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.

The Young lab also focuses on neural development, especially the action of Drosophila’s neurogenic genes. Mutations to these genes determine some of the earliest cell fates in the developing embryo. For example, loss of these genes alters development of the embryonic ectoderm through overproduction of neuroblasts. This occurs at the expense of presumptive hypodermal (skin) cells, implying that cell fates have been rerouted. Notch, which codes for a large transmembrane protein, is the bestcharacterized of the neurogenic loci.

Several years ago, members of the Young lab observed that expressing a truncated form of the Notch protein that includes only its cytoplasmic domain resulted in Drosophila embryos with an enlarged hypodermis and a strongly reduced nervous system. This truncated protein was also found to contain nuclear localization signals that moved it to the nucleus in cultured cells. This led Dr. Young to suggest that Notch, which is usually bound to the cell membrane, might be cleaved when it is activated, thereby producing a nuclear signal. His lab and others have since verified this in both cultured cells and flies, and in mammals.

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.