Right on. Let’s talk about the history and chemistry of chloroquine and quinine. This will be a longish thread -- I promise payoff including one staggering "oops" and some tentative reflections about how all this relates to what's going on right now. 1/
So, as you have presumably heard, chloroquine and hydroxychloroquine are the "decades-old antimalarial drugs" that have been getting lots of hype over the past few days as prospective covid-19 therapeutics. 2/
Most of this discussion explains it along the lines of this WSJ article: "Chloroquine is a synthetic form of quinine, a centuries-old compound for malaria that is found in small amounts in products such as tonic water."
wsj.com/articles/docto… (3/
wsj.com/articles/docto… (3/
If you're a historian of science / medicine, you probably know at least a bit about the history of quinine -- a therapeutic derived from the bark of the cinchona tree native to the Andes, found to be effective in fighting "periodic fevers." 4/
Thus the alternative name "Peruvian bark"; the cinchona tree is one of three symbols on Peru's national coat of arms, along with the vicuna (a llama relative), and a big old pile of coins, representing the nation's animal, vegetable, and mineral wealth. en.wikipedia.org/wiki/Coat_of_a… 5/
As a botanical medicine, cinchona / Peruvian bark was more like a class of related substances than a single drug. For example, an 1822 compendium by Harvard professor of materia medica Jacob Bigelow discusses about 20 different varieties. 6/
"As the kinds which originally enjoyed the greatest celebrity shall become scarce, it is not improbable that they will by degrees be superseded by others of more easy acquisition." (p. 126) babel.hathitrust.org/cgi/pt?id=hvd.… 7/
Speaking of easy acquisition: Dutch and British colonial botanists spirited away cinchona trees from the Andes and cultivated them in other colonial settings, e.g. Java and India. 8/
There, cinchona was both a plantation agricultural product in its own right and, as an antimalarial, enabled other forms of colonial activity -- keeping laborers and soldiers sufficiently healthy to engage in intensive plantation agriculture and military + police activities. 9/
Cinchona, the botanical medicine, became quinine, the chemical drug, in the labs of French and German pharmaceutical chemists circa 1820, amidst an "alkaloid rush" to isolate the pharmacologically active substances within medicinal plants. 10/
Opium--> morphine; styrchnos nux vomica --> strychnine; coffee --> caffeine; etc. There is a nice article by John Lesch on this: doi.org/10.2307/277574…
All these plants contained *multiple* bioactive chemicals. But a push for standard therapeutics, chemical improvement of plant products & production processes, and synthetic analogs (a distant prospect in the early 19th c.) focused chemists on individual substances like quinine.
Contemporaneously, European chemists started investigating another source of carbon-containing "organic" compounds: coal tar, the liquid fraction left over when coal was distilled into coal gas (for illumination), and solid coke (for steel-making & low-smoke fuel).
The German chemist Friedrich Ferdinand Runge, formerly a participant in the alkaloid gold such (he discovered caffeine), isolated a handful of coal-tar constituents that turned out later on to be quite significant synthetic chemical products and starting materials.
E.g. carbolic acid (phenol), Joseph Lister's secret sauce for antiseptic surgery & a starting material for dyes, drugs, explosives, and the polycarbonate plastic monomer bisphenol A (BPA). And cyanol, aka aniline, which became super-important in chemical research and dye-making.
One of Runge's coal tar substances, leucol (white oil), turned out to be identical to quinoline, a substance derived through decomposition of quinine. (Aniline could similarly be derived from both degredation of plant-derived indigo and coal tar).
At the time, one practical consequence was that coal-tar substances could be used as chemically simpler, more easily obtained models for research relevant to production and use of plant-derived drugs like quinine and dyes like indigo.
August Wilhelm Hofmann was a particular proponent of such work; it was in the course of such work that his student William Henry Perkin stumbled upon the coal-tar derived dye "mauve." (See the work of Catherine Jackson on this, e.g. doi.org/10.1525/hsns.2…)
We're getting to chloroquine, I promise.
Quinoline, the compound first isolated from coal tar and from the degradation of quinine, became widely used in chemical research and as an ingredient for synthetic dyes and drugs. Here's its structure. 
Note the quinoline subunit in the structure of quinine (determined in the 1900s).
In the 1920s, chemists at the German chemical & pharmaceutical firm Bayer started synthesizing quinoline derivatives to test out as potential malaria drugs. This was based in part on the presence of quinoline in the structure of quinine.
