Category Archives: Genetic Engineering

Using biotechnology, researchers have developed cassava crops that are resistant to brown streak and mosaic, and have been tested in research stations across the country, to understand their adaptability to different agro-ecologies, with the participation of farmers.

Yes it works, Barisiyoy Jemimah contrasts the diseased Nase 13 Cassava with a resistant Nase 13 GMO. PHOTOS: Prossy Nandudu

Using biotechnology, researchers have developed cassava crops that are resistant to brown streak and mosaic, and have been tested in research stations across the country, to understand their adaptability to different agro-ecologies, with the participation of farmers.

Five years ago, Jemima Barisiyoyi cleared her five acres of land to plant cassava. She aimed to sell cuttings to the National Agriculture Advisory Services (NAADS) and also keep some for home use.

Using planting materials from neighbours and friends, she raised enough seeds for the five acres. At the start, cassava stems looked healthy with no sign of disease.

"I started planning on how I would use the money because of the assured market I had with the NAADS team that was procuring seed for distribution," said Barisiyoyi in an interview at the National Crop Resources Research Institute recently.

After four months, she realised some plants were not growing taller; some had white things like ash which were spreading faster.

Disturbed by what she saw, she contacted the Wakiso district extension officer, who connected her to researchers at Namulonge.

Upon inspecting her garden, they informed her that the garden had been infested by cassava diseases spread by whiteflies.

Diseases spread by the whitefly include brown streak and mosaic diseases that cause 100% yield loss. To bypass such diseases, she had to look out for disease-free planting materials. According to her, the option which is NASE 14 can only resist such diseases for three years.

She narrated her experience on Wednesday during the harvest of GMO cassava, organized by SCIFODE with support from the VIRCA Plus cassava project and the National Crop Resources Research Institute in Namulonge.

"I have been participating in these harvests which all show that there are cassava seeds that resist diseases, but when the law will come into place," said Barisiyoyi.

She was backed by Nakanwagi Aida, another farmer who wondered whether NARO cannot use other laws to release the varieties to farmers as they wait for the pending the law. The importance of involving farmers in the GMO harvests is part of the recommendations by the Cartagena Protocol on Biosafety that encourages participation of stakeholders like farmers who are direct beneficiaries of biotechnology research products.

The importance of involving farmers in the GMO harvests is part of the recommendations by the Cartagena Protocol on Biosafety that encourages participation of stakeholders like farmers who are direct beneficiaries of biotechnology research products.

For the two farmers and others to get resistant varieties, they will have to wait for varieties developed through biotechnology. With biotechnology, traits for resistance to a particular disease are taken from one crop and introduced into another to increase its ability to resist diseases and pests, explained Dr. Titus Alicai from NaCRRI.

Using biotechnology, researchers have developed cassava crops that are resistant to brown streak and mosaic, and have been tested in research stations across the country, to understand their adaptability to different agro-ecologies, with the participation of farmers.

Although farmers are demanding for resistant varieties, those developed through biotechnology can only be released under a clear regulatory framework, he added.

The Genetic Engineering Regulatory Act (GERA) that was meant to provide a unifying regulatory framework is currently in parliament after it was sent back by the President for the second time, added Isaac Ongu, the executive director of SCIFODE.

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Wakiso Farmers Want Naro To Fast Track The Release Of Disease Free Cassava Seeds - New Vision

As the world endures the impacts of a rapidly changing climatesea level rise, extreme weather events, warming and acidifying oceans (among many others)policy makers and the public should critically examine how food production contributes to these worrying trends. Animal agriculture may be the best place to start since, many scientists argue, its the single biggest cause of biodiversity loss and a significant source of greenhouse gas emissions.

Over a quarter of the worlds land surface is currently dedicated to raising animals for food, but that practice can be exceptionally wasteful. Despite taking up almost 80 percent of global agricultural land, livestock represents less than 20 percent of the worlds calories. Proper stewardship of the land, which absorbs nearly one-third of global greenhouse gas emissions, is critical in our fight against climate change, but human activities degrade roughly a quarter of it, and livestock production is perhaps the primary culprit.

To help combat these growing environmental challenges, concerned citizens around the world are eating more sustainable and arguably healthier diets that partially or entirely replace meat with fish, crustaceans, and other aquatic animals. Fish production generally has a lower environmental impact than land animal farming, owing to the fact that fish require less feed. Most fish are poikilotherms, which means they dont use energy to heat their bodies. And unlike most land animals (homeotherms), fish dont need to constantly maintain their body temperatures, which tend to fluctuate with their external environment. Moreover, the density of water carries the weight of the fish, eliminating the requirement for heavy bones.

Despite its lower environmental footprint, global fish productionwhich includes wild capture and aquaculture (fish farming)has its own sustainability issues. Around one-third of the worlds marine fish stocks have reached unsustainable levels due to overfishing. Simultaneously, the global demand for fish and nutritional oils containing omega-3 fatty acids is increasing rapidly as more consumers recognize that consuming them is linked to reduced cardiovascular disease risk. Saturation in capture fishing since the early 1990s means aquaculture is filling consumer demand for fish. But without significant changes, aquaculture isnt a long-term solution.

Fortunately, a valuable but misunderstood tool can help the industry become more sustainable. Of course, Im talking about biotechnology. Genetic engineering has sped up the production of fish, and enabled the development of sustainable fish feed sources and nutritional oils. All three innovations are marching toward commercialization, and the evidence indicates their collective impact will be enormous.

While commercial fish farms have greatly improved their production systems over the years, feeding fish with fish (primarily fishmeal and oils) still poses a significant sustainability threat. In 2018, global fish production reached around 179 million tons, and humans ate about 88 percent of the produce (156 million tons) while about 10 percent (18 million tons) went towards producing fishmeal and fish oils. Finding alternative feed sources would slash the environmental footprint of aquaculture and contribute to global food security goals.

Breeding better fish

Fish maturity is based on physical features such as shape and size. The faster fish grow, the lower their environmental impact, so innovators have targeted faster growth rates as a solution to the industrys sustainability problem. In 2015, the Food and Drug Administration (FDA) approved a bioengineered Atlantic salmon for consumption after decades of rigorous scientific review. The FDA concluded that the genetically engineered AquAdvantage salmon is as safe to eat as any non-genetically engineered Atlantic, and also as nutritious. This salmon is approved for sale in Canada and is slated for commercialization in the US.

Scientists at the biotech firm AquaBounty introduced two different bits of genetic information from other fish species into a bioengineered salmon: a growth hormone gene from the fast-growing Chinook salmon controlled by a DNA switch (promoter) from the ocean pout. Because the Chinook growth hormone gene works overtime, AquaBountys salmon grows to full size in about half the time required by conventional salmonand consumes 25 percent less feed as a result.

Faster growth means the energy and carbon emissions required to produce the fish are lower. And since AquaBountys land-based aquaculture facilities are located in Canada and the US, transporting these fish to market generates lower carbon emission than delivering conventional salmon by air or ship. Additionally, the expansion of genetically engineered fish production could significantly reduce overfishing, since some of salmon feed comes from other wild fish.

Some environmentalists have voiced concerns about the consequences of bioengineered fish escaping into the wild. In theory, genetically engineered fish may flee to the wild, breed with their wild relatives and create a hybrid that could out-compete other fish in the marine ecosystem. Quite rightly, these are serious concerns that require proper attention and strong mitigation plans.

Considering the trade-off between hypothetical risks and the demonstrated benefits of biotechnology in fish production helps us evaluate the situation. AquAdvantage salmon are produced in land-based facilities and are sterile. Regulators at the FDA have therefore concluded its extremely unlikely that the fish could escape and establish themselves in the wild.

Shorter production time and lower feed and energy requirements clearly outweigh the low risk of fish escaping into the wild. And we get all these without compromising the nutritional value of the fish itself. AquaBounty is scheduled to begin producing its bioengineered salmon in the US before the end of 2020, making it the first genetically engineered food animal to hit US markets. As COVID-19 continues to put pressure on food supplies, the introduction of genetically engineered salmon helps illustrate how biotechnology can help solve critical problems.

Alternative fish feeds and fish oils

Bioengineered fish is an important step in the right direction, but it doesnt fully address aquacultures sustainability issues. The industry has developed non-fish based feeds, cutting use of fishmeal and fish oil from 30 million tons in 1994 to about 18 million tons in 2018. But there are concerns that fish products grown on alternative feeds arent providing the same nutritional value as those fed real fish, which is high in omega-3 oils. To understand why, we need to look at the chemistry of these fatty acids.

Omega-3 oils are long-chain polyunsaturated fatty acids existing mainly in three types: -linolenic acid (ALA); eicosapentaenoic acid (EPA); and docosahexaenoic acid (DHA). Plant oils contain ALA, which is the shorter version of EPA and DHA omega-3 fatty acids, typically found in marine organisms like microalgae and phytoplankton.

Our bodies cant make omega-3, so we mostly get it from eating fish, which incidentally also cant make omega-3 but accumulate it by eating microalgae and phytoplankton. As vegetable oils replace fish oil in aquafeeds, the level of beneficial fatty acids, EPA and DHA, have also declined considerably, reducing the nutritional value that fish offer. Therefore, the aquaculture industry needs to identify aquafeeds that are derived from alternative sources and provide the same level of nutrition.

Algae are a promising source to replace fish oil, but extracting algal oil is more expensive than producing fish oil and fishmeal, though the extraction technology is rapidly developing. Additionally, algae cultivation for aquafeed is sometimes limited to species that only produce DHA fatty acids, which means the algae-fed fish lack EPA, compromising their final nutritional value.

Again, scientists have turned to biotechnology to address this problem. Research teams have engineered plants like camelina and canola that contain high levels of EPA and DHA in their seed oil. These plants naturally produce the shorter version of omega-3, ALA, and scientists introduced microalgal genes that convert ALA into EPA and DHA omega-3 fatty acids typically found in fish. Research shows that fish fed with seed oil from these camelina plants show good growth, maintain feed efficiency and dont lose nutritional valueindicating that genetically engineered plants can provide a sustainable substitute for fish oil feeds.

Now innovators are aiming to produce omega-3 oils from camelina for aquafeeds and nutritional supplements. Biotech startup Yield10 Bioscience has fused artificial intelligence with synthetic biology to create a technology that identifies trait targets to produce better plants. Using their technology platform and genome editing, they have generated camelina plants that produce double seed yields with a high content of both EPA and DHA omega-3 oils. The company has recently launched field trials of their genome-edited seeds. They are scaling seed production, aiming to plant thousands of acres of camelina to produce plant-based omega-3 oil products for fish feed and human nutrition soon. Crucially, the USDA announced in January 2020 that it wont regulate gene-edited camelina, accelerating development of this sustainable omega-3 oil source.

