Monthly Archives: October 2021

Researchers have used unsupervised machine learning to predict disease-causing properties in more than 36 million genetic variants across more than 3,200 disease-related genes.

In the process theyve advanced the classification of more than 256,000 genetic variants whose propertieshelpful, harmful or neitherhave been unknown.

The work was conducted at Harvard Medical School and Oxford University. The resulting study is posted online in Nature.

Quantifying the pathogenicity of protein variants in human disease-related genes would have a marked effect on clinical decisions, yet the overwhelming majority (over 98%) of these variants still have unknown consequences, write co-lead authors Jonathan Frazer, Mafalda Dias and colleagues to contextualize their pursuit.

In principle, computational methods could support the large-scale interpretation of genetic variants, they add. However, state-of-the-art methods have relied on training machine learning models on known disease labels.

For the current project, the team sought to overcome this limitation by modeling the distribution of sequence variation across organismsand over vast swaths of time.

In so doing, they hypothesized, they would isolate fitness-maintaining features in protein sequences.

Calling their model EVE for evolutionary model of variant effect, the authors report their technique proved more accurate than labeled-data AI approaches.

Whats more, it can equal or improve upon predictions from more commonly used approaches.

The team states their work with EVE suggests models of evolutionary information can provide valuable independent evidence for variant interpretation that will be widely useful in research and clinical settings.

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AI predicts gathering disease with a deep dive into evolutionary genetics - AI in Healthcare

Aetna's Gene-based Cellular and Other Innovative Therapies network is aimed at curbing million-dollar costs of the gene therapy market. Separately, the National Institutes of Health and the Food and Drug Administration launched a public-private partnership to speed up gene treatments.

Modern Healthcare:Aetna To Cover Multi-Million Dollar Gene TherapiesAetna debuted a network focused on curbing the rising costs of the growing gene therapy market, the insurer announced on Thursday. Structured like a Center of Excellence program, the company's Gene-based Cellular and Other Innovative Therapies network includes more than 75 providers who treat inherited retinal diseasewhich impacts approximately 2 million people worldwideand spinal muscular atrophy, which impacts an estimated 9,000 Americans. Treatment for these conditions comes in the form of gene therapy, where providers manipulate genes at the cellular level. (Tepper, 10/27)

Stat:Partnership Aims To Accelerate Gene Therapies For Rare DiseasesThe National Institutes of Health and U.S. Food and Drug Administration unveiled a public-private partnership Wednesday aimed at accelerating gene therapies for the roughly 30 million Americans living with a rare genetic disease. Theyve waited a long time for something to be focused this way to address the incredibly wrenching stories we see all around us of children and adults with rare diseases where we can do a diagnostic test to tell them what they have but beyond that havent had much to offer, Francis Collins, the pioneering genetics researcher and longtime NIH director, told STAT. (Molteni, 10/27)

Stat:The Vast Majority Of Genes Have Been Tied To Cancer, Complicating ResearchJoo Pedro de Magalhes scours the human genome for clues that might help us understand why people age and what we might do to stop that. Without fail, each time hes done one of these studies, nearly every gene ends up having some kind of link to cancer. Always, he said. You always have some cancer-related genes in there. (Chen, 10/27)

In other pharmaceutical industry news

Stat:Feds Probe Novartis Over Entresto Marketing And Compensation To DoctorsIn what might become a new scandal for Novartis, federal investigators recently demanded information from the drug maker (NVS) about the pricing and marketing of one of its biggest-selling drugs, and the focus of the probe includes compensation paid to physicians. Last month, the U.S. Department of Justice issued a civil investigative demand about Entresto, a heart failure drug that generated $924 million in sales in the third quarter, a 46% gain. The demand was disclosed by the company in a regulatory filing, but further details were not made available (see page 36). (Silverman, 10/27)

Stat:CytoDyn Knew Its FDA Application Was Incomplete When It Filed, Docs ShowCytoDyn and its CEO Nader Pourhassan have known the companys long-delayed HIV drug was in far more trouble with the Food and Drug Administration than was disclosed to investors, according to new documents filed this week as part of an ongoing civil lawsuit. The documents reveal that in May 2020, CytoDyn submitted a marketing application for its drug called leronlimab with the FDA, despite knowing the filing was missing crucial information and was largely incomplete. (Feuerstein, 10/28)

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Gene Therapies Given Boost In NIH-FDA Partnership, New Aetna Network - Kaiser Health News

Peyrot, M. in Aspects of Globalisation: Mobility, Exchange and the Development of Multi-Cultural States 1217 (2017).

