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“We never created a supervirus.” Ralph Baric explains gain-of-function research.



“We never created a supervirus.” Ralph Baric explains gain-of-function research.

[Baric is referring to a 2015 collaboration with Zhengli Shi of the Wuhan Institute of Virology, or WIV, in China, which created a so-called chimera by combining the “spike” gene from a new bat virus with the backbone of a second virus. The spike gene determines how well a virus attaches to human cells. A detailed discussion of the research to test novel spike genes appears here.]

However, the sequence was repeatedly requested after the covid-19 pandemic emerged, and so after discussion with the NIH and the journal, it was provided to the community. Those who analyzed these sequences stated that it was very different from SARS-CoV-2.

How did that chimeric work on coronaviruses begin?

Around 2012 or 2013, I heard Dr. Shi present at a meeting. [Shi’s team had recently discovered two new coronaviruses in a bat cave, which they named SHC014 and WIV1.] We talked after the meeting. I asked her whether she’d be willing to make the sequences to either the SHC014 or the WIV1 spike available after she published.

And she was gracious enough to send us those sequences almost immediately—in fact, before she’d published. That was her major contribution to the paper. And when a colleague gives you sequences beforehand, coauthorship on the paper is appropriate.

That was the basis of that collaboration. We never provided the chimeric virus sequence, clones, or viruses to researchers at the WIV; and Dr. Shi, or members of her research team, never worked in our laboratory at UNC. No one from my group has worked in WIV laboratories.

And you had developed a reverse-genetics technique that allowed you to synthesize those viruses from the genetic sequence alone?

Yes, but at the time, DNA synthesis costs were expensive—around a dollar per base [one letter of DNA]. So synthesizing a coronavirus genome could cost $30,000. And we only had the spike sequence. Synthesizing just the 4,000-nucleotide spike gene cost $4,000. So we introduced the authentic SHC014 spike into a replication-competent backbone: a mouse-adapted strain of SARS. The virus was viable, and we discovered that it could replicate in human cells.

So is that gain-of-function research? Well, the SARS coronavirus parental strain could replicate quite efficiently in primary human cells. The chimera could also program infection of human cells, but not better than the parental virus. So we didn’t gain any function—rather, we retained function. Moreover, the chimera was attenuated in mice as compared to the parental mouse-adapted virus, so this would be considered a loss of function.

One of the knocks against gain-of-function research—including this research—is that the work has little practical value. Would you agree?

Well, by 2016, using chimeras and reverse genetics, we had identified enough high-risk SARS-like coronaviruses to be able to test and identify drugs that have broad-based activity against coronaviruses. We identified remdesivir as the first broad-based antiviral drug that worked against all known coronaviruses, and published on it in 2017. It immediately was entered into human trials and became the first FDA-approved drug for treating covid-19 infections globally. A second drug, called EIDD-2801, or molnupiravir, was also shown to be effective against all known coronaviruses prior to the 2020 pandemic, and then shown to work against SARS-CoV-2 by March 2020.

Consequently, I disagree. I would ask critics if they had identified any broad-spectrum coronavirus drugs prior to the pandemic. Can they point to papers from their laboratories documenting a strategic approach to develop effective pan-coronavirus drugs that turned out to be effective against an unknown emerging pandemic virus?

Unfortunately, remdesivir could only be delivered by intravenous injection. We were moving toward an oral-based delivery formulation, but the covid-19 pandemic emerged. I really wish we’d had an oral-based drug early on. That’s the game-changer that would help people infected in the developing world, as well as citizens in the US.

Molnupiravir is an oral medication, and phase 3 trials demonstrate rapid control of viral infection. It’s been considered for emergency-use authorization in India.

Finally, the work also supported federal policy decisions that prioritized basic and applied research on coronaviruses.

What about vaccines?

Around 2018 to 2019, the Vaccine Research Center at NIH contacted us to begin testing a messenger-RNA-based vaccine against MERS-CoV [a coronavirus that sometimes spreads from camels to humans]. MERS-CoV has been an ongoing problem since 2012, with a 35% mortality rate, so it has real global-health-threat potential.