Biotechnology is already accelerating production of environmentally friendly salmon, and is poised to provide more sustainable fish feed and nutritional oils in the coming years. It could also bring aquaculture production costs down, reducing incentives to overfish our oceans, which will no doubt be better for the marine ecosystem.

Surging fish demand will only be met by sustainable, low-cost solutions, enabled in key instances by biotechnology. Technical details aside, the benefits of broader biotechnology adoption in aquaculture will extend beyond the developed world to improve the lives of those most in needimpoverished people in the developing world.

Rupesh Paudyal holds a PhD in plant science and covers agriculture and the environment as a freelance writer. Visit his website and follow him on Twitter @TalkPlant

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Viewpoint: Fish farming has a sustainability problem and genetic engineering might be the solution - Genetic Literacy Project

DAVIS, Calif.--(BUSINESS WIRE)--BioConsortia, Inc., innovator of microbial solutions in crop protection, soil fertility, and yield improvement, welcomes Dr. Damian Curtis to the company as Director of Synthetic Biology and Genomics. He will lead new technology development in strain improvement and engineering for BioConsortias next generation of biopesticides, biostimulants and nitrogen fixation products.

Damian has 15 years of industrial experience with Bayer, AgraQuest and Exelixis. He is a recognized technology leader in genetic engineering and most recently he managed the microbial genetics functions in Biologics R&D at Bayer CropScience, where he also supported global projects including the Poncho/VOTiVO 2.0 product.

Damian holds a PhD in molecular biology & biochemistry from Oregon Health and Sciences University and a BS in molecular biology & chemistry from San Jose State University.

Damian is an exceptional leader in technology innovation and is well recognized for his talent in microbial genetics and engineering in the Ag biological space, said Hong Zhu, SVP Research & Development for BioConsortia. I am very pleased to have him join our R&D leadership team, especially as we are entering a new, exciting phase of growth and technology expansion to solve tough agricultural problems such as nitrogen overuse and to bring more high-performance biologicals to our partners and growers.

With a pipeline of highly effective conventional microbial fungicides, nematicides and biostimulants moving into the registration phase, BioConsortia is turning its focus to advance the next generation of products from their synthetic biology program.

As leader of the in-house Gene Editing and Synthetic Biology Platform, Damian will improve the genetics of BioConsortias already robust, spore-forming microbial leads in order to enhance performance of the naturally occurring nitrogen fixation bacteria. In addition to the development of new nitrogen fixation solutions, the team will also develop next generation biostimulants, fungicides, insecticides, and nematicides.

Damian Curtis said, I was first attracted to BioConsortia by their unique microbial discovery platform, and as I dug deeper into their library, leads, and products, as well as their current work on gene editing, I became more excited by the potential. I look forward to helping deliver products that will substantially change the industry.

Weve built a pipeline of highly effective natural products, and moved a number of effective biopesticide and biostimulant solutions into the registration phase, said Marcus Meadows-Smith, CEO. We are now implementing a program for next generation products. With Damians leadership we will magnify the natural capabilities of our nitrogen fixing microbes and deliver solutions that can replace the growers reliance on synthetic products, thereby opening up the $200 Billion fertilizer market for transformation.

About BioConsortia

BioConsortia, Inc. is developing effective microbial solutions that enhance plant phenotypes and increase crop yields. We are pioneering the use of directed selection in identifying teams of microbes - working like plant breeders and selecting plants based on targeted characteristics, then isolating the associated microbial community. Our proprietary Advanced Microbial Selection (AMS) process enriches the crop microbiome, allowing us to identify organisms that influence the expression of beneficial traits in plants. We are focused on developing products with superior efficacy, higher consistency, and breakthrough technologies in 3 key areas:1) Biopesticides: a pipeline of several biofungicides and nematicides with superior efficacy2) Biostimulants: growth promoting products that further increase yields in standard, high-yielding as well as stressed, agronomic conditions3) Nitrogen-fixation and fertilizer use efficiency: developing products for major non-legume row crops (such as corn and wheat)Our products are foliar, drench, seed treatment, in-furrow and granule products for a wide range of crops.

For inquiries and further information, please contact info@bioconsortia.com

Link:
BioConsortia Welcomes Dr. Damian Curtis to Lead New Gene Editing and Synthetic Biology Platform for Next Generation Biopesticides, Biostimulants and...

The research report on Genetic Engineering Industry market provides a granular analysis of this industry vertical wherein notable market activities are thoroughly researched. Various market segmentations based on product type, application spectrum, and regional terrain are surveyed in-depth, while estimated share held by each segment by the end of forecast period is encompassed in the report.

The report also highlights the current remuneration of the market and offers an insight regarding the growth rate attained over the analysis timeframe. Vital parameters which will influence the market growth positively as well as negatively are enlisted. Further, the impact of COVID-19 pandemic outbreak on Genetic Engineering Industry market is also documented in the report.

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Additional insights from Genetic Engineering Industry market report:

Major Points Covered in TOC:

Overview:Along with a broad overview of the global Genetic Engineering Industry market, this section gives an overview of the report to give an idea about the nature and contents of the research study.

Analysis of Strategies of Leading Players:Market players can use this analysis to gain a competitive advantage over their competitors in the Genetic Engineering Industry market.

Study on Key Market Trends:This section of the report offers a deeper analysis of the latest and future trends of the market.

Market Forecasts:Buyers of the report will have access to accurate and validated estimates of the total market size in terms of value and volume. The report also provides consumption, production, sales, and other forecasts for the Genetic Engineering Industry market.

Regional Growth Analysis:All major regions and countries have been covered in the report. The regional analysis will help market players to tap into unexplored regional markets, prepare specific strategies for target regions, and compare the growth of all regional markets.

Segmental Analysis:The report provides accurate and reliable forecasts of the market share of important segments of the Genetic Engineering Industry market. Market participants can use this analysis to make strategic investments in key growth pockets of the market.

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Genetic Engineering Industry Market Research Growth by Manufacturers, Regions, Type and Application, Forecast Analysis to 2025 - CueReport

In brief

COVID-19 vaccines are being developed with a previously unimaginable urgency. More groups are working faster than ever before to develop shots that will protect us from the novel coronavirus, and hopefully bring an end to the pandemic. At first glance, the more than 160 vaccine programs seem remarkably similar, mostly focused on inducing immunity to the coronavirus spike protein. A closer look reveals many differences, including the types of vaccine technologies deployed, how the spike protein is modified and displayed to our immune systems, and the kinds of immune responses these different approaches will elicit.

There was a moment, just over 200 days ago, when wed never heard of a coronavirus, when everything we did wasnt shrouded with the specter of COVID-19. We crammed into living rooms, sang, danced, clinked glasses, showed 2019 out the door. We eagerly welcomed the new decade, filled calendars, and planned trips. Hugs and handshakes werent a health threat. Walking past someone in a crowded grocery store wasnt anxiety inducing. Pictures of crowded beaches and bars didnt evoke anger. How the world has changed.

In early January, no one could have known how truly catastrophic this novel coronavirus would be. Yet before this particular virus, SARS-CoV-2, was discovered, a few prescient people had already begun preparing for it. For decades, virologists have warned of an impending pandemic. Were overdue, they said. Some groups even had the foresight to begin developing vaccines for a different coronavirus. Once SARS-CoV-2 emerged, those groups had a template to begin making vaccines for the yet-to-be-named disease, COVID-19.

As the pandemic grew, other companies and academic teams started working on their own vaccines for COVID-19. By early April, more than 100 programs were reportedly underway. Even then, vaccines remained a distant prospect. Amid shutdowns and social distancing, we simply yearned for summer, for a break from the virus. The reprieve never came.

Vaccines, for all intents and purposes, were the backup plan. Now, we need them more than ever.

Without a vaccine, I dont think we can put a lid on this, says Paul Young, a virologist developing a COVID-19 vaccine at the University of Queensland. It will continue to be a fire that rages through the world for quite some time until literally everyone is infected unless we are able to intervene.

For nearly 7 long months, SARS-CoV-2 has pushed us to our limits. By mid-July, the virus had infected more than 13 million people and killed more than 580,000. About a quarter of those recorded cases and deaths belong to the US, a fraction likely to rise as so many Americans seemingly give up on the simple public health precautions that other countries have used to curtail the spread of the virus.

Yet there is cause for hope. In those same 7 short months, scientists have made strides that might normally take 7 years. Companies are beginning large trials with tens of thousands of people this month to see if their experimental vaccines can prevent disease. The pandemic has spurred the fastest vaccine development programs in history. While some groups are pushing to have vaccines available this winter, maybe sooner, others think such timelines are preposterous, and potentially reckless. Many questions remain, but there are two things that nearly everyone can agree on.

First, we need a vaccine to end this pandemic. There is no doubt, says Daria Hazuda, vice president of infectious diseases discovery at Merck Research Laboratories. Given how widespread this is globally I just dont think it is going to go away by itself. Second, scientists are confident that at least one vaccine, and hopefully more, will eventually work. There is every reason to believe that we can make a vaccine against this kind of virus, says Paul Offit, a pediatrician and director of the Vaccine Education Center at Childrens Hospital of Philadelphia. I think it is very likely that we will have an effective vaccine by the middle of next year, he adds.

From that consensus, however, opinions diverge.

On the surface, all COVID-19 vaccine candidates have the same goal: generate an immune response that protects you from the virus. But under the hood, these vaccines use a range of technologiesfrom tried and true to new and untestedto teach our bodies how to defend itself against the virus.

This summer, C&EN interviewed more than three dozen scientists, doctors, and business leaders to illuminate the complementary, and occasionally conflicting, strategies employed by groups developing the most advanced and well-funded COVID-19 vaccines. Theres much to learn still, and more definitive answers will come in time, but we already know the questions we need to be asking to make an effective vaccine.

Heres how we get back to normal.

I. How hard is it to make a vaccine against a virus?

Scientists have devised many ways to protect against an infection. In mid-July, the World Health Organization had counted 23 COVID-19 vaccine programs in clinical testing, and another 140 in preclinical development. This is just an unprecedented effort, every possible vaccine strategy is being used, including ones that have never been used before, Offit says.

The most traditional approach to making a vaccine is to simply use the virus itself, allowing your immune cells to learn how to fight it without you actually having to suffer through the disease. Viruses can either be left alive but attenuatedwhere scientists take all the chutzpah out of itor they can be killed with chemicals and heat that leave them unable to replicate. Historically, some of the most effective vaccines, such as those for measles, polio, and smallpox are attenuated or inactivated vaccines.

