PRESCRIPTION FOR DISASTER
GQ India|December 2020
The story of hydroxychloroquine is a strange and twisted tale pitting power against knowledge. Let’s not repeat it
ADAM ROGERS
CHAPTER ONE: THE JESUIT BARK

In the mid-1600s, a Jesuit priest serving in Peru got a useful tip. The indigenous people there, he learned, were using the bark of a particular kind of tree to treat fevers. The priest, who’d probably gone a few rounds himself with the local diseases, got ahold of some of the reddish-brown bark from this “fever-tree” and shipped it back to Europe. In the 1670s, what came to be called Jesuit bark had made its way into a popular patent medicine, along with rose leaves, lemon juice and wine.

That was the beginning of the impressively effective bark’s role in pharmacology (and its side career in mixology). In the mid-1700s the prolific Swedish taxonomist Carl Linnaeus gave the tree’s genus its name – having heard a fanciful (and untrue) tale about the bark’s success treating the Spanish Countess of Chinchón, he dubbed it Cinchona. In 1820, French chemists isolated the active ingredient, a plant alkaloid they named quinine. Its bitter flavour became not only a hallmark of the prevention and treatment of malaria but also the basis for a medicinal fizzy water – a “tonic” – that mixed well with the gin that Europeans brought with them to their equatorial conquests. Today, quinine can be found in bitters, vermouth and absinthe; next time you order a Manhattan or a Sazerac, give a little l’chaim to the Peruvians.

Medicine that treats a deadly disease but grows only on certain finicky trees is the kind of thing chemists live for. A failed attempt to synthesise quinine in the 1800s had accidentally produced the first synthetic pigment (a lovely shade of mauve); after World War I, when endemic malaria arguably did almost as much as Allied soldiers to limit Germany’s expansionist ambitions, that country set its scientists to solving a problem. A dye company called Bayer took up the quinine challenge, synthesised some reasonably useful replacements and became a pharmaceutical powerhouse with a global market. When World War II denied the US access to both German drugs and the quinine-producing cinchona trees of Java, the Americans basically stole a recipe from German prisoners of war and turned that into a successful treatment.

That drug was called chloroquine. It has a slightly better- tolerated cousin, hydroxychloroquine. You may have heard of them.

So, yeah: A drug extracted from indigenous knowledge to lubricate European colonialist impulses went on to power the military adventures of the latter 20th century and save millions of lives. But even as the parasites that cause some strains of malaria began to develop resistance to chloro quine, newer science started to hint at a second life for the drug. Some lab studies suggested that it could fight viruses, and that it could suppress overreactions by the human immune system. By the mid-1950s, doctors were using hydroxychloroquine to treat the autoimmune disorders lupus and rheumatoid arthritis. The drug was readily available. It had manageable side effects. And because it’s so old, no pharmaceutical company holds a patent on it. So it’s cheap.

Viable. Safe. Available. Inexpensive. What more could you ask for?

It made sense, then, that when a novel coronavirus appeared in Wuhan, China, in December 2019, people started speculating about the old drug. Chloroquine’s virus-fighting reputation preceded it. Four centuries of the history of science came crashing into the newly apocalyptic present. By February, several Chinese research teams had spun up small trials of chloroquine and hydroxychloroquine against the new disease, and some were soon reporting success. A simple, familiar drug was offering hope.

Still, though. Before you start giving a drug to the thousands, soon to be millions, of people affected by a pandemic virus, you want to be very, very sure it’s safe and effective, that the benefits of administering it outweigh the risks and side effects. The Chinese studies of chloroquine were, so far, preliminary and small-bore. And because of language barriers, limited access to international journals, and some mutual distrust, Chinese data doesn’t always make it into the global information ecosystem. Nobody really knew, authoritatively, if the drug actually worked.

