What is in a name?

What is in a name?

Resistance to scientific ideas is not always due to lack of communication resulting from language Carriers. Resistance can also arise out of preferred bias. And because of calling things by the wrong name. The story of circadian rhythms in bees is instructive here. Beling (1929), a student of Karl von Frisch, had strong evidence in 1929 that his bees were orienting in time with the help of endogenous clocks. Time training experiments in which food was daily offered at a given hour, had to be 24 h apart and the insects would not (en)train to 19 h cycles. Three years later, Otto Wahl demonstrated that the rhythm, which the members of the von Frisch school called variously Zeitsinn (time sense) or Zeit-gedachtnis (time memory), was inborn not learnt, and that honey bees that had never experienced light: dark cycles could still be entrained to 24 h cycles of restricted feeding in total darkness. There was a great reluctance to call the phenomenon by its right name of circadian rhythm. This cannot be seen in retrospect as an eccentricity or as a harmless fad. Having called it Zeitsinn the bee researchers began concentrating on environmental parameters such as the sun’s azimuth, polarization of light, landmarks, humidity, wind direction and wind speed as possible causes, to the detriment of progress in rhythm research. Renner (1955) later performed the by now famous translocation experiments on honey bees, training them to search for food in Paris and flying them to New York, to see if they relied on endogenous time keeping or responded to local (New York) time cues. Pittendrigh (1993) commented: “While in Munich in 1959, I asked Martin Lindauer why they (the von Frisch laboratory) had still not reset the bee’s clock with a Hoffmann-like shift of the light: dark cycle” (referring to K Hoffmann’s demonstration that a time-shift in the light: dark cycle caused a proportional shift in the orientational clock in starlings). “Because”, he replied “bees don’t have clocks, they have Zeitgedachtnis”. That is what is in a name. That is also why so few people outside Germany knew about the monumental contributions of these early workers to chronobiology.

There are calendars sold now in supermarkets which inform the owner of his good and bad days, the days on which some things may be done, and days on which certain things may not be done. This pseudoscience called ‘biorhythms’ threatened for a while the newly won respectability of chronobiology of the biological rhythms kind. Believers in the cult of biorhythms proclaim the existence of the 23-day male cycle, 28-day female cycle, 33-day intellectual cycle, a 38-day compassion cycle, a 43-day aesthetic cycle, a 48-day self-awareness cycle and 53-day spiritual cycle. An author of a book on this subject (Gittelson 1983) states that Dr Wilhelm Fliess of Berlin started it all in 1880. This Fliess was an otolaryngologist, a member of the Berlin Board of Health, President of the German Academy of Sciences and a friend and mentor of Sigmund Freud. There is no evidence that Fliess impressed even his contemporaries with his notions regarding biorhythms. By the time of his death in 1928 he was yet to see biorhythms accepted as any kind of science in his native land, let alone elsewhere. As for a modern opinion on biorhythms here is the trenchant comment of Pittendrigh: “I consider this stuff an utter, total and unadulterated fraud' I consider anyone who offers to explain my life in terms of 23-day rhythms a numerological nut, just like somebody who wants to explore the rhythms of pig-iron prices to 14 decimal places”. A National Institute of Mental Health (USA) paper classifies biorhythms as mythology. With all its absurdities, the concept of biorhythms has an obvious attraction for the sort of people who are drawn to parapsychology, astrology, horoscopes and to a belief in UFOs (Gittelson 1983).

Pacemakers, hourglasses and oscillators

An early researcher who caught my undergraduate imagination was Janet Harker of Cambridge, UK. From 1954 to 1956, Harker published papers in British journals on factors influencing diurnal rhythms in the locomotor activity of the cockroach Periplaneta americana (Harker 1954, 1956). She had been the first to show the participation of the endocrine system in the locomotor activity of an insect. She also reported results of exciting experiments in which cockroaches were made arhythmic in continuous light and then joined back-to-back in parabiosis with rhythmic cockroaches. The arhythmic member of the pair was mobile but the legs of the upper rhythmic member were removed. The locomotor activity of the mobile animal was then said to follow the circadian rhythm of the upper cockroach. She maintained that the pacemaking oscillator in the roach was housed in the sub-oesophageal gland. If she cooled the organ in situ for 4 h the clock was delayed for 4 h at all phases. Enthusiastic efforts by Shephard Roberts, a Ph.D. student of Pittendrigh at Princeton, failed to confirm Harker’s findings. The uneasy relationship between Harker and Pittendrigh is reflected in the discussion that followed her presentation in the Cold Spring Harbor Symposium of 1960. In her 1960 paper (Harker 1960) Harker referred to the work of just two other authors on biological rhythms; oddly, she did not cite her own review of 1958, among the earliest on diurnal rhythms (Harker, 1957). She did not straightaway endear herself to Pittendrigh by posing the question: can one can speak of a biological clock when one worked on eclosion rhythms in populations of pupae (as Pittendrigh did)? This was an unnecessary caveat since Pittendrigh had beautifully demonstrated the precision of the process of gating of the eclosion rhythm in D. pseudoobscura, which showed that the rhythms in individual flies were in synchrony. She also believed that her 4 h of delay at all phases of the rhythm of the roach was an “argument against regarding the rhythm as being dependent on a relaxation oscillator”. Many of Harkers findings have not been confirmed even though research on cockroach rhythms has flourished and is still in progress. Later Nishiitsutsuji-Uwo and Pittendrigh (1968) reported that the locus of the driving oscillation might be the optic lobe, a finding that has since been repeatedly confirmed.

