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Serendipity

Blog entry posted by anciendaze, Oct 13, 2011.

The title word may not be familiar. Indeed, for those speaking languages other than English, it is difficult to translate. It can be traced to a Persian tale, "The Three Princes of Serendip", and was coined in English by Horace Walpole. The princes in the story have a series of adventures which might fit the Arabian Nights, since there are stories nested within stories. In the process, they make many remarkable discoveries, partly by accident. From the standpoint of definition the important feature is that these were discoveries of things they were not seeking in their quest.

The scientist most aware of the role of chance in medical discovery was Louis Pasteur, who famously said "Chance favors the prepared mind." He remained tactfully silent about what happens with the wrong kind of preparation.

We can try to fit his discoveries into a modern research paradigm, just for amusement. First, there is the question of credentials. He was trained as a chemist. Did this give him any special qualifications to understand the diseases of silkworms, chickens, cattle, sheep, dogs or people? Rejecting that grant proposal would be a slam dunk. We might also wonder about the kind of five-year plan leading to the treatment of rabies he might propose. The idea of immunization could be thrown out early on, since you did not know who needed the vaccine until they were bitten by a rabid animal, and the cost of immunizing the entire population would be prohibitive, even if the vaccine carried no risk. Clearly, there was no point in even pursuing this work, except as an academic exercise, which takes us back to credentials.

While Pasteur did not originate the germ theory of disease (we could for example credit Friedrich Henle or Agostino Bassi,) he was a notable early proponent. Had you proceeded on the basis of consensus, none of his papers would have appeared in medical literature. (Semmelweis did not publish medical papers on the transmission of puerperal fever, he let others publish descriptions of his work, but delayed his own publication until he could publish a separate monograph. Even so, the eminent Rudolph Virchow, sometimes called the founder of cell biology, felt compelled to ridicule the versions of Semmelweis' unpublished ideas he had heard.)

Pasteur was fighting an uphill battle concerning bacterial disease. This didn't stop him from investigating viral diseases, not that he, or anyone else, knew what a virus was. The discovery of even a large virus in plants, tobacco mosaic virus, had to wait until 1892 (Ivanovsky) and 1898 (Beijerinck). This virus was not merely filterable, it was visible under an ordinary microscope. Most viruses were not imaged until the invention of the electron microscope. The term virus was simply taken from the common Latin term for an unknown poison or slime. (Curiously, the etymology of this word in Latin takes us back to vir for man. Originally, virus meant human semen, an astonishing parallel considering HIV.)

Next, let us consider Pasteur's relationship with patients. After Pasteur had completed his early work on animals, a nine-year old boy named Joseph Meister was bitten by a rabid dog. We now know the risk of developing a fatal case of rabies after a bite from a rabid animal is about 15%, though the extensive wounds Meister suffered might have increased this risk. Pasteur did not know for certain, but he did know the disease was not merely fatal -- it was a nightmare out of a horror story. Lewis Thomas has said that this was one exception to his idea that dying people usually suffered less than others imagined. In this case they were fully and horribly aware of the destruction of their brain and nervous system while it was happening.

Pasteur took a chance, and gave Meister the painful series of shots needed to immunize before the disease spread to the central nervous system. Meister survived, and Pasteur avoided prosecution. Meister went on to become the watchman at the Pasteur Institute. This would be a happy ending if that was where we stopped the story. Honesty compels me to say that Meister was there in WWII when Nazis took control, and went home and shot himself with his WWI service revolver. No one could say that patients were emotionally neutral about Pasteur, or vice versa.

Finally, we might consider the famous case of the Russian peasants bitten by a rabid wolf. Hearing that Pasteur had a treatment for rabies, the Tsar sent a special train to take them to Paris, where they arrived barely able to say "Pasteur". He was reluctant to treat them, because too much time had elapsed since they were bitten. (He felt a week was as long as one could wait.) Still, he warned everyone it might not work, and took a chance, 16 survived and returned home. In a modern version, those Russians would be told it would take three months to complete ethics review.

Pasteur has not escaped modern attention. He has been charged with fraud. Even success is no defense. You can also find claims on-line that not one in a hundred people bitten by rabid animals will develop fatal rabies. There are good reasons this is not a majority opinion. Majorities are not always right, but neither are they always wrong.