Credit: Andrew Caballero-Reynolds/AFP via Getty Images

A vial with an experimental COVID-19, vaccine at Novavax ln Gaithersburg, Maryland

Today, the most popular approaches for making new vaccines all focus on isolating the specific part of the virus believed to be most important for immunity. For SARS-CoV-2, that part is incontrovertibly the spike proteinimmediately recognizable in cartoons of the virus as the mushroom-like knobs studding its spherical surface. The coronavirus uses these spike proteins to grab hold of a human protein called ACE2, the first step in an infection. Nearly every COVID-19 vaccine candidate shares the objective of trying to prevent this interaction between the spike protein and ACE2.

Giving our immune cells target practice with a harmless form of the spike protein should allow them to halt the real virus in its tracks. A large number of groups are working on making the spike protein itself, detached from the virus, as the primary vaccine ingredient. Genetic engineering allows scientists to easily copy and paste the genetic code of the spike protein into cells that are optimized to grow in large vats, where they crank out large quantities of the protein. Vaccines for hepatitis B, shingles, and other diseases are made with this approach, which yields whats known as a subunit protein vaccine.

But developing manufacturing processes for any of these more traditional vaccines typically takes months, if not much longer. Making attenuated or inactivated vaccines requires special facilities with extra safety precautions to grow large numbers of the actual virus, while subunit protein vaccines require scientists to optimize cells that can make the viral protein and then patiently wait for the cells to multiply.

Recently, theres been growing excitement for experimental vaccines that take a different and faster route. Based on newer technologies, these vaccines simply contain the genetic code for the spike protein, and come in several forms, including DNA, messenger RNA, and viral vectorswhere a harmless virus is rejiggered into a gene-delivery vessel. But the end goal for all of them is the same: transport the genetic instructions for the spike protein into human cells in order to temporarily turn those cells into spike protein factories. No DNA or mRNA vaccines have ever received regulatory approval, and only two viral vector vaccinesboth to prevent Ebola virushave been licensed for humans.

Without a vaccine, I dont think we can put a lid on this, It will continue to be a fire that rages through the world for quite some time until literally everyone is infected unless we are able to intervene.

Paul Young, virologist, University of Queensland

Frank DeRosa, the chief technology officer of the mRNA company Translate Bio, explains that mRNA vaccines let our own cells make the spike protein just like they would if we were infected with the real virus. These vaccines, along with DNA and viral vector vaccines, allow the spike protein to be trafficked to the cell membrane surface where it is displayed, or else chopped up and presented in pieces to immune cells. You are just letting the body do what it would do normally, DeRosa says. Thats one of the advantages of mRNA.

Gene-based vaccines should also allow the protein to undergo glycosylation, a cellular process of tacking sugars onto the protein in specific patterns, which will give the immune system a more accurate mug shot of the spike protein. These sugar patterns can differ in subunit proteins, depending on the kinds of cells used to manufacture them.

Genetic vaccines have another key advantage: they are breathtakingly fast to design and produce. The only thing that changes significantly between two genetic vaccines is the segment of code being delivered. The manufacturing process for one RNA is a lot like the manufacturing process for another RNA, says Phil Dormitzer, Pfizers chief scientific officer for viral vaccines. The same is largely true for DNA vaccines, and true to a lesser degree for viral vector vaccines. Its why most of the fastest moving programs for COVID-19 are gene-based vaccines.

The current record speed for making a modern vaccine is Mercks viral vector vaccine for Ebola, which took 5 years to design, test, and earn government approval. For COVID-19, many companies say that process could be collapsed into a year or two. Some firms, including AstraZeneca, Moderna, and Pfizer, expect to have efficacy data this fall, and the US government plans to preorder 300 million doses ready for distribution by January 2021.

Those timelines have plenty of skeptics. The notion that we can have something done by the fall is frankly ludicrous, that is just not going to happen, says Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development. I would suspect that by this time next year we are still going to be looking forward to when that first vaccine hits the market.

More than 160 vaccines are in the works to prevent COVID-19. Here are the major types of technologies being used to make them.

Attenuated and inactivated virus vaccines

Attenuated virus vaccines contain a living but weakened version of SARS-CoV-2. Inactivated virus vaccines contain SARS-CoV-2 that has been killed with heat or chemicals like -propiolactone or formalin. Several childhood vaccines are attenuated or inactivated virus vaccines.

Subunit protein vaccines

Subunit protein vaccines contain the SARS-CoV-2 spike protein, which the virus uses to enter human cells. These vaccines often include adjuvants, which are molecules that stimulate the innate immune system to help simulate a natural infection. More groups are developing subunit protein vaccines for COVID-19 than any other technology.

Viral vector vaccines

Viral vector vaccines use a different virussuch as the adenovirus, measles virus, or vesicular stomatitis virusthat is genetically engineered to carry the gene for the SARS-CoV-2 spike protein, which will be made by our cells. Viral vector vaccines for preventing Ebola have recently been approved, but others are still experimental.

Nucleic acid vaccines

Nucleic acid vaccines encode genetic instructions for the SARS-CoV-2 spike protein into DNA, delivered into our cells with an electric shock, or RNA, delivered into our cells via a lipid nanoparticle. These vaccines can be rapidly designed and manufactured, but no DNA or RNA vaccine has been approved for humans.

II. Does the immune system view all vaccines equally?

Most vaccine developers believe that the potential protection offered by these vaccines hinges on teaching our immune cells to make the right kind of antibodies. In theory, antibodies can bind to any part of the spike protein, but only certain ones, the so-called neutralizing antibodies, bind to the spike protein in a manner that prevents the virus from infecting our cells.

Neutralizing antibodies are the most important biomarker to follow in the vaccine studies, and higher the antibody titers, the better, says John Shiver, senior vice president for global vaccines R&D at Sanofi.

You might imagine that the best way to get those high levels of neutralizing antibodies is to simply present the spike protein in its most natural form. But the spike protein is a wily shapeshifter, and many groups think that tweaking the spike protein will be necessary to induce a good neutralizing antibody response.

After the spike protein binds to ACE2, it undergoes a dramatic transformation. A spring-loaded portion of the spike shoots into the human cell membrane and then pulls the virus and cell so close together that their membranes fuse. This allows the virus to spill its genes and guts into the cell, where it begins replicating.

So scientists think there are probably two major ways an antibody can prevent infection: it can either directly block the spikes interaction with ACE2 in the first place, or it can gum up the spikes spring-loaded machinery and impede its fusion with our cells.

In 2016, while scientists were studying the spike protein of a different coronavirus, they discovered that embedding two prolinesthe most rigid of amino acidsin a particular part of the spike helped lock it into the shape that it takes before binding ACE2. Many researchers believe it is crucial to show your immune cells this so-called prefusion form of the spike protein in order to make antibodies that prevent infection. In contrast, if the vaccine teaches the immune system to make antibodies to the postfusion form, the shape the spike protein takes after binding to a cell, those antibodies will bind to the spike too late to prevent infection, says Andrew Ward, a structural biologist at Scripps Research who co-led the study.

Before the pandemic, that double proline mutation, called the 2P mutation, proved generalizable to several coronavirus spike proteins. So when SARS-CoV-2 emerged in early January, researchers were able to quickly add this mutation into the design of a COVID-19 vaccine. The mRNA company Moderna and researchers at the National Institute of Allergy and Infectious Diseases (NIAID) made a somewhat risky decision to begin manufacturing a COVID-19 vaccine based on the viruss spike sequence and the addition of the 2P mutation without any further experiments, explains Barney Graham, deputy director of the Vaccine Research Center at NIAID.

Since then the 2P mutation has made its way into subunit protein vaccines, mRNA vaccines, and viral vector vaccines. Jason McLellan, the scientist who discovered the 2P mutation, is now looking for other promising ones. His lab at the University of Texas at Austin has tested more than 100 additional mutations, which led to the creation of a novel prefusion spike protein dubbed HexaPro. Its more stable, and, when plugged into an mRNA vaccine, causes cells to make 10 times the amount of spike protein. He says companies making COVID-19 vaccines are already testing HexaPro in lab studies, and his lab is working on further improvement. We are always tweaking, he says. You can kind of do this forever but at some point you just have to pick something and move it forward.

Credit: Jason McLellan

The HexaPro spike protein, invented by Jason McLellans lab at the University of Texas at Austin, contains 6 proline mutations (red and blue spheres) that help stabilize the SARS-CoV-2 spike protein in its prefusion structure. The S1 subunit (transparent white) contacts the human cell and the S2 subunit (colored ribbons) contains the spring-loaded machinery that helps the virus fuse with the cell.

Other groups are making their own unique modifications to the prefusion spike. Scientists at the University of Queensland have made a subunit protein vaccine where the trimer of the spike is held together by what Queensland virologist Keith Chappell calls a molecular clamp. It is gripped at the base, and the top has natural flexibility, he says.

Other groups are forgoing the prefusion conformation in favor of a more natural, functional spike protein. That includes the DNA vaccine company Inovio Pharmaceuticals, which used this approach to elicit neutralizing antibodies in people who got its experimental MERS vaccine.

One of Mercks two viral vector vaccines is based on vesicular stomatitis virus (VSV), also used to make the firms recently licensed Ebola vaccine, Ervebo. Unlike the adenoviral vector vaccines under development for COVID-19, which just carry the genetic instructions for the spike protein, the VSV viral vector is designed to display the SARS-CoV-2 spike protein on its surface, where it can be used to enter human cells. It is kind of an authentic presentation, says Christopher Parks, whose lab led the design of the vaccine at IAVI, before Merck said it would test it in humans.

We can make effective vaccines quite quickly. But safety is not something that can be measured in a single time point. It has to be observed over a period of time.

David Dowling, vaccine researcher, BostonChildrens Hospital

Another strategy is to use just a key fragment of the spike protein. It turns out that the most potent neutralizing antibodies made by people who recover from COVID-19 almost always target a particular part of the spike protein. That key section, called the receptor-binding domain (RBD), sits at the top of the spike, where it makes direct contact with ACE2 on human cells. For this reason, some groups are developing vaccines that simply use the RBDeither made as a subunit protein or encoded in mRNA.

RBD-based vaccines could have the advantage of helping the immune system focus on developing neutralizing antibodies to the part of the protein that matters the most. Its also a relatively small part of the large spike protein, which could make these vaccines cheaper to manufacture.

But its small size has drawbacks too. Scientists say we typically develop better immune responses against larger proteins. And researchers are starting to discover neutralizing antibodies that bind to other regions of the spike protein outside the RBD as well, ones that might work by halting the viruss fusion to the human cell, rather than by blocking its binding to ACE2. In general, having neutralizing antibodies to multiple sites should limit the viruss ability to mutate and escape neutralization.

