The Pittendrigh-Aschoff Lecture 2024

Abstract

Chronobiology is one of the broadest disciplines in science – we can study and apply this system from molecules to shiftwork, from individuals to populations, from physiology to psychology, from mechanisms to medicine. Since I have an aversion against thinking in boxes, chronobiology was the only discipline I could faithfully live in for the past 55 years, giving me the privilege to witness its epitaxy from its pioneers to circadian medicine. I have tackled chronobiological questions with many different methods, but by far my favorite tool to understand are concepts.

It is a great honor for me to present a lecture, the title of which names two of my three mentors in chronobiology. To reflect my personal relationship with these mentors, I would have loved to change the lecture’s title to “Aschoff-Hastings-Pittendrigh Lecture 2024.”

Preparing such a lecture is a great opportunity for looking back at a life that—while it happens—is perceived far less consciously and reflectively than when it is remembered. The present is always a hypothesis that combines the (albeit subjective) data from the past with hypotheses about the future. The data/hypotheses ratio is obviously much smaller at the beginning of one’s life than closer to its end. A rule of thumb for a good lecture or paper is talk/write about what you know well. This is why I will keep this manuscript rather autobiographical, especially since I have been in the field for about 55 years and therefore witnessed both the development of chronobiology and that of my activities within the field for quite some time. Autobiographical stories can help others to make important reflections and decisions for their own careers by using the narrative as a cautionary and/or an inspirational tale.

My Scientific Childhood

This and the next chapter titles are meant literally and not figuratively.

In the late 1950s, the German Max-Planck-Gesellschaft (MPG, i.e., Max-Planck-Society) asked the Austrian Konrad Lorenz and the German Erich von Holst to establish a Max-Planck-Institut (MPI) focusing on Behavioral Physiology (Verhaltensphysiologie). They accepted and, given the opportunity to create such an institute from scratch, they recruited other colleagues as co-directors—among them Jürgen Aschoff. While most physiologists primarily needed labs to conduct their work, Lorenz and his cofounders needed—in addition to labs—a lake, hundreds of large aviaries, fishtanks, and a “bunker.”

The institute was built in “Seewiesen,” a rural area around a small lake in southern Bavaria, situated between two bigger and beautiful lakes in the Alpine foothills: the lake of Starnberg and the Ammersee. Although Aschoff was a co-director at the MPI for Behavioral Physiology, his institute building was a couple of miles west of the Seewiesen campus, in Erling-Andechs, closer to the Ammersee and a 30-minute hike from the famous, monastery-based Bavarian brewery, Kloster Andechs. The campus was situated on a small hill, into which Aschoff—a medical doctor and physiologist—and Rütger Wever—a physicist—built a temporal isolation facility (the “bunker”), with two apartments that were insulated from anything happening outside—from light and sound, from vibrations, and even from changes in earth’s electromagnetic field (Wever, 1979).

From the age of 10, I had strong connections with the work performed at Seewiesen because I went to high school in Starnberg, as did the majority of the children of Seewiesen’s faculty. Many of them lived on the Seewiesen campus—many miles away from their school friends. Their parents therefore encouraged them to bring friends home, who often also slept over and went back to school with the Seewiesen school bus the next day. I was very much a part of this group of friends and spent a lot of time at Seewiesen, where I was submerged in the exciting atmosphere of pioneering science.

The innovation of Verhaltensphysiologie lies in the name itself. The term “physiology” was already used in ancient Greece, but it was Jean Fernel, a French physician in the 16th century who basically defined it as biomedical science. For hundreds of years, physiology investigated organs and tissues in all phyla with increasingly sophisticated methods.

Physiology is the science of life. It is the branch of biology that aims to understand the mechanisms of living things, from the basis of cell function at the ionic and molecular level to the integrated behaviour of the whole body and the influence of the external environment. (The Physiological Society, n.d.)

While this modern definition of physiology includes “behavior,” it was Konrad Lorenz (initially University of Vienna, AT, and then Seewiesen, DE), Niko Tinbergen (initially University of Leiden, NL, and then Oxford University, UK), and Karl von Frisch (LMU Munich, DE), who expanded physiology from the function of organs to the mechanisms of behavior. They had a prominent pioneer in Charles Darwin, who already had explored physiology beyond morphic functions, in the context of evolution—in this case, emotions (Darwin, 1872). Darwin proposed that the mechanisms underlying emotions are part of physiology and thus inheritable.

