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Interview of Wayne Hendrickson by David Zierler on April 13, 2020,
Niels Bohr Library & Archives, American Institute of Physics,
College Park, MD USA,
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In this interview, David Zierler, Oral Historian for AIP, interviews Wayne Hendrickson, Violin Family Professor of Physiology and Cellular Biophysics at Columbia University. Hendrickson recounts his childhood on a dairy farm in Wisconsin and explains how this environment fostered his interest in the natural world. He describes his undergraduate experience at the University of Wisconsin at River Falls, and his formative work at Argonne Lab where he studied Caesium-137 levels in beagle dogs. Hendrickson describes his intent to focus on biophysics in graduate school and his decision to accept at offer at Johns Hopkins, where he became interested in protein crystallography and electron microscopy. He discusses his dissertation research under the direction of Warner Love and the importance of the research conducted at Woods Hole which influences his work on studying hemoglobin in lampreys. Hendrickson describes the importance of computational biology and the promises this offered protein crystallography, and he explains the influence of Linus Pauling in advancing the field. He explains why he stayed on at Hopkins after his defense because he felt there was more work for him to complete on the Patterson function. Hendrickson discusses his work at the Naval Research Laboratory on parvalbumin molecules and his developing interests in anomalous scattering techniques. He discusses how the field matured and had gained broader acceptance, and he surmises how these trends led to recruitment efforts that led to his tenure at Columbia in the 1980s. Hendrickson explains the labyrinthine nature of his many appointments and affiliations at Columbia, and the opportunities he has had to teach and to mentor graduate students within an environment that is primarily research-focused. He discusses the improvement of technology over the course of his time at Columbia, and he discusses his work on beamlines at Howard Hughes and Brookhaven. Hendrickson describes his work as scientific director of the New York Structural Biology Center, and he explains how his research has moved closer toward clinical motivations in recent years. At the end of the interview, Hendrickson reflects on his long career in biophysics, and he draws on the story of HIV infectivity as an example of how the field can progress from a place of really not understanding basic biological problems, to developing effective therapies.
It is April 13th, 2020. This is David Zierler, oral historian for the American Institute of Physics. It’s my great pleasure to be here with Dr. Wayne Hendrickson. Dr. Hendrickson, thank you so much for being with me today.
It is a pleasure.
Let’s start right at the beginning. Tell me about your early childhood in Wisconsin.
Oh, that’s nice. I grew up on a farm in Wisconsin, a little town called Spring Valley. And my parents were the children of Norwegian immigrants, so I'm a first-generation, total Norwegian otherwise. Second generation, I should say. But anyway, they were dairy farmers, and so I grew up on a farm, and went to the local high school. My parents, not having had high school educations, didn't really know what that was much about, but they were very supportive and so on. And I had no idea what I would do exactly, but the principal of the high school, when I was a senior in high school, asked me, “Vell, Vayne, vhat vill you do?”—good Norwegian guy that he was, as well. And I said, “Well, you know, I'll probably help my dad on the farm.” I had taken agriculture and brought home a few tricks from the ag teacher. So we were—I was much into that. And he looks at me a little while and he says, “You vill go to college.”
And so I did that.
Now, did your parents inherit the farm from their parents, or this was a new enterprise on their part?
No, actually there were some little disputes of my dad with his mother. His father died when I was a baby—one year old or something like that. And he worked on his father’s farm for quite some time, but it didn't work out, and he then set out on his own. So it was a farm that he set up, bought, when I was, I think, two years old, three years old, something like that. So it’s the only place I know.
And growing up, did you actively help with the operations on the farm?
Oh, yes. Well, we did chores. Everybody—it was a very sexist operation. My sisters did the dishes, and we did the cows.
I was a family of seven. I mean, seven children. I'm the oldest of seven children.
Oldest of seven. Wow, OK. And did growing up on a farm, looking back, did that influence your curiosity about how the natural world works?
Yes, very much so. I spent a lot of time in the woods around our place. I had a little camera that I got. Now, you can do much better with any iPhone that you could possibly get. And it didn't have very good depth of field or depth of range. So I had a tripod that I built, and took pictures of birds in their nests and things like that. So, yeah, it really helped a lot. It sparked a curiosity in nature that never ended.
