A repurposed antidepressant might help treat COVID-19, a remarkable study found. The way this research was funded highlights a big problem—and bigger opportunity—in American science.
Two stories in science are worth cheering right now: the amazing amount of knowledge humanity is gathering about COVID-19 and the quietly revolutionary ways we’re accelerating the pace of discovery.
First, the knowledge: Last week, a large clinical trial concluded that the cheap antidepressant drug fluvoxamine dramatically lowers the chance that people with COVID-19 will get hospitalized or die.
Researchers found that patients who took the drug for at least eight days saw a 91 percent reduction in death rate. Fluvoxamine, which has been used for decades to treat depression and obsessive-compulsive disorder, also reduces inflammation, which alerted scientists to its potential to calm the immune-system storms caused by COVID-19. “This is exciting data,” Daniel Griffin, the chief of infectious disease at the health-care-provider network ProHealth New York, told The Wall Street Journal. “This may end up being standard of care.”
So far, so wonderful. But what makes this study even more remarkable were six boring-sounding words in the paper’s acknowledgments: “The trial was supported by FastGrants.”
Last year, in the chaotic opening innings of the coronavirus pandemic, the George Mason University economist Tyler Cowen and Patrick Collison, the CEO of the payment-processing company Stripe, co-founded a new program for quickly funding scientific research on COVID-19. They called it Fast Grants. Pulling together a small team of early-career scientists to vet several thousand ideas, they sent out the first round of money in about 48 hours. In 2020, they raised more than $50 million and awarded more than 260 grants that supported research on saliva-based tests, long COVID, and clinical trials for repurposed drugs—including fluvoxamine.
Like many new ideas, Fast Grants is an innovation embedded in a critique of the status quo.
Most scientific funding in the United States flows from federal agencies such as the National Institutes of Health and the National Science Foundation. This funding is famously luxurious; the NIH and NSF allocate about $50 billion a year. It is also infamously laborious and slow. Scientists spend up to 40 percent of their time working on research grants rather than on research. And funding agencies sometimes take seven months (or longer) to review an application, respond, or request a resubmission. Anything we can do to accelerate the grant-application process could hugely increase the productivity of science.
The existing layers of bureaucracy have obvious costs in speed. They also have subtle costs in creativity. The NIH’s pre-grant peer-review process requires that many reviewers approve an application. This consensus-oriented style can be a check against novelty—what if one scientist sees extraordinary promise in a wacky idea but the rest of the board sees only its wackiness? The sheer amount of work required to get a grant also penalizes radical creativity. Many scientists, anticipating the turgidity and conservatism of the NIH’s approval system, apply for projects that they anticipate will appeal to the board rather than pour their energies into a truly new idea that, after a 500-day waiting period, might get rejected. This is happening in an academic industry where securing NIH funding can be make-or-break: Since the 1960s, doctoral programs have gotten longer and longer, while the share of Ph.D. holders getting tenure has declined by 40 percent.
Fast Grants aimed to solve the speed problem in several ways. Its application process was designed to take half an hour, and many funding decisions were made within a few days. This wasn’t business as usual. It was Operation Warp Speed for science.
In the past few years, I’ve had many conversations with entrepreneurs, researchers, and writers about the need for a new scientific revolution in this country. These thinkers have diagnosed several paradoxes in the current U.S. science system.
First is the trust paradox. People in professional circles like saying that we “believe the science,” but ironically, the scientific system doesn’t seem to put much confidence in real-life scientists. In a survey of researchers who received Fast Grants, almost 80 percent said that they would change their focus “a lot” if they could deploy their grant money however they liked; more than 60 percent said they would pursue work outside their field of expertise, against the norms of the NIH. “The current grant funding apparatus does not allow some of the best scientists in the world to pursue the research agendas that they themselves think are best,” Collison, Cowen, and the UC Berkeley scientist Patrick Hsu wrotein the online publication Future in June. So major funders have placed researchers in the awkward position of being both celebrated by people who say they love the institution of science and constrained by the actual institution of science.
Second, there is a specialization paradox. Despite considerable domain specialization in the sciences, individual scientists cannot focus enough on doing hard research in their chosen field.
