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Credit: Douglas Brash
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Interview of Douglas Brash by David Zierler on July 7, 2020,Niels Bohr Library & Archives, American Institute of Physics,College Park, MD USA,www.aip.org/history-programs/niels-bohr-library/oral-histories/XXXX
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In this interview, David Zierler, Oral Historian for AIP, interviews Douglas Brash, Professor in the Department of Therapeutic Radiology in the Yale School of Medicine. Brash recounts his childhood in a rural community outside of Cleveland, and then in Chicago, and he describes his early interests in science and his determination to become a physicist by the third grade. He discusses his education at Illinois where he majored in engineering physics, and he describes his formative summer job at Livermore Laboratory which helped to compel him to pursue biophysics for graduate school. Brash discusses his research at Ohio State under the supervision of Karl Kornacker, and the work of his graduate adviser, Ron Hart who was focused on DNA repair. Brash discusses his interests in aging and molecular biology which was the foundation for his dissertation, and he provides an overview of biophysics as a discrete field in the 1970s. He discusses the distinctions in his research regarding basic science and clinically relevant therapies as it relates to understanding cancer, and he describes the varying interests in environmental carcinogenesis and retroviruses as a basis for cancer research. Brash explains the origins of the discovery of oncogenes and the connection leading to his specialty in skin cancer research. He describes his postdoctoral research at Harvard and the Dana Farber Institute with Bill Haseltine working on DNA damage and mutagenesis. Brash discusses his subsequent work at the NIH where he continued his research in cell mutation and where he began to study the effect of UV rays on skin cancer. He explains the circumstances leading to his decision to join the faculty at Yale, where he realized he had greater opportunity to continue examining UV rays and skin cancer. Brash offers an overview of the major advances over the last two decades in skin cancer research, and he describes the central importance in DNA sequencing and Chemiecxitation. He discusses the many research advantages associated with having an appointment in a medical school, and at the of the interview, Brash describes the value of bringing a physics approach to cancer research, and some of the policy and communication implications that come with working at the cutting edge of the field.
Okay. This is David Zierler, oral historian for the American Institute of Physics. It is July 7, 2020. It is my great pleasure to be here with Professor Douglas Brash. Doug, thank you so much for joining me today.
Oh, my pleasure.
All right. So to start, would you please tell me your title and institutional affiliation?
I'm Professor in the Department of Therapeutic Radiology in Yale School of Medicine, with a joint appointment in Dermatology. The detailed title changes every once in a while.
So your appointment is in the medical school.
Yeah, it’s in the medical school. Therapeutic Radiology anywhere else is called Radiation Oncology, but it’s a very interesting department because much of molecular biology at Yale started here. Much of the field of DNA repair started in this department for historical reasons, because of the people who happened to be here. So the department continues to be interested in research.
Do you have any clinical aspects of your research? Do you work with patients directly at all?
No, although we often study tissue samples from patients, volunteers, or tissue banks. I’m a PhD and started out with a physics background, so not an MD and seeing patients was never going to be my thing. But if there’s anything that we can do in learning about how the world works that turns out to be useful for patients, that’s great.
And all of your teaching is done within the medical school, or do you have joint teaching responsibilities in like the department of physics or biology or chemistry?
Alas, no. At Yale the medical school and main campus are two very different worlds. They did overlap for a little while about 15 years ago, when for a few years I was working in the Yale College’s Dean’s Office running the Office of Undergraduate Research. That role comes with a course for some of the newly arriving science majors where we try to introduce them to the different kinds of science done at Yale, and get them working in a lab during the summer. So that was really nice; I got to see undergrads. Other than that, we see grad students and on occasion give guest lectures in a course or two. I really wish there was more teaching.
Mm-hmm [yes]. Well, let’s take it right back to the beginning now, Doug. Let’s first start with your parents. Where are they from?
Ah! My dad was born in England. He moved here when he was three (or, rather, his parents moved him here when he was three). They settled in Ohio outside of Akron. My mom's parents were, generations ago, Scottish, but she can trace ancestors going all the way back to the Daughters of the American Revolution. They were from far western Pennsylvania north of Pittsburgh, which was largely agricultural. Her father came back from WWI, moved into the city, and had a number of jobs during the Depression including making bricks, eventually becoming for many years the chief clerk of courts; her mom was the society columnist for the newspaper. After Pearl Harbor, my mom dropped out of college, moved to Cleveland, and got a job. My dad was in the Army Corps of Engineers in the Pacific, and was on a ship headed for the invasion of Japan when the bomb was dropped. After the war, he moved to Cleveland and got a job with GM. The two of them happened to be in a rooming house together. Back then there was a post-war housing shortage, the captains of industry in Cleveland, which at one time was sort of like Detroit for making cars, had enormous mansions on the lakefront. The widows who now owned these mansions would rent the rooms out and hold dances on the estate lawn, and so that’s how my parents met. They were from New Castle, PA and near Newcastle, UK; I've wondered if that was part of their first conversation.
Now what were the circumstances of your father’s family emigrating from England? That’s relatively late historically to be coming to America from England.
I’ve never gotten the direct story on that, but from my reading I have an impression. They were in the north of England, shipbuilding country. That side of my family goes back for several generations of engineers, ship's engineers, and ship captains.
My impression is that after World War I there was a depression, and so my grandparents and my dad’s older brother first moved to Canada. My grandmother didn't like Canada. They were off in Winnipeg, the snow country as my grandmother saw it, and they moved back to England where my dad was born. England didn't work out and they moved back to the New World. By then they had relatives in Ohio, so they moved to Ohio. So I think it was economic.
Now did you grow up in Cleveland?
In the very outskirts of Cleveland, which was wonderfully fortunate. What happened was that, right at the edge where Cleveland ends and the farms began, it was getting built up with housing developments kind of like what I now know about Levittown, New York—you know, tiny little houses, but the ex-GIs could afford them. It was just absolutely wonderful because you had lots of little houses, so lots of kids nearby. We had five or six kids my age on our street, more on the next street, and behind our house was a field left over from Mrs. Petchler's farm. It wasn’t big enough to put a whole street through, so I grew up with this field, strawberries, raspberries, blackberries, trees to climb, apples, pears— everything you could imagine. One of the neighbors kept some of it mowed so we had a baseball diamond back there. Then a couple blocks the other direction was a stream with trees. So basically we’d go out in the morning and come home for lunch and come back to watch Roy Rogers at 5:00. That was life growing up on the outskirts of Cleveland in the ’50s, which we thought was undistinguished, but it was great!
Quite pastoral, it sounds.
Yeah, yeah, yeah. Yeah, very much. Very much.
Did you go to public schools throughout your childhood?
Yeah, and that was another bit of good fortune. I was thinking about this a little after you called. We weren't even in the Cleveland public school system. The first town outside of Cleveland is called Berea, which was founded around a sandstone mining operation to make millstones. We were in their school district. For some reason, this little town on the edge of Cleveland had the New Math – a Yale invention, by the way. It was one of the test sites for the New Math, and so we had these yellow paperback math books for several years. They all had "Yale" and "SMSG" on the cover, the letters standing for "School Mathematics Study Group" but we kids used to say it stood for "Some Math, Some Garbage". So I learned about sets, base 2, a proof that all numbers are interesting (it follows from the Well-Orderedness Property) and lots of cool stuff. I was really, really fortunate in the teachers. I had a great reading teacher in first grade, and the librarian would let us check out books above our grade level. Isaac Asimov writing under a pseudonym, I later found out. In fourth grade, the teacher would let us take time off from class to sit around the radio and listen to the Mercury spacecraft launches. You know, I was lucky in having the teachers I did.
Another bit of good fortune was that, in the 50s in the Midwest, if your last name started with B you sat in the front row. I don't hear very well; the school diagnosed this in fourth grade and I've been wearing hearing aids ever since. That meant I spent ten years hearing parts of what was going on and being able to deduce what the rest of the story was. So I think I acquired a talent for looking at a mass of disorganized data and figuring out, okay, where in there is worth paying attention to? What’s the pattern?
When did you start to get interested in science, Doug? Was it even before your formal education?
Ah. [Chuckles] So first grade—I think it started in first grade. There was a girl I wanted to impress, and so I thought I’d be an astronaut. Then I decided I space was really interesting and when our teacher asked what our favorite color was, I said black. By second grade it was more dinosaurs and after that it kind of broadened out to science in general. Because of Sputnik, you could go down to the local department store and buy these science kits, so I would get them or I’d get them for Christmas. You’d make a little steam engine or you’d make a motor, and then there were the A. C. Gilbert chemistry and Erector sets, of course. Another New Haven invention, it turns out. Oh, and there were plenty of books about science and scientists, the moon and Mars. I still have those. And then in 1957 there was the International Geophysical Year, which is where geologists across the world were getting together and trying to figure out how the Earth worked. Life magazine had these beautiful color layouts of what they had discovered over the last week or month, and so it was a great time to be interested in science. I had a lab in my bedroom, where I looked at pond water under the microscope. The father of one of my best friends was the principal of the high school and he'd take my drawings to the biology teacher, who would write a note saying that I was looking at a Daphnia. I had a telescope, but building a bigger one out of a newsprint roll and bicycle mirror was less of a success.
Did your high school have a strong math and science program?
So by high school… In fifth grade my dad got transferred. He was at General Motors and he got transferred to Chicago. It’s interesting to think about what would have happened if we’d stayed because anytime the high school was going to throw away science equipment, the high school principal would just scarf it up and bring it home and give it to me. I now realize that one of these was a beautifully made Cavendish torsion balance. So that was great.
