2017 Nobel Prize Winner Michael Rosbash on His Life and Work

Marc Gozlan, MD

Disclosures

October 19, 2017

Michael Rosbash, PhD, 73, is an American geneticist, a professor and Howard Hughes Medical Institute investigator at Brandeis University in Waltham, Massachusetts, and as of October 2, a recipient of the Nobel Prize in Physiology or Medicine.

Dr Rosbash (along with co-recipients Jeffrey Hall and Michael Young) was instrumental in revealing the molecular basis of circadian rhythms. Using the fruit fly, Drosophila, he identified genes and proteins involved in regulating the clock. Drs Rosbash and Hall proposed a mechanism by which a molecular 24-hour clock might work: a transcriptional negative-feedback loop. Their model still holds up, despite discoveries of additional circadian rhythm genes. In essence, the genes that are part of this loop activate the production of key proteins until a critical activity of each accumulates and turns off transcription.

In addition to his most recent accolade, Dr Rosbash is a recipient of the 2013 Shaw Prize in Life Science and Medicine, the 2013 Wiley Prize in Biomedical Sciences, the 2012 Canada Gairdner International Award, the 2012 Massry Prize, the 2011 Louisa Gross Horwitz Prize for Biology or Biochemistry, and the 2009 Neuroscience Prize of the Peter and Patricia Gruber Foundation.

Dr Rosbash spoke with physician and journalist Marc Gozlan, MD, for Medscape.

An Immigrant Family From Eastern Europe

Medscape: Unlike some researchers, your interest in science doesn't trace back to early childhood.

Dr Rosbash: I was interested, but not more than in other things, not especially. I was playing with toy trains and watching the Red Sox when I was an adolescent. I found biology to be very interesting in high school. It wasn't the most interesting that I ever studied, necessarily. I just enjoyed academics in general very much, but I especially enjoyed biology.

Medscape: Your parents fled Nazi Germany in 1938.

Dr Rosbash: My mother was born and raised in Berlin and my father in Baden-Baden. They married in late 1937, maybe early 1938. The last place they lived together was Wroclaw, which is now in Poland. My father was a cantor, a hazzan, a Jewish clergyman who sings or chants prayers.

Medscape: What did your mother and father do when they arrived in America?

Dr Rosbash: During the first 6 months, she worked in a hotel cleaning toilets in New York City, because they had no jobs, no money. My father was looking for work and she earned the money while he was doing that.

Medscape: Your father was looking for job as a cantor?

Dr Rosbash: Exactly. He did that in Germany before. In Germany a clergyman was a civil servant paid by the state, and even included 38 Jews! The German passion for order occasionally even superseded their antisemitism. Even after my father died, my mother collected from Germany's widow's pension from that 1 year of work. My father could not find a job in New York, of course, because there were 500 applicants for every spot.

Medscape: Your parents ended up moving to Missouri.

Dr Rosbash: My father could get a job in Kansas City. My mother worked in a bookstore. Then she had two children. I was born in March 1944, in Kansas City. She stayed home when we were little.

Medscape: Then your family moved to Boston when you were 2 years old?

Dr Rosbash: Correct. My mother had been in medical school in Germany. Then, all the Jews were ejected from university. She was ready to rematriculate in Boston as a medical student. She had been accepted to medical school in 1954, the first year my brother was in school full-time.

Then my father died the week that university was supposed to start. He died of a heart attack at 42 years old. So it was tough business. I was 10 and my brother was 6. So my mother could not go to medical school. That was another blow for her. My mother had a hard time emotionally, and this tragedy affected the emotional stability of my small family. A difficult home life continued until I left for college when I was 17.

Caltech to Brandeis

Medscape: You took an undergraduate biology course at the California Institute of Technology (Caltech) in Pasadena.

Dr Rosbash: Correct. I was interested in mathematics and then got sort of seduced by biology and chemistry at Caltech. In fact, I chose to go to Caltech not only because of its reputation but also because it was 3000 miles from my home in Newton, Massachusetts. I realized somehow that a new start at a good place and far from home was important.

Medscape: You spent a summer working in Norman Davidson's lab in biological research, correct?

Dr Rosbash: That was pivotal moment, yes. I graduated from Caltech in 1965 with a degree in chemistry. I spent a year (1965-66) at the Institut de Biologie Physico-Chimique in Paris on the Fulbright Scholarship. I can speak French. I obtained a doctoral degree in biophysics in 1970 from the Massachusetts Institute of Technology (MIT) in Cambridge.

Medscape: Did you have a mentor?

Dr Rosbash: Many of my professors were enthusiastic about their research and this was very contagious. In particular, Sheldon Penman, my PhD adviser, was brilliant and fun. He was a great mentor. After spending 3 years (1971-74) on a postdoctoral degree in genetics at the University of Edinburgh, Scotland, I joined the Brandeis University faculty in 1974.

Medscape: Why Brandeis University?

Dr Rosbash: Brandeis asked me to apply. They had a new institute and that means they made a lot of money. They had a committee that was looking for faculty for the institute and they asked me to apply for a job there. That was an unusual circumstance because usually the applicants apply for jobs—not the other way around! So they asked me earlier than I wanted to leave my post-doc, and I said I wasn't ready to take a job yet. They said, "Oh, just come interview anyway."