By early 2020, we had a tremendous amount of data showing that in the mouse model that we had developed, these mRNA spike vaccines were really efficacious in protecting against lethal MERS-CoV infection. If designed against the original 2003 SARS strain, it was also very effective. So I think it was a no-brainer for NIH to consider mRNA-based vaccines as a safe and robust platform against SARS-CoV-2 and to give them a high priority moving forward.

Most recently, we published a paper showing that multiplexed, chimeric spike mRNA vaccines protect against all known SARS-like virus infections in mice. Global efforts to develop pan-sarbecoronavirus vaccines [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] will require us to make viruses like those described in the 2015 paper.

So I would argue that anyone saying there was no justification to do the work in 2015 is simply not acknowledging the infrastructure that contributed to therapeutics and vaccines for covid-19 and future coronaviruses.

The work only has value if the benefits outweigh the risks. Are there safety standards that should be applied to minimize those risks?

Certainly. We do everything at BSL-3 plus. The minimum requirements at BSL-3 would be an N95 mask, eye protection, gloves, and a lab coat, but we actually wear impervious Tyvek suits, aprons, and booties and are double-gloved. Our personnel wear hoods with PAPRs [powered air-purifying respirators] that supply HEPA-filtered air to the worker. So not only are we doing all research in a biological safety cabinet, but we also perform the research in a negative-pressure containment facility, which has lots of redundant features and backups, and each worker is encased in their own private personal containment suit.

Another thing we do is to run emergency drills with local first responders. We also work with the local hospital. With many laboratory infections, there’s actually no known event that caused that infection to occur. And people get sick, right? You have to have medical surveillance plans in place to rapidly quarantine people at home, to make sure they have masks and communicate regularly with a doctor on campus.

Is all that standard for other facilities in the US and internationally?

No, I don’t think so. Different places have different levels of BSL-3 containment operations, standard operating procedures, and protective gear. Some of it is dependent on how deep your pockets are and the pathogens studied in the facility. An N95 is a lot cheaper than a PAPR.

Internationally, the US has no say over what biological safety conditions are used in China or any other sovereign nation to conduct research on viruses, be they coronaviruses or Nipah, Hendra, or Ebola.

The Wuhan Institute of Virology was making chimeric coronaviruses, using techniques similar to yours, right?

Let me make it clear that we never sent any of our molecular clones or any chimeric viruses to China. They developed their own molecular clone, based on WIV1, which is a bat coronavirus. And into that backbone they shuffled in the spike genes of other bat coronaviruses, to learn how well the spike genes of these strains can promote infection in human cells.

Would you call that gain-of-function?

A committee at NIH makes determinations of gain-of-function research. The gain-of-function rules are focused on viruses of pandemic potential and experiments that intend to enhance the transmissibility or pathogenesis of SARS, MERS, and avian flu strains in humans. WIV1 is approximately 10% different from SARS. Some argue that “SARS coronavirus” by definition covers anything in the sarbecoronavirus genus. By this definition, the Chinese might be doing gain-of-function experiments, depending on how the chimera behaves. Others argue that SARS and WIV1 are different, and as such the experiments would be exempt. Certainly, the CDC considers SARS and WIV1 to be different viruses. Only the SARS coronavirus from 2003 is a select agent. Ultimately, a committee at the NIH is the final arbiter and makes the decision about what is or is not a gain-of-function experiment.

Definitions aside, we know they were doing the work in BSL-2 conditions, which is a much lower safety level than your BSL-3 plus.

Historically, the Chinese have done a lot of their bat coronavirus research under BSL-2 conditions. Obviously, the safety standards of BSL-2 are different than BSL-3, and lab-acquired infections occur much more frequently at BSL-2. There is also much less oversight at BSL-2.

This year, a joint commission of the World Health Organization and China said it was extremely unlikely that a lab accident had caused SARS-CoV-2. But you later signed a letter with other scientists calling for a thorough investigation of all possible causes. Why was that?

