As a child I had none. In my earliest adolescence I wanted to become a poet (and recently indulged again in this pastime 7). My father, to whom I owe more than I can express in words – an international attorney who would have preferred to be a physician himself – kindly urged me to take up medicine, which I did. I in turn urged my daughters to do the same, not by words but by example and deeds as a family affair 891011121314.

I started in high school accompanying physician friends of my parents in their practice and helping out in hospitals during vacation, when not travelling. Thus, as an interested student, I was just in time, before I went to medical school, to learn first-hand that cases of pneumonia for which there was then no treatment as yet, lasted about a week, before recovery or death, or as it was put in antiquity, before the occurrence of the lysis or crisis. This was my first encounter with timing in disease, namely with the biological week, which was known to Hippocrates in Greece, to Galen who had settled in Rome, and to the Islamic physician Ibn Sina (Avicenna) in Persia. They all knew that many diseases lasted about 7 days, the very lesson that I would have missed about single stimulus-"induced", or rather -"manifested", circaseptan periodicity, had I not observed patients before the advent of sulfonamides and penicillin 1516171819.

During medical school, I dabbled in endocrinology and infectious disease research, including a study in a Rockefeller Institute in Budapest and at an institute on Lake Balaton. While trying to help in the improvement of a vaccine for typhoid, I managed to catch a severe case of it myself, perhaps by not washing my hands thoroughly before playing tennis over the noon hour. Subsequently, with an interest in the adrenal cortex in post-World War II Innsbruck, I was a university assistant, who, i.a., lectured to students in physical education who skied or otherwise exercised during the daytime and came fatigued to evening classes (I was popular with them since after a sentence or two I turned out the lights, showed slides and allowed those so inclined to sleep). At meetings, I also learned, only in theory, about the importance of probability in close contacts with the physicist Arthur March, a friend of Erwin Schrödinger, and wrote briefly about "rather than" vs. "yes/no" 20. But the major findings of that time in health care seemed to be fully deterministic. The discoveries first of sulfonamides and thereafter of penicillin attracted the attention of many, including myself 21. My concern earned me a much appreciated invitation to work with Sir Alexander Fleming, the discoverer of penicillin, in the bacteriology department of St. Mary's Hospital in London. I did not accept this invitation since I preferred a fellowship at Harvard in endocrinology (my love in classical medicine), but gratefully kept the few packages of cigarettes Sir Alexander kindly offered when he visited Innsbruck.

The successes of both sulfonamides and penicillin were splendid and changed the practice of health care insofar as certain infectious diseases were concerned. Seemingly no statistics were needed. We dealt with true wonder drugs, we believed then, if not now. (Concern arising from findings of bacterial resistance came later.) By the 1940s, patients who received these antibiotics recovered, say from pneumonia, or so it appears, irrespective of treatment time. The ~7-day interval between the onset of a certain disease and its end, one way or another, was soon forgotten. To keep abreast clinically while it also helped to augment my income, I further took care of a dermatology and venereal disease ward in a French-occupation army hospital, where two cases stimulated my interest in timing to the point of producing a publication 22.

Arthur March had taught me caution, so I did not generalize when, on the same day, I diagnosed gonorrhea, again without statistics, in two young soldiers and started their treatment with penicillin concurrently 22. In talking to the soldiers, I learned that they had had sexual intercourse with the same prostitute a day apart. As the treatment continued, the one who had been exposed later was first to show a negative smear for the infectious agent. The result suggested that the time elapsed between the infection and start of treatment could be important. With only two cases to compare, there was no way to attach any probability to the interpretation that timing was important, as stated in print 22.

In Innsbruck, I also regularly took vaginal smears from prostitutes, stained by Erhard Haus, to follow changes in mucus described in a book by George Papanicolaou, another excursion into a cycle, but for whatever reason we could not find the reported changes. Mapping of changes with an about-monthly period had to wait 16.

