Interview: Dr. Leonid Krugly, Expanded Version
When did you begin to think about science?
If you asked me in second grade what I wanted to do, I would have said I want to be a scientist. I was interested in math and science. What I was really interested in first was astronomy and astrophysics and the solar system and the planets — how the whole thing was organized. We had a school project in second or third grade about the solar system, and you had to pick a planet and describe all the things that were different about it. I don’t remember if that was the trigger or if I had already been reading about this, but my interest began as soon as I realized there is a bigger world out there and that people have been trying to understand how it all works.
What was your first experiment?
Anything that I did experimentally when I was a kid generally was a total failure. For a science project in high school biology, I was going to investigate the effect of acid rain on plants. I had these plants, and I was going to water them with solutions with different acidity. But I think I wasn’t very good at watering any of them and so they all died, which made it hard to see any results. In college physics, one of the standard lab experiments was to have an air table on which you slide around discs — an air hockey sort of thing. There is an overhead camera that takes a strobe picture of them, and you’re supposed to slide one, hit the other that’s stationary and watch them both rebound, and compute conservation of momentum. The picture from my experiment was of one puck sitting totally stationary where it is and the other one missing completely and going right by it. Its momentum was conserved because it just kept going.
Who is your science hero?
Einstein is sort of an obvious one when you’re a physicist. Richard Feynman was another one. But if I were to pick one now, it would be Gregor Mendel. I’m a geneticist, and he is the founder of genetics. I feel that a lot of the questions we ask today are exactly the same questions that he asked back in the middle of the 19th century. A lot of the answers we still don’t have. He focused on the more simple aspects of inheritance, and we now focus on more complex ones. But I feel like a lot of our experiments I could explain to him and he would be interested. The thing that’s notable about him, and the sort of thing that speaks to me today, is that he took a very complex phenomenon and he boiled it down to a pretty simple set of experiments. And he knew what to leave in and what to ignore. If you tried to understand all the complexities back then, it would have been a total mess because none of the knowledge base, none of the foundations for even thinking about them, were there. And they’re questions we struggle with even now. But he pulled out the simple essence of the problem. What was really different about him was that he thought about the problems quantitatively because he also had mathematical training and he looked at things mathematically and statistically. He was able to infer, from seeing very precise ratios, the idea of these genetic factors that underlie inheritance, and that each parent has two of them and randomly transmits one to each offspring. None of that is obvious from looking at the data and the patterns until you start to count and see these very precise ratios, of three-to-one or one-to-one or one-to-two, showing up over and over again. And then being able to make predictions: If I do this experiment, what should the ratio be? And being able to come up with a non-obvious number like 9/16ths and then do the experiment and show that what you get is quite close to 9/16ths. That marriage of taking a set of very complex phenomena and experiments and zeroing in on the simple essence of the matter and then being quantitative about it to really understand the hidden underlying level of information that is translated to all these phenomena — that is something that really speaks to me.
Where are you happiest?
I really like being out on the trails in the Santa Monica Mountains on my mountain bike. I enjoy the combination of physical exertion and challenge and natural beauty. You are in the brush in the mountains and then you turn a corner and you get a wide-open view of Santa Monica Bay and Catalina Island — I’ve been doing it for years, and it still takes my breath away every time. And there’s the wildlife. I have seen coyotes and snakes and bobcats — all sorts of animals.
What has been your finest achievement?