One study in monkeys testing six different DNA vaccines all encoding various versions of the spike protein found that the full-length spike protein induced higher levels of neutralizing antibodies than the RBD. A small study testing four variations of subunit proteins in rabbits found the opposite: the RBD vaccine induced the highest levels of neutralizing antibodies.

The RBD might be good enough. And when you are making a vaccine, you just need to make it good enough, NIAIDs Graham says. But, he adds, we just think it is not quite as good as the whole thing.

Pfizer, which is working with the German mRNA company BioNTech, may be the only group that is hedging its bets by testing multiple vaccines in humans: two encoding the full prefusion spike protein and two encoding the RBD. Although you can do plenty of testing preclinically, some questions you really have to answer in clinical trials, says Pfizers Dormitzer.

If a particular paradigm proves most promising, it will be easy to construct a narrative about why one brilliant group had the right idea all along. You can reason your way into believing that any one front-runner vaccine will rise above the others just as easily as you can convince yourself that one approach is destined for failure. But as it stands, we dont know which vaccines will work the best. Although animal studies can give clues about what wont work in humans, the only way to determine how a vaccine will protect against infection is to test it in people.

III. How will our immune system protect us from the virus?

Key milestones in the rapid design, clinical testing, and funding of vaccines for COVID-19

Jan. 10: The first genome sequence of the novel coronavirus, later named SARS-CoV-2, is posted online.

Jan. 13: Moderna announces plans to develop an mRNA vaccine for the novel coronavirus.

Jan. 23: The Coalition for Epidemic Preparedness Innovations (CEPI) announces vaccine funding for Inovio Pharmaceuticals, Moderna, and the University of Queensland.

March 16: CanSino Biologics and Moderna dose first volunteers in Phase I clinical trials of their vaccines.

March 17: Pfizer announces partnership with BioNTech to develop and test multiple mRNA vaccines.

March 30: Biomedical Advanced Research and Development Authority (BARDA) and Johnson & Johnson announce they are committing more than $1 billion to develop an adenoviral vector vaccine for COVID-19.

April 16: BARDA awards Moderna up to $483 million to develop and manufacture its mRNA vaccine.

April 30: AstraZeneca announces it will develop the University of Oxfords adenoviral vector vaccine for COVID-19.

May 11: CEPI commits $384 million to Novavaxs COVID-19 vaccine, its largest investment ever.

May 15: US President Donald J. Trump announces Operation Warp Speed to supply 300 million vaccines to the US by January 2021.

May 18: Moderna announces preliminary Phase I data from its vaccine trial via press release.

May 21: BARDA says it will provide up to $1.2 billion for 300 million doses of AstraZenecas vaccine with the first shots arriving in October.

May 22: CanSino publishes the first peer-reviewed data of a Phase I COVID-19 vaccine trial.

May 26: Merck & Co. says it will develop two COVID-19 vaccines originally designed at Themis Biosciencean Austrian company that it acquiredand IAVI.

May 29: Moderna doses the first volunteers in its Phase II clinical trial of its mRNA vaccine.

June 20: A Phase III trial testing the University of Oxfords adenoviral vector vaccine begins in Brazil.

June 24: The state-owned China National Pharmaceutical Group (Sinopharm) announces plans for a Phase III trial of its inactivated virus vaccine for COVID-19.

June 28: 10 million people have been infected and 500,000 people have died from COVID-19.

July 7: BARDA and the US Department of Defense sign a $1.6 billion contract with Novavax for 100 billion doses of its vaccine.

All these vaccine efforts are grounded in the notion that producing high levels of potent neutralizing antibodies will prevent the virus from infecting our cells. Measuring those antibodies, however, is fraught with challenges, and we dont even know what levels we should aim for.

Methods used to quantify that neutralizing antibody response are imperfect. Researchers infect cells in a petri dish with either a real or artificial version of SARS-CoV-2 to see how much of the virus is blocked with a particular concentration of antibody-containing plasma. The real and artificial methods yield different results. And, although those results have been cited as rationale for moving COVID-19 vaccines into large, late-stage trials, there is no standard for how these measurements should be reported.

For instance, some groups report the level of neutralizing antibody that inhibits 50% of the virus, while others use higher bars of 80, 90, or 100%. If you make antibodies that neutralize 90% of the virus, that may not be good enough, NIAIDs Graham says. You want a neutralization that is 100% effective.

The number you get depends on the specifics of the assay you run, so comparing one companys numbers to another companys numbers is tricky, Pfizers Dormitzer says. Until we really establish what a protective level of antibodies is, the numbers may be a relative yardstick, but they dont tell you if you are going to have protection or not.

So far, companies have been using as their baseline the levels of neutralizing antibodies found in convalescent plasma of people who have recovered from COVID-19. But research shows that COVID-19 survivors make relatively low levels of antibodies, and one small study suggests they might only stick around for 2 to 3 months.

Credit: Brian Stauffer

Such studies suggest that a vaccine that mimics a natural infection is a pretty low bar. Immunity equivalent to natural infection may not be enough for this virus. It might need to be higher, says David Corry, an immunologist and allergist at Baylor College of Medicine.

On average, each coronavirus has a couple hundred spike proteins that it can use to grab onto a cell, so the number of neutralizing antibodies circulating in our bodies likely needs to be much higher than the number of viruses attempting to establish an infection. If the antibody levels are not high enough, we may end up with only partial protectionwhere we still get an infection, and might even be able to spread the virus to others, but would be safe from progressing to the most severe forms of COVID-19 that hospitalize people.

But even determining the level of antibodies needed to lessen the brutality of the disease is not straightforward. A level of antibodies in one person might send them off without any symptoms at all, while the same level of antibodies in another person may still leave them very sick, Scripps immunologist Dennis Burton says.

Some scientists say that partial protection is a fine goal for the first generation of COVID-19 vaccines. If you can keep people out of the hospital, to me that is a tremendous success, says Gregory Glenn, president of R&D at Novavax. Such vaccines could save lives, and in a hypothetical world where everyone is vaccinated, most individuals could deal with mild cases of COVID-19, and society could return to normal.

Although vaccine makers have focused on neutralizing antibodies, this type of immune response might not last forever. In a study of 191 people tested for cold-causing coronaviruses over a period of 19 months in New York City, researchers found that 9 people were infected with the same virus twice, and 3 were infected with the same virus three separate times. We dont know if either natural immunity or vaccines can prevent these kind of reinfections with SARS-CoV-2. One experiment showed that monkeys who were infected with high levels of SARS-CoV-2 were protected from reinfection 5 weeks lateralthough that study comes with the major caveat that monkeys dont develop full-blown COVID-19 in the first place.

Theres reason to believe that other parts of the immune system, such as T cells, may be important for longer-lasting immunity. Scientists found that people who were infected with SARS-CoV-1, the virus that caused the eponymous severe acute respiratory syndrome (SARS) outbreak in 2003, still had neutralizing antibodies to the virus 2 years after infection, but not 5 years later. In contrast, researchers recently discovered that some people infected with SARS-CoV-1 back in 2003 still have T cells that recognize the virus all these years later.

While antibodies prevent viruses from infecting cells in the first place, T cells can spot cells that are already infected and selectively kill them, thereby halting the spread of the virus. T cells are also better than antibodies at targeting different parts of the virus. Antibodies target proteins on the outside of the virus, which for SARS-CoV-2 is the spike protein. Yet the spike is just one of 27 proteins encoded in the SARS-CoV-2 genome. The other proteins are located inside the virus, or are made by our own cells when the virus is replicating. T cells, unlike antibodies, can learn to spot molecular fingerprints of these proteins in virus-infected cells.

DNA vaccines and viral vectors are better at inducing T cell responses, while subunit protein vaccines primarily induce antibodies. The traditional attenuated virus vaccines that use a live virusand therefore have all those internal proteinsare good at inducing both T cells and antibodies. Every formulation or platform is different, says Surender Khurana, a vaccine scientist at the US Food and Drug Administration. These different platforms can have different kinds of immune responses, and we dont know which immune response is most relevant.

IV. How good is good enough for a COVID-19 vaccine?

Some vaccines, like the one for measles, provide lifelong immunity to nearly every single person who receives them. Others, such as flu vaccines, are needed every year, and even then sometimes only work 30% of the time. For COVID-19 vaccines, the FDA is aiming for something in-between those extremes. The FDAs recently issued guidelines for COVID-19 vaccine development state that the agency expects a vaccine to either prevent disease, or reduce its severity, in at least 50% of vaccinated people.

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What will it take to make an effective vaccine for COVID-19? - Chemical & Engineering News

Women researchers are strongly influencing the adoption of agricultural biotechnology in Africa.

As African women, we are the ones who suffer most whenever drought and food shortages strike, despite the availability of technological solutions to these problems, said Dr. Felister Makini, deputy director general in charge of crops at the Kenya Agricultural and Livestock Research Organization (KALRO).

We are looking for new solutions and how we can use technology to give our people and ourselves better and improved crop varieties to fight hunger and improve the quality of living, said Dr. Priver Namanya Bwesigye, who leads Ugandas banana research program at the National Agricultural Research Laboratories (NARL) at Kawanda. We also need varieties that can give us more in terms of nutrients.

Throughout Africa, women are in labs developing crops that produce high yields and can tolerate or resist disease, as well as healthier, more productive livestock. They are also found in meeting rooms and gardens informing the public about their innovations and how these improved crops can aid the fight against hunger across both the continent and the globe.

It is time to tell the public about the positive side of biotechnology, said Professor Caroline Thoruwa, chairperson for African Women in Science and Engineering.

In Uganda, where bananas are an important staple food and cash crop, Bwesigye is in charge of developing varieties that offer farmers better options.

She and her team are using the tools of genetic engineering to develop banana varieties that are resistant to nematodes, bacterial wilt and weevils. The most advanced of these genetically modified varieties is a banana biofortified to provide vitamin A. It should reach farmers immediately after Uganda implements a legal biosafety framework guiding the use of GMOs.

We have trialled the technology in multiple locations all the four banana planting regions of Uganda and it will be ready by the time we have a legal framework, Bwesigye said. We have to do this [multi-location field trials] before we can give it to the farmers. We want to be sure that different farmers across the country can plant the variety and have similar results. In this case, all the banana yields should be rich in pro-vitamin A.

But Bwesigyes program does much more than develop improved bananas using biotechnology. It also employs conventional plant breeding tools to produce heartier varieties, including a banana resistant to black sigatoka disease. When shes not in the lab, Bwesigye conducts extensive outreach to farmers and young people to explain agricultural biotechnology and why Uganda, Africa and the world need this tool.

