Michael Rosbash | |
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Born | Michael Morris Rosbash March 7, 1944 Kansas City, Missouri, U.S. |
Alma mater | California Institute of Technology (BS) Massachusetts Institute of Technology (MS, PhD) |
Spouse | Nadja Abovich |
Awards | Gruber Prize in Neuroscience (2009) Nobel Prize in Physiology or Medicine (2017) |
Scientific career | |
Fields | Genetics Chronobiology |
Institutions | University of Edinburgh Brandeis University Howard Hughes Medical Institute |
Thesis | Membrane-bound protein synthesis in hela cells (1971) |
Doctoral advisor | Sheldon Penman |
Michael Morris Rosbash (born March 7, 1944) is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University [1] and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop [2] for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm". [3] [4]
Michael Rosbash was born in Kansas City, Missouri. His parents, Hilde and Alfred Rosbash, were Jewish refugees who left Nazi Germany in 1938. [5] His father was a cantor, which, in Judaism, is a person who chants worship services. Rosbash's family moved to Boston when he was two years old, and he has been an avid Red Sox fan ever since.
Initially, Rosbash was interested in mathematics but an undergraduate biology course at the California Institute of Technology (Caltech) and a summer of working in Norman Davidson's lab steered him towards biological research. Rosbash graduated from Caltech in 1965 with a degree in chemistry, spent a year at the Institut de Biologie Physico-Chimique in Paris on the Fulbright Scholarship, and obtained a doctoral degree in biophysics in 1970 from the Massachusetts Institute of Technology under Sheldon Penman. After spending three years on a postdoctoral fellowship in genetics at the University of Edinburgh, Rosbash joined the Brandeis University faculty in 1974.
Rosbash is married to fellow scientist Nadja Abovich and he has a stepdaughter named Paula and daughter named Tanya. [6]
Rosbash's research initially focused on the metabolism and processing of mRNA; mRNA is the molecular link between DNA and protein. After arriving at Brandeis, Rosbash collaborated with co-worker Jeffrey Hall [7] and investigated the genetic influences on circadian rhythms of the internal biological clock. They used Drosophila melanogaster to study patterns of activity and rest. In 1984, Rosbash and Hall cloned the first Drosophila clock 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 the circadian 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 and tim that they proceeded to call dClock. [9] Also in May 1998, Rosbash et al. discovered in Drosophila the clock gene cycle, a homolog of the mammalian bmal1 gene. [10] In November 1998, Rosbash et al. discovered the crybDrosophila mutant, which led to the conclusion that cryptochrome protein is involved in circadian photoreception. [11]
Rosbash began studying mRNA processing as a graduate student at Massachusetts Institute of Technology. His work in the Saccharomyces cerevisiae has 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 as Alzheimer's disease, so this work is essential for better understanding and treatment of diseases. [12]
In 1990, Rosbash, Hall, and Hardin discovered the role of the period gene (per) in the Drosophila' 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 the Drosophila circadian clock. [8]
They also looked at two other single missense period mutations, perS and 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 perS and perL1 also display clear rhythmicity. Like locomotor activity the peak expression is shifted earlier for perS and later for perL1. [8]
They transformed the period0 null mutation flies with a 7.2-kb piece of functional per DNA, and measured per mRNA levels at the per0 locus and new locus. Following transformation, per mRNA levels were rhythmic at both the original and new locus. The per0 locus 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 per0 locus. [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 to Zeitgeber Time (ZT). Other evidence for transcriptional regulation is that per gene promoter is sufficient to confer cycling to heterologous mRNA. [13]
The Akhilesh Reddy group has shown, using a range of unbiased -omics techniques (RNA-sequencing, proteomics, metabolomics) that Drosophila S2 cells display circadian molecular rhythms. [14] These cells do not express known "clock genes" including per and tim. [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]
A likely homolog of the previously discovered mouse gene Clock was identified by Rosbash et al. by cloning of the Drosophila gene defined by the Jrk mutation. This gene was given the name Drosophila Clock. dClock has been shown to interact directly with the per and tim E-boxes and 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]
In 1998, Rosbash et al. discovered the novel clock gene cycle, a homolog of the mammalian Bmal1 gene. Homozygous cycle0 mutants are arrhythmic in locomotor activity and heterozygous cycle0/+ flies have robust rhythms with an altered period of rhythmicity. Western blot analysis shows that homozygous cycle0 mutants have very little PER and TIM protein 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]
In 1998, Rosbash et al. discovered a Drosophila mutant exhibiting flat, non-oscillating levels of per and tim mRNA, due to a null mutation in the cryptochrome gene. This mutation was dubbed crybaby, or cryb. The failure of cryb mutants to synchronize to light dark cycles indicates that cryptochrome’s normal function involves circadian photoreception. [11]
In Drosophila, certain lateral neurons (LNs) have been shown to be important for circadian rhythms, including dorsal (LNd) and ventral (LNV) neurons. LNV neurons 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 LNV produced 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 LNV neurons were the critical circadian pacemaker neurons and that PDF was the principal circadian transmitter. [18]
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]
A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.
Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.
CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.
Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.
Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.
In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.
Ronald J. Konopka (1947-2015) was an American geneticist who studied chronobiology. He made his most notable contribution to the field while working with Drosophila in the lab of Seymour Benzer at the California Institute of Technology. During this work, Konopka discovered the period (per) gene, which controls the period of circadian rhythms.
Pigment dispersing factor (pdf) is a gene that encodes the protein PDF, which is part of a large family of neuropeptides. Its hormonal product, pigment dispersing hormone (PDH), was named for the diurnal pigment movement effect it has in crustacean retinal cells upon its initial discovery in the central nervous system of arthropods. The movement and aggregation of pigments in retina cells and extra-retinal cells is hypothesized to be under a split hormonal control mechanism. One hormonal set is responsible for concentrating chromatophoral pigment by responding to changes in the organism's exposure time to darkness. Another hormonal set is responsible for dispersion and responds to the light cycle. However, insect pdf genes do not function in such pigment migration since they lack the chromatophore.
Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix–loop–helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include basic helix-loop-helix ARNT-like protein 1 (ARNTL) and Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2).
Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the doubletime protein in fruit flies. Michael Young and his team at Rockefeller University first identified and characterized the gene in 1998.
Jeffrey Connor Hall is an American geneticist and chronobiologist. Hall is Professor Emeritus of Biology at Brandeis University and currently resides in Cambridge, Maine.
Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.
Paul H. Taghert is an American chronobiologist known for pioneering research on the roles and regulation of neuropeptide signaling in the brain using Drosophila melanogaster as a model. He is a professor of neuroscience in the Department of Neuroscience at Washington University in St. Louis.
Jeffrey L. Price is an American researcher and author in the fields of circadian rhythms and molecular biology. His chronobiology work with Drosophila melanogaster has led to the discoveries of the circadian genes timeless (tim) and doubletime (dbt), and the doubletime regulators spaghetti (SPAG) and bride of doubletime (BDBT).
Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.
Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Many behaviors are under circadian control including eclosion, locomotor activity, feeding, and mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.
Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.
dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.
In the field of chronobiology, the dual circadian oscillator model refers to a model of entrainment initially proposed by Colin Pittendrigh and Serge Daan. The dual oscillator model suggests the presence of two coupled circadian oscillators: E (evening) and M (morning). The E oscillator is responsible for entraining the organism’s evening activity to dusk cues when the daylight fades, while the M oscillator is responsible for entraining the organism’s morning activity to dawn cues, when daylight increases. The E and M oscillators operate in an antiphase relationship. As the timing of the sun's position fluctuates over the course of the year, the oscillators' periods adjust accordingly. Other oscillators, including seasonal oscillators, have been found to work in conjunction with circadian oscillators in order to time different behaviors in organisms such as fruit flies.
Ravi Allada is an Indian-American chronobiologist studying the circadian and homeostatic regulation of sleep primarily in the fruit fly Drosophila. He is currently the Executive Director of the Michigan Neuroscience Institute (MNI), a collective which connects neuroscience investigators across the University of Michigan to probe the mysteries of the brain on a cellular, molecular, and behavioral level. Working with Michael Rosbash, he positionally cloned the Drosophila Clock gene. In his laboratory at Northwestern, he discovered a conserved mechanism for circadian control of sleep-wake cycle, as well as circuit mechanisms that manage levels of sleep.