Damgaard, P. et al. 137 ancient human genomes from across the Eurasian steppes. Nature 557, 369374 (2018).

CAS PubMed Article ADS PubMed Central Google Scholar

Hemphill, B. E. & Mallory, J. P. Horse-mounted invaders from the Russo-Kazakh steppe or agricultural colonists from western Central Asia? A craniometric investigation of the Bronze Age settlement of Xinjiang. Am. J. Phys. Anthropol. 124, 199222 (2004).

PubMed Article PubMed Central Google Scholar

Betts, A., Jia, P. & Abuduresule, I. A new hypothesis for early Bronze Age cultural diversity in Xinjiang, China. Archaeol. Res. Asia 17, 204213 (2019).

Article Google Scholar

Li, C. et al. Evidence that a West-East admixed population lived in the Tarim Basin as early as the early Bronze Age. BMC Biol. 8, 15 (2010).

PubMed PubMed Central Article CAS Google Scholar

Li, C. et al. Analysis of ancient human mitochondrial DNA from the Xiaohe cemetery: insights into prehistoric population movements in the Tarim Basin, China. BMC Genet. 16, 78 (2015).

PubMed PubMed Central Article CAS Google Scholar

Ning, C. et al. Ancient genomes reveal Yamnaya-related ancestry and a potential source of Indo-European speakers in Iron Age Tianshan. Curr. Biol. 29, 25262532 (2019).

CAS PubMed Article PubMed Central Google Scholar

Zhou, X. et al. 5,200-year-old cereal grains from the eastern Altai Mountains redate the trans-Eurasian crop exchange. Nat. Plants 6, 7887 (2020).

CAS PubMed Article PubMed Central Google Scholar

Wang, T. et al. Tianshanbeilu and the isotopic millet road: reviewing the late Neolithic/Bronze Age radiation of human millet consumption from north China to Europe. Natl Sci. Rev. 6, 10241039 (2019).

CAS PubMed Article PubMed Central Google Scholar

Zhang, Y. et al. Holocene environmental changes around Xiaohe Cemetery and its effects on human occupation, Xinjiang, China. J. Geogr. Sci. 27, 752768 (2017).

Article Google Scholar

Hong, Z., Jian-Wei, W., Qiu-Hong, Z. & Yun-Jiang, Y. A preliminary study of oasis evolution in the Tarim Basin, Xinjiang, China. J. Arid Environ. 55, 545553 (2003).

Article ADS Google Scholar

Jia, P. & Betts, A. A re-analysis of the Qiemuerqieke (Shamirshak) cemeteries, Xinjiang, China. J. Indo-Eur. Stud. 38, 275317 (2010).

Google Scholar

Peyrot, M. The deviant typological profile of the Tocharian branch of Indo-European may be due to Uralic substrate influence. Indo-Eur. Linguist. 7, 72121 (2019).

Article Google Scholar

Bouckaert, R. et al. Mapping the origins and expansion of the Indo-European language family. Science 337, 957960 (2012).

CAS PubMed PubMed Central Article ADS Google Scholar

Allentoft, M. E. et al. Population genomics of Bronze Age Eurasia. Nature 522, 167172 (2015).

CAS PubMed PubMed Central Article ADS Google Scholar

Mallory, J. P. & Mair, V. H. The Tarim Mummies: Ancient China and the Mystery of the Earliest Peoples from the West (Thames & Hudson, 2000).

Barber, E. W. Mummies of Urumchi (W. W. Norton & Co., 1999).

Mair, V. H. Prehistoric Caucasoid corpses of the Tarim Basin. J. Indo-Euro. Stud. 23, 281307 (1995).

Google Scholar

Mair, V. H. in The Bronze Age and Early Iron Age Peoples of Eastern Central Asia Vol. 2 835855 (Institute for the Study of Man and the University of Pennsylvania Museum, 1998).

Mallory, J. P. The Problem of Tocharian Origins: an Archaeological Perspective (Univ. Pennsylvania Press, 2015).