But it was likely just as much a matter of convenience -- quinoline was easy to come by and its chemistry was well understood. The Bayer researchers specifically focused on aminoquinolines. (this is based on Lesch, The First Miracle Drugs) global.oup.com/academic/produ…
Quinine was NOT an aminoquinoline. I suspect (haven't dug into this) that familiarity and convenience that got Bayer researchers looking at aminoquinolines specifically. Aminoquinoline chemistry was likely more familiar & supple than most other quinoline derivatives would've been
The Bayer researchers landed on a compound they called plasmoquine (aka pamaquine): first in a generation of aminoquinoline-based synthetic antimalarials (sometimes used in combination with quinine or other drugs) developed by Bayer researchers and others riffing on this model.
These aminoquinoline drugs included primaquine, *chloroquine*, & *hydroxychloroquine*, among others. Atabrine (aka mepacrine aka quinacrine), another Bayer drug first marketed in 1932 and widely used as an antimalarial over the following decade, was chemically closely related.
(Note that artemisinin, the current preferred malaria therapeutic, is a quite chemically different substance, with more direct connection to plant-based medicines. See Tu Youyou's Nobel address for her discovery of artemisinin, doi.org/10.1002/anie.2…)
But wait! Wasn't chloroquine supposed to be the result of a crash WWII US government antimalarials research program? Well: yes and no.
During the 1940s, the US government did indeed sponsor a crash program to catalog & investigate malaria prophylactics and therapeutics. The program cast a wide net, testing out about 16,000 compounds -- seemingly everything researchers could get their hands on.
See great article by @leobslater on this program (https://10.1179/amb.2004.51.2.107) and a new book by @KarenMMasterson (really looking forward to reading -- alas, I am sheltering in a place far from my office, where it's sitting on my shelf) penguinrandomhouse.com/books/315246/t…
As Slater points out, this and other screening programs set an important model for how subsequent US federally-sponsored pharma programs worked, e.g. cancer drug screening and (arguably) screening of environmental & occupational toxic substances.
But if this program was a model, it was in large part a negative model. Like many WWII era programs, this was a large project involving collaboration on an unprecedented scale among many institutions and government agencies.
Program administrators called it "kaleidoscopic." What they meant, it seems, was "kind of a mess." This WWII program was sort of an organizational disaster -- so, grain of salt re: arguments that we need a 21st century Vannevar Bush, e.g. wsj.com/articles/the-h…
(Here I'm drawing on an account by one of the administrators: doi.org/10.4269/ajtmh.…)
In 1939, Bayer chemists patented a collection of novel aminoquinoline antimalarials they'd been researching since 1934. These included compounds called Resochin and Sontochin. Spoiler: **Resochin = Chloroquine.**
Resochin was quite similar to atabrine. It just had a two-ring quinoline core in place of atabrine's three-ring acridine core, also dropping the methoxy subunit that quinine contained.
Bayer's US affiliate, Winthrop, patented the compounds as well; they passed them along to researchers at Rockefeller Institute, which found them to be promising antimalarials.
This information got passed along to administrators of the antimalarials program. Despite the similarity of these compounds to atabrine, then considered the best synthetic antimalarial available, they got filed away as not worth pursuing.
(A **nomenclature error** seems to have played a role: somebody mistook the 4-aminoquinoline sontochin, with its analogy to atabrine, for an 8-aminoquinoline more structurally similar to plasmoquine.)
After US and allied forces captured Tunis in 1943, a French clinical researcher turned over samples of Bayer's Sontochin (methylated derivative, a chemical sibling of Resochin/chloroquine) to US military officers, along with clinical data.
This information made its way to the antimalarials program officers, who realized that one of the first substances they'd considered and dismissed, was not only the focus of German antimalarials research but had actually been patented by Bayer in the US as an antimalarial.
!!! Oops.
The US program administrators' attention turned to sontochin and resochin. Resochin turned out to be most effective; it was officially christened "chloroquine" in 1946, and quickly became a standard antimalarial.
Such organizational snafus, as much as the successes of WWII R&D, was what motivated scientist-administrators like Vannevar Bush to call for improved technologies of information management and a federal bureaucracy for the organized sponsorship of basic research. --> NSF NIH etc
So the chloroquine that Bayer is shipping chloroquine to the US in the face of its speculative prescription as an covid-19 therapeutic -- that chloroquine was originally a Bayer investigational drug reuters.com/article/us-hea…
I offer this mostly just as a story. But I guess I owe anyone who has made it this far some sort of lesson.
