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Saturday, March 2, 2024

Chafing Against Regulation, Silicon Valley Pivots to Pandemic

Early in the evening on March 19, the prominent Silicon Valley investor and serial entrepreneur Balaji Srinivasan kicked off a tweet storm with a techno-libertarian call to arms:

“To all biotech & tech people: The Manhattan Project for the virus is going to end up being the Palo Alto Project. It’s on us. The state doesn’t have tech talent anymore. Can’t fix that overnight. But we can get them to legalize biomedical innovation with expanded right-to-try.”

Srinivasan did not respond to WIRED’S request for comment, but a subsequent tweet clarified that he was using the term Palo Alto Project to encapsulate the world of venture-backed “tech/biotech” companies that he envisions mobilizing to solve the mysteries of Covid-19 with the same awesome resolve with which J. Robert Oppenheimer and company cracked the atom.

In normal times, an exhortation by one of the Valley’s more extreme apostles of technological triumphalism to relax the biotech regulatory process would be dismissed as typical Silicon Valley “move fast, break things, ask forgiveness later” rhetoric. But these are not normal times. Spurred by an existential threat to society, Silicon Valley startups—and biotech companies in general—are pivoting en masse to address Covid-19. As ICU wards desperately expand their capacity to keep up with the influx of patients and death totals mount, the question of whether the regulatory apparatus can keep pace with biotech seems worth asking.

Over the past two decades the rate of biotechnological progress has been nothing short of breathtaking, fueled most notably by a dramatic fall in the cost of sequencing genomic data (faster than Moore’s law), the development of a suite of tools that enable the direct editing and programming of genetic code (namely Crispr-Cas9), and, most recently, the application of big data analytics and machine learning algorithms to our near-infinitely burgeoning databases of biological information. In this new world of so-called synthetic biology, scientists are no longer limited to what nature hands them on a plate.


We can design, program, and manufacture at scale genetic constructs tailored to do exactly what we want, at a speed unthinkable just a few years ago. Srinivasan is hardly the only observer who sees the challenge of developing treatments, diagnostic tests, and eventually a vaccine for Covid-19 as the perfect opportunity to deploy these new tools. For scientists pushing at the biotechnological frontier, fighting back against the pandemic is a duty they’ve been training their whole lives for.

Srinivasan’s tweet storm included a formidable list of ongoing Covid-19-related tech projects. The roster included synthetic biology startups working on bleeding-edge approaches to antibody discovery and drug manufacturing, two different groups working on coronavirus tests, and a promising potential vaccine in development.

Some of the companies he singled out were nowhere near Palo Alto, and the vaccine development project is actually a collaborative effort between the government and private sector, but Srinivasan’s snapshot of the intersection of biotech, computing, and Covid-19 nevertheless did an effective job of capturing the current moment.

The very first entry on his list, Swiftscale Biologics, a synthetic biology startup founded last year that aims to rapidly mass manufacture antibodies that could be deployed to treat Covid-19 patients, offers an instructive path into both the huge potential of this maturing new world and the regulatory roadblocks that constrain it.

Antibodies are proteins produced by the body’s immune system to target invasive bacteria, viruses, and other malevolent invaders—a home-brewed cure, as it were, for what ails you. As the world waits for a vaccine that could potentially provide prophylactic protection against contracting Covid-19 in the first place, dozens of efforts are underway to locate effective antibodies that could be used in the short term to treat patients who are already suffering from the disease.

Swiftscale is in discussions with Centivax, a San Francisco antibody development company run by the computational immunologist Jacob Glanville (recently, and presciently, featured in the Netflix documentary Pandemic.) Glanville has spent his career perfecting algorithmic and bioengineering methods that vastly speed up the process of finding antibodies. As described in a Medium post by Swiftscale investor Joe Lonsdale, “by combining [Glanville’s] ultra-fast therapeutic engineering with SwiftScale’s ultra-fast manufacturing, we can make a medicine in time for when it is needed most.”