Necessity, not choice. First, I encountered great variability as an assistant in medicine at the Brigham, and again across the street at Harvard, where I had been given a laboratory to develop, as already noted, a bioassay based on the depression by corticoids of counts of circulating eosinophil cells. In Minnesota, where I had a chance to continue work on the same topic thereafter, I could not confirm my own results, Figs. 1,2,3,4, until I solved the puzzles of opposite results that are sooner or later the inescapable finding at different clock-hours or weeks apart, whenever one unknowingly compares a group of animals with phase-shifted, Fig. 4, or one with phase-drifting (Figure 19 (IA)) rhythms, on the one hand, with a group that has the usual light-dark synchronized rhythm on the other hand 32. This confusing situation applies to all rhythmic variables, whatever the period involved. Coping with variability led me to differing rhythms in inbred strains of mice 34. The timing of rhythms and remove-and-replace approaches led me to a built-in adrenocortical cycle in humans 46 as well as in mice 34, that in turn led to free-runs 154748 and thence to the ubiquity and critical importance of temporal organization 4950.

The first time I probably considered the term must have been when a dear friend (best man at my wedding), Henry Nash Smith, brought it up. In his time, Henry was rated by others as the foremost scholar in the field of American Studies; it must have been before 1951 when he left Minnesota for the English department at the University of California-Berkeley, where he eventually became head and editor of the Mark Twain Papers and literary executor of Twain's estate, and in 1969 served as national president of the Modern Language Association. Before he left, Henry polished the English on many of my early papers and would in fact have been a first, or at least a co-author on them had he allowed it. McKeen Cattell, the head of pharmacology at Cornell Medical School, was then editor of the Journal of Pharmacology and Experimental Therapeutics, where I submitted a paper with Henry's help 51. Cattell knew me from when he had been a guest lecturer in Innsbruck, where I was an assistant to the dean, and had hosted me personally in New York after my arrival in the U.S. He accepted the paper on receipt, but it must have amused Henry greatly when Cattell added that I should consult someone conversant in English!

By the 1950s 34, I had found several kinds of differences among inbred mouse strains in counts of circulating blood eosinophils, namely in daily averages, and in extent of change within a day (Figs. 1,2,3,4,5,6,7,8,9,10,11). I had thus also learned about several already-noted puzzles 32 by the use of rectal temperature as a marker rhythm and the finding of periods that were one of the major reasons prompting the "circa" in "circadian": after blinding, rectal temperature showed an about (circa) 24-hour periodicity in each mouse, all happening to differ from precisely 24 hours, all happening in my hands (in the mouse, not in the rat) to be shorter than 24 hours and with the periods varying further among some of the mice themselves, Fig. 19. Another friend, Earl E. Bakken 52, the developer of the first implantable pacemaker for long-term use (and founder of the Medtronic company) 53, brought up the analogy of a free-running vs. 24-h synchronized oscillator, a master engineer's view of "circadian" vs. "dian" (Figs. 20 and 21).

Relatively early, I had become a member and later, for several decades, chairman of the nomenclature committees of the International Society for the Study of Biological Rhythms (now the International Society for Chronobiology), as well as being for decades the society's president 54, even though I resisted that invitation, urged by Arthur Jores, for many years. While batting for the society, nomenclature, designs, methods of sampling and analysis and popularization, notably in schools 91055 then became my long-term concerns, as was and remains the development of standardized units to arrive at the equivalent of a metric system for spatio-temporal diversity, for what could turn out to be the ensemble of chronomics complementing genomics and vice versa 56. I also served on a glossary committee of the International Union of Physiological Sciences (presumably nominated by Nathaniel Kleitman).

In Stockholm in 1955, I proposed "diel" and "dieloid" as terms intended to replace the ambiguous "diurnal", which was then confusingly used in health care to describe both the daylight hours (e.g., diurnal vs. nocturnal epilepsy or asthma) and the full 24-hour day. "Diel" was rejected with the argument, I believe it was from Frank A. Brown Jr, that its coiner from Harvard had not done meritorious work (I had only added "dieloid" to separate 24-hour synchronized from desynchronized rhythms). Eventually I reverted, for the same reason, to "circadian" and "dian" again 57, again with the intent to separate environmentally synchronized from free-running rhythms. At the time other committee members rightly objected to the use of two terms, which would create confusion since one would have had to document free-running by lengthy circadian studies before using the term, and not everybody could be persuaded to free-run in caves or in the laboratory before the proper term could be applied to one's rhythm, an overwhelming argument. References to the nomenclature of the time are discussed in reviews 3557 and nomenclature used by us is defined in a glossary 58, and in encyclopedias of time 59, statistics 60, aging 61 and shift-work 62.

