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What does it mean to be a Physician Scientist

Jordan Shavit is a professor of Pediatrics and Human Genetics, and the Henry and Mala Dorfman Family Professor at the University of Michigan. Dr. Shavit’s research interests are the genetics of hematologic and cardiovascular diseases, including hemophilia and bleeding disorders, as well as excessive clotting, such as myocardial infarction, stroke, and deep vein thrombosis. He has used genome editing to produce mutations in the relevant pathways, with the surprising finding that fish tolerate disturbances that are embryonic lethal in mammals. Dr. Shavit is Vice President/President-Elect of the Hemostasis and Thrombosis Research Society, a recent chair of the Megakaryocyte and Platelet Scientific Subcommittee of the American Society of Hematology, and co-chair of the Hematology Research Interest Group of the Zebrafish Disease Models Society.

Hannah Huston: Hello and welcome to 17 Minutes of Science, our show that explores the world of science and how it affects both the starting academic and the seasoned professional. I am Hannah Huston, and today I am joined by Dr. Jordan Shavit. Jordan is a professor of pediatrics in human genetics and the Henry and Mala Dorfman Family Professor, at the University of Michigan. Dr. Shavit’s research interests are the genetics of hematologic and cardiovascular diseases, including hemophilia and bleeding disorders, as well as excessive clotting, such as myocardial infarction, stroke and deep vein thrombosis. He has used genome editing to produce mutations in the relevant pathways, with the surprising finding that fish tolerate disturbances that are embryonic lethal in mammals. Dr. Shavit is vice president, president-elect of the Hemostasis and Thrombosis Research Society. A recent chair of the Platelet Scientific Subcommittee of the American Society of Hematology and Co-Chair of the Hematology Research Interest Group of the Zebrafish Disease Model Society. Welcome, Dr. Shavit. Thank you for joining us today.

Dr Jordan Shavit: I thank you. It’s great to be here.

Hannah Huston: So let’s start at the very beginning. How did you get into science?

Dr Jordan Shavit: So I actually have an MD and a PhD, but way back when, when I graduated high school, I had excelled in math and science and I liked working with people. So I said, I want to be a doctor. And my parents said, “well, if you’re going to be a doctor, you should know how to do research,” which I don’t know, I think is sort of a funny conclusion. But anyway, they -we happen to have a family friend who ran a research lab and she got me a job in in another lab in her department. And I, I washed dishes that summer, and I washed dishes the next summer. And I really liked being in the lab. And I like the environment. And it’s actually the second summer I was working with a graduate student and I remember them talking about their experiments and they were saying, “well, it could be this or that.” And I said, “what’s the right answer?” And they said, “we don’t know. That’s why we do the research.” And a light bulb went off. I was like, Oh, now I get it. And that’s what got me excited. And from then on, I kept working in labs and, you know, eventually went to medical school and graduate school. And here I am.

Hannah Huston: Wow. That’s a great way to get into science then. So can you tell us a little bit more about the research that you do today?