The innovation of expanding physiology to behavior went along with another conceptual revolution. For the longest time, the physiology of organs was regarded as a marvelous product of divine genesis, but the work in Seewiesen was entirely built on the concepts of evolution. I fondly remember wonderful discussions as a teenager with Seewiesen’s scientists (the parents of the children I visited) about selfish genes, kin selection, altruistic behavior, and inclusive fitness. This was around the time when Jacques Monod published his book about the main driving forces of evolution, chance, and necessity (Monod, 1970) and well before Richard Dawkins published his famous book “The Selfish Gene” (Dawkins, 1976). These years also primed my understanding of humans being an animal species. Viewing humans as an animal species may be normal and logical to most scientists, yet I still encounter scientifically minded people—for example, medical doctors—who are startled when I say/write “humans and other animals.” The human animal was an integral part of ethology at both the Seewiesen and the Erling-Andechs sites. Another member of the Seewiesen faculty, Irenäus Eibl-Eibesfeldt, took the physiology of behavior to humans, founding a new field, “Human Ethology” and Aschoff was the first to investigate the circadian clock in many different animal species, including humans in the Erling “bunker.”

Notably, chronobiology appears to be a key discipline when it comes to studying behavior with modern scientific methods. The chronobiologist Aschoff was a pioneer for Behavioral Physiology and the chronobiologists Seymour Benzer and Ron Konopka were pioneers for Behavioral Genetics.

The Seewiesen campus was always buzzing with faculty and students quantifying behavior, in ponds, lakes and fish tanks, in aviaries and other (quasi-) natural habitats. I remember seeing Konrad Lorenz walking across the campus in Wellingtons on many of my visits; I also remember him performing his famous goose-imprinting experiments (goslings adopt the first thing they see as their mother, ranging from their actual mother to a ball to Lorenz). My memory also recollects him swimming with the geese in the campus’ lake, but now I am not certain whether this memory is real or whether my brain has sneaked in one of the respective famous photos.

Without realizing it at the time, my childhood found itself at the forefront of interdisciplinary physiological science. I am still in contact with many of the “Seewiesen children” more than 50 years after I had the privilege of frequent sleepovers with them.

My Scientific Adolescence

The Seewiesen gang in my high school, included most of the six Aschoff children. They lived in a wonderful, large villa, the “Schloss,” on the Erling-Andechs campus (see also Daan, 2000) and they too were encouraged by their parents, to invite friends to visit and stay. From the age of 17 on, I very much became part of the Aschoff family, as a friend not only of the children but also of the parents. During my school holidays and on weekends, I worked as a technician at the institute and developed strong bonds with Jürgen Aschoff, who must have enjoyed my scientific curiosity. To all the biological and adopted children of the Aschoffs, Jürgen was “der Alte” (the old one) and his wife Hilde—the human center of the institute—equivalently, “die Alte.” The “Schloss” had a huge kitchen, which was the hub not only for the extended family but also for many of the staff and faculty and above all for the frequently visiting scientists. My discussions with “der Alte” and his mentoring dominated my first years in science. When I was abroad, I often wrote him letters with questions, and he always responded promptly with letters that he created on an old typewriter that was characteristic for punching the small “o”s out of the thin airmail paper he liked to use.

Our topics were mostly concepts and he very early on encouraged me to challenge any of his theories. I cannot remember the exact words, but he once said, “You should always have great respect for the work of a scientist but allow yourself to be disrespectful in challenging his findings no matter how established or famous he is.” On several occasions, I took this advice and, over the years, certainly challenged concepts devised by Aschoff or Pittendrigh (e.g., Merrow et al., 1999; Roenneberg and Merrow, 1998; Roenneberg et al., 2010).

During my time in Erling-Andechs, I met most of the leaders of our field during their frequent visits to the institute: Serge Daan, Jim Enright, Sato and Ken-Ichi Honma, Fred Turek, Benji Rusak, Mike Menaker, Woody Hasting, and, of course Colin Pittendrigh, who was called “Pitt” by most people, but was “The Pope” for Jürgen and strictly “Colin” for Hilde.

And again, Colin and I loved to discuss concepts, some of which had no immediate relationship with chronobiology. I remember that we once spent an entire afternoon discussing the laws of thermodynamics, especially entropy (that was when I had started physics at university). He obviously enjoyed that too—or was amused about my enthusiasm. In many of our subsequent conversations, he came back to entropy and occasionally even introduced me to others with “this is Till, he is Mr. Entropy.”

I met Serge Daan, at that time the “youngster” among the pioneers, in Erling-Andechs, with whom also I remained a close friend until he died in March 2023. And again, our major topic of discussion were concepts.