Chen, K. & Hiebert, F. T. The late prehistory of Xinjiang in relation to its neighbors. J. World Prehist. 9, 243300 (1995).

Article Google Scholar

Han, K. Craniometric study on the ancient individuals from the Gumugou site, Xinjiang (in Chinese). Kaogu Xuebao 361384 (1986).

Kuzmina, E. E. in Archeology, Migration and Nomadism, Linguistics Vol. 1 6393 (Univ. Pennsylvania Museum Publications, 1998).

Li, Y. Agriculture and palaeoeconomy in prehistoric Xinjiang, China (3000200 BC). Veg. Hist. Archaeobot. 30, 287303 (2021).

Article Google Scholar

Frachetti, M. D. Multiregional emergence of mobile pastoralism and nonuniform institutional complexity across Eurasia. Curr. Anthropol. 53, 238 (2012).

Article Google Scholar

Narasimhan, V. M. et al. The formation of human populations in South and Central Asia. Science 365, eaat7487 (2019).

CAS PubMed PubMed Central Article Google Scholar

Feng, Q. et al. Genetic history of Xinjiangs Uyghurs suggests Bronze Age multiple-way contacts in Eurasia. Mol. Biol. Evol. 34, 25722582 (2017).

CAS PubMed Article PubMed Central Google Scholar

Jeong, C. et al. Bronze Age population dynamics and the rise of dairy pastoralism on the eastern Eurasian steppe. Proc. Natl Acad. Sci. USA 115, E11248E11255.

Yu, H. et al. Paleolithic to Bronze Age Siberians reveal connections with first Americans and across Eurasia. Cell 181, 12321245 (2020).

CAS PubMed Article PubMed Central Google Scholar

Jeong, C. et al. A dynamic 6,000-year genetic history of Eurasias Eastern Steppe. Cell 183, 890904 (2020).

CAS PubMed PubMed Central Article Google Scholar

Fu, Q. et al. The genetic history of Ice Age Europe. Nature 534, 200205 (2016).

CAS PubMed PubMed Central Article ADS Google Scholar

Wang, C.-C. et al. Genomic insights into the formation of human populations in East Asia. Nature 591, 413419 (2021).

CAS PubMed PubMed Central Article ADS Google Scholar

Li, J.-F. et al. Buried in sands: environmental analysis at the archaeological site of Xiaohe Cemetery, Xinjiang, China. PLoS ONE 8, e68957 (2013).

CAS PubMed PubMed Central Article ADS Google Scholar

Qiu, Z. et al. Paleo-environment and paleo-diet inferred from Early Bronze Age cow dung at Xiaohe Cemetery, Xinjiang, NW China. Quat. Int. 349, 167177 (2014).

Article Google Scholar

Yang, Y. et al. Proteomics evidence for kefir dairy in Early Bronze Age China. J. Archaeol. Sci. 45, 178186 (2014).

CAS Article Google Scholar

Xie, M. et al. Identification of a dairy product in the grass woven basket from Gumugou Cemetery (3800 BP, northwestern China). Quat. Int. 426, 158165 (2016).

Article Google Scholar

Yang, R. et al. Investigation of cereal remains at the Xiaohe Cemetery in Xinjiang, China. J. Archaeol. Sci. 49, 4247 (2014).

CAS Article Google Scholar

Zhang, G. et al. Ancient plant use and palaeoenvironmental analysis at the Gumugou Cemetery, Xinjiang, China: implication from desiccated plant remains. Archaeol. Anthropol. Sci. 9, 145152 (2017).

Article ADS Google Scholar

Yu, J. & He, J. Significant discoveries from the excavation of Jimunai Tongtiandong site (in Chinese). Wenwubao 8 (2017).

Hollard, C. et al. New genetic evidence of affinities and discontinuities between Bronze Age Siberian populations. Am. J. Phys. Anthropol. 167, 97107 (2018).

PubMed Article PubMed Central Google Scholar

Li, C. et al. Ancient DNA analysis of desiccated wheat grains excavated from a Bronze Age cemetery in Xinjiang. J. Archaeol. Sci. 38, 115119 (2011).

CAS Article Google Scholar

Stevens, C. J. & Fuller, D. Q. The spread of agriculture in eastern Asia: archaeological bases for hypothetical farmer/language dispersals. Lang. Dyn. Change 7, 152186 (2017).