Dr Jordan Shavit: Yes. So I study blood and cardiovascular disorders. I went on, you know, after I got my M.D., my Ph.D., I did a residency in pediatrics and then I did a fellowship in pediatric hematology and oncology. And during those fellowship, it includes a postdoctoral fellowship time. So I worked in the research laboratory of David Ginsberg, who does the genetics of -primarily blood clotting disorders. And so what I learned there is how to combine both my clinical background along with my basic science background. That was the training I had during my PhD, and learn how to put those together. And what I do is I look at the patients that I see and I see what are the things that we’re missing and how can I make this into a laboratory problem that I can, you know, answer using basic science techniques? So for example, one thing that I’ve seen clinically is I see a lot of our patients, pediatric patients are on oral contraceptives and oral contraceptives will predispose you to a risk of what’s called thrombosis. That’s pathologic blood clotting. Clotting when it’s occurring inside a vessel, when it’s not supposed to, that will block blood flow and can cause a lot of problems. Actually, pathological blood clotting or thrombosis underlies heart attack and stroke as well. So I would see this in patients, in young girls who were taking oral contraceptives for good reasons. Sometimes it was to regulate their periods which are too heavy. Sometimes it was because they wanted birth control if they were sexually active. Other times it was for things like acne. But we could never predict who was going to get clots. It’s the minority, fortunately, but we couldn’t predict who is going to get it and we had no way of preventing it. And so when I look through the literature, I realized we didn’t know the mechanism of how this happens. Well, why don’t we know the mechanism? One is we didn’t have a good animal model. Mice actually don’t develop thrombosis when they’re treated with estrogen. Estrogen is the primary component of birth control that causes this. And so we actually got to this serendipitously. But I think in the interest of time, I’ll just tell you, we tested Estrogen in zebrafish, which is our primary model, and we found that it caused thrombosis. So all of a sudden now we had a model to try to figure out how this occurs. And so I think that leads to something else, you know, the way I talk about my research, is – I call it clinically directed basic science, which is the description I just gave you: taking clinical problems and making them into basic science questions. So in order to answer the kinds of questions that I’m posing that we wanted is we really needed disease models in zebrafish. And so that’s where we got into genome editing. And genome editing has been around now, it’s very easy to do with CRISPR and all that, but when we started, this was back around 2008 and all we had was zinc finger nucleases that didn’t work very well. I think your company knows a lot about this history. Keith Young at Massachusetts General Hospital was somebody who was at the forefront of getting zinc finger nucleases to the masses. I mean, they’re really hard to make and they don’t work well at all. I mean, they’re so 2008, we don’t use those anymore. And so, but we had to make disease models and we use those and then eventually TALENs and now CRISPR to make models. And once we had the models, we could use the advantages of zebrafish technology to answer these questions.

Hannah Huston: Right. And those questions are so important to answer. So thank you for the work you’re doing. Have you always worked with zebrafish? It sounds like you mentioned mice earlier, or have you worked with any other models?

Dr Jordan Shavit: Yeah. So my PhD was in mice and I – the first half of my postdoc was using mice as well. And actually the reason that I switched to zebrafish, I thought it was an interesting model and when I joined my postdoc lab, I heard about the work going. But it was very it was very new. We were not a traditional zebrafish lab. And so, the PI at the time did not want to expand it out. It was kind of experimental, if you will. But then the postdoc who was working on that for personal reasons, had to leave. And so I took over the project and I just love working with zebrafish as a model. I mean, there’s there’s so many advantages to them, right? The main advantage is being their fecundity. They can produce hundreds of offspring on a weekly basis, and that enables a lot of genetic screens and small molecule screens, which is some of the kinds of experiments that we’re doing. And the other advantage, I mean, and that’s the power of genetic studies is to have large pedigrees and, you know, mice, right a single mating pair of the mouse can produce five or ten offspring every couple of weeks, whereas fish can do hundreds on a weekly basis. And then the the other advantage being the rapid development of zebrafish that go from a single cell to a free swimming larva that has nearly every major organ system within just a couple of days. But for blood clotting work, one of the major focuses of our lab, a lot of the work that you need to do is be able to draw blood from an animal and then test that blood in vitro with a whole lot of clotting assays that are out there. And in fish, you can get maybe 5 microliters if you’re lucky from an adult fish, whereas a mouse you can get a couple of hundred. And most of the clotting assays are adapted for the latter. So we – you know what I foresee in the future is that once we’ve made certain conclusions in fish, we may look in the mouse and do some of the clotting assays that we can’t do in the fish.

Hannah Huston: Yeah. That would that would make sense to approach it from that multimodal perspective.

Dr Jordan Shavit: You know, I think well, let me just say you’re right about that, really. We are primarily a fish lab right now because of the way experiments have gone. But the way I think about things is I’m answering questions. I’m not just basing my questions on a model. Right? I’m answering questions using whatever model is available to me.

Hannah Huston: Right. And so I know that in a in a previous conversation, you had talked a little bit about an electronic model that you use. Would you be able to tell us a little bit more about that?

