Interview Willing to Do the Math: An Interview with Jane Gitschier

avid Botstein’s name came up Lewis-Sigler Institute. What are you any kind of science had been falling for twice when the PLoS Genetics trying to do here? the last 30 years. And the conventional editors tossed around ideas wisdom is that it is all about K–12 D David Botstein: Actually, I came here for potential interviewees, and with education. good reason. First, he is now director of to do something about science I don’t believe that for a second. an exciting development on the education, an experiment, if you like. campus, the As you know, I was at MIT JG: And why is that? Lewis-Sigler Institute for Integrative [Massachusetts Institute of Technology] DB: I’ll tell you the argument. There are Genomics, which weaves the physical, for many years and taught three arguments why this is not right. computational, and biological sciences undergraduate and graduate courses, One is that it is a mistake to think into a cohesive endeavor. Second, his and was director of the graduate that the high schools were ever so good. scientific discoveries have run the program. Beth Jones and I invented the There is zero argument to say that they gamut of organisms, from phage P22 to whole project lab system. We were have gotten any worse. If you ask about yeast to humans. And third, David is no instructors at that time [1969], a non- the absolute number of kids who get shrinking violet; he has a deeply held tenure track appointment. You worked in somebody’s lab, but you did calculus in high school, it has risen 10- opinion about everything, and he isn’t teaching. or 20-fold in the last 30 years. When I afraid to voice it. went to college in the late 50s, I actually For those of you who are familiar JG: Whose lab were you in? did have advanced placement, but it with David, these words will likely fly was rare! off the page. There is little need to ply DB: I was with Maury Fox. Beth brought Second argument is that if you look him with pre-formed questions; once yeast to Boris’s [Magasanik] lab. I at the outcomes of kids who get degrees you get him going, he is a verbal brought P22 to Fox’s lab. We weren’t in science and then go to graduate tsunami. His zeal is legendary, and his randomly chosen to do this. I think the school—this is actually a Tom Cech delight in people and ideas is palpable. idea was that they brought people who study published in the Daedalus just I met David at his office in the Carl were particularly good before he became head of the Icahn Laboratory on a chilly February experimentalists to teach these lab Hughes—and you ask where the morning after the snow had melted. courses. graduate students come from, it turns The building is the elegant design of We were given this really awful out that small colleges, like Rafael Vinoly. Its airy entranceway, course to teach, and we made a Swarthmore, who draw from exactly which spans the length of the curved proposal to teach it in a better way, the same pool as the big universities glass fac¸ade, embraces a small cafe´, a which involved major changes in the like Princeton, Harvard, and Stanford, cylindrical seminar hall, and, jarringly, curriculum, and they [the older faculty] are many-fold better at motivating the 30-year-old lead-clad prototype of a went along with it. And in fact, I got a students to become professional Frank Gehry house, which David aptly job [as Assistant Professor] out of it. scientists. It’s something like 5-fold. refers to as the ‘‘armadillo.’’ Double- There is something about teaching Third argument is that who was helical shadows are cast by latticed that makes you a better researcher. I teaching whom in the 50s and 60s was aluminum pillars that hug the portico’s know this is very countercultural very different [than now]. I had arc, and altogether too stylish, white, wisdom, but I believed it all along. Tom Vac and Pierre Paulin ‘‘Orange Luria, Magasanik, and Levinthal all Slice’’ chairs populate the space. Yet believed it. Levinthal and Luria both tucked into a corner were six dowdy had a very strong influence on me in Citation: Gitschier J (2006) Willing to do the math: this regard. An interview with David Botstein. PLoS Genet 2(5): Revcos and an ice-o-matic, signaling e79. DOI: 10.1371/journal.pgen.0020079 that this building is not just a pretty That’s one part of the story! DOI: 10.1371/journal.pgen.0020079 face. The other part of the story is that I powered up my fancy new digital through the Academy [National Copyright: Ó 2006 Jane Gitschier. This is an open- access article distributed under the terms of the Marantz recorder, stoked with a high- Academy of Sciences], I became very Creative Commons Attribution License, which capacity flash card, and pushed the interested in the question of why it is permits unrestricted use, distribution, and that there are fewer and fewer kids in reproduction in any medium, provided the original record button. Here follow excerpts author and source are credited. from what proved to be the first in a America who are interested in . And through the Academy studies, it Jane Gitschier is in the Department of Medicine and double-header interview. Pediatrics, University of , San became clear from the statistics that Francisco, California, United States of America. E-mail: Jane Gitschier: Let’s start with the the total number of kids interested in [email protected]