My Scientific Early Adulthood

After being exposed to the field of circadian biology for about 4 years, it was time to actually study and I surely would choose a science subject. Aschoff had studied medicine, but regarded himself as a physiologist and claimed to have no clue about the “modern” facets of biology, such as biochemistry and genetics. It was predominantly Pittendrigh’s influence that made me enroll at the Ludwig-Maximilian University in Munich (LMU), choosing physics as my major (“the mother of all sciences”). But after 1 year, I realized that while physicists may have all the mental and mathematical tools to understand the world on a sub-organismal level, they had little interest in actual biology, that is, the enormous power of the simple rules of evolution—chance mutations and natural selection based on the number of genome copies passed on to the next generation.

Since the only species I ever was interested in was Homo sapiens, I switched to medicine, which obviously had been such a wonderful base for the research career of my scientific father. But again, I was disappointed: during the pre-clinical years, physics, chemistry, and biology were no more than crash courses for the future doctors—nothing was treated with any depth. At the transition from the pre-clinical to the clinical phase, I realized that my urge to understand how humans function was greater than the urge to help the sick and therefore I switched to biology which remained my academic box (I prefer the German word “Schachtel”) until the end of university.

In my final years (experimental Diploma thesis), and during my PhD studies (in the early 1980s), I embraced neurophysiology—I wanted to know how the brain works (Roenneberg and Pöppel, 1985). But that interest entailed a huge problem: it meant killing animals. I was torn between the fascination of deciphering brain function and anesthetizing, operating, and finally euthanizing animals. I investigated the visual system, using cats as model organisms and learnt firsthand from top researchers of vision-research the various concepts of how this central sensory system works.

It was a time of deconstructing brain function, and the peak of this period produced the famous “grandmother cell” (Gross, 2002), claiming that a single cell in the brain of a goat, a cat, or a human would store the memory of a specific other goat, dog, or grandmother. As much as I appreciated that the dissection of incoming information was a specialized and localized function, I always viewed the synthesizing processes of the brain as states that were functionally but not necessarily topographically distinct. So while individual grandmother cells may have been crucial for the visual aspect of the memory of my grandmother, the memory itself was a state combining many senses and associated emotions.

As part of an academic exchange program, I studied the neurophysiology of color vision with Semir Zeki at the University College in London (1980). During this time, I learnt an enormous amount beyond color vision. The famous location of the Biological Department in Central London’s Gower Street offered great opportunities to meet many prominent scientists who worked on different aspects of the brain, as diverse as research on vision, memory, and pain.

Yet, despite my fascination for brain research, no field could match the unlimited possibilities of Chronobiology. In Chronobiology, one could do anything from working on protein structure and basic molecular control of cellular functions, to the clock’s neurophysiology to optimizing social schedules for the biological system of an individual instead of for the convenience of the social system (e.g., school times and shift schedules). I therefore returned for my first post-doc period to my mentor Aschoff, investigating annual rhythms in humans, which combined my favorite species (humans) with my favorite biological field (chronobiology). I investigated world-wide statistics (mainly birthrates) for their seasonality (Roenneberg and Aschoff, 1990a, 1990b). It was a colossal undertaking: we collected vital statistics from 203 populations representing 3304 years of monthly birth rates, amounting to ≈10¹⁰ births. Some datasets went back to the 17th century; some were almost complete from the 19th century to the present (i.e., 1981).

This kind of data mining was not conducted at Seewiesen/Erling-Andechs, so, I had to reach out to many colleagues at the LMU, who taught me statistics, programming, and handling large databases. At that time, statistics was only touched upon in biology education. When I—much later in my career—got back to working with large human datasets, the statistics education of biologists was still quite rudimentary. At the time, most modern biologists proved their points and tried to convince their peers by showing single RNA, DNA, or protein electrophoresis gels and rarely made enough of these to allow proper statistics. There was, however, a department in German universities that taught excellent statistics: psychology. No wonder that most of my later graduate students and post-docs were students of psychology. I gave them a thorough education in biology, with special emphasis on conceptual thinking, and they continued to teach me statistics and prevented grave statistical mistakes from sneaking into the papers we published. Thus, when you choose students, try to choose those who know some aspect of life better than you do, thereby creating a reciprocal exchange of knowledge. This situation is much more fun than one-way-mentoring and fosters mutual respect. I am lucky to still be very close with many of my former students and post-docs.

The next step in my early career as an “adult” chronobiologist was moving to John Woodland “Woody” Hastings’ lab at Harvard University (1985-1988). I wanted to learn more about the cellular/molecular mechanisms of the clock and loved the idea that I would not have to sacrifice animals in the process. Already at our first encounter at the University of Konstanz, where he visited, Woody and I got on like “a house on fire.” After some correspondence (on paper, i.e., before email) about a potential post-doc, I seized the opportunity.