Whatever I tried to do rests on the discovery of hormones and many other contributions to the current invaluable body of physiological information. Otherwise, there would be no circadians and no chronobiology. We should all be particularly indebted to those who founded the study of life and health, whether by endocrinology and metabolism, the brain or a micro-organism 6364. These and earlier pioneers, up to and including me, as the endocrinologist with the "cosinor beast", as Jürgen Aschoff put it, are listed in a pictorial background to the field by Aschoff himself 65. I am indebted to him for this genealogy, leading up to my contribution in the also-pictorial Capri 666768 and elsewhere 6970, and to Agostino Carandente for the settings he provided for courses that invariably led to many discussions Aschoff, Pittendrigh and Reinberg were invariably on top of my list of lecturers, even if Colin declined so of ten that eventually we had our meetings in Italy, bar one, without him.

Another bit of history is written in the context of a gallery of chronobiologists, which I began with Earl E. Bakken, the developer of the chronotherapeutic device par excellence, the cardiac pacemaker 5253. When asked to write such a gallery, which I plan to do should I live long enough to continue it, I wish to submit it to those concerned, a task which is no longer possible with the scholars selected by the editor, to my very sincere regret. The gallery started with Earl Bakken, also apart from the cardiac pacemaker, since for well over 50 years Earl has kept tabs on what we are doing and reviewed the evidence underlying an approach to diseases of civilization, my most urgent task 52. I appreciate his help and that of others who kindly wrote succinctly 71, giving me a new forum to report on what we are doing. Some of the past is recorded by my wife Erna 72 and, in more detail, by my most appreciated co-worker and teacher Germaine Cornélissen 73 who has become the leader in what has developed into chronomics. Germaine's is perhaps the most extensive spelling out of what I tried to contribute, matched by biographical detail and comments by John Pauly and Lawrence Scheving 54. What they all fail to mention is that others very often carried the lion's share, as did the innumerable past co-authors and current participants in the large-scale studies, replicated in the 1950s on the cell cycle and now in BIOCOS 56, with focus on the cosmos. With my first wife Erna, I shared 333 publications, and so far I have 95 titles with my second wife Othild.

I probably did more venipunctures on myself around the clock than most others; carried, with Erna, more rectal probes than others for years at a time (except for unavoidable removals) and had cuffs on my arm for years, second only to Erna and now to cardiologist Yoshihiko Watanabe. I also did more eosinophil counts on humans, mice, rats, monkeys, dogs and other species than most others in the past or present. Erna and others filled the counting chambers, e.g., during a full week when I bent sleeplessly over a microscope. (I had forgotten this until Dr. Dennis Lofstrom, while visiting, kindly reminded several of us, adding that I played tennis in between. Figuratively as well as literally, I tried to return every ball, and was University of Minnesota faculty champion in singles while playing figurative doubles with Erna and very many others who came to work with us.) During that sleepless week, Erna noticed, fortunately early, that we had counting chambers with two different depths, a non-periodic (purely artifactual) reason for a large variability; of course the more one focused on biological variability in its own right, the more the control of technical variability becomes essential, and vice versa. As on many other occasions, Erna's perspicacity saved the product of that week. In another case in Japan, her charm and down-to-earth personality mediated the successful implementation of an ambitious mapping of over two dozen clinical chemical variables on two continents.

My daughters Francine and Julia pulled their oar in 120 or 56 published titles, respectively. Both Francine and Julia had experience with several daily temperature and other psychophysiological self-measurements, Francine over 6 pertinent years, Julia over 4 years; they demonstrated among many other findings, very different individualized changes in relation to menarche 7475. As a family we traveled a great deal, always with research as our aim: often to Italy where Erna planned and then cared for a laboratory in L'Aquila; repeatedly all over India for the Smithsonian Institution; and repeatedly to Japan. In Chandigarh, India, Francine (then a high school student, now a radiation oncologist), Erna and I had an opportunity to plan a study with B.D. Gupta, implemented by Akhil Deka, using the peak in serial temperatures of accessible oral tumors as a marker for timing treatment. Thus, a first marker rhythm-guided tumor chronoradiotherapy doubled the 2-year disease-free survival rate of patients with advanced perioral cancers, Fig. 131114. The promise of chronochemotherapy is shown in Fig. 146.

