Jeffrey C. Hall

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Jeffrey C. Hall
Jeffrey C. Hall EM1B8737 (38162359274).jpg
Jeffrey C. Hall at Nobel Prize press conference in Stockholm, December 2017
Born
Jeffrey Connor Hall [1]

(1945-05-03) May 3, 1945 (age 78)
New York City, U.S.
Education Amherst College (BA)
University of Washington, Seattle (MS, PhD)
Known forCloning the period gene
Awards Genetics Society of America Medal (2003)
Gruber Prize in Neuroscience (2009)
Louisa Gross Horwitz Prize (2011)
Gairdner Foundation International Award (2012)
Shaw Prize (2013)
Wiley Prize (2013)
Nobel Prize in Physiology or Medicine (2017)
Scientific career
Fields Genetics
Institutions Brandeis University
University of Maine
Thesis Genetic analysis of two alleles of a recombination-deficient mutant in drosophila melanogaster  (1971)
Doctoral advisor Lawrence Sandler
Other academic advisors Seymour Benzer, Herschel L. Roman

Jeffrey Connor Hall (born May 3, 1945) is an American geneticist and chronobiologist. Hall is Professor Emeritus of Biology at Brandeis University [2] and currently resides in Cambridge, Maine.

Contents

Hall spent his career examining the neurological component of fly courtship and behavioral rhythms. Through his research on the neurology and behavior of Drosophila melanogaster , Hall uncovered essential mechanisms of the circadian clocks and shed light on the foundations for sexual differentiation in the nervous system. He was elected to the National Academy of Sciences for his revolutionary work in the field of chronobiology, and nominated for the T. Washington Fellows [3]

In 2017, along with Michael W. Young and Michael Rosbash, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm". [4] [5]

Life

Early life and education

Jeffrey Hall was born in Brooklyn, New York and raised in the suburbs of Washington D.C., while his father worked as a reporter for the Associated Press, covering the U.S. Senate. Hall's father, Joseph W. Hall, [6] greatly influenced him especially by encouraging Hall to stay updated on recent events in the daily newspaper. Hall attended Walter Johnson High School in Bethesda, Maryland, graduating in 1963. [7] As a good high school student, Hall planned to pursue a career in medicine. Hall began pursuing a bachelor's degree at Amherst College in 1963. However, during his time as an undergraduate student, Hall found his passion in biology. [3] For his senior project, to gain experience in formal research, Hall began working with Philip Ives. Hall reported that Ives was one of the most influential people he encountered during his formative years. [8] Hall became fascinated with the study of Drosophila while working in Ives' lab, a passion that has permeated his research. Under the supervision of Ives, Hall studied recombination and translocation induction in Drosophila. The success of Hall's research pursuits prompted department faculty to recommend that Hall pursue graduate school at University of Washington in Seattle, where an entire department was devoted to genetics. [3]

Early academic career

Hall began working in Lawrence Sandler's laboratory during graduate school in 1967. Hall worked with Sandler on analyzing age-dependent enzyme changes in Drosophila, with a concentration on the genetic control of chromosome behavior in meiosis. Hershel Roman encouraged Hall to pursue postdoctoral work with Seymour Benzer, a pioneer in forward genetics, at the California Institute of Technology. [3] In an interview, Hall regarded Roman as an influential figure in his early career for Roman fostered camaraderie in the laboratory and guided nascent professionals. [8] Upon completing his doctoral work, Hall joined Benzer's laboratory in 1971. In Benzer's lab, Hall worked with Doug Kankel who taught Hall about Drosophila neuroanatomy and neurochemistry. Although Hall and Kankel made great progress on two projects, Hall left Benzer's laboratory before publishing results. In Hall's third year as a postdoctoral researcher, Roman contacted Hall regarding faculty positions that Roman had advocated for Hall. Hall joined Brandeis University as an Assistant Professor of Biology in 1974. [3] He is known for his eccentric lecturing style.[ according to whom? ]

Academic adversities

During his time working in the field of chronobiology, Hall faced many challenges when attempting to establish his findings. Specifically, his genetic approach to biological clocks (see period gene section) was not easily accepted by more traditional chronobiologists. When conducting his research on this particular topic, Hall faced skepticism when trying to establish the importance of a sequence of amino acids he isolated. While working on this project the only other researcher working on a similar project was Michael Young. [3]

Hall not only faced hurdles when attempting to establish his own work, but also found the politics of research funding frustrating. In fact these challenges are one of the primary reasons why he left the field. He felt that the hierarchy and entry expectations of biology are preventing researchers from pursuing the research they desire. Hall believed the focus should be on the individual's research; funding should not be a limiting factor on the scientist, but instead give them the flexibility to pursue new interests and hypotheses. Hall expressed that he loves his research and flies, yet feels that the bureaucracy involved in the process prevented him from excelling and making new strides in the field. [8]

