Inside Scoop: How a DARPA Scientist Helped Usher in a Game-Changing Covid Treatment
Amy Jenkins is a program manager for the Defense Advanced Research Projects Agency's Biological Technologies Office, which runs a project called the Pandemic Prevention Platform.
Amy Jenkins was in her office at DARPA, a research and development agency within the Department of Defense, when she first heard about a respiratory illness plaguing the Chinese city of Wuhan. Because she's a program manager for DARPA's Biological Technologies Office, her colleagues started stopping by. "It's really unusual, isn't it?" they would say.
At the time, China had a few dozen cases of what we now call COVID-19. "We should maybe keep an eye on that," she thought.
Early in 2020, still just keeping watch, she was visiting researchers working on DARPA's Pandemic Prevention Platform (P3), a project to develop treatments for "any known or previously unknown infectious threat," within 60 days of its appearance. "We looked at each other and said, 'Should we be doing something?'" she says.
For projects like P3, groups of scientists—often at universities and private companies—compete for DARPA contracts, and program managers like Jenkins oversee the work. Those that won the P3 bid included scientists at AbCellera Biologics, Inc., AstraZeneca, Duke University, and Vanderbilt University.
At the time Jenkins was talking to the P3 performers, though, they didn't have evidence of community transmission. "We would have to cross that bar before we considered doing anything," she says.
The world soon leapt far over that bar. By the time Jenkins and her team decided P3 should be doing something—with their real work beginning in late February--it was too late to prevent this pandemic. But she could help P3 dig into the chemical foundations of COVID-19's malfeasance, and cut off its roots. That work represents, in fact, her roots.
In late February 2020, DARPA received a single blood sample from a recovered COVID-19 patient, in which P3 researchers could go fishing for antibodies. The day it arrived, Jenkins's stomach roiled. "We get one shot," she thought.
Fighting the Smallest Enemies
Jenkins, who's in her early 40s, first got into germs the way many 90s kids did: by reading The Hot Zone, a novel about a hemorrhagic fever gone rogue. It wasn't exactly the disintegrating organs that hooked her. It was the idea that "these very pathogens that we can't even see can make us so sick and bring us to our knees," she says. Reading about scientists facing down deadly disease, she wondered, "How do these things make you so sick?"
She chased that question in college, majoring in both biomolecular science and chemistry, and later became an antibody expert. Antibodies are proteins that hook to a pathogen to block it from attaching to your cells, or tag it for destruction by the rest of the immune system. Soon, she jumped on the "monoclonal antibodies" train—developing synthetic versions of these natural defenses, which doctors can give to people to help them battle an early-stage infection, and even to prevent an infection from taking root after an exposure.
Jenkins likens the antibody treatments to the old aphorism about fishing: Vaccines teach your body how to fish, but antibodies simply give your body the pesca-fare. While that, as the saying goes, won't feed you for a lifetime, it will last a few weeks or months. Monoclonal antibodies thus are a promising preventative option in the immediate short-term when a vaccine hasn't yet been given (or hasn't had time to produce an immune response), as well as an important treatment weapon in the current fight. After former president Donald Trump contracted COVID-19, he received a monoclonal antibody treatment from biotech company Regeneron.
As for Jenkins, she started working as a DARPA Biological Technologies Office contractor soon after completing her postdoc. But it was a suit job, not a labcoat job. And suit jobs, at first, left Jenkins conflicted, worried about being bored. She'd give it a year, she thought. But the year expired, and bored she was not. Around five years later, in June 2019, the agency hired her to manage several of the office's programs. A year into that gig, the world was months into a pandemic.
The Pandemic Pivot
At DARPA, Jenkins inherited five programs, including P3. P3 works by taking blood from recovered people, fishing out their antibodies, identifying the most effective ones, and then figuring out how to manufacture them fast. Back then, P3 existed to help with nebulous, future outbreaks: Pandemic X. Not this pandemic. "I did not have a crystal ball," she says, "but I will say that all of us in the infectious diseases and public-health realm knew that the next pandemic was coming."
