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Michael Rosbash

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Michael Rosbash
Michael Rosbash in Nobel Prize press conference in Stockholm, December 2017
Born
Michael Morris Rosbash

(1944-03-07)March 7, 1944(age 80)
Kansas City, Missouri,U.S.
Alma materCalifornia Institute of Technology(B.S.)
Massachusetts Institute of Technology(MS,PhD)
SpouseNadja Abovich
AwardsGruber Prize in Neuroscience(2009)
Nobel Prize in Physiology or Medicine(2017)
Scientific career
FieldsGenetics
Chronobiology
InstitutionsUniversity of Edinburgh
Brandeis University
Howard Hughes Medical Institute
ThesisMembrane-bound protein synthesis in hela cells(1971)
Doctoral advisorSheldon Penman

Michael Morris Rosbash(born March 7, 1944) is an Americangeneticistandchronobiologist.Rosbash is a professor and researcher atBrandeis University[1]and investigator at theHoward Hughes Medical Institute.Rosbash's research group cloned theDrosophilaperiod genein 1984 and proposed the Transcription Translation Negative Feedback Loop[2]forcircadian clocksin 1990. In 1998, they discovered thecyclegene,clockgene, andcryptochromephotoreceptorinDrosophilathrough the use offorward genetics,by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to theNational Academy of Sciencesin 2003. Along withMichael W. YoungandJeffrey C. Hall,he was awarded the 2017Nobel Prize in Physiology or Medicine"for their discoveries of molecular mechanisms controlling the circadian rhythm".[3][4]

Life[edit]

Michael Rosbash was born inKansas City,Missouri. His parents, Hilde and Alfred Rosbash, wereJewishrefugees who leftNazi Germanyin 1938.[5]His father was acantor,which, in Judaism, is a person who chants worship services. Rosbash's family moved toBostonwhen he was two years old, and he has been an avidRed Soxfan ever since.

Initially, Rosbash was interested in mathematics but an undergraduate biology course at theCalifornia Institute of Technology(Caltech) and a summer of working inNorman Davidson'slab steered him towards biological research. Rosbash graduated fromCaltechin 1965 with a degree in chemistry, spent a year at theInstitut de Biologie Physico-Chimiquein Paris on theFulbright Scholarship,and obtained a doctoral degree in biophysics in 1970 from theMassachusetts Institute of Technologyunder Sheldon Penman. After spending three years on a postdoctoral fellowship in genetics at theUniversity of Edinburgh,Rosbash joined theBrandeis Universityfaculty in 1974.

Rosbash is married to fellow scientist Nadja Abovich and he has a stepdaughter named Paula and daughter named Tanya.[6]

Research[edit]

Rosbash's research initially focused on the metabolism and processing ofmRNA;mRNA is the molecular link betweenDNAandprotein.After arriving at Brandeis, Rosbash collaborated with co-workerJeffrey Hall[7]and investigated the genetic influences on circadian rhythms of the internal biological clock. They usedDrosophila melanogasterto study patterns of activity and rest. In 1984, Rosbash and Hall cloned the firstDrosophilaclock gene,period.Following work done by post-doctoral fellow,Paul Hardin,in discovering that period mRNA and its associated protein (PER) had fluctuating levels during the circadian cycle, in 1990 they proposed a Transcription Translation Negative Feedback Loop (TTFL) model as the basis of thecircadian clock.[8]Following this proposal, they looked into the elements that make up other parts of the clock. In May 1998, Rosbash et al. found a homolog for mammalian Clock that performed the same function of activating the transcription of per andtimthat they proceeded to call dClock.[9]Also in May 1998, Rosbash et al. discovered inDrosophilathe clock gene cycle, a homolog of the mammalian bmal1 gene.[10]In November 1998, Rosbash et al. discovered the crybDrosophilamutant, which led to the conclusion that cryptochrome protein is involved in circadian photoreception.[11]

Chronology of major discoveries[edit]

  • 1984: Cloned theDrosophilaperiod gene
  • 1990: Proposed the Transcription Translation Negative Feedback Loop[2]forcircadian clocks
  • 1998: Identified theDrosophilaClock Gene
  • 1998: Identified theDrosophilaCycle Gene
  • 1998: Identifiedcryptochromeas aDrosophilaCircadian Photoreceptor
  • 1999: Identified LNVNeurons as the PrincipalDrosophilaCircadian Pacemaker

mRNA research[edit]

Rosbash began studying mRNA processing as a graduate student atMassachusetts Institute of Technology.His work in theSaccharomyces cerevisiaehas revealed the enzymes, proteins, and subcellular organelles and their convergence upon mRNA in a specific order in order to translate mRNA into proteins. Missteps in this process have been linked to diseases such asAlzheimer's disease,so this work is essential for better understanding and treatment of diseases.[12]