Dr Jordan Shavit: Yeah. So right, the model that we’re talking about is is humans. And there’s two ways we can look at that. Obviously, we can’t do the manipulative experiments that we do on mice and fish. We can’t do that in humans. I mean, there are clinical trials that go on, but those are very expensive and time consuming and something that I could see us being involved in in the future. But in the meantime, we had made a particular discovery in fish. We had found actually a compound that prevented thrombosis due to estrogen. And it was pretty potent. It was it’s a very common drug that is over-the-counter and used by thousands or probably hundreds of thousands of people. So we said, let’s look in the electronic medical record, which is easy to access now, and see if we can see that signal in in the human population that we saw in the fish population. And if so, then we would think about whether we could do a trial or whether we just need to alert people to this. And we found actually the opposite effect. Very robustly in different databases, we found actually that this compound enhanced thrombosis in humans, which is concerning. And so it’s something that – it probably about doubles the rate of thrombosis or so, well actually no, 2-4 times increases the rate. And right now we’re working on some hypotheses of why we saw the opposite effect in this electronic medical record. And for those who don’t know. Right, this is we’re talking about patient records that are all acquired. It’s all HIPAA protected data that we get special permission to use. We have to go through an institutional review board to access this data, but it could lead to some ideas or clinical trials or at least alert to clinicians like, ‘Hey, you may need to think about this while you’re treating patients.’ The other way we’re using humans as sort of a model is human evolution. So genome wide association studies are very common these days, and that’s where you take a population of patients with a disease and then a population of patients without the disease. And you look at their genetics between the two and you see, are there any genetic variants in certain genes that correspond to one population or the other? And this comes from databases now of tens or hundreds of thousands of individuals. So we collaborated with a group here at the University of Michigan who had access to these databases, and they found a number of different genes that were associated with thrombosis. And then we went from that data to our fish and we knocked down, using CRISPR, we knocked down those genes in fish, and were able to confirm that indeed those genes they identified were associated with thrombosis in a in a functional assay.

Hannah Huston: Wow. That is a really fascinating way that you’re able to kind of build out – see the data and then build out these hypotheses and test them in the fish. So are these just U.S. records or these are – is this like worldwide?

Dr Jordan Shavit: Oh, yeah. Great question. So the first one was just U.S. Records. There was a network in the United States that we access for the for one of our data sets. And the other data set was just University of Michigan data. For the genome wide association studies that is actually worldwide. And I can’t – the, our collaborators are part of a network that has access to data across the world, including the UK Biobank, for example. And I forget the others, but with probably several million total individuals. But we just, well, they just accessed a subset of that. It was a million individuals without disease and I think it was 200,000 who had had an episode of thrombosis. But, but it spanned the world.

Hannah Huston: Wow. To get a data set that large, though, that must be – that must be like Christmas Day.

Dr Jordan Shavit: Yeah. Yeah. It’s funny. One thing I said in a talk once was for us, doing mutagenesis screens is something that we’re doing in zebrafish. Those are quite expensive. And I said this human data set, it was we just got the human data and we just knocked it down and fish that was much cheaper. But then I had to step back and say, Well, the people who collected that data spend a lot of money on that.

Hannah Huston: That is true. Yes. You are a beneficiary of their work.

Dr Jordan Shavit: Yes. Yes.

Hannah Huston: So I understand you’re a physician scientist. Can you tell us more about how you are trying to solve clinical problems in your lab?

Dr Jordan Shavit: Yeah. Well, so it’s the like the examples I told you about where we see the patients in clinic, see what the problems are that we can’t answer, and then take it back to the lab. Another example is when it comes to blood clotting disorders, we know the coagulation cascade, what’s responsible for blood clotting? Either that or platelets is the other arm of blood clotting. And we can measure all of those factors. We can measure the level of platelets and the level of all the individual blood clotting factors – there’s about 10 to 15 of them. But we can have patients who have the same low level of a blood clotting factor that puts them at risk of bleeding or the same mutation in a particular blood clotting factor. Yet their phenotypes might be very different. Somebody might have a lot of bleeding and somebody not much at all. And again, we don’t really know how that is. We have data that suggests that it’s what we call modifier genes, genes outside of the coagulation cascade that modify that effect. But to find that in human populations, to do genetic studies, to find those is very hard when you can’t manipulate the pedigree, you can do GWAS (Genome-wide association studies). And that’s given some answers. But to really drill down to individual genes, the zebrafish is a big, beneficial model where we can do widespread mutagenesis using a chemical to individually mutagenesis each gene across the genome and then look at the effects of that in a rapid manner and cost effective manner and one we can manipulate. And then when we find those modifier genes, we can then look back to our human populations and say, okay, does that explain some of the differences we’re seeing and then use that in the future to either identify patients at higher or lower risks of a of a bleeding or a clotting phenotype, or to find those as new targets. Those genes as targets for therapies for  those patients.