Three days after a January 2020 meeting with P3 researchers, COVID-19 appeared in Seattle, then began whipping through communities. The time had come for P3 teams to swivel. "We had done this," she says. "We had practiced this before." But would their methods stand up to something unknown, racing through the global population? "The big anxiety was, 'Wow, this was real,'" says Jenkins.
While facing down that realness, Jenkins was also managing other projects. In one called PREPARE, groups develop "medical countermeasures" that modulate a person's genetic code to boost their bodies' responses to threats. Another project, NOW, envisions shipping-container-sized factories that can make thousands of vaccine doses in days. And then there's Prometheus—which means "forethought" in Greek, and is the name of the god who stole fire and gave it to humans. Wrapping up as COVID ramped up, Prometheus aimed to identify people who are contagious—with whatever—before they start coughing, and even if they never do.
All of DARPA's projects focus on developing early-stage technology, passing it off to other agencies or industry to put it into operation. The orientation toward a specific goal appealed to Jenkins, as a contrast to academia. "You go down a rabbit hole for years at a time sometimes, chasing some concept you found interesting in the lab," she says. That's good for the human pursuit of knowledge, and leads to later applications, but DARPA wants a practical prototype—stat.
"Dual-Use" Technologies
That desire, though, and the fact that DARPA is a defense agency, present philosophical complications. "Bioethics in the national-security context turns all the dials up to 10+," says Jonathan Moreno, a medical ethicist at the University of Pennsylvania.
While developing antibody treatments to stem a pandemic seems straightforwardly good, all biological research—especially that backed by military money—requires evaluating potential knock-on applications, even those that might come from outside the entity that did the developing. As Moreno put it, "Albert Einstein wasn't thinking about blowing up Hiroshima." Particularly sensitive are so-called "dual-use" technologies—those tools that could be used for both benign and nefarious purposes, or are of interest to both the civilian and military worlds.
Moreno takes Prometheus itself as an example of "dual-use" technology. "Think about somebody wearing a suicide vest. Instead of a suicide vest, make them extremely contagious with something. The flu plus Ebola," he says. "Send them someplace, a sensitive environment. We would like to be able to defend against that"—not just tell whether Uncle Fred is bringing asymptomatic COVID home for Christmas. Prometheus, Jenkins says, had safety in mind from the get-go, and required contenders to "develop a risk mitigation plan" and "detail their strategy for appropriate control of information."
To look at a different program, if you can modulate genes to help healing, you probably know something (or know someone else could infer something) about how to hinder healing. Those sorts of risks are why PREPARE researchers got their own "ethical, legal, and social implications" panel, which meets quarterly "to ensure that we are performing all research and publications in a safe and ethical manner," says Jenkins.
DARPA as a whole, Moreno says, is institutionally sensitive to bioethics. The agency has ethics panels, and funded a 2014 National Academies assessment of how to address the "ethical, legal, and societal issues" around technology that has military relevance. "In the cases of biotechnologies where some of that research brushes up against what could legitimately be considered dual-use, that in itself justifies our investment," says Jenkins. "DARPA deliberately focuses on safety and countermeasures against potentially dangerous technologies, and we structure our programs to be transparent, safe, and legal."
Going Fishing
In late February 2020, DARPA received a single blood sample from a recovered COVID-19 patient, in which P3 researchers could go fishing for antibodies. The day it arrived, Jenkins's stomach roiled. "We get one shot," she thought.
As scientists from the P3-funded AbCellera went through the processes they'd practiced, Jenkins managed their work, tracking progress and relaying results. Soon, the team had isolated a suitable protein: bamlanivimab. It attaches to and blocks off the infamous spike proteins on SARS-CoV-2—those sticky suction-cups in illustrations. Partnering with Eli Lilly in a manufacturing agreement, the biotech company brought it to clinical trials in May, just a few months after its work on the deadly pathogen began, after much of the planet became a hot zone.