And this formative conversation you had in high school where it seems to have first dawned on you that college was in your future, did you demonstrate a particular aptitude for the sciences and perhaps math when you were growing up?
Well, yes. You know, it was a school—I was one of 54 graduates. And we had a math teacher, Fred Leach [?], who realized that I was not challenged by what they were doing, so he had me set aside. I had a little special class in algebra, for example. But as compared to my—I have a daughter who’s in 11th grade now, and she’s doing calculus beyond anything I did until I was well into college. We had no calculus. I had very limited exposure to much of anything. It was a pretty feeble education. I went to a local—University of Wisconsin at River Falls was then a River Falls State Teachers College, of which I think there were nine or something like that. I ended up doing things in student government, so I was very much involved with that whole thing for the state of Wisconsin when I was in college. But I went there thinking I would do two years of pre-engineering and then go on to the University of Wisconsin, [??] wonderful things in many fields, including engineering. But I was captivated essentially by the philosophy courses and other things, and went to—excuse me, I'm going to close the door here.
I think we're suffering from winds.
Anyway, I went through college and gained an interest in many things. My eyes were opened by many of these courses, and decided that I would do liberal arts rather than some engineering curriculum. And I guess just to go on that theme, then, the key event was after my sophomore year in college, what was I going to do that summer was at issue, and one of the options was a history program at the University of Oslo and another option was to go to Argonne National Laboratory, so the science direction. So it was a pivotal decision. Would I do something—?
That’s a true fork in the road, it sounds like.
Yeah, it was. It was a fork in the road, so I took it. [laugh] Anyway, I ended up going to Argonne, and so on. And then I did majors both in—so I was an eager beaver kind of student, and did a lot of courses, did well in them. And I had a double major of history—sorry; no history, although I had a lot of history. My double major was biology and physics. So with that simple amount [laugh] of understanding of things, I then applied to programs in biophysics, and that led me into graduate school in biophysics at Johns Hopkins.
So what was the opportunity at Argonne? How did that opportunity come your way?
I don’t really quite remember. I believe they had some kind of special program that they advertised for summer work from college kids. The program that I went into had to do with the biology department. This was post-war—Cold War, I should say, really. So Sputnik was happening sometime in there, and so on. So we measured Caesium-137 in natural abundance in beagle dogs. They had a colony of beagle dogs. And so that was my program. We built a device to do those measurements. So it was an interesting—it gave me an insight, although it wasn’t really the biochemistry and so on that I have come to do. You know, it was whole-body kinds of measurements and so forth. But one got to think about what was the biology of the system, using physical techniques to do that, and that’s sort of the theme that I have followed, is use elements of physics to study biology.
And so even as an undergraduate, you figured out to combine physics and biology to pursue these interests.
Yeah. I was very naïve. I didn't have any good idea what I was getting into, but I was interested in trying to understand, in a very fundamental way, aspects of life.
And did you think about going to graduate school directly after undergraduate, or were you thinking about taking some time off?
I never entertained taking time off. I went directly. I should overlay that at that point, we're in the middle of the Vietnam War, so taking time off was not a smart move. And I actually don’t remember—there was a draft, so you had a number. [laugh] Your liability to go to hunt down the Viet Cong or whatever you were supposed to be doing was serious. And so many of us went—so you might have read just recently, with Tony Fauci, he was one of the so-called “Yellow Beret” at NIH, and I had a friend that I went through college, through graduate school with, also went ultimately there.
Did you have a card, and did you know what your number was?
No, I don’t remember it. And I may have the timing wrong. It may not have been until I was in graduate school that that heated up.
Well, you will have entered graduate school what year? 1964?
1963, yeah. Right. So that’s still—I mean, it’s 1965—
It’s a little ahead.
Things are happening—
Well, you know, the most formative thing, when I was in graduate school, now that I'm getting my timing straight, was John Kennedy was shot, in November. I went into graduate school in September. And he was responsible for getting us into that mess, at some level, but it wasn’t heated up until another few years.