The names of F A Brown Jr and J Harker were hardly ever mentioned even in passing in the weekly seminars of Bünning’s Botanisches Institut in Wilhelmstrasse in the period 1964-67 when I worked there. In fact even the views of A D Lees, who had demonstrated for the aphid Megoura viciae that the photoperiodic time measurement was being mediated by something much like an “hourglass”, were seldom critically discussed in Tubingen. This could have been the result of Bunning’s own attitude towards controversies, to steer clear of them. Like Medawar he preferred to avoid controversies of any kind. The organisers of an international meeting on Circadian Rhythmicity at Wageningen had invited both Lees and Bunning and were hoping there would be animated discussion between those who subscribed to the ‘hourglass’ hypothesis and the others who subscribed to the ‘endogenous oscillations’ hypothesis. Lees spoke reverentially of Professor Bunning’s hypothesis but concluded that the aphids may be in a separate class in themselves. Bunning had earlier given the chairman’s address and sat impassively in the front row. The chairman of this session, de Wilde, asked, “Does Professor Bünning have anything to say?”. Bunning replied “I have extensively written and spoken about the role of circadian rhythms in photoperiodism. As for Lees’ findings, I believe them, and nature has certainly more ways than just one, to solve problems.” Interestingly, it was Lees who displayed a slide of the Bunning model—not Bunning—showing the phase relationships of the hypothetical rhythm of light sensitivity under long and short day conditions (Lees 1971).

The clock gene and after

On one winter evening in Berkeley in 1968, Pittendrigh suddenly surprised me with the statement: “Once we succeed in finding the clock gene ... boy, we’d lick the problem of mechanisms...” (of circadian rhythms). His musings made it sound as though the eventuality were distant and wistful. A year later, in his laboratory Ron Konopka, a student of Seymour Benzer, hit upon the clock gene in Drosophila melanogaster. The formal paper with details was published soon after (Konopka and Benzer 1971). Biological rhythms research was now entering the new age. But it is proper to remember that the first evidence for the genetic basis of circadian rhythms was provided by Bünning (1932). ‘Clock genes’ have now been reported in the bread mould Neurospora, Arabidopsis and cyanobacteria. There was much rejoicing at the identification and cloning of the first clock gene in mammals—the mouse—by the researchers in the Center for Biological Timing at Northwestern University, Chicago, led by Joseph Takahashi (Antoch et al 1997). This, a landmark event, has been hailed as a nugget of circadian gold. Because of the known relationships between the Mus and Homo genomes, it is only a matter of time until someone identifies the homologous gene in humans.

The importance of circadian rhythms in human biology is impressive. They are directly or indirectly implicated in variations in hormonal levels, pharmacokinetics, timing of heart attacks, intensity of asthma, jet -lag, adjustments to shift work, sleep disorders and seasonal affective disorders (winter blues). Barely 20 years ago it was erroneously believed (Wever 1979) that human circadian rhythms, unlike those in other animals, were impervious to exposure to light and darkness. It was later discovered that this misconception arose since earlier work had employed light intensities much below the threshold for entrainment. A paper published this year (Campbell and Murphy 1998) challenges the widely held belief that mammals are incapable of extraretinal circadian phototransduction. The authors showed that circadian rhythms in body temperature and melatonin concentration in humans could be phase shifted by light pulses presented to the popliteal region (behind the knee).

Just as the Cold Spring Harbor Symposium of 1960 on Biological Clocks gave chronobiology respectability, the convening of the Gordon Research Conferences on Chronobiology every two years since 1981 in Europe or the USA has further invigorated the field. Also, a Society for Research on Biological Rhythms meets every year and there are several national societies that deal with the subject area; there is even a Society for Light Treatment and Biological Rhythms for the treatment of seasonal affective disorders. It is heartening for chrono- biologists that their subject has made the transition from the presumed status of metaphysics to the high altar of molecular biology. My personal opinion is that for those of us who have always been fascinated by the myriad behavioural expressions of biological clocks, the exciting era has just, started. There are many vital questions that remain to be answered. For example, the relationship between the family of lunar (or tidal) rhythms and circadian clocks remains to be elucidated. One is not even sure of the exact nature of the entraining agents (‘Zeitgebers’) responsible for the lunar rhythms; and what the molecular biology of circannual rhythms might be, remains entirely obscure.

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