By UO Student Lili Wagner
Joseph S. Takahashi, PhD ’81, studies what makes us tick. He wants to understand why we get out of bed in the morning and what helps us sleep at night, questions he works to answer through molecular and genetic analysis of mammalian circadian rhythms.
Current Chair of the Department of Neuroscience at University of Texas Southwestern Medical Center, Takahashi discovered research by a lucky stroke as an undergraduate.
“I didn’t learn that you could do research until I was a junior in college. I was studying biology at Swarthmore College and at that time all of the biology students were, by default, pre-medical students. I was lucky enough to have two or three incredible professors who pointed me in the direction of research,” he says. “There were labs that went along with every science course, and they were pretty sophisticated. I was fascinated by that.”
Almost immediately, Takahashi discovered his interest in watching the clock.
“I helped study electric fish and their electrical discharge, which is actually very easy to measure. I decided to measure them over a longer period of time, overnight, and found that the first electric fish only fired at night, which was unusual.”
Working with a professor, Kenneth Rawson, who was doing research on the physiological basis of animal behavior, Takahashi decided to conduct his senior thesis on the firing patterns of electric fish, placing his work in a larger body of research of circadian rhythms.
Upon completing his undergraduate degree, Takahashi spent a year working in a marine biological institution before beginning his graduate studies in the lab of Michael Menaker, a prominent circadian rhythm researcher then grounded at the University of Texas, Austin. Menaker was recruited to the University of Oregon in 1979 and brought his lab, and Takahashi, along with him.
“I was only at the UO for two years, but it was extremely beneficial to study in two different places, two completely different environments. UO was more focused on neuroscience and molecular biology, so I was exposed to different areas.”
Takahashi’s graduate work on circadian rhythms focused on the question of how the circadian clock works in vertebrates. Studying birds and rodents, he and other researchers were able to identify brain regions that regulate circadian functions in vivo, and to isolate them in culture to study them in vitro.
Through his work on mice, Takahashi unearthed what he considers his most influential finding, the discovery of the CLOCK gene. By randomly mutagenizing mice—exposing them to a chemical inducing mutations—and carefully screening their circadian behavior, Takahashi and his lab were able to isolate the strains with altered circadian behavior and to use these mutant mice to determine the location of genes controlling circadian rhythms. Through genetic mapping they were able to locate where the gene was likely to be and to isolate DNA fragments from the region to produce a physical DNA map and ultimately identify the candidate genes. The herculean effort of 10 researchers working over a three-year period—30 years of combined research effort—provided a major key in unlocking understanding of circadian rhythms.
This work not only revealed newfound information about circadian rhythms, but also utilized advanced techniques including that of forward genetics, which does not require any pre-existing knowledge of the underlying mechanisms involved. Instead forward genetics begins with a function or phenotype, to determine genes related to circadian behavior. This approach, popular in simpler model organisms, was not thought to be feasible in mice and was the technical innovation required for the monumental cloning of the first mammalian circadian clock gene. This breakthrough led to an avalanche of discovery from which Takahashi and his peers have been able to assemble an autoregulatory feedback pathway describing the clock mechanism in mammals.
“Where once we were working to determine the location of one gene related to circadian rhythms, we now know that there are 3,000 genes in the liver alone controlled by CLOCK, which is a master regulator of many genes enriched for metabolic pathways,” Takahashi explains.
That is, mammalian sleep patterns are intertwined with eating patterns. Indeed, the study of metabolic defects is a major area in which understanding of mammalian circadian rhythms is applied.
“We learned that if we delete or remove CLOCK or BMAL1 in pancreatic islets in mice that they developed diabetes.”
The applications of understanding circadian rhythms have notable significance to the biomedical field. In addition to his current position as chair of the Department of Neuroscience at University of Texas Southwestern Medical Center, Takahashi is also a Howard Hughes investigator. The Howard Hughes Medical Institute is one of the largest private biomedical institutes in the country. The institution’s Investigator Program funds people, not projects, a unique way of supporting scientific innovation. For his discoveries, Takahashi has been elected to the American Academy of Arts and Sciences, the National Academy of Sciences and the National Academy of Medicine.
Takahashi’s current research projects seek to answer questions including how CLOCK works at a mechanistic level, what other components make up the pathway, and how circadian rhythms work chemically.
Though his research has carried him leaps and bounds from his time at UO, the university will always have a place in his heart. Takahashi remembers the University of Oregon as a stimulating environment, academically and personally.
“It’s a beautiful part of the country. In the spring I spent a lot of time running on the trails behind campus. There were great things going on. I loved living in Eugene.”