In Chicago, we were in the suburbs, which had, in retrospect, really outstanding high schools. The one I went to was in La Grange, straight west of Chicago. It was one of these places where every year there would be 15 or 20 National Merit Finalists and National Honor Society members. I'd hoped my junior high teachers would recommend me for honors science classes and to my surprise I was put into honors science, math, and English. Again, I had outstanding math and science teachers, and outstanding literature teachers, for that matter. I thought I didn't like poetry or Shakespeare, but after freshman year with that teacher, I loved those things, too. Again, a great place to grow up.
Were you a stand-out student in the sciences in high school?
Yeah. We had 1,157 people in our graduating class, and I graduated sixth, I think. Maybe a little lower at the end because I took a typing course senior year. We used to pout when we only got a 786 on an SAT test. The top five did well; one of them rose fairly high in the EPA, another founded a prominent Silicon Valley law firm, another went to Harvard Medical school. Actually, dozens of the other students did really well.
Yeah. So I had the National Honor Society, National Merit and several other awards, and then we had honors classes. This was before AP courses were really a thing, but there was an AP chemistry course, and so I was in those. There was a collection of about 20 of us, guys and girls, who were always in these advanced courses, but it was interesting because we never had the nerd atmosphere that you hear about. Every one of us was in some sport or another. We just happened to be. I was a pole vaulter and the guys I mentioned earlier were on the basketball team or football team. So there were these two different worlds, but it was all just perfectly normal.
When you were thinking about college, were you thinking specifically about physics programs, or that came later on?
Oh, no. I knew since I was in third or fourth grade I wanted to be a physicist. It’s so odd. I thought the world was like that, but as part of that course for Yale undergrads I mentioned, we instituted a bit where the invited faculty member would spend five minutes talking about the kinds of questions that you're asking. We tended to have like National Academy members and the like, you know, the big shots. None of them started really being interested in science until college or maybe even later. So I wonder if it was a bad idea to be interested in science early, but… I always knew I wanted to be a physicist.
As I mentioned, the grade school librarian would let me check out books above my grade, and for some reason I got my hands on a relativity book. In retrospect, I don't even know what a relativity book was doing in a grade school library, but anyway, I remember asking my third grade teacher, “What’s the difference between a square and a square root?” because I could see all these square roots in the special relativity equation. Now I think in retrospect I didn't understand any of this, but I was trying. So yeah, always physics. The main motivator for me was somewhere around third or fourth grade. I realized I wanted to know why space and time – the laws of physics – were the way they are. The way I would say it now is we don't directly see the world in terms of Hamiltonians. So you know what I’m talking about there?
So we don't see it that way. We see "things" and relationships between them, so Newton’s laws seemed like a pretty reasonable way to frame laws, but nobody in real physics uses Newton’s laws. So why is that?
What do you mean, real physics, Doug?
Oh. if you're designing an airplane engine or if you're designing a cyclotron for that matter, you basically use Hamiltonians. The Schrödinger equation is a Hamiltonian. It’s not a Newton’s law expression. It involves operators operating on energy and momentum, and those aren’t things that you and I directly see the world in terms of. So like ... what’s with this and why don't we?
In the middle of college, I began to think, oh, well, maybe this is a biology problem and not entirely a physics problem. My major remained physics, but I started looking into other subjects, and a real turning point… None of this, by the way… Well, it only indirectly has anything to do with DNA damage repair and cancer, but there’s a path that sort of gets there.
I’m curious. Did you think about engineering, because your degree is specifically engineering physics.
Right. Well, first of all, I wanted to go Stanford, but my parents wouldn't let me apply to any place they couldn't drive to because we didn't have that much money. In retrospect I can see their point. I was again very fortunate because Illinois had an outstanding physics department and an outstanding engineering college. It’s typically rated third or fourth in the country. I can still see John Bardeen coming down the steps followed by a flock of reporters the morning he got his second Nobel Prize. Anyway, at Illinois, you could do physics in either engineering or liberal arts. So I had that conversation with the dean of engineering the first week in college. He was very kind to take the time out, and he convinced me that the engineering route would be more rigorous.
So I was lucky there. However, state schools differ from a place like Yale in that people are not looking out for individual students and trying to see their talents and help them along.
And the tuition was pretty good at Illinois, too, for you.
Yes. I got a scholarship for tuition, so all we had to pay was the room and board. I had summer and Christmas jobs. Those would pay for one semester of room and board and my parents could pay for the other semester and that’s how we got along.
Now the engineering physics program—did you take all of the same physics courses as a physics major would have?
Yes, or rather it was the Physics major; the only difference was in the non-physics courses that people took. We Physics majors had the same classes in physics that anybody else would have, including the engineers, plus courses on engineering per se like engineering drawing. I think that was a flaw in the system. It would have been nice to have course sections made of Physics majors and probably we should have taken math courses beyond calculus. We didn't have to take as many language courses as we would have had to take in liberal arts. I had had German in high school, so I talked them into letting me take computer science and call that my language requirement. I'd proficiencied out of the first year and a half of English and other non-major courses, so I took courses on modern literature, art appreciation, and public speaking.
I’m not sure what engineering physics is supposed to do, either design bombs or design cyclotrons, but it was a different way of looking at things. We were with engineering students who built actual objects that had to work. If I were going to do it, if I were running the program, I would have had special sections for Physics majors so that you could go into more theoretical and more advanced topics. But being mixed up with the engineers, the courses also had to cover the calculational, computational stuff that the engineers were going to have to do in two years. Analytic mechanics, in particular, was taught as a calculation method.
What convinced you to switch over to biophysics? Were you getting more interested in biological aspects of physics as an undergraduate?
Right, I was going to tell you about the turning point… Should I go back with that?
Where I was living was on the other end of campus from the physics department. It’s a huge campus and a 20-minute walk. So one winter it’s bitter cold and I’m walking across campus for my 8:00 physics class. I take a shortcut through some of the engineering buildings because you could go pretty much the whole way through a row of engineering buildings. There was this little building out back and I hadn't been through it before. I went in, wound around, and there was a sign on one of the doors that said, “Biological Computing Laboratory.” What is that? So I made a mental note to find out, and I went back later. So that was Heinz von Foerster, a cyberneticist who…
Oh, do you know that name?
Oh! So then I’d be interested in what you know. That was quite a charismatic orbit that he had assembled, with visitors ranging from Humberto Maturana to Buckminster Fuller, and so I took all of the courses of his that I could and started taking more and more biophysics. I would take some real biophysics like… Oh, I remember that Govindjee, who worked on photosynthesis, taught a couple of lectures, and Floyd Dunn, who I see is in your archives. He was doing acoustics and hearing. But really it was this issue of cognition and "what is your brain doing?" that grabbed my attention. None of the things your brain is operating on are out there where you see them; they are in here, so your brain is working with internal representations of the external world. It’s kind of like Kant, although Heinz didn't talk about it that way. He was Wittgenstein's nephew, so I was introduced to that world, too.
The summer afterward, I had a job with the fusion power project at Lawrence Livermore Laboratory, where my boss just gave me a book and said "Read this and design a neutron detector to measure the cross-section of Niobium-Tin." The neutrons from the fusion reaction were destroying the superconductivity of the Nb-Sn magnets, which were supposed to hold the plasma in place. I did it, but being a cog in a vast wheel didn't appeal to me.
So then I switched into biophysics for graduate school to pursue the cognition angle. It was purely this issue of cognition and how much of the laws of physics were determined by the way your brain is wired. I spent the summer after graduation teaching myself biology from Asimov's The Intelligent Man's Guide to Science and went to Ohio State to work with a particular person in theoretical biophysics.
Who was that?
Karl Kornacker, who had done a double major in biology and physics at MIT before double majors were a thing, and he knew some of these same people that von Foerster knew from MIT. He was using statistical theory to mathematicize both neural membranes and the concept of making living processes out of nonliving parts. He had a number of useful warnings and perceptive comments about biology. One was that biology courses expected you to memorize stuff and repeat it back. The exact opposite of physics, where you could bring any book to the final exam that you wanted, but the test was to calculate the energy levels if atoms had mu mesons instead of electrons. Another was that there are three flavors of biophysics. The flavor that attracted me is that physicists have a view of the world where you want to find a small number of facts that explain a large number of facts. That’s not how biologists think. They mostly want to collect facts and don't believe that there are basic principles.
The second flavor of biophysics is to work with a physics-based instrument that collects biological data. The classic example of that is Hodgkin and Huxley and the neuron action potential. You're using basically electronic machines to measure parameters of ion flows in axons, so that’s biophysics. This is what Biophysics mostly means today, for example x-ray crystallography or atomic force microscopes.
The third type of biophysics was the University of Chicago school where you're bringing in math to characterize in detail the properties of blood flow in a vein or stresses and strains on cells as an embryo is developing, which I find uninteresting because unless you can show that this is what is causing a biological phenomenon, that’s just sort of stuff that happens. So my interest was in the first. And I really enjoyed it.
But I quickly found out… Actually in a summer school at Yale on membrane biophysics, I quickly began to realize that, oh, you couldn't actually do experiments to prove any of this stuff. Nowadays you can – Karl has gone into genomics and bioinformatics– and so you come out at the end knowing something. But one thing I did notice is that, compared to the neuroscientists sticking electrodes into brains, when the molecular biologists were done with an experiment they really knew for sure what had happened. So I decided to get myself into a molecular biology lab to find out how that worked – what made a powerful experiment – so that I could try to apply some of whatever that magic was to these cognition questions. I never quite got back to the cognition questions as a day job, although I still think on my nights and weekends, such as they are, about those other kinds of questions. But the molecular biology studies quickly had a few successes, particularly once I got to Bill Haseltine’s lab at Harvard as a postdoc, where I happened to be the right person with the right background at the right time and we discovered a few things. That’s what was fundable, so I kept doing that. That’s how the DNA repair stuff started.