PLoS Genetics | www.plosgenetics.org0641 May 2006 | Volume 2 | Issue 5 | e79 from Konrad Bloch. This was Konrad Bloch before he got the Nobel Prize. He had nothing better to do than teach 120 kids biochemistry. He did it very well. He took it very seriously. He did not go to the dean and say, ‘‘Oh, I have this grant and I’m about to win a Nobel Prize and therefore I should be free to do research.’’ He understood, as I think we all understood, that there is an organic connection between teaching and research. So I came with all this baggage. And , and basically the MIT school, had that baggage. You remember what it was like! Luria taught 7.01 [introductory biology]; Boris taught . Gene Brown had 7.05 [biochemistry]. The leaders were leading from the front! For various reasons, there were issues at Stanford, and I was motivated at DOI: 10.1371/journal.pgen.0020079.g001 least to look at my alternatives. I had David Botstein been talking on and off with Shirley [Tilghman], because this institute was started and Shirley was going to be the grade. You teach these people later, faculty, a sort of Noah’s ark of science, director, and then they made her and you realize that they are sit every Monday at lunch for two to president [of Princeton]. And she had unteachable, to a first approximation. I three hours and simply ask the incorporated the idea, which I think have never failed as a teacher, except following question for all of these fields was really very smart, that there was when trying to teach genetics to at the most introductory level: Is this already at Princeton an unusually close relationship between the molecular medical students. problem or this idea or this concept biologists and the physicists. I knew that reform was impossible. fundamental, or merely traditional? We There came a moment when I called The word reform never passes my lips. collected all the fundamentals and did Shirley and said I had ideas about what Instead, what I proposed was that we the best we could to make them into a could been done with such a place. It use this building, which could house as coherent sequence. was a substantial departure from what many as 15 or 16 new faculty, and use We tell the students, ‘‘This is not the she had intended. I submitted myself to resources in the various fields to mount low-energy path to medical school.’’ the formal process and tried to an alternative introductory curriculum When they come here, they have fear convince everybody to do what we’re in the first two years—at a very high and trepidation, but I tell them, doing—which was to say, ‘‘Let’s see if level for students who are willing to do privately anyway, ‘‘Look, if you don’t get we can do something for a subset of the math, students who want to learn too many Cs and you work in students who, I believe, are computation—and offer incoming somebody’s lab and do a good job, you’ll underserved in the university.’’ freshmen a choice. Students could get into any graduate school in the Students who are not going to medical learn in the usual way, with the country. So stop worrying about the school, necessarily, but who are actually standard, well-worked out curriculum. grades. If you get a B in everything that interested in physics or chemistry or Math—you can go back 200 years, and we do, you’ll be a heroine or a hero.’’ —who in high school you can’t find a new thought. The adventurous students, the risk hadn’t advanced so far that they Chemistry is taught in exactly the same takers, come to us. They know how already differentiated into physicists or way that Linus Pauling prescribed in deadening it is to be part of premedical chemists or biologists. his book published, I think, in 1926. or preprofessional education. It is a What happens to students who come Or the students could participate in mistake to underestimate the to college wanting to learn this new experiment in which we’ll perceptiveness of children, as you know! biochemistry? They find themselves teach computer science, physics, The breadth of the program has first in a chemistry class with a hundred chemistry, and molecular biology really been its great strength. Morale is students with absolutely no interest in corresponding to the introductory very high. The other day, one of our chemistry. All of those students drill a level in six semesters of work—four in students came to me and said she was hole in the head of the instructors and the first year, two in the second year— thinking of majoring in computer each other to get the best possible and then major in any of those areas. science. She said, ‘‘I knew nothing, and grade because all they want is the What we did was we had eight senior I was terrified of it, and I had no idea. If