On November 10—Jenkins's favorite day at the (home) office—the FDA provided Eli Lilly emergency use authorization for bamlanivimab. But she's only mutedly screaming (with joy) inside her heart. "This pandemic isn't 'one morning we're going to wake up and it's all over,'" she says. When it is over, she and her colleagues plan to celebrate their promethean work. "I'm hoping to be able to do it in person," she says. "Until then, I have not taken a breath."
Pioneering XPRIZEs, Longevity and Mindset with Dr. Peter Diamandis
XPRIZE founder and chairman Peter Diamandis launches XPRIZE Healthspan at an event on November 29.
A new competition by the XPRIZE Foundation is offering $101 million to researchers who discover therapies that give a boost to people aged 65-80 so their bodies perform more like when they were middle-aged.
For today’s podcast episode, I talked with Dr. Peter Diamandis, XPRIZE’s founder and executive chairman. Under Peter’s leadership, XPRIZE has launched 27 previous competitions with over $300 million in prize purses. The latest contest aims to enhance healthspan, or the period of life when older people can play with their grandkids without any restriction, disability or disease. Such breakthroughs could help prevent chronic diseases that are closely linked to aging. These illnesses are costly to manage and threaten to overwhelm the healthcare system, as the number of Americans over age 65 is rising fast.
In this competition, called XPRIZE Healthspan, multiple awards are available, depending on what’s achieved, with support from the nonprofit Hevolution Foundation and Chip Wilson, the founder of Lululemon and nonprofit SOLVE FSHD. The biggest prize, $81 million, is for improvements in cognition, muscle and immunity by 20 years. An improvement of 15 years will net $71 million, and 10 years will net $61 million.
In our conversation for this episode, Peter talks about his plans for XPRIZE Healthspan and why exponential technologies make the current era - even with all of its challenges - the most exciting time in human history. We discuss the best mental outlook that supports a person in becoming truly innovative, as well as the downsides of too much risk aversion. We talk about how to overcome the negativity bias in ourselves and in mainstream media, how Peter has shifted his own mindset to become more positive over the years, how to inspire a culture of innovation, Peter’s personal recommendations for lifestyle strategies to live longer and healthier, the innovations we can expect in various fields by 2030, the future of education and the importance of democratizing tech and innovation.
In addition to Peter’s pioneering leadership of XPRIZE, he is also the Executive Founder of Singularity University. In 2014, he was named by Fortune as one of the “World’s 50 Greatest Leaders.” As an entrepreneur, he’s started over 25 companies in the areas of health-tech, space, venture capital and education. He’s Co-founder and Vice-Chairman of two public companies, Celularity and Vaxxinity, plus being Co-founder & Chairman of Fountain Life, a fully-integrated platform delivering predictive, preventative, personalized and data-driven health. He also serves as Co-founder of BOLD Capital Partners, a venture fund with a half-billion dollars under management being invested in exponential technologies and longevity companies. Peter is a New York Times Bestselling author of four books, noted during our conversation and in the show notes of this episode. He has degrees in molecular genetics and aerospace engineering from MIT and holds an M.D. from Harvard Medical School.
Show links
- Peter Diamandis bio
- New XPRIZE Healthspan
- Peter Diamandis books
- 27 XPRIZE competitions and counting
- Life Force by Peter Diamandis and Tony Robbins
- Peter Diamandis Twitter
- Longevity Insider newsletter – AI identifies the news
- Peter Diamandis Longevity Handbook
- Hevolution funding for longevity
XPRIZE Founder Peter Diamandis speaks with Mehmoud Khan, CEO of Hevolution Foundation, at the launch of XPRIZE Healthspan.
Hevolution Foundation
Matt Fuchs is the editor-in-chief of Leaps.org and Making Sense of Science. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him @fuchswriter.
Important findings are starting to emerge from research on how genes shape the human response to the Covid virus.
From infections with no symptoms to why men are more likely to be hospitalized in the ICU and die of COVID-19, new research shows that your genes play a significant role
Early in the pandemic, genetic research focused on the virus because it was readily available. Plus, the virus contains only 30,000 bases in a dozen functional genes, so it's relatively easy and affordable to sequence. Additionally, the rapid mutation of the virus and its ability to escape antibody control fueled waves of different variants and provided a reason to follow viral genetics.