Now was the Ohio State department a biophysics department proper, or it was sort of a rump of the physics program?
It was a Biophysics department proper, springing up from a sensory biophysics group. It had recently assembled faculty from various disciplines who were now primary appointees in that department but had come from Physiology, Psychiatry, or an independent sensory biophysics institute, plus new hires. There was a biological thermodynamics guy, an x-ray crystallography guy, and an electrophysiologist. Karl was their theoretical guy. The molecular biologist I eventually did my thesis with, Ron Hart, was a DNA repair guy, having worked with Dick Setlow – the discoverer of DNA excision repair – on a couple of interesting projects. One of these showed that if you looked across species, a mammal's ability to repair cyclobutane dimers, a UV-induced lesion, was increased the longer the species' lifespan was. Nobody believed that it was cyclobutane dimers that were regulating lifespan, but it was clearly an assay for something. At the moment, I would guess accessibility to chromatin or something like that. This discovery focused attention on the idea that lifespan might be extendable and that evolution had already done it.
So I went to work with Ron on those kinds of questions because they seemed to me…solvable. You know, aging was a fairly deep question. At that time, people didn't even believe that cancer was a solvable problem, never mind aging. So DNA repair looked like an entrée into both, and essentially it did turn out that way, I think. Particularly for cancer, DNA repair was an entrée, and I still am aiming to go back to those experiments on aging's relation to repair. We now have the tools to do it from our last paper. So that’s my September grant to write.
Doug, I’m curious how you developed your dissertation. Was it a problem that Karl had given you to work on? Did you mostly develop it on your own?
Oh, Karl was my initial advisor and somewhere before my quals I decided to do the molecular biology and aging and DNA repair studies with Ron Hart, so he became my advisor. Karl could see the point of doing experiments, so he didn't mind too much. I still work with him, and he’s now the bioinformaticist on our projects.
So the thesis project was actually with Ron Hart, and what I was most interested in was the aging question. We were going to go back and do in vivo the initial aging experiment that Hart and Setlow had done in tissue culture cells. Ron had set up this system of two rodents that were very similar—Mus musculus, a regular mouse, and Peromyscus leucopus, which looks like a mouse, but it’s several million years away evolutionarily and it lives six or eight years. But the biology is otherwise very similar. He had set up the colonies and so we were going to look at DNA repair in these two species.
That paper did eventually come out; I’m a middle author on it because it got finished up after I left. It turned out interesting. The damage accumulation rate is different. Both species die at about the same final level of spontaneously accumulating DNA damage, so I still think there’s something interesting there.
But as far as getting a thesis, the time came to move on and I had developed all the methods for measuring damage and repair in vivo because everybody up till then had been doing repair studies in tissue culture.
What was different, Doug, about… Why couldn't you rely on tissue culture research?
Oh, because it’s cells growing in a dish. Well, two levels. As somebody put it, a tissue culture is a wound that never heals, so it’s not a normal cell. And most studies were only on fibroblasts. On the other hand, in vivo you’ve got all kinds of other things going on, like multiple cell types, hormones, and the immune system, and who knows what is affecting what. So it’s always of interest to know what’s going on in vivo. And for chemical carcinogens you have metabolism intervening to make non-carcinogens carcinogenic. One of the nice things about ultraviolet light is you don't have to deal with metabolism – UV DNA damage is just physics. So I worked out methods to label DNA fluorescently after you’d done the experiment, and then what you did in those day was you looked for DNA damage using alkaline sucrose gradients. Those experiments were quite involved, and at one point I decided, okay, it’s been long enough. I’m getting a PhD. I’m going to write up what I’ve got, so that’s what the thesis is.
Did you think of yourself-- I mean, it’s so interesting. If you hear people, especially in the 1970s, places like Princeton, they didn't even think biophysics was physics, right? They didn't know what to make of it in places like that. I’m curious how you thought of yourself. Did you… Was the program’s identity strong enough where you could just say, “I’m a biophysicist,” and it was like that? Or were you more like a physicist with biological interests, or a biologist with physicist interests?
Oh, that’s an interesting thing. For sure, I was initially a physicist with biologist interests in an environment that was sympathetic to that. I rapidly became more of a biologist, and other researchers in the field just saw us as molecular biologists. Maybe there wasn't much of a distinction because the original molecular biologists had started out as physicists or mathematicians. You’ve probably seen that there is sort of a battle between these two intuitions, with the biologists seeing physicists as somebody who starts off saying, “Well, first assume a spherical chicken,” and then the physicists looking at the biologists as just data collectors. So then the question is how do you navigate between the two?
In my case, it was by choosing a biological problem that I thought was important and might reveal some underlying principle, and attacking it with physical techniques and mathematics. You probably noticed that biologists are kind of allergic to mathematics. But to do things like the alkaline sucrose gradients, you need to know how to calculate the molecular weight distributions and so forth and so on.
Much of that technology was set up by Dick Setlow, who was very much a physicist. He started off as a spectroscopist and got into DNA damage and then asked, “Okay, which DNA damage is causing the biological effects?” So he definitely migrated in sideways. And then Dick Setlow was Ron Hart’s advisor, and so my sort of scientific grandfather. Setlow also wrote a textbook on biophysics. That was with Ernie Pollard, when they were both at Yale.
But I think even now there’s a problem in having the biologist do biophysics. Can you find a person who can think both biologically and physically? It’s now kind of hard for me to go back and do the math. I can do it, but I have to work at it. What you want is a generation of kids who are learning to do both. There are a few people I know who can do that, but still not many. And going after big questions in this way requires the belief that there are principles in biology.
Doug, I’d like to ask a question that I hope is a recurring theme as we develop this discussion, and that is starting with your dissertation, did you have initial clinical interests and motivations? Was there a problem that you saw your research that would ultimately lead to better outcomes in patients? Or did you have more of a basic science research and if it did have clinical value, wonderful?
Yeah, the second. It’s not like I’m out there trying to cure patients. You could see that the money for basic science and DNA repair in particular was drying up, at least in the U.S. Well, one thing that happened was the discovery of oncogenes, which led to a defunding of most everything else in the cancer field. My clinical migration started as "If the DNA damage studies are useful for something besides aging, what would it be?" which led to cancer and particularly skin cancer. Well, let’s see. Go back a little earlier. So you know the history of cancer research? If I do that, then I’ll forget to answer your question, so let me answer your question first.
So my research was definitely trying to find something that’s useful for patients, but which presents an intellectually interesting problem. Otherwise you just wind up going down rabbit holes that are infinitely complicated and may never come to an end. Like the gene for Huntington's Disease, which was the first disease gene cloned and we still haven't got a cure.
But for me it’s important to actually answer something, and so you're doing this delicate balance between framing a scientific question that’s interesting, asking Is it solvable with the tools that you have this year, and Is it fundable? It’s been a continuing battle. When we were first starting trying to find the gene that got hit by sunlight on the way to cancer – that was in my last couple of years at NIH and my first few years here at Yale – the general consensus was, “Oh, well, that’s impossible. There are 100,000 genes. How are you going to ever find it?” That's a tools question. But that wasn't the funding objection, which was: We already know the answer, sunlight causes skin cancer by suppressing the immune system. Well, we now obviously know that wasn't the whole story.
Then in the background there was this other thing that you're balancing about funding. It’s probably true for all of NIH and NSF, but I happen to know about cancer. It jumps from one fad to another. The war on cancer started with the conviction that, oh, it’s a retrovirus and we’ll have this wrapped up in three years. That’s how they sold Nixon on the war on cancer, and then…
Doug, how well did researchers share that view that this was really about retroviruses? Was that a mainstream view in the cancer research community?
Well, that’s an interesting question. I think that before 1980, environmental carcinogenesis was a large component, coming to the forefront with Bruce Ames's finding that carcinogens were mutagens. With Ron Hart I was in the environmental carcinogenesis group. Bill Haseltine had started off doing retroviruses and got into repair, I think because he saw the opportunity with environmental carcinogenesis coming to the fore. Then AIDS came along and he went back to retroviruses and played a major role ¬in solving ... an infectious disease.
The major players in cancer were working on retroviruses and that was considered the sexy area. It became clear that the retroviruses weren't really going to account for much of mammalian cancer sometime around when I was a post-doc. Then around 1980 with the discovery of oncogenes, particularly RAS, money dried up for DNA damage, DNA repair, and to a large extent environmental carcinogenesis. So then you're finding ways to fund it, and the skin cancer work you could at least get money for. It wasn’t well-funded, but you could at least occasionally get money to do it. I thought that my 1991 paper on p53 being mutated by sunlight would change that by connecting mutations in a tumor suppressor gene to environmental carcinogenesis by the UV mutagen, but it really didn't change things. The oncogene people were the former retrovirus people, the virologists. You could sort of see it: we’ve got genes here and genes are neat, tidy, and rigorous. The switch from retroviral genes to endogenous genes was pretty much the same crowd wresting the situation away from Bruce Ames and the environmental carcinogenesis group. NIH followed suit. I think that another factor was that oncogenes offered the prospect of therapy, whereas environmental carcinogenesis was more useful for prevention. U.S. medicine is treatment-driven, in contrast to Europe and especially Japan, which are more interested in preventing people from getting sick in the first place.
How did the post-doc with Bill Haseltine come together?
