Chronobiology an Internal Clock L for All Seasons

Eommsnts” EUGENE GARFIELD ~: INSTITUTE FOR SCIENTIFIC lNFORMATION~ 3501 MARKET ST,, PHILADELPHIA, PA 19104

%;%%%?% Chronobiology An Internal Clock L for All Seasons. Part 1. The Development of the Science k of Biological Rhythm

Number 1 January 4, 1988

The lives of virtually all plants and animals, from the simplest one-celled organisms to humans, are governed by a variety of internal biological rhythms. This essay (the first of two parts) discusses chronobiology, the study of these biological clocks. Biological periodicities may range from ultradian and circadian to circahmar and circasrnualcycles. Using ISI” data, we trace the development of the field from its earliest underpismirrgsin botany and zoology and identify the authors of Citation Ck.rsics”, such as Jurgen Aschoff, Erwin Burming, and Colin S. Phtendrigh.

Living organisms exhibit myriad cycles. ing to the daily rise and fall of the sun. In- Annually, the leaves of deciduous trees in deed, so familiar are these rhythms that, ac- the temperate zones turn brilliant hues of cording to pharmacologists Joseph S. Tak- yellow, orange, and red as the days shorten ahashi and Martin Zatz, Laboratory of Clin- and winter approaches. Each year, anirnrds ical Science, National Institute of Mentaf go through cycles related to reproduetion; Health, Bethesda, Maryland, they did not most of those in the temperate zones also elicit systematic, scholarly investigation until experience rhythms that prepare them for the the 1700s.7 Since that time, however, the period of inactivity that comes with winter. study of these biological rhythms has Cycles that take less than a year to com- slowly coalesced into the science of chro- plete are also plentiful. Daily rhythms in- nobiology. clude the folding and unfolding of the leaves Some of the foundations of chronobiology of certain plants, such as the “sensitive were laid in the 1930s. But as the first part plant” (Mimosa pudica) and the tamarind of this essay shows, activity in this field re- tree (Thnrars”ndusindicus), and the rise and mained fairly constant at a relatively low fall of the body temperature of animals (in- level until the 1950s and 1960s. Since then, cluding humans). 1(p. 5, 14) Numerous or- according to a review by Akin Reinberg, ganisms inhabiting the earth’s tidal zones, director of research, National Center of from plankton and diatoms to crabs and aea- Scientific Research, Paris, France, and birds, exhibit cycles of physical and behav- Michael H. Smolensky, associate professor ioral change ranging from 12 hours to two of envirorunental sciences, University of weeks to a month in length, matching the Texas Herdth Sciences Center, Houston, complex, interacting effeets of the sun and chronobiology has been art active, rapidly the moon on the tides.z In fact, even cells growing, multidisciplinary field.b The sec- exhibit some type of periodicity in their ac- ond part of this essay focuses on the latest tivities, often in cycles lasting fractions of research in this dynamic science. a seeond.j-s The importance of rhythms in nature has Biological Rhythms and Their been appreciated for thousands of years:b Sigrdfkance people plant their crops in tune with the cy- A vast array of periodicities in functions cle of the seasons and eat and sleep accord- or activities are exhibited by virtually every