One of the reasons I signed the letter in Science was that the WHO report didn’t really discuss how work was done in the WIV laboratory, or what data the expert panel reviewed to come to the conclusion that it was “very unlikely” that a laboratory escape or infection was the cause of the pandemic.

There must be some recognition that a laboratory infection could have occurred under BSL-2 operating conditions. Some unknown viruses pooled from guano or oral swabs might replicate or recombine with others, so you could get new strains with unique and unpredictable biological features.

And if all this research is being performed at BSL-2, then there are questions that need to be addressed. What are the standard operating procedures in the BSL-2? What are the training records of the staff? What is the history of potential exposure events in the lab, and how were they reviewed and resolved? What are the biosafety procedures designed to prevent potential exposure events?


The hunter-gatherer groups at the heart of a microbiome gold rush



The hunter-gatherer groups at the heart of a microbiome gold rush

The first step to finding out is to catalogue what microbes we might have lost. To get as close to ancient microbiomes as possible, microbiologists have begun studying multiple Indigenous groups. Two have received the most attention: the Yanomami of the Amazon rainforest and the Hadza, in northern Tanzania. 

Researchers have made some startling discoveries already. A study by Sonnenburg and his colleagues, published in July, found that the gut microbiomes of the Hadza appear to include bugs that aren’t seen elsewhere—around 20% of the microbe genomes identified had not been recorded in a global catalogue of over 200,000 such genomes. The researchers found 8.4 million protein families in the guts of the 167 Hadza people they studied. Over half of them had not previously been identified in the human gut.

Plenty of other studies published in the last decade or so have helped build a picture of how the diets and lifestyles of hunter-gatherer societies influence the microbiome, and scientists have speculated on what this means for those living in more industrialized societies. But these revelations have come at a price.

A changing way of life

The Hadza people hunt wild animals and forage for fruit and honey. “We still live the ancient way of life, with arrows and old knives,” says Mangola, who works with the Olanakwe Community Fund to support education and economic projects for the Hadza. Hunters seek out food in the bush, which might include baboons, vervet monkeys, guinea fowl, kudu, porcupines, or dik-dik. Gatherers collect fruits, vegetables, and honey.

Mangola, who has met with multiple scientists over the years and participated in many research projects, has witnessed firsthand the impact of such research on his community. Much of it has been positive. But not all researchers act thoughtfully and ethically, he says, and some have exploited or harmed the community.

One enduring problem, says Mangola, is that scientists have tended to come and study the Hadza without properly explaining their research or their results. They arrive from Europe or the US, accompanied by guides, and collect feces, blood, hair, and other biological samples. Often, the people giving up these samples don’t know what they will be used for, says Mangola. Scientists get their results and publish them without returning to share them. “You tell the world [what you’ve discovered]—why can’t you come back to Tanzania to tell the Hadza?” asks Mangola. “It would bring meaning and excitement to the community,” he says.

Some scientists have talked about the Hadza as if they were living fossils, says Alyssa Crittenden, a nutritional anthropologist and biologist at the University of Nevada in Las Vegas, who has been studying and working with the Hadza for the last two decades.

The Hadza have been described as being “locked in time,” she adds, but characterizations like that don’t reflect reality. She has made many trips to Tanzania and seen for herself how life has changed. Tourists flock to the region. Roads have been built. Charities have helped the Hadza secure land rights. Mangola went abroad for his education: he has a law degree and a master’s from the Indigenous Peoples Law and Policy program at the University of Arizona.

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The Download: a microbiome gold rush, and Eric Schmidt’s election misinformation plan



The Download: a microbiome gold rush, and Eric Schmidt’s election misinformation plan

Over the last couple of decades, scientists have come to realize just how important the microbes that crawl all over us are to our health. But some believe our microbiomes are in crisis—casualties of an increasingly sanitized way of life. Disturbances in the collections of microbes we host have been associated with a whole host of diseases, ranging from arthritis to Alzheimer’s.

