Michael W. Young

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Michael W. Young
Michael W. Young D81 4345 (38162439194).jpg
Michael W. Young in Nobel Prize press conference in Stockholm, December 2017
Born
Michael Warren Young

(1949-03-28) March 28, 1949 (age 75)
Miami, Florida, U.S.
Education University of Texas, Austin (BA, PhD [1] )
Known for Circadian rhythms
Awards Nobel Prize in Physiology or Medicine (2017)
Scientific career
Fields Chronobiology
Biology
Institutions University of Texas, Austin
Stanford University School of Medicine
Rockefeller University
Thesis Non-essential sequences, genes, and the polytene chromosome bands of drosophila melanogaster  (1975)
Doctoral advisor Burke Judd
Doctoral students Leslie B. Vosshall

Michael Warren Young (born March 28, 1949) 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 . [2]

Contents

At Rockefeller University, his lab has made significant contributions in the field of chronobiology by identifying key genes associated with regulation of the internal clock responsible for circadian rhythms. He was able to elucidate the function of the period gene, which is necessary for the fly to exhibit normal sleep cycles. Young's lab is also attributed with the discovery of the timeless and doubletime genes, which makes proteins that are also necessary for circadian rhythm. He was awarded the 2017 Nobel Prize in Physiology or Medicine along with Jeffrey C. Hall and Michael Rosbash "for their discoveries of molecular mechanisms controlling the circadian rhythm". [3] [4]

Life

Early life

Michael W. Young was born in Miami, Florida, on March 28, 1949. [5] His father worked for Olin Mathieson Chemical Corporation managing aluminum ingot sales for the south eastern United States. His mother worked for a law firm as a secretary. Despite no history of science or medicine in either of their backgrounds, Young’s parents were supportive of his interest in science and provided the means of scientific exploration through microscopes and telescopes. They lived in an environment close to private zoos, where occasionally some of the animals would escape into their backyard and spark Young's scientific interest. [6]

Michael Young grew up in and around Miami, Florida. [2] Then, his family moved near Dallas, Texas, where he graduated from L. D. Bell High School. [7] In his early teens, Michael’s parents gifted him one of Darwin’s books on evolution and biological mysteries. The book described biological clocks as the reason why a strange plant he had seen years earlier produced flowers that closed during the day and opened at night. The location and composition of these clocks were unknown, and this sparked Michael Young’s interest at an early age. [6]

Family life

While working as a graduate student at the University of Texas at Austin, Michael Young met his future wife Laurel Eckhardt. Later, both moved to Stanford University, where Michael worked as a postdoctoral fellow and Laurel pursued her PhD with Len Herzenberg. Today, she is a Professor of Biology at Hunter College. Michael and Laurel still work close to each other. Together, they have two daughters, Natalie and Arissa. [6]

Academic career

Young earned his undergraduate degree in biology from University of Texas at Austin in 1971. [2] After a summer of research with Burke Judd on the Drosophila genome, Young stayed at the UT to complete a Ph.D. in genetics in 1975. [5] It was during his time here that Young became fascinated with research focused on Drosophila . [6] During his graduate work, he learned of Ron Konopka and Seymour Benzer’s work with Drosophila circadian mutants, which led to his future work in cloning the period gene. [6]

Michael Young continued his studies through postdoctoral training at Stanford University School of Medicine with an interest in molecular genetics and particular focus on transposable elements. [2] He worked in Dave Hogness’ lab and became familiar with the methods of recombinant DNA. [6] Two years later, he joined Rockefeller University as an assistant professor. From 1978 on he was involved in the University, serving as associate professor in 1984 and later named professor in 1988. [8] In 2004, Young was appointed Vice President for Academic Affairs and was also granted the Richard and Jeanne Fisher Chair. [5]

Scientific career

Discovery of PER

At The Rockefeller University in the early 1980s, Young and his two lab members, Ted Bargiello and Rob Jackson, further investigated the circadian period gene in Drosophila. They constructed segments of recombinant Drosophila DNA, amplified them in bacteria, and injected them in per mutant animals. A locomotor behavior monitor was used to assay behavioral activity. The team watched and recorded fly activity through the day and night to show that the fly restored circadian behavioral rhythms by transferring a functional per gene. [9] Later, by determining the sequence of the gene on the X chromosome, they found that the arrhythmic mutation produced a functionless protein, while long-period and short-period mutants of per changed the amino acid sequence of a still functional protein. [10] [11]