Oh! He had an ad in Science and I answered the ad. I had been to Harvard the year before, having been recommended to someone, and I decided that position wasn’t for me. After I sent in the application, I get a phone call from Bill and… Well, I had done my homework and I found these retrovirus papers, and so I said, “Oh, well, this is really interesting, but I don't see how that’s going to connect with DNA repair.” He said, “Well, it’s not really all published yet, but there’s this paper in the Cold Spring Harbor Symposia from a conference. You can go look at that. We’re using DNA sequencing.”
So I read it and saw what they were trying to do. Basically, Bill realized that it was possible to go at questions relating DNA damage to mutations using the DNA sequencing technology. He had been in the Harvard Biolabs right across the hall from Maxam and Gilbert when they were developing their sequencing method. Then the idea was, well okay, if you can convert the DNA damage into a nick using a DNA repair enzyme—which may not have been his idea, but he saw the utility of it—then now you were back to having a DNA sequencing problem – finding the nick – and you could answer questions you couldn't answer before. So he called me back and said, “What do you think?” I said, “Oh! This is going to completely change the field!” and that was evidently the right thing to say! [Laughter] So he hired me and then…
Why, Doug? Why instantaneously did you appreciate that this was going to change the field?
Oh! One of the things I learned from Bill was the value of strong techniques. This goes back to the same thing. When you're done, do you really know the answer or are there six other possible explanations? In biology, that power is essential; physicists often don't appreciate this. So what we could do, the experiment we had in a Nature paper, was to map both the mutation sites and the DNA lesion sites in the same gene. So you could see that the places with the most frequent mutations were the most frequently damaged. That all seems obvious now, but one of the alternative candidates at the time was Does the DNA damage induce a generalized elevated mutagenesis? Which, by the way, it also does as we and other people found out a few years later. But even in that generalized mutagenesis, those error-prone enzymes still work at the DNA-damaged site. So that’s a question that you could not answer by digesting whole genomic DNA and analyzing the mixture by chromatography or even HPLC or mass spectrometry. You just could not ask that question.
Doug, I’m curious. By the time you got to Harvard, just to foreshadow a little bit, was the Human Genome Project something that anybody was talking about or is that too far afield at this point?
Too far in the future. It was still a month's work to sequence 100 bases. At the time I arrived, it was still the case that people would come back from vacation and say, “Hey, anybody cure cancer while I was gone?” because everybody knew that of course you hadn't. You don't hear that joke anymore.
And the Genome Project… I was a post-doc from ’80 to ’84, and even when I was next at NIH and trying to find the gene that got hit by sunlight, we thought there were 100,000 genes and so how was I ever going to find it? The Genome Project really didn't become a thing until after I got to Yale in1989, 1990 or so, and so it was still a matter (in my case) of guessing what genes to look at from the list of known genes. Gee, I must have been here three or four years – well after our initial p53 papers – when the first Genome Project papers came out and we found out it wasn’t really 100,000 genes. It was maybe 25,000.
I sent an email to Pratt and Whitney, the jet engine people up in Hartford, asking “How many parts are there in a jet engine? How many of them are parts that do something and how many of them are like screws that hold things together? How many of them are the same thing, but left and right versions?” The vice president emailed me back and said, “You know, we’ve never ever thought about that,” and so they spent a few days going over their parts list and it turns out it’s about 50,000 parts. So you and I are about as complicated as a jet engine, and you could surmise that E2F1, 2, 3, 4, 5, and 7 are all like screws, but slightly different-sized screws. I don't know. So that’s the genome project putting an interesting perspective on how big is big. But in any event, the way we got p53 was just by astute guessing.
Did you do two post-docs at Harvard, or it was one post-doc with two components?
Yeah, it was really two components of the same thing. I think this had to do with grants that Bill had written with Eric Eisenstadt in Public Health. Eric was doing the mutation assays Jeffrey Miller in Wally Gilbert’s lab had worked out a genetic way to sequence genes. I think he should have gotten a Nobel Prize, and if he had published it a year earlier, then maybe he would have. Anyway.
So there was this genetic way of mapping mutations, and Eric had set that up. Bill was going to do the damage measurement and we’d put the two together. Bill asked me, “Oh, before you come here, write a fellowship application.” I actually wrote it on mapping mutations from benzo[a]pyrene, a chemical carcinogen. So I was initially paid off a Public Health grant, but then got that fellowship with a 1.0 score, the only 1.0 score I’ve ever gotten in my life; my position then switched officially from Harvard School of Public Health to the Dana-Farber Cancer Center. But I was going back and forth the whole four years. John Cairns was over there at the time, too. I was physically at Dana-Farber the whole time, but worked with both sides.
Did you stay at Dana-Farber after Harvard on a more full-time basis?
No. What happened is we kept doing more and more experiments and Bill kept saying, “You’ve got to get a job at some point,” and he was right. Despite the Nature paper, a PNAS paper, and some others, I must have sent out about 50 or 80 job applications. Low interest in DNA damage and repair, but also nobody ever told me how to write a job application, so in retrospect, these applications did not have enough detail about what experiment I was going to do once I got there. Bill said, “You like to eat, don't you?” So in any event, I got a job at NIH with a person Bill had spoken to just as the money was running out at Harvard. That job was supposed to be like an assistant professorship. It was an odd beast, and it wasn’t quite like that. So it was nice to get to Yale after a while. But I was able to do some experiments on my own at NIH to keep the UV work going.
What were some of your key research accomplishments during your time at NIH?
Ah! Well, two big ones. One is we showed what the mutagenic lesion actually was in E. coli. That was a project I’d started at Harvard—so Bill is a middle author on it—and working with people at the National Institute of Environmental Health Sciences, NIEHS, who were doing the mutation assays. They had a clever idea… We had shown that both the UV-induced cyclobutane dimer and the (6-4) photoproduct were candidates for being the mutagenic lesion, and we knew that cytosine methylation blocked the (6-4) photoproducts. The guys at NIEHS – Roel Schaaper and Barry Glickman – had this clever idea to get mutant bacteria that can't methylate the cytosine. So okay, we would do the UV-damage and UV-mutation assays in normal or mutant bacteria and see whether we get the mutations or not. We were able to show what the mutagenic lesion was in E. coli and it was the (6-4) photoproduct, this new lesion that Bill’s lab had basically rediscovered. It had been found 15 years earlier and nobody paid attention to it and then he rediscovered it. In the Nature paper, it was present at the same mutation hotspots in E. coli as the cyclobutane dimer by and large, with a little better correlation. Here, it re-appeared in the methylation-deficient bacteria at exactly the same sites where mutations now appeared. That was a PNAS paper.
Then I worked with people at NIH – Michael Seidman and Ken Kraemer – who were studying mutations in human cells using shuttle vectors, where you’d irradiate a plasmid, put it into the cell, let it replicate, and then sequence the vector. By removing the cyclobutane dimers first, we could show that, oh, in human cells the cyclobutane dimer is the main mutagenic lesion. So those were the two big things there.
Then I started working on the issue of trying to find out what genes were hit by UV in skin cancers. We didn't get it there. We finally found the right gene when we got to Yale. This was all almost side projects because when I got there, I found out that my boss wanted me to actually work on something else. At NIH your boss controls your budget and his boss controls his budget, so it’s more like a corporate situation than I realized. So there are all these other things that we also had to do, but for UV, those were the main things.
Doug, I want to ask a little broader question about your time at NIH. You were there a little over a decade after Nixon declared the so-called war on cancer. I’m curious. You know, being a decade out and being at one of the world’s premier cancer research institutions, had that goal seemed… By the time you were there, was that sort of more of a moon shot? Were people still thinking about solving cancer across the board, or had the research progressed to the point where that just seemed to be an impossible kind of thing to achieve in any sort of near-term future?
Ah! I had not thought about it that way. So initially it seemed impossible. Then with the discovery of oncogenes, everybody decided, “Hey, this is really maybe going to be solvable. Separate from retroviruses or anything, we have these mutant oncogenes.” So NCI at the time was very much into oncogenes and finding new oncogenes and there was a great deal of confidence that knowing them would solve the cancer problem. The chief guy leading that was Bob Weinberg at MIT; in competition was Geoff Cooper at Dana-Farber. At NIH, the third one really into this was Mariano Barbacid, who started before the idea was popular. He’s now head of the Spanish cancer research institute, but then he was in Stu Aaronson’s lab. Stu Aaronson was a big shot, making tumor-derived cell lines. Eventually, the NCI's scientific director was pushing everyone to relate their work to this topic.
So there was very much a focus on finding oncogenes. Then the idea of tumor suppressor genes came along, and there was initially very much not an idea of tumor suppressor genes as being real. Then all of a sudden it was like, “Okay. Starting in January, everybody drops oncogenes and starts on tumor suppressor genes.” Then there were people proposing that, well, maybe DNA damage and repair is important and a repair enzyme would be a tumor suppressor gene. That was mainly Bruce Howard, who had invented the first expression vector with Paul Berg. The DNA repair version of tumor suppression didn't go over very well at that time.
But I think there was still this conviction that, oh, we’re going to be able to solve this. We just have to be able to find all the oncogenes and all the tumor suppressor genes for each of the tumor types. At the time I left, people were just starting on p53. So everybody had been doing RAS and then it was p53, but also some other oncogenes, like SIS and ABL. But there was still the complete conviction that, gee, this is going to be solvable. I think it wasn’t for another ten years before it began to look like, okay, even if we have all the oncogenes, this is still going to be a hard problem.
Were you recruited to Yale? Were you looking to leave the NIH system?