Article Google Scholar

Abuduresule, I. Archaeological report of Xiaohe cemetery of 2003 (in Chinese). Wenwu 442 (2007).

Abuduresule, Y., Li, W. & Hu, X. in The Cultures of Ancient Xinjiang, Western China: Crossroads of the Silk Roads 1951 (Archaeopress, 2019).

Reimer, P. J. et al. The IntCal20 Northern Hemisphere radiocarbon age calibration curve (055 cal kBP). Radiocarbon 62, 725757 (2020).

CAS Article Google Scholar

Ramsey, C. B. Methods for summarizing radiocarbon datasets. Radiocarbon 59, 18091833 (2017).

CAS Article Google Scholar

Dabney, J. et al. Complete mitochondrial genome sequence of a Middle Pleistocene cave bear reconstructed from ultrashort DNA fragments. Proc. Natl Acad. Sci. USA 110, 1575815763 (2013).

CAS PubMed PubMed Central Article ADS Google Scholar

Rohland, N., Harney, E., Mallick, S., Nordenfelt, S. & Reich, D. Partial uracilDNAglycosylase treatment for screening of ancient DNA. Philos. Trans. R. Soc. B 370, (2015).

Peltzer, A. et al. EAGER: efficient ancient genome reconstruction. Genome Biol. 17, 60 (2016).

PubMed PubMed Central Article CAS Google Scholar

Schubert, M., Lindgreen, S. & Orlando, L. AdapterRemoval v2: rapid adapter trimming, identification, and read merging. BMC Res. Notes 9, (2016).

Li, H. & Durbin, R. Fast and accurate short read alignment with BurrowsWheeler transform. Bioinformatics 25, 17541760 (2009).

CAS PubMed PubMed Central Article Google Scholar

Jun, G., Wing, M. K., Abecasis, G. R. & Kang, H. M. An efficient and scalable analysis framework for variant extraction and refinement from population-scale DNA sequence data. Genome Res. 25, 918925 (2015).

CAS PubMed PubMed Central Article Google Scholar

Jnsson, H., Ginolhac, A., Schubert, M., Johnson, P. L. F. & Orlando, L. mapDamage2.0: fast approximate Bayesian estimates of ancient DNA damage parameters. Bioinformatics 29, 16821684 (2013).

PubMed PubMed Central Article CAS Google Scholar

Renaud, G., Slon, V., Duggan, A. T. & Kelso, J. Schmutzi: estimation of contamination and endogenous mitochondrial consensus calling for ancient DNA. Genome Biol. 16, 224 (2015).

PubMed PubMed Central Article Google Scholar

Korneliussen, T. S., Albrechtsen, A. & Nielsen, R. ANGSD: Analysis of Next Generation Sequencing Data. BMC Bioinformatics 15, 356 (2014).

PubMed PubMed Central Article Google Scholar

Jeong, C. et al. The genetic history of admixture across inner Eurasia. Nat. Ecol. Evol. 3, 966976 (2019).

PubMed PubMed Central Article Google Scholar

Lazaridis, I. et al. Genomic insights into the origin of farming in the ancient Near East. Nature 536, 419424 (2016).

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The genomic origins of the Bronze Age Tarim Basin mummies - Nature.com

SARS-CoV-2 is highly likely to transmit from one person to the members of their household.

One 2020 review suggests that on average, the likelihood of SARS-CoV-2 transmitting to household contacts is 16.9%. But this increases to 41.5% in households made up of the person with the infection and one other contact.

Yet some people do not develop the infection even after prolonged contact with household members who have it. This suggests that these people may be resistant to SARS-CoV-2 infection.

Genetic factors are known to play a significant role in determining response to infectious disease.

A recent review published in Nature Immunology summarizes current evidence about genetic factors that could explain the variability in individual response to SARS-CoV-2 infection. Specifically, it describes genes that may result in increased susceptibility to SARS-CoV-2 and those that could potentially confer resistance.

The review was authored by researchers participating in the COVID Human Genetic Effort, an international collaboration that aims to understand the genetic and immune factors underlying SARS-CoV-2 infection.