My daughter Julia, now a physician specializing in occupational medicine with an MS in public health, also worked on a master's thesis in biology 12 with Phil Regal, the ecological chronobiologist at the University of Minnesota, another dear friend. Joined by her mother Erna, Julia measured the blood pressure of groups of ~40 spontaneously hypertensive stroke-prone Okamoto rats in 24-hour profiles repeated at intervals of months over the lifetimes of these animals. Since it took about 4 hours by tail sphygmomanometry after immobilization and heating under a gooseneck lamp to complete a measurement series on 40 rats, they were sleepless for 24 hours. They detected circadian hyper-amplitude-tension occurring transiently before an increase in the MESOR (chronome-adjusted mean), i.e., before MESOR-hypertension in the laboratory, as subsequently shown in humans by Yuji Kumagai 76, who also taught self-measurements to his two daughters Eureka and (no longer so "little") Erna, the latter the namesake of my late first wife (see Additional file: 1, Additional file: 2), Additional file: 3).

From there several steps led toward using the circadian amplitude of blood pressure as a risk marker in cooperation with Paolo Scarpelli, who introduced chronobiologically interpreted self-measurements into his routine clinical endeavors in Florence, Italy, with Max Halhuber in Germany and Japanese friends Teruo Omae, Terukazu Kawasaki and Keiko Uezono; Kohji Tamura and Yoshihiko Watanabe (see Additional file: 1, Additional file: 2, Additional file: 3). Kuniaki Otsuka, more than most, contributed critical data demonstrating a disease risk syndrome of an over-threshold blood pressure variability, an under-threshold heart rate variability, and an excessive pulse pressure as a group phenomenon, Figs. 15 and 16. Kuniaki extended his original research on a city-wide basis to individuals each monitored for a week up front (see Additional file: 2). From a clinical viewpoint, he started to meet the greatest challenge today: stroke prevention by 24-h/7-day blood pressure and heart rate monitoring for detection of changes in variability 83877787980 and their treatment, Fig. 1738808182. He has now also started a similar city-wide project in a second location.

Concomitantly, another 24-h/7-day monitoring endeavor at St. Anna Hospital in Brno, Czech Republic (Mendel's home city), is being carried out by Pavel Homolka under the initiative of Jarmila Siegelova, Professor and Head of the Department of Functional Diagnostics and Rehabilitation at Masaryk University in Brno, and Bohumil Fiser, Head of the Institute of Physiology at Masaryk University and former Czech minister of health, now associated with WHO. Far beyond my personal family, I have been fortunate to have a broad international academic family. In this family, many members became independent, which is natural; others cooperated lifelong, and of course have my special recognition in a personal context 15528385136. A major lesson I learned is the merit of the inseparable activities in science and self-help in health care that can be an academic family affair today and perhaps a civic duty tomorrow 8.

Along with many other investigators, I started cartography in the mouse, Fig. 22; humans, Fig. 238485; and other species; we documented the amenability of circadians to phase-shifting at various levels of organization by manipulating lighting 8687 and/or feeding in humans as in rodents 288. In systematic studies, we learned about differences between advances of a circadian rhythm (which are usually slower than delays) and about polarity in such a way that in the same organism, some rhythms advanced while others delayed. In the laboratory, we were able to phase-shift a circadian rhythm in mitoses by studying the rodents for a sufficiently long time span and thus debunked the earlier view by others that mitotic rhythms cannot be phase-shifted 89. Again at the cellular level, we phase-shifted circadians in RNA and DNA formation, in serum corticosterone and in susceptibility to audiogenic seizures. Different rates of phase-shifting 90 were found for liver glycogen in the first vs. the next 4 days following an abrupt change in lighting regimen and the rules of phase-shifting were mapped for circadians and only explored thus far for the much more slowly adjusting circaseptans that may be phase-shifted by 180° (after a transmeridian round-trip flight over 7 or more time zones). A transequatorial phase-shift of a circannual rhythm in the pre-trans-year era studied with the Marques family 314 awaits extension by a consideration of an even broader spectrum of intermodulating multifrequency rhythms.

