Science and Prizes
Earlier this year the Nobel Prize in Physiology and Medicine was awarded to Michael Rosbash, Jeffrey Hall, and Michael Young, for their discoveries relating to circadian rhythms – the 24 hour clocks that are built into all of our bodies and control our sleep/wake cycles as well as many other aspects of our daily lives. As often happens, there was another person equally if not more deserving of the prize, but who had the bad luck to die before it was awarded: Ronald Konopka, aka “The Kapusta Kid”. He died in 2015, of a heart attack, at the age of 68. Had he lived a couple of years longer, there is a good chance that he would have been one of the recipients; but Nobel Prizes are never awarded to the dead.
Interest in daily rhythms can be traced back at least as far as the ancient Greeks, but the first serious scientific work was done in the early twentieth century, most notably by the psychologist J. S. Szymanski, who placed animals in conditions of complete darkness for extended periods, and saw that they still showed sleep-wake cycles lasting about 24 hours. Even more importantly, these cycles usually drifted out of alignment with the external world, which clearly meant that they were not being controlled by any sort of subtle influence from outside. Over the following decades a lot more work along the same lines was done. In 1938 the sleep scientist Nathaniel Kleitman and his student Bruce Richardson carried out a famous experiment in which they lived for a month deep inside Mammoth Cave, completely cut off from the world, and measured how their body activity varied over the course of each day. Putting all of this information together, by the 1960s there was a clear understanding that the bodies of animals, as well as plants had fungi, contained internal time-of-day clocks – but there was virtually no understanding of where the clocks are located or how they work.
Interest in daily rhythms can be traced back at least as far as the ancient Greeks, but the first serious scientific work was done in the early twentieth century...
The next major advance came in the 1970s. There had already by then been indications that circadian rhythms involved a small but very important brain area called the hypothalamus, but a paper published in 1972 showed clearly that the critical role was played by a tiny sector of the hypothalamus called the suprachiasmatic nucleus. (This tongue-twisting name only means that the nucleus is located above the optic chiasm, where the optic nerves coming from the two eyes cross.) Damaging this nucleus, and nothing else, in experimental animals could abolish their daily rhythms. Later experiments found that if this small group of brain cells was removed surgically and placed in a dish of warm nutrient solution, the cells would continue to show patterns of activity lasting roughly 24 hours, for as long as they remained healthy.
At around the same time in the early 1970s, Ron Konopka, who was then a graduate student at Cal Tech working with the pioneering geneticist Seymour Benzer, decided that it would be interesting to look into the genetics of circadian rhythms – a topic about which absolutely nothing was known, and which most circadian researchers didn’t even think was interesting. Konopka and Benzer decided to work with fruit flies, for several reasons: first, a lot was already known about their genetics; second, their lifespan is very short, only about two weeks for the full cycle from fertilization of an embryo to reproduction by the adult, so many generations could be examined in a short time; third, their tiny size meant that huge numbers could be maintained in a small laboratory; fourth, it was easy to induce mutations in their genes; fifth, they showed clear circadian rhythms, even when maintained in constant light or darkness. Konopka and Benzer decided to induce mutations using a chemical called ethyl methanosulphate, and to focus on a behavior called “eclosion”, a fancy term that simply means the emergence of an adult from the pupal case. Eclosion was chosen because it tends to occur at a particular time of day, and is easy to spot even amongst a large mass of insects. Picking out flies that eclosed at the wrong time, and separating them from the other flies, was a relatively simple task.
Konopka went through this process for a whole bunch of flies, and in the end was able to isolate a number of mutated strains that showed differences from normal flies in their circadian rhythms. Three of the mutated strains seemed particularly interesting, because by examining how the mutations were passed on to offspring it was possible to figure out that (a) all of the mutations affected genes on the X chromosome (the chromosome that females have two copies of and males only one); and (b) as a matter of fact, all three mutations affected the same gene. This gene was given the name “per”, short for “period”, because the mutants all showed circadian rhythms whose periods differed substantially from 24 hours. (Actually one was arrhythmic; one showed a period of 19 hours; the third showed a period of 29 hours.) The short paper by Konopka and Benzer describing these results has been called “perhaps the single most influential paper in circadian rhythms”.
Further Circadian Exploration
There then followed several years in which Konopka and others used a set of techniques that nowadays seem incredibly baroque and laborious to gradually narrow down the location of the per gene to a small region near the center of the X chromosome. By 1980 or so, a number of groups of scientists began to feel that it might be possible to isolate and clone the gene, and several set out to do so. Michael Rosbash and Jeffrey Hall, two of the Nobel Prize winners, were the first to succeed. Their accomplishment opened the door to a whole series of advances: deciphering the basic mechanism underlying per’s circadian functions; discovery of numerous other circadian-related genes; etc. One of the most remarkable and important discoveries came in 1997, when several groups of scientists reported finding genes in mammals very similar to the fruit fly per gene. It turned out that we mammals actually have three versions of the per gene, and that they play essentially the same role in our circadian rhythms as the single per gene does in fruit flies. This is pretty amazing, because our evolutionary histories diverged over 500 million years ago – our last common ancestor was some sort of extremely primitive worm-like thing.
Meanwhile Ron Konopka continued to work on circadian rhythms for several years, but ultimately dropped out of science. He joined the faculty at Cal Tech in 1974, but like many other brilliant scientists he was slow to publish his research, and eventually was denied tenure because of his weak publication record. He moved to Clarkson University, but was unable to get tenure there either (for obscure reasons), and in 1990 moved back Pasadena, where he spent the next 25 years doing small jobs such as tutoring. His health gradually began to deteriorate, and in 2015 he passed away – missing out by just a few years on his share of the glory.