2017 Nobel Prize for Physiology Or Medicine
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NEWS Celebrating clocks and flies – 2017 Nobel Prize for Physiology or Medicine At a time when most ‘Nobel watchers’ single gene mutations could yield sig- Around the same time, two adjacent expected the much coveted prize in nificantly large effects on rhythmic laboratories in nearby New England were physiology or medicine to go to CRISPR behaviour. Understandably, clocks were engaged in a similar quest to unravel the technology or even to immunotherapy, expected to be a more complex entity mysteries of period. Piqued by the find- the announcement to award discoveries with built-in redundant machinery that ing that the period gene which has an made using fruit flies, in deciphering the was unlikely to be laid bare by mutations effect on daily rhythms also impacts high molecular underpinnings of the funda- in single genes. frequency rhythms in courtship songs, mental biological process of time- Michael W. Young, one of the the foundations of a highly fruitful col- keeping, is reassuring to scientists en- awardees, was a graduate student at the laboration between two professors, Jef- gaged in basic research across the world. University of Texas in 1971, when frey C. Hall and his friend and neighbour The humble fly has had its share of period mutants were described and hap- at the Biology Department in Brandeis recognition from the Nobel Committee in pened to be studying the Drosophila University, Michael Rosbash were laid. the past; the earliest with Thomas Hunt genome using classical cytogenetic Soon the duo was harnessing the power Morgan for the fundamental idea of the methods. He had fly lines with chromo- of molecular genetics, that had just be- Chromosomal Theory of Inheritance somal rearrangements on the X chromo- come available, to isolate period gene (1933) followed by his student Hermann some, including one with a break in the and elucidate its properties. Nearly si- J. Muller for his discovery of mutagene- region predicted by the Benzer study, multaneously as the group from Rocke- sis by radiation (1946). Developmental which he would use only later. While a feller, the Brandeis labs published their biologists Edward B. Lewis, Christiane post-doc at Stanford, Young recalls hav- first collaborative paper on the molecular Nüsslein-Volhard and Eric F. Wieschaus ing heard a highly animated and persua- analysis of the period locus, and showed were recognized in 1995, Linda Buck sive talk by Seymour Benzer who evidence of the rescue of a null mutation and Richard Axel for their discoveries of likened his genetic dissections of behav- by P-element mediated transformation. olfactory receptors (2004) were followed iour to those of surgical lesions that had These studies can be considered as the by Jules Hoffman for his discoveries in been used previously to localize the sites official start of a race that was some- innate immunity (2011). of brain functions. Incidentally, the times bitter, but in hindsight may have In the early 1980s, the three awardees suprachiasmatic nucleus, a structure in been the catalyst for the speed with for this year’s Nobel Prize ventured forth the mammalian brain had been localized which studies progressed in the direction in an attempt to uncover genes that may to be the site of the circadian pacemaker of understanding the biochemical and play central roles in circadian (~24 h in 1972 using surgical lesions. In 1978 cell biological basis for self-sustained, periodicity) rhythm generation, mainte- when Young had a faculty position at the near-24 h rhythm generation. Thus, within nance and synchronization to the geo- Rockefeller Centre in New York City he a decade of isolating and mapping the physical day and night, at a time when was able to pursue the idea of locating period gene, all the other molecular giants in the field of chronobiology or and mapping the period gene using a players involved in circadian rhythm the study of biological rhythms, were chromosomal walk (a method of posi- generation were identified and character- skeptical of such an approach. However, tional cloning). With Thaddeaus Bar- ized. Today we celebrate what circadian another discovery made more than a dec- giello, a post-doctoral fellow at his new biologists now agree was a rivalry that ade before, by Seymour Benzer and laboratory, the precise location and size put forth a highly conserved mechanism Ronald Konopka1 was pivotal in steering of period was described, followed by the that has since been found in the vast ma- the efforts of the trio. Konopka and demonstration that P-element mediated jority of organisms examined. Benzer showed that a locus on the transformation of mutant arrhythmic flies In the early 1980s the question re- X-chromosome of the fly is critical for with the wildtype copy of the gene can mained as to how a single gene