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

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“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?

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How the idea of a “transgender contagion” went viral—and caused untold harm

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How the idea of a “transgender contagion” went viral—and caused untold harm


The ROGD paper was not funded by anti-trans zealots. But it arrived at exactly the time people with bad intentions were looking for science to buoy their opinions.

The results were in line with what one might expect given those sources: 76.5% of parents surveyed “believed their child was incorrect in their belief of being transgender.” More than 85% said their child had increased their internet use and/or had trans friends before identifying as trans. The youths themselves had no say in the study, and there’s no telling if they had simply kept their parents in the dark for months or years before coming out. (Littman acknowledges that “parent-child conflict may also explain some of the findings.”) 

Arjee Restar, now an assistant professor of epidemiology at the University of Washington, didn’t mince words in her 2020 methodological critique of the paper. Restar noted that Littman chose to describe the “social and peer contagion” hypothesis in the consent document she shared with parents, opening the door for biases in who chose to respond to the survey and how they did so. She also highlighted that Littman asked parents to offer “diagnoses” of their child’s gender dysphoria, which they were unqualified to do without professional training. It’s even possible that Littman’s data could contain multiple responses from the same parent, Restar wrote. Littman told MIT Technology Review that “targeted recruitment [to studies] is a really common practice.” She also called attention to the corrected ROGD paper, which notes that a pro-gender-­affirming parents’ Facebook group with 8,000 members posted the study’s recruitment information on its page—although Littman’s study was not designed to be able to discern whether any of them responded.

But politics is blind to nuances in methodology. And the paper was quickly seized by those who were already pushing back against increasing acceptance of trans people. In 2014, a few years before Littman published her ROGD paper, Time magazine had put Laverne Cox, the trans actress from Orange Is the New Black, on its cover and declared a “transgender tipping point.” By 2016, bills across the country that aimed to bar trans people from bathrooms that fit their gender identity failed, and one that succeeded, in North Carolina, cost its Republican governor, Pat McCrory, his job.  

Yet by 2018 a renewed backlash was well underway—one that zeroed in on trans youth. The debate about trans youth competing in sports went national, as did a heavily publicized Texas custody battle between a mother who supported her trans child and a father who didn’t. Groups working to further marginalize trans people, like the Alliance Defending Freedom and the Family Research Council, began “printing off bills and introducing them to state legislators,” says Gillian Branstetter, a communications strategist at the American Civil Liberties Union.

The ROGD paper was not funded by anti-trans zealots. But it arrived at exactly the time people with bad intentions were looking for science to buoy their opinions. The paper “laundered what had previously been the rantings of online conspiracy theorists and gave it the resemblance of serious scientific study,” Branstetter says. She believes that if Littman’s paper had not been published, a similar argument would have been made by someone else. Despite its limitations, it has become a crucial weapon in the fight against trans people, largely through online dissemination. “It is astonishing that such a blatantly bad-faith effort has been taken so seriously,” Branstetter says.

Littman plainly rejects that characterization, saying her goal was simply to “find out what’s going on.” “This was a very good-faith attempt,” she says. “As a person I am liberal; I’m pro-LGBT. I saw a phenomenon with my own eyes and I investigated, found that it was different than what was in the scientific literature.” 

One reason for the success of Littman’s paper is that it validates the idea that trans kids are new. But Jules Gill-Peterson, an associate professor of history at Johns Hopkins and author of Histories of the Transgender Child, says that is “empirically untrue.” Trans children have only recently started to be discussed in mainstream media, so people assume they weren’t around before, she says, but “there have been children transitioning for as long as there has been transition-related medical technology,” and children were socially transitioning—living as a different gender without any medical or legal interventions—long before that.

Many trans people are young children when they first observe a dissonance between how they are identified and how they identify. The process of transitioning is never simple, but the explanation of their identity might be.

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Inside the software that will become the next battle front in US-China chip war

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screenshot of KiCad software for circuit board design and prototyping


EDA software is a small but mighty part of the semiconductor supply chain, and it’s mostly controlled by three Western companies. That gives the US a powerful point of leverage, similar to the way it wanted to restrict access to lithography machines—another crucial tool for chipmaking—last month. So how has the industry become so American-centric, and why can’t China just develop its own alternative software? 

What is EDA?

Electronic design automation (also known as electronic computer-aided design, or ECAD) is the specialized software used in chipmaking. It’s like the CAD software that architects use, except it’s more sophisticated, since it deals with billions of minuscule transistors on an integrated circuit.

Screenshot of KiCad, a free EDA software.

JON NEAL/WIKIMEDIA COMMONS

There’s no single dominant software program that represents the best in the industry. Instead, a series of software modules are often used throughout the whole design flow: logic design, debugging, component placement, wire routing, optimization of time and power consumption, verification, and more. Because modern-day chips are so complex, each step requires a different software tool. 

How important is EDA to chipmaking?

Although the global EDA market was valued at only around $10 billion in 2021, making it a small fraction of the $595 billion semiconductor market, it’s of unique importance to the entire supply chain.