Since 1970, the number of years the average Ph.D. student in the biosciences spends in graduate school has grown from a little more than five years to almost eight years. Producing experts is taking longer, and those experts are getting less productive. In the famous paper “Are Ideas Getting Harder to Find?,” the Stanford University economist Nicholas Bloom and his colleagues found that research productivity has declined sharply across the board since the 1970s. Research from the University of Chicago scholar James Evans has found that as the number of researchers has grown, progress has slowed down in some fields, perhaps because scientists are so overwhelmed by the glut of information they have to process that they’re clustering around the same safe subjects and citing the same few papers.
But in the bigger picture, today’s scientists can’t really specialize in science, because so many of them are forced to devote at least one day a week to begging for money. In the Fast Grants survey, a majority of respondents saidthey spend “more than one quarter of their time on grant applications.” This is absurd. It’s the height of irrationality, wastefulness, or both that the U.S. education system takes great pains to train scientists to be monkish specialists, only to dump them into an arms race for scarce funding that elbows out the work of doing science.
A third feature of American science is the experimentation paradox: The scientific revolution, which still inspires today’s research, extolled the virtues of experiments. But our scientific institutions are weirdly averse to them. The research establishment created after World War II concentrated scientific funding at the federal level. Institutions such as the NIH and NSF finance wonderful work, but they are neither nimble nor innovative, and the economist Cowen got the idea for Fast Grants by observing their sluggishness at the beginning of the pandemic. Many science reformers propose spicing things up with new lotteries that offer lavish rewards for major breakthroughs, or giving unlimited and unconditional funding to superstars in certain domains. “We need a better science of science,” the writer José Luis Ricón has argued. “The scientific method needs to examine the social practice of science as well, and this should involve funders doing more experiments to see what works.” In other words, we ought to let a thousand Fast Grants–style initiatives bloom, track their long-term productivity, and determine whether there are better ways to finance the sort of scientific breakthroughs that can change the course of history.
Four hundred years ago, the first scientific revolution overthrew old ways of looking at the world and embraced experimentation over tradition. We could use a similar revolution today. The U.S. relies on a fleet of scientific agencies—the CDC, FDA, NIH, and NSF—that are decades old and that, in many cases, act their age. The CDC publishes excellent research, but it utterly failed to respond quickly and adequately in the face of a national emergency. The FDA protects Americans from some terrible medical products, but its protectiveness also deprives Americans of some very good and urgently needed products. The NIH and NSF fund a lot of brilliant research, but their hegemony over scientific funding makes it hard to know whether we could be doing much, much better.
American science needs more science. That means, above all, that we need more experiments. We shouldn’t have to depend on 20th-century institutions to guide 21st-century progress. The lesson of Fast Grants is that we don’t have to.Page 2 of 2
Before the state of Oklahoma put John Marion Grant through the 12-minuteordeal of convulsions, vomiting, and heaving that eventually concluded with the 60-year-old’s death, it gave him a choice: How would he like to die?
There were a number of options. There was pentobarbital, the barbiturate most recently made infamous by the Trump administration’s last-minute federal-execution spree; sodium thiopental, a near-extinct anesthetic once used in medicine and, prompting its eradication from the market, lethal injections; compounded versions—meaning iterations made without FDA approval—of either drug; the state’s preference, a three-drug cocktail starting with midazolam, a benzodiazepine used for sedation and seizure control and the occasional overtly inhumane execution; or a firing squad, the good old-fashioned kind of killing in which the killers at least pay their prey the respect of no pretense.
Since the Supreme Court’s strange and consequential opinion in the 2015 case of Glossip v. Gross, in which Justice Samuel Alito wrote that “because capital punishment is constitutional, there must be a constitutional means of carrying it out,” death-row prisoners who challenge their states’ methods of execution have been tasked with producing a suitable alternative. How about old age? their attorneys often volunteer, sardonically. But when states demand that complainants select a “known and available alternative method of execution” that presents a substantially lower risk of severe pain than the method on offer, they mean one the state, rather than nature, can inflict.