Dr. Barbara Mugwanya Zawedde is also championing the adoption of agricultural biotechnology in Africa. Shes currently director for research at Ugandas Zonal Agricultural Research and Development Institute in Mukono, which is under the jurisdiction of the National Agricultural Research Organization (NARO).

But before that, she was the coordinator for the Uganda Biosciences Information Center (UBIC) NAROs knowledge and information-sharing hub. It champions an appreciation of modern biosciences research for agricultural development and works to educate stakeholders on the importance of biosafety.

In that role, Zawedde engaged religious leaders, local communities, farmers, extension agents, legislators, public ministries, women in agriculture, students and others to raise awareness about new technologies and their safety.

After earning a doctorate in plant breeding, genetics and biotechnology from Michigan State University, Zawedde returned home to Uganda in 2013 to discover we had gaps in communication as well as in regulation, she recalled.

So, she worked with Dr. Yona Baguma, now deputy director general for NARO, to set up the biosciences information center. Their goal was to bring to the fore these new technologies that people were not talking about and to emphasise the importance of regulating them.

The regulatory framework [we have been calling for] is not just for the introduction of these new technologies, but for their regulation as well, Zawedde said.

To an extent, Zawedde and UBIC have been successful.

Parliament passed the National Biotechnology and Biosafety Bill on two occasions, though President Yoweri Museveni has yet to sign it into law. Additionally, more Ugandans now appreciate the science and what it can do to improve their lives. Biotechnology and biosafety elements also have been included in the countrys school curriculums.

It will be easier to adopt these technologies [once we have a regulatory framework] because more people today understand these technologies and how they can help improve agriculture and food security in Uganda and the region, Zawedde said

Similarly, the Women in Biosciences Forum is working in Kenya to make everyone sure knows about the value of biotechnology and the role that women are playing to advance the science.

We need to raise the status of women in biotechnology and also encourage women to network in order to achieve the noble goal of sharing their science, Thoruwa said. Women must be involved for Africa to advance in agri-biotech.

Several African countries have approved the cultivation of GMO crops and others have conducted trials for GM crop varieties. But in many of the countries that are conducting research, GM seeds have yet to reach farmers and consumers because the political leadership is swayed by opposition and remains afraid to adopt biotechnology, the women scientists observed.

We need to speak with one voice and advocate for a predictable policy environment, said KALROs Makini.

The detractors will always be there, Bwesigye said. But we need to understand that these technologies, pretty much like everything else in life, have advantages and disadvantages. We just have to harness the advantages.

One such advantage is being able to develop a staple food crop, like a banana, that delivers vitamin A, a crucial nutrient that is lacking in almost 30 percent of Uganda children below the age of 5. It is a no brainer, Bwesigye said about the value of adopting the pro-vitamin A banana.

Despite the political obstacles, Bwesigye and her colleagues remain undiscouraged. Zawedde said that women will continue to conduct communication and outreach, calling on governments to give farmers a chance to plant some of these improved crops.

We only need awareness, awareness and more awareness, Bwesigye said. Then mind-sets will change and adoption of these technologies will be easier.

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African women are leading biotechnology's advance across the continent - Alliance for Science

A college of images of cells, each of which was collected from a 384 well plate using high throughput imaging.

Courtesy of Tanmay Lele

A new faculty member in the Department of Biomedical Engineering at Texas A&M University recently received a multi-million dollar grant to support groundbreaking cancer research.

In May, Tanmay Lele received a $5 million Recruitment of Established Investigators grant from the Cancer Prevention and Research Institute of Texas(CPRIT) to further knowledge about cancer and how it progresses.

Leles research focuses on mechanobiology the mechanical aspects of biology where he works to understand how cells sense external mechanical forces as well as how they generate mechanical forces, and how these mechanical forces impact cell function.

In cancer, both cellular mechanical forces and the mechanical properties of resisting cellular structures go awry. These errors cause abnormalities in cell structure. A particularly striking feature of cancer cells is the highly irregular and/or distended shape of the nucleus.

The nuclei in normal tissue have smooth surfaces, but over time the surfaces of cancer nuclei become irregular in shape, Lele said. Now, why? Nobody really knows. Were still at the tip of the iceberg at trying to figure this problem out. But nuclear abnormalities are ubiquitous and occur in all kinds of cancers breast, prostate and lung cancers.

Pathologists study biopsies and note abnormalities in the shape of the cell and its nucleus to grade the severity of cancer. Lele and his team are computerizing the analysis of nuclear shapes to research the cause of abnormal cancer structures.

Using photos of nuclei and cells in human tissue taken by a pathologist, Leles team has developed a computational algorithm to measure the degree of irregularity in the nucleus. With the algorithm, the team can run statistical analyses of the abnormalities and search for correlations between the extent of the irregularity, changes to genetic or molecular signatures in tumors and, ultimately, patient outcomes.

Leles research aims to help the medical community develop new knowledge of human cancers and how they progress, to better diagnose and manage cancers. Understanding the mechanisms behind the abnormalities can help develop therapies to better treat cancers by targeting the nucleus.

Like any other basic field, we are trying to make discoveries with the hope that they will have long-term impacts on human health, Lele said.

Lele will have two laboratories, one in College Station and one in the Texas A&M Health Science Centers Institute of Biosciences & Technology in Houston. The cancer grant from CPRIT is a collaborative effort with Dr. Michael Mancini and Dr. Fabio Stossi from the Baylor College of Medicine. He said he is looking forward to collaborating with researchers in both College Station and Houston.

Lele received his doctoral degree in chemical engineering from Purdue University. Before coming to Texas A&M, he served as the Charles A. Stokes Professor of Chemical Engineering at the University of Florida. At Texas A&M, in addition to being in biomedical engineering, he will be a joint faculty member in the Artie McFerrin Department of Chemical Engineering.

All my career has been spent in chemical engineering departments, but my research is also now in the biomedical space, Lele said. The move to Texas A&M was an opportunity for me to also be part of a different culture, if you will, of research. Being in the biomedical engineering department, in addition to the chemical engineering department, brings new opportunities to collaborate with researchers who have closely shared research interests.

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Biomedical Engineering Researcher Receives $5 Million Grant To Further Cancer Studies - Texas A&M University Today

Jul 18th 2020

A Dominant Character: The Radical Science and Restless Politics of J.B.S. Haldane. By Samanth Subramanian. W.W. Norton; 400 pages; $40. Atlantic Books; 20.

TOWARDS THE end of his life, J.B.S. Haldane was inseparable from a pebble that had been found in the Valley of Elah in Israel, where David felled Goliath with a similar projectile. A king-size man who towered over British biology for several decades in the middle of the 20th century, Jack Haldanethe half-Danewas a more obvious Goliath, but he always took the side of the underdog.

That is the contradiction at the heart of Samanth Subramanians astute and sympathetic biography. An Eton- and Oxford-educated communist, who with a handful of others fleshed out Darwins theory of natural selection by marrying it to genetics and grounding it in maths, Haldane was born into privilege but came to identify himself with the masses. And if his unconscious sense of entitlement can sometimes be grating, it is more than offset by his humour, facility for language, intellectual generosity andthe product of all thishis giant contribution to the popularisation of science.

Science was his first and most enduring love. Aged three, studying blood trickling from a cut, he is supposed to have asked, Is it oxyhaemoglobin or carboxyhaemoglobin? Thus began a life of inquiry in which he was always either being experimented onnotably by his father, the physiologist J.S. Haldaneor experimenting on himself or others. Bertrand Russell thought that science could rarely be beautiful, but for Haldane beauty came through understanding. Until I took to scientific plant-breeding, he wrote, I did not appreciate the beauty of flowers.

Haldane wrote a great deal, in learned journals but also in the popular press and in response to letters from the scientifically curious, and on a breathtaking range of subjects. Please send me no more caterpillars, he pleaded on one of the many occasions that his mailbag threatened to overwhelm him. As he coped with his own and other peoples inquisitiveness, world events intruded. He wrote parts of a paper on genetic linkagewhereby two genes that sit close to each other on a chromosome are more likely to be inherited togetherwhile serving in the trenches during the first world war.

It was in the trenches, too, that Haldanes rejection of his birthright crystallised. As disappointed by the officer class as he was by army chaplains, he wrote to his mother that, when the revolution came, the people would strangle the last Duke in the guts of the last parson. But he was attracted to Marxism for more than just its egalitarian ideals; it struck him as practical, transparentin short, scientific. Though he kept his distance from the Communist Party of Great Britain (CPGB) until 1942, MI5 had him down as a subversive from the time of his only visit to the Soviet Union, in 1928.

Haldanes politics and his science clashed mightily in 1948, when as the CPGBs foremost intellectualand, by then, one of the most influential geneticists in the worldhe refused to publicly condemn the pseudoscience of Trofim Lysenko. Stalins favourite agronomist claimed that he could drum desirable traits into wheat by altering its environment, just as Jean-Baptiste Lamarck had once believed giraffes had stretched their necks through practice. In the Soviet Union scientists who disagreed with Lysenko vanished. One of them, Nikolai Vavilov, had hosted Haldane in Moscow. Haldanes own science contradicted Lysenkoism. Nobody who knew him could fathom his stance.

Mr Subramanian doesnt defend it either. He makes it clear that Haldane ignored overwhelming evidence of Vavilovs internment and death in the gulag. But he uses the episode to illustrate a wider truth, which is that science cannot be extricated from politics. Today many scientists describe their research as apolitical, but Haldane knew that was impossible: I began to realise that even if the professors leave politics alone, politics wont leave the professors alone.

It meant that he was prepared to change his mind. Eugenics was a mainstream theory when he entered biology, and he partially embraced it. But he also warned that genetics was too young a science to be applied successfully. His ideas evolved until they fell into line with those of the scientists now wielding genetic-engineering tools to improve humanity (though they would reject the eugenics label).

Haldane changed his mind too slowly about the Soviet Union, but having done so he found new hope in India, where he moved in 1957. Its bureaucracy maddened him and he said so loudly and oftenflashing his white male privilege like a peacocks tailbut its tropical profusion provided him with a natural laboratory, and the climate was kinder to a body damaged by decades of self-experiment. When he died there in 1964, still holding the stone from Elah, it was no surprise to anyone that he donated his body to science.

This article appeared in the Books & arts section of the print edition under the headline "Trial and error"

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The flawed brilliance of J.B.S. Haldane - The Economist

Photograph by Nathaniel St. Clair

In all the discussions of the origin of the COVID-19 pandemic, enormous scientific attention has been paid to the molecular character of the SARS-CoV-2 virus, including its novel genome sequence in comparison with its near relatives. In stark contrast, virtually no attention has been paid to the physical provenance of those nearest genetic relatives, its presumptive ancestors, which are two viral sequences named BtCoV/4991 and RaTG13.