Starting about a week after I got there, yeah. [Laughter] At two levels—one there is the lack of freedom and the other is the bureaucracy. I would be in the hallway stomping up and down and my boss’s secretary would come out and say, “Now Doug, remember where you work,” you know? You had to do competitive bidding if you wanted to buy something—it was just endless stuff.
The other way to look at it, though, is at least at NIH you didn't have to worry about writing grants all the time.
That’s true, and that’s why I thought it would be great to go there. But in government there’s always somebody telling you what experiment they think you should be doing, so that was the flip side of it. That varied very widely from one part of NIH to another, but NCI was very much like that.
Besides the frustrations with the bureaucracy, how was the quality of the science at NIH in terms of the colleagues you worked with, in terms of the instrumentation that you had at your disposal?
Interesting. The instrumentation was good. If your boss wanted an instrument or if you could convince him to get that instrument, then you could get it. It was almost a little too casual. People would buy a big, fancy instrument and if it didn't work for their experiment, it would go up on the top shelf.
The quality of the science was good. I think there was—and to some extent is, but things have changed—a tendency to say, “Let’s measure everything because then we surely will have measured the important things”. They had a budget where they could do that. I think that may not be wise. The institutes with less money, like the Child Health Institute and so forth, … We used to joke that the institutes with the low numbers like Buildings 2 and 4, they had all the really clever experiments because they didn't have any money. [Laughs] I may delete that from the transcript! But NCI certainly was able to hire a lot of smart people. I think there were a lot of frustrated people, so it was some kind of mixture. There were certainly smart people there, which is the direct answer to your question.
So how did the opportunity at Yale come together?
Oh, another ad. There was an ad in Science and then I applied for it. Paul Howard-Flanders, another founder of the DNA repair and recombination field, had retired and they wanted to replace him. They liked the idea that I was going for the gene hit by UV, and I think the other thing that might have sold it was that I had begun using PCR. This was in very early days, and I had jumped onto it. So in looking for what gene got hit, I had these candidates, and I was initially trying to do it by hybridization to mutant probes to see if I could find the mutants in a Southern blot of tumor DNA. Then PCR came along and as soon as it got to the point where there was a thermostable enzyme I jumped in. Well, let me think through this. Initially, at every cycle you had to put in a new enzyme because you’d fried it at 95° when you denatured the DNA, but as soon as there was a thermostable enzyme available, I decided it was realistic to do PCR. That was back before PCR cyclers existed, and we would sit there moving these tubes around from one water bath to the other 40 or 50 times. It was very boring, but that’s how you did PCR. So I think another attraction for Yale was probably the fact that I had experience with PCR and I could bring that in, but also because this particular department had a history about DNA repair and ultraviolet light. Even though it’s a radiation oncology department, I think that was attractive also.
Doug, did you view the switch as an opportunity to broaden or change to some degree the course of your research at NIH, or were you looking essentially to continue on the same path in a new environment?
There was a lot of pressure at NIH to drop the UV work.
Because it wasn’t what… I’m trying to figure out how to say it diplomatically, given this is going on the record. There was this hierarchy. There’s a head of an institute. He has a scientific director, and depending on the institute, the scientific director decides, oh, what should everybody be working on? He’s the guy who says, “Okay, oncogenes were last year. We’re doing tumor suppressor genes now.” Either the lab chiefs jump when he says jump or they don't, and then that percolates down to you, and doing environmental carcinogenesis or UV were not in the cards. I was explicitly told, “Well, we think you can get you tenure here if only you’ll stop working on the ultraviolet light stuff.” So the Yale opportunity came in the nick of time to rescue that and continue it. Also, at NCI, or at NIH, you could say it’s an attraction to not be teaching, but I kind of wish they were teaching, so that was another attraction of Yale. In fact, I wish there was more teaching at Yale's medical school.
Doug, at this time, what were some of the biggest misconceptions about exposure to ultraviolet light from the sun?
Oh. I think everybody was on to the fact that it was carcinogenic. That wasn’t in question.
But carcinogenic for everybody? I mean, isn't part of the mystery why some people develop skin cancer and others do not?
I’m pretty sure that back then people were clear on the fact that dark skin protected you and light skin didn't. I think that we knew that red hair and blond hair were more susceptible just on epidemiological grounds. As far as mechanism, there was this notion of oncogenes… I’m not sure there was really so much of a notion of oncogenes getting mutated. I think people didn't really want to think about that, and that may have been why our paper continues to be cited so much. For skin cancer in particular, it was assumed that UV was mutating genes. Margaret Kripke at NCI had shown that UV causes immunosuppression, so the prevailing dogma was that the way UV causes skin cancer was by causing immunosuppression. Now, you could say, “Okay. Well, what is it immunosuppressing?” Something had to have happened so that the skin had an abnormal cell that was worthy of being immunosuppressed, which was my point of view, but that’s not really the way the world thought about it. So that was something of an oversimplification or a misconception. But I think by and large the world had the right viewpoint; they just didn't know how it worked. Oh, and we knew about xeroderma pigmentosum; that’s a hereditary syndrome where the patients can't do DNA repair and they have a 2,000-fold elevated skin cancer incidence. So that was quite clear.
What were some of the frontiers in skin cancer research that you saw as the most productive avenues to pursue by the time you got to Yale?
Ah. So I was clearly focused on what the gene was that was getting hit. Issues of clonal expansion were not something that I was thinking about or anybody was thinking about. Apoptosis wasn’t anything anybody was thinking about. There were people trying to find oncogenes for every tumor going, and the way that was working at the time I was at NIH and for a few years later was the Bert Vogelstein approach. His approach was that, if we know the chromosomal abnormalities in these tumors, let’s use those to map the regions that are commonly abnormal in different patients' tumors and use that map to find genes. Then we’ll find out what genes are in those regions, and that’s how we’ll find the oncogenes.
As I mentioned before, we guessed at genes that might be mutated by UV. We started with the three RAS oncogenes because the DNA sequence of their mutatable sites would be targets for UV – we could predict that from my postdoc work. We didn't see many mutations in skin tumors. Then Arnie Levine gave a lecture at Yale in which he mentioned finding p53 mutations in tumor cell lines. So, knowing a bit about skin viruses and SV40, I ordered PCR primers for p53 and RB and, voila! p53 had mutations in many of the tumors and they were UV-like. I then called up Joe Fraumeni to ask if Li-Fraumeni syndrome patients, who have inherited p53 mutations, got skin cancer and he said "You're the third phone call like that I've gotten this week." That was the beginning of the p53 tsunami.
I did start to try to clone a tumor suppressor gene using a PCR variation of subtractive hybridization, to find the gene for hereditary basal cell carcinoma. The post-doc on that didn't get very far, and by the time we got it working, another guy at Yale – Allen Bale – had cloned the gene the traditional way. So that’s how the PTCH gene was cloned. We then looked to see what kinds of mutations Allen's tumors had in PTCH and half of these were clearly UV-induced.
After the p53 and PTCH mutation discoveries, we wondered what p53 did for a living. Here's an example of where seeing patterns in a mass of data was helpful. It was known that P53 caused cell cycle arrest, so the dogma was that inducing P53 allowed time for DNA repair although the evidence for that was slim to none. My thinking was that skin cells are going to slough off in three weeks anyway, so why not discard them instead? Also in the literature, but not yet famous, was a phenomenon called apoptosis, in which cells died by rounding up, shrinking, and being scavenged rather than by exploding in necrosis. The apoptotic cells had dense nuclei and hot pink cytoplasm when stained with hematoxylin and eosin. Skin had cells like that after a sunburn, but it was thought that they had a keratinization problem that made them stain pink. We used p53-knockout mice and a DNA end-labeling scheme to show that the sunburn cells were apoptotic and this required p53. Later, we and another lab showed separately that this process reduced the number of eventual mutant cells.
So it looked like p53 mutations were an early event in skin cancer after UV. Then normal skin should have p53 mutations but not the other mutations needed for skin cancer. We thought if we were lucky we might find a few mutant cells. Instead we found thousands and they were already proliferating as clones of mutant cells, just waiting for the next mutation to hit one of them. But the skin appeared normal even under the microscope. We then used mice to show that UV drives this clonal expansion, by at least two routes. One involves apoptosis backfiring and becoming dangerous. The other involves stem cell differentiation pathways.
See, biology and even pathology can be logical, like physics!
What were some of the major advances in DNA sequencing that were useful for your research?
[Pauses] Let me think. Interesting. So there were a couple phases of the DNA sequencing. One was the original Maxam-Gilbert method, which worked on plasmids. So there I was mapping the DNA damage and I was doing it on plasmids because you had to have some simple DNA to look at. One of the things that we invented at Yale was a way to do the same thing – radioactively labeling one end of one DNA fragment – on a genomic DNA. Then for E. coli we got it to work where you could nick the DNA at a cyclobutane pyrimidine dimer and then end label one particular fragment in E. coli DNA and then do the DNA damage mapping. So we got a PNAS paper out of that, and showed that some sites are very slowly repaired. But that method got superseded by ligation-mediated PCR, which was able to do human genomic DNA. Our method, having only one oligonucleotide primer, couldn't hybridize specifically enough to handle something as complex as human DNA. Ligation-mediated PCR had two primers, so the square of specificity, and was able to do that; the cost was the unknown unevenness of ligation and PCR from site to site. We were actually going to try to do that, but NIH wouldn't fund us to do it. The guy who did do it was in a department that already had funding to look at 5-methylcytosine using ligation-mediated PCR, so he adapted it to DNA damage. So that worked.