A number of lifetime studies simulated shift-work on laboratory animals and a few studies of nearly yearly intercontinental flights complement circaseptan aspects of schedule shifts on insects with Dora K. Hayes and on Acetabularia with Hans-Georg Schweiger. These establish circaseptan aspects of circadian phase-shifting beyond a reasonable doubt, as does follow-up investigation by Mirian Marques, albeit the underlying mechanisms remain an unsolved, important puzzle. As many others did, we also studied circadians on mice kept in continuous darkness or continuous light, resulting, among others, in the persistence of a cell cycle, including rhythms in RNA and DNA formation 91. The most impressive finding was that as a function superficially of clock-hour, the same physical stimulus, such as noise or whole-body irradiation or a drug, such as ouabain or many anticancer agents, or another chemical, or a bacteriological agent, such as alcohol or an endotoxin, respectively, would all have predictably (insofar as they are rhythmically) changing effects, as drastically different as survival vs. death, albeit only on a statistically (but not individually) highly significant basis. An individual dies just once, of course, but the point I am making is that we were dealing with differences in percent survival as a function of timing rather than with all or none responses. The context of these findings is described in puzzles, if not as paranoias, which is exactly what some were called at the time.

My clinical work followed in the footsteps of Arthur Jores, who was for long the president of the International Society for the Study of Biological Rhythms as well as of the German Society for Internal Medicine and that for Endocrinology. I grew up with his textbook 92 and one by Henri Simonnet, who hosted me in Paris as a young man and led me to the pineal and, indirectly, to pineal feedsidewards, demonstrated by the indefatigable experimenter Salvador Sanchez de la Peña (Fig. 19). Jores fought what he called the "idiocy [Stumpfsinn] of 'three times a day'" 93, and wrote a critical review of the field in the 1930s 94 and hardly left a problem in chronomedicine untouched 93949596979899100101102103104105106107108109110111112113114. Werner Menzel, Jores' associate in chronomedicine, both in Hamburg, initiated curve-fitting, albeit without inferential statistical considerations, introduced a pump for clinical drug administration according to a preset schedule, and wrote a book on rhythms and shift-work, a source to the early literature 115, along with a book by Arne Sollberger 116. These sources complement other books and the proceedings of other meetings 117118119120121122123124125126127.

In the perspective of the past half-century, I owe a great deal to Alexander Chizhevsky 128129130131132, whom I never met, whose hard data on a circadecadal rhythm in the incidence of cholera documented what he and Frank A. Brown Jr. independently called pervasive effects 133, albeit without inferential statistical time series analyses. In relation to sleep and other problems, Nathaniel Kleitman 134 was always supportive. He had monitored the physiology of his family, but unfortunately many of these records were lost. His daughter Esther Kleitman, however, provided us with self-measurements for many years, in which, among others, the new trans-year of human heart rate would be demonstrated. When Nathaniel turned 100 years of age, he offered to have his blood pressure and heart rate monitored for 24 hours. I felt that it was more important for his health to monitor for 7 days. He refused, and I lost out. I had re-used Kleitman's term "synchronizer", which was defined in the same way as Aschoff's subsequently defined Zeitgeber. Since both Aschoff and Pittendrigh had really spread, not only the word but also the concept of a self-sustaining oscillator much more than I would have done alone, it would have been only fair on my side to reciprocate. But all three of us redefined our terms, they a zeitgeber and I a synchronizer (as primary or secondary), respectively, as an external agent, usually a cycle that does not "give" time and merely synchronizes existing body time with its own (e.g., 12-hourly alternating light and darkness) schedule 48. In discussing this view, I indeed referred to Aschoff's original demonstration and interpretation that "changes in length of cycle have been observed for the rhythm in bodily activities of rodents, kept in continuous darkness", i.e., that body time was rhythmic ("given") in the absence of a zeitgeber 48. But he, like I, defined what could be called a Uhrzeit (clock-time) or Kalendarzeit (calendar-time) giver, whereas the internal time structure was given in the absence of the synchronizer. The use in chronobiology of "synchronizer" preceded that of the less ambiguous "entraining agent", a good synonym for "synchronizer". But why should we use two words instead of one, and in using "synchronizer", why not honor Nathaniel Kleitman? Brevity and ringing bells are the main criteria in coining terms.