This neglect is surprising because their provenance is more than interesting. BtCoV/4991 and RaTG13 were collected from a mineshaft in Yunnan province, China, in 2012/2013 by researchers from the lab of Zheng-li Shi at the Wuhan Institute of Virology (WIV). Very shortly before, in the spring of 2012, six miners working in the mine had contracted a mysterious illness and three of them had died (Wu et al., 2014). The specifics of this mystery disease have been virtually forgotten; however, they are described in a Chinese Masters thesis written in 2013 by a doctor who supervised their treatment.

We arranged to have this Masters thesis translated into English. The evidence it contains has led us to reconsider everything we thought we knew about the origins of the COVID-19 pandemic. It has also led us to theorise a plausible route by which an apparently isolated disease outbreak in a mine in 2012 led to a global pandemic in 2019.

The origin of SARS-CoV-2 that we propose below is based on the case histories of these miners and their hospital treatment. This simple theory accounts for all the key features of the novel SARS-CoV-2 virus, including ones that have puzzled virologists since the outbreak began.

The theory can account for the origin of the polybasic furin cleavage site, which is a region of the viral spike protein that makes it susceptible to cleavage by the host enzyme furin and which greatly enhances viral spread in the body. This furin site is novel to SARS-CoV-2 compared to its near relatives (Coutard, et al., 2020). The theory also explains the exceptional affinity of the virus spike protein for human receptors, which has also surprised virologists (Letko et al., 2020; Piplani et al, 2020; Wrapp et al., 2020; Walls et al., 2020). The theory further explains why the virus has barely evolved since the pandemic began, which is also a deeply puzzling aspect of a virus supposedly new to humans (Zhan et al., 2020; van Dorp et al., 2020; Chaw et al., 2020). Lastly, the theory neatly explains why SARS-CoV-2 targets the lungs, which is unusual for a coronavirus (Huang et al., 2020).

We do not propose a specifically genetically engineered or biowarfare origin for the virus but the theory does propose an essential causative role in the pandemic for scientific research carried out by the laboratory of Zheng-li Shi at the WIV; thus also explaining Wuhan as the location of the epicentre.

The apparent origin of the COVID-19 pandemic is the city of Wuhan in Hubei province, China. Wuhan is also home to the worlds leading research centre for bat coronaviruses. There are two virology labs in the city, both have either collected bat coronaviruses or researched them in the recent past. The Shi lab, which collected BtCoV/4991 and RaTG13, recently received grants to evaluate by experiment the potential for pandemic pathogenicity of the novel bat coronaviruses they collected from the wild.

To add to these suggestive data points, there is a long history of accidents, disease outbreaks, and even pandemics resulting from lab accidents with viruses (Furmanski, 2014; Weiss et al., 2015). For these and other reasons, summarised in our article The Case is Building that COVID-19 Had a Lab Origin, we (a virologist and a geneticist) and others have concluded that a lab outbreak is a credible thesis. Certainly, a lab origin has at least as much circumstantial evidence to support it as does any natural zoonotic origin theory (Piplani et al., 2020; Segreto and Deigin, 2020; Zhan et al., 2020).

The media, normally so enamoured of controversy, has largely declined even to debate the possibility of a laboratory escape. Many news sites have simply labelled it a conspiracy theory.

The principal reason for media dismissals of the lab origin possibility is a review paper in Nature Medicine (Andersen et al., 2020). Although by Jun 29 2020 this review had almost 700 citations it also has major scientific shortcomings. These flaws are worth understanding in their own right but they are also useful background for understanding the implications of the Masters thesis.

The question of the origin of the COVID-19 pandemic is, in outline, simple. There are two incontrovertible facts. One, the disease is caused by a human viral pathogen, SARS-CoV-2, first identified in Wuhan in December 2019 and whose RNA genome sequence is known. Second, all of its nearest known relatives come from bats. Beyond any reasonable doubt SARS-CoV-2 evolved from an ancestral bat virus. The task the Nature Medicine authors set for themselves was to establish the relative merits of each of the various possible routes (lab vs natural) by which a bat coronavirus might have jumped to humans and in the same process have acquired an unusual furin site and a spike protein having very high affinity for the human ACE2 receptor.

When Andersen et al. outline a natural zoonotic pathway they speculate extensively about how the leap might have occurred. In particular they elaborate on a proposed residence in intermediate animals, likely pangolins. For example, The presence in pangolins of an RBD [Receptor Binding Domain] very similar to that of SARS-CoV-2 means that we can infer that this was probably in the virus that jumped to humans. This leaves the insertion of [a] polybasic cleavage site to occur during human-to-human transmission. This viral evolution occurred in Malayan pangolins illegally imported into Guangdong province. Even with these speculations there are major gaps in this theory. For example, why is the virus so well adapted to humans? Why Wuhan, which is 1,000 Km from Guangdong? (See map).

The authors provide no such speculations in favour of the lab accident thesis, only speculation against it:

Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system. (italics added).

[Passaging is the deliberate placing of live viruses into cells or organisms to which they are NOT adapted for the purpose of making them adapted, i.e. speeding up their evolution.]

It is also noteworthy that the Andersen authors set a higher hurdle for the lab thesis than the zoonotic thesis. In their account, the lab thesis is required to explain all of the evolution of SARS-CoV-2 from its presumed bat viral ancestor, whereas under their telling of the zoonotic thesis the key step of the addition of the furin site is allowed to happen in humans and is thus effectively unexplained.

A further imbalance is that key information needed to judge the merits of a lab origin theory is missing from their account. As we detailed in our previous article, in their search for SARS-like viruses with zoonotic spillover potential, researchers at the WIV have passaged live bat viruses in monkey and human cells (Wang et al., 2019). They have also performed many recombinant experiments with diverse bat coronaviruses (Ge et al., 2013; Menachery et al., 2015; Hu et al., 2017). Such experiments have generated international concern over the possible creation of potential pandemic viruses (Lipsitch, 2018). As we showed too, the Shi lab had also won a grant to extend that work to whole live animals. They planned virus infection experiments across a range of cell cultures from different species and humanized mice with recombinant bat coronaviruses. Yet Andersen et al did not discuss this research at all, except to say:

Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world

This statement is fundamentally misleading about the kind of research performed at the Shi lab.

A further important oversight by the Andersen authors concerns the history of lab outbreaks of viral pathogens. They write: there are documented instances of laboratory escapes of SARS-CoV. This is a rather matter-of-fact allusion to the fact that since 2003 there have been six documented outbreaks of SARS from labs, not all in China, with some leading to fatalities (Furmanski, 2014).

Andersen et al might have also have noted that two major human pandemics are widely accepted to have been caused by lab outbreaks of viral pathogens, H1N1 in 1977 and Venezuelan Equine Encephalitis (summarised in Furmanski, 2014). Andersen could even have noted that literally hundreds of lab accidents with viruses have resulted in near-misses or very localised outbreaks (summarised by Lynn Klotz and Sam Husseini and also Weiss et al., 2015).

Also unmentioned were instances where a lab outbreak of an experimental or engineered virus has been plausibly theorised but remains uninvestigated. For example, the most coherent explanation for the H1N1 variant swine flu pandemic of 2009/10 that resulted in a death toll estimated by some as high as 200,000 (Duggal et al., 2016; Simonsen et al. 2013), is that a vaccine was improperly inactivated by its maker (Gibbs et al., 2009). If so, H1N1 emerged from a lab not once but twice.

Given that human and livestock viral outbreaks have frequently come from laboratories and that many scientists have warned of probable lab escapes (Lipsitch and Galvani, 2014), and that the WIV itself has a questionable biosafety record, the Andersen paper is not an even-handed treatment of the possible origins of the COVID-19 virus.

Yet its text expresses some strong opinions: Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus..the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used backbone.the evidence shows that SARS-CoV2 is not a purposefully manipulated virus.we do not believe that any type of laboratory-based scenario is possible. (Andersen et al., 2020).

It is hard not to conclude that what their paper mostly shows is that Drs. Andersen, Rambaut, Lipkin, Holmes and Garry much prefer the natural zoonotic transfer thesis. Their rhetoric is forthright but the evidence does not support that confidence.

Indeed, since the publication of Andersen et al., important new evidence has emerged that undermines their zoonotic origin theory. On May 26th the Chinese CDC ruled out the Huanan wet market in Wuhan as the source of the outbreak. Additionally, new research on pangolins, the favoured intermediate mammal host, suggests they are not a natural reservoir of coronaviruses (Lee et al., 2020; Chan and Zhan, 2020). Furthermore, SARS-CoV-2 was found not to replicate in bat kidney or lung cells (Rhinolophus sinicus), implying that SARS-CoV-2 is not a recently-adapted spill over Chu et al., 2020).

In our own search to resolve the COVID-19 origin question we chose to focus on the provenance of the coronavirus genome sequences BtCoV/4991 and RaTG13, since these are the most closely related sequences to SARS-CoV-2 (98.7% and 96.2% identical respectively). See FIG 1. (reproduced from P. Zhou et al., 2020).

For comparison, the next closest virus to SARS-CoV-2 is RmYN02 (not shown in Fig 1.) (H. Zhou et al., 2020). RmYN02 has an overall similarity to SARS-CoV-2 of 93.2%, making its evolutionary distance from SARS-CoV-2 almost twice as great.

BtCoV/4991 was first described in 2016. It is a 370 nucleotide virus fragment collected from the Mojiang mine in 2013 by the lab of Zeng-li Shi at the WIV (Ge et al., 2016). BtCoV/4991 is 100% identical in sequence to one segment of RaTG13. RaTG13 is a complete viral genome sequence (almost 30,000 nucleotides) that was only published in 2020, after the pandemic began (P. Zhou et al., 2020).

Despite the confusion created by their different names, in a letter obtained by us Zheng-li Shi confirmed to a virology database that BtCoV/4991 and RaTG13 are both from the same bat faecal sample and the same mine. They are thus sequences from the same virus. In the discussion below we will refer primarily to RaTG13 and specify BtCoV/4991 only as necessary.

These specifics are important because it is these samples and their provenance that we believe are ultimately key to unravelling the mystery of the origins of COVID-19.

The story begins in April 2012 when six workers in that same Mojiang mine fell ill from a mystery illness while removing bat faeces. Three of the six subsequently died.

In a March 2020 interview with Scientific American Zeng-li Shi dismissed the significance of these deaths, claiming the miners died of fungal infections. Indeed, no miners or deaths are mentioned in the paper published by the Shi lab documenting the collection of RaTG13 (Ge et al., 2016).

