Abstract
Sadly for the field of circadian biology, Michael Menaker passed away on Sunday 14 February 2021. “Mike” or “Menaker” as he was known to us needs no introduction to the circadian community. Mike was a giant in the field and one of the pioneers in the physiological analysis and identification of circadian pacemakers in the vertebrate nervous and endocrine systems.
Born on 19 May 1934 in Vienna, Austria (US Citizen by birth), Mike received his BA in Biology from Swarthmore College in 1955. On 4 June of that year, he married his Swarthmore sweetheart, Shirley Lasch Menaker. Their profound partnership fueled his professional and personal life. For graduate school, Mike studied with Colin S. Pittendrigh at Princeton University and received his PhD in 1960. He was a postdoctoral fellow with Donald Griffin at Harvard University from 1959 to 1962. Mike then began his academic career as an Assistant Professor in the Department of Zoology at the University of Texas, Austin and rose through the ranks to Professor. In 1979, Mike was recruited to the University of Oregon, Eugene, where he served as Director of the Institute of Neuroscience. In 1987, Mike was then recruited as Chairman of Biology at the University of Virginia, where he remained as Professor of Biology, until his retirement in 2020.
Among his awards were the following: Guggenheim Fellowship, University of Montpellier, France, 1971-1972; Fellow of the American Association for the Advancement of Science in 1983; Commonwealth Professor of Biology, University of Virginia, 1987; Fellow, Japan Society for the Promotion of Science, 1992; Fellow, American Academy of Arts & Sciences, 1999; American Society of Photobiology, Lifetime Achievement Award, 2002; Virginia’s Outstanding Scientists: Life Achievement in Science Award, 2003; and Peter C. Farrell Prize in Sleep Medicine, 2007.
I knew Mike since the beginning of my career because I was a PhD student with him at the University of Texas at Austin and the University of Oregon in Eugene over 4 decades ago. Menaker and I had a very close working relationship, and I was fortunate to be able to continue collaborative work over many years. Before describing Menaker’s research accomplishments, let me emphasize that Michael Menaker was an exceptional individual who had an unusual talent for innovative discovery and insight in biology. During his career, he was able to stimulate and foster the research careers of a substantial number of individuals who went on to contribute significantly to the fields of neuroscience and biology. Menaker was a profound thinker, listener, and integrator of knowledge. He was charismatic and a delight to be around. He was very open and readily shared both his intellectual and political experience and opinion with his students and peers. All of these qualities contributed greatly to his success. But perhaps his most important talent was his belief in his own judgment and his “nose” for interesting biological questions. He was an inspiring leader and a true pioneer.
Menaker’s Most Significant Scientific Contributions
Below I will highlight what I consider Menaker’s most important discoveries. In each section, I have listed key publications relevant to the discovery.
The Discovery of Extraretinal Photoreception for Entrainment of Circadian Rhythms in Birds
Early in his career, Menaker discovered that nonretinal photoreceptors were sufficient for entraining (or synchronizing) circadian rhythms of activity in birds to light cycles. This finding was met with great skepticism at first, but has now been shown by a multitude of subsequent studies to be a general feature of all nonmammalian vertebrates. Indeed, among vertebrates, mammals are the exception in having dominant retinal photoreceptors for photic entrainment. Menaker also went on to show that extraretinal photoreceptors control the photoperiodic response of reproductive state in birds. Thus, at least two important physiological functions, circadian rhythms and photoperiodism, were mediated by extraretinal photoreceptors in birds.
Menaker M (1968) Extraretinal light perception in the sparrow, I: entrainment of the biological clock. Proc Natl Acad Sci USA 59:414-421.
Menaker M and Keatts H (1968) Extraretinal light perception in the sparrow, II: photoperiodic stimulation of testis growth. Proc Natl Acad Sci USA 60:146-151.
The Discovery That the Avian Pineal Gland Is a Circadian Pacemaker
One of Menaker’s most significant discoveries was the localization of the first vertebrate circadian pacemaker in 1968. This work predates the analogous localization of the suprachiasmatic nucleus in mammals by 4 years. A series of key experimental results were obtained. First, removal of the pineal gland in birds led to the abolition of circadian rhythms at the behavioral level. Second, transplantation of the pineal gland into arrhythmic pinealectomized hosts could restore circadian rhythmicity, and importantly the restored phase of the rhythm was determined by the phase of the donor pineal. This was the first demonstration of a circadian “pacemaker” role in a vertebrate using transplantation of phase or period. Again, this work predates analogous work in mammals (also done by Menaker by the way—see below) by 11 years. Finally, Menaker showed that the pineal gland itself was capable of expressing circadian oscillations in enzyme activity and melatonin release in isolation in vitro, thus demonstrating that the pineal was an autonomous circadian oscillator. Again, this was a first in vertebrates.
Gaston S and Menaker M (1968) Pineal function: the biological clock in the sparrow? Science 160:1125-1127.