Investigators coming to our laboratory included both medical and graduate students and accomplished scientists who became collaborators and are highly valued co-authors, including Kenneth Berge, Anand P. Chaudhry, Halvor Vermund and Ed Flink in the early 1950s, and thereafter Bernhard Arbogast, Brian Brockway, Franca Carandente, Yoshihiko Chiba, Gabriel Fernandes, Leopoldo Garcia Alonso, Mauricio Garcia Sainz, Denis Gubin, Erhard Haus, Ramon Hermida, Yuji Kumagai, Helmut Künkel, Francis Levi, Cristina Maggioni, Mirian and Nelson Marques, Norberto Montalbetti, Ana Portela, Alain Reinberg, Salvador Sanchez de la Peña, Kalva Shankaraiah, Michael Smolensky, Brunetto Tarquini, Zhengrong Wang, Yoshihiko Watanabe, Wu Jinyi and Rina Zaslavskaya, to mention just a few. I regard them all as my teachers, among many others who cooperated, sometimes with teams of their own, such as Teruo Omae with Terukazu Kawasaki and Keiko Uezono; Kohji Tamura, and in particular Kuniaki Otsuka, who co-initiated BIOCOS and a series of meetings with original focus on chronoastrobiology. Institutionally, Italy's Hoechst Foundation in Milan and the University of Florence, under the leadership of Mario Cagnoni, were homes away from home. We have a long-term relation with Theodor Hellbrügge, who singlehandedly built social pediatrics in Munich, and who sent us a long series of advanced medical students who wrote their MD theses in Minnesota 135136. A lifelong personal friendship with Theo culminated in a recent symposium on chronomics in child development 137.

With respect to the editor's specific questions concerning Curt Richter, Jürgen Aschoff and Colin Pittendrigh, I emphasize that we were complementary, although Colin, according to Cambrosio and Keating 138, fought the idea of chronobiology as a science in its own right. For these influential opinion leaders, and for Frank A. Brown Jr, Erwin Bünning, Arthur Jores, Nathaniel Kleitman and Gregory Pincus among other distinguished scholars, rhythms then and now were mainly phenomena to be displayed in the time domain, preferably by typical examples (time-macroscopically), a very convincing yet selective approach, missing, more often than not, even one, or usually all inferential statistical estimates of characteristics of the period, amplitude, acrophase and waveform involved. For me in turn, the t-test sufficed in 1950 34 and the analysis of variance until 1953 139, yet by 1954, in the case of longitudinal series, the periodogram became desirable 47140141, temporarily replaced by some too-conservative power spectra 142143, soon replaced by cosinors, as prior information accumulated concerning the reproducibility of rhythmic change in a given aspect of a circadian system 144145. Resolution in the frequency (or period) and phase domains became indispensable as an essential, albeit most of the time complementary time-microscopy, even when the computation of a periodogram in the desk-calculator era of the 1950s took a week to complete and another week to check.

I had a lengthy conversation with Curt Richter only once, at a Cold Spring Harbor symposium in 1960, where he did not contribute a paper and did not accept as yet the proposition by most of us that there was a feature of endogenicity to circadians. I presented him with evidence about the extent of maintenance of an internal, albeit free-running structure, e.g., in time relations among rhythms in serum corticosterone and liver glycogen rhythms after blinding in mice and rest/activity, rectal temperature and urinary 17-hydroxycorticosteroid of humans in isolation from society, when the period synchronized is equated to 360°, Fig. 19 (ID) 15.

At that time, Richter had not yet discovered free-running in his rats. The rats I studied in continuous darkness had periods very close to 24 hours, in my hands usually 24.1–24.3 hours, lengthening with increased light intensity 146, in keeping with "Aschoff's rule" concerning rodents which Aschoff had earlier postulated and documented. After 1960, however, Curt Richter found free-running, as Colin Pittendrigh had earlier, and Aschoff before that 147. It was my pleasure and privilege to fully support Richter's application for studies in chronobiology that I had to referee; he had made great scholarly contributions, already apart from chronobiology, again in our field, and he was a chronobiologist.

