A new idea for how to fight pandemics came to David Fedson as he walked through Lausanne on a sunny spring afternoon in 2004. That a global catastrophe was on Fedson’s mind even as he made his way along the Swiss city’s scenic streets was not unusual. Fedson, who studied medicine at Yale and trained at Johns Hopkins, had served on a number of national vaccination committees in the United States.
Prior to his retirement in 2002, he’d been the director of medical affairs at the now defunct French vaccine company Aventis Pasteur MSD, where he’d helped to launch an international pandemic vaccine supply task force. A global catastrophe had been on his mind for much of the previous 30 years.
If Fedson was uniquely knowledgeable about the importance of vaccines in fighting pandemics, he was also uniquely aware of the limitations of the approach. He knew that the doses of a vaccine needed to fight a deadly new virus, like the H5N1 “bird flu” that had resurfaced in 2003, would far surpass the world’s industrial capacity. Antiviral drugs, if they worked at all, would be in short supply in wealthy countries. Poorer countries would be left to fend for themselves. It wasn’t a problem of molecular biology, Fedson told a biosecurity journal, but of arithmetic.
By 2004, Fedson, now 82, had reached a scientific dead end. But, as he walked through Lausanne, his thoughts rerouted sharply. If it would never be possible to stop a pandemic viral infection with vaccines and antivirals in some countries, maybe the virus itself was the wrong thing to treat. Maybe it made more sense to treat people’s bodies, once they became infected, so that they could withstand whatever the virus had in store for them.
There would never be vaccines available on the first day of a pandemic, at least not for the vast majority of people on the planet, but there were already cheap generic drugs that appeared to act on the very cellular mechanisms that malfunction in deadly respiratory infections. The supply chains needed to distribute these drugs to hundreds of countries were already in place. And the generic drugs were already known to be safe, meaning that if one or more proved effective, it could be rolled out immediately without the risks of unanticipated side effects that come with newer drugs.
One drug might bolster the delicate cells that line the inner surfaces of our blood vessels so that they would leak less fluid into the lungs, another could dampen the overactive immune response, a third might enhance metabolic function throughout the body. The virus would keep landing its blows, but, like a resilient boxer leaning against the ropes, the body would endure for one more round, long enough for its own immune system to win the bout.
Ever since the idea came to him, Fedson, an American who lives in the countryside of Eastern France with his wife, has been a literal voice in the wilderness. He says he has repeatedly discussed his ideas with officials at WHO and the CDC. He has reached out to private charities and has written one scientific article and “letter to the editor” after another, calling for the experiments that would put his idea to the test.
While some generic drugs seem promising based on population and laboratory studies, the randomized clinical trials that could actually determine whether Fedson’s plan could save lives have never been done. Until about a month ago, very few people seemed interested in Fedson’s thinking at all. Then, late last year, some 15 years after Fedson’s memorable walk through Lausanne, people in central China starting dying of a mysterious respiratory illness.
Fedson had been thinking of his plan to fight pandemics by targeting the body with generic drugs in the context of underdeveloped nations, the places that would be least likely to get the vaccines and antivirals in time. But, as Covid-19 has ravaged the globe, the question of whether readily available generic drugs might save lives is newly urgent in every country. Vaccines are said to be 18 months or more away, and the effectiveness of existing antivirals are mostly unknown, although many are being furiously studied. In recent weeks, a number prominent researchers have publicly discussed whether the generic drugs Fedson has been talking about for years might help in the fight against Covid-19.
These drugs, like the blood pressure medication known as an angiotensin receptor blocker and the diabetes treatment metformin, are far from miracle cures. If anything, they are the opposite of miracle cures. They are old, well-studied molecules. If they help at all with Covid-19, they will likely have only a modest effect. But a modest effect could be the difference between life and death for tens of thousands of people.
Some in the scientific community are coming around to Fedson’s thinking. “My gut feeling is that in the end some simple treatment to reduce respiratory crisis might be all we need to reduce mortality,” says Yale’s Ruslan Medzhitov, among the world’s most distinguished immunology researchers. “I don’t think there is a good scientific reason these ideas are not taken seriously.”
Fedson likes to say that to arrive at the right answer, you have to frame your question in the right way. The critical question, he has insisted since his memorable walk in 2004, is what the vast majority of people on earth who lack vaccines and antivirals will be able to turn to on day one of a pandemic. As the death count from Covid-19 rises and the need for effective treatments grows more desperate, another critical question has become harder to ignore: Should we have been listening to David Fedson all along?
In cancer science, Fedson’s distinction between the disease and the tissues of the body where it resides is sometimes explained with the metaphor of “seed and soil.” The phrase is typically attributed to Stephen Paget, a 19th century British physician who noticed something odd while reviewing records of patients with metastatic breast cancer. Cancers of the breast, Paget saw, were far more likely to spread to some organs than others. Of 735 cancer cases Paget reviewed, 241 had spread to the liver but only 17 to the spleen. Breast cancer often ends up in the bones, but never, it seemed, in the bones of the hands or feet. “When a plant goes to seed,” Paget wrote in The Lancet in a brief article on his findings, “its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.”