Swiftscale’s technology has yet to be tested in any meaningful commercial sense. But on March 31, Glanville announced that his team had already identified thousands of antibodies he believed had strong potential as treatments for Covid-19. Glanville told WIRED that he is intrigued by Swiftscale’s manufacturing approach but also concerned about how much time it will take to steer their process through what he describes as a cumbersome FDA approval process. “It is a nightmare,” Glanville says. “If we have a medicine right now and we dick around nine months to produce it, you are not talking about having it available to humans until 2021.”

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There are, of course, good reasons to be skeptical about cutting corners when applying new technologies or business models to public health. The Theranos saga, in particular, stands as a case study explaining why it is necessary to have a robust regulatory process guarding against unethical hustlers playing fast and loose in the medical domain. Every call for “legalizing biomedical innovation” has to be balanced against the profit incentives that motivate entrepreneurs. That’s the FDA’s job.

But the FDA isn’t entirely immune from criticism at the moment. The agency has come under particular fire for impeding the rollout of mass testing in the early going of the current crisis, significantly hampering the ability of public health authorities to contain the pandemic. Even the former Trump-appointed FDA commissioner Scott Gottlieb wrote an article for The Wall Street Journal calling for the FDA to pick up the pace.

“This feels to a lot of people like an all-hands-on-deck moment,” says Seth Bannon, cofounder of the venture capital firm Fifty Years, which has investments in 17 different companies that are attempting to address some aspect of the Covid-19 outbreak. “It feels like our World War II.”

Fifty Years is hardly the only venture capital fund with a portfolio of companies scrambling to be Covid-19 relevant. The early stage startup accelerator Y Combinator is touting a list of more than 25 “bio or health care” companies that are addressing the crisis in some fashion. DCVC, a venture capital firm that specializes in deploying what it calls machine learning “deep tech” on a wide variety of fronts, has investments in nearly a dozen more health-care-related companies which could potentially help with Covid 19.

The approaches are all over the map, ranging from the obvious to the seemingly opportunistic. For example, it was not much of a stretch for the DCVC portfolio company AbCellera, which specializes in using artificial intelligence techniques to accelerate therapeutic antibody discovery to apply itself to Covid-19. But the direct-to-consumer digital public health firm Nurx (part of Fifty Years’ portfolio), which started out as a provider of birth control pills and HIV prevention medication and more recently offered at-home testing and treatment for sexually transmitted diseases, ended up looking a little overeager when it announced on March 20 that it would start offering at-home testing for Covid-19, before having to hastily backtrack when the FDA put the kibosh on at-home testing, at least for now.

There can be no doubt that financial self-interest plays a role in the Silicon Valley Covid-19 pivot. An average economic recession is usually dire news for startups that aren’t generating positive cash-flow, but the global economic collapse following in Covid-19’s wake is an extinction-level event. If a fledgling startup can’t find a way to be Covid-19 relevant today, there is a good chance it won’t be around tomorrow.

But it would also be unfair to see self-interest as the sole motivating force behind Silicon Valley’s sudden Covid-19 fixation. Everyone—scientists, programmers, investors—is trying to figure out how to be relevant during this crisis. This seems especially true of scientists who have spent their careers developing new biotechnological techniques. .

A good example is Michael Jewett, one of the cofounders of Swiftscale Biologics, and the director of the Center for Synthetic Biology at Northwestern University. Jewett is a pioneer in the development of what is known as “cell-free” bioengineering, a technique for extracting molecular machinery out of the clunky, imperfectly understood world of the living cell into a more carefully and easily controlled setting for the purpose of tasks such as protein synthesis.

Swiftscale was founded to commercialize a particular approach to cell-free protein manufacturing before Covid-19 was on anyone’s radar, but given the severity of the pandemic, it would be more notable if the company had refrained from joining the fight. “I think we are all redirecting some of our activities,” Jewett says, referring to the larger biotech community, “to think about how we can science this.”

