JUNE 2020 Michael Rosbash, M.D. NOT FOR PUBLIC DISTRIBUTION Mishka Richards My name is Mishka Richards from Indiana and South Carolina and it is my honor to introduce Dr. Michael Rosbash. Dr. Rosbash’s research focuses on the metabolism and processing of mRNA, the molecular link between DNA and protein. His research ultimately led to him receiving the Nobel Prize in Physiology or Medicine. He and his colleagues identified a gene that encodes a protein that accumulates during the night, which is degraded during the day. They also identified additional proteins that form parts of a self-regulating biological clockwork, applicable to a range of animals and plants. Dr. Rosbash, welcome to the Congress of Future Medical Leaders. Dr. Rosbash Thank you very much, Mishka. It's a pleasure to be here. And so I don't forget I want to not only thank Mishka and Richard for that gracious introduction and accurate, I might add, but also to Angelina Bucci, who's going to lead the question and answer session that follows. So, I'm going to begin this talk with a few personal thoughts that will give you a little bit of insight into my history. And I think if there's an overarching summary of these few minutes, it's really that there are many ways to arrive at your goal. There's not just one formula. So where should we begin? Like, the White Rabbit said in Alice In Wonderland, I think the place to begin is at the beginning, and then you continue until you come to the end, and then you stop. That's my personal journey, and it will be yours as well. So I thought I'd start at the beginning and show you a picture of my father's so called Frenton Pass. This was the pass that the German authorities gave to Jewish citizens when they revoked their citizenship. And that's shown on the left. And on the right is my dad's visa to the United States, which was signed in June of 1938. And one month later, he and my mother sailed as newlyweds to the United States where I was born. So that's my cultural background, if you will. I want to point out the fact that, you know, I then had a journey like everybody beginning with childhood, and ending with Brandeis where I am currently, where I've been for a long time. And I want to say a word about childhood. Just to put this a bit in perspective. My father died in 1954 when I was 10 years old. And so that was a real blow to be into my family and made for a rocky beginning. And in fact, there is aspects of my journey, which are far from smooth, rocky is probably a good adjective to describe them. And they've often been attributed to this blow I suffered when I was 10 years old, that is the loss of my father. And that's a reasonable hypothesis, but of course, it's not an exclusive one. And I thought you might like to see and be amused by my report card from first grade, which my mother dutifully kept. And I can't see the details here because it's a bit blurry on my screen. OFFICIAL TRANSCRIPT NATIONAL ACADEMY OF FUTURE PHYSICIANS AND MEDICAL SCIENTISTS © 2020 ALL RIGHTS RESERVED 1 JUNE 2020 But you'll notice that for some of these categories, my report was less than Sterling. It was unsatisfactory for a couple of those behavioral criteria. And of course, this is first grade when I was six years old. And my dad died when I was 10. So I think this is a strong indication that some of the rougher parts of my personality, some of the difficulties I had along the way, were not solely due to my father's death, because they really showed up before I ever, years before that occurred. So the importance of data to try to distinguish between hypotheses. And then let me say a word about the big middle features here on this journey. My undergraduate years at Caltech, a year I spent in Paris, between undergraduate school at Caltech and graduate school at MIT. And then four to five years I spent at MIT as a PhD student. So those two universities, Caltech and MIT have a distinguishing feature that is, they're really meritocracies. They care about what you do, and not where you come from. And in my particular case, they are quite liberal about not paying attention to some behavioral idiosyncrasies that might count against one, in other locations. So I'm very grateful to those places for having ignored what could have been real liabilities in other institutions. And I'm really very thankful to that year in Paris that I managed to have for giving me an appreciation to the wider world. Some of the comments about Vietnam by the previous speaker reminded me of the warm place in my heart that those very formative year at the age of 21 holds for me in Paris. So let me end by simply saying that I ended up at Brandeis as an assistant professor. And it was really an accident that I went there. I didn't know about any of these things. And it was really at Brandeis that I met Jeff Hall, who became my partner for 20 years as a collaborator. Jeff was one of the three co recipients, one of my two co recipients for this Nobel Prize. And it was through Jeff, that I learned not only about genetics, but also about circadian rhythms. I was a nucleic acid biochemist, knew nothing about that sort of thing. And it's really through him that I learned it. So let me begin and tell you a little bit about circadian biology. So it is really a biological phenomena that arose in response to this inexorable rotation of the Earth, the light dark cycle that accompanies all of life. And it turns out that many, most organisms have a circadian clock, and arguably the oldest one is in cyanobacteria, which is responsible for oxygenating the atmosphere more than 2 billion years ago, a photosynthetic organism as you can appreciate from the green color. And circadian rhythms really have four defining characteristics. The rhythms are not exactly 24 hours, they're about 24 hours, but they become 24 hours by, in training or becoming in sync by the light dark cycle. And the purpose of this is really anticipation. Knowing what is going to happen, the early bird gets the worm, and the early worm avoids being eaten by the bird. And there's some evidence that internal biochemistry, internal coherence is also regulated by circadian rhythms. And I want to point out that locomotor activity is really a striking phenotype for circadian biology. That is the active phase indicated in this hamster running wheel picture, by those little ticks. And you can see that the hamster is keeping a not exactly 24 hour period in constant darkness. OFFICIAL TRANSCRIPT NATIONAL ACADEMY OF FUTURE PHYSICIANS AND MEDICAL SCIENTISTS © 2020 ALL RIGHTS RESERVED 2 JUNE 2020 It's shorter than 24 hours, but in a light dark cycle. It's exactly bang on 24 hours. And the mantra of genetics is really like real estate, which is location, location and location. And for genetics is phenotype, phenotype, phenotype. So locomotor activity is a fantastic phenotype. And this locomotor activity phenotype was recapitulated for Drosophila by Konopka and Benzer, who assayed fruit flies running back and forth in a little tube as shown here with some food at the bottom and a stopper on the top. And this genetic screen that Konopka and Benzer did in the in the late 60s, published in 70, early 70s, managed to identify three mutants of fruit flies, which had altered circadian rhythms. And those three mutants, an arrhythmic mutant, a short period mutant, and a long period mutant, were all alleles of a single gene called period. And it was that gene and the cloning of that gene as Misha described, which really was the beginning of our circadian journey and I want to point out to you, and you'll notice that about why genetics. So I want to emphasize here that this is not to distinguish between you and me, or to ask, how are we different, and is that genetic. It's really as an entree into a mysterious process. There's no way to get at circadian biology, except through genetics. And that's really what we did. And so that really led to this conserved negative feedback loop at the level of transcription, where transcription factors drive the synthesis of their own negative regulators. And those negative regulators feedback, and turn off their own synthesis. And that turns out to be a conserved process, not just the process itself. But the actual genes are conserved between flies and mice, which is what gave this whole process its importance. And so I want to point out some future challenges that someone like you might keep in mind if you become interested or maintain an interest in circadian biology. First of all, on the basic science front, we really don't understand why the cycle is about 24 hours. Why isn't it 17? Why isn't it 28, we really don't know what the rate limiting steps are. And that's because of a paucity of biochemistry, the system has not been mammalian system, or the eukaryotic system has not been recapitulated in vitro.