So I don’t have my timing right on that. I don’t think it was a factor. I wanted to go to school.
Were you specifically intent on biophysics programs?
That’s all I applied to, yes.
I know Hopkins had a developed biophysics program at that point. What were the other developed biophysics programs at that point?
Well, there was—I'm not quite sure. There might have been one at Yale, and a guy named Ernest Pollard—Ernie Pollard—had a program at Yale and then moved it to Penn State. So Penn State was an option. And I was accepted to a few. I think I was accepted to all the places I applied to, actually, but it was only a few. Well, that’s not quite true. I also—there was a biophysics program at the University of Cambridge and I applied there. It was headed up by Francis Crick. I didn't know who Francis Crick was. He won the Nobel Prize that year after I had made this application. He rejected me. [laugh] He said, “We seldom, if ever, take Americans.” This is on the heels of his having collaborated with an American.
Now, when you got to Hopkins, coming from a smaller school, I assume you had fellow students who were coming from bigger schools. I wonder how well prepared you felt relative to your colleagues in graduate school?
That’s a very good question and very apt. I came in—for my school, I was a super good student, so I felt pretty cocky, at some level. But I was taken down several pegs immediately, because my colleagues—there were only six of us altogether; I had five colleagues in my class, together with another four times that many or so total students in the program in biophysics, plus other students all through the place, and they were marvelous. Incredibly well prepared, well versed, not just in the sciences, but broadly speaking, in a way that I was not. So I had a lot of catch-up to do. Besides which, I wish I had a record of my speech at that time before I trained myself, basically. But, you know, my parents didn't know grammar. Their speech patterns were—and my whole community was not very educated. And the characteristics of the Midwest speaking pattern are also legendary, if you've seen some of these programs like—I can’t remember it now, but, you know, it’s a classic pattern. And I've sort of trained myself away from that. Still not very lucid, but so it goes.
[laugh] Now, was your understanding—I mean, biophysics by definition has a hybrid nature to it, and at different programs, there are different—is it fundamentally a physics program that has a biological component? Is it a biology program that has a physics program? How well meshed was the Hopkins program, and what was the background of most of the professors who taught in that department?
That’s a great question in the sense that it really does differentiate the programs. I don’t even know if I really did it so consciously, but the great thing about the Hopkins program, for me anyway, is that it was very broad. There were six professors. They each had a completely different take on things. Whereas, for example, the Ernest Pollard school was really on radiation biophysics. Again, fallout of the Cold War, and the concern about radionuclides and things like that. So radiation physics was high, and radiation biology—you know, the effect of radiation on biological systems was of great concern. And that’s a legitimate study, it’s an interesting study, and I've done a little dabbling in that, but it’s hardly biophysics. It’s certainly not what I like about what I'm doing now. And so the people that were in the program, one was a vision physiologist. Another was a muscle physiologist. Two people were neurobiologists. And then there was an electron microscopist and an X-ray crystallographer. And we each went through—it was different from the kind of programs that we now do in our graduate programs, having people do rotations in labs doing projects that are part of the research program of whichever professor you're doing the rotation in, so you find out what you're going to be doing. In that case, at Hopkins, we went through each of these six professors and did projects that were sort of cookie-cutter projects that had—all six of us did the same thing, or did the same kinds of assaysand learning the techniques of each of those fields. So it’s a very different way of doing things, but it gave you some idea. And I was very attracted to the crystallographic aspects of things. I might have been attracted to the electron microscopy in a way that wasn’t feasible, then. Because there, at that time, the electron microscopy was quite crude. It was state of the art for the time, but it wasn’t getting at molecular things as we now can do. But the crystallography had that possibility, and it could give definitive answers, so I was really taken by it.
Aha. So when you came in, you just knew very generally that you were interested in biophysics, but it was really the breadth of the program that gave you exposure to all of these different subfields that allowed you—
And so in terms of you gravitating towards the crystallography, was it a particular mentor? Was it methods? Was it theory? What was it about crystallography that attracted you?