When it came to choosing positions, it seems that the relationship with my mentors was even more important to me than the research topic. Although it may not be the right approach for everyone, I do recommend it. It is also related to what I experienced as a PI: the most brilliant student may be more harmful than beneficial for the group, if he or she does not get along well with the rest of the team. Like Aschoff, Woody also became friend and mentor until he died (Johnson et al., 2014). When I started to work in Woody’s lab (overlapping with Carl Johnson and David Morse for several years), I was bubbling with ideas, both experimental and conceptual. Retrospectively, I admire Woody’s patience because I must have entered his office almost on a daily basis laying out a new idea. I think what helped him tolerate this bubbling thought-fountain was that he enjoyed having a student who had a profound education in circadian concepts.

I base this retrospective analysis on my own experience as an established scientist; it is so much fun to meet a “bubbling” young colleague! I can now appreciate what Aschoff, Colin, and Woody enjoyed in my “bubbling” and I strongly encourage young researchers to approach their established colleagues. By jumping over your shy shadow, you will always create a win-win situation. It does not matter if you do not “get on like a house on fire” with a potential mentor whom you might approach at some meeting; you have learnt that this mentor candidate is not your best match and that you must keep on looking. If you present your “bubbling” self to as many senior colleagues as possible, you eventually will find the right mentor for the next step in your career.

The Best Scientific Advisory Board Ever

Due to my scientific adolescence at Erling-Andechs, I knew many chronobiologists and knew a lot about circadian biology, but until I started in Woody’s lab, I had never officially been part of the field. I remember my first Gordon Conference at Plymouth State College (it was either 1985 or 1987) where Serge Daan happily greeted me as an old Erling-Andechs pal, and then made the following statement which I will never forget: “Why are you entering this field? All the big questions have practically been solved.” Serge Daan had worked both with Colin Pittendrigh and Jürgen Aschoff. With Colin, he published a series of five back-to-back papers that became a “bible” of circadian concepts, the famous “A functional analysis of circadian pacemakers in nocturnal rodents” papers (Daan and Pittendrigh, 1976a, 1976b; Pittendrigh and Daan, 1976a, 1976b, 1976c). So yes, he had a point: most of the conceptual questions had been solved, but there were so many other levels still waiting their turn—for example, the genetic and subsequent molecular research, that eventually led to our field’s Nobel Prize, had only begun.

Chronobiology is not like the Krebs cycle or photosynthesis that have a definable scientific life expectancy between asking the first questions and solving the puzzle. Chronobiology is so pervasive and so basic in all aspects of life that it still will have decades of vibrant scientific life, either as its most recent iteration, “circadian medicine,” or in solving so many unsolved societal aspects, ranging from daylight saving time (DST) to school-start times or shift-work schedules.

I was extremely lucky in being close to Aschoff, Pittendrigh, and Hastings. All three invested an enormous amount of time in mentoring me. For many years of my early career, they were my “scientific advisory board” when it came to conceiving and writing grants and papers. I often sent manuscripts to Colin—he either wrote back using a typewriter (delivered in an envelope either by mail or by fax; see example in Figure 1) and, over the years, increasingly via the upcoming email possibilities. In his later years, he more frequently spoke his comments on tape.

Figure 1.

Example of the correspondence with Colin S. Pittendrigh, who always was a great mentor. Mentioned names are redacted for privacy reasons. The term “Tangos” refers to a misunderstanding of me singing one of my letters with Till and Company (Tanco), which he misread as “Tango.”

All my students can testify that I am obsessive-compulsive when it comes to manuscript writing. Any student/early-career researcher who gets the first draft of his or her manuscript back with hardly any space untouched by their mentor should only have one happy thought: “I have an excellent mentor!” If there are only few comments, either you are a once-in-a-life-time genius or you should look for alternative mentoring possibilities, because teaching how to write scientific communications is an essential part of mentoring.

I still remember my shock when my supervisor returned the first draft of my diploma thesis; it was red all over (in those days, all comments were written with a red pen on actual paper). Whenever an early-career scholar in the digital age receives a lot of homework to improve a manuscript, he or she should pause his or her frustration and consider what this meant for earlier generations. For many years of my education and early career, I wrote every version of my manuscripts on real paper with a typewriter; the mentor used a red pen to make his marks, comments, and suggestions all over this once clean, beautiful, black and white physical oeuvre with many arrows moving things around or indicating connections to other pages. This meant that the next version had to be typed all over again (even the few untouched parts) before it was “destroyed” again in the next round.

Before I prepared this 2024 Pittendrigh-Aschoff lecture, I had forgotten how much I had learnt my obsessive-compulsive approach to scientific writing from my mentors. As I went through the boxes of scientific memories, finding corrected manuscripts and review-letters from Pittendrigh and Aschoff and listening—after decades—to Colin’s famous tapes, it all came back. I did to my students what my mentors did to me—and that is exactly how it should be.

