Thursday, June 30, 2005

"Take a flier on it"...

Apprentice to Genius: The Making of a Scientific Dynasty- Robert Kanigel (MacMillan, New York, 1986)

The past and present of our civilization is replete with famous (infamous?) dynasties, mainly political and business families; the Nehru dynasty, the Bush dynasty, the DuPont dynasty, the Kennedy dynasty and so on.
Less famous are scientific dynasties, generations of mentors and their students who contribute to a growing body of knowledge, frequently as pioneers. Many times, the unique streak and style of research as well as values developed by the original scientific patriarch endures in an unmistakable manner, and his scientific children, grandchildren and beyond distinctly display that streak in bringing important work to fruition.

One such important scientific dynasty begins with James Shannon in the late 1940s. I don't how many of you know this name, but I had not heard it till I began reading Robert Kanigel's engaging and inspiring account of a brilliant scientific dynasty; Apprentice to Genius. James Shannon was the man who almost singlehandedly founded the famous National Institutes of Health, the biggest biomedical research organization in the world, with a budget that is truly staggering, and research that has played a key role in our fight against disease and our efforts in the continuation of good health, over the past half century.

Kanigel (author of the very readable book on Srinivas Ramanujan; 'The Man who knew Infinity: A life of the genius Ramanujan') chronicles five generations of prize-winning pioneers who revolutionized the very important field of neuropharmacology, the science of how drugs act on the brain. Shannon was the trendsetter who first extolled a very simple but far reaching principle, namely the measurement of drug levels in the blood. This technique was revolutionised in all its glorious forms by his student, Bernard 'Steve' Brodie (the 'father of drug metabolism'). Brodie then passed on the scientific mantle to his student, Juliux Axelrod, who won a Nobel Prize for his research into the metabolism of noradrenaline, one of the key neurotransmitters in our body. Axelrod then trained HIS esteemed student, Solomon Snyder (at Johns Hopkins) who passed on the legacy to Candace Pert (author of the controversial 'Molecules of Emotion'). All these scientists essentially perfected various techniques for measuring the levels of various drugs and other foreign substances in the blood, in the brain, and in other organs, and then acting on the knowledge gained in these endeavors, both to find out more about the basic workings of our body and brain, and to design new drugs. If all this sounds technical and mundane, consider the following; by using this technique, Brodie discovered Tylenol, after Aspirin probably the most widely consumed drug in the world; by using this technique, he and Axelrod discovered crucial enzymes called microsomal enzymes in the liver, which act to metabolize each and every foreign substance introduced in our body; by using this technique, Axelrod and Snyder discovered a host of important enzymes, crucial for drug metabolism; by using this technique, Snyder and Pert discovered proteins called opiate receptors, the seat of pain and pleasure in our body, and key targets for tackling drug addiction...
These men (and one woman) completely changed the science of drug metabolism, and their research is the backbone of each and every drug which makes it to the market today. Their methods, their concepts and ideas, have become so seamlessly integrated into modern drug discovery, that their names are sometimes forgotten.

Kanigel paints an absorbing portrait of each of these characters, of their personalities and peccadilloes. Most importantly, he seeks to explain how they constituted an exclusive family of mentors and students, in the true sense of the terms. Mentor the Greek was a close friend of Ulysses, to whom the great king entrusted his son, Telemachus, when he left for the Trojan War. Mentor was supposed to be Telemachus's friend, philosopher and guide, a role model, and a constant force to steer the boy's complete development in the path that was chosen for him. A chapter at the end of the book talks about the general sociological ramifications of scientific research and mentorship. Thomas Kuhn's 'paradigm shifts', always a favourite of natural as well as social scientists, makes a cameo appearance in the chapter, to explain how scientific revolutions are frequently blazed by such dynasties. Kanigel has a good facility in bringing to life each of these stalwarts (all but two of whom are dead now- Snyder and Pert both are very much visible). Each one of these trail blazers trained a host of students throughout the world, who went back to their universities and laboratories, and donned the robe of style, taste, and discrimination in research conferred upon them by their mentors.