Then the more straightforward aspect of sequencing… When we were looking for tumor mutations, we would PCR up the candidate gene and then we’d be looking to see if there was a mutation in a tumor but not in saliva. To do that, we were among the first to come up with a way to sequence PCR fragments. The problem you have in sequencing PCR is that the two strands are going to reanneal so fast that you can't get your sequencing primer to bind there, and so we worked out ways to dodge that problem and that’s what actually let us do the p53 papers.
For the genomic studies, what we’ve been doing lately is making a nick at a cyclobutane dimer, putting a linker on the end, making a library out of nicked, linkered fragments, and then all we have to do is sequence to find the linker. Now you can do the whole genome instead of a gene fragment like in ligation-mediated PCR. It costs a little money, but you can do it. So that’s the way we’ve been looking to find which regions of the human genome are most sensitive to UV.
Is this relevant for both melanoma and non-melanoma skin cancers?
Yeah. The initial money came for melanoma because people cared about melanoma.
Why is that? Because it’s more prevalent?
The non-melanoma skin cancers are actually the most frequent skin cancers in humans, equal to about all the other cancers combined—lung, bladder, breast, all of them combined. But usually the patient or physician sees them and a surgeon cuts them out – so the patients don't die. The number of patients dying is about the same as for melanoma simply because they’re so prevalent.
But they are not on the NCI’s list of things they care a lot about, and not high on the lists of those people who sit on the grant-review study sections, whereas melanoma, because it’s deadly and because it hits younger people, it seems to be on the list. So there was more money for melanoma than there was for non-melanoma. We’re now doing keratinocytes – the main cell type in skin – to map the DNA damage in the keratinocytes and we can compare that to mutations. We have one grant for mapping damage and another grant for mapping mutations, both in normal-appearing skin. The reason those got funded is that we should then be able to come up with a predictor so the family physician can take a little sample of your skin, essentially measure your past sun exposure, and predict your future skin cancer risk so you know whether to be seen regularly by a dermatologist. NIEHS and NCI both have programs that are interested in that, so that’s how we got that done rather than any basic science interest for it.
Doug, I’m curious about this concept of chemiexcitation. Can you explain what this new word means and how it’s relevant to your research, particularly from a physics perspective?
An endlessly interesting subject. I had high hopes that during the COVID shutdown I would study all these physical chemistry and photochemistry textbooks I brought home, but I’m still pretty much an amateur. Chemiexcitation is really interesting and really frustrating. It’s like studying pixie dust because these are such transient states. It has a fascinating history and really interesting people in the field.
The short version is that in biology we think of ATP as being an energy-carrying molecule, and it actually has about this much energy [hands close together]. Then if you're a plant outside and get hit by visible photons, you get about this much energy [hands far apart], and that’s enough to drive chemical reactions in a chloroplast. What’s happening is it’s enough energy to now excite an electron, and when you excite electrons, you can get chemical reactions occurring that can't happen in just the ordinary ground state. A lot of that has to do with not only the energy, but also the geometry because now the orbital shapes are as if they'd rotated 90°. It depends on the particular molecule.
In the case of ultraviolet light, which now kicks the electron up to even higher energies, what happens is that DNA can make these mutagenic cyclobutane dimers where it has adjacent pyrimidines (thymine or cytosine). About one every 10,000 bases. Before UV, there is a double bond on each pyrimidine; after UV, these have sometimes both opened up at the same time and made two single bonds between the two bases. Now if you change the orbitals, you not only have more energy, but now these orbitals are pointing outward like this and the double bonds can break and point toward the other base. That makes a square ring, something like this. That’s what a cyclo-butane is, a four-membered ring, and that kind of coordinated reaction just can't happen in the ground state, for basic quantum mechanical reasons called the Woodward-Hoffmann rules. One of my chemistry postdocs and I debated whether this was physics or chemistry.
When people initially started studying this reaction, they said, “Well, this is all really cool, but it will never happen in biochemistry because the energy is too high.” Well, it turns out that’s what fireflies do and it underlies bioluminescence in marine organisms. So there are chemical ways of making molecules that can generate that much energy, and that’s what chemiexcitation is – a chemical excitation to these same high energy levels. The usual way Nature does it is to make a peroxide, with two oxygens that are bound to each other now binding two carbons that are bound to each other, and so you get this four-membered ring that has two oxygens in it, called a dioxetane. You can appreciate that it’s strained because four is a pretty small circle. Chemistry can make these small circles in a couple of different ways, involving either nitrogen radicals or reactive oxygen species.
We very much stumbled onto this, in our case because in melanocytes (the cells that make the skin pigment melanin and lead to melanoma) the cyclobutane dimers continued being made even after we turned the UV lights off. It took us the longest time to figure out what could even do this —"us" being me in this case looking at the actual work the people in the lab had done and then reading the literature and making phone calls to earn my keep on this grant by doing something. I stumbled into the old literature from the 70's, and then I eventually found researchers at the University of Sao Paulo who still study reactions like this. Notably Etelvino Bechara, who was a student of the pioneers at Harvard and University of Sao Paulo. With his guidance, we were eventually able to show that this is happening because the UV is turning on two enzymes that make nitric oxide and superoxide. Those combine to make peroxynitrite, which oxidizes melanin. The oxidized melanin reacts with ambient oxygen to make the dioxetane. The dioxetane breaks spontaneously and releases the energy that was stored in the radical plus the O–O bond plus the C–C bond.
For the longest time we were trying to figure out what molecule is getting oxidized to the dioxetane, and one day we realized it was staring us in the face. “Oh. Well, the melanin!” Except that melanin is not in the nucleus; it's in melanosomes in the cytoplasm. So how did it get in the nucleus? That was a whole other problem. Anyway. So we got this sorted out and it looks like UV-triggered enzymes are oxidizing the melanin and that now could transfer the energy to DNA and you now have the same high energy level as a UV photon delivers in a picosecond.
Then what we’ve been working on since is… Well, one, narrowing down just what the reaction mechanism is, so we’ve got a grant to do that. In another month or so we’re going to start doing NMR experiments to nail down what the intermediates are. I was fortunate. I’ve got a real chemist in the lab again, and he has experience in studying antioxidants and free radicals, so it’s just perfect. We also want to know how UV turns on those enzymes. I thought five minutes on PubMed would tell me, but it seems to be unknown.
Then another question is, is melanin the only molecule that can do this? The properties of melanin that seem relevant seem to be that it can lose an electron rather easily. The same is true of a number of other molecules that have similar chemical structures. Some of those are neurotransmitters and hormones. You could think, “Uh-oh,” and so far it’s turning out that it does look like uh-oh. So we’re trying to nail that down and this will be the next paper once we’ve totally nailed it down.
A practical question is, how could you block this? Is there something you could put in the sunscreen, or are there other ways that you could block these events? Plants, of course, have this problem on very sunny days and that’s what lycopene is doing in tomatoes and what beta-carotene is doing in a chloroplast. Well, there are two isomers of beta-carotene. One of them helps absorb sunlight not caught by chlorophyll; the other's job is to siphon off excess energy from excited electrons and turn it into heat before it can go and do a lot of harm.
So we’ve been looking at candidate molecules, in particular natural products, to find ones that can interrupt the cycle. Antioxidants can do it by interrupting the free radical part of the reaction, but people trying vitamin E and other antioxidants to prevent cancer have found out that they actually can be problematic; you can wind up with more cancers instead of fewer because free radicals and hydrogen peroxide are actually also normal signaling molecules. So we’re leaning toward the other direction of siphoning off the energy rather than blocking the free radicals. But this is all experimentally difficult and not my main expertise, and so we’re amateurs in that field.
Right, but clearly it’s promising. It’s worth further investigation.
I think so. So I wrote a review and organized a conference asking what other diseases could be caused by this process, because melanin shows up in a lot of places that get diseases with unsolved mechanisms. These range from macular degeneration, where you can kind of imagine what would happen because you know you’ve got melanin in the back of the eye, to places you hadn't really thought about like Parkinson’s disease where there is neuromelanin in specifically the cells that die. Is the upstream event not really so much Lewy bodies and amyloid, but some kind of chemiexcitation mechanism that’s actually causing the killing? Every one of these diseases comes with a different set of technical problems, but we’re working on it.
Doug, I wonder if you can talk a little bit about some of the assets of being part of a medical school for your research agenda. In other words, in what ways is being rooted in the Yale medical school advantageous in a way that, say, if you were in a biophysics program or even if you were at a pharmaceutical company in terms of the kind of research that you want to do—what are some of the ways that it’s advantageous being in a medical school environment?
There are two benefits that come to mind. One is access to tissue. I know that companies, for example, have trouble getting access to tissue, and for that matter, access to patients. This becomes much more feasible here because you build up relationships with the doctors and they trust you and you trust them and you have these back-and-forths about how to get the tissue without interfering with what the patients are actually in the doctor’s office for.
Another benefit is that your neighbors are thinking about these processes. We have people studying melanoma, for example, and we stumbled onto the chemiexcitation phenomenon because I got talked into being on a grant by a melanoma researcher who was interested in… Let’s see, this takes some explanation. When a melanocyte synthesizes melanin, it generates a lot of reactive oxygen, and Ruth Halaban wondered whether that was part of the reason that these cells get tumors. I thought that was sort of interesting, and so I agreed to be on the grant and we decided to do some of those experiments. But I never would have even started irradiating melanocytes without having her as a neighbor talking me into doing that. Just on my own I would have thought, “Well, people have already irradiated fibroblasts and keratinocytes, and melanocytes are just one more cell type. We’ll get around to it when we get around to it.” But it turned out to actually be interesting. Well, I guess one of my contributions was to recognize that cyclobutane dimers appearing after the UV light was turned off was the tip of something interesting.