In one of the earlier tapes, Colin said, “. . . I suspect that if what you sent me is the manuscript that went to Science, it couldn’t have been accepted in that form, and my comments may still be useful to you in going about some revisions” . . .

I’m going to try and go through the manuscript paragraph by paragraph and itemize, nitpicking details, . . . but I must say, I’m, a little disappointed in the writing and in how you handle these important findings. . . . In the abstract, the second to last sentence, “. . . since other ATP synthesis inhibitors also accelerated the clock, we suggest that this effect . . .,” it took me a while to find out what you meant by “this effect,” and of course, it’s the acceleration. So why not say, we suggest that this acceleration is due to a decreased rate of ATP synthesis.

As you can see, my early manuscript drafts were disappointing. But Colin went through my drafts word by word, sentence by sentence and made me aware of all the inconsistencies and far-from-stringent sentences. Both Aschoff and Colin taught me how to polish my writing and I must have progressively improved, receiving much more favorable reviews for later manuscripts (see example in Figure 2). Over the years, I collected a set of rules and recommendations, which I called “Scientific Poet” (Figure 3). Some of them seem trivial, but as an ensemble, they really helped improve my students’ writing.

Figure 2.

An example of how Colin S. Pittendrigh served as an internal reviewer of manuscripts that I sent him. This one is more positive than the tape in response to an earlier manuscript. Although he always used the term “Tangos” (see legend to Figure 1), he had forgotten its origin. In this letter, he refers to himself as “this alte,” a reference to the nickname of Jürgen Aschoff. It is unbelievable that Colin was then only 5 years older than I am now!

Figure 3.

“The Scientific Poet” summarizes the writing rules that I inherited from Aschoff, Pittendrigh, and Hastings and expanded over the years as a result of mentoring many students on many theses, papers, and grants.

During my “recherche du temps perdu” for this manuscript, I came across a letter that Aschoff wrote me in October 1998 (Figure 4), which made me realize that he was aware how close Colin and I had become over the years. In retrospect, once I worked on cellular topics, I did send more manuscripts to Colin than to Aschoff—even long after I had returned to Munich. Aschoff repeatedly made comments about “the close Till-Colin relationship” that had a flare of jealousy (that also comes through in this letter). Despite Aschoff and Pittendrigh being close friends, they always were scientific competitors. At the 25th International Congress of Physiological Sciences (IUPS) that Aschoff organized in Munich, 1971), I was asked to buy two water pistols. After Pittendrigh’s talk, the two pioneers launched an intense controversial discussion on phase versus velocity response curves that culminated in the two pulling their respective pistols, and squirting water at each other. More than three decades later, Carl Johnson and I re-staged this duel at an SRBR trainee day lecture that we both were asked to give.

Figure 4.

A letter by Jürgen Aschoff opposing my siding with Colin Pittendrigh in using the term “circadian program.” Translation: English translation: Dear colleague Roenneberg, during our very stimulating, though unfortunately short get-together in the blue salon of the castle in Tutzing, you pointed out, among other things, that you—apparently following our Pope Colin—prefer the term “program” to the previously common term “clock.” One of the arguments you put forward for this was that our conventional clocks have a constant angular velocity, whereas circadian clocks have a changing one. You are right that our pocket and other clocks run at a constant rate—they are not self-excited oscillators in the strict sense. We (Pittendrigh) have always assumed this when we have talked about “biological clocks.” Even in Cold Spring Harbor, I took the liberty of pointing out the changing angular velocity of the systems we examined (see page 14, right column, middle, and page 28, discussion with Rawson). I would like to go a step further: as important as the term “program” is, it misses the most important thing: the reference to cyclical repetition. A program—for example, that of the conference in Tutzing—runs its course and that is that. The “biological clocks” we have studied are self-excited oscillators, in which numerous programs start again and again precisely because of the “self-excitedness” of this clock. Best wishes from house to house—and from spouse to spouse! Your ever attentive student, The Old One (Der Alte).

The Importance of Large Numbers

When I investigated the circadian clock in Woody’s lab, using the bioluminescence rhythms in the single-cell alga Gonyaulax polyedra (now called Lingulodinium polyedra) as an output, the recordings produced extremely clean rhythms (e.g., Roenneberg et al., 1988), mainly due to the large number of “participants” (each recording vessel housed 30,000 individual single cells), all producing the bioluminescent signal under circadian control.

