Michael Morris Rosbash(born March 7, 1944) is

anAmericangeneticistandchronobiologist. Rosbash is a professor 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 were Jewish
refugees who left Nazi Germany in 1938.[5]His father was acantor, which, in
Judaism, is a person who leads the congregation in prayer. Rosbashs 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 Davidsonslab steered him towards biological research. Rosbash
graduated fromCaltechin 1965 with a degree in chemistry, spent a year at the
Institut de Biologie Physico-Chimique in Paris on theFulbright Scholarship, and
obtained a doctoral degree in biophysics in 1970 from theMassachusetts Institute of
Technology. 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 38-year-old
stepdaughter named Paula and 27-year-old daughter named Tanya.[6]
Research[edit]
Rosbashs 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 lead 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 LN Neurons as the PrincipalDrosophilaCircadian Pacemaker
V
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 a negative
feedback loop[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]
Discovery ofDrosophilaClock Gene[edit]
A likelyhomologof the previously discovered mouse geneClockwas identified by
Rosbash et al. by cloning of theDrosophilagene defined by the Jrk mutation. 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]