The mentor was a guy named Warner Love, who died about two years ago. And [laugh] he was an interesting character, but he was not a super-achiever of the field, I would say. So it was the field. I liked the field, and he gave us good texts [?]. I should also add to it that after my first year, and thanks to Warner, because Warner would go in the summertimes to Woods Hole, the laboratory in Woods Hole, and he would take on a lab there and work there for the summer. And so he was big on the MBL, Marine Biological Laboratory. And they have summer courses at the Lab, one of which is called the physiology course. It goes on today and is still a highly sought and ambitious program, and that was true then. And there, there were another, I don’t know, six or eight people that were doing projects for the physiology students. Lectures as well, but you did projects in the lab. And they were diverse, and again, a little bit like the Hopkins program—many different things. And not just simple biophysics; there was molecular biology as well and physiological things as well, biochemistry. So it gave you a big exposure. And that was also very formative for me, because I got exposure to another cache of really eminent scientists.
Such as who? Who else was there?
So there’s a guy named Hans Krebs, who was a biochemist from England. I'm not quite sure which school now; I don’t remember. Who else? Bill Harrington from Hopkins’ biology department was there. A guy, an immunologist from Penn, whose name I don’t remember. I can’t think of another one right now.
And what was the point at which you decided on a topic for your dissertation? How did that come about?
I was going to do crystallography and I was doing it in the laboratory of Warner Love. This was very early in biological crystallography, protein crystallography. He chose to work on lamprey hemoglobin. When I entered graduate school, there had been one protein molecule done by crystallography; that was sperm whale myoglobin by John Kendrew. While I was in school, Max Perutz published the structure of hemoglobin, David Phillips on lysozyme, and so on. So these things started falling out while I was in school. And the project that Warner was working on was the structure of this hemoglobin from lampreys. And so that was the project of the lab, and that was the option. I didn't consider trying to do something different from what my mentor was doing. So that’s what I did. And then while I was there, other people did other worm hemoglobins and other things as well, and I got a little bit involved in some of those. But this was my project.
Was the study on animals directed ultimately towards human health science research, or did it just follow in terms of it’s relevant towards animals, and the research would go wherever it went at that point?
At these early stages, what we were trying to do, and what everybody in the field was trying to do, is to understand protein molecules. Any protein molecule. We had no idea what any of them looked like. So it was any of these things would be good. It had to be a protein that you could get a hold of. Bear in mind, there’s no cloning yet. We don’t know how to make proteins ourselves. We can only take what we can find. And blood is easy to get from anything, right? Or, in principle. Some animals might be harder to bleed than others [laugh], I suppose, and the lamprey—so that’s another story. The lampreys are—you have to get them when they're around, but Warner was big on that, and he got the lampreys at Woods Hole. So that’s another story. He had a stock of—he had a supply of lamprey blood, so that was not a problem. We could purify the protein. And then ultimately, we had to get more blood. So then at some point, I went with him in April to Woods Hole to get lampreys. But in my year, the lampreys weren’t running, so we didn't have much of that. So I spent my time in the library.
Now on the spectrum from experimentalist to theorist, where did you see yourself in this work?
That’s a very interesting question. It’s certainly a question in physics. My colleagues in physics, or students in physics—and I've had some physics students in my time—come into the program, and they're segregated into theorists and experimentalists at an early stage. That’s not so much the case in biophysics. Most people are experimentalists in the field. And the people who are theoreticians—and we didn't have any of that at Hopkins, people doing calculations. I should say, at that time, computers were new. So the computer that Warner Love had gotten a hold of was called the LGP-30. It was a computer that had a magnetic drum with 4,096 words of memory in that drum. They were coded in binary codes that we used in 16-character letters, words, namely hexadecimal is the term for it. And we programmed this computer in the language that was—the manual that I had for programming was written by John von Neumann.