Drosophila courtship behavior

Hall's work with Drosophila courtship behavior began as a collaborative work with Kankel to correlate courtship behaviors with genetic sex in various regions of the nervous systems using fruit fly sex mosaics during the last months of his postdoctoral years in Benzer's laboratory. This work triggered his interest in the neurogenetics of Drosophila courtship and led him to the subsequent career path of investigation into Drosophila courtship. [3]

Discovery of period connection

In the late 1970s, through a collaborative work with Florian von Schilcher, Hall successfully identified the nervous system regions in Drosophila that contributed to the regulation of male's courtship songs. [9] Hall realized from this study that courtship singing behavior was one of the elegantly quantifiable features of courtship and decided to study this topic further. In the subsequent research with a postdoctoral fellow in his lab, Bambos Kyriacou, Hall discovered that Drosophila courtship song was produced rhythmically with a normal period of about one minute. [3]

Suspecting the period mutation for abnormal sleep-wake cycles—generated by Ron Konopka in the late 1960s—might also alter courtship song cycles, Hall and Kyriacou tested the effect of mutations in the period on courtship song. [3] They found that period mutations affected the courtship song in the same way they changed the circadian rhythms. pers allele produced a shorter (approximately 40 second) oscillation, perl allele produced a longer (approximately 76 second) oscillation, and pero produced a song that had no regular oscillation. [10]

Neurogenetics

In his research, Hall mainly focused on flies with the fruitless gene , which he began studying during his postdoctoral years. The fruitless (fru) mutant was behaviorally sterile. Furthermore, they indiscriminately courted both females and males, but did not try to mate with either. This behavior was identified in the 1960s, but it had been neglected until Hall's group began to investigate the topic further. In the mid-1990s, through a collaborative work with Bruce Baker at Stanford University and Barbara Taylor at Stanford University, Hall successfully cloned fruitless. Through subsequent research with the cloned fruitless, Hall confirmed the previously suspected role of fruitless as the master regulator gene for courtship. By examining several fru mutations, Hall discovered that males performed little to no courtship toward females, failed to produce the pulse song component of courtship song, never attempted copulation, and exhibited increased inter-male courtship in the absence of FruM proteins. [11]

Circadian rhythm of period gene and protein

Hall worked primarily with Drosophila to study the mechanism of circadian rhythms. Rather than using the more traditional method of measuring eclosion, Hall measured locomotor activity of Drosophila to observe circadian rhythms. [12]

Discovery of PER protein self regulation

In 1990, while in collaboration with Michael Rosbash and Paul Hardin, Hall discovered that the Period protein (PER) played a role in suppressing its own transcription. While the exact role of PER was unknown, Hall, Rosbash, and Hardin were able to develop a negative transcription-translation feedback loop model (TTFL) that serves as a central mechanism of the circadian clock in Drosophila. In this original model, per expression led to an increase of PER. After a certain concentration of PER, the expression of per decreased, causing PER levels to decrease, once again allowing per to be expressed. [13]

Discovery of synchronization between cells

In 1997, Hall was a part of group with Susan Renn, Jae Park, Michael Rosbash, and Paul Taghert that discovered genes that are a part of the TTFL are expressed in cells throughout the body. Despite these genes being identified as necessary genes to the circadian clock, there was a variety of levels of expressions in various parts of the body; this variation was observed on the cellular level. Hall succeeded in entraining separate tissues to different light-dark cycles at the same time. Hall didn't discover the element that synchronizes cells until 2003. He found that the pigment dispersing factor protein (PDF) helps control the circadian rhythms, and in turn locomotor activity, of these genes in cells. This was localized to small ventral lateral neurons (sLNvs) in the Drosophila brain. From this data, Hall concluded the sLNvs serve as the primary oscillator in Drosophila and PDF allows for synchrony between cells. He was awarded the 2017 Nobel Prize in Medicine or Physiology. [12] [14]

Refining the transcription-translation negative feedback loop model

In 1998, Hall contributed to two discoveries in Drosophila that refined the TTFL model. The first discovery involved the role Cryptochrome (CRY) plays in entrainment. Hall found that CRY is a key photoreceptor for both entrainment and regulation of locomotor activity. [15] He hypothesized CRY may not be just an input to the circadian system, but also a role as a pacemaker itself. In the same year, Hall discovered how the Drosophila per and timeless (tim) circadian genes were regulated. Hall discovered that CLOCK and Cycle (CYC) proteins form a heterodimer via the PAS domain. Upon dimerizing, the two proteins bind to the E box promoter element of the two genes via the bHLH domain to induce expression of per and tim mRNA. [15]

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

<span class="mw-page-title-main">Seymour Benzer</span> American geneticist

Seymour Benzer was an American physicist, molecular biologist and behavioral geneticist. His career began during the molecular biology revolution of the 1950s, and he eventually rose to prominence in the fields of molecular and behavioral genetics. He led a productive genetics research lab both at Purdue University and as the James G. Boswell Professor of Neuroscience, emeritus, at the California Institute of Technology.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

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.