Because my mother lived in Boston, I went for 3 or 4 days and was interviewed for the job. I gave a seminar and they offered me the job. They immediately agreed to delay the offer for a year so that I could finish my post-doc. It was very lucrative—not from the point of view of salary, of course, because that's more or less the same everywhere; but there was a lot of laboratory money. I did not have to go on the job market, worried about where I was going to go, or spend 3 months touring different places. It was a good place and I had good colleagues. It was a place I knew well because it is 5 miles from where I grew up.

Colleagues in Rhythm

Medscape: How did you become interested in the influence of genes on behavior in Drosophila? When did you first become interested in circadian rhythms in flies?

Dr Rosbash: I was always interested in behavior. It's like being interested in who we are and the origin of our own appetites, failures, and personalities. So when neurogenetics became possible to do, I started to pay attention.

Then, and more important, I would say, I had this very good friend here at Brandeis named Jeff Hall. We came to Brandeis within 6 months of each other, are almost the same age, were both single, both liked sports and politics, and both enjoyed each other's company. So we spent a lot of time together, independent of work.

We also played a lot of basketball together. Every day we talked at 1:00, at lunchtime, at the end of the basketball game, and that went on for many years. After one of those games we had a serious conversation. It became clear that we could make some progress by pooling our talents in attacking the circadian rhythms in Drosophila, which was really a molecular biology problem.

Medscape: Did Jeffrey Hall introduce you to the landmark study by Ron Konopka[1] showing that mutations at the X chromosomal period (per) locus cause abnormally short or long rhythm periods or lead to arrhythmic phenotype?

Dr Rosbash: Yes, of course! I didn't know anything about this article. It was so far from my field of interest.

Medscape: Your research was centered on the role of RNA in the many steps between the transcription of the DNA sequence that forms a gene to the assembly of a finished protein, one of the most fundamental processes in biology.

Dr Rosbash: Exactly. I was a gene expression molecular biologist. This is a world where you might not even go to a seminar in that other area.

Medscape: You were well positioned to apply cutting-edge molecular genetics techniques to the problem of circadian clocks, as you had been a graduate student at MIT from 1966 to 1970.

The Gears Beneath the Circadian Clock

Medscape: Can you sum up the main features of circadian rhythm gene expression in the case of Drosophila?

Dr Rosbash: PER and TIM proteins repress their own transcription. CLOCK and CYCLE activate the transcription of the negative regulators. And then early in the cycle the RNA levels increase, the proteins increase and get activated, and then eventually with a temporal delay, which is important, they migrate from the cytoplasm into the nucleus and turn off their own transcription. And as they turn off their own transcription, the transcription rates fall. The RNA levels decay with little or no new synthesis. The protein levels decay. And when the protein levels get low enough, the cycle begins again.

Additional key events in that process contribute to timing. These are the modification of those transcription factors; for instance, modification of PER and TIM—and even CLOCK and CYCLE—by key kinases which regulate the activity, turnover, and half-lives of those proteins. And the most important of those kinases is DOUBLETIME.

Evolutionary speculations suggest that circadian clocks have arisen at least twice, maybe more, in evolution... We can also assume that multiple origins also implies its importance.

The connection with the outside world, namely with the light-dark cycle, is largely the job of the CRYTOCHROME protein which contributes to accurate timing by phase-shifting the clock in response to light. Photon capture by CRYTOCHROME (a blue-light-absorbing substance) in the morning, for example when the lights come on, leads to confirmational change in CRYTOCHROME. That confirmational change leads to an interaction with TIM, which accelerates the degradation of TIM and the whole clock process, leading to a phase shift. So the process can run in constant darkness, but it does not run terribly accurately and is shifted to the right time every day, by light.

And so there you are: CLOCK and CYCLE; the negative regulators PER and TIM; the kinases, the most important of which is DOUBLETIME; the photoreceptor CRYTOCHROME; and its relationship to TIM degradation.

Medscape: Let's talk about the evolution of circadian clocks. Could you summarize the thoughts about the separate origins of the circadian clocks?

Dr Rosbash: Evolutionary speculations suggest that circadian clocks have arisen at least twice, maybe more, in evolution: once in animal progenitors and once in cyanobacteria progenitors. Separate origins are supported by the total lack of sequence conservation between cyanobacterial and animal circadian clock proteins.

Medscape: So would you say that the simple phylogenetic diversity of clocks argues against a purely common origin?

Dr Rosbash: Right. We can also assume that multiple origins also implies its importance. So its contribution to natural selection is so strong that once it happens by accident, it really gets fixed.

Open Questions and Future Research

Medscape: It appears that transcriptional interconnected feedback loops do not constitute all of the molecular bases for circadian clocks. A delay between synthesis and feedback is necessary for circadian oscillations to occur. Furthermore, the magnitude of this delay may dictate the daily oscillatory frequency.