One first-order lesson just emphasizes a pretty obvious point: chloroquine is a reminder of the significance of organizational work and long-term institutional continuity that goes into large-scale scientific research.
Resochin/chloroquine was the result of long-term investigational trajectory at Bayer. Effective scientific bureaucracy & information management can't be taken for granted, in the US or elsewhere.
Creating them took considerable time and work. So does maintaining them. They aren’t just something you can trust in the capacity to spin up in an emergency without a good helping of stumbles.
You probably didn't need this chloroquine story to convince you of that. Still, it’s this last point—the perverse and counterproductive dimensions of the project, stemming from the perceived requirements of mass mobilization for total war—that I have been thinking about most.
Much of my research is about the history, legacies, advantages, and shortcomings of chemical-by-chemical ways of addressing the material world, particularly re: the synthetic chemicals industry and environmental health.
These are analogous in many ways to germ-by-germ understandings of disease. (There are also historical connections linking these conceptions of germs and chemicals as causal agents of illness in environmental and occupational health. See e.g. Linda Nash's jstor.org/stable/25473292)
A germ is something one can have a war against. Even the “cure is worse than the disease” arguments I have seen have tended to embrace the “war against coronavirus” metaphor. E.g. nytimes.com/2020/03/20/opi…
What happens if we think about the current state of affairs not as a "war against coronavirus" but a no less urgent collective effort to protect, improve, and sustain pulmonary health—the ability to breathe comfortably?
(Including *everyone* who might benefit from access to ventilators and masks and...)
Not to mention cleaner air! Here I am thinking with the great work of many many scholars:
Kristen Simmons culanth.org/fieldsights/se…, @murphyatglad culanth.org/articles/926-a…, @greggmitman yalebooks.yale.edu/book/978030014…
Kristen Simmons culanth.org/fieldsights/se…, @murphyatglad culanth.org/articles/926-a…, @greggmitman yalebooks.yale.edu/book/978030014…
as well as @profmikefortun and Kim Fortun and their collaborators theasthmafiles.org/about, and of course general work on air pollution who.int/health-topics/… and smoking and health who.int/news-room/fact…
And many more.
“Ok sure, but come on: we can worry about big vague things like pulmonary health later. We must focus on the war against the coronavirus and mitigating its collateral damage.” But isn’t the collateral damage the result of the “war”?
“Ok sure, but come on: we can worry about big vague things like pulmonary health later. We must focus on the war against the coronavirus and mitigating its collateral damage.” But isn’t the collateral damage the result of the “war”?
Might it not possibly be more effectively to focusing data-gathering, intervention, and other forms of attention on different objects of concern – e.g. caring for people’s capacity to breathe as opposed to interdicting viruses? This may well land on many of the same interventions
But with greater perspective. (All of this is really just a restating what social scientists who study disaster have long called for – attention to disaster as process, not event. E.g. @USofDisaster, whose #COVIDcalls I have found really enlightening.)
Keep coming back to this @USofDisaster op-ed of a year and a half ago: nytimes.com/2018/09/13/opi…
Anyway, I'm sure that that medical professionals and many others are thinking about the current challenges they face in this way. I am just really struck by the "war against coronavirus" focus of articles I read, graphics I see, complaints about the need for better data, etc.
So that’s where I'm left. Wherever we’re sitting at the moment, can we step back and ask whether “war on coronavirus” ways of addressing the world are getting us closer to or farther from the stuff we care about.
Might we be overlooking any new "chloroquines," whether pharmaceuticals or entirely different ways of advancing urgent causes of heath and well-being that we care about, through war-on-coronavirus thinking?
end.
end.
(oops, spelled it wrong in that sketch. *mepacrine*. nomenclature is hard.)
Oh, one more thing by way of citing my sources. These reflections on "war on disease" are inspired by the end of Susan Sontag's AIDS and its Metaphors:
"No, it is not desirable for medicine, any more than for war, to be “total.” Neither is the crisis created by AIDS a “total” anything. We are not being invaded. The body is not a battlefield. The ill are neither unavoidable casualties nor the enemy.
"We—medicine, society—are not authorized to fight back by any means whatever…. About that metaphor, the military one, I would say, if I may paraphrase Lucretius: Give it back to the war-makers."