<i>Cycle</i> (gene)

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 ARNTL and 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.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University 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 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".

<span class="mw-page-title-main">Michael W. Young</span> American biologist and geneticist (born 1949)

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.

Amita Sehgal is a molecular biologist and chronobiologist in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania. Sehgal was involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism. Sehgal also played a pivotal role in the development of Drosophila as a model for the study of sleep. Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology.

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.

<i>Drosophila</i> circadian rhythm

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. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during 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.

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.

References

  1. ↑ American Men and Women of Science: The physical and biological sciences. Bowker. October 2, 1989. ISBN   978-0-8352-1127-7 . Retrieved October 2, 2017– via Google Books.
  2. ↑ Jeff Hall – Brandeis Faculty Guide
  3. 1 2 3 4 5 6 7 8 9 Nuzzo, Regina (November 15, 2005). "Profile of Jeffrey C. Hall". PNAS. 102 (46): 16547–16549. Bibcode:2005PNAS..10216547N. doi: 10.1073/pnas.0508533102 . PMC   1283854 . PMID   16275901.
  4. ↑ Cha, Arlene Eujung (October 2, 2017). "Nobel in physiology, medicine awarded to three Americans for discovery of 'clock genes'". The Washington Post . Retrieved October 2, 2017.
  5. ↑ "The 2017 Nobel Prize in Physiology or Medicine – Press Release". The Nobel Foundation. October 2, 2017. Retrieved October 2, 2017.
  6. ↑ Hall, Jeffrey C. (September 16, 2009). The Stand of the U.S. Army at Gettysburg. Indiana University Press. ISBN   978-0-253-00329-4 . Retrieved October 2, 2017– via Google Books.
  7. ↑ Rees, Ian (November 1, 2017). "WJ Alum wins Nobel Prize in Medicine". The Pitch. Retrieved March 2, 2018.
  8. 1 2 3 Hall, Jeffrey (December 12, 2008). "Jeffrey C.Hall" (PDF). Current Biology.
  9. ↑ Clyne, Dylan (April 2008). "Sex-Specific Control and Tuning of the Pattern Generator for Courtship Song in Drosophila". Cell. 133 (2): 354–63. doi: 10.1016/j.cell.2008.01.050 . PMID   18423205. S2CID   17127836.
  10. ↑ Greenspan, R. J.; Ferveur, J. F. (2000). "Courtship in Drosophila". Annual Review of Genetics. 34: 205–232. doi:10.1146/annurev.genet.34.1.205. ISSN   0066-4197. PMID   11092827.
  11. ↑ Rideout, Elizabeth J.; Dornan, Anthony J.; Neville, Megan C.; Eadie, Suzanne; Goodwin, Stephen F. (April 2010). "Control of sexual differentiation and behavior by the doublesex gene in Drosophila melanogaster". Nature Neuroscience. 13 (4): 458–466. doi:10.1038/nn.2515. ISSN   1546-1726. PMC   3092424 . PMID   20305646.
  12. 1 2 Dunlap, JC (January 1999). "Molecular Bases for Circadian Clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID   9988221. S2CID   14991100.
  13. ↑ Gekakis, Nicholas; Staknis, David; Nguyen, Hubert B.; Davis, Fred C.; Wilsbacher, Lisa D.; King, David P.; Takahashi, Joseph S.; Weitz, Charles J. (June 5, 1998). "Role of the CLOCK Protein in the Mammalian Circadian Mechanism". Science. 280 (5369): 1564–1569. Bibcode:1998Sci...280.1564G. doi:10.1126/science.280.5369.1564. ISSN   0036-8075. PMID   9616112.
  14. ↑ Bell-Pedersen, Deborah; Cassone, Vincent M.; Earnest, David J.; Golden, Susan S.; Hardin, Paul E.; Thomas, Terry L.; Zoran, Mark J. (July 2005). "Circadian rhythms from multiple oscillators: lessons from diverse organisms". Nature Reviews Genetics. 6 (7): 544–556. doi:10.1038/nrg1633. ISSN   1471-0056. PMC   2735866 . PMID   15951747.
  15. 1 2 Kume, K; Zylka, MJ; Sriram, S; et al. (July 1999). "mCRY1 and mCRY2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop". Cell. 98 (2): 193–205. doi: 10.1016/S0092-8674(00)81014-4 . PMID   10428031. S2CID   15846072.
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