But “Does it work?” is a harder question to answer than it sounds. Few drugs are penicillin-size successes; most drugs have more moderate effects. That means those possible effects are hard to distinguish from what may just be statistical noise. Under normal conditions, distinguishing one from the other requires painstaking, time-consuming research protocols and statistical analysis. But the urgency of a pandemic makes conditions abnormal in the extreme. Faced with intensive care units full of the severely ill, physicians begin to feel they can’t wait for statistics before their patients become one. Politicians start looking for a win, or something to signal they’re dealing with the problem. And the world’s technical and economic elite start looking for quick fixes and opportunities to make a sale, spreading their opinions (whether quarter-, half-, or fully baked) on social media. After all, influencer and influenza share the same etymological root.

At issue here is more than just whether a drug treats a disease. The heart of the scientific method is the process of formulating a hypothesis and collecting data to test it. This is how to reliably be sure that (in this case) a drug does what you say it does – that the effects you think you see are not coincidence or luck or mirage. It sounds simple, but, in practice, it’s ambiguous, messy and often contentious. The twisted tale of hydroxychloroquine is actually about how to know stuff, the question that has defined every existential decision since the early 20th century – climate change, vaccines, economic policy. We’ve learned from failure and bitter experience that only when we take the time to find the truth do we at least have a chance to make good decisions. We also know that it’ll be a struggle – that grifters, power-seekers and fantasists will push their own versions of truth while scientists and policymakers grapple with the lumbering process and nuanced outcomes of the scientific method. Because there will be other pandemics, other disasters. And just as with Covid-19, only science and its tools will soften their impact. But also as with Covid-19, humans will do that science and wield those tools, and that makes things messy. What happened with hydroxychloroquine was a debacle, but retelling the story might help avert the same kind of chaos next time around.

CHAPTER TWO

IT WORKS IN THE LAB

Viruses aren’t alive, exactly – they’re just genetic material wrapped in fat, starch and protein. But because they use living things to reproduce and spread, evolutionary forces effectively shape them, synchronising viruses with the specifics of their targets. Viruses land on cells and viruses’ landing gear, as it were, are shaped to lock onto the exact topologies of proteins on their surfaces. Once clicked onto that docking site, a virus forces the cell to engulf it in a little bit of membrane. Like a fighter jet on an aircraft carrier deck, the virus gets elevatored into the cells’ innards. Down there, the viral genes slide into the cell’s own genome and take over, forcing the cell to pump out more copies of the virus. Eventually the cell bursts open, the new virus copies spread, and the process starts all over.

Hypothetically, chloroquine and hydroxychloroquine can mess all that up. They interfere with the biochemistry that lets the landing gear touch down, a process called glycosylation. And it seems like the drugs change the acidity of the elevator shaft, of that bit of involuted membrane bubble, making it inhospitable to a virus and preventing infection.

It works in the lab, anyway. Over decades, researchers have tried chloroquine and hydroxychloroquine against a bunch of viruses, including the human immunodeficiency virus that causes AIDS. The new pathogen that emerged in 2019, SARS-CoV-2, belongs to a family called coronaviruses – as did its prequel, SARS-CoV, which caused severe acute respiratory syndrome. In 2004, a team of Belgian researchers tried chloroquine on SARS-1 in the lab, and it seemed successful – apply the drug to cells and the virus has trouble replicating.

Cells in a petri dish aren’t people, but even with such crappy evidence, it made sense in the early days of the pandemic to try the drug again. Emergency rooms and intensive care units were filling up with sick people who couldn’t breathe, and frankly, frontline caregivers didn’t have much else to give them.

By March 9, the US was facing a shortage of hydroxychloroquine and chloroquine. About a week later, with a surge of Covid-19 patients slamming New York City, I talked to Liise-anne Pirofski, the chief of the Division of Infectious Diseases at Montefiore Medical Center and the Albert Einstein College of Medicine. Chloroquine was standard for patients with Covid-19, along with a repurposed HIV anti viral – even though, at the time, there was only the thinnest data recommending either drug. “Everybody gets that unless they have some contra indication,” Pirofski told me. What else could they do? Her hospital was participating in a clinical trial of a then-experimental antiviral called remdesivir, but it was still unavailable outside that study. Pirofski herself was advocating the use of convalescent plasma, a decades-old treatment made from the blood of people who’ve recovered from a disease, which also hadn’t been tested against Covid-19. They were throwing everything they had at the virus. People were sick and dying. You go to war with the drugs you have, not the drugs you wish you had.