In my first independent position (at the Fred Hutchinson Cancer Research Center in Seattle), I was supposed to run a purely computational group. I talked them into giving me one bench of lab space. Their response was, “Fine, we’ll do it as a recruiting thing, but we don’t expect you ever to use it.” Around that time, I got an idea for a new type of experiment that at the time seemed a little farfetched, and when I tried to pitch experimental labs to collaborate with me on it, nobody was buying into the design. Whenever I or any of the members of my group would present it, we got a lot of negative feedback — it was “too difficult” or it was “not interesting” or it “won’t pay off,” that sort of thing. Finally, I thought that the only way this would get done is if we rolled up our sleeves and started our own experimental lab from scratch — which I had no training to do. I spent a summer working with a very brave MIT undergraduate who was spending the summer back home in Seattle and wanted a job in a lab doing something different, and it was sort of the blind leading the blind trying to get these experiments going. And then my first, very brave post-doc joined the project, and she also had no background in any of the stuff we were doing. And together we figured it all out, and we went from an empty room to a publication on that project in the journal Science in about two years. And, since we did that, it’s a design that has been very widely adopted and is now a core part of what human disease geneticists do to try to understand the connection, on the more mechanistic level, between genes and diseases. And it’s been done in many other species. So there’s now a whole field that started around that set of experiments.
What is your defining characteristic?
I’m extremely competitive. That runs through everything I do. I used to play chess at a reasonably competitive level. I participated in a lot of math competitions when I was in high school. I want to get to the top of a hill ahead of somebody else on a mountain bike. It certainly translates into a desire to be first in science, to come up with a new idea and execute on it before anybody else does.
What are the qualities that go into being a great scientist?
Problem choice: What are going to work on? You have to be able to recognize that it is a question that hasn’t really been addressed, that it is worth addressing and that the impact is going to be large. And, also, it has to be attainable. It can’t be the kind of problem where the answer is 50 years away. You have to consider that if the issue you want to explore really is important and attainable, then it probably would already have been done by someone else, or a lot of other people would already be working on it. So you have to find something that’s just a little bit out there — because the idea is sufficiently creative that nobody had come up with it yet or because you have some insight into how to make something attainable that the rest of the field doesn’t yet think is attainable. It’s easy to come up with dozens of incredibly important science and technology problems for which we’d all like to see solutions but for which we have absolutely no idea where to begin now in 2018. It’s also easy to come up with a ton of projects that are doable but which are not really worth doing. Coming up with that combination — is it important and worth doing and can it be done? — is really hard. Sometimes you get it wrong in one or the other dimension. Either, you do it and realize it wasn’t as cool as you thought it was going to be, or you try to do it and really give it a good go and realize it’s not as attainable as you thought. You do always learn something from those types of experiences. But I think what really distinguishes people who make an impact is the ability to make that right choice over and over again.
What is your greatest virtue?
I have a pretty good recollection of what it was like for me to be at different career stages — undergraduate, graduate school, post doc, young investigator — and I remember how different folks higher up the ladder treated me and what I liked and I remember what I didn’t like. I try to act toward others in ways that I would have appreciated when I was at that stage.
What is your greatest fault?
I am impatient and easily bored. When I was just starting to work in genetics, I wrote a proposal to the National Human Genome Research Institute for a fellowship that was explicitly designed to convert people like me — physicists, mathematicians, computer scientists — to become researchers in genomics. I got a very nice set of reviews, but one of the more critical notes said something like, “We notice that Dr. Kruglyak has made frequent and wide shifts in his research focus.” I had published as an undergraduate on quantum electrodynamics and on astrophysics, and as a PhD student on statistical physics, neural networks, and neuroscience. And now I was proposing to do genetics and genomics research. So I think that “frequent and wide shifts” was a polite way of saying “easily bored.” And it went on to say, “We don’t presume to say whether this is a strength or a weakness, but it does raise the question of how long he’s going to stick with this field.” Well, the field has proven to be so intellectually engaging and dynamic that it’s continued to hold my interest.
When don’t you think about science?
If I’m on my bike going downhill and the trail is technically challenging, then I’m definitely not thinking about science — or anything else; I’m just focused on my line and making the right next decision. But if I’m grinding uphill, and if there’s been a puzzling result in the lab or something that I’m trying to work out, I will be working it out in my head on the bike. Or in the shower. Or wherever I happen to be. If there’s a question that I’m obsessing about at a given moment, then I will probably obsess about it no matter what else is going on.