I was quite taken in by the style of research described, that was inculcated in all of them, primarily by Steve Brodie. According, to Kanigel, Brodie's style of research, particularly exemplified by Axelrod, was to consider research as mainly fun. Unlike many other students and researchers (such as myself) Axelrod would never get stuck with the small and tedious experimental details, or the detailed statistical analyses. He had an eye, or more correctly, a nose, for what the essential elements in the big picture were. He would never go for the details, but would look for the one decisive experiment, most of the times incredibly simple, that would turn everyone's heads. He would do the experiment in the most 'quick and dirty' manner possible, and then publish the results, leaving bottom feeders (like me) to slog over the muck of tedium. That style of his, and then of Snyder's, drew students to him like flies to honey. When they came into his lab, there were just two 'requirements' if any; a capacity for hard-work, and an open and cheerful mind. Axelrod's students (unlike me) would never be seen groping with glazed eyes through weighty tomes in the library. Instead they would be in the lab all the time, doing quick, even if sloppy, experiments. These experiments were remarkably simple and revealing, and blazed paths through previously unthought of territory- a tribut to Axelrod's uncanny 'nose'. Axelrod himself continued to work at the bench even after his retirement, eschewing the benefits of the Nobel, the mark of a truly dedicated scientist. Needless to say, there was magic in this approach. In Axelrod's own words, when he wanted to investigate an interesting phenomenon, he would tell his students to 'take a flier on it'. The phrase stuck, and got passed on to Snyder and Pert.
Long after leaving Axelrod's lab, Solomon Snyder would frequently wonder aloud when faced with a particularly recalcitrant problem; "What would Julie think about this?" if seeking divination. Kanigel's description of scientific research makes everything sound exciting, insouciant, and almost effortlessly flowing. Follow your nose, take a flier on something, do whatever you feel like doing- these are phrases that would be music to a graduate student's ears. Unfortunately, it DOES take a Brodie, an Axelrod, and a Snyder, to turn those phrases into spectacular reality, and most of us only achieve success by groping for the door in the dark room, lacking the seemingly infrared goggles that such stalwarts wear, with which to guide their students. However, I have not lost hope, and I think that attitude does count...

The most interesting part of Kanigel's account is the petty and glorious rivalries and other conflicts between the scientists, that threatened to destroy their reputations and credibility. Because they were involved in such important advances, the question of how to apportion the credit for discoveries invariably snubbed its ugly nose into the fray. When Axelrod discovered microsomal enzymes in the liver (a discovery which I think alone would have guaranteed him the Nobel; they are an essential, indispensable part of drug research today), the paper announcing their success had Steve Brodie's name on it as the main author, because he after all was the lab chief, and he had initiated the project in the first place, had provided crucial hints and so on. Now, this graduate student-principal investigator conflict has always been a dilemma, and to this day remains a fiercely disputed matter. More vehement was the debate over the discovery of the so-called opiate receptors. In 1971, Richard Nixon had declared an all-out war on narcotic drugs in a much publicised speech; the Vietnam war had driven many young men to addiction, and suddenly, intense interest and money was channeled into drug addiction research. Many vied for the prize, but the ones to finally get it were Snyder and Pert, who, in 1973 discovered a natural protein in the body that is required for agents like cocaine to elicit their euphoric reaction. Two years later, after another fiercely competitive scramble, Hans Kosterlitz and John Hughes in Aberdeen, Scotland, discovered a natural chemical agent in the body, enkephalins, that bind to this protein and bring about the same mitigating effect on pain. The search for the perfect painkiller has always been one of the hottest topics in medical research, and Snyder and Pert in the process opened up a whole new milieu, that continues to promise exciting insights into our understanding of the nature of physical (and mental) pain and pleasure. Unfortunately, the humdrum world of materialistic rewards is not as idealistic as the world of future possibilities. In 1975, Snyder, Hughes and Kosterlitz were chosen to be awarded the famous Lasker Award for Basic Medical Research. The award is significant, in that almost 80% of its winners have gone on to win the Nobel. Now here at last was the kind of Bronze Ring for which every scientist works all his life...except that there was a significant omission; Candace Pert, the graduate student in Snyder's lab who had done the work. Not surprisingly, the omission was pounced upon by Pert and a host of other groups as being the typical kind of male dominated lobbying that is insidious to all feminism. On one hand, Pert's rancour was justified; she bore the same relationship to Snyder as Hughes bore to Kosterlitz. Yet she was neglected and Hughes was chosen. On the other hand, she created such a furor about the whole incident, that Snyder's name, along with hers, was inadvertently dragged into the mud; the speculation was, and is, rampant that he has missed the Nobel because his reputation was embellished by this controversy. Nonetheless, as one of the most famous neuroscientists in the world, Snyder is yet a worthy candidate for the prize. Pert later published a book called 'Molecules of Emotion' (1997) that explained her part in the tale. During recent years, Pert has become an ardent activist of alternative medicine; maybe she seeks to resurrect her reputation, that in the minds of many has always remained embroiled in the opiate controversy.