Paul Bastard, a doctoral student at Imagine Institute, in Paris, and a collaborator in the COVID Human Genetic Effort, explained the significance of identifying genes that may confer natural resistance against SARS-CoV-2 to Medical News Today:

This would be of major importance, as it could help identify the pathways involved in the fight against COVID-19. It could help us better understand the pathogenesis of COVID-19. In addition, it could potentially lead to the development of new therapeutics.

Previous studies have shown that possessing certain genetic variants can increase susceptibility to tuberculosis. These genes generally encode proteins that are involved in the immune response.

Similarly, scientists have found mutations in genes that are involved in or influence the type-1 interferon response in people with severe COVID-19. Type-1 interferons are important chemical messengers in the immune system and are crucial to our antiviral response.

Certain gene variants can also, however, protect a person from severe illness and even confer resistance to an infectious disease.

For instance, people with a mutation in the gene that encodes the CCR5 receptor are naturally resistant to HIV-1. The CCR5 receptor binds to chemokines, a family of immune proteins, and is used by HIV-1 to enter human cells and spread in the body. People with a CCR5 gene mutation express a shorter version of the CCR5 protein, preventing HIV from entering and infecting cells.

The discovery of this natural resistance led to the development of drugs that block the receptor. This example shows how characterizing genes that confer natural resistance can facilitate the development of treatments for infectious diseases.

Likewise, scientists have identified several candidate genes that could potentially confer resistance against SARS-CoV-2 infection.

SARS-CoV-2 enters human cells by binding to the angiotensin-converting enzyme 2 (ACE2) protein, which is expressed on the surface of a wide variety of cells.

A recent preprint study, which has yet to be peer reviewed, showed that a rare gene variant located close to the ACE2 gene is associated with a lower risk of SARS-CoV-2 infection and severe illness.

Moreover, the study suggests that these protective effects may result from the variant genes ability to reduce ACE2 expression and, thus, potentially influence the entry of SARS-CoV-2.

Other laboratory studies have identified human proteins that interact with SARS-CoV-2 and facilitate processes essential for viral infection. Variants of these genes could thus potentially confer resistance to SARS-CoV-2.

The characterization of genes that confer resistance to SARS-CoV-2 requires the identification of individuals with a natural resistance to the infection. However, there are a few major methodological obstacles.

One is demonstrating that a person has contracted SARS-CoV-2 in the past. Polymerase chain reaction (PCR) tests using nasal swabs or other respiratory samples only provide information about recent exposure to the virus. While detecting antibodies in plasma samples can provide information about a prior SARS-CoV-2 infection, a small percentage of individuals who have had the infection do not have detectable levels of antibodies.

It can also be challenging to distinguish individuals who have never been exposed to the virus from those who possess natural resistance.

The authors of the Nature Immunology review are currently conducting a study to characterize genes that may confer resistance to SARS-CoV-2 infection and propose a strategy to address these challenges.

To identify people with natural resistance to SARS-CoV-2 infection, the authors intend to enroll participants who do not have the infection but have a household member, especially a spouse or partner, with symptomatic COVID-19. They also intend to include people without the infection who have been in contact, without protective equipment, with a symptomatic person during the first 35 days of their infection.

And in addition to PCR and antibody testing, they propose to assess the participants T-cell responses.

The immune response to a SARS-CoV-2 infection is characterized by the production of antibodies and a response by T cells, a type of white blood cell. The absence of a T-cell response specific to the virus, along with negative PCR and antibody tests, could thus help confirm the absence of a prior SARS-CoV-2 infection.

After analyzing the genomes of these participants to identify genes associated with natural resistance to SARS-CoV-2 infection, the authors will conduct subsequent studies to determine the role of the genes in the infection process.

Dr. Nikolai Klebanov, of the Harvard Dermatology Residency Program, in Boston, told MNT:

Studying host genetic predisposition for susceptibility or resistance to COVID-19, through genome-wide association studies or whole exome or genome sequencing, could uncover potential viral entry points and key pathways of immune resistance to the virus. This could allow for the development of new, targeted drugs or vaccines for COVID-19, as well as to better risk-stratify vulnerable populations.

For live updates on the latest developments regarding the novel coronavirus and COVID-19, click here.