If you were not a scientist, what would you be?
I would like to think that I might be a climbing guide or mountain biking guide, or something along those lines. Maybe a personal trainer. But I think, really, that it would be something that would involve numbers and computers. Sabermetrics, if you want to combine it with sports, maybe. Or quantitative stock analyst. Or artificial intelligence programmer.
What keeps you up at night?
I try not to let things keep me up at night. Being reasonably well rested is super important to functioning optimally. So I really work hard to not let stuff stress me out. I try to chill out and meditate and get whatever may be worrying me out of my head so it doesn’t mess with my sleep. And I feel like I often succeed in dong that. But sometimes I fail.
To which superhero do you most relate?
I’ve watched all the Marvel movies, and I don’t know if there’s a specific superhero that I identify with, but it would definitely be the more human and vulnerable ones. It is hard for me to identify with the all-powerful ones like Superman.
Where does your inspiration come from?
A lot of it comes from conversations with members of my group and other scientists, and it may be triggered by a paper we’ve read or a seminar we’ve heard. And then we’ll start considering it from every direction and trying to think about whether we can learn something, is this a new tool that we can apply, do we know how to build on it.
What is the best moment of your day?
I ride my bike to work, and the route I take drops down to the ocean and goes along the beach path for a while. When you’re riding your bike right by the ocean and the weather is beautiful — especially if it’s in January! — it’s pretty great. It’s hard to feel bad about anything when you see dolphins popping out of the water and all the beach birds running along the surf.
What has been your biggest “aha” moment?
When I was a post doc, my mentor assigned me to solve a problem that had to do with connecting the inheritance of DNA variations in the genome to the inheritance of disease in human families. It was very clear what it was that you wanted to compute, but it was a computation that, at the time, was thought to be too hard for computers to do. My mentor asked me to find a way to make it tractable. I thought about it, and after a while I saw a connection between this problem and the fast Fourier transform, which is an algorithm used in engineering and physics. A Fourier transform is a mathematical method of going from time-space to frequency-space, and it is computationally difficult and slow. But there is a very clever algorithm called the fast Fourier transform. I saw that the computation I was trying to do in genetics was analogous to that. I knew about that set of tricks, and I realized that the same set of tricks appropriately formulated for this other class of problems in a similar mathematical language would allow you to do the genetic calculations much faster. Once I saw the connection, I was able to write about 10 lines of code that solved the problem. When I first started to describe the results at conferences, people would be like, “Did you just say you can calculate this? That’s impossible.”
What music do you listen to while you work?
I don’t. I like quiet to concentrate. That has changed over the years. When I was in school, I would play rock music fairly loud while I was trying to do hard math. Now I need peace and quiet to concentrate.
Whom would you like to have at your dinner table?
Charles Darwin, Gregor Mendel and William Bateson, the English biologist who coined the term “genetics.” That would be one heck of a dinner party. Having Darwin and Mendel together would be really fun. Darwin struggled with questions of inheritance and variation, how is variation generated, and pretty much at the same time, Mendel figured out exactly that question. He sent his manuscript to all the well-known scientists of the time — of which Mendel was definitely not one, he was some obscure monk — and one of those people was Darwin. One version of the story goes that this is back when you had to cut the pages of a manuscript open to read it. So the book came to Darwin sealed, and the story goes that the manuscript was found in Darwin’s papers but it had never been cut open. I wonder what would have happened if Darwin had read it and been exposed to that information and been able to understand it. It would really have filled in the answers to some of the major questions that he had. I would love to be able to introduce them to each other and say, “Hey, you guys were going at two different ends of this problem at around the same time, and one of you was luminary of Victorian science and the other was an obscure unknown monk, and now you’re both in the Pantheon of scientists and biologists and you could have had a lot to say to each other at the time. It is too bad a meeting like that never happened. And then there is Bateson, who was one of the principle rediscoverers of Mendel at the start of the 20th century.