Zimmerman NH and Menaker M (1979) The pineal gland: a pacemaker within the circadian system of the house sparrow. Proc Natl Acad Sci USA 76:999-1003.
Kasal CA, Menaker M, and Perez-Polo JR (1979) Circadian clock in culture: N-acetyltransferase activity of chick pineal glands oscillates in vitro. Science 203:656-658.
Takahashi JS, Hamm H, and Menaker M (1980) Circadian rhythms of melatonin release from individual superfused chicken pineal glands in vitro. Proc Natl Acad Sci USA 77:2319-2322.
The Discovery That Photoperiodism in Mammals Uses a Circadian Clock to Measure Daylength
Menaker was the first to demonstrate that a circadian clock was used to measure daylength (photoperiodism) to control reproduction in a mammal. These experiments set the stage for an entire field which subsequently emerged to study how photoperiod controls reproduction in mammals. Menaker pioneered this work.
Gaston S and Menaker M (1967) Photoperiodic control of hamster testis. Science 158:925-928.
Elliott J, Stetson M, and Menaker M (1972) Regulation of testis function in golden hamsters: a circadian clock measures photoperiodic time. Science 178:771-773.
The Discovery of a Novel Retinal Photoreceptor System That Mediates Entrainment in Mammals
By determining the threshold and spectral sensitivity for phase-shifting circadian rhythms in mammals, Menaker described a novel photoreceptor system in the retina which did not behave functionally or anatomically as a classical rod- or cone-mediated photoresponse. Subsequent work by Ignacio Provencio, David Berson, Samer Hattar, and Russell Foster, to name a few, showed that a new class of melanopsin photoreceptor in the ganglion cell layer existed and mediated much of the photic entrainment response in mammals. The work in Menaker’s laboratory first made it clear that a novel pathway must exist and laid the groundwork for this new area.
Takahashi JS, DeCoursey PJ, Bauman L, and Menaker M (1984) Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 308:186-188.
Foster RG, Provencio I, Hudson D, Fiske S, DeGrip W, and Menaker M (1991) Circadian photoreception in the retinally degenerate mouse (rd/rd). J Comp Physiol A 169:39-50.
The Discovery of the tau Mutation and the Prominence of the Suprachiasmatic Nucleus (SCN)
Menaker’s laboratory was the first to discover a single-gene mutation that profoundly affected circadian period in a mammal (the golden or Syrian hamster, Mesocricetus auratus). This animal model provided a wealth of discoveries for the field, the most prominent being the demonstration that transplantation of SCN tissue could determine the period of the restored rhythm depending on the genotype (mutant or wild type) of the donor tissue irrespective of the host genotype. Later, in work we performed with Menaker, the tau mutation was found to be caused by a missense mutation in casein kinase 1 epsilon which is a key post-translational regulator of the PERIOD and CRYPTOCHROME proteins in the mammalian circadian clock mechanism.
Ralph MR and Menaker M (1988) A mutation of the circadian system in golden hamsters. Science 241:1225-1227.
Ralph MR, Foster RG, Davis FC, and Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975-978.
Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, and Takahashi JS (2000) Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288:483-491.
The Discovery of Autonomous Circadian Oscillators in Peripheral Tissues in Mammals
Perhaps one of Menaker’s most profound discoveries was the finding that virtually every tissue and organ in mammals contains autonomous circadian oscillators. Importantly, Menaker found that each of these oscillators had its own properties which led to marked variations in the resetting responses of peripheral organs to shifts in the day-night cycle. This led to important insight into the physiological changes occurring during “jet lag” with the finding that the entire set of organs in the body are literally out of sync during jet lag. This work and complementary work from Ueli Schibler’s lab catalyzed a groundswell of research and discovery on the role of peripheral circadian oscillators in a multitude of physiological processes such as metabolism, immune function, and cancer. Again, Menaker was a pioneer in this work.
Yamazaki S, Numano R, Abe M, Hida A, Takahashi R-I, Ueda M, Block GD, Sakaki Y, Menaker M, and Tei H (2000) Resetting central and peripheral circadian oscillators in transgenic rats. Science 288:682-685.
Stokkan K-A, Yamazaki S, Tei H, Sakaki Y, and Menaker M (2001) Entrainment of the circadian clock in the liver by feeding. Science 291:490-493.
Menaker has Contributed Many Invited Publications. I Consider these to be Among the Most Influential
Menaker M, editor (1971) Biochronometry. Paper presented at: Proceedings of Symposium held at Friday Harbor, WA.
Menaker M (1972, March) Nonvisual light reception. Scientific American:22-29.
Menaker M (1974) Aspects of the physiology of circadian rhythmicity in the vertebrate central nervous system. In: Schmidt FO and Worden EC, editors. The neurosciences: third study program. Cambridge (MA): MIT Press. p. 479-489.
Menaker M and Zimmerman N (1976) The role of the pineal in the circadian system of birds. Amer Zool 16:45-55.