But Shis assessment does not tally with any other contemporaneous accounts of the miners and their illness (Rahalkar and Bahulikar, 2020). As these authors have pointed out, Sciencemagazine wrote up part of the incident in 2014 as A New Killer Virus in China?. Science was citing a different team of virologists who found a paramyxovirus in rats from the mine. These virologists told Science they found no direct relationship between human infection and their virus. This expedition was later published as the discovery of a new virus called MojV after Mojiang, the locality of the mine (Wu et al., 2014).

What this episode suggests though is that these researchers were looking for a potentially lethal virus and not a lethal fungus. Also searching the Mojiang mine for a virus at around the same time was Canping Huang, the author of a PhD thesis carried out under the supervision of George Gao, the head of the Chinese CDC.

All of this begs the question of why the Shi lab, which has no interest in fungi but a great interest in SARS-like bat coronaviruses, also searched the Mojiang mine for bat viruses on four separate occasions between August 2012 and July 2013, even though the mine is a 1,000 Km from Wuhan (Ge et al., 2016). These collecting trips began while some of the miners were still hospitalised.

Fortunately, a detailed account of the miners diagnoses and treatments exists. It is found in a Masters thesis written in Chinese in May 2013. Its suggestive English title is The Analysis of 6 Patients with Severe Pneumonia Caused by Unknown viruses.

The original English version of the abstractimplicates a SARS-like coronavirus as the probable causative agent and that the mine had a lot of bats and bats feces.

The six ill miners were admitted to the No. 1. School of Clinical Medicine, Kunming Medical University, in short succession in late April and early May 2012. Kunming is the capital of Yunnan province and 250 Km from Mojiang.

Of the descriptions of the miners and their treatments, which include radiographs and numerous CAT scans, several features stand out:

1) From their admission to the hospital their doctors informed the medical office of a potential outburst of disease i.e. a potential epidemic outbreak. Thus, the miners were treated for infections and not as if they had inhaled noxious gases or other toxins.

2) The symptoms (on admission) of the six miners were: a) dry cough, b) sputum, c) high fevers, especially shortly before death d) difficulty breathing, e) myalgia (sore limbs). Some patients had hiccoughs and headaches. (See Table 1).

3) Clinical work established that patients 1-4 had low blood oxygen for sure it was ARDS (Acute Respiratory Distress Syndrome) and immune damage considered indicative of viral infection. Additionally, a tendency for thrombosis was noted in patients 2 and 4. Symptom severity and mortality were age-related (though from a sample of 6 this must be considered anecdotal).

4) Potential common and rare causes of their symptoms were tested for and mostly eliminated. For patients 3 and 4 these included tests for HIV, Cytomegalovirus, Epstein-Barr Virus (EBV), Japanese encephalitis, haemorrhagic fever, Dengue, Hepatitis B, SARS, and influenza. Of these, only patient 2 tested positive for Hepatitis and EBV.

5) Treatment of the six patients included ventilation (patients 2-4), steroids (all patients), antivirals (all except patient 5), and blood thinners (patients 2 and 4). Antibiotics and antifungal medications were administered to counter what were considered secondary (but significant) co-infections.

6) A small number of remote meetings were held with researchers at other universities. One was with Zhong Nanshan at Sun Yat-Sen University, Guangdong. Zhong is the Chinese hero of the SARS epidemic, a virologist, and arguably the most famous scientist in China.

7) Samples from the miners were later sent to the WIV in Wuhan and to Zhong Nanshan, further confirming that viral disease was strongly suspected. Some miners did test positive for coronavirus (the thesis is unclear on how many).

8) The source of infection was concluded to be Rhinolophus sinicus, a horseshoe bat and the ultimate conclusion of the thesis reads the unknown virus lead to severe pneumonia could be: The SARS-like-CoV from the Chinese rufous horseshoe bat. Thus the miners had a coronavirus but it apparently was not SARS itself.

These findings of the thesis are significant in several ways.

First, in the light of the current coronavirus pandemic it is evident the miners symptoms very closely resemble those of COVID-19 (Huang et al, 2020; Tay et al., 2020; M. Zhou et al., 2020). Anyone presenting with them today would immediately be assumed to have COVID-19. Likewise, many of the treatments given to the miners have become standard for COVID-19 (Tay et al., 2020).

Second, the remote meeting with Zhong Nanshan is significant. It implies that the illnesses of the six miners were of high concern and, second, that a SARS-like coronavirus was considered a likely cause.

Third, the abstract, the conclusions, and the general inferences to be made from the Masters thesis contradict Zheng-li Shis assertion that the miners died from a fungal infection. Fungal infection as a potential primary cause was raised but largely discarded.

Fourth, if a SARS-like coronavirus was the source of their illness the implication is that it could directly infect human cells. This would be unusual for a bat coronavirus (Ge et al., 2013). People do sometimes get ill from bat faeces but the standard explanation is histoplasmosis, a fungal infection and not a virus (McKinsey and McKinsey, 2011; Pan et al., 2013).

Fifth, the sampling by the Shi lab found that bat coronaviruses were unusually abundant in the mine (Ge at al., 2016). Among their findings were two betacoronaviruses, one of which was RaTG13 (then known as BtCoV/4991). In the coronavirus world betacoronaviruses are special in that both SARS and MERS, the most deadly of all coronaviruses, are both betacoronaviruses. Thus they are considered to have special pandemic potential, as the concluding sentence of the Shi lab publication which found RaTG13 implied: special attention should particularly be paid to these lineages of coronaviruses (Ge at al., 2016). In fact, the Shi and other labs have for years been predicting that bat betacoronaviruses like RaTG13 would go pandemic; so to find RaTG13 where the miners fell ill was a scenario in perfect alignment with their expectations.

How does the Masters thesis inform the search for a plausible origin of the pandemic?

In our previous article we briefly discussed how the pandemic might have been caused either by a virus collection accident, or through viral passaging, or through genetic engineering and a subsequent lab escape. The genetic engineering possibility deserves attention and is extensively assessed in an important preprint (Segreto and Deigin, 2020).

We do not definitively rule out these possibilities. Indeed it now seems that the Shi lab at the WIV did not forget about RaTG13 but were sequencing its genome in 2017 and 2018. However, we believe that the Masters thesis indicates a much simpler explanation.

We suggest, first, that inside the miners RaTG13 (or a very similar virus) evolved into SARS-CoV-2, an unusually pathogenic coronavirus highly adapted to humans. Second, that the Shi lab used medical samples taken from the miners and sent to them by Kunming University Hospital for their research. It was this human-adapted virus, now known as SARS-CoV-2, that escaped from the WIV in 2019.

We refer to this COVID-19 origin hypothesis as the Mojiang Miners Passage (MMP) hypothesis.

Passaging is a standard virological technique for adapting viruses to new species, tissues, or cell types. It is normally done by deliberately infecting a new host species or a new host cell type with a high dose of virus. This initial viral infection would ordinarily die out because the hosts immune system vanquishes the ill-adapted virus. But, in passaging, before it does die out a sample is extracted and transferred to a new identical tissue, where viral infection restarts. Done iteratively, this technique (called serial passaging or just passaging) intensively selects for viruses adapted to the new host or cell type (Herfst et al., 2012).

At first glance RaTG13 is unlikely to have evolved into SARS-CoV-2 since RaTG13 is approximately 1,200 nucleotides (3.8%) different from SARS-CoV-2. Although RaTG13 is the most closely related virus to SARS-CoV-2, this sequence difference still represents a considerable gap. In a media statement evolutionary virologist Edward Holmes has suggested this gap represents 20-50 years of evolution and others have suggested similar figures.

We agree that ordinary rates of evolution would not allow RaTG13 to evolve into SARS-CoV-2 but we also believe that conditions inside the lungs of the miners were far from ordinary. Five major factors specific to the hospitalised miners favoured a very high rate of evolution inside them.

i) When viruses infect new species they typically undergo a period of very rapid evolution because the selection pressure on the invading pathogen is high. The phenomenon of rapid evolution in new hosts is well attested among corona- and other viruses (Makino et al., 1986; Baric et al., 1997; Dudas and Rambaut 2016; Forni et al., 2017).

ii) Judging by their clinical symptoms such as the CT scans, all the miners infections were primarily of the lungs. This localisation likely occurred initially because the miners were exerting themselves and therefore inhaling the disturbed bat guano deeply. As miners, they may already have had damaged lung tissues (patient 3 had suspected pneumoconiosis) and/or particulate matter was present that irritated the tissues and may have facilitated initial viral entry.

In contrast, standard coronavirus infections are confined to the throat and upper respiratory tract. They do not normally reach the lungs (Perlman and Netland, 2009). Lungs are far larger tissues by weight (kilos vs grammes) than the upper respiratory tract. There was therefore likely a much larger quantity of virus inside the miners than would be the case in an ordinary coronavirus infection.

Comparing a typical coronavirus respiratory tract infection with the extent of infected lungs in the miners from a purely mathematical point of view indicates the potential scale of this quantitative difference. The human aerodigestive tract is approximately 20cm in length and 5cm in circumference, i.e. approximately 100 cm2 in surface area. The surface area of a human lung ranges from 260,000-680,000 cm2 (Hasleton, 1972). The amount of potentially infected tissue in an average lung is therefore approximately 4500-fold greater than that available to a normal coronavirus infection. The amount of virus present in the infected miners, sufficient to hospitalise all of them and kill half of them, was thus proportionately very large.

Evolutionary change is in large part a function of the population size. The lungs of the miners, we suggest, supported a very high viral load leading to proportionately rapid viral evolution.

Furthermore, according to the Masters thesis, the immune systems of the miners were compromised and remained so even for those discharged. This weakness on the part of the miners may also have encouraged evolution of the virus.

iii) The length of infection experienced by the miners (especially patients 2, 3 and 4) far exceeded that of an ordinary coronavirus infection. From first becoming too sick to work in the mine, patient 2 survived 57 days until he died. Patient 3 survived 120 days after stopping work. Patient 4 survived 117 days and then was discharged as cured. Each had been exposed in the mine for 14 days prior to the onset of severe symptoms; thus each presumably had nascent infections for some time before calling in sick (See Table 2 of the thesis).

In contrast, in ordinary coronavirus infections the viral infection is cleared within about ten to fourteen days after being acquired (Tay et al., 2020). Thus, unlike most sufferers from coronavirus infection, the hospitalised miners had very long-term bouts of disease characterised by a continuous high load of virus. In the cases of patients 3 and 4 their illnesses lasted over 4 months.

iv) Coronaviruses are well known to recombine at very high rates: 10% of all progeny in a cell can be recombinants (Makino et al., 1986; Banner and Lai, 1991; Dudas and Rambaut, 2016). In normal virus evolution the mutation rate and the selection pressure are the main foci of attention. But in the case of a coronavirus adapting to a new host where many mutations distributed all over the genome are required to fully adapt to the new host, the recombination rate is likely to be highly influential in determining the overall speed of adaptation by the virus population (Baric et al., 1997).