Incidentally, I supported all applications by scholars in the field of rhythms, whether or not their views differed from mine. Once when I chaired a site visit to a chronobiologist in New York, the late Dorothy Krieger, who also served on this visit, was astonished that I very strongly supported an applicant (who indeed received his support) who emphasized the merit of expressing time series as a percentage of the series mean 139. Not only was the project not particularly novel or meritorious in her view or mine, but Krieger said that the applicant had nothing good to say about me. I thanked her and reminded her that the applicant was a chronobiologist after all, and in the land of the blind those with tunnel vision deserve support if they are to serve others.

I do not recall whether Jürgen Aschoff and I met before 1953, but we had several very friendly conversations that year at meetings of the International Society for the Study of Biological Rhythms in Basel 148 and thereafter of the German Physiological Society in Homburg/Saar 47. We immediately "sent in the same frequency", but with different methods. At the latter meeting, I reported on free-running after blinding with periodograms. In the proceedings' discussion (Aussprache), Aschoff, as he invariably did in our relation when we met, wrote positively:

Halberg's investigations are so important because they are some of the very few experiments available at this time on the endocrine control of 24-hour periodicity ... that consider to a sufficient extent the possible effects of disturbance and have led for the first time to clear results.

(Halbergs Untersuchungen sind deswegen so wichtig, weil sie unter den wenigen bisher vorliegenden Experimenten zur endokrinen Steuerung der 24 Std-Periodik (siehe Lewis-Wright) die möglichen Störeinflüsse genügend berücksichtigen und zum ersten Mal zu klaren Ergebnissen führten.) 47

As Aschoff and I conversed afterward, Albrecht Bethe, then the grand old man of German physiology, who had worked on the cardiac cycle, walked past. He said a few polite words to me, then turned to Aschoff and pointed out that his (Aschoff's) name had not been on the program. With his ready wit, Aschoff riposted that he had not been aware that cycles with a frequency lower than that of the pulse and respiration (Bethe's concerns) had become acceptable (salonfähig) in German physiology. Subsequently, Aschoff did as much as, if not more than anybody else to achieve this goal.

My wife Erna and I were delighted to have Aschoff and his wife as our house guests in Minnesota, I presume in the early 1950s. Later, my daughter Julia and I were pleased when Jürgen picked us up at the Munich airport in his nightshirt. We enjoyed his subsequent hospitality, I repeatedly on other occasions as well. It was a pleasure to have him regularly at our meetings in L'Aquila, Italy, as a guest of the Hoechst Foundation, which gave me a laboratory in L'Aquila and the journal Chronobiologia for two decades. Jürgen and I had both separately reinterpreted Johnson's data 149 as free-running, albeit Jürgen viewed them time-macroscopically while I preferred time-microscopy and laid primary emphasis on the genetic differences among inbred strains of mice, Figs. 1,2,3,4,5,6,7,8,9,10,11. We both interpreted documented free-running as an important tool, just as Colin Pittendrigh and Erwin Bünning did subsequently, albeit with a lag of some years. When Erwin Bünning visited Minnesota, we showed him Fig. 24, and he was also surprised to see the great difference in phase. We hosted each other in Tübingen and Minneapolis. When I was Bünning's guest and he gave a party for me, I requested that he show me his laboratory. He insisted that we wait until all the guests had departed; we then went to his lab, unannounced in the early morning hours, and found someone active in each room. Bünning certainly knew how to motivate his students!