While Woody’s lab was mainly interested in free-running circadian rhythms (in line with the Pittendrigh school) probing the cellular/molecular mechanisms of the circadian clock and of bioluminescence, I introduced (in line with the Aschoff school) investigating Gonyaulax also under entrained conditions as well as probing the algae’s daily behavior (Roenneberg et al., 1989). The algae were cultured in a room kept under a 12 h:12 h light:dark (LD) cycle, but when they entered constant light conditions (LL; as photosynthesizing organisms, they cannot survive for long in constant darkness, DD), the amplitude of the population rhythm in bioluminescence stayed relatively stable over the course of the experiments (usually a week; see Figure 1 in Roenneberg et al. (1988)). This could either mean that the free-running periods of the single cells were very precise and stable or that they entrained each other via their medium (or both). It turned out that the algae do indeed modify their medium with metabolites (Broda et al., 1986), and we later showed that the Gonyaulax clock can be phase shifted both by changes in nitrogen concentration (Roenneberg and Rehman, 1996) and pH (Eisensamer and Roenneberg, 2004).

These circular effects, that is, modifying the medium with rhythmic outputs that feed back on the circadian system, gave rise to the zeitnehmer (“time taker”) concept (Roenneberg et al., 1998). The German term zeitgeber (“time giver”) was coined by Aschoff in the 1950s, and defined as those environmental signals that can affect the circadian phase and therefore are part of the entrainment process. While the (environmental) signals summarized by the zeitgeber concept are independent of the circadian system, the zeitnehmer concept describes outputs of the circadian system: that is, signals that both are dependent on the circadian system and feed back onto the system. Such zeitnehmer feedbacks could range from metabolites modifying the medium of unicells, receptors, or other components of an input pathway that oscillate in abundance/responsiveness (McWatters et al., 2000) under the control of the circadian oscillator, all the way up to the self-created darkness during human sleep (being under circadian control) in an otherwise almost constant light environment (as in some of Aschoff’s bunker experiments or in extreme forms of industrialized/urbanized lifestyles; Roenneberg et al., 2019).

Although I continued my Gonyaulax work when I returned to Munich in 1988 as a faculty member at LMU, the fact that I was working in a medical school teaching medical psychology (with topics ranging from epistemology to communication skills) encouraged me to return to my favorite species, the human. Humans are often called the worst experimental animals not only because of their supposedly high individual variability but also because researchers often do not trust them, especially when humans answer questionnaires. It is remarkable how we humans insist on our individuality, yet when you try to look at our species through the eyes of biology, you will find that human individuality is highly exaggerated and overrated. How humans court, interact with babies, or respond to stress may be individual in small details (as behavior is in many animal species), but in general, most of human behavior is more species-specific than individual (as I will describe later, this similarity also holds for changes in human entrainment across ages). The Seewiesen researcher Irenäus Eibel-Eibesfeldt (e.g., Eibl-Eibesfeldt, 1970) extensively showed how generalizable human behavior is (1970), with one of my favorite stereotypes being the eyebrow greetings that he documented in practically all cultures of the world (Eibesfeldt accumulated the largest film archive on human behavior).

Being a student of Aschoff, I learned that entrainment was the most important aspect of the circadian system. The more I learnt from controlled experiments in the laboratory, be it with algae, canaries, ground squirrels, or fungi, the more I wanted to know how these findings relate to the real world, and entrainment was the most important facet of the clock in that context. In the real world, a free-running, or as I call it a “through-running,” non-24-h clock is a dead end in evolution. Humans are an exception; since they are protected from many selection pressures, they can survive without stable entrainment, as exemplified by the non-24 syndrome (Malkani et al., 2019).

Evolution clearly took advantage of spatial niches (e.g., aquatic and terrestrial organisms), but in adapting organisms to a cyclic environment, it also used temporal niches (e.g., nocturnal and diurnal organisms; Roenneberg, 1992). To do this efficiently, it was essential to accurately predict time within the environmental temporal structure, including the availability/presence of resources, predators, and competitors (Roenneberg et al., 2015). Thus, entrainment was at the core of biological rhythms and the mechanisms that ensured entrainment were—at least for me—the most important to understand.

But how could we investigate the clock in real life? Few colleagues tried to study lab animals in the real world—Patricia DeCoursey et al. (1997) and Serge Daan et al. (2011) published two such attempts. I realized that the possibility to study the “circadian program” in the real world—especially if one tried to achieve large numbers—was realistic for only one “lab animal” species, humans.