In comparison, there are many more genes of the human immune system and cellular functions that affect viral replication, with about 3.2 billion base pairs. Human studies require samples from large numbers of people, the analysis of each sample is vastly more complex, and sophisticated computer analysis often is required to make sense of the raw data. All of this takes time and large amounts of money, but important findings are beginning to emerge.
Asymptomatics
About half the people exposed to SARS-CoV-2, the virus that causes the COVID-19 disease, never develop symptoms of this disease, or their symptoms are so mild they often go unnoticed. One piece of understanding the phenomena came when researchers showed that exposure to OC43, a common coronavirus that results in symptoms of a cold, generates immune system T cells that also help protect against SARS-CoV-2.
Jill Hollenbach, an immunologist at the University of California at San Francisco, sought to identify the gene behind that immune protection. Most COVID-19 genetic studies are done with the most seriously ill patients because they are hospitalized and thus available. “But 99 percent of people who get it will never see the inside of a hospital for COVID-19,” she says. “They are home, they are not interacting with the health care system.”
Early in the pandemic, when most labs were shut down, she tapped into the National Bone Marrow Donor Program database. It contains detailed information on donor human leukocyte antigens (HLAs), key genes in the immune system that must match up between donor and recipient for successful transplants of marrow or organs. Each HLA can contain alleles, slight molecular differences in the DNA of the HLA, which can affect its function. Potential HLA combinations can number in the tens of thousands across the world, says Hollenbach, but each person has a smaller number of those possible variants.
She teamed up with the COVID-19 Citizen Science Study a smartphone-based study to track COVID-19 symptoms and outcomes, to ask persons in the bone marrow donor registry about COVID-19. The study enlisted more than 30,000 volunteers. Those volunteers already had their HLAs annotated by the registry, and 1,428 tested positive for the virus.
Analyzing five key HLAs, she found an allele in the gene HLA-B*15:01 that was significantly overrepresented in people who didn’t have any symptoms. The effect was even stronger if a person had inherited the allele from both parents; these persons were “more than eight times more likely to remain asymptomatic than persons who did not carry the genetic variant,” she says. Altogether this HLA was present in about 10 percent of the general European population but double that percentage in the asymptomatic group. Hollenbach and her colleagues were able confirm this in other different groups of patients.
What made the allele so potent against SARS-CoV-2? Part of the answer came from x-ray crystallography. A key element was the molecular shape of parts of the cold virus OC43 and SARS-CoV-2. They were virtually identical, and the allele could bind very tightly to them, present their molecular antigens to T cells, and generate an extremely potent T cell response to the viruses. And “for whatever reasons that generated a lot of memory T cells that are going to stick around for a long time,” says Hollenbach. “This T cell response is very early in infection and ramps up very quickly, even before the antibody response.”
Understanding the genetics of the immune response to SARS-CoV-2 is important because it provides clues into the conditions of T cells and antigens that support a response without any symptoms, she says. “It gives us an opportunity to think about whether this might be a vaccine design strategy.”
Dead men
A researcher at the Leibniz Institute of Virology in Hamburg Germany, Guelsah Gabriel, was drawn to a question at the other end of the COVID-19 spectrum: why men more likely to be hospitalized and die from the infection. It wasn't that men were any more likely to be exposed to the virus but more likely, how their immune system reacted to it
Several studies had noted that testosterone levels were significantly lower in men hospitalized with COVID-19. And, in general, the lower the testosterone, the worse the prognosis. A year after recovery, about 30 percent of men still had lower than normal levels of testosterone, a condition known as hypogonadism. Most of the men also had elevated levels of estradiol, a female hormone (https://pubmed.ncbi.nlm.nih.gov/34402750/).
Every cell has a sex, expressing receptors for male and female hormones on their surface. Hormones docking with these receptors affect the cells' internal function and the signals they send to other cells. The number and role of these receptors varies from tissue to tissue.