It was a paper of John von Neumann which laid out that if you used these 16 particular instructions, you could carry out machine-directed computation. And that was to be coded in this hexadecimal language. It’s really a binary coding of it. But memory is very limited, so there’s a lot of back and forth. But the point is, there wasn’t any computational biology, really. So that is a development that happened later. I might have drifted to that, but it wasn’t really an option. If you're going to do theory, you would be doing some kind of mathematical formulation. And I did get into that. And I had a colleague—I was fascinated by it. I have a colleague, Ed Lattman—I don’t know if you're interviewing Ed. That would be another great subject matter, I would say. But he and I were—he was one year ahead of me in class, and he was also in Warner’s lab, and we worked on some theoretical things. But he started out—and that’s also instrumental in my own life—we had, at that time, there was a lot of excitement about work that—which was totally theoretical, by Jerome Karle and Herbert Hauptman, what we call direct methods, the scheme by which you can use relationships among the diffracted X-rays to find out what the phases are. Which is our big problem—the phase problem. And I was fascinated by that. I had to solve it for my lamprey hemoglobin problem, et cetera. And so I really got involved with that. But there was a manual that these guys had written—Hauptman and Karle—“Solution of the Phase Problem,” I think it was called. And Ed went through this and gave lectures to the rest of us in the lab about the mathematics behind—trying to interpret the mathematics that they had in this paper. So that was an introduction to mathematics. Ed was way better as a mathematician than I. And so then when I ended up doing my first real paper, I engaged Ed, and we wrote that paper together.
Now, your use of the computer at this time—given its relative lack of memory and power, was it more of a novelty because it was available to you, or did it really improve your research in a way that would not have been possible had the technology not been available?
Yes. So it was instrumental and crucial to everything that we did. Other things that were happening were using other kinds of computers. There was, say, an IBM computer that had been developed sort of while I was in school, and it ended up being something that we did some things on. But the thing about this LGP-30 was that it made out the program to run the diffractometer. And one of the things that Warner had done was to develop a system for measuring our diffraction patterns that was recording the diffraction with an electronic counter rather than photographic film. And the people in Europe largely used the photographic film and developed that and did densitometry of the film. But Warner was a little ahead of his time, this way, and did these measurements with the diffractometer measuring one reflection at a time, and the dictation of how this diffractor machine would be operated to go from one point to the other point was controlled by a punch paper tape that was made by the computer. So it would make these punch paper tapes. Our error reading thing was to make two copies and look up and see that the holes were in the same places [laugh] and so on. It was very primitive, but it worked, and it led us to that. And then the output was on punch paper tapes as well. So then we could take directly the measurements and begin to do calculations on them. So we developed—I wrote a whole system of programs to do my thesis, actually, on this machine. And, well, others before me had done some of these things, but I did a lot of stuff as well.
It sounds like your research really had a very happy and fortuitous convergence between these two emerging technologies—computational biology and crystallography.
My question on the crystallography part is, was it already demonstrated that crystallography was going to be a way to better understand proteins than other methods? Or was that a theoretical proposition at that point, and your research was part of that transition to actually demonstrate that that was in fact the case?
No, I think it had been demonstrated already. The work from John Kendrew and sort of simultaneously [??] resolution by Max Perutz on hemoglobin, but the myoglobin one was at adequate resolution by the time—now I'm not remembering. Is that right? Anyway, I don’t remember the timing now, actually, but the structure of myoglobin, I believe by the time I started, was already at two-angstrom resolution or something, where you could see where the atoms are. So we knew a lot already. That was the only one that was anything like atomic level. But it was already apparent that this was the way to do it. If you really wanted to understand where the atoms are in the molecule, you had to do it with crystallography. And that was known from small-molecule things. And I've done some reviews of all of the early work in X-ray diffraction from Lawrence Bragg, onward. And so it was completely known to everybody that you needed a tool that could see specifically where the atoms were, if you really wanted to understand the atomic structures of molecules. And without that kind of depth of understanding, maybe you could do some of that by modeling at some point, but this is way ahead of the possibility to do serious modeling. You couldn't do that without, first of all, having a better basis, as we learned it, from crystallography of biological—of protein molecules, largely, and DNA as well. And of course the DNA structure, which happened a little ahead of me, was a model based on Rosalind Franklin’s diffraction patterns, essentially. But it was an atomic model based on the principles from Linus Pauling. And so the real thread of this is from Pauling, driving to understand in atomic detail what was going on. That really motivated everybody a lot. And the structure of DNA fulfilled that. It gave a detailed model that had a lot of relevance to a lot of biology. So it was a great motivational tool, and it said, “We need this for everything.” And when the structure of myoglobin came out—as contrasted with DNA, it’s complicated. DNA as a structure is very simple, and the principles are immediately evident. That’s not true with proteins in general, and that was already apparent from—there was nothing very regular about—there were all these helices, but they were at all skewed angles, and it was inscrutable. So we knew that we needed a lot of information about a lot of different proteins. And it was pretty clear that this was the tool to do it. There was no glimmer that this was something we could do by electron microscopy at that time. We now know.