Inside the miners a large tissue was simultaneously infected by a population of poorly-adapted viruses, with each therefore under pressure to adapt. Even if the starting population of virus lacked any diversity, many individual viruses would have acquired mutations independently but only recombination would have allowed these mutations to unite in the same genome. To recombine, viruses must be present in the same cell. In such a situation the particularities of lung tissues become potentially important because the existence of airways (bronchial tubes, etc.) allows partially-adapted viruses from independent viral populations to travel to distal parts of the lung (or even the other lung) and encounter other such partially-adapted viruses and populations. This movement around the lungs would likely have resulted in what amounted to a passaging effect without the need for a researcher to infect new tissues. Indeed, in the Masters thesis the observation is several times made that areas of the lungs of a specific patient would appear to heal even while other parts of the lungs would become infected.

v) There were also a number of unusual things about the bat coronaviruses in the mine. They were abnormally abundant but also there were many different kinds, often causing co-infections of the bats (Ge et al., 2016). Viral co-infections are often more infectious or more pathogenic (Latham and Wilson, 2007).

As the WIV researchers remarked about the bats in the mine:

we observed a high rate of co-infection with two coronavirus species and interspecies infection with the same coronavirus species within or across bat families. These phenomena may be owing to the diversity and high density of bat populations in the same cave, facilitating coronavirus intra- and interspecies transmissions, which may result in recombination and acceleration of coronavirus evolution. (Ge et al., 2016).

The diversity of coronaviruses in the mine suggests that the miners were similarly exposed and that their illness may potentially have begun as co-infections.

Combining these observations, we propose that the miners lungs offered an unprecedented opportunity for accelerated evolution of a highly bat-adapted coronavirus into a highly human-adapted coronavirus and that decades of ordinary coronavirus evolution could easily have been condensed into months. However, we acknowledge that these conditions were unique. They and their scale have no exact scientific precedent we can refer to and they would be hard to replicate in a lab; thus it is important to emphasize that our proposal is fully consistent with the underlying principles of viral evolution as understood today.

In support of the MMP theory we also know something about the samples taken from the miners. According to the Masters thesis, samples were taken from patients for scientific research and blood samples (at least) were sent to the WIV.

In the later stage we worked with Dr. Zhong Nan Shan and did some sampling. The patient* tested positive for serum IgM by the WuHan Institute of Virology. It suggested the existence of virus infection (p62 in the section Comprehensive Analysis.)

(*The original does not specify the number of patients tested.)

The Masters thesis also states its regret that no samples for research were taken from patients 1 and 2, implying that samples were taken from all the others.

We further know that, on June 27th, 2012, the doctors performed an unexplained thymectomy on patient 4. The thymus is an immune organ that can potentially be removed without greatly harming the patient and it could have contained large quantities of virus. Beyond this the Masters thesis is unfortunately unclear on the specifics of what sampling was done, for what purpose, and where each particular sample went.

Given the interests of the Shi lab in zoonotic origins of human disease, once such a sample was sent to them, it would have been obvious and straightforward for them to investigate how a virus from bats had managed to infect these miners. Any viruses recoverable from the miners would likely have been viewed by them as a unique natural experiment in human passaging offering unprecedented and otherwise-impossible-to-obtain insights into how bat coronaviruses can adapt to humans.

The logical course of such research would be to sequence viral RNA extracted directly from unfrozen tissue or blood samples and/or to generate live infectious clones for which it would be useful (if not imperative) to amplify the virus by placing it in human cell culture. Either technique could have led to accidental infection of a lab researcher.

Our supposition as to why there was a time lag between sample collection (in 2012/2013) and the COVID-19 outbreak is that the researchers were awaiting BSL-4 lab construction and certification, which was underway in 2013 but delayed until 2018.

We propose that, when frozen samples derived from the miners were eventually opened in the Wuhan lab they were already highly adapted to humans to an extent possibly not anticipated by the researchers. One small mistake or mechanical breakdown could have led directly to the first human infection in late 2019.

Thus, one of the miners, most likely patient 3, or patient 4 (whose thymus was removed), was effectively patient zero of the COVID-19 epidemic. In this scenario, COVID-19 is not an engineered virus; but, equally, if it had not been taken to Wuhan and no further molecular research had been performed or planned for it then the virus would have died out from natural causes, rather than escaped to initiate the COVID-19 pandemic.

Our proposal is consistent with all the principal undisputed facts concerning SARS-CoV-2 and its origin. The MMP proposal has the additional benefit of reconciling many observations concerning SARS-CoV-2 that have proven difficult to reconcile with any natural zoonotic hypothesis.

For instance, using different approaches, numerous researchers have concluded that the SARS-CoV-2 spike protein has a very high affinity for the human ACE2 receptor (Walls et al., 2020; Piplani et al., 2020; Shang and Ye et al., 2020; Wrapp et al., 2020). Such exceptional affinities, ten to twenty times as great as that of the original SARS virus, do not arise at random, making it very hard to explain in any other way than for the virus to have been strongly selected in the presence of a human ACE2 receptor (Piplani et al., 2020).

In addition to this, a recent report found that the spike of RaTG13 binds the human ACE2 receptor (Shang and Ye et al., 2020). We proposed above that the virus in the mine directly infected humans lung cells. The main determinant of cell infection and species specificity of coronaviruses is initial receptor binding (Perlman and Netland, 2009). Thus RaTG13, unlike most bat coronaviruses, probably can enter and infect human cells, providing biological plausibility to the idea that the miners became infected with a coronavirus resembling RaTG13.

Moreover, the receptor binding domain (RBD) of SARS-CoV-2, which is the region of the spike that physically contacts the human ACE2 receptor, has recently been crystallised to reveal its spatial structure (Shang and Ye et al., 2020). These authors found close structural similarities between the spikes of SARS-CoV-2 and RaTG13 in how they bound the human ACE2 receptor:

Second, as with SARS-CoV-2, bat RaTG13 RBM [a region of the RBD] contains a similar four-residue motif in the ACE2 binding ridge, supporting the notion that SARS-CoV-2 may have evolved from RaTG13 or a RaTG13-related bat coronavirus (Extended Data Table 3 and Extended Data Fig. 7). Third, the L486F, Y493Q and D501N residue changes from RaTG13 to SARS CoV-2 enhance ACE2 recognition and may have facilitated the bat-to-human transmission of SARS-CoV-2 (Extended Data Table 3 and Extended Data Fig. 7). A lysine-to-asparagine mutation at the 479 position in the SARS-CoV-2 RBD (corresponding to the 493 position in the SARS-CoV-2 RBD) enabled SARS-CoV to infect humans. Fourth, Leu455 contributes favourably to ACE2 recognition, and it is conserved between RaTG13 and SARS CoV-2; its presence in the SARS CoV-2 RBM may be important for the bat-to-human transmission of SARS-CoV-2 (Shang and Ye et al., 2020). (italics added)

The significance of this molecular similarity is very great. Coronaviruses have evolved a diverse set of molecular solutions to solve the problem of binding ACE2 (Perlman and Netland, 2009; Forni et al., 2017). The fact that RaTG13 and SARS CoV-2 share the same solution makes RaTG13 a highly likely direct ancestor of Sars-CoV-2.

A further widely noted feature of SARS-CoV-2 is its furin site (Coutard et al., 2020). This site is absent from RaTG13 and other closely related coronaviruses. The most closely related virus with such a site is the highly lethal MERS (which broke out in 2012). Possession of a furin site enables SARS-CoV-2 (like MERS) to infect lungs and many other body tissues (such as the gastrointestinal tract and neurons), explaining much of its lethality (Hoffman et al., 2020; Lamers et al., 2020). However, no convincing explanation for how SARS-CoV-2 acquired this site has yet been offered. Our suggestion is that it arose due to the high selection pressure which existed in the miners lungs and which in general worked to ensure that the virus became highly adapted to the lungs. This explanation, which encompasses how SARS-CoV-2 came to target lung tissues in general, is an important aspect of our proposal.

The implication is therefore that the furin site was not acquired by recombination with another coronavirus and simply represents convergent evolution (as suggested by Andersen et al., 2020).

An intriguing alternative possibility is that SARS-CoV-2 acquired its furin site directly from the miners lungs. Humans possess an epithelial sodium channel protein called ENaC-a whose furin cleavage site is identical over eight amino acids to SARS-CoV-2 (Anand et al., 2020). ENaC-a protein is present in the same airway epithelial and lung tissues infected by SARS-CoV-2. It is known from plants that positive-stranded RNA viruses recombine readily with host mRNAs (Greene and Allison, 1994; Greene and Allison, 1996; Lommel and Xiong, 1991; Borja et al., 2007). The same evidence base is not available for positive-stranded animal RNA viruses, (though see Gorbalenya, 1992) but if plant viruses are a guide then acquisition of its furin site via recombination with the mRNA which encodes ENaC-a by SARS-CoV-2 is a strong possibility.

A further feature of SARS-CoV-2 has been the very limited adaptive evolution of its genome since the pandemic began (Zhan et al., 2020; van Dorp et al., 2020; Starr et al., 2020). It is a well-established principle that viruses that jump species undergo accelerated evolutionary change in their new host (e.g. Baric et al., 1997). Thus, SARS and MERS (both coronaviruses) underwent rapid and readily detectable adaptation to their new human hosts (Forni et al., 2017; Dudas and Rambaut, 2016). Such an adaptation period has not been observed for SARS-CoV-2 even though it has now infected many more individuals than SARS or MERS did. This has even led to suggestions that the SARS-CoV-2 virus had a period of cryptic circulation in humans infections that predated the pandemic (Chaw et al., 2020). The sole mutation consistently observed to accumulate across multiple studies is a D614G substitution in the spike protein (e.g. Korber et al., 2020). The numerically largest analysis of SARS-CoV-2 genomes, however, found no evidence at all for adaptive evolution, even for D614G (van Dorp et al., 2020).

The general observation is therefore that Sars-CoV-2 has remained functionally unchanged or virtually so (except for inconsequential genetic changes) since the pandemic began. This is a very important observation. It implies that SARS-CoV-2 is highly adapted across its whole set of component proteins and not just at the spike (Zhan et al., 2020). That is to say, its evolutionary leap to humans was completed before the 2019 pandemic began.

It is hard to imagine an explanation for this high adaptiveness other than some kind of passaging in a human body (Zhan et al., 2020). Not even passaging in human cells could have achieved such an outcome.

More:
A Proposed Origin for SARS-CoV-2 and the COVID-19 Pandemic - CounterPunch

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