PLoS Genetics | www.plosgenetics.org0642 May 2006 | Volume 2 | Issue 5 | e79 I hadn’t taken this thing, I would never eating lunch together was probably not many famous musicians who he have learned to program, but I love it!’’ going to be good enough to actually get sponsored to go to conservatory from Well, that’s what we’re here for! people to talk to each other seriously. that area of Poland. He survived the The students had a final exam last People need to have some common Holocaust, and I knew him. spring, worth half their entire grade for task that is orthogonal to their own My mother was a pediatrician. She the year, and all of them showed up in research, and eventually, before you was [Guido] Fanconi’s assistant. She was identical T-shirts they had designed. can turn around, they are doing stuff in fact the first to show that cystic These students are really terrific. I together. fibrosis is inherited. haven’t seen students like this since 20, This endeavor is not a solo endeavor 25 years ago at MIT. They are really of mine. Bill Bialek in physics and in JG: How did she show that? turned on. the Lewis-Sigler Institute is the DB: A family study in Switzerland We have an endowment for five architect of the syllabus itself, and the during the war. Dorothy Anderson did Lewis-Sigler Fellows. We search the main lecturer in the first semester. The the same thing at Columbia Babies country for the best experimentalists laboratory parts of the freshman course Hospital, and our literature was all we can find, right out of graduate were designed and run by two fellows— Anderson [because Fanconi published school, no post-doc. And we say, Maitreya Dunham, a geneticist, and only in German]. It was Fanconi, of ‘‘Instead of being a post-doc, we’ll give Will Ryu, a physicist. These fellows are course, who discovered cystic fibrosis. four benches, $250K a year for terrific. I’m organizing everything so research, and you can stay for five that by the time I retire in seven years, JG: I didn’t know that. years—but you have to teach the lab everything will run on younger people, part of the undergraduate curriculum.’’ and they won’t actually need me. I’m no DB: Failure to thrive, just like Fanconi’s And they are fantastic. spring chicken! anemia. Both my parents were physicians. My JG: Sounds like you’ve recreated your JG: Let’s talk a bit about your roots. father was what you would call today a old job at MIT! What about the Your younger brother Leon is a well- radiation oncologist. He was the first in graduate program? known conductor, and I read this country to use betatrons. somewhere that you also considered a DB: The graduate school is a more career in music. JG: difficult problem, and it’s a problem we Was your father Swiss? haven’t solved—yet—but we’re working DB: Briefly. When I was in college, I did DB: Neither was Swiss. They were there on it. We started this Quantitative and take harmony and counterpoint and in medical school [in Zurich], and they Computational Biology Program. This was in the music scene. I was doing that stayed there as residents and then the is being led by Leonid Kruglyak, who and physics. But physics was taking war broke out. He was from Poland graduated from Princeton summa cum most of my time. also. Actually, the family comes from laude in physics. So the idea is that we What I was interested in was choral Odessa. The other side comes from are going to do exactly the same thing conducting. I was a singer. I sang in the Vilnius. that we did with the undergraduates, in Harvard glee club, and I was the My mother was Fanconi’s oberartz— a way. All the participating rehearsal conductor sometimes. I still the chief resident. Ania Wyszewianska, departments, of which there are many, remember trying to get people to get later Anne Botstein. When she came to are going to admit a bunch of students the rhythm right in Stravinsky’s Oedipus this country, she was offered positions who might be interested in the other Rex. It’s not that hard, but it’s amateur in various places, but she started to lose field, and we’ll try to teach them a few singers. I don’t have such a great voice, her hearing—she had Meniere’s things together. but I knew about music. disease. She went into private practice. We have one such course called She worked in one of the first HMO’s in Method and Logic in Quantitative JG: Are you a baritone? , a place called the HIP at Biology, and we teach the classic papers, many of which are forgotten DB: Yes. In those days I could do bass; I Montefiore hospital where she was because they can’t be taught now had an acceptable F and an audible E, Chief of Pediatrics for 25 years, so she because people don’t understand the so it was enough. I was pretty good in was very successful. My father went math. You may remember reading the midrange. The high notes were not academic and was a professor at Luria and Delbruck, and you may too challenging for me. I sang for many, Einstein. And he is very well known. His remember that nobody understood many years. I sang, memorably, when residents are all over the country. Luria and Delbruck because they didn’t Kennedy was killed. A huge pick-up JG: So you lived where? have the math—and these were MIT group sang the Mozart Requiem in graduate students! Poisson Symphony Hall. That was really an DB: In the Bronx, in Riverdale, on the distribution—don’t bother me. occasion. corner of the Hudson River, and on the Yonkers border. JG: The teaching enterprise is the big JG: Did your parents sing? glue that is holding this institute JG: You were born in Switzerland? together. DB: My mother’s family was heavily into music in the old country in Poland. My DB: Yes. DB: And that’s part of why they hired grandfather was a great patron of the me, because they understood that arts; he was a very rich man. There were JG: Did you have Swiss citizenship?