Dr Rosbash: What you said is correct. Evidence is accumulating that posttranslational regulation of certain circadian rhythm proteins is crucial to setting up these delays and therefore to timing feedback. It makes a huge contribution to timing. It is a big part of the 24-hour cycle, so that it seems to be a lot of the plasticity or a lot of the mutants manifest themselves either on the delay step or on turnover of the proteins before the next round of transcription begins. Therefore, posttranslational regulation of the protein either before transcription or after has a major effect on the length of the cycle.

Medscape: Do we have any idea of the percentage of the whole genome that is under circadian control?

Dr Rosbash: I always use the estimates of John Hogenesch from the University of Pennsylvania School of Medicine in Philadelphia. He estimates around 50% of the mammalian genome cycle is under circadian control, so about 10% to 15% in the liver and 10% in every tissue you look at. Much of that 10% is different from one tissue to another.

The idea is that there is a substantial fraction of the genome under circadian control, but by no means a majority in any one tissue. But because the overlap is rather modest between tissues, it ends up that a large fraction of the body is under circadian control in the animal. In fact, those kinds of experiments are just more difficult to do in the fly, so it's hard to know. I do not consider the fly a very good system from that standpoint, but those experiments are easy in mammals because you can take out the liver, kidney, lung, muscle, or skin. Indeed, it has been reported that circadian rhythmicity can be seen in many physiologic processes, including body temperature, activity, sleep, metabolism, heart rate, blood pressure, and hormone and neurotransmitter secretion.

Medscape: What are the greatest challenges in the next 15 years in terms of the understanding of the circadian clocks?

Dr Rosbash: Research published in Nature in 2011[2] showed that another circadian posttranscriptional modification—superoxidation of peroxiredoxin proteins—was shown to occur independently of transcription and translation in mammalian red blood cells. I believe the experiments, but you will notice that there are no other groups that have reproduced them. It doesn't have the richness of repetition yet, [whereas] hundreds of groups have worked on transcription and posttranslational feedback loops. So we will just have to see exactly whether that turns out to be a major or minor piece of the story.

Another question will be to know which diseases are impacted by circadian biology and how. If so much of the genome is under circadian control, then how many disorders are impacted by the disruption of the circadian cycle, and can one do anything about it?

Also, I think the understanding of temperature compensation—the ability of the clocks to maintain this period independent of external temperature—is going to be my next field of research. Some people feel that that's understood, but I don't. I think that is still out there as an important challenge. I think why the timing is so precise is another one. In other words, how does timing really get so precisely set? It is not exactly 24 hours, but the amount of variation within any one species is very small.

I am interested in gene regulation, specifically as it contributes to circadian biology. We are working on sleep only in flies: anatomy, neurons, molecules, and mechanisms. I am quite interested in the how and the why of sleep.

Medscape: So you do believe that flies sleep, really? There is a debate on that, so you consider the matter closed?

Dr Rosbash: For me, there is no debate. I realize that some mammalian biologists doubt this. The simple problem is that the gold standard for mammalian sleep is an EEG, and we cannot do an EEG in flies. The brain is too small and it is really organized differently in flies than in mammals, so probably something else is substituting. In other words, an EEG, in my view, is not a canonical approach.

Medscape: Now that each major clock gene has been identified, would you agree with Winston Churchill that "This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning" when it comes to the chapter of biological clocks' machinery?

Dr Rosbash: I love that quote. It's a good idea. Sure, I would agree with that.

Qualities of a Nobel Prize Winner

Medscape: What are your main talents as a scientist?

Dr Rosbash: There are so many different ways to be successful in science, but probably persistence more than anything else is my guess. That is a personality trait I think I share with the members of my family. Just never give up. I also probably have pretty good math-related skills. I have a good feeling for quantitative as well as qualitative features of biology.

Medscape: How do you explain how you stayed so long in the field of circadian biology?

Dr Rosbash: Somebody in our business said, "Data are addictive." I think that's a good phrase. Having a lab and getting new data and seeing new results is really quite addictive. You are always making progress, there is always something new going on. And so, it's exciting. It keeps you young, in a way.

By the way, it's just amazing what's happened, how the field has exploded and how much has been learned and how important the clocks are. Who would have imagined. So all of that is a big surprise!

Medscape: What are your hobbies?

Dr Rosbash: I like the outdoors. I have always liked sports of various kinds. I played football in college. I played basketball for 20 years, until I was in my late 30s. Then I played tennis for a long time. Then I started to ride, swim, and then bicycle. I still bicycle.

I also like reading and politics. I am interested in the world and how it works. I can speak French pretty well. We travel quite a bit. My wife, Nadja Abovich, was a scientist for 20 years. She is retired now. She is from Chile, so we go there quite a bit. And we are good about taking vacations and seeing exotic places.

Medscape: What about your interest in language and travel? Your mother has a bit of the same tendencies. So, whether through genetics or environment, you have probably inherited these same interests.

Dr Rosbash: Correct! My mother certainly spoke very good English despite it not being her native language. She was a big traveler.

Medscape: Thanks a lot for talking to me.

Dr Rosbash: You're more than welcome. I appreciate your interest.

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