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Roadmaps, translational research, and childish curiosity

2005; Wiley; Volume: 19; Issue: 13 Linguagem: Inglês

10.1096/fj.05-1101ufm

1530-6860

Gerald Weissmann,

Pharmaceutical industry and healthcare

The Eighteenth Century, of course, had its defects, but they were vastly overshadowed by its merits. It got rid of religion. It lifted music to first place among the arts. It introduced urbanity into manners, and made even war relatively gracious and decent. It took eating and drinking out of the stable and put them into the parlor. It found the sciences childish curiosities, and bent them to the service of man, and elevated them above metaphysics for all time. — H. L. Mencken, 1931. The twenty-first century seems preoccupied with reversing each and every one of the accomplishments of the eighteenth. Indeed, in the United States these days, “childish curiosity”—the root of all good science—is more likely to be bent to the service of politics than to human needs. In no aspect of public life is the subversion of original science to bureaucratic need more evident than in the recurrent effort of the NIH to centralize the direction of biomedical research. First, the doyens of D.C. produced a Byzantine “Roadmap” for experimental biology (1). Then, they had a go at developing “a new discipline of clinical and translational sciences” (2) by creating an on-again, off-again empire of “translational research centers.” In keeping with the custom of their band, the central planners were marching to music written a generation ago. In 1974, Lewis Thomas complained that It is administratively fashionable in Washington to attribute the delay of applied science in medicine to a lack of planning… Do we need a new system of research management, with all the targets in clear display, arranged to be aimed at? (3) Thomas's “new system of research management, with all the targets in clear display” aptly describes the Roadmap and the Translational Research Centers of 2005. We might remind the Centrists, as one could call them, that the discipline of clinical science is not new; it dates from 1908 when the American Society for Clinical Investigation was founded. We might also remind the Centrists that all research is translational. When W. T. Astbury of Leeds first defined molecular biology in 1961 as “predominantly three-dimensional and structural [but also] inquiring into genesis and function,” (4) he was translating the Bragg equation, nλ = 2dsinθ, from solid-state physics into structural biology. In turn, the Bragg equation was itself a translation of Euclid's second theorem into Newton's Opticks. When Daniel J. McCarty used the Bragg equation to determine that crystalline, but not amorphous monosodium urate, caused gout he was translating physics into rheumatology (5), and when nλ = 2dsinθ was used to show that aging human aortas accumulate hydroxyapatite (bone), physics had been translated into gerontology (6). New science indeed! We ought to remind our leaders that if we want to nourish original science we need to support the childishly curious, not the politically astute. If it's the atomic bomb you want, start recruiting for the Manhattan Project. But if it's atomic theory you're after, look for the lone thinker who comes up with e = mc2. You can plug through the base pairs of the human genome with a consortium or a company but you'll never come up with Erwin Chargaff's discovery that … the molar ratios of total purines to total pyrimidines, and also of adenine to thymine and of guanine to cytosine, were not far from 1. (7) And while you can support an assembly line of hackers working their way through cancer SNP's, you'll never generate a hypothesis as prescient as Chargaff's: We must realize that minute changes in the nucleic acid, e.g., the disappearance of one guanine molecule out of a hundred, could produce far reaching changes…; and it is not impossible that rearrangements of this type are among the causes of the occurrence of mutations”.