CHAPTER THREE

SCIENCE IN ACTION

The possibilities in early 2020: Hydroxychloroquine might help. Or it might not. Or it might make people worse. No one knew.

One of the first people to leap into that breach was David Boulware, a diligent infectious disease researcher and professor of medicine at the University of Minnesota. Back in 2015, he’d worked on an Ebola drug trial with the National Institutes of Health, and he quickly raised his hand to work on trials of treatments for the new virus.

In early March, he and his team were supposed to be at an HIV conference in Boston, but by that point nobody was travelling anywhere. “We all had four days free to totally focus on this task,” Boulware told me then. His group used the time to put together a plan to study hydroxychloroquine.

Right here – the stage where scientists come up with these “research protocols” – is where how-to-know starts getting complicated. It’s a cliché because it’s true: The answers you get depend on the questions you ask. In this case, Boulware’s team decided not to test the drug on hospitalised patients, when the disease becomes severe. “If it was going to work, you’d have a better chance to alter the disease course early on,” Boulware said.

They hoped it worked. But they didn’t know. To find out, they proposed a classic structure: A couple hundred people would get the drug; a similar number would get a placebo – an inert fake. The ones getting the placebo would be the “control group,” experiencing all the same things except for the drug, to isolate its effects. Neither researchers nor participants would know who got which until the end; that’s called a “double-blind” study. And people would be assigned to the groups at random, to avoid even unconscious bias on the part of the researchers and prevent differences between groups of humans – socioeconomic, demographic, and so on – from throwing off the results.

That is, in other words, a large, double-blinded, randomised controlled trial. Boulware’s team proposed two. One would look at whether hydroxychloroquine could prevent illness in people with exposure to an infected person – “post-exposure prophylaxis” – and another would see if taking the drug close to the onset of symptoms could keep those symptoms from getting worse. That was “early treatment”. On March 13, the US Food and Drug Administration approved the study, a blisteringly fast green light from a typically cautious, plodding agency. The responses of the federal government’s scientific policymaking would falter in key ways over the next few months, but this wasn’t one of them.

Boulware started enrolling people almost immediately. For statistical validity, they’d need enough people so that some in the experimental groups and some in the controls would get Covid-19. The researchers would run the numbers, ask who got what, and they’d have an answer in weeks. They’d write up the results, publish in a journal and it would be science.

Except Boulware’s reasonable expectation that things would work the way they were supposed to didn’t take into account the viral social-media blender that was spinning up its blades – making a viscous gazpacho out of Silicon Valley opportunism and the hottest of hot takes from the president of the United States.

The way they were supposed to? Yeah, no.

CHAPTER FOUR

THE TECH SOLUTION

Even the stodgiest of scientists don’t believe that waiting months or years for a formal write-up of an experiment to penetrate a wall of skeptical reviewers, receiving an inscrutable thumbs-up to get published – in ink! on paper! that gets mailed! to libraries! – is an ideal system for disseminating new knowledge today. Yet, that’s still mostly how things work, despite the existence of the online version of most journals. But the Covid-19 pandemic came at a weird moment in the history of how information spreads. For one thing, that formal system was already in the process of breaking down. Due to the pressures of publication and academic seniority, some of the science that gets into peer-reviewed journals doesn’t hold up to scrutiny, and many scientists are internalising the hard truth of that “reproducibility crisis.” Formal peer review and publication doesn’t make something true. That’s part of the reason the biomedical sciences were embracing a newer approach, one that their colleagues across the quad in the physics and math buildings had arrived at years before: “prepublication” or “prepress” articles that could go online as soon as their authors finished typing them.

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