Menaker M, Takahashi JS, and Eskin A (1978) The physiology of circadian pacemakers. Ann Rev Physiol 40:501-526.
Michael Menaker, The Person
Arguably Mike Menaker’s most profound trait was his personality. His magnetic personality drew people in toward him and allowed him to engage at a deep level with almost anyone. It is of course not surprising that his students, postdocs, and lab members loved him, but beyond the lab, everyone loved Mike. Undergraduates in his classes adored him and sought out his laboratory. Department staff, the custodial staff, and the animal care facility staff all loved Mike. It was Mike’s acceptance of all individuals no matter their origin or stature that made him so open and receptive. I know that many graduate students and postdocs from other labs were also able to talk to Mike and interact with him. I am certain that if you ask anyone who was touched by Mike, they would have many fond memories of him.
In my case, I first met Mike when I visited his lab at the University of Texas at Austin for an interview for graduate school in 1975. Mike met and picked me up at Austin airport, which was very nice, and then drove me back in his 1954 MG TD. The moment we first met I knew that Mike was special and that we had much in common. We both went to Swarthmore College, loved nature, and loved sports cars (I had a 1970 Austin Healey Sprite). I knew that Mike was the right person to work with and joined his lab that fall. Mike’s lab was an exciting place to be in at the time. The lab was engaged in photoperiodism in hamsters led by Jeff Elliot and Fred Turek. Till Zimmerman was conducting the pineal transplant experiments that demonstrated the pineal was a circadian pacemaker. The initial work showing the pineal was a circadian oscillator in vitro was being done by Chuck Kasal. And, later after we moved the lab to the University of Oregon at Eugene, Pat DeCoursey spent a sabbatical in the lab, and we did the action spectrum experiments for phase-shifting the clock in hamsters. Mike’s lab was the perfect environment for independent and motivated individuals. Mike had many resources that included the main lab on the UT Austin campus in Patterson Laboratories, and he had a “field” lab on the outskirts of town named Balcones Research Center, which was an abandoned magnesium plant built by the federal government during World War II and was acquired and owned by UT Austin. There we had our aviaries for birds and our very large-scale facilities for locomotor activity recording in house sparrows. At the time, Menaker had many hundreds of recording channels with automated computer collection of the data. This technology was led by Ed Kluth, a PhD in physics, who masterminded the data collection system. This was in the late 1970s and computers were only beginning to become available to labs. We used 8-bit PDP computers that communicated by punch tape! Despite these ancient relics, we were able to view our computer-generated actograms every week at lab meeting. We then transitioned the activity data collection system from birds to rodents, and many innovations for large-scale recording of circadian activity rhythms were developed by the Menaker lab back then. This system was very influential to my career because we and the field have spent the last 50 years optimizing and scaling our ability to collect circadian data in an automated fashion ever since.
Mike was a big thinker and was always interested in evolution and “why” things in life were the way they were. He gave us great latitude in the lab and was not detail-oriented. Indeed, we all knew that Mike was not a hands-on mentor and was happy to admit that he was not very good with his hands. Instead, Mike trained our brains. He was a critical thinker and our lab discussions about every subject were sharply focused on logic and evolutionary biology which of course is not always logical. Many great ideas were discussed at length and then each of us would go off and try to design and organize the best experiments to test our ideas. If you could make a good case for an experiment, then Mike would give you the green light and you were off to the races. It was a wonderful environment to conduct research and to learn the ways of the scientific world. Mike let us all in on the inner workings of the faculty and department politics. Thus, Mike trained us not only in how to do good science, but also how to survive and maneuver the world of publishing, grant writing, and university politics. Finally, Mike was an exceptional writer and he took great pride in writing and trying to transfer these skills to us. In retrospect, I can see clearly how rare this was and how fortunate we as trainees of Mike have been.
One profound regret that I have (despite continuous nominations since 2004) is that Mike was not elected into the National Academy of Sciences (NAS), which was a distinction that he clearly deserved. Since 2003, over a dozen individuals working in the field of circadian rhythms were elected to the NAS: including Jeff Hall (2003), Michael Rosbash (2003), Joe Takahashi (2003), Woody Hastings (2003), Aziz Sancar (2005), Mike Young (2007), Steve Kay (2008), Jay Dunlap (2009), Susan Golden (2010), Louis Ptacek (2012), Xinnian Dong (2012), Amita Sehgal (2016), Mitch Lazar (2017), and Ying-Hui Fu (2018). The most obvious and prominent omission from the NAS in our field is Michael Menaker.
In closing, Mike will truly be missed by all of his friends, colleagues, and family. Mike is survived by his daughter, Ellen Briones, his son, Nicholas Menaker, his son-in-law, Jon Briones, and his grandchildren, Demetris, Nikkita, and Izzy. I feel extremely fortunate and grateful for Mike’s unwavering support and friendship all these years. It is truly an honor to be part of the Menaker family.
Footnotes