Period and Timeless proteins bind together to form a stabilized dimer, which allows the two to enter the nucleus. Phosphorylation of period by double-time initiates degradation. PER and TIMELESS Interaction.jpg
Period and Timeless proteins bind together to form a stabilized dimer, which allows the two to enter the nucleus. Phosphorylation of period by double-time initiates degradation.

Discovery of timeless

Following the discovery of per, the Young lab looked for additional circadian genes. In late 1980s, Amita Sehgal, Jeff Price, Bernice Man helped Young use forward genetics to screen for additional mutations that altered fly rhythms. A new gene located on chromosome 2 was named timeless (tim) and was successfully cloned and sequenced. They found strong functional connections between tim and per. Tim mutants interfered with per mRNA cycling. In 1994, Leslie Vosshall, a graduate student in Young's lab, discovered that if PER proteins were protected from degradation, they would accumulate without TIM, but could not move to the nuclei. Later Young and others found that TIM proteins did not accumulate in nuclei in per mutants. They concluded that PER and TIM worked together. [12] Another lab member Lino Saez, saw that PER and TIM associate with each other to stabilize each other and to allow their nuclear accumulation. [13] Later studies by the Young, Sehgal, and Edery labs revealed that light causes the rapid degradation of TIM and resets of the phase of the circadian rhythm. [14] [15]

Doubletime phosphorylation

In 1998, Jeff Price from the Young lab discovered a kinase called doubletime (Casein kinase 1) that phosphorylates PER on certain serine residues. This signal marks it for degradation. When PER and TIM are bound, doubletime does not seem to be able to phosphorylate PER, allowing it to accumulate. [16] Young’s discovery of doubletime mutants in 1998 was soon followed by the 2001 discovery of a form of Familial Advanced Sleep Phase Syndrome (FASPS) in humans, which is linked to an hPer2 polymorphism that removes a serine normally phosphorylated by Casein kinase 1. [17] Other forms of FASPS are caused by mutations that alter the Casein kinase 1 gene. Doubletime mutations in Drosophila alter the phosphorylation and degradation of PER protein. This affects the regularity in period of the organism. This discovery solidified doubletime as a necessary part of the circadian clock. [18]

Positions and honors

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.

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.

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

<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.

<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">Jeffrey C. Hall</span> American geneticist and chronobiologist (born 1945)

Jeffrey Connor Hall is an American geneticist and chronobiologist. Hall is Professor Emeritus of Biology at Brandeis University and currently resides in Cambridge, Maine.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

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.

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.