Paget might have been the first to think of cancer in terms of “seed and soil,” but the metaphor was already in use among the new bacteriologists of the late 19th century. The seeds were not cancer, but bacteria, the newly discovered bacilli that the German scientist Robert Koch was then connecting to one disease after another. Paget’s own paper notes that his cancer findings were supported by thinking on how such invisible organisms spread through our bodies. The “lesions of tuberculosis” Paget wrote, also revealed the “dependence of the seed upon the soil.”
And yet, like cancer scientists, infectious disease specialists of the 20th century would spend little time thinking about the conditions of the soil. The bias against soil-focused thinking can be heard even in Paget’s paper of 1889: “The best work in the pathology of cancer” was being done by those “studying the nature of the seed.” Wrote Paget, “They are like scientific botanists.” Someone like himself, who was merely reviewing records to determine if the soil played a role in the progression of a disease, was merely “a ploughman.”
In the 19th century, when infectious diseases remained mysterious, doctors could do little more than tend to the soil. To fend off infections, people were told to keep sanitary conditions, to follow proper nutrition. But by the early 20th century, a new metaphor had arrived. Even as Paget was busily counting cancers, the famed German scientist Paul Ehrlich was injecting animals with chemical dyes in the hope of targeting specific invaders in the body. Ehrlich called his precision weapons “magic bullets,” a metaphor that has captured the scientific imagination ever since. When, in 1909, he created a bullet that could hit syphilis, the concept of “seed and soil” ended up as collateral damage. Who wanted to be a lowly ploughman in the age of the sniper?
Fedson’s idea of treating the body rather than targeting the virus was soil-focused thinking. That he had returned to an idea from generations past may have been more than a coincidence. His home, in France’s Auvergne-Rhône-Alpes region, is more than three centuries old. When he looks up from his work in his home office, he can see the peak of Mont Blanc through the window.
To this day, Fedson can’t comprehend why almost no one has been interested in his idea of battling pandemics by targeting the body—what researchers refer to as the “host response”—with generic drugs. When he talks about the idea, the exasperation comes out in almost every other sentence. “Why we can’t have the imagination to take advantage of what we’ve already got is just beyond me,” he says.
At least part of the explanation is clear enough. Fedson’s idea is counterintuitive, a bit like telling people that the way to stop a mass shooter is not to shoot back but to wear bulletproof vests until the shooter runs out of bullets. New treatments are hard to test on critically ill patients, and, because no pharmaceutical company stands to make huge profits from a generic drug, there is no financial incentive to test the idea. Another obstacle, Yale’s Medzhitov says, is “the general inertia of clinical science.”
It hasn’t helped Fedson’s case that statins, a class of generic drugs that has been tested as a therapy for acute respiratory illness caused by infections, has shown only mixed results. “The clinical trial data on statins in injured lungs are not promising,” says Warren Lee, a researcher at the University of Toronto who studies how the endothelial cells of the lung’s blood vessels respond to infections.
Fedson continues to believe that statins have not been given a fair test. The study often cited as evidence that statins are unhelpful, he notes, was done on patients who were already on mechanical ventilation for days. “These people were almost on the way to the morgue,” he says.
Still, in the context of Covid-19, Fedson sees more hope in angiotensin receptor blockers, based on the evidence that such drugs can help maintain the cellular barriers between the blood vessels and lung tissue. Preliminary observational evidence from China suggests that elderly adults with elevated blood pressure who were already taking ARBs when they became infected fared better than those with elevated blood pressure who were not taking ARBs.
Such studies, to be sure, are very far from good evidence of an effect. At most, they provide hints as to which drugs might be worthy of clinical trials. Fedson suspects that, if the proper randomized controlled trials are ever done, the most effective therapy might turn out to be a combination of several different generics. In cardiovascular studies, he notes, statins and ARBs together often prove more beneficial than either treatment alone.
Fedson’s frustration notwithstanding, the most surprising part of his story may not be the way in which his thinking failed to gain traction in public health circles but the way in which it slipped into mainstream academic science through a back door. Unbeknownst to Fedson, as he was spending his retirement as a full-time gadfly buzzing about world health officials, a graduate student named Janelle Ayres was arriving at a similar line of thinking by studying actual flies in a microbiology and immunology lab at Stanford.
Ayres is now a physiologist at the Salk Institute, where her lab stands out for its hot-pink decor—it matches the hot-pink lipstick and rubber gloves Ayres favors. She began by injecting thousands of fruit flies carrying different genetic mutations with bacteria and waiting to see which survived the longest. In some cases, she found that one fruit fly would live longer than another even though the two flies had the same amount of bacteria in their bodies. Ayres knew that the flies had the same genes for immune function, meaning that such genes couldn’t explain the difference between the lifespans of the flies.
Ayres went searching through the genomes of the flies for answers. What she found turned our understanding of immunology on its head: The longer-lived flies weren’t better at fighting the bacteria. They were better at living with it. The longer-surviving flies had genes that allowed their bodies to limit tissue damage and maintained bodily functions even as the pathogens inside went about their destructive business. Their immune systems could take a pathological punch.