Gabriel began her search by examining whole exome sequences, the protein-coding part of the genome, for key enzymes involved in the metabolism of sex hormones. The research team quickly zeroed in on CYP19A1, an enzyme that converts testosterone to estradiol. The gene that produces this enzyme has a number of different alleles, the molecular variants that affect the enzyme's rate of metabolizing the sex hormones. One genetic variant, CYP19A1 (Thr201Met), is typically found in 6.2 percent of all people, both men and women, but remarkably, they found it in 68.7 percent of men who were hospitalized with COVID-19.
Lung surprise
Lungs are the tissue most affected in COVID-19 disease. Gabriel wondered if the virus might be affecting expression of their target gene in the lung so that it produces more of the enzyme that converts testosterone to estradiol. Studying cells in a petri dish, they saw no change in gene expression when they infected cells of lung tissue with influenza and the original SARS-CoV viruses that caused the SARS outbreak in 2002. But exposure to SARS-CoV-2, the virus responsible for COVID-19, increased gene expression up to 40-fold, Gabriel says.
Did the same thing happen in humans? Autopsy examination of patients in three different cites found that “CYP19A1 was abundantly expressed in the lungs of COVID-19 males but not those who died of other respiratory infections,” says Gabriel. This increased enzyme production led likely to higher levels of estradiol in the lungs of men, which “is highly inflammatory, damages the tissue, and can result in fibrosis or scarring that inhibits lung function and repair long after the virus itself has disappeared.” Somehow the virus had acquired the capacity to upregulate expression of CYP19A1.
Only two COVID-19 positive females showed increased expression of this gene. The menopause status of these women, or whether they were on hormone replacement therapy was not known. That could be important because female hormones have a protective effect for cardiovascular disease, which women often lose after going through menopause, especially if they don’t start hormone replacement therapy. That sex-specific protection might also extend to COVID-19 and merits further study.
The team was able to confirm their findings in golden hamsters, the animal model of choice for studying COVID-19. Testosterone levels in male animals dropped 5-fold three days after infection and began to recover as viral levels declined. CYP19A1 transcription increased up to 15-fold in the lungs of the male but not the females. The study authors wrote, “Virus replication in the male lungs was negatively associated with testosterone levels.”
The medical community studying COVID-19 has slowly come to recognize the importance of adipose tissue, or fat cells. They are known to express abundant levels of CYP19A1 and play a significant role as metabolic tissue in COVID-19. Gabriel adds, “One of the key findings of our study is that upon SARS-CoV-2 infection, the lung suddenly turns into a metabolic organ by highly expressing” CYP19A1.
She also found evidence that SARS-CoV-2 can infect the gonads of hamsters, thereby likely depressing circulating levels of sex hormones. The researchers did not have autopsy samples to confirm this in humans, but others have shown that the virus can replicate in those tissues.
A possible treatment
Back in the lab, substituting low and high doses of testosterone in SARS-COV-2 infected male hamsters had opposite effects depending on testosterone dosage used. Gabriel says that hormone levels can vary so much, depending on health status and age and even may change throughout the day, that “it probably is much better to inhibit the enzyme” produced by CYP19A1 than try to balance the hormones.
Results were better with letrozole, a drug approved to treat hypogonadism in males, which reduces estradiol levels. The drug also showed benefit in male hamsters in terms of less severe disease and faster recovery. She says more details need to be worked out in using letrozole to treat COVID-19, but they are talking with hospitals about clinical trials of the drug.
Gabriel has proposed a four hit explanation of how COVID-19 can be so deadly for men: the metabolic quartet. First is the genetic risk factor of CYP19A1 (Thr201Met), then comes SARS-CoV-2 infection that induces even greater expression of this gene and the deleterious increase of estradiol in the lung. Age-related hypogonadism and the heightened inflammation of obesity, known to affect CYP19A1 activity, are contributing factors in this deadly perfect storm of events.
Studying host genetics, says Gabriel, can reveal new mechanisms that yield promising avenues for further study. It’s also uniting different fields of science into a new, collaborative approach they’re calling “infection endocrinology,” she says.