The semiconductor ecosystem today can be seen as a triangle, says Mike Demler, a consultant who has been in the chip design and EDA industry for over 40 years. On one corner are the foundries, or chip manufacturers like TSMC; on another corner are intellectual-property companies like ARM, which make and sell reusable design units or layouts; and on the third corner are the EDA tools. All three together make sure the supply chain moves smoothly.

From the name, it may sound as if EDA tools are only important to chip design firms, but they are also used by chip manufacturers to verify that a design is feasible before production. There’s no way for a foundry to make a single chip as a prototype; it has to invest in months of time and production, and each time, hundreds of chips are fabricated on the same semiconductor base. It would be an enormous waste if they were found to have design flaws. Therefore, manufacturers rely on a special type of EDA tool to do their own validation. 

What are the leading companies in the EDA industry?

There are only a few companies that sell software for each step of the chipmaking process, and they have dominated this market for decades. The top three companies—Cadence (American), Synopsys (American), and Mentor Graphics (American but acquired by the German company Siemens in 2017)—control about 70% of the global EDA market. Their dominance is so strong that many EDA startups specialize in one niche use and then sell themselves to one of these three companies, further cementing the oligopoly. 

What is the US government doing to restrict EDA exports to China?

US companies’ outsize influence on the EDA industry makes it easy for the US government to squeeze China’s access. In its latest announcement, it pledged to add certain EDA tools to its list of technologies banned from export. The US will coordinate with 41 other countries, including Germany, to implement these restrictions. 

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Bright LEDs could spell the end of dark skies

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a satellite view of Earth on the hemisphere away from the sun with city lights visible


A global view of Earth assembled from data acquired by the Suomi National Polar-orbiting Partnership (NPP) satellite.

NASA

Specifications in the current proposal provide a starting point for planning, including a color temperature cutoff of 3,000 K in line with Pittsburgh’s dark-sky ordinance, which passed last fall. However, Martinez says that is the maximum, and as they look for consultants, they’ll be taking into account which ones show dark-sky expertise. The city is also considering—budget and infrastructure permitting—a “network lighting management system,” a kind of “smart” lighting that would allow them to control lighting levels and know when there is an outage. 

Martinez says there will be citywide engagement and updates on the status as critical milestones are reached. “We’re in the evaluation period right now,” she says, adding that the next milestone is authorization of a new contract. She acknowledges there is some “passionate interest in street lighting,” and that she too is anxious to see the project come to fruition: “Just because things seem to go quiet doesn’t mean work is not being done.”

While they aren’t meeting with light pollution experts right now, Martinez says the ones they met with during the last proposal round—Stephen Quick and Diane Turnshek of CMU— were “instrumental” in adopting the dark-sky ordinance.


In recent months, Zielinska-Dabkowska says, her “baby” has been the first Responsible Outdoor Light at Night Conference, an international gathering of more than 300 lighting professionals and light pollution researchers held virtually in May. Barentine was among the speakers. “It’s a sign that all of this is really coming along, both as a research subject but also something that attracts the interest of practitioners in outdoor lighting,” he says of the conference.

There is more work to be done, though. The IDA recently released a report summarizing the current state of light pollution research. The 18-page report includes a list of knowledge gaps to be addressed in several areas, including the overall effectiveness of government policies on light pollution. Another is how much light pollution comes from sources other than city streetlights, which a 2020 study found accounted for only 13% of Tucson’s light pollution. It is not clear what makes up the rest, but Barentine suspects the next biggest source in the US and Europe is commercial lighting, such as flashy outdoor LED signs and parking lot lighting. 

Working with companies to reduce light emissions can be challenging, says Clayton Trevillyan, Tucson’s chief building officer. “If there is a source of light inside the building, technically it’s not regulated by the outdoor lighting code, even if it is emitting light outside,” Trevillyan says. In some cases, he says, in order to get around the city’s restrictions, businesses have suspended illuminated signs inside buildings but aimed them outside. 

Light pollution experts generally say there is no substantial evidence that more light amounts to greater safety.

For cities trying to implement a lighting ordinance, Trevillyan says, the biggest roadblocks they’ll face are “irrelevant” arguments, specifically claims that reducing the brightness of outdoor lighting will cut down on advertising revenue and make the city more vulnerable to crime. The key to successfully enforcing the dark-sky rules, he says, is to educate the public and refuse to give in to people seeking exceptions or exploiting loopholes. 

Light pollution experts generally say there is no substantial evidence that more light amounts to greater safety. In Tucson, for example, Barentine says, neither traffic accidents nor crime appeared to increase after the city started dimming its streetlights at night and restricting outdoor lighting in 2017. Last year, researchers at the University of Pennsylvania analyzed crime rates alongside 300,000 streetlight outages over an eight-year period. They concluded there is “little evidence” of any impact on crime rates on the affected streets—in fact, perpetrators seemed to seek out better-lit adjacent streets. Barentine says there is some evidence that “strategically placed lighting” can help decrease traffic collisions. “Beyond that, things get murky pretty quickly,” he says.

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