1 organism, from single-celled plants and an- Environmental Influences on imals to such complex creatures as human Biological Rhythms beings.s These rhythms are intrinsic to the For centuries it was believed that biolog- organism and enable it to measure the pas- ical periodicities were cuused by the envi- sage of time. For many organisms, the most ronmental rhythms with which they were important interval measured by their inter- synchronized.b But in 1729 French astron- nal clocks is the 24-hour cycle of light and omer Jean Jacques d’Ortous de Mairan dark. Rhythms that coincide with this cycle (1678-1771) conducted an experiment show- are called “circadian,” from the Latin cir- ing that, even in total darkness, the leaves ca (about) and dies (day).g (p. 2, 10) of a “sensitive heliotropic plant’‘—probably Other important biological periodicities Mimosa pudical (p. f+—-continue to fold include’ ‘circatidal” rhythms, matching the and unfold in a 24-hour cycle that was pre- period of daily high and low tides, and “cir- viously thought to be in response to day- casyzygic” rhythms, which match the cy- light. 10 cle of unusually high and low tides occur- The idea that the circadian movements of ring each fortnight, when the sun and moon plants are indepmdent of the daily light-dark are in the proper alignment. ‘‘Circahmar” cycle was confirmed by a series of experi- rhythms are synchronized with the monthly ments performed by the Oerman botanist, waxing and waning of the moon. ‘‘Circan- Wilhelm F.P. Pfeffer (1845-1920),6,1 I nual” periodicities are cycles of about a (p. 61-2) in the late 1800slz and early year.g (p. 9-10) It should be noted, 1900s.13As Reinberg and Smolens& note, however, that circannual rhythms are not the however, it was not until the 1950s “that end of the story; for example, the 7-year and Pfeffer’s findings were clearly understood 17-year locusts that emerge from their long and appreciated.”6 puprd incubation in the ground are cycles It was another Oerman botanist, Erwin that span longer periods. Bihming, University of Ttibingen, who first An innate ability to measure the passage conclusively established the accepted foun- of time has adaptive significance. A sense dations of chronobiology: that organisms use of time helps birds to accurately use the sun, their biological rhythms to measure the pas- moon, and stars as navigational aids during sage of time and that these rhythms are in- migration. Internal clocks also enable orgrm- herent to the organism. Bunning proved the isms to synchronize their breeding behav- genetic origin of biological rhythms in the iors with one another as well as with the mid- 1930s while working at the BotardcaJ most favorable environmental conditions for Institute of the University of Jena. He found raising young. In fact, biologicrd rhythms that circadian rhythms persisted in the help organisms match a number of activities bean plant Phaseolus14 and the fmit fly to the times when those activities can be car- Drosophila, 15even though generation after ried out most effectively. For example, as generation had km raised in environments noted by zoologist David S. Saunders, Uni- completely lacking cues to the passage of versity of Ediiburgh, ScotJand, circadian time.b.11(p. 146-8) The 1936 paper on fruit rhythms allow animals of different spexies flies has been cited over 180 times, accord- tosharethe same foodsources without direct ing to the Science Citation Index” (SCF ). competition because some animals are ac- A Citation Ckz.rsic@, 16it is the most-cited tive ordy during hours of darkness (i.e., they paper ever published by Berichre der are nocturnaf) while others are active only Deutschen tlotanischen Gesellschq?, the during the day (diwnuf). The advantage to journal of the Oerman Society of Botanists. having a built-in methcd of responding to Bunrting’s work with Drosophila eventu- light and darkness, rather than relying on ally led him to conclude that the fruit fly actual changes in light as a cue, is that, in “knew” when to emerge from the pupal effect, the organism is prevented from stage of its development because its circa- “sleeping late” and missing the optimal time dian rhythm had cycled a given number of of day for foraging.g (p. 12) times, indicating that a season had passed.

