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EMBL/EMBO Joint Conference 2004

Ueli Schibler, University of Geneva, Switzerland

Biography

Ueli Schibler was born in 1947 in Olten, Switzerland, studied biology at the University of Bern and obtained his Ph.D. in 1975. During his thesis project, he compared the secondary structure of pre-ribosomal and ribosomal RNA during vertebrate evolution. From 1975-78 Schibler worked as a postdoctoral fellow on mRNA 5ë-capping and immunoglobulin mRNA processing in Robert Perryës laboratory at the Fox Chase Cancer Center in Philadelphia. He then joined the Swiss Institute for Experimental Cancer Research (ISREC), first as a junior group leader (1978-81) and then as a senior group leader with tenure (1981-1984). At ISREC, he investigated the tissue-specific expression of alpha-amylase genes in collaboration with Otto HagenbÕchle and Peter Wellauer. These studies resulted in the discovery of alternative promoter usage and differential splicing. In 1984, Schibler joined the Department of Molecular Biology at the University of Geneva as a full professor. His Geneva research team developed a tissue-specific in vitro transcription system using nuclear proteins from solid rat tissues. This simple biochemical assay system allowed the rapid identification of cis-acting elements of model genes and their trans-acting cognate transcription factors. One of these transcriptional regulatory proteins, DBP, was found to be expressed in a strongly circadian fashion in the liver. This unexpected finding motivated Schibler and his coworkers to study circadian clocks in peripheral tissues. Recently, they showed that even cultured fibroblast cell lines contain cell-autonomous and self-sustained circadian oscillators. Schibler is a member of several scientific associations, including EMBO, European Academy of Sciences, Swiss Academy of Medical Sciences, Faculty of 1000, and Union of Swiss Societies in Experimental Biology. He received the Friedrich Miescher Award of the Swiss Biochemical Society in 1983, the Cloëtta Prize for Medicine in 1986, the Otto Naegeli Prize for Medicine in 1996, and the Louis Jeantet Prize for Medicine in 2000.

Abstract

The time measuring systems of cells and organisms

Many biochemical and physiological processes fluctuate in a temporal fashion. Cycles with a period length (t) of approximately 24 hours are considered to be circadian, while rhythms with substantially shorter and longer period lengths are called ultradian and infradian, respectively. Virtually all light-sensitive organisms – from cyanobacteria to humans – contain circadian oscillators, and in mammals most vital processes are subject to circadian variations. Thus sleep-wake cycles, locomotor activity, heartbeat, blood pressure, renal plasma flow, body temperature, sensorial perception, and the secretion of many hormones fluctuate during the day in an orderly fashion. The mammalian master circadian pacemaker resides in the suprachiasmatic nucleus (SCN) at the base of the brain's hypothalamus. The phase of this SCN clock is reset every day via the retino-hypothalamic tract, which transmits light information from the retina directly to SCN neurons. Circadian pacemakers were originally believed to exist only in a few specialized cell types, such as SCN neurons. However, in recent years, this view has been challenged by the discovery that circadian clocks exist in most peripheral cell types, even in immortalized tissue culture cells. As feeding time is the major Zeitgeber for peripheral clock, the SCN may synchronize peripheral oscillators mostly by driving rest-activity cycles, which in turn determine feeding time. On the molecular level, circadian oscillations are generated by interconnected eedback loops in gene expression, involving the transcriptional repressors CRY1, CRY2, PER1, PER2, and REV-ERBa, the transcriptional activators CLOCK and BMAL1, and several protein kinases (e.g. protein kinase 1e). The molecular clock drives the cyclic accumulation and/or activity of downstream regulators, which in turn govern the rhythmic expression of enzymes and thus circadian physiology. One family of such downstream regulators will be discussed in detail.