Personally, I have read another splendid account of the whole opiate business; Jeff Goldberg's 'Anatomy of a Scientific Discovery', and while Pert definitely did play a crucial role in the work, I think that Hughes's contribution to the enkephalin discovery, made in the dingy and cold labs of Aberdeen, sounds more commendable; Goldblum's vivid descriptions of the most crude and fundamental kind of research that Hughes did, which involved dragging bloodied pig's brains from the local slaughtering house (in exchange for some fine bottled spirits) and literally re-slaughtering them with an ice pick on the floors of his lab, makes morbidly fascinating reading. After comparing the two books, I could not help but feel that Hughes's contributions were much more dedicated and self-initiated than Pert's who after all doggedly worked on the project, but only after Snyder managed to convince her about it's crucial importance. The readers are urged to read both these accounts, written in a very popular kind of style, with the minimal amount of technical details scattered through them, and then too when their description is absolutely necessary for the integrity of the story. They very much read like a fast paced novel.

Thus, Kanigel again hammers home the point; scientists, without exception all of them, are all too human, and not assuming that they are so leads to many of the public's misconceptions about the dealings that go on at the highest level in the halls of research. Research is always as human and exciting an activity as politics or sports (Ugh!). The line between the pursuit of potential benefits, and promising work that gets smothered is thin, and is best exemplified by scientific dynasties, with all their glories and flaws.

Postscript: Of all the emotions, I think the most mysterious one may be love. What is it exactly, that makes us don spectacles of that emotion, through which the whole world suddenly starts appearing different? Could the research of these pioneers lead us to an understanding of the 'molecules of emotion' that Pert talks about, in this case, ones that lead to wistful longing and dreamy-eyed monologues? I don't know, but it would explain the quintessential love potions that have been part of so much folklore from Cinderella to the tales of King Arthur, chemical cocktails that they were purported to be. In any case, many think that if we really find a chemical formula for love, it would undermine it's essential human ingredient. Quite the opposite I think. An understanding of the precise chemical balances in our body, combined with social conditioning that leads people to irrational unexplained actions, specifically designed to win the heart of another human being, would only increase the fascination that we have for that universal emotion, spanning centuries, continents, and races. The fact that such a profound human ethos should be explained by the same kind of molecular interactions that constitute inanimate matter around us, would only add to the magic, i think, and never subtract from it.


Blogger Hirak said...

Interesting thought on the 'love potion'. A definite Nobel prize in that.
Would make the Nobel prize for literature quite redundant if we could find chemicals for love, hate, etc.
For now they are still magical. Thank God for that!

9:57 AM  
Anonymous Anonymous said...

It is surprising that scientific insight can be taught and passed on. Techniques certainly can be, but passing on insight would be like creating an algorithm to find insight.

10:59 PM  
Blogger Ashutosh said...

Anon: Insights are not passed on per se, but students pick up the style of the mentor and it definitely shows. Robert Oppenheimer's school of physics in the 1930s is a great example of this, where his students picked up not just his style, but even his mannerisms; the dry cough, the hesitant and interrupted speech, and the lopsided, itinerant manner of walking.

7:37 AM  

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