Michael W. Young, Ph.D.
Vice President for Academic Affairs
Richard and Jeanne Fisher Professor
Laboratory of Genetics
E-mail: young@rockefeller.edu
Circadian rhythms are genetically regulated. Dr. Young is interested in how interactions among certain genes and their proteins set up a network of molecular oscillations that are autonomously generated in most tissues and that establish overt rhythms in physiology and behavior. His lab’s findings have implications for sleep and mood disorders, as well as for dysfunctions related to the timing of gene activities underlying visual functions, locomotion, metabolism, learning and memory.
Biological clocks are internal mechanisms that
control the timing of daily activities in living
organisms. In Drosophila, these circadian clocks
are regulated by a small group of genes including
per (period), tim (timeless), dbt (double-time), clk
(Clock), cyc (cycle), sgg (shaggy), Pdp1 (PARdomain
protein 1) and vri (vrille) loci. Mutations
in any of these genes can lengthen or shorten the
period of behavioral and other circadian rhythms,
or can abolish the rhythms altogether. The abundance
of per, tim, vri, Pdp1 and clk RNA and
their encoded proteins changes rhythmically with
a circadian period in wild-type flies. Mutations
affecting any of these genes have corresponding
effects on behavioral and molecular rhythms.
Dr. Young has been studying circadian clocks for nearly three decades with a focus on their cellular and molecular machinery. Research from the Young lab led to the discovery of most of the genes listed above. Two of the genes make key proteins, TIM and PER, that shift their subcellular location in a 24-hour cycle. Dr. Young and his colleagues found that these two proteins accumulate, pair up in the cell’s cytoplasm and then migrate into the nucleus where their presence switches off their production by shutting down the per and tim genes. These events are strictly timed within the cell, as PER and TIM are retained in the cytoplasm for a fixed interval lasting several hours. This delay promotes RNA and protein rhythms and determines the period of the clock. Another of his laboratory’s discoveries is that the enzyme casein kinase 1 (DBT) regulates the pace of this 24-hour molecular clock by restricting the longevity of the PER protein in this process. It has recently been shown by others that faulty interactions between casein kinase 1 and PER are responsible for certain heritable disorders of sleep in humans.
Dr. Young’s laboratory is currently using
oligonucleotide microarrays that represent all
14,000 fly genes to study the gene expression
programs regulated by the molecular clock.
They have found that in the Drosophila head,
approximately 400 to 500 genes — about six to
seven percent of all genes active in the head —
are expressed with a circadian rhythm. Genes
composing this large circadian program influence
almost every aspect of the fly’s biology,
and subsets of these genes are switched on and
off with phases representing every hour of the
day and night. When genes that compose the
clock are mutated, this program of temporally
sequenced gene expression disappears even if
environmental cycles are present, indicating
that the temporal program is thoroughly dependent
on the molecular oscillator.
Recently, in collaboration with investigators at Weill-Cornell
Medical College, Young's laboratory has been collecting behavioral
and molecular data from human subjects with a history of delayed
timing of the major sleep episode, which could indicate dysfunction
in the circadian system. In model animal systems, mutations that
affect the period of circadian behavioral rhythms produce correlated
effects that are evident at the level of oscillating gene activities
in peripheral cells such as liver, muscle and skin. The Young lab is
therefore analyzing subject-derived, dermal fibroblast cultures for
evidence of an altered circadian clock. Transfection of these
fibroblasts with circadian reporters has allowed a detailed
characterization of the circadian rhythms of such subjects, and is
providing evidence that delayed patterns of sleep can be associated
with substantial changes in the human circadian clock.
CAREER
Dr. Young received his undergraduate degree
in biology in 1971 and his Ph.D. in genetics
in 1975, both from the University of Texas,
Austin. Following postdoctoral work in
biochemistry at Stanford University School
of Medicine, he was appointed assistant professor
at Rockefeller in 1978 as part of The
Rockefeller University Fellows Program.
He was named associate professor in 1984
and professor in 1988, and in 1991 he was
appointed head of the Rockefeller Unit for
the National Science Foundation’s Science and
Technology Center for Biological Timing. He
was also named the university’s vice president
for academic affairs and Richard and Jeanne
Fisher Professor in 2004.
Dr. Young was an investigator at the
Howard Hughes Medical Institute from 1987
to 1996, and is a fellow of the American
Academy of Microbiology and a member of
the National Academy of Sciences.