Discovery of circadian TTFL inDrosophila[edit]

In 1990, Rosbash, Hall, and Hardin discovered the role of the period gene (per) in theDrosophila'circadian oscillator. They found that PER protein levels fluctuate in light dark cycles, and these fluctuations persist in constant darkness. Similarly, per mRNA abundance also has rhythmic expression that entrains to light dark cycles. In the fly head, per mRNA levels oscillate in both 12-hour light, 12-hour dark cycles as well as in constant darkness. Per mRNA levels peaked at the beginning of the subjective night followed by a peak in PER protein levels about 6 hours later. Mutated per genes affected the cycling of per mRNA. From this experimental data, Rosbash, Hall, and Hardin hypothesized that PER protein is involved in anegative feedbackloop[2]that controls per mRNA levels, and that this transcription-translation feedback loop is a central feature of theDrosophilacircadian clock.[8]

They also looked at two other singlemissenseperiod mutations, perSand perL1.These mutations cause the peak of the evening activity to occur earlier and later, respectively, compared to wildtype per+flies. They found that RNA levels for perSand perL1also display clear rhythmicity. Like locomotor activity the peak expression is shifted earlier for perSand later for perL1.[8]

They transformed the period0null mutation flies with a 7.2-kb piece of functional per DNA, and measured per mRNA levels at the per0locus and new locus. Following transformation, per mRNA levels were rhythmic at both the original and new locus. The per0locus was able to transcribe normal per mRNA and translate normal PER protein, meaning that rhythmicity was rescued by functional PER protein transcribed and translated from the 7.2-kb piece of per DNA. There is a feedback loop at play in which cycling of PER protein levels at the new locus feeds back to dictate cycling of per mRNA levels at the original per0locus.[8] In 1992, Rosbash again collaborated with Jeffrey Hall and Paul Hardin to more closely examine the mechanisms of the TTFL. They wondered specifically about the regulation of period mRNA level fluctuations, and found that per mRNA levels were transcriptionally regulated. This was supported by the evidence that per precursor RNA cycles with the same phase as mature transcripts, and oscillate with respect toZeitgeberTime (ZT). Other evidence for transcriptional regulation is that per gene promoter is sufficient to confer cycling toheterologousmRNA.[13]

Challenges to the TTFL model inDrosophila[edit]

TheAkhilesh Reddygroup has shown, using a range of unbiased -omics techniques (RNA-sequencing, proteomics, metabolomics) thatDrosophilaS2 cells display circadian molecular rhythms.[14]These cells do not express known "clock genes" includingperandtim.[14][15][16]Introduction of PER and TIM proteins into the cells does not cause rhythmicity of these cells as read out by abundance or phosphorylation of PER and TIM proteins.[16][17]These cells were thus regarded as "clock-less" by the fly field until now.[17][16]These findings substantiate the work above in demonstrating the TTFL model of the fly clockwork cannot explain the generation of circadian rhythms.[14]

Discovery ofDrosophilaClock Gene[edit]

A likelyhomologof the previously discovered mouse geneClockwas identified by Rosbash et al. by cloning of theDrosophilagene defined by theJrkmutation. This gene was given the nameDrosophilaClock. dClock has been shown to interact directly with theperandtimE-boxesand contributes to the circadian transcription of these genes. The Jrk mutation disrupts the transcription cycling of per and tim. It also results in completely arrhythmic behavior in constant darkness for homozygous mutants and about half demonstrated arrhythmic behavior in heterozygotes. The Jrk homozygotes expressed low, non-cycling levels of per and tim mRNA as well as PER and TIM protein. From this, it was concluded that the behavioral arrhythmicity in Jrk was due to a defect in the transcription of the per and tim. This indicated that dClock was involved in the transcriptional activation of per and tim.[9]

Discovery ofDrosophilaCycle Gene[edit]

In 1998, Rosbash et al. discovered the novel clock genecycle,ahomologof the mammalianBmal1gene.Homozygouscycle0mutants are arrhythmic in locomotor activity andheterozygouscycle0/+ flies have robust rhythms with an altered period of rhythmicity.Western blotanalysis shows that homozygous cycle0mutants have very little PER andTIMprotein as well as low per and tim mRNA levels. This indicates that lack of cycle leads to decreased transcription of per and tim genes. Meiotic mapping placed cyc on the third chromosome. They discovered bHLH-PAS domains in cyc, indicating protein binding and DNA binding functions.[10]

Discovery of cryptochrome as aDrosophilacircadian photoreceptor[edit]