Ayres published her findings in 2008. A small number of other researchers were arriving at similar findings at approximately the same time. The concept itself, that tolerating an infection, can be an evolutionary-ingrained defense strategy, wasn’t entirely new. It was already well known to botanists. Ayres, who is known for eclectic reading habits, notes that in the late 19th century, botanists had found that some wheat crops were mysteriously better at living with a fungus called leaf rust than others. The new discovery was that the same phenomenon—Ayres now calls it “disease tolerance”—occurs in animals as well.
In Paget’s dichotomy, Ayres is the scientific botanist and the ploughman all in one, an expert on “the seed” who has returned to “the soil.” Much of her works is focused on learning how bacteria and nutrients can enhance the body’s natural tolerance mechanisms so that otherwise dangerous infections might become tolerable. (When Ayres won a prestigious grant in 2018, a newspaper headlined its story, “$1M Award for Salk Scientist Janelle Ayres, Who Befriends Our Microbial Enemies.”)
Ayres was not focused on viral pandemics in the third world when she arrived at the concept of disease tolerance. Nor is she studying the generic drugs that have captured Fedson’s imagination. But if Ayres is not on the front lines of the global health debates, she does not see her work as a scientific abstraction. In 2015, she lost her father to sepsis, a bacterial infection that creates the same type of deadly immune response that is now killing many Covid-19 patients. The aim of her research is to save lives, and her thinking on Covid-19 is entirely in keeping with Fedson’s outlook.
She would like to see treatments that support physiological function and so “buy the patient time” to withstand the infection. “This is what we are currently doing with supportive care—oxygen, ventilators, etc.,” Ayres notes. Drugs that target the body rather than the virus might function in a similar manner.
Both Fedson and Ayres agree on something else as well. Any discussion of how our bodies can be made more resilient must include an appreciation of metabolic function. As Ayres puts it, “We are finding metabolism is what drives disease tolerance.” At the moment, no one can say why two people harboring the same viral load of the new coronavirus experience the infection in dramatically different ways, and there is a wide range of plausible biological explanations. That many younger adults in good health have become severely ill and, in some cases, died suggests that Covid-19 can strike down even the healthiest among us.
And yet, if the preliminary data on Covid-19 patients can be trusted, important clues may be emerging. That children fare much better against the virus than adults is clear, a clue that Fedson calls “gobsmackingly important.” Meanwhile, obesity, diabetes, cardiovascular disease, and high blood pressure appear to be associated with worse outcomes for Covid-19. All of these conditions are classic hallmarks of a condition known as metabolic syndrome, which also happens to be associated with uncontrolled immune responses and a breakdown in the function of the cells of the blood vessel that protect us from infections.
Focusing on broader metabolic health to treat an acute illness like Covid-19 can sound almost laughably anachronistic in the age of magic bullets, but one particular diabetes drug, metformin, which can be purchased for pennies a pill, is increasingly coming up in discussion of Covid-19 as a potential “add-on” to other therapies. (A team of cancer researchers recently announced that in their study of mice, the combination of metformin and either chloroquine or hydroxychloroquine—two malaria drugs now being used as antivirals in the treatment of Covid-19—could be deadly.)
Metformin, already among the most commonly prescribed drugs in the world, lowers blood glucose—elevated blood glucose is also associated with poor outcomes in severe infections. That much is well known. Less well known is that before metformin became a blockbuster diabetes drug it was being used to treat influenza and malaria. And it is used off-label to treat all of the metabolic conditions that appear to make one more likely to die of Covid-19.
Nir Barzilai, the director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, has been studying metformin and marveling over its ability to protect elderly adults from chronic disease for years. “It make sense to concentrate on the offensive plans in the war on Covid-19, that is, treatments against the virus,” Barzilai says. “But, in parallel, we need defensive measures that will allow the older adults to have better immune function and so be resilient to the sickness.” For that reason, added Barzilai, “metformin should be tested.”
Navdeep S. Chandel, a renowned metabolism researcher at Northwestern University, studies how metformin influences cellular metabolism and function. Even if metformin is found to be useful therapy for Covid-19, Chandel explains, it’s not clear that current dosages that are considered safe would be safe or sufficient in the context of intensive care treatment.
Nevertheless, metformin is intriguing as a Covid-19 drug, Chandel says, because it seems able to both help regulate the immune response and protect tissues throughout the body from damage. Particularly, interesting, Chandel says, is recent research in the new field of disease tolerance—the field that Ayres helped to launch. Medzhitov’s lab at Yale found that the difference between how well a body tolerates an infection can be traced to one’s ability to produce a hormone known as GDF-15. “You can see it humans,” Chandel says. “And metformin is one of the drugs that has been shown to increase GDF-15 in humans.”
In theory, metformin could have direct effects on the virus as well. In the face of a pandemic, it is, perhaps, not necessary to know exactly how it works, only if it will work. As Fedson has noted, when Edward Jenner arrived at his smallpox vaccine, he had no way of understanding any of the biological mechanisms at play. All he knew was that it was a sensible idea and that it saved lives. Sixteen years after David Fedson had his own idea while strolling through Lausanne, it would be helpful to know if it might do the same.
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