several years ago, researchers produced a super broccoli with high amounts of sulforaphane. Consumers couldnt taste the difference, and it was later shown to be effective in preventing and slowing prostate cancer and in lowering cholesterol.

But one advantage with rocket is that it doesnt need cooked to be eaten. Heating other Brassicales, like broccoli, to over 65 inactivates myrosinase, which is an enzyme in their tissues that converts compounds called glucosinolates into sulforaphane and other isothiocyanates when people chew these plants. If the myrosinae is inactivated, consumers will receive little or none of the associated health benefits, no matter how much are bred into the plants.

Chewing aside, theres some evidence to suggest that our gut microflora possess their own myrosinase and can convert glucosinolates to isothiocyanates for us. The amounts this produces are likely to be quite small, but release may be sustained, exposing our cells to compounds like sulforaphane for longer periods.

But the biggest barrier to people getting these beneficial molecules from rocket is the taste. This depends on when and where rocket crops are grown. In the summer, leaves can be extremely spicy and pungent, whereas in the winter they can be bland and tasteless.

Growth temperature likely plays a big role in determining the amounts of isothiocyanates released from leaves. Probably a stress response by the plants, it means hotter countries like Italy may produce more pungent leaves.

You can test this effect at home. Get two small pots and some rocket seeds from a local garden centre or supermarket. Plant two or three seeds in each. Keep one well watered and relatively shaded, and the other in direct sunlight, watering infrequently. After a few weeks, taste the leaves from each pot one should taste much hotter.

The taste and flavour of rocket also varies because of the genetics of different varieties. Not only do leaves contain hot, pungent isothiocyanates, but also sugars (which create sweetness); pyrazines (which can smell earthy and pea-like); aldehydes (which smell like grass); alcohols (one in particular smells just like mushrooms); and many other types yet to be identified.

Recently, the worlds first rocket genome and transcriptome sequence was produced from the Eruca sativa species, allowing researchers to understand which genes may be responsible for making the compounds related to taste and flavour. Its genome contains up to 45,000 genes, which is more than the 42,611 genes humans are thought to have.

The research also found that different varieties produce more isothiocyanates and sugars than others. This explains why leaves can taste so different in the supermarket, even when bought from the same shop at the same time of the year. By knowing which genes are expressed in tissues and when, we can select rocket plants with improved taste and flavour profiles and breed new and improved cultivars.

To further complicate matters, our own genetics mean we dont all taste chemical compounds the same. We have many thousands of different odour receptors in our brains, and many different combinations of taste receptors on our tongues. These genetic differences are one of the reasons why coriander tastes different to different people. Those with a variant of the OR6A2 gene perceive the leaves as having a soapy flavour, which is thanks to the aldehyde compounds in coriander that activate this receptor variant.

Depending on whether you have a functioning or non-functioning copy of certain taste receptor genes, you may not be able to taste certain compounds at all. In the other extreme, if you have two working copies of a particular gene, some foods may taste unbearably bitter and unpleasant.

Another classic example is Brussels sprouts. Some people love them, while others loathe them. This is because of the gene TAS2R38 which gives us the ability to taste the bitter glucosinolate compounds in these vegetables as well as rocket.

Those people with two working copies of the gene are bitter supertasters. People with only one are medium tasters, while those with no working copies are blind to these compounds. So what is intense and inedible to one person might be pleasant and mild to another.

This partly explains peoples general food preferences and rocket leaves are an excellent example of these processes in action. A consumer study of rocket leaves showed that some people like them hot and pungent, others like them sweet and mild, and others just dont like them at all.

However, peoples culture and life experience probably also determine whether they like rocket and other foods. A previous study of rocket showed that peoples genetic differences are not necessarily an indicator of whether they will like something. Its perfectly possible to be a bitter supertaster and like rocket and Brussels sprouts depending on your upbringing and exposure to them.

Another study showed that preference for flavour and pungency of white radish is linked to differences in geography and culture. Japanese and Korean people liked pungency created by an isothiocyanate much more than Australians. Pickled radish is a common condiment in Asian countries: being regularly exposed to a food may predispose people to like it, irrespective of their taste sensitivity.

Very little is currently known about the interactions between plant and human genotypes. But ongoing research aims to find out which compounds people with different TAS2R38 genotypes are sensitive to. This will make it possible in the future to selectively breed in (or out) certain genes, and produce rocket types tailored to a persons preferences.