In 1998, Rosbash et al. discovered aDrosophilamutant exhibiting flat, non-oscillating levels ofperandtimmRNA, due to anull mutationin thecryptochromegene. This mutation was dubbed crybaby,or cryb.The failure of crybmutants to synchronize to light dark cycles indicates that cryptochrome’s normal function involves circadianphotoreception.[11]

LNVneurons as principalDrosophilacircadian pacemaker[edit]

InDrosophila,certain lateral neurons (LNs) have been shown to be important for circadian rhythms, including dorsal (LNd) and ventral (LNV) neurons. LNVneurons express PDF (pigment dispersion factor), which was initially hypothesized to be a clock output signal. Mutants for the pdf neuropeptide gene (pdf01) as well as flies selectively ablated for LNVproduced similar behavioral responses. Both entrained to external light cues, but were largely arrhythmic in constant conditions. Some flies in each cases showed weak free-running rhythmicity. These results led the researchers to believe that LNVneurons were the critical circadian pacemaker neurons and that PDF was the principal circadian transmitter.[18]

Current research[edit]

In more recent years, Rosbash has been working on the brain-neuronal aspects of circadian rhythms. Seven anatomically distinct neuronal groups have been identified that all express the core clock genes. However, the mRNAs appear to be expressed in a circadian and neuron-specific manner, for which his lab has taken interest in determining whether this provides a link to the distinct functions of certain neuronal groups. He has also researched the effects of light on certain neuronal groups and has found that one subgroup is light-sensitive to lights on (dawn) and another is light-sensitive to lights off (dusk). The dawn cells have been shown to promote arousal while the dusk cells promote sleep.[19]

Today, Rosbash continues to research mRNA processing and the genetic mechanisms underlying circadian rhythms. He has also published an amusing reflection on his life in science.[20]

Positions[edit]

Awards[edit]

See also[edit]

References[edit]

