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Assembling a Multi-Cellular Circadian
Nearly all organisms possess an endogenous circadian clock that regulates biological processes in the temporal domain. While it is now known that the basic circadian oscillatory mechanism is intracellular, much less is known about how these molecular clockworks are entrained by light and how they ultimately gain expression beyond the cell. In fact, behavioral rhythms in insects and mammals appear to be the product of complex brain pacemakers that are composed of multiple individual cellular circadian oscillators coupled together in neuronal networks. In large part, the elucidation of molecular clocks was catalyzed by the fantastic cross-talk between researchers working on insects and mammals. This workshop was organized to actively foster a similar collaboration at the neural circuit level of analysis, seeking principles of circuit organization across invertebrate and vertebrate brains. Our aim was to promote a new dialogue by bringing together senior and junior scientists – including insect and mammalian anatomists, physiologists, photobiologists, molecular / cellular biologists, and mathematicians – to work together on this problem in an informal but intensive way.
In addition to the 4 organizers, 39 invited participants from Europe, the United States, Japan, and Argentina were joined by 9 graduate and post-doctoral students from the Netherlands. Each invitee had a short, formal speaking role, either in one of the seven plenary sessions (presented by balanced teams of insect and mammalian researchers), or in one of the corresponding discussion groups, or in a mathematical theory / modeling tutorial. In addition, time was allotted for four 1-hr "hot data" sessions and for free, uninhibited general discussion.
The opening question of the workshop – how is it that circadian timekeeping is accomplished using 150 neurons in fruit flies but requires 10,000 in rodents – surfaced repeatedly throughout the 5 days. The problem was not solved, but in the course of the discussions several analogies between the two systems were revealed. As examples, the photic entrainment system in insects now appears to be more like that in mammals than previously thought, and the mechanisms for intercellular coupling include peptides with notable similarities (pigment dispersing factor in fruit flies and vasoactive intestinal polypeptide in mice). New data, perspectives, and ideas were also presented with respect to the role(s) of the cell membrane in clock function, novel properties of "clock" gene products, the regulation of arousal, network plasticity and history dependence, and the significance of glia, among others.
By all measures, the workshop was a resounding success. There was full attendance at every session and discussion group with contributions from every participant (and a notable lack of concurrent e-mailing and internet surfing from laptop computers), and nearly 80% attendance at the concluding morning session. Participants were asked to provide a rating (on a scale of 1 - 10, 10 being highest), grading (a) the overall workshop experience and (b) their enthusiasm for holding a similar type of meeting in the future; the scores were 9.56 and 9.88, respectively, with no individual score less than 9. The written comments included several superlatives; notation of the successful and unique discussion format, which was lively, inclusive, candid, and shared by insect and mammalian researchers; and a pointed characterization of the workshop as "...the feeling of a lab meeting between some of the best researchers in the world."
In retrospect, there were several factors that we believe contributed to the success of the workshop. The subject was timely, catalyzed by recent experimental findings and new technical approaches. The organizers selected participants based on their lucid teaching and speaking abilities, collegiality, and willingness to attend for the full 5 days of the workshop; and in turn the participants were prepared to contribute to a unique workshop that would clearly differ from the usual meetings in our field. The Lorentz facilities were superb, with the layout and offices putting participants "in residence," essentially on sabbatical for 5 days. Of note, discussion was enhanced by arranging our meeting room in a classroom, rather than in an amphitheatre, configuration.
Many thanks to the Lorentz Center staff, especially to Ms. Pauline Vincenten and Drs. Mieke Schutte and Henriette Jensenius, and to generous funding by the Lorentz Center, National Institute of Neurological Disorders and Stroke, United States Air Force Office of Scientific Research, Servier Laboratories, Philips Lighting, and Greiner Bio-One.
C. Helfrich-Förster (Würzburg, Germany)
J.H. Meijer (Leiden, Netherlands)
L.P. Morin (Stony Brook, U.S.A.)
W.J. Schwartz (Worcester, U.S.A.)