Since I lectured about circadian clocks to pre-clinical medical students, I wanted a tool that I could use in class, involving the students themselves. With entrainment being at the center of my chronobiological interest, we—Martha Merrow, who was at the time a post doc in my lab, and Anna Wirz-Justice, the grand dame of human circadian biology and a long-time friend—developed a questionnaire that was aimed to assess an individual’s phase of entrainment, which is now generally called “chronotype.” We called it the Munich ChronoType Questionnaire, MCTQ (Roenneberg et al., 2003). During its first year, we collected paper questionnaires, mainly from students, and went through the cumbersome task of digitizing them. If we really wanted large numbers, we had to develop an online version of the MCTQ.

I have always been fascinated by people, who fill out lifestyle questionnaires in magazines—one can easily spot them in waiting rooms. These questionnaires often address salacious themes like “Are you a good lover?,” and—based on your answers—you receive immediate feedback how you relate to others. When we programmed the online version of the MCTQ, I insisted on incorporating this obvious fascination by providing the participants with a PDF that did exactly that, for example, you are a short sleeper and an early chronotype (using arrows on the sleep duration and the chronotype distribution plots to indicate where participant fell in reference to the growing MCTQ population).

When new items are introduced on the Internet that should be seen widely, it is important to initially accumulate a substantial population size, which then starts to multiply by recommendations (note this was the time when social media just started, where this “influencing” phenomenon is now well known). One of my doctoral students, Tim Kühnle, persuaded one of the biggest German survey institutes, TNS Emnid, to send an email containing information about our study to approximately 50,000 individuals in their database; in addition, we managed to launch a small article about the biological clock and chronotypes together with the link to the newly developed online MCTQ in the widely read newsletter of the German Automobile Association (ADAC). At that time, I was regularly contacted by the media for interviews about sleep, DST, or seasonal issues; I used these opportunities to advertise our chronotype study. Between 2002 and 2005, we were able to collect 34,000 questionnaires, and at the end of the study in 2017, we had accumulated ≈300,000 entries into our MCTQ database.

I was once asked by a colleague why I continued to collect beyond a certain number of entries since the aim of statistics was to extrapolate from a relatively small representative population to the population at large. The answer was easy; if you want to ask detailed questions concerning many sub-populations of your database, such as sex, age, body mass index (BMI), geographical location, different times of year, work times, commute duration, or nicotine/caffeine/alcohol consumption (all of which we had collected), you very quickly end up with very small groups. The cleanness of all of our graphed results substantiates this approach (Figure 5; errors of the mean are hidden by the drawn data symbols).

Figure 5.

Chronotype depends on age. We are born as “larks,” transition to be extreme “owls” throughout childhood, puberty, and adolescence. Once we reached this peak of late chronotypes, we gradually become earlier again until we reach—what Germans call—“Senile Bed-flight” and are “larks” again. This age trajectory is sex-dependent, with women reaching their peak of lateness at around 19 years of age, while men continue to around 21 years, consistent with earlier puberty in women.

The Importance of Concepts

The late Arnold Eskin once asked me over drinks at some conference “What are you?” What he meant was “to what camp do you belong”? At the time, the field of chronobiology consisted of many camps. I am not mentioning representatives by name because that always leaves people out (also note the frequent use of the useful word “mainly” in in the following sentences). When I entered the field, the predominant camp was the physiology and behavior camp (mainly using rodents, birds, humans, and occasionally plants; among them, the human camp was almost a separate exclusive camp). There was the biochemical camp (mainly using single cells, fungi, and plants), the neurophysiology camp (mainly using mollusks, birds, and rodents), the molecular camp (mainly using insects, fungi, and rodents), and the genetic camp (mainly using plants, insects, and rodents). The molecular and the genetic camps were highly interactive and sometimes hard to separate. Then there was the ecology camp (mainly using plants, insects, birds, and rodents) and the clock-and-health camp (applying epidemiology in humans or experiments in rodents), and then there was the conceptual, theoretical, and modeling camp. At the time, the main representative of the clock-and-health camp was Franz Halberg (who was referred to as “Onkel Franz” in the Aschoff world). Halberg was a pioneer in gathering data about human clinical parameters from healthy controls and patients in a circadian context. He was actually the father of the term “circadian” (Halberg, 1959). The Halberg world and the Pittendrigh-Aschoff world were not always on the best of terms, which was based on the different approaches, the clinical approach, mainly collecting data (“botanizing”) and the conceptual and mechanistic approach that used controlled experiments. As I will argue below (see also Roenneberg, 2025), the botanizing approach has often been unfairly criticized, especially since the data collection of the Halberg school may come in extremely useful, when we systematically botanize in the youngest iteration of circadian research, circadian medicine. “Botanizing” (“botanisieren” in German) was practiced by the early botanists, long before the term received a negative connotation by modern biologists.