Doug, to bring the conversation up to the present day, what are some of the areas of research that you're involved in currently?
We have four projects on DNA damage topics. One of them is to find a molecule that you can put in a sunscreen to block or dissipate the chemiexcitation. Another is to work out the mechanisms of chemiexcitation in skin and find out whether there are other molecules and other diseases where it’s relevant. The other two projects are for predicting skin cancer risk, one of them by looking in a person's skin for levels of DNA damage that have persisted since sun exposure and the other project looking for levels of mutations that have persisted. Once we have that data, then building it into a model that’s a statistical tool that predicts skin cancer risk.
To pull that together, we need strong techniques that will measure where in the genome are mutations in normal skin. So we’re collaborating with liquid biopsy people to use some of those techniques on skin. For the DNA damage side, it’s a continuation of what we’ve been doing—what we did for the melanocytes but moving to keratinocytes—and there’s a large statistical and bioinformatics component afterward. Before any of this, there is a large patient component. To do this rigorously, we have to tie the molecular measurements together with people who actually have skin cancer. How do you know what the risk is unless you have molecular exposure measurements on people with different levels of risk? So we have patients coming from a number of different situations clinically.
For example, there are some diseases where the treatment is UV, so we know exactly what the UV dose is that the patient has received. Then if they are willing to donate a biopsy, we can look at the damage. Other patients have had skin cancer, so we know what their risk is and then now we measure their normal skin. Then there are other questions like, how far back in time can we look? The way we approach that is to work with veterans who were in a sunny area like Iraq 5 years ago or 10 years ago or 20 years ago and we’ll see how far back we can see. Then we’ll have some sense of what the assay sees and whether it’s predictive of anything.
Doug, I want to ask some sort of broader questions now that we’ve reached a point in the conversation where we’re up to your current research. So the first one is can you describe… I mean, I’m sure there are many of your colleagues in the skin cancer research world who do not have physics backgrounds, right—who have more cancer, biological backgrounds. What does physics and your knowledge of photons and electrons—what does that bring to the table as a member of a broader collaboration to understand how skin cancer occurs?
I have not thought about that one, so let me see. At one level, they kind of appreciate it even if they don't understand it. From their point of view, it’s nice to have somebody else who can think about it. More broadly, I think I bring more of a commitment to asking, What’s the whole mechanism here? It’s not that, okay, if we find a gene, then we’re done, if you see what I mean.
And in particular, a gene that’s mutated in tumors. You know, it’s one thing to find a gene that has UV-like mutations – that tells you a lot about the mechanism. But only finding a gene that has some mutations, that doesn't tell you how the mutation got there. It will tell you about the downstream events, what pathways the mutation could have screwed up in the cell. But what happened upstream between the carcinogen and the gene is in my ballpark.
The skin cancer community and the dermatologists have been very welcoming. You know, different fields have different personalities, and some of them are quite competitive. The dermatologists have been great, and even when there’s something that I didn't know, they patiently explain it to me and they’re not really upset. I still remember the day, when I was at the National Cancer Institute, that I was explaining to the cancer dermatologist I was working with about how I was going to find the gene mutated by sunlight in non-melanoma skin cancers. He said, “Now, Doug, you know there are two kinds of non-melanoma skin cancer, don't you?” and I said, “Well, no. I didn't know that.” [Chuckling] He didn't give me any grief, so it’s been a very nice community to work with. I think everybody appreciates the part that each of us can play.
Doug, can you talk a little bit about some of the policy implications of your research? In other words, skin cancer is so prevalent. It’s something that affects so many people. It’s something that we all have to think about simply because we expose ourselves to sunlight, right?
Yes, the first sentence of the 1991 paper is "Sunlight is a carcinogen to which everyone is exposed."
What have been some turning points in the course of your career in this research that you felt have reached the level of these are the kinds of things that need to be understood beyond our research circles, beyond the basic science research, beyond the journals, right? What are the kinds of things that really need to be communicated by—you tell me—the surgeon general, the American Dermatological Association? Where have you seen those opportunities that your research needs to have a public policy arm to it?
So that’s an interesting question. At one level, you could say that we already know just from epidemiology that you ought to stay out of the intense sun, or wear a hat or at least not go out at noon. We’ve known that for 40 years. When we first published the 1991 paper, that was evidently a very big deal in Australia where they have a real problem with skin cancer. They had a real effort to communicate to the public…because the Australians were happy to go out and have a barbecue where everybody gets sunburned, you know? They’re just crazy. Even though they kind of knew from epidemiology “Here’s the cause,” after our paper there was a psychological consequence of being able to say, “Hey, here’s how it works.” So that, I'm told, had an impact on the ability for the public communication of policy advice more directly or locally. And in the last 20 years, the Aussie public relations campaign has turned that situation around.
The biggest policy implication… Well, that’s interesting. Initially, when I started out, NIEHS did not fund this kind of thing because they didn't regulate sunshine. [Laughter] I think someone even told me that. They were in charge of smokestacks. Now, they are one of the Institutes funding our risk prediction grants. So that’s changed.
The biggest policy effect is probably the sunbeds. You know, should the government regulate sunbeds? The FDA had a group that was trying to at least find some safe way to do it because there’s a tremendous sunbed lobby, and the biggest change – having nothing to do with me, really – is that the epidemiological evidence now is that sunbeds do matter. They're banned in Australia and Brazil and regulated for minors in Europe. In the U.S., it varies by state.
Now that you’ve got me thinking about this, from our own work there could be two policy implications. There was the initial mutation discovery, the smoking gun for sunlight, and then the later work on clonal expansion where we showed that UV exposure drives a mutated single cell to expand into a clone. So sunlight is doing two things. One is the initial mutation, which in cancer is called tumor initiation, and afterward the other effect – clonal expansion—comes from steps that wouldn't matter if the cell didn't already have the mutation; that's called tumor promotion. Tumor promotion works only when done repetitively or chronically. A lot of what’s in tobacco smoke are tumor promoters, not mutagens, and the same principles apply to sunlight.
So you could say that a second policy consequence of our work, although I think less widely understood, is that UV is not only causing the initiation but also the promotion and driving cancer to go on to the next step. A lesson would be, if you are going to go out in the sun, do it once; just don't do it again and again and again. Of course, that can't be a governmental policy, but it is a wise personal one.
As I think about it, the biophysics paper that had the greatest influence on public policy was probably Dick Setlow's 1974 PNAS paper calculating the skin cancer incidence expected from an ozone hole. This contributed to the Montreal Protocol banning chlorofluorocarbons.
I know, Doug, that your motivations continue to come from a basic science perspective, but I am curious if you have experienced any of the pleasures or moments of pride in seeing how your research might connect in some way to clinically valuable applications, either epidemiologically or therapeutically.
Yeah. Certainly the epidemiologists all cite that p53 work, I think as a rationale for “Hey, we’re not just making stuff up. There’s some mechanism to all this.” As far as putting chemicals in a bottle, for sunscreen or an after-sun prevention lotion, not quite there yet. Certainly there are people making improved sunscreens, sunscreens that are embedded in nanoparticles, for example, so that they’ll stick to your skin instead of washing off as soon as you go into the ocean and killing the coral, but that could have gone on even without us. We’re not quite there yet with regard to preventing the chemiexcitation, and we're just starting on risk prediction. But all three will happen, so it does give a feeling of being useful to real people. Definitely a different world from designing weapons.
What are some of the long-term goals in skin cancer research, and what would it take to achieve them?
So… Let’s see.
I mean, is it as simple as is the endpoint a world without skin cancer? Is it as simple as that?
Well, that should be doable, you know, because you’ve got three shots at it. One, not getting a sunburn in the first place—so that translates to wear sunscreen. The same for chronic exposure even without a sunburn, if you're a fisherman or farmer. Wear a hat. Don't go out between 10 and 2. Be extra careful if you have light skin. That’s one shot. Another shot is removing the cancer while it's curable, before metastasis. Medically, of course, the focus is on removing the cancer or removing a precancer to prevent it from becoming a precancer…curing a disease once you have it because now you have a patient who’s really motivated. In between these two shots are other modes of prevention, like dissipating chemiexcitation energy. Prevention, as we’ve seen with COVID, is a bit of a sell.
Early detection works really well. One of our strategies is, if we show a risk, then what do you, the patient, do about that risk? Well, you get screened by a dermatologist more regularly so you catch it while it’s early. Even melanoma, if you catch it early, can be removed and you have a 90-something percent cure rate.
A large fraction of the field is still trying to find oncogenes and tumor suppressor genes on the idea that these will give you a drug target for the tumor after it has appeared. There’s a big shift now to understanding immunotherapy because that looks so promising in the clinic, for example finding out who is likely to benefit from immunotherapy and who is not. That may be partly a matter of the tumor, partly a matter of your own genotype—how your immune system responds to signals. If we give you immunotherapy and that triggers autoimmune disease, that’s not so great, and so there is a large effort to find out who’s a good candidate for immunotherapy. I've seen a lot of fads, but this one does look promising.
Another aspect of skin cancer that people don't really understand is racial disparities. Blacks have about 1/100 the risk of Caucasians, and Asians 1/10, but Blacks do get what are called acral melanomas which are under the fingernails or on the heels. I have some thoughts on how that might happen involving chemiexcitation, but we haven't had time to do any of those experiments.
What is your response? I know this is a little outside your field, but a lot of people will say, “The sun is good for you. It’s a source of vitamin D, for example,” right?