In the case of Glanville, you could argue that his entire life has been leading up to this crisis. As a principal scientist at Pfizer and then as the founder and CEO of his own firm, Glanville has devoted his career to refining algorithmic and bioengineering techniques that help identify promising antibodies for therapeutic purposes. One of the main narrative threads of the documentary Pandemic was his quest for a universal flu vaccine—a single shot that would defend against a relentlessly mutating enemy.

In late January, just days after the documentary debuted on Netflix, Glanville says he was attending the annual Biothreats conference in Washington, DC, when he heard Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, declare that, in all likelihood, the virus could no longer be contained in China.

“I also noticed he wasn’t shaking people’s hands,” Glanville says. “I went upstairs, and I immediately contacted my teams and I had them start working on what became our antibody discovery program for Covid-19.”

Glanville’s team started with five antibodies that were known to neutralize the SARS virus from the outbreak in 2003. (The molecular structure of the original SARS virus is about 75 percent similar to the Covid-19 virus, Glanville says, which made those antibodies a promising starting point.).

Glanville describes what he does as a combination of both big data algorithmic manipulation and traditional physical manipulation of biological materials. On the digital side, his team took the genomic data for their starting antibodies, virtually mutated them into trillions upon trillions of variations, and then used specialized software to analyze the likelihood that any of those mutated versions displayed genetic structures most likely to grapple onto and neutralize Covid-19. The subset of mutated antibodies with the highest likelihood of success were then physically “stitched” together and exposed to the relevant portion of the Covid-19 molecule. It was a “computer-guided wet lab experiment,” Glanville says.

But just as Glanville felt his lab was on the verge of significant progress, the Bay Area’s shelter-in-place order came down. Even though the March 16 order included an exception for biotech companies, Glanville shut down all his commercial work. He was on the verge of closing up shop completely but decided to give his team the option of continuing to work on the Covid-19 project.

“I went home and I went to bed feeling kind of defeated,” Glanville says. “We were so close and it got pulled out from under us right when we might need it. And then the next morning I woke up to an army. All of my people were ‘no, fuck you, we are going to go do this.’ And it actually accelerated things because at that point we really did pivot. The company’s normal operations were shutting down, and we had everybody focusing on this project.”

On March 31, he claimed success. His team had identified antibodies that were binding to the Covid-19 molecule. Taking advantage of a previously existing relationship with the US military, he arranged to send samples of his antibodies to USAMRIID, the Defense Department's medical research lab, for further testing and started trying to figure out his next step. What was the fastest way he could get his antibodies through the initial FDA approval process, into human trials, and mass manufactured?

The major stumbling block, he says, is the FDA Good Manufacturing Process requirement, a set of regulations designed to “assure proper design, monitoring, and control of manufacturing processes and facilities.” 

In what Glanville calls peace time it can take 18 months to get manufacturing approval. In the current crisis environment, the necessary time frame is more like nine months or less. But Glanville says that in theory, Swiftscale could cut the approval process down to just six weeks or so, because its technological approach allows it “to skip a bunch of steps.”

To cover his bases, Glanville has also partnered with a contract research organization whose process has already been approved by the FDA.

“I think [Swiftscale’s] method would be one of the fastest that I’ve been able to find in terms of being able to run GMP,” Glanville says, “but the risk at this point is that they have not yet had that conversation with the FDA to get approval.”

He adds, “My attitude is I just want to work with whoever can get the drug out as quickly as possible.”

Michael Jewett describes Swiftscale’s cell-free engineering approach as “akin to taking a car, opening the hood, pulling the engine out, and then repurposing the engine to do something else.

“We are taking cells,” Jewett says, “we’re ripping off their cell walls, we’re collecting the insides of the cells and then we’re using those outside of the living context to carry out molecular transformations.”

As Jewett explains it, there are numerous drawbacks to working with living cells—not least of which is that they have to be kept alive.

“These organisms have evolved with evolutionary objectives that are oftentimes diametrically opposed to what we as engineers want to do,” Jewett says. “So we are fighting this tug of war between the cell trying to keep itself alive and all of a sudden being stressed out because we are trying to make a recombinant protein therapeutic.”