Link:
COVID-19: Studying genetic predisposition to disease severity - Medical News Today

THOUSAND OAKS, Calif., Oct. 26, 2021 /PRNewswire/ --Amgen (NASDAQ: AMGN) today announced that it has been selected as one of the World's Best Workplaces for 2021 by Fortune magazine and Great Place to Work. Amgen ranked eighth among the 25 companies named to the list. Those on the list were selected from 10,000 companies, representing the voices of nearly 20 million employees in more than 100 countries.

"We are very proud of this honor," said Robert A. Bradway, Amgen's chairman and chief executive officer. "To be recognized on a global scale demonstrates our ongoing commitment to providing staff with an environment in which they are able to grow and thrive even during challenging times."

"The World's Best Workplaces are the most sweeping and consistent examples of inclusive company cultures we've ever known," said Michael C. Bush, chief executive officer of Great Place to Work. "In a global workforce, alignment is everything, and these companies are fortifying their culture around the world a nearly impossible feat. Even when tested by the pandemic, these companies recognize sub-communities in each region and their leaders carry an equitable employee experience across cultures."

Earlier this year, Amgen was ranked by Great Place to Work as the seventh best workplace in Europe. Additionally, 25 Amgen affiliates around the world have either been certified or recognized by Great Place to Work nationally. The Fortune World's Best Workplaces list is available at https://www.greatplacetowork.com/best-workplaces-international/world-s-best-workplaces/2021.

About AmgenAmgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to beone ofthe world'sleadingindependent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visitwww.amgen.comand follow us onwww.twitter.com/amgen.

CONTACT: Amgen, Thousand OaksMegan Fox, 805-447-1423 (media)Trish Rowland, 805-447-5631(media)Arvind Sood, 805-447-1060 (investors)

SOURCE Amgen

http://www.amgen.com

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Fortune and Great Place to Work Name Amgen One of the World's Best Workplaces in 2021 - PRNewswire

Where did the Covid-19 pandemic come from? Almost since the beginning of the outbreak, a bitter and explosive controversy has raged over the origins of the novel coronavirus known as SARS-CoV-2. The rapid shut-down of the Huanan Seafood Wholesale Market in Wuhan immediately suggested to Western observers that the Chinese government itself thought that the market was the source, especially since 26 out of 47 of the original cases could be linked to it. An article published in Nature in March 2020 seemed to leave no doubt: The viruss genome showed every evidence of natural origins.

But the story did not stop there. Many writers and researchers suggested that the presence of a high-containment laboratory in Wuhan, the Wuhan Institute of Virology, could point to a laboratory origin for the pandemic: a bioweapons experiment; or gain-of-function research, in which genetic manipulation adds some new feature to an existing germ; or simply the laboratory escape of a lethal bat virus. Since many lab escapes have happened in the past, some argue, a lab leak is a plausible explanation for this devastating explosion of disease. While a team convened by the World Health Organization declared in March that a lab leak was extremely unlikely and suggested wildlife farms that supplied the market could be the culprit, a new group of scientists is now set to revisit the issue.

Still, there remains, as of this writing, no physical evidence linking the pandemics origins with a laboratory escape. And furthermore, from a logical and evolutionary viewpoint, there is something fundamentally wrong with all lab-leak arguments. SARS-CoV-2 is a human-adapted virus capable of effective, stealthy transmission from person to person. Lab escape theories cannot clearly account for the adaptation of the virus to its new host, or, in other words, for the evolution of human-to-human transmissibility.

In order for a virus to adapt to a new species, it needs to evolve to a point where it can easily and readily spread within that species. This is not the work of an instant, but rather the end result of a long chain of adaptation and transmission. Thats an evolutionary process. Human-to-human transmissibility has never been produced deliberately in laboratory experiments because no one knows exactly how to make a virus more transmissible among people. Its not something that can happen accidentally, because the genetics of transmission are so subtle and complex the result of numerous specific tiny adaptations. And a virus thats readily transmissible among humans in the way that SARS-CoV-2 is has never been found in the wild, because animal viruses are adapted to their own host species. To make a human-to-human transmissible disease, you need human beings, a lot of human beings, to be exposed to a pathogen. And you need the repeated action of natural selection on the pathogen spreading among those human beings.