What I want to emphasize now is the role of productive mistakes. Roentgen may have had a clue about what would happen during his experiments with a cathode ray tube, but we can no longer be sure what he really expected to find when he discovered X-rays, founding medical radiology. We can be sure about Henri Becquerel's discovery of radioactivity. He, his father, uncle and grandfather were experts on luminescence, fluorescence and phosphorescence. He expected to discover that Roentgen's X-rays were powered by something like stored solar energy. Instead he found that the emanations which fogged photographic plates were completely independent of sunlight, and persisted despite an absence of any external power source. He made a mistake, but a remarkably productive one.

(To avoid any implication that the mainstream work of the Becquerel family was unimportant, I want to emphasize that besides fluorescent lights, modern biological assays like FISH derive from work in their field. This is only a tiny part of their legacy.)

Regular readers of my posts will have heard that Enrico Fermi's Nobel Prize for the creation of trans-uranium elements was a mistake, both on his part and on the part of the prize committee. He was barely through with the award ceremony when news arrived that he had actually found induced nuclear fission. The primary people who thought he should be stripped of his prize were politicians who do not do well in modern history books. (He and his Jewish wife used the opportunity presented by the Nobel Prize award ceremony to leave Italy and immigrate to the U.S.) He himself wasted no time fighting allegations, immediately investigating this new field opened up by the mistake. He is credited with designing and building the first fission reactor only a few years later, perhaps the most rapid large-scale application of an obscure scientific discovery in the history of technology.

Perhaps the best example of serendipity in medicine is Alexander Fleming's discovery of penicillin. He had left some bacterial culture dishes open for a while, then put them away while he was on holiday. When he returned he found a fungus, identified by a colleague as penicillium notatum, growing in a spot in the culture. Around it he noticed a ring devoid of bacteria from the colonies he had started. He conjectured the fungus was producing a substance that inhibited the growth of bacteria.

Fleming's work didn't lead to large scale production of penicillin until the discovery of sulfa drugs made it clear there was enormous potential for what was then called chemotherapy for bacterial diseases. He gained many honors, but avoided demonstrating the discovery experiment requested by journalists. The exact conditions under which bacteria and fungus must be cultured to produce what he saw turned out to be hard to reproduce. It can be done, but it is not at all easy.

How does this relate to current controversy? At the time a virus was reportedly discovered in prostate cancer tissues one might have guessed it would affect the immune system, but no one really knew. While discoverers believed it would exhibit a preference for human cells, they could not be sure. The idea that it would have a tropism for sexual organs would not be much of a stretch, though this need not have any connection with immune response. Nobody was prepared to go out on a limb and say this virus could enter the human central nervous system via a Trojan horse approach using infected T-cells. Right or wrong, the resulting research has produced a string of instructive surprises. If the virus is no more than a laboratory artifact unrelated to prostate cancer or diseases of the immune or nervous systems none of these secondary discoveries make any sense. They are anomalies which most researchers have decided to ignore. Their advice to others is remarkably short on leads to elucidate etiology of anything.

Where does this research have the potential to lead? Let me quote one of the investigators of a forgotten outbreak, David Poskanzer, who went on to teach neurology at Harvard Medical School while also a neurologist at Massachusetts General Hospital:

You can find this in his open letter to BMJ in 1970. He also makes good points about why they considered and rejected an explanation based on hysteria.

Hysteria as a theory of etiology has had a very long run in medicine (2,300 years?), which has done nothing to reduce the incidence of this problem. (In fact Freud had to fight to get male doctors to admit there was such a thing as "male hysteria".) The cost of mental illnesses, direct and indirect, is staggering, not even counting pain and suffering. Isn't it time to follow up a clue which might offer hope of actually checking the steady increase in incidence -- even possibly curing presently incurable disease?
anciendaze

About the Author

As the name suggests, I am old and dazed. The avatar illustrates my rule of thumb: "Hang on! This ride isn't over."
  1. Enid
    I much enjoyed this on a purely personal level anciendaze - high dose amoxcillan given by my Dentist for specific root infection following extraction had a marvellous effect on GI problems going untreated by my Doc. Now there's a thing, struck lucky by a bad tooth (well 4 bad teeth) - connection missing from my medics.