Hannah Huston: So you’ve kind of already hinted at this. But my next question is going to be, what are the next steps of your current research?

Dr Jordan Shavit: Yeah, ongoing we have we’ve made a number of models. We’ve basically knocked out the entire coagulation cascade in zebrafish, and that was relatively easy and cheap to do compared to to mice. It still takes about the same amount of time to, as you I think know well, to make a mutant fish as it does to take a mutant mouse. But the costs are much lower. So we’ve spent most of the last 5 to 10 years doing that. And now we’re getting into mutagenesis screens where we take these models, mutagenesis the genome, you know, make random mutations in every every gene, which is something that has been done in zebrafish for many years. And then. Find those modifier genes and study them, learn their mechanisms and hopefully look for signals for them in human populations. And then the other thing is to use small molecule screens, right, where we can take – because zebrafish are like – the little [zebrafish] larva at three days of life are like little mini organisms, as your company knows, we can take those little larva, we can put them into 96 well plates, which are multi well plates for those who aren’t familiar with that, that’s like having a plate of test tubes – and in each one of those we can put a couple of larva and then we can put a compound into each well. A different compound, from what we call a library of compounds, and look for treatments, new treatments for the diseases we’ve modeled. Find a compound that will reverse that. And that’s how we found the drug I was telling you about that reverses estrogen induced thrombosis.

Hannah Huston: That’s – the the impacts that your research will have is it’s going to be pretty great.

Dr Jordan Shavit: Thank you.

Hannah Huston: So now we’re going to take a big picture, step back a little bit. Did you have any mentors who helped inspire you to pursue science? I know you said that your parents were influential, but did you have anyone else?

Dr Jordan Shavit: Yeah, I mean, all along the way, actually, I did science fair projects with my father in middle school where I learned how to do linear regression and learned how to do the scientific method. But then professionally, I mean mentors all along the way. Those labs have worked in after high school and through college. One of them was Meena (Dr Mrinalini Rao) at the University of Illinois in Chicago. She was the first lab I worked in. Dr. Geula Gibori was the family friend who got me involved with Meena and I also worked in Geula’s lab the next summer really got me started. I actually, Meena it just came back to visit Michigan. Just by coincidence, this was in Chicago, but by coincidence, she happened to be the first graduate student in the program that one of the programs that I’m in here and she came back for the 50 year anniversary and it was really great to see her. And I could tell her how she inspired me because without that being such a great experience, I wouldn’t have gone on. And then all along the way, I mean, somebody at Loyola in Chicago, Jawad Fareed, really in a fellowship there, gave me my first sort of independent project that got me thinking and really solidified the fact that I wanted to do both clinical work and research work. And then my, my PhD mentor, who really taught me basic science, Doug Engle. And then after that, really the penultimate mentor was David Ginsberg, who was my post-doctoral mentor, who was a physician scientist and really taught me how to combine the two. Doug actually said to me, I taught you basic science. Go work in David’s lab and learn how to do both and bring them together. And really, having a physician scientists I could follow really taught me how I could combine the two together, which is something I actually didn’t think I would do. After I worked in Doug’s lab, I thought, You know what? I’ll be a doctor and then I’ll do some research and they probably won’t even be connected. But the beauty of what I do is that they’re connected together. And as I told you right, they really play off each other. And it’s really my dream job. It’s what I’ve always wanted to do, to be able to do that, because I can’t be a doctor that knows everything about medicine. Right, and run a basic science lab. So I really need to have these little corners of the world that I can combine, that I’m the expert, and I guess you could say one of the world’s experts in the coagulation of zebrafish and in modeling that. And I just love it.

Hannah Huston: Well, the fact that you get to go to work every day and that your work brings you a smile and is going to have big impacts on the world, it’s a great, great thing. So thank you for the work you do. And thank you for joining us today on 17 Minutes of Science. It was wonderful to talk with you and to learn more about your research.

Dr Jordan Shavit: It was great to be here. Thank you so much for having me.

Hannah Huston: Well, thank you, everyone, for tuning in. That was the end of 17 minutes of science today. We will see you next time.

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