Transmission is key to a pathogens adaptation. In SARS-CoV-2, transmission is effective, silent, and relentless because the virus replicates at high levels in the upper respiratory tract, making it easy to spread through coughing, sneezing, talking, and breathing. According to coronavirus expert Susan Weiss of the University of Pennsylvania, SARS-CoV-2 replicates better at slightly lower temperatures than some other viruses, allowing it to populate nasal passages and the upper airways, where the temperature is lower than in the lungs. Though it has not been proven, Weiss said it would make logical sense that better replication at lower temperatures could permit the virus to shed early in the infection, before symptoms set in.

In contrast, highly pathogenic H5N1 avian flu, for instance, never acquired the ability to transmit from person-to-person at all, despite a fair number of fatal human infections. This is, at least in part, because the virus attaches to receptors deep in the lungs, and not, unlike SARS-CoV-2, in the upper airways.

How would you design a virus to spread stealthily in the ways that SARS-CoV-2 does, either for general research or for nefarious purposes? You wouldnt. You wouldnt know how. Theres a vanishingly low likelihood that you could design a virus so that it spreads asymptomatically, says Weiss.

Human-to-human transmissibility has never been produced deliberately in laboratory experiments because no one knows exactly how to make a virus more transmissible among people.

Transmission is a subtle thing, involving many genes and many functions. Only natural selection, in the context of repeated spread from host to host within a single species, can guide its evolution. The idea that all of these traits could be accidentally picked up in laboratory experiments and introduced into a bat virus seems no more likely than the idea that they were consciously designed by researchers. Huge mink farms in Denmark and the Netherlands, where, in several instances, infected workers introduced SARS-CoV-2 to the crowded animals, show us how this adaptive evolutionary process works: The human-adapted virus rapidly evolved, several times over, to be a mink-adapted disease which may be better at transmitting among minks than people.

No one really understands the genetics of transmissibility for any virus. The closest scientists have come is in a notorious series of experiments, the results of which were published in 2012. Two laboratories, one in the Netherlands, one in Wisconsin, separately showed that by changing one aspect of transmission, the receptor by which highly pathogenic H5N1 bird flu attach to cells in the respiratory tract, they could, by repeatedly passing their altered strain through ferrets, ultimately infect ferrets via the airborne route. Many scientists insisted that this gain-of-function research was inherently dangerous, and the labs agreed to a voluntary year-long moratorium.

But as Columbia University virologist Vincent Racaniello points out, that work actually did not produce a more dangerous virus. By shifting receptors to those high in ferrets airways, the virus lost its virulence. None of the ferrets died. Weiss quips that sometimes gain-of-function research actually involves loss of function.

The closest anyone has come to creating an entirely novel virus is likely an experiment conducted by Ralph Baric and colleagues at the University of North Carolina, the U.S. Food and Drug Administration, and the WIV, among other institutions, in which the researchers used the spike protein of an existing bat coronavirus and spliced it to the backbone of a mouse coronavirus. Baric, who was not available for comment, showed his chimera could infect and replicate in human airways cells in vitro and the lungs of living mice. Then the scientists tried to develop a full-length virus, but that proved significantly attenuated both in human airway cells and mice. It would need, according to the study, further adaptation to become an effective pathogen. And theres no evidence at all that that derived virus could spread.

Even less is known about the genetics of coronavirus transmissibility, which remains a black box, even as variant after variant has emerged and spread. Racaniello describes these new, spreading variants as simply more fit. But other virologists, including Stephen Goldstein, a researcher at the University of Utah School of Medicine, think that in this case fitness implies more effective transmission. The take-home is that that these new variants are worse because they spread more quickly and to more people, he says. It all adds up to greater transmissibility. Evolution towards increased transmissibility is, indeed, a likely scenario, as more transmissible strains should outcompete less transmissible ones, and that seems to have happened here.

But we still do not thoroughly understand the genetics of viral transmission for SARS-CoV-2, or, for that matter, for any other pathogen.

Some people propose that an accidental release of a natural virus, probably a bat virus, triggered the pandemic but that scenario is no more likely. First, no one has found a bat virus close enough genetically to be the culprit. The bat virus until recently believed to be most closely related to SARS-CoV-2, RATG13, is 96 percent similar. That doesnt mean, according to coronavirus expert Weiss, that one small stretch (4 percent of the genome) is different and the rest is identical. It is different in small ways all across the genome.