could rhythmic behaviours such as adult emer- restore both adult emergence as well as bring about rhythmic phenomenon? The gence from pupal cases in populations of activity rhythms. first breakthrough came in the form of a flies and the locomotor activity of indi- vidual flies. Allelic mutations at this locus either rendered flies arrhythmic in both behaviours or altered the periodicity of the rhythms in opposite directions (either lesser than or greater than 24 h), thus prompting them to name it period. This landmark study took the chronobi- ology community by storm, partly due to the remarkably clear and robust pheno- type obtained by a random mutagenesis screen. At that time, the field was domi- nated by scientists who did not think that Jeffrey C. Hall Michael Rosbash Michael W. Young CURRENT SCIENCE, VOL. 113, NO. 8, 25 OCTOBER 2017 1497 NEWS discovery by Paul Hardin, a post- ments. In a primary screen of about 7000 and CYCLE were shown to physically doctoral fellow with Rosbash who fly lines, a candidate was found on the interact with one another and bind to E- showed that period mRNA from fly second chromosome that did not show Box elements on the period and timeless heads exhibited a circadian oscillation the normal preference for dawn adult genes, thus providing evidence of being and that the oscillation was affected by emergence and instead emerged more-or- members of the core-clock. Further stud- mutations in the gene. Subsequently the less equally throughout the day and ies showed that in fact CLOCK–CYCLE same group showed that the precursor night, which they named timeless4. Like activity was inhibited by PERIOD and and mature forms of period mRNA have the period null mutant, these flies also TIMELESS. In later years a second similar amplitude and are in-phase and showed arrhythmicity in locomotion. feedback loop comprising of vrille-pdp1 that the period gene promoter can pro- Strikingly, this mutation also affected the as transcriptional regulators was pro- duce oscillation even to heterologous oscillation of period mRNA, such that it posed by the laboratory of Justin Blau9. mRNA. Most importantly, they found was no longer rhythmic, suggesting an In the same year, a more complex model that the period protein oscillation is de- interaction between the period and time- of interlocked feed-back loops incorpo- layed in phase by 6 hours from the pe- less loci. Leslie Vosshall and colleagues rating both the loops (PERIOD– riod mRNA oscillation. Around that in the same lab showed that indeed the TIMELESS and VRILLE-PDP1) bound time, it became known that PERIOD timeless mutant has profound effects on by a common requirement of the shuttles between the cytoplasm and the the PERIOD protein, the latter’s ability CLOCK-CYCLE complex for transcrip- nucleus2 in a temporally restricted man- to enter the nucleus at a certain specific tional activation, was put forth by the ner in brain neurons (the proposed loca- time of day was contingent upon timeless studies of Paul Hardin’s laboratory10. tion of the fly clock) and that its amino function, leading to the hypothesis that While the above studies explained how acid sequence showed similarity with timeless and period are both part of one a self-sustained clock machinery with a two other proposed transcriptional regula- intracellular mechanism that generates a near 24 h period might be generated in tors (SINGLE MINDED and ARNT). self-sustained oscillation. Subsequently, the absence of external time cues, it was This led to the hypothesis that the lag in timeless mRNA was also shown to cycle, also necessary to explain how such PERIOD accumulation may be due to and PERIOD and TIMELESS proteins clocks might synchronize with the exter- negative regulation of itself. For the first were shown to interact in order to enter nal environment – the phenomenon of time ever, there was reasonable evidence the nucleus. entrainment. Previously, the behavioural to propose that period mRNA and its In a flurry of reports that followed, yet attributes of entrainment had been the protein product influence each other3, other mutants that affect the nature of subject of intense study mostly using through a negative feedback mechanism the activity/rest rhythm via defects in the mammalian systems of a wide hue (series that had been proposed as the basis for underlying TTFL were isolated by the of papers by Pittendrigh and Daan, self-sustained oscillators. Although it Young and the Hall-Rosbash laborato- 1976). Light, a major entraining agent seems obvious today that this may well ries. Jeffery Price, Brian Kloss and col- (‘zeitgeber’ or time-giver in German) be the case for a bonafide circadian clock leagues at the Young Lab demonstrated was shown to impact the fly circadian gene, many coincident factors were criti- that a protein DOUBLETIME affects the clock via TIMELESS degradation. The cal to establishing this idea.