  1. ^"Life Sciences Faculty – Michael Rosbash".bio.brandeis.edu.Retrieved2 October2017.
  2. ^abc"The Drosophila Molecular Clock Model – HHMI's BioInteractive".hhmi.org.Archived fromthe originalon 17 February 2013.Retrieved2 October2017.
  3. ^Cha, Arlene Eujung (2017-10-02)."Nobel in physiology, medicine awarded to three Americans for discovery of 'clock genes'".Washington Post.Retrieved2017-10-02.
  4. ^"The 2017 Nobel Prize in Physiology or Medicine – Press Release".The Nobel Foundation. 2017-10-02.Retrieved2017-10-02.
  5. ^"Americans win Nobel medicine prize for circadian rhythm work".The Times of Israel.Retrieved2 October2017.
  6. ^"Michael Rosbash, PhD - HHMI.org".Retrieved2 October2017.
  7. ^"Life Sciences Faculty – Jeffrey Hall, Emeritus".bio.brandeis.edu.Retrieved2 October2017.
  8. ^abcdHardin, P. E.; Hall, J. C.; Rosbash, M. (1990). "Feedback of theDrosophila periodgene product on circadian cycling of its messenger RNA levels ".Nature.343(6258): 536–540.Bibcode:1990Natur.343..536H.doi:10.1038/343536a0.PMID2105471.S2CID4311836.
  9. ^abAllada, R.; White, N. E.; So, W. V.; Hall, J. C.; Rosbash, M. (1998)."A Mutant Drosophila Homolog of Mammalian Clock Disrupts Circadian Rhythms and Transcription of period and timeless".Cell.93(5): 791–804.doi:10.1016/S0092-8674(00)81440-3.PMID9630223.S2CID1779880.
  10. ^abRutila, J. E.; Suri, V.; Le, M.; So, W. V.; Rosbash, M. (1998)."CYCLE Is a Second bHLH-PAS Clock Protein Essential for Circadian Rhythmicity and Transcription of Drosophila period and timeless".Cell.93(5): 805–814.doi:10.1016/S0092-8674(00)81441-5.PMID9630224.S2CID18175560.
  11. ^abStanewsky, R.; Kaneko, M.; Emery, P.; Beretta, B.; Wager-Smith, K.; Kay, S. A.; Rosbash, M.; Hall, J. C. (1998)."The crybMutation Identifies Cryptochrome as a Circadian Photoreceptor in Drosophila ".Cell.95(5): 681–682.doi:10.1016/S0092-8674(00)81638-4.PMID9845370.S2CID6996815.
  12. ^"Michael Rosbash, PhD - HHMI.org".Retrieved2 October2017.
  13. ^Hardin, P. E.; Hall, J. C.; Rosbash, M. (1992)."Circadian oscillations in period gene mRNA levels are transcriptionally regulated".PNAS.89(24): 11711–11715.Bibcode:1992PNAS...8911711H.doi:10.1073/pnas.89.24.11711.PMC50626.PMID1465387.
  14. ^abcRey, Guillaume; Milev, Nikolay B; Valekunja, Utham K; Ch, Ratnasekhar; Ray, Sandipan; Silva Dos Santos, Mariana; Nagy, Andras D; Antrobus, Robin; MacRae, James I; Reddy, Akhilesh B (2018-08-01)."Metabolic oscillations on the circadian time scale in Drosophila cells lacking clock genes".Molecular Systems Biology.14(8): e8376.doi:10.15252/msb.20188376.ISSN1744-4292.PMC6078164.PMID30072421.
  15. ^Saez, Lino; Young, Michael W. (1996-11-01)."Regulation of Nuclear Entry of the Drosophila Clock Proteins Period and Timeless".Neuron.17(5): 911–920.doi:10.1016/S0896-6273(00)80222-6.ISSN0896-6273.PMID8938123.S2CID2106981.
  16. ^abcDarlington, Thomas K.; Wager-Smith, Karen; Ceriani, M. Fernanda; Staknis, David; Gekakis, Nicholas; Steeves, Thomas D. L.; Weitz, Charles J.; Takahashi, Joseph S.; Kay, Steve A. (1998-06-05). "Closing the Circadian Loop: CLOCK-Induced Transcription of Its Own Inhibitors per and tim".Science.280(5369): 1599–1603.Bibcode:1998Sci...280.1599D.doi:10.1126/science.280.5369.1599.ISSN0036-8075.PMID9616122.
  17. ^abSaez, Lino; Young, Michael W (November 1996)."Regulation of Nuclear Entry of the Drosophila Clock Proteins Period and Timeless".Neuron.17(5): 911–920.doi:10.1016/S0896-6273(00)80222-6.PMID8938123.S2CID2106981.
  18. ^Renn, S. C. P.; Park, J. H.; Rosbash, M.; Hall, J. C.; Taghert, P. H. (1999)."ApdfNeuropeptide Gene Mutation and Ablation of PDF Neurons Each Cause Severe Abnormalities of Behavioral Circadian Rhythms inDrosophila".Cell.99(7): 791–802.doi:10.1016/S0092-8674(00)81676-1.PMID10619432.S2CID62796150.
  19. ^"Rosbash Lab".Rosbash Lab.Retrieved2 October2017.
  20. ^Rosbash, Michael (2017-11-30)."Life Is an N of 1".Cell.171(6): 1241–1245.doi:10.1016/j.cell.2017.11.027.ISSN0092-8674.PMID29195068.
  21. ^"National Center for Behavioral Genomics".bio.brandeis.edu.Retrieved2 October2017.
  22. ^"Rosbash receives new Gruber neuroscience chair – BrandeisNOW".BrandeisNOW.Retrieved2 October2017.
  23. ^"Hypnion, Inc.: Board of Directors – Bloomberg".investing.businessweek.Archived fromthe originalon November 5, 2012.Retrieved2 October2017.
  24. ^Colten, Harvey R.; Altevogt, Bruce M.; Research, Institute of Medicine (US) Committee on Sleep Medicine and (2 October 2017).Sleep Disorders Research Advisory Board Membership.National Academies Press (US).Retrieved2 October2017– via ncbi.nlm.nih.gov.
  25. ^"John Simon Guggenheim Memorial Foundation Fellows".Retrieved2 October2017.[permanent dead link]
  26. ^"Helen Hay Whitney Foundation Fellows".Archived fromthe originalon 6 October 2015.Retrieved2 October2017.
  27. ^ab"The Louisa Gross Horwitz Prize – Columbia University Medical Center".cumc.columbia.edu.26 November 2013.Retrieved2 October2017.
  28. ^Sample, Ian (2017-10-02)."Jeffrey C Hall, Michael Rosbash and Michael W Young win 2017 Nobel prize in physiology or medicine – as it happened".The Guardian.ISSN0261-3077.Retrieved2017-10-02.
  29. ^"Wiley: Twelfth Annual Wiley Prize in Biomedical Sciences Awarded to Dr. Michael Young, Dr. Jeffrey Hall and Dr. Michael Rosbash".wiley.Retrieved2 October2017.
  30. ^Lebovits, Susan Chaityn (14 August 2012)."Rosbash awarded Massry for circadian rhythms work | BrandeisNOW".BrandeisNOW.Retrieved2017-10-02.
  31. ^"Michael Rosbash – Gairdner Foundation".Retrieved2 October2017.
  32. ^abc"Society for Research on Biological Rhythms".Archived fromthe originalon 25 February 2010.Retrieved2 October2017.
  33. ^"California Institute of Technology Distinguished Alumni Awards"(PDF).Archived fromthe original(PDF)on 18 July 2012.Retrieved2 October2017.

External links[edit]

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