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. ↑ "University of Texas at Austin Alum Michael W. Young Awarded Nobel Prize".
  2. 1 2 3 4 5 6 7 8 "2009 Neuroscience Prize- Michael W. Young". Biology. Gruber Foundation. Retrieved April 6, 2015.
  3. ↑ Cha, Arlene Eujung (October 2, 2017). "Nobel in physiology, medicine awarded to three Americans for discovery of 'clock genes'". Washington Post . Retrieved October 2, 2017.
  4. ↑ "The 2017 Nobel Prize in Physiology or Medicine – Press Release". The Nobel Foundation. October 2, 2017. Retrieved October 2, 2017.
  5. 1 2 3 "Biographical Notes of Laureates". Biology. The Shaw Foundation. Retrieved April 6, 2015.
  6. 1 2 3 4 5 6 "Autobiography of Michael Young". Biology. The Shaw Foundation. Retrieved April 6, 2015.
  7. ↑ Tom Uhler (October 4, 2017). "This North Texas high school claims a Nobel Prize winner". Fort Worth Star-Telegram . Retrieved November 14, 2017.
  8. 1 2 3 4 5 "Mike Young to Receive Shaw Prize". The Rockefeller University. Retrieved October 2, 2017.
  9. ↑ Bargiello, Thaddeus; Rob Jackson; Michael Young (1984). "Restoration of circadian behavioral rhythms by gene transfer in Drosophila". Nature. 312 (5996): 752–754. Bibcode:1984Natur.312..752B. doi:10.1038/312752a0. PMID   6440029. S2CID   4259316.
  10. ↑ Jackson, Rob; Thaddeus Bargiello; Suk-Hyeon Yun; Michael Young (1986). "Product of per locus of Drosophila shares homology with proteoglycans". Nature. 320 (6058): 185–188. Bibcode:1986Natur.320..185J. doi:10.1038/320185a0. PMID   3081818. S2CID   4305720.
  11. ↑ Baylies, Mary; Thaddeus Bargiello; Rob Jackson; Michael Young (1986). "Changes in the abundance or structure of the per gene product can affect the periodicity of the Drosophila clock". Nature. 326 (6111): 390–392. doi:10.1038/326390a0. PMID   2436052. S2CID   4253390.
  12. ↑ Sehgal, Amita; Adrian Rothenfluh-Hilfiker; Melissa Hunter-Ensor; Yifeng Chen; Michael Myers; Michael Young (1995). "Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation". Science. 270 (5237): 808–810. Bibcode:1995Sci...270..808S. doi:10.1126/science.270.5237.808. PMID   7481772. S2CID   38151127.
  13. ↑ Saez, Lino; Michael Young (1996). "Regulation of nuclear entry of the Drosophila clock proteins period and timeless". Neuron. 17 (5): 808–810. doi: 10.1016/s0896-6273(00)80222-6 . PMID   8938123. S2CID   2106981.
  14. ↑ Myers, Michael; Karen Smith; Adrian Hilfiker; Michael Young (1996). "Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock". Science. 271 (5256): 1736–1740. Bibcode:1996Sci...271.1736M. doi:10.1126/science.271.5256.1736. PMID   8596937. S2CID   6811496.
  15. ↑ Lee, Choogon; Vaishali Parikh; Tomoko Itsukaichi; Kiho Bae; Isaac Edery (1996). "Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex". Science. 271 (5256): 1740–1744. Bibcode:1996Sci...271.1740L. doi:10.1126/science.271.5256.1740. PMID   8596938. S2CID   24416627.
  16. ↑ Price, Jeffrey; Justin Blau; Adrian Rothenfluh; Marla Abodeely; Brian Kloss; Michael Young (1998). "double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation". Cell. 94 (1): 83–95. doi: 10.1016/s0092-8674(00)81224-6 . PMID   9674430. S2CID   14764407.
  17. ↑ Toh, Kong; Christopher Jones; Yan He; Erik Eide; William Hinz; David Virshup; Louis Ptacek; Ying Fu (2001). "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome". Science. 291 (5506): 1040–1043. Bibcode:2001Sci...291.1040T. CiteSeerX   10.1.1.722.460 . doi:10.1126/science.1057499. PMID   11232563. S2CID   1848310.
  18. ↑ Kloss, Brian; Jeffrey L. Price; Lino Saez; Justin Blau; Adrian Rothenfluh; Cedric S. Wesley; Michael W. Young (1998). "The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase Iε". Cell. 94 (1): 97–107. doi: 10.1016/s0092-8674(00)81225-8 . PMID   9674431. S2CID   15931992.
  19. ↑ "Michael W. Young | The Gruber Foundation". gruber.yale.edu. Retrieved October 2, 2017.
  20. ↑ "Wiley: Twelfth Annual Wiley Prize in Biomedical Sciences Awarded to Dr. Michael Young, Dr. Jeffrey Hall and Dr. Michael Rosbash". Biology. John Wiley & Sons, Inc. Retrieved April 6, 2015.
  21. ↑ Sample, Ian (October 2, 2017). "Jeffrey C Hall, Michael Rosbash and Michael W Young win 2017 Nobel prize in physiology or medicine – as it happened". The Guardian. ISSN   0261-3077 . Retrieved October 2, 2017.
  22. ↑ "Election of New Members at the 2018 Spring Meeting | American Philosophical Society".
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