(7) The work of Einstein, of the Braggs, of Chargaff—of most good scientists since the enlightenment—has been the work of adults who permit themselves to follow their curiosity in the way children do. True amateurs of science, they discovered the new because of their love for the game. Look at any dictionary—the Oxford English Dictionary will do—and you'll find two definitions of amateur; only one of them is complimentary. The first derives from the Latin amare (to love) and describes an amateur as “one who loves or is fond of; one who has a taste for anything.” This kind of amateur has a choice, and could as easily love claret as the clarinet, or prefer mussels to fossils. In the heady days of the enlightenment all of science was done by amateurs; indeed, “scientist” didn't supplant the term “natural philosopher” until William Whewell produced it upon the request of Coleridge in 1833 (8). Voltaire and his mistress Madame du Chatelet, those amateurs of natural philosophy, performed serious experiments in thermodynamics; John Dryden and Christopher Wren debated natural science with Robert Hooke and Robert Boyle before the Royal Society; Goethe learned about electricity from Jean Paul Marat. But then Lavoisier lost his head on the guillotine and soon enough natural philosophers were expected to become card-carrying professionals: the term “amateur” assumed its more common, negative connotation. The O.E.D.'s second definition of amateur is: “One who cultivates anything as a pastime, as distinguished from one who prosecutes it professionally; hence, sometimes used disparagingly, as dabbler, or superficial student or worker.” In support of this definition, the O.E.D. continues by equating amateurism with “dilettantism.” I'd bet that the Centrists are drafting their Roadmaps and plotting Translational Research Centers because they suspect that some scientist, somewhere out there, is pursuing science as a pastime, as an amateur in thrall to childish curiosity. Let me introduce another example of why biomedical science does very well, thank you, without Road-maps or Translational Research Centers. The newspapers are in high dudgeon about Merck's Vioxx debacle. And that story of billions gained and billions lost began with two curious amateurs of science. Prostaglandins were discovered seventy-five years ago by an obstetrician, Raphael Kurzrok, and a pharmacologist, Charles C. Lieb. Kurzrok wondered why a woman in Brooklyn had lower abdominal pain each time she had sexual intercourse and decided that his patient's pain was very much like the pain of uterine contraction during childbirth. Kurzrok and Lieb speculated that there might be a substance in human semen that caused the smooth muscle of the uterus to contract. Aided by Sarah Ratner, a fledgling biochemist, and after the usual trial and error, they were able to provide a partial validation of their theory. In 1931 they reported in the Proceedings of the Society for Experimental Biology and Medicine (not the trendiest of scientific journals) that when one centiliter of human seminal fluid was added to a strip of human uterus suspended in a water bath, the uterine muscle sometimes contracted (9). Later, in Sweden, the contracting substance of Kurzrok and Lieb was named prostaglandin by U. S. von Euler, since it was presumed to come from the prostate gland. Other Swedish scientists (Sune Bergström, Bengt Samuelsson) translated the story of prostaglandins into physiology, then into synthetic biochemistry and finally into medicinal chemistry. Without a roadmap, the path of pure curiosity led straight to the Nobel Prize. By 1971 the late Sir John Vane—another Nobelist with a grand streak of childish curiosity—announced “I think I know how aspirin works” and popped into the lab to show he'd got it right. Among other effects, aspirin and aspirin-like drugs do indeed inhibit the COX enzyme(s) of prostaglandin synthesis (10). Vane's discovery was followed by Philip Needleman bumping into the COX 2 enzyme and distinguishing how its inhibitors differed from inhibitors of aspirin-like drugs with respect to gastric toxicity. The crystal structure of each COX enzyme was solved (nλ = 2dsinθ, again) and ever more specific inhibitors were synthesized. What was being translated and in what direction? Chemistry took over from pharmacology what structural biology learned from gastroenterology which in turn borrowed from pathology etc., etc. (11). It's all of FASEB in one class of drugs! Now that these adventures in translational research have been trumped by an unwanted, clinical effect of COX 2 inhibition, I've looked in vain on that Roadmap or Center directory for guidance. I'd bet that one lone, curious scientist, someone following up a hunch in another field (say cell-cell adhesion), will come up with the answer as to why Vioxx is a plus/minus. And she'll get there before those chaps looking at Roadmaps. But, we already have a counter to the best-laid plans of NIH mice and men, to the notion that protocols from above can direct our science. Here's Lewis Thomas again: What [research] needs is for the air to be made right. If you want a bee to make honey, you do not issue protocols on solar navigation or carbohydrate chemistry, you put him together with other bees … and you do what you can to arrange the general environment around the hive. If the air is right, the science will come in its own season, like pure honey. (12)