Do you just sort of reject that kind of thinking out of the box, or is there some gray area in terms of some kind of benefits from exposure to the sun in certain circumstances?
I was on a committee a year ago that was looking at that question, and there have been prior committees. My take is that there are three things we know for sure. One is that vitamin D is good for you. The evidence is pretty convincing on that score and there are multiple benefits. Two is that there are sunlight effects that don't depend on vitamin D, for example directly generating nitric oxide in your skin, which is a vasodilator and lowers blood pressure. There are epidemiology studies showing death from all causes is lower in people who have sunlight exposure than not, independent of what they died of. So clearly there are benefits and harms, and their dose-responses may differ, leaving a gray area in between and maybe even overlapping the benefits. There is no guarantee that there is a purely safe dose region.
That's plausible from an evolutionary point of view. Evolution is designed only to get you past childbearing years. It can't select on your genotype after that (except to the extent that you're a great grandparent who helps your grandchildren's survival and reproduction). If sunlight helps your reproduction rate, for example by helping folic acid production, but gets you a melanoma or a non-melanoma skin cancer when you're 50, evolution doesn't care. So it’s quite possible that there is a gray area of sunlight benefit and harm just because that’s the way evolution works.
The other thing that’s clear is that this relationship gets quite complicated. The sunbed people would like you to use their sunbeds. The dermatologists would like you to stay out of the sun and take vitamin D pills. It seems clear to me that those are both oversimplifications. In addition to the vitamin D and nitric oxide stories, the high energy of sunlight makes other products besides vitamin D— similar, very closely related molecules, in the same pathway – and it’s not known whether those are important or not. It would be great to know those answers and people trying to fund those studies have had a hard time. For all you know, vitamin D is not the only actor.
Then there’s a question of how much vitamin D do you need. Being vitamin D deficient is clearly bad epidemiologically. Whether vitamin D supplementation helps is not at all clear to me. And then to what extent is the vitamin D level in your skin just a proxy for your sun exposure, just a marker for your sun exposure, while what really mattered was some other effect of sunlight? So it’s quite complicated. The physicist in me wants the in vivo UV dose response for each of these effects of sunlight, while the biologist in me knows that these dose-responses are not going to get measured. Now what do you do, especially for making policy?
Doug, this is a very broad question, one before my last question, and that is in what ways are the challenges in skin cancer research as they relate to both epidemiological questions and of course the enormous complexity of the biology and the chemistry and the physics just in understanding these pathways and these mechanisms—in what ways does skin cancer research share these challenges with other cancer research fields, and in what ways is skin cancer unique?
Well, we know the carcinogen. In breast cancer we don't even know the carcinogen. At least some of it is spontaneous damage from body temperature, which is not very susceptible to experimental manipulation.
And when you say you know the carcinogen, you simply mean what causes the cancer.
Yeah, right. The ultraviolet light.
In other cases, it may just be polymerase errors or body temperature deaminating or depurinating DNA and you don't know. So we got a break there. Actually, that tractability was why I decided to focus on it.
And on that point about simply asserting that we know the carcinogenic source, are there any flat-earthers out there in the research community who will deny that sun is a source of skin cancer? Not wackos on the web, but I mean people in the field.
The reason I’m pausing is some distant corner of my brain is tingling, but I can't remember what it is. Maybe the fact that only about half of PTCH mutations look UV-like. Certainly, there are other sources of skin cancer. Blacks can get skin cancers in burn scars, which may be again a chemiexcitation story; I don't know yet. In India or Pakistan, you can get skin cancers in the winter. They have a clay bowl full of hot charcoal or something and hold that close to the body to stay warm, and this leads to skin cancers. And there are some viruses that will cause skin cancers. So that’s all real; it’s just that sunlight is the main cause, certainly in Caucasians. For the flat-earthy kinds of proposals, I can't think of anything.
Doug, for my last question, it’s a forward-looking question, and that is, you know, you’ve already discussed sort of broadly the top-line goals of skin cancer research, but I want to ask more pointedly about you personally. What are your goals for the remainder of your career? What is it that you specifically want to accomplish in your research agenda?
Ah! So another thoughtful question.
No problem! Take more time to think about the question. [Laughs]
Okay. So long-term goals. So mid-term goal… Well, aside from wrapping up… So the short-term is to finish up the chemiexcitation studies and…
And to read those textbooks!
Yeah! I would love to! It’s sort of like getting to learn physics again…
…and put it in some order. So the thing about physics is there’s an order that you can put things into. There are some fundamentals and you build up, and then other things come from that. Then maybe you can predict something from here, whereas in biology it’s much more of a hodgepodge. I think the way I’ve been able to get through the hodgepodge is the ability to see patterns in disorganized data. I can do that in biology, but I would much rather have it organized. [Chuckles] So it would be a real pleasure to go back and do the physical chemistry sort of stuff and try to then import that into the biology and the chemiexcitation. That’s, in a way, what motivated the skin cancer studies, which is: okay, here is a tumor, but can you put some order here and tell me what the mechanism is, starting with a photon hitting DNA? What gene did it land in? What’s the function of that gene, like apoptosis ... and get some orderly mechanistic path. Now I was answering something. What was it?
That it would be a delight to look at the textbooks and relearn physics.
Oh yeah, yeah, right. Right, right. So that would be a delight to put all that in an organized pattern, and it would be even cooler if we could find some normal biology that required chemiexcitation, which is what the Brazilians were trying to do for 30 years and it never quite showed up. I have some ideas, but to go any further there I need to know more. The other… There are three or four thoughts. I’m trying to figure out which ones to bring down. Perhaps I should say that I think in parallel, and linearizing it in order to communicate is an extra step.
I want to wrap up the aging question by going back and doing the DNA damage and repair measurements across the genome, across species, and find out what parts of the genome are repaired differently in you and me compared to the mouse. What is it that Nature has figured out that it has to watch out for? That could well be causal. It’s unclear because evolution would have you tuning up everything to the same lifespan – there’s no sense building part of your car out of platinum if the rest of it’s made out of tin. So it may be that improving DNA repair just means you’ll have some other problem, but maybe not. Maybe we can buy some lifespan by controlling the repair process. And in any event, it annoys me that it’s left over from grad school and we weren't able to wrap that up.
Beyond that, if you ask what I’d like to get wrapped up it goes back to these cognition issues and why does physics look like it does? So to explain it in physics terms, you’d say, “Well, okay. Our brains hand us a basis vector set.” [holds up three fingers] My professor could always do this; I can't do it—you know, where you make three axes out of your fingers. Which fingers…? Anyway, you get the idea. And then the way you look at the world depends on how you resolve it along those three axes that your brain handed you. So what is that world view? It’s obviously not Hamiltonians; it’s something else, and in particular, getting back to understanding what time and space are. As I said, I think that’s a biological and a cognitive problem, so I continue to work on it. I think language is an intermediate, and I have some clues on how that works.
So you really have some truly fundamental work ahead of you.
Oh, that’s the goal – fundamental stuff. The epitome to me, the archetype, is Copernicus. The data was out there, but instead of looking at the data from here, you look at it from over here and now you say, “Aha!” If we say that the Earth goes around the sun, suddenly the same couple of facts explain a whole lot of other facts. I think the same point-of-view property holds for cognition and for any fundamental question. Otherwise it would have been solved already. That’s in a way a very physicist worldview that the biologists don't have, even though there are biologists trying to find fundamental principles. Although not by looking for new points of view, now that I think about it. One of the people looking for biophysical principles is at Princeton; I found it funny that you mentioned that they had issues with biophysics in the past. Have you interviewed Bialek at Princeton?
I don't know him, but he wrote a textbook – Biophysics: Searching for Principles. Did I send you the causality article I wrote?
Oh, I’ll have to check. I’ll have to check.
It finally came out, so at least I can send you the final version. BioEssays asked me to write an essay on causality. I had been thinking about the relationship between causality in physics and causality in biology. In biology, the strategy for testing the causal role of an object is knock it out or upregulate it. That has its limits, and the essay forced me to think about the implications. What do you do experimentally when you have hierarchies of levels and the causality can go both up and down, and you can also have feedback to earlier parts of the pathway?
So I wrote out the various oddities you find in biology that you don't often find in physics, but they are present in various places in physics. That’s really what thermodynamics was, dealing with hierarchies, but you only had two levels. There are other physical phenomena that I cite, but in biology the problem is ubiquitous.
Oh, and I mention at the end that if biologists really got serious about this… Well, one of my predictions is they would find quantized organisms that can't be in just any state. I mention a couple of biologists like Bialek as believing in principles, and that there are some biological principles out there. Kinetic proofreading is probably one. That’s something I would like to get back to, and then the question is how to do it in a way that’s just not sitting in your armchair and puffing out thoughts. So hopefully the mathematics and data-intensive biology get there.
Well, Doug, I said that was my last question, but I can't help myself now. [Chuckles]
I’m not in a hurry. Go ahead.
I wonder if to some degree skin cancer is… I don't want to say merely, but is it to some extent a vehicle for you to explore these much more fundamental questions that can be accessed in any number of ways?
Yes, for example biology provides much better examples of hierarchies and feedback than physics does. If I had it to do over again, developmental biology probably would have been a better way to do that and would tie more closely to those larger questions, but you know what you know when you know it. Pathology has more noise in it than development, and maybe I learned some useful lessons about noise. Hard to say.
Well, Doug, it’s been so much fun talking with you today. I really appreciate our time together.
Okay, great. Yeah, I enjoyed it, too. You're good at this. It was a pleasure talking to you.
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