Some might not be completely gone, though. Scientists believe many might still be hiding inside the intestines of people who don’t live in the polluted, processed environment that most of the rest of us share. They’ve been studying the feces of people like the Yanomami, an Indigenous group in the Amazon, who appear to still have some of the microbes that other people have lost. 

But there is a major catch: we don’t know whether those in hunter-gatherer societies really do have “healthier” microbiomes—and if they do, whether the benefits could be shared with others. At the same time, members of the communities being studied are concerned about the risk of what’s called biopiracy—taking natural resources from poorer countries for the benefit of wealthier ones. Read the full story.

—Jessica Hamzelou

Eric Schmidt has a 6-point plan for fighting election misinformation

—by Eric Schmidt, formerly the CEO of Google, and current cofounder of philanthropic initiative Schmidt Futures

The coming year will be one of seismic political shifts. Over 4 billion people will head to the polls in countries including the United States, Taiwan, India, and Indonesia, making 2024 the biggest election year in history.

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Navigating a shifting customer-engagement landscape with generative AI



Navigating a shifting customer-engagement landscape with generative AI

A strategic imperative

Generative AI’s ability to harness customer data in a highly sophisticated manner means enterprises are accelerating plans to invest in and leverage the technology’s capabilities. In a study titled “The Future of Enterprise Data & AI,” Corinium Intelligence and WNS Triange surveyed 100 global C-suite leaders and decision-makers specializing in AI, analytics, and data. Seventy-six percent of the respondents said that their organizations are already using or planning to use generative AI.

According to McKinsey, while generative AI will affect most business functions, “four of them will likely account for 75% of the total annual value it can deliver.” Among these are marketing and sales and customer operations. Yet, despite the technology’s benefits, many leaders are unsure about the right approach to take and mindful of the risks associated with large investments.

Mapping out a generative AI pathway

One of the first challenges organizations need to overcome is senior leadership alignment. “You need the necessary strategy; you need the ability to have the necessary buy-in of people,” says Ayer. “You need to make sure that you’ve got the right use case and business case for each one of them.” In other words, a clearly defined roadmap and precise business objectives are as crucial as understanding whether a process is amenable to the use of generative AI.

The implementation of a generative AI strategy can take time. According to Ayer, business leaders should maintain a realistic perspective on the duration required for formulating a strategy, conduct necessary training across various teams and functions, and identify the areas of value addition. And for any generative AI deployment to work seamlessly, the right data ecosystems must be in place.

Ayer cites WNS Triange’s collaboration with an insurer to create a claims process by leveraging generative AI. Thanks to the new technology, the insurer can immediately assess the severity of a vehicle’s damage from an accident and make a claims recommendation based on the unstructured data provided by the client. “Because this can be immediately assessed by a surveyor and they can reach a recommendation quickly, this instantly improves the insurer’s ability to satisfy their policyholders and reduce the claims processing time,” Ayer explains.

All that, however, would not be possible without data on past claims history, repair costs, transaction data, and other necessary data sets to extract clear value from generative AI analysis. “Be very clear about data sufficiency. Don’t jump into a program where eventually you realize you don’t have the necessary data,” Ayer says.

The benefits of third-party experience

Enterprises are increasingly aware that they must embrace generative AI, but knowing where to begin is another thing. “You start off wanting to make sure you don’t repeat mistakes other people have made,” says Ayer. An external provider can help organizations avoid those mistakes and leverage best practices and frameworks for testing and defining explainability and benchmarks for return on investment (ROI).

Using pre-built solutions by external partners can expedite time to market and increase a generative AI program’s value. These solutions can harness pre-built industry-specific generative AI platforms to accelerate deployment. “Generative AI programs can be extremely complicated,” Ayer points out. “There are a lot of infrastructure requirements, touch points with customers, and internal regulations. Organizations will also have to consider using pre-built solutions to accelerate speed to value. Third-party service providers bring the expertise of having an integrated approach to all these elements.”

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