Death is a difficult thing to ponder under ordinary circumstances. Planning one’s own death under duress complicates matters further. For one thing, as Grant’s attorneys argued in a motion filed three days before his scheduled execution date, forcing him to select the means by which the state would put him to death would violate his sincerely held religious objection to suicide. The Tenth Circuit Court of Appeals was unmoved. And so Grant did what his conscience compelled him to do: He refused to choose.
It was a fatal decision. If Grant had told Oklahoma how to kill him, he would still be alive.
This fresh madness is only the latest layer of lunacy heaped atop the mountain of nonsense and tortured reasoning that constitutes the legal edifice of capital punishment in the United States. The Eighth Amendment, which theoretically bars cruel and unusual punishment, ought to—at least, per the interpretation of the Supreme Court—move the country ever further toward humane and civilized justice. Yet challenges to methods of execution that have produced clearly cruel deaths—such as that of John Grant (and others before him, including Clayton Lockett, also of Oklahoma)—have resulted in a freakishly sadistic execution schema in which people aren’t just killed by the state but are also recruited as participants in their own demise, in clear violation of their religious principles and despite the obvious psychological terror such a regime inflicts.
“The reason it’s so offensive is that being executed by the state is the ultimate involuntary act,” Marc Bookman, a co-founder and the executive director of the Atlantic Center for Capital Representation, told me. “What could be less voluntary? They give you the whole Camus business about when you’re going to be executed and whatnot. And then the state tasks you with coming up with a means of execution that’s constitutional. And what that does is it converts an involuntary act into a collaboration between you and the people who’re trying to kill you.”
Moreover, Oklahoma was able to move forward with Grant’s execution only because he hadn’t submitted an affirmative choice of execution method. People on death row who challenged the state’s protocol (a medley of midazolam, vecuronium bromide, and potassium chloride) and did select an alternative method remain plaintiffs on an active lawsuit headed to trial early next year; until that litigation concludes, their executions cannot be carried out.
Further, the options available aren’t necessarily as available as they seem. While some states and the federal government have acquired pentobarbital in secret to protect their suppliers from the protests of anti-capital-punishment activists, other states have yet to set up such clandestine sourcing. Oklahoma has been unable to secure a stock of pentobarbital since early 2014. The following year, evidently strapped for lethal drugs, the state mistakenly used a chemical manufactured to de-ice airplane wings in the execution of Charles Warner. And while death by firing squad remains on the books in Oklahoma, the state has not executed a single prisoner thusly since it began documenting its executions in 1915.
Which left, for Grant, the Oklahoma protocol—beginning with midazolam.
Theoretically, the first drug in the sequence ought to prevent the person being killed from experiencing the pain of their own death. Midazolam works to reduce electrical activity in the brain, Joel Zivot, an associate professor of anesthesiology and surgery at the Emory School of Medicine and a senior fellow in Emory’s Center for Ethics, told me. It can promote sleep, decrease anxiety and restlessness, or, in certain cases, stop persistent seizures. But it is not a pain reliever, and it does not necessarily produce a comatose-like loss of consciousness.
To inject midazolam, Zivot explained, you first need to dissolve it in an acid; to render enough to fully and deeply sedate an adult man, you need to introduce a very large quantity of hydrochloric acid into the bloodstream very quickly, which perhaps accounts for the evident agony of Grant’s final moments. Having reviewed the autopsies of many executed people, Zivot believes that lethal injection very often produces similarly painful results, though sometimes the people happen to be paralyzed by other drugs first, and are thus unable to communicate what they’re going through. “This is not unusual in terms of what is happening beneath the skin,” he said. “It’s just unusual in that we could see it this time.”
Others remain on Oklahoma’s death row who are eligible for execution. The state very well may put them to death the same way it put Grant to death, and it may do so in spite of the furor sparked by the agony of his demise—or because of it. In the pursuit of killing its own citizens, this country has wrenched from its constitutional protection against cruelty a regime more bestial than one invented with total indifference to the concept; the constitutionally sacred right to religious liberty, too, has already been sacrificed on this pyre.
All this to put a 60-year-old man to death. Oklahoma, sans one more soul, likely sleeps no sounder, and we are all a little less human. Zivot scoffed when I lamented that we kill people like worn-out working dogs in this country.
“Putting down animals is done better,” he said. “Much better.”
All Rights Reserved for Derek Thompson