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Rocket, arugula, rucola: how genetics determines the health benefits and whether you like this leafy green - The Conversation UK

Intravacc, a translational research and development vaccine institutes, with a track record in developing viral and bacterial vaccines, has announced more details on its development of an intranasal vaccine against COVID-19. The vaccine will be developed through a newly established public private partnership that combines the vaccine development technology from Intravacc, the viral vector technology and animal technologies from Wageningen Bioveterinary Research (WBVR) based in the Netherlands, and the coronavirus expertise from Dutch Utrecht University.The aim of this partnership is to develop an intranasal vaccine to protect humans against COVID-19. The vaccine will consist of a Newcastle disease virus (NDV) vector that expresses the immunogenic spike (S) protein of SARS-CoV-2, which is an important target for neutralizing antibodies. NDV has been shown to be safe for intranasal/intratracheal delivery in mammals, including non-human primates.The advantage of a nasal vaccination is that it induces both mucosal and systemic immunity, whereas an intramuscular vaccination primarily induces an antibody response. In addition, intranasal vaccination may also confer protection against infections at other mucosal sites, such as the lungs, intestines and genital tract. On top of this, the nasal cavity is also easily accessible.Intravacc will develop a scalable vaccine production process using its FDA-approved Vero cell platform, in preparation of GMP productions. WBVR has developed a technique called reverse genetics, which allows the genetic modification of Newcastle disease virus (NDV). NDV can cause disease in birds but is harmless for mammalian species including humans. WBVR has used the reverse genetics technique to develop NDV as a vaccine vector against human and animal infectious diseases. This vector technology will now be used to generate a vaccine against COVID-19.Intravaccs strength is its ability of bridging the gap between academia and research centers towards pharma. Together with our partners WBVR and Utrecht University, we combine our expertise in developing an intranasal corona virus vaccine, commented Dr. Jan Groen, CEO of Intravacc. Our safe Vero cell platform, widely used for the production of Polio vaccines, put us in the position to fast track the production of pilot lot of this NCD vector-based vaccine concept and to subsequently transfer this to large vaccine manufactures.

Excerpt from:
Intravacc Partners with Wageningen Bioveterinary Research and Utrecht University - Contract Pharma

West Asia, which includes Anatolia (present-day Turkey), the Northern Levant and the Southern Caucasus is seen in a partial map obtained by Reuters June 1, 2020. An international team of researchers showed populations from Anatolia and the Caucasus started genetically mixing around 6,500 BC and that small migration events from Mesopotamia 4,000 years ago brought further genetic mixture to the region. The orange marker shows the route from Central Asia. DNA from a lone ancient woman revealed proof of long distance migration during the late Bronze age about 4,000 years ago from Central Asia to the Mediterranean Coast. Courtesy of Max Planck-Harvard Research center for the Archaeoscience of the Ancient Mediterranean/Handout via REUTERS

WASHINGTON (Reuters) - The bones of a woman of Central Asian descent found at the bottom of a deep well after a violent death in an ancient city in Turkey are helping scientists understand population movements during a crucial juncture in human history.

Researchers have dubbed her the lady in the well and her bones were among 110 skeletal remains of people who lived in a region of blossoming civilization running from Turkey through Iran between 7,500 and 3,000 years ago.

The study provided the most comprehensive look to date of genetics revealing the movement and interactions of human populations in this area after the advent of agriculture and into the rise of city-states, two landmarks in human history.

The remains of the lady in the well, found in the ruins of the ancient city of Alalakh in southern Turkey, illustrated how people and ideas circulated through the region.

Her DNA showed she hailed from somewhere in Central Asia - perhaps 2,000 miles (3,200 km) or more away. She died at about 40 to 45 years old, the researchers said, probably between 1625 BC and 1511 BC. Her body bore signs of multiple injuries.

How and why a woman from Central Asia - or both of her parents - came to Alalakh is unclear, said Ludwig Maximilian University Munich archaeologist Philipp Stockhammer, co-director of the Max Planck-Harvard Research Center for the Archaeoscience of the Ancient Mediterranean and co-author of the study published in the journal Cell.

Trader? Slaves? Marriage? What we can say is that genetically this woman is absolutely foreign, so that she is not the result of an intercultural marriage, Stockhammer added. Therefore, a single woman or a small family came this long distance. The woman is killed. Why? Rape? Hate against foreigners? Robbery? And then her body was disposed in the well.

Reporting by Will Dunham; Editing by Sandra Maler

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'Lady in the well' sheds light on ancient human population movements - Reuters

RIO GRANDE VALLEY, Texas According to a release, UTRGV is increasing the number of COVID-19 tests it can process from 150 to 1,000 daily.

The release attributes this increase to an automated extraction machine called the Thermo Fisher Kingfisher Flex.

The Kingfisher will dramatically expand our testing capacity, said Dr. John Thomas, assistant professor in the Department of Human Genetics at the UTRGV School of Medicine and director of the UT Health RGV Clinical Laboratory, It will help us support the local, county, regional and state demands for testing to meet the federal guidelines for reopening the state economy and getting Texas back to a more normal setting.

Previously UTRGV could only run 150 samples per day with manual extraction, said the release.

Dr. John H. Krouse, Dean of the UTRGV School of Medicine and executive vice president for Health Affairs also said that they are looking to bring antibody testing and contract tracing capabilities to UTRGV as quickly as possible.

You can schedule an appointment to be screened for COVID-19 by calling 1-833-UTRGVMD, they have four drive-thru testing sites located in Edinburg, Mercedes, Harlingen, and Brownsville.

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COVID-19 testing capacity increased to 1,000 daily for UTRGV - KGBT-TV