PLoS Genetics | www.plosgenetics.org0643 May 2006 | Volume 2 | Issue 5 | e79 DB: No, there is no such thing as Swiss Stanford. So Roth finagled that we, one of which would now be called SNPs citizenship for foreigner Jews. Swiss Davis and I, would be outside readers [single nucleotide polymorphisms] and citizenship is hereditary. for the training grant that Utah had. the other, which we expected would be We were stateless, and then my The genetics training program had a more common, was insertion parents got a visa for the United States retreat in Alta. sequences, movements of in 1949. They had applied for an We had to listen to all the talks, and transposons—because in yeast, that was American visa in 1935 when they were one of the talks was by one of [Mark] what was going on. You see, Davis’s part married, but the Polish quota was full. Skolnick’s students, the guy who did of this was TY1. Remember what my Fourteen years later, one of their hemochromatosis, what’s his name? If history is. In 1978, what was I known friends was at the US consulate, and you’re gonna make history you gotta for? they had just posted a list on the door look all this up. [Meanwhile, David does JG: Uh, I give up. of who had a visa, and they noticed that a quick PubMed search.] This kid got my parents were on the list. My parents up and talked about how there were DB: Tn10! We were one of the groups had two weeks’ notice to make up their two ways to think about that discovered transposons in minds as to whether they would come. hemochromatosis and one of them . Russell Chan, Nancy And they did. involved linkage to HLA [human Kleckner—making mutations, I remember that trip very well. I was leukocyte antigen]. And the linkage to mobilizing genes. It was a really big seven. My mother had a cousin in New HLA would make hemochromatosis deal. So the first thing we thought of York, and they had letters of recessive. And you could build a was, ‘‘Oh, there are going to be recommendation from their bosses in reasonable model, and they had a transposons all over the place!’’ Switzerland who were very well known. likelihood score for that possibility. We were surprised to discover that My mother tells the story of taking the Kerry Kravitz! 1978! the really good markers were all these boards in pediatrics, and it was all There were, at Utah, a lot of hard CA repeats. We did not anticipate that. ‘‘anonymous.’’ She had Nelson, of the heads, mainly immunologists, and these But I understood pretty much the famous textbook in Pediatrics, as her immunologists said, ‘‘This is bull; it’s whole thing, and then the rest of that examiner, and they talked about polio got to be physiological because HLA meeting was—we sat in the bar, we and this and that, and then he says, affects all this other stuff, and you guys drank, and we figured out how we ‘‘Well, you really know these statistics are talking through your hats.’’ They could make a map of the human genome: how it would work and how very well. I’m not supposed to do this, didn’t like Skolnick’s approach. They many markers we would need. The but I know you are not Fanconi—you didn’t like the whole idea. whole 1980 paper. Everything in there must be Botstein!’’ And then they Now, of course, it’s 1978, nobody was there in outline by the end of the gossiped the rest of the time. It’s the knows what a LOD [logarithm of the day. same thing as if Sydney Brenner tried odds] score is, and the only person in I went home and I explained it all to to interview Ira Herskowitz. the room who knows, besides Skolnick and Kravitz, is Botstein. So I find myself Maury Fox, and he understood why this My mother is still alive, and she lives was interesting, and he understood the in an apartment right next to my in the middle of this argument. This argument erupts, and I am defending math. And I persuaded Ray White to brother, and I see them nearly every look for polymorphisms because he had this student because the student and I week now. My brother and I have been doing this transposon jumping understand what he did, and nobody always been very close. He’s the famous around business in introns and else does, and he has not managed to one. And deservedly so. He’s a real ribosomal DNA in Drosophila. And it explain it. Skolnick isn’t explaining it innovator in teaching, too! wasn’t going anywhere. He had the either. None of these guys are great right technology. And then he and JG: Since I’m a human geneticist, I can’t explainers. It’s a medical school, okay! Arlene Wyman found what is now help but ask you about the genesis of So finally I say something like, ‘‘Look called D14S1, and we were off. there is nothing special about HLA. the 1980 mapping paper with Davis and What was really noticeable at the What’s good about HLA is that it has colleagues [in American Journal of Human time was that the human geneticists many alleles, and because it has many Genetics]. didn’t get it. At all. At all, at all, at all. It alleles, you can tell if you have linkage, took a really long time. Skolnick was DB: That’s famously been written up a and if you have many multiallelic beating the drum. In 1983, I went to the number of times. The account in markers all over the genome, you can ASHG [American Society of Human Bishop and Waldholtz’s book Genome is map anything!’’ And as soon as the Genetics] meeting, and I gave this long actually very accurate, as I recall. words were out of my mouth, I look at discussion of how it all would work, and Davis, Davis looks at me, and we both I had to explain Southern blot and this JG: I want to hear it in your words. understand that of course there are and that. I went to NIH [National such markers, and we could make a DB: I was teaching with [Ron] Davis and Institutes of Health] and tried to get map of the human genome tomorrow. [John] Roth, at Cold Spring Harbor, the money, and Ruth Kirschstein looked at bacterial genetics course in 1978. Jim JG: What kind of markers were you me and said, ‘‘We don’t do things like [Watson], typically, was too cheap to thinking of? that.’’ That was the origin of her allow us to get together. Roth was in opposition to the genome project, I’m Utah, I was in Boston, and Davis was at DB: We were thinking of two things, sure.

PLoS Genetics | www.plosgenetics.org0644 May 2006 | Volume 2 | Issue 5 | e79 Then [Jim] Gusella did his number people started to look with random DB: The eighth! The eighth! The prior [mapped Huntington disease]. On the markers. And the statistics! probability of finding it in eight one hand, it gave the idea some markers was zero! I knew that! credibility; on the other, it did JG: They were so lucky; it was the JG: Well, for once, ignoring the math everybody a huge disservice, because twelfth marker! paid off! “

PLoS Genetics | www.plosgenetics.org0645 May 2006 | Volume 2 | Issue 5 | e79