LC: So I know that in undergrad you got a job washing fly bottles on the weekends and you said “This, the sort of lab environment, is something I could do.” And then later you went into graduate school at Yale initially. Graduate school to me seems like a large step, a commitment to an academic career field. Were you intimidated? Were you confident that you wanted to do lab science for the rest of your life?
EFW: I wasn’t sure what I wanted to do for the rest of my life. Because I liked being in the lab, because I liked doing science, it seemed like I would just do that for now–go to graduate school. I knew that I didn’t want to go into medicine, it just seemed like what I wanted to do, go to the lab to discover stuff. I can’t say it was practical in the sense of thinking about a job or what was going to happen to me ten years down the road or something.
LC: And then in 1981 you came to Princeton. What caused this move back to the United States?
EFW: That I ended up in Europe was an accident. I had never been outside of the United States. Eventually the man, Walter Gehring, whose lab I was working in while in New Haven had an offer to go back to Switzerland and he decided to go, and he offered me that I could go with him. I was actually the only person in his lab that went over to Basel. It was easy for me–I was kind of young and unattached–it was like a big adventure. I lived and did postdoc in Zurich and then my first job was at the European Molecular Biology Laboratory (EMBL) in Heidelberg. I spent about ten years in Europe, and I had convinced myself that I had become very sophisticated and very European and could live in Europe forever.
EMBL at the time was a place that was supposed to provide opportunities for young scientists but not long term careers, and so I had to think about getting a job or position somewhere, and the academic situation in Europe is more hierarchical and structured. Full professors had associate professors under them who had assistant professors under them, and it seemed to me that, from what I understood in the states, if you had a job at a university you were expected to have a lab the same size as any full professor in the department. You can look, the way it generally is is that assistant professors, associate professors, full professors in American universities have little independent lab units and they’re probably on average about the same size.
I knew I wanted that level of independence. Now the EMBL lab was a great place to be, and if you were a group leader there you had access to lots of resources and you didn’t teach. You didn’t have any obligations other than running your lab, so that was an attractive thing, but it wasn’t going to be a long-term solution. So I had to figure out what to do.
I looked at jobs a little bit in Europe and there weren’t that many and it wasn’t where I wanted to be anyway from a scientific standpoint, so I went on the job market, had an offer, came to Princeton, have been in New Jersey ever since.
LC: Right it’s been a while now. I am wondering if you could talk a little bit about the evolution of your field and your research since you have arrived at Princeton. In introductory biology courses they teach about the screen but that’s about as deep as we get into developmental biology…
EFW: So it was an interesting time. The screen was a great experiment to have done, and people had never approached developmental biology that way before–it was interesting immediately when we did it. What of course made it have the impact that it really had on the world was that while Janni and I were doing the screen, other scientists all over the world were struggling to get the practicalities of molecular–cloning genes, sequencing, all of those things. So by the time we completed the screen and had characterized this terribly complicated process of development–that you could see it in terms of parts and interactions and hierarchies and steps–and all of that described in terms of gene activity, it had become possible to clone genes, identify genes, analyze those genes, analyze the proteins they make, figure out if those proteins were fly specific or whether they were found in other species, and whether the pathways worked the same.
That process is essentially what happened from 1981 for the next ten years; the 80s was just an extraordinary transformative time in that molecular biology was possible. It was even possible if you had never done molecular biology to learn how to do it well enough to clone genes and understand all of those technologies. Having a biological problem that was as well defined as early fly development, and the fact that the genes that were identified in flies had homologs in humans with similar activities, all of that was kind of worked out in the next 10-15 years. And that kind of transformed how science was done. The great power of genetics is that you don’t have to know very much to do it. You just kind of bash away, things happen, and you kind of collect and see what you get. Then you think and organize and you learn stuff. And you learn stuff without the biases or preconceptions. Up to that point, until you had the concept of the genetic approach you would always start as a scientist from your very limited knowledge, your limited bias, and then try to get that thing to work. Very often you would choose something because it was abundant enough that you could do biochemistry on it.
So developmental biology and then therefore cell biology transformed into genetically, molecularly defined fields. We got all the molecular tools to approach these cell biological questions but at a much more mechanistic level.
And you could choose the mechanistic level. You could get down into individual little proteins and protein shapes and interactions, but you could stay at a somewhat higher level of interactions. I think for the next 10-15 years that transformation occured.
My own personal transformation was when I came back to the states I saw development increasingly as a cell biology problem. So can we understand the visual morphological changes that occur in an embryo in terms of cell biology? Does the power of the embryo give us a tool to really understand cell biological processes in a way that you wouldn’t if you just had tissue culture cells?
The other great technology that was transformative that I didn’t appreciate as much was computer science. Everybody saw that happening at some level, and it was kind of happening in the background, but to the point where, around 1995 or 2000 it attempted to transform the questions that we ask into larger scale what we call genomics questions or big data questions. Because the molecular technologies had reached a point where you could do big data, it would’ve been pointless if you didn’t have a tool that would allow you to search that data or to organize it. And so computer science transformed the field in ways that I’m not sure have been totally useful, because I think there is a danger that you stay on a very superficial population level of molecules and not ask deeply mechanistic questions if you are too tied into the big data approaches in computer science.
And my friends often think that you don’t think about questions until you have all the data. You collect all the data and then you see what questions emerge out of the data. And that’s certainly a valid way of thinking about science, but I think our brains are better than that–they are able to approach questions in defined phenomena even before you have your data. Having questions before you do experiments in small scale science: “What are all the genes that are required zygotically in an embryo to develop a normal pattern?” is a question that starts and then you figure out how you can address that question. Or another would be you have a bunch of mutants in a genetic perspective and they all produce the same phenotype, how do you organize them into a pathway. That initial question-driven approach most often is going to be a smaller kind of science than big data genomics. That’s the transformation that we’re in right now.
My own work by about the late 1990s, it seemed to become more and more detail oriented. I don’t know quite why this happened to me, but I started hanging around physicists. And the nice thing about that is that I’m very comfortable not knowing stuff. I’m very comfortable in knowing some details, but not feeling like I have to know all the details. And I can tell you this, physicists have that arrogance in spades, that they don’t feel they need to know stuff or they don’t need to know details. The whole goal is to abstract as soon as possible away from details and get to some fundamental generalization.
The other interesting aspect of the interface is the tools that become possible. So we began using optical traps and things on early embryos right as they were developed. I hung around these people that would have different kinds of ways of looking at things or optically examining or measuring phenomena. A lot of it has to do with measurement, a lot of it has to do with math and dealing with data and significance.
It was a learning thing for me, you know biologists kind of like you have a sample and you have an average value, a mean, and then you have a variance, and biologists generally hate the variance. They want the variance to be small enough that it means there’s a difference and they can claim they’ve discovered something. Physicists actually believe that there’s information in the variance and that you can extract how processes work by understanding the noise, understanding the variability. And to do that you have to have a certain valid, sophisticated kind of math. And it was those things that made hanging with physicists, collaborating with physicists, so interesting. Cell biology, cell shapes, cell mechanics, how cells move or how a ball of cells would build a fold–it’s a physics and a mechanics question. But then also things like how an enhancer would measure concentrations of a transcriptional activator in a concentration-dependent way that can produce accuracies of ten percent, things that we can’t do with the microscopes but cells are able to do that. That approach is something that’s really really powerful and, since I know how to do stuff in the lab, it kind of allows me to bring something to an effort that I find very fascinating and a great opportunity to hang around these people who are so smart.