Meet the Endocrinologist: Joseph Takahashi, expert on the genetic and molecular basis of circadian rhythms

Meet Joseph Takahashi, Professor of Neuroscience at the Howard Hughes Medical Institute at UT Southwestern Medical Centre. His research focuses on the genetic and molecular basis of the circadian clock in mammals. He has been awarded the SfE Transatlantic Medal and will be delivering his Medal Lecture at SfE BES 2018, 19-21 November in Glasgow. In our latest interview, he tells us more about his career, research and what he is looking forward to at the SfE BES 2018 conference. 

Can you tell us a little about your current position and research?

I’m an Investigator in the Howard Hughes Medical Institute, and Professor and Chair of the Department of Neuroscience at the University of Texas Southwestern Medical Center in Dallas, Texas. My lab studies the genetic and molecular basis of the circadian clock in mammals. More broadly we are interested in the genetic basis of behavior. My lab is known for discovering the first circadian gene in mammals known as the Clock gene.

One of the initial surprises from cloning the mammalian clock genes was that they are ubiquitously expressed. This eventually led to the discovery that the circadian clock is cell autonomous and that virtually every cell in the body has the capacity for circadian oscillation. Thus, all of our major organ systems contain intrinsic circadian oscillators. This has led to a revolution in studies aimed at understanding the role of clocks in peripheral tissues as well as studies focused on understanding the systems level organisation of the multiple clocks in the body. The core circadian molecular pathway regulates thousands of genes in mammals, and this has led to the discovery of direct molecular links to a myriad of molecular, cellular and physiological pathways. These include direct links to endocrinology, metabolism, immune function, cell growth and cancer.

Can you tell us about your career path, and what you are most proud of?

I have been incredibly fortunate to have had great mentors and colleagues as well as research institutions and funding agencies that have supported me throughout my career.  In college, I was interested in biology, but did not know what careers one could pursue except for med school. Later I had the good fortune to do an independent research project and learned that one could go to graduate school in biology(!). That was the beginning of my research career.  I took a post-baccalaureate year to work with Patricia DeCoursey, one of the pioneers in mammalian circadian rhythms, and then went to work with Michael Menaker for graduate studies. Menaker was the perfect mentor for me. He had a free and open lab environment that encouraged creativity, independence and scale and automation. We pioneered long-term ex vivo culture of tissues that contained and expressed circadian rhythms in the late 1970’s. These initial forays continue to pay off decades later as the entire circadian field uses large-scale data collection, automation and long-term in vitro circadian models.

After graduate school, I did a 2-year post doc with Martin Zatz at the NIH where we worked on the pharmacology circadian rhythms in the chick pineal in vitro.  I was then recruited to Northwestern University by Fred Turek. As an independent faculty member at Northwestern, my lab focused on reductionist dissection of the circadian oscillator in the chick pineal.  In addition to pharmacology, we worked on the biochemistry of various circadian pathways in the pineal.  However, eventually we were stymied, and my interest in the molecular biology and genetics of circadian rhythms was growing.  We knew that molecules and genes had to be important for mammalian circadian rhythms, but how to get there?  That was the beginning of my ‘second career’ as a geneticist.  Ironically as an undergraduate, I was not very interested in molecular biology or genetics (I was interested in animal behavior), but luckily I ‘had’ to take these courses.

In 1990, Larry Pinto, Fred Turek and I decided to use mouse genetics to try to find circadian rhythm mutants. We collaborated with William Dove at the University of Wisconsin-Madison, and Martha Vitaterna conducted our first screen of mice that were ENU mutagenised in the Dove lab.  In our first screen, we isolated the Clock mutant mouse which has a 28-hour period length and a loss-of-rhythm phenotype in circadian activity.  This mutant mouse then provided the means to identify the Clock gene by positional cloning. The isolation of the Clock mutant and the positional cloning of gene was the crowning achievement of my lab.

What are you presenting in your Medal Lecture at SfE BES 2018?

I plan on giving an historical account of our forward genetic approach to finding clock genes in mammals. The effort to clone Clock was massive.  Ten members of my lab worked together as a team for three years to complete the project. In the 1990’s there was no genome sequence. The Clock gene turned out to be huge: it had 24 exons and covered over 90 kB of genomic DNA. Then I will discuss more recent molecular and genomic analyses of the circadian clock gene network. Finally, I will describe our new work on the importance of time and caloric restriction for aging and longevity.

What are you looking forward to at this year’s conference?

I am very much looking forward to seeing all the advances in the field of endocrinology as well as the plenary lectures.

What do you think are the biggest challenges in research right now?

It is of paramount importance to support research in basic science. It is very important to translate these basic science discoveries, but one must remember where these advances had their beginnings.  It is impossible to predict new discoveries and how they will impact medicine in the future.

What do you think will be the next major breakthrough in your field?

Many important breakthroughs in the circadian field will be their connections to all aspects of cell biology, cancer and metabolism. New views of metabolism and longevity are already being linked to circadian biology.

What do you enjoy most about your work?

I love the fact that we are supported to pursue knowledge and discovery of biological systems.  Making scientific discoveries is like a treasure hunt for adults.  It never gets old, and one discovery always opens the door to countless new questions.  Also, as an academic, we have intellectual freedom that is rare in other professions.

Who do you most admire professionally?

My role models have been: Seymour Benzer at CalTech, who pioneered genetic approaches to complex behaviors; Eric Kandel at Columbia, whose systematic and scholarly approach to understanding learning and memory in simple model systems was fundamental; and Denis Baylor at Stanford, whose biophysical analysis of phototransduction was a thing of beauty.

Any words of wisdom for aspiring researchers out there?

My mantra is:  Always begin with first principles. What I mean by this is that you must understand what you are doing. To an electrophysiologist or biophysicist this is self-evident. But in today’s world of molecular biology and informatics, the kits that you use in the lab and the computer programs that you employ are frequently applied without a fundamental understanding what they are doing and how they work.

 

You can hear Professor Takahashi’s SfE Transatlantic Medal Lecture, “Circadian Clock Genes and the Transcriptional Architecture of the Clock Mechanism” on Monday 19 November, in the Lomond Auditorium at 18:00. Find out more about the scientific programme for SfE BES 2018.

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