After a decade of incremental bioengineering improvements, scientists have now figured out how to duplicate the molecular engineering processes that a cell uses to create things like proteins outside of the constraints of a cell. The result is more akin to chemistry than biology, Jewett says. Cell-free engineering reduces the normal processes of living organisms to what he describes as “liquid handling,” which is amenable to automation and large-scale manufacturing.

And while the particular approach to cell-free engineering adopted by Swiftscale has yet to get FDA approval, Jewett says that a company specializing in a different cell-free manufacturing approach, Sutro Biopharma, has already taken cell-free manufactured products into clinical trials and their process has received the FDA’s seal of approval. What Swiftscale is doing, therefore, according to Jewett, is not completely alien to the existing regulatory process. “I think it’s reasonable to expect that cell-free, bio-manufactured therapeutics can be part of the solution to Covid-19,” Jewett says.

The FDA declined to address any specific questions regarding Swiftscale or Centivax, but provided a more general statement via e-mail: “The FDA continues to work across all sectors to expedite the development of numerous, innovative potential prevention and treatment approaches,” wrote Michael Felberbaum from the FDA’s Office of Media Affairs. “We are committed to maximizing our regulatory flexibility and providing regulatory advice, guidance, and technical assistance to all sponsors as quickly as possible—including working to gather the information needed to ensure that the drug or biologic is manufactured consistently from lot to lot.”

Most of the venture capitalists, scientists, and doctors interviewed for this article chose their words carefully when asked if they were dissatisfied with how fast the FDA was moving on Covid-19.

“We’ve actually found that they are incredibly reasonable and thoughtful people,” says Fifty Years’ Seth Bannon.

“There is a natural friction,” says DCVC’s Scott Barclay, “but we always err toward trying to be foot forward while working with the regulators and with our companies and we are getting great progress every single day.”

“We believe that the FDA wants to work with digital health providers to make home testing available,” says Christopher Hall, a doctor with extensive experience in infectious diseases who is one of Nurx’s medical advisers. “I am sure that they have internal reasons for taking the time that they are taking.”

A significant exception to this rule is 8VC’s Joe Lonsdale, which is funding Swiftscale Biologics. On March 30 he published an article on Medium which he says was rejected as an op-ed by several newspapers.

“The FDA has been allowed to inappropriately delay key responses to COVID-19,” wrote Lonsdale, “even with the economy and lives on the line.”

Like Balaji Srinivasan, Lonsdale is part of what for better or worse can be called the Peter Thiel wing of government-skeptical Silicon Valley. Lonsdale started his career as an intern at PayPal, which was cofounded by Thiel, and he and Thiel are both cofounders of Palantir, the data analytics company with deep ties to the defense establishment. So it’s not really that much of a surprise to hear him lash out at the FDA.

But in the context of an overall federal approach to Covid-19 that seems to be significantly lagging that of other nations, and the sheer exigency of the pandemic, there’s a funny way in which Silicon Valley impatience, right now, sounds a little less greedy and a little more appropriate.

“I’m a little concerned about how slowly the FDA is moving,” Lonsdale says. “It’s frustrating to me how they work in this insular way. [Swiftscale’s] whole purpose for existing is to quickly scale these antibody therapeutics and it should be doing this fast. So hopefully we can get something to work there. These things are so risky and you never know for sure, but it’s worth trying.”

In normal times, hearing a Silicon Valley venture capitalist talking about risk in the context of public health would send alarm bells ringing everywhere from Washington to Palo Alto. There’s no getting around the fact that there will always be significant tension between capitalist imperatives and the public health. And there’s certainly no guarantee that Swiftscale or Centivax will succeed in delivering a cure for Covid-19. But it’s also not hard to imagine a future in which the astonishing new capabilities of synthetic biology and bioinformatics are safely deployed in real time to combat threats like an out-of-control global pandemic. The real question is whether that future is now.

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