2 His work has been extensively cited. A de- To describe the environmental cues from finitive, German-language edition of Bun- which biological rhythms are derived, ning’s work in this area, entitled Die Aschoff coined the word ‘‘Zeitgeber, ” physiologische Uhr (The Physiological meaning “time giver. “z] Colin S. Pit- Clock), 17was originally published in 1958 tendrigh, Stanford University, California, and reprinted in 1963. Using the 1955-1964 later introduced the term “entraining SCI, 18we determined that the former has agent” ;Z6still later, Halberg and colleagues received about 100 citations. The reprint has proposed the word “synchronizer.’ ’27A1- been cited at least 120 times. An English though these authors each give a somewhat translation appeared in 19649 and has been different definition of their terms, it has be- reprinted twice since then. The various edi- come common practice in the field to use tions have been explicitly cited in almost 700 them interchangeably.b publications, making l?re Physiological Clock a Citation Ckmsic.20 Aithough biological rhythms are innate, The Emergence of the Diacipiine of they nevertheless function to k=p organisms Chronobiohgy in tune with their environment and are thus Despite the discoveries of Pfeffer, Bun- responsive to various environmental, or ex- ting, Aschoff, and others, chronobiology ogenous, cues. In 1954 Jiirgen Aschoff, pro- did not really begin to coalesce as a distinct fessor of physiology and director, Max discipline until the 1960s.6 in part, accord- Phmck Institute for Behavioral Physiology, ing to Reinberg and Smolens@, this was be- Seewiesen iiber Starnberg, Federal Republic cause chronobiology lacked some of the at- of Gemmny,zl and Franz Halberg, Univer- tributes that help a field establish its own sity of Minnesota Medcal School, Minne- identity. For example, until recently chro- apolis, and Cambridge State School and nobiology was not taught in schools as a sub- Hospital, Minnesota, and colleagueszz in- ject in its own right, and no departments or dependently and aimost simultaneously de- chairs of chronobiology existed. This meant veloped an explanation of the role that en- that those who studied chronobiology nec- vironmental factors play in the functioning essarily came to the subject from other of internal clocks.6 fields, often by accident. As a result, the au- These environmentai factors-such as thors write, “the number of active and weii- light and dark, ambient temperature, noise, trained chronobiologists was quite small.’ ‘b and even interactions with other members Again, until recently, there were few of the same species%wt to keep biological scholarly societies devoted to chronobiolo- cycles in phase with periodic fluctuations in gy, which may have hampered communi- the environment. in the absence of such cues cation between the widely scattered mem- (which owurs when plants and anirnais are bers of the chronobiologicai community. removed to controlled laboratory condi- It is otlen beiieved that the true emergence tions), the cycles continue but begin to drift of a specialty is hampered by a lack of jour- out of phase with clock time and become nais focused on that field. Untii recently no “free-running.” Within their own free-run- joumais devoted exclusively to chronobiol- ning cycles, though, they are remarkably re- ogy were being published. In this respect, sistant to perturbation.6 In fact, several it is worth quoting Victor A. McKusick2s studies by Aschoff demonstrated that, be- and Frank H. Ruddle, editors-in-chief of Ge- yond certain narrow Mnits, the presence or nomics, on their justification for launching lack of environmental cues has no effect on a new journal. In an editoriai in the first is- biological rhythms.zs-zs One of these pa- sue, they said that they viewed the journal pers, entitled’ ‘Exogenous and endogenous “as a common meeting ground for molee- components in circadian rhythms,’ “24 is uiar biologists and biochemists, human and Aschoff’s most-cited paper; published in somatic cd geneticists, cytogeneticists, pop- 1960, this Citation Ciassic has been cited ulation and evolutionary biologists, genetic over 470 times. epidemiologists, clinical geneticists, thtm-