At a meeting in Pittendrigh's home to which Colin had invited Jürgen and me in Princeton, they advocated the importance of clocks as a way to interest the public in what we did. I favored a ubiquitous, critically important time structure that could be the subject of a new science. Of course, I had enthusiastically cited Johnson's "exceptionally substantial and durable self-winding and self-regulating physiological clock" in 1953 46149, for the case of the adrenal cortex, my first clock, still critical albeit no master clock. The adrenocortical cycle naturally led to the pituitary and the hypothalamus by studies in vivo and in vitro 85150151152, not as a dictator – the sole head of an up-down hierarchical axis – but as a link in a democratic collateral hierarchy, which included, with the pineal-hypothalamic-pituitary-adrenal and broader neuroendocrine and paracrine network, an "oscillator" in each cell (49). Feedsidewards qualified in time were postulated for this network first in relation to a 3-way pineal/pituitary/adrenal interaction along the circadian scale 85152 and were extended to the circaseptan scale 15, Fig. 19 (IIE) to replace time-unqualified feedbacks and feedforwards that acted as gods from a machine, without consideration of external and/or internal cycles. There was a sequence of time-varying effects ranging from stimulation, over no-effect, to the inhibition of corticosterone production by melatonin, as a function of timing, Fig. 19 (IIC). Feedsidewards also characterized the effect of ACTH upon DNA labelling, Fig. 19 (IID). Eventually, I encountered the ubiquity of circadian mechanisms beyond an adrenal clock and the importance of the circadians in tipping the scale between life and death for the body as a whole. To me, circadian systems, for which I subsequently organized a Ross Pediatric Conference 153, were much broader in scope than timekeeping. Mechanisms underlying diversity in time complement genetic diversity in space. A spatio-temporal view of the BIOsphere and the COSmos is the inescapable conclusion of the accumulating chronobiological evidence 56.

Aschoff was aware of the ever broadening scope of time structures and had the term in the title of a broad and scholarly review of rhythms with different frequencies in different physiological systems 154. Again, we were complementary since I endeavored to tease out many frequencies in one and the same variable, notably in 17-KS to start 16155 and thereafter in many other variables 56 (see Figs. 25,26,27,28,29,30,31,32,33 for the prominence of the biological week over circadians in the human newborn but not in adulthood for the case of blood pressure and heart rate). Aschoff was much more than a clock-watcher (again honi soit qui mal y pense), but he did not use the inferential statistical tools that are needed to map some of the less prominent structures time-microscopically. May the following summarize my attitude toward him: Many of the participants at a meeting on "Circadian Clocks" 156 went to the Andechs brewery near Aschoff's institute in Erling-Andechs for a drink and a meal. The late Josef Rutenfranz (a collaborator of the active Theodor Hellbrügge) was sitting next to me. We and many others saw Aschoff accosted by two rowdies. I asked Rutenfranz whether the incident was to be taken seriously. Rutenfranz said it could indeed be serious and was a common occurrence in breweries. Although Aschoff was great in wit and had an imposing voice, he was physically small, and I believe I was the only person there who went to help him. The incident proved to be a joke after all, with the "troublemakers" (unknown to me and Rutenfranz for sure) being two of Aschoff's non-professional employees in his institute.

I also appreciated that Aschoff advised Fred Sargent to send Michael Smolensky to me, as he sent his own medical disciple Jürgen Kriebl. I regret that my letter failed to persuade Aschoff to come to Minnesota for a blood pressure and heart rate variability profile; but I tried, as I did with others, e.g., Gunther Hildebrandt, Nathaniel Kleitman and Hans-Georg Schweiger. The offer to all interested parties of a 1-week profiling of blood pressure and heart rate, now extended by Germaine Cornélissen http://corne001@umn.edu, still stands as long as we can afford it.

Colin Pittendrigh was the clock-watcher par excellence, as he emphasized himself by the title of the summary of his life's work in the Annual Reviews of Physiology 157. The field owes him a great deal, and hence and for other reasons, so do I, although some sociologists saw us as antagonists 138. Our positions were very different: he was a powerful dean, on a number of important committees, while I had lost my laboratory over several of my puzzles. The development of temperature and other telemetry in the service of circadian systems might have been delayed for years had he not advocated with Woody Hastings and others that I might represent chronobiology in the task of preparations for a NASA Biosatellite study of free-running rhythms in extraterrestrial space 146. While our experiment never led to a flight, that project resulted in much quantitative technical information, notably on the persistence of the temperature rhythm and other variables after the histologically validated ablation of the SCN, Figs 34 and 35. I enjoyed the opportunities to contribute to Colin's and Jürgen's meetings, and very greatly regretted that Colin came (with Jürgen) to only one of those meetings in Italy that I was asked to organize in the 1950s. To my particular regret, both Jürgen and Colin did not attend