Results posted on the preprint server Research Square in September, which have not yet been peer reviewed, suggest three new viruses identified in bats in Laos are even more closely related to SARS-CoV-2. But even assuming that scientists in Wuhan cultured such viruses in the lab which they told investigators early this year was not the case this doesnt mean that a bat-adapted virus escaped from the WIV could have seeded the Covid pandemic. A virus is never going to come out of a bat ready to go, says Racaniello. It never has.

Bat-borne viruses, including Hendra, Nipah, Marburg, and rabies, can kill people, but they dont easily spread from person to person. While, in theory, a bat virus that has the ability to infect people via the ACE-2 receptor might be able to spread from person to person, there is no known record of any bat virus (or any other wild animal virus) having done so. Six cases of SARS-like illnesses among miners cleaning bat feces from a bat cave in Yunnan province have been reported, but there is no indication that these cases (three of which were fatal) spread to anyone else. There are known instances of a bat-adapted disease transmitting among people, but always, as in the case of Nipah virus, through very close contact or exposure to bodily fluids, not via airborne transmission. Lab releases of a wild bat virus would necessarily mean that lab workers had to be infected many of them, to allow transmissibility to evolve but despite speculation, there have been no reported Covid infections among lab researchers at the WIV.

We still do not thoroughly understand the genetics of viral transmission for SARS-CoV-2, or, for that matter, for any other pathogen.

Proponents of the lab-release explanation also point to prior accidental releases as evidence that this could have happened in Wuhan. Proponents cite the six times SARS-CoV, a related virus that infected more than 8,000 people and killed 774 in 2002-2003, escaped from research laboratories by infecting scientists who passed it on. Or they bring up Janet Parker, who died of smallpox in 1978 when a British scientist, experimenting with smallpox virus, apparently allowed the virus to move through the ventilation system and infect Parker, who was working in a room just above the laboratory.

The difference between SARS-CoV-2 and these instances is that none of them involve new pathogens. Citing instances of the release of pathogens that have already established transmissibility among humans doesnt begin to address the question of Covids origins. And that remains the fundamental question.

But the actual key to Covids origins has been there all along. According to Weiss, SARS-CoV and SARS-CoV-2 are more closely related to each other than either is to other human coronaviruses. But Weiss says both are also closer to related bat viruses than they are to each other. After more than a decade of research, its been established that the SARS-CoV originated in a bat and then moved, in the live-animal market of Guangdong in southern China, into intermediate hosts, civets, and likely raccoon dogs. Infecting other animals seems to disentangle, so to speak, a well-adapted bat virus from its original host, making it, for a time, something of a generalist, able to infect a range of species, including humans.

SARS-CoV-2 probably evolved in similar circumstances. It is likely that, again, civets, raccoon dogs, or other species acquired a bat-borne virus and spread it to other animals and then to people: keepers, customers, passers-by in the 1,000-stall Huanan market, where wild animals of many different species were caged together in crowded, filthy conditions. These live animal markets are essentially disease factories, effective laboratories for the evolution of deadly pathogens. Huanan was soon shut down. No outsiders were permitted to examine it, or test workers for seroprevalence, which is, according to Goldstein, a critically important step.

According to the Chinese Academy of Engineering, as of 2016, the exotic food trade was a $19 billion industry in China, out of $76 billion for the overall wildlife industry. Countless live wild animals are sold for the luxury market each year. A lot of money is involved, and theres a lot of incentive to keep quiet. Though the Huanan market remains shuttered and the wildlife trade for food banned, other markets, selling live animals such as chickens, ducks, and pigs, apparently remain open, and in regions far from the main centers trade in wildlife may continue. Live wild animals are also sold in markets throughout Asia.

Obsession with the lab leak hypothesis, combined with the secrecy and lack of cooperation showed by the Chinese government in helping the world understand the origins of the virus, has taken energy and focus away from an important step that can be taken now to prevent future outbreaks of new viruses. We remain at risk for the evolution of new pathogens, of other pandemics, until all wet markets, worldwide, are shuttered for good.

Wendy Orent, who holds a Ph.D. in anthropology, has been writing about biological weapons and the evolution of infectious disease for 25 years.

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Opinion: Why I Still Believe Covid-19 Could Not Have Originated in a Lab - Undark Magazine