3 Table 1: Selected list of joumds reponingonbasicand journals, the smaller, new journals will have appliedstudyof physiologicalrhythms. A = title and a tough time. publisher.B= 19S6impsct factor. Since the 1960s, however, several A B changes have begun to take place that have enabled chronobiology to gain recognition American Journal of Physiology 3.29 American Physiological Society and intluence as a discipline in its own right. Bctheada, MD Three journals that report solely on chro- Brain Research 2.86 nobiological research, the Internutioncd Elsevier Science Polishers Journal of Chronobiofogy, Chrorwbiologia, Ammerdam, The Netherlands and Chronobiology Itiemutional, have been Chronobiologia 0.72 founded. Table 1 lists these and other jour- Casa Editrice Mifrm, hfy nals in which chronoblologists publish. The Society for the Study of Biological Rhythm, Chronoblology Intemationsl Pergamon Press, Inc. founded in 1937 but relatively dormant un- Ehrrsford, NY til 1953, changed its name to the Intern- International Jourmd of Chronoblology — ationalSociety for Chronobiology in 1971 Gordon & Breach Science publishers Ltd. and has been highly active ever since. Other London, United Kingdom scholarly societies and associations that pro- JoumaJ of Biological Rhythms — mote chronoblological research are listed in Guilford Publications New York, NY Table 2. A favorable intellectual climate also Journal nf ClinicslEndwrinologysod 4,20 Metabolism played a role in helping to establish chro- EndncrineSnciety nobiology as a distinct discipline. Reinberg Bsftimore,MD and Smolensky refer to the 19~Os as the Jourmd of Comparative Physiology A— 0,90 “golden age of molecular biology” and note Sensory, Neural, and J3efraviomJ Physiology Springer-Verlag New York, hrc, that it coincided with a flowering of chro- New York, NY nobiological research. 6 In part, they say, Joumaf of Insect Physiology 1.60 the emergence of cbronobiology was aided Pergarnon Press, inc. by the burgeoning interest of molecular bi- Oxford, United Kingdom ologists in cellular periodicities. At the same Jnurnaf of fnterdiaciplinary Cycle Research 1.46 time, as both a cause and an interactive re- Swets & Zeitlinger BV sult of this heightened interest, new statis- Lisse, The Netherlands tical approaches for detecting and measur- Journal of Pkwal Research 1.25 ing biological periodicities were being de- Alan R, Liss, Inc. New York, NY veloped. These were especially useful in Physiology and Behavior 1.43 studying ultradian rhythms, which include Pergrmron Press, Jnc. cycles that range from a fraction of a second Elms ford, NY to a fraction of a day. Psychiatry Research 2.30 Pittendrigh organized a symposium at Elaevier Scientific publishers Irehmd Ltd. CoId Spring Harbor, New York, in 1960 to Shannon, Irclsnd address the standards that chronobiology had sleep 1.50 to meet to develop further as a modem, Raven Press New York, NY quantitative biological science.b Among the topics discussed were more rigorous meth- retical biologists, and computational scien- ods of data sampling and gathering and sta- tists, all interested in the biology and genet- tistical amdysis.zq,zb.~ ‘l%e1960 paper Pit- ics of human and other complex ge- tendrigh wrote for the symposium, entitled nomes ~’29 However, not every field best “Circadian rhythms and the circadian or- serves itself by jumping into separate pub- ganization of living systems,’ ’26 is hk lication. As long as the most important ar- most-cited work. This Citation Classic has ticles remain in the bigger, mukidiseiplinary been cited in over 450 works.

4 Table Z Selectedlistof aasnciations promoting research greatly increased since the 1960s. This has and providing information on various aspezts of enabled chronobiologists to produce what chronobiology and circadian rhytbma. Reinberg and Smolens& call “a critical International Commission on Circadian Rhythms and mass of experimental evidence” that has sleep overcome previous theories that” slowed or Department of Physiology Harvard Medical School inhibited the advance of chronobiologic hy- 25 Shattuck Street potheses and concepts. “e Boston, MA 02115 These theories included the idea, taught International Snciety of Mathematical Biology to “generations of students, ” as Reinberg 11 bk avenue de la Providence F-92 160 Arremry and Smolensky note, that the regulatory F- mechanisms of biological systems are pro- Intemational Society for Chronobiology cesses that attempt to maintain a constant, Chronobiology Laboratories or steady, state, called homeostasis. University of Minnesota Schnol of Medicine Although Reinberg and Smolens~ do not 380 Lyon Laboratories Mirmeapnlis, MN 55455 discount the importance of homeostatic regulatory mechanisms, they point out that the body’s “set points” fluctuate within a This symposium and the subsequent ac- narrow range in a distinct rhythm. Such tivity and debate that surrounded the estab- physiological phenomem as the levels of lishment of chronobiology as a discipline plasma cortisol, testosterone, circulating have been the objects of considerable interest Iymphoeytes, and blood pressure and body among historians and sociologists of science, temperature, to mention just a few, vary in according to Alberto Cambrosio and Peter predictable rhythms over a 24-hour peri- ~.6 Keating, Institute of History and Sociopol- itics of Science, University of Montreal, This concludes our discussion of the Quebec, Canada.Bl We discussed some of development of chronobiology as a distinct discipline. In Part 2 of this essay, we will the characteristics of the emergence of a new describe current chronobiology research. discipline in a previous essay on biomedical engineering. 32 ***** As a result of the founding of journals and societies and advances in techniques, the My thanks to Stephen A. Bonaduce and number of researchers engaged in chrono- C.J. Fiscus for their help in the preparation biology and, consequently, the number of of this essay. papers concerning various aspects of it have 619WISI

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