On many occasions, I heard from people who came into the field, how much it felt like a family, which was absolutely true (and still is). I also hear from people leaving the field that we are unique in this respect and that they are homesick for the atmosphere in chronobiology. This family atmosphere was partly due to the fact that we were a relatively small field but also because—at each conference—every camp listened to the presentations of the others. Our pioneers—above all Jürgen Aschoff—contributed to the family nature of our field. These pioneers tended not to separate home and work, so that all their students and many of their colleagues “came home” to work with them (which sometimes included excellent parties).

There was a clear generational gap between the pioneers, who often were at home in many of these camps (this was not surprising since they basically laid the bases for the individual camps) and the next generation that tended to specialize into one of them. Although I certainly was aware of these camps, I never gave this “segregation” much thought. Mimicking the approach of the pioneers, I did not see them as separate “homes” but as “specialized shops” which could be visited when needed while following a line of thinking.

When preparing this lecture, I was reminded of the many named lectures that my friends and I listened to over the course of our careers (while having fun with snide comments in the back of the lecture hall). In many of these lectures, the laureates showed one title page of their papers after the other, which we back benchers thought a bit mindless but funny. Yet, during the preparation for this special lecture, I realized that I cannot completely ignore my papers since they so obviously are the backbone of my work and form a “diary” of my development. I therefore decided to show them all in one slide. This was initially meant as an insider joke (for my back-bench friends), but then I realized that I could actually apply some taxonomy to this “paper quilt,” as I called it. I was reminded of Arnold Eskin’s question over drinks that I never had properly answered and decided to mark the papers (admittedly rather subjectively) according to the camps that I visited (Figure 6). I have visited almost all of the initial camps of our field, but once I saw the color-coded figure, it became clear what my predominant camp was—concepts, theory, and modeling.

Figure 6.

My “paper quilt” showing the title pages of my publications, from oldest to youngest arranged from top-left to bottom-right. Papers are color-coded according to the field’s “camps” mentioned in the text. Lilac: (neuro-)physiology and behavior; green: biochemistry; orange: molecular genetic; maroon: clock and health; yellow: conceptual.

If research is directed toward curing syndromes, it also has to understand the mechanisms behind the phenomenon which will hopefully elucidate both the mechanisms that lead to the syndrome and the mechanisms that sustain health. I have called this important part of research “Implementation Biology” (Figure 7). What many younger researchers tend to forget is that in order to ask a good scientific question, we need to have done a lot of work beforehand in the form of “Conceptual Biology.” We need to collect observations/datapoints (botanize); we need to play with the collected observations/datapoints (manipulations) which will lead to initial results (analysis). Only then can we discover a phenomenon. Further manipulations lead to physiological and then formal descriptions of the phenomenon, leading eventually to a concept. While phenomena are the prerequisites of concepts, concepts are the prerequisites of the mechanistic descriptions of “Implementation Biology” (see legend of Figure 7 and Roenneberg, 2025, for more details).

Figure 7.

Modern biology is predominantly “Implementation Biology” that solves a scientific question by mechanistically uncovering how a phenomenon works (such as the generation of a circadian oscillation by molecules in a cell). Do not forget that in order to ask a good scientific question, we need to have done a lot of work beforehand in form of “Conceptual Biology.” To illustrate these steps, I have labeled them with stages of our chronobiological research history (in red). This part of the lecture was published elsewhere (Roenneberg, 2025).

“Conceptual Biology” is the foundation of “Implementation Biology” and not just some less powerful approach from the past. Conceptual and Implementation Biology should be practiced side by side to generate more launchpads for exciting new questions. Yet, it seems a forgotten art, which should be revived and passed along before those who grew up in the “conceptual era” are all gone.

Epilogue

Preparing this Pittendrigh-Aschoff lecture was an incentive to reminisce on 55 years of growing up in biological rhythms research. It made realize how privileged I was—how privileged we were as a generation. Fewer scientists were competing for jobs at any level and therefore there was less pressure, there were far fewer administrative rules, and there was much more administrative assistance. These conditions allowed us to (mostly) concentrate on the fun-stuff in science—on forming hypotheses, designing and performing experiments and analyses, crunching data, and discussing the results with the group.

I still love data as much as I did 55 years ago. My relationship with data is a relationship in the strictest sense. It starts with a fascination (the falling-in-love stage), gradually matures to understanding (so that the data start talking, telling stories), and progresses to mutual appreciation.

I also still love my scientific family. I met my best friends in the field, and we still share many wonderful moments with each other. I still love teaching and mentoring. My joy in helping younger colleagues to get grants, to perfect their papers, or to infect them with falling in love with their data is as intense as it was decades ago. My love for all aspects of science prevented me from learning what actual work is for most people.