Because the resolutions—nobody had gotten anything like atomic-level detail from electron microscopy. Not even at that point—not even from minerals. And now we—subsequently, one could get atomic detail of minerals, and it became clear later on that the big problem with electron microscopy is the radiation damage problem, and how we were going to overcome that became a big issue, and there are many thoughts on that. So that’s sort of another subject. But at the time, there wasn’t really any thought that we could do any—that there was any tool besides crystallography that could get us to atomic detail.
So on a technical note, I wonder if you can explain what is it about crystals that allow for this level of resolution for which no other technology can compete?
I think I can, a little bit. What crystals do wonderfully, and the physics of it is that the regular array of molecules within the crystal lattice means that when we have X-rays illuminating that edifice, we end up having the scattering go off coherently into specific directions dictated by the crystal lattice. And all of that—each of those diffracted points that’s going out is reflecting a coherent examination of that lattice. Even though the light comes in incoherently, each of the photons is illuminating the entire edifice, and what goes out is coherent in all directions, in each direction that’s specified by the lattice, the Bragg diffraction, and those Bragg spots are integrating from all of the lattice, and so it’s an enormous—and because of the principles of the diffraction, it’s amplifying as the square of the number of elements in that diffracting edifice. So it’s a very strong amplifier, and it selects [?] into the directions. And it turns out retrospectively that we didn't really appreciate at the time—it’s great, because you can just from the diffraction pattern orient the sample as well. So that has become very instrumental in using free electron lasers to do this. We can immediately get the orientation right. But the problem is that we now, in this, when we record the X-ray diffraction from that diffracted—that is diffracted from the crystal, we lose the information that has to do with the phases of that, and we only can record the amplitudes. And it means that in order—and what people have already known for a long time is that if you know both the phases and the amplitudes, that you can easily record from the diffraction pattern but not the phases, one can then, by Fourier synthesis, obtain an image of where the atoms are. So it’s a great amplifier, and that, I think, is a major secret of it. And it amplifies—the number of molecules in a crystal is huge. Trillions of atoms in each crystal that we examined.
So now, in the mid to late 1960s, you're literally operating on new frontiers. You're seeing things that have never been seen before. And I'm curious—what is the relationship between this work and theory? In other words, there are theoretical understandings for these molecular and atomic structures, but they're essentially unproven until there’s a means to actually observe them. So is your work—is it confirming theory? Is it overturning theory? Is it seeing things that have never been theorized before? What’s the basic relationship at this point between what you're actually seeing and the theoretical basis for what you would have expected to see, absent this technology?
I think the theory of X-ray diffraction and that part of things was in a pretty sound position. There wasn’t really any dispute about what was happening. The part that was pretty much a black box was, what are the foundational principles of how molecules are put together into biological macromolecules, into proteins? Which are, as I was trying to say, quite complicated in their structures. What are their underlying principles? And there wasn’t any good basis for saying what those underlying principles would be. We needed the empirical evidence from more examples. And I think, here again, Pauling was instrumental. What Pauling did was to do laborious studies of crystals, of individual amino acids and nucleotides and dipeptides and so on, and from that collected enough information that he had sound basis for understanding some of the fundamental principles of quantum mechanical understanding of how molecules are put together, of the chemistry. And then with that in hand, he could do something like build, in principle, the structure of DNA. He tried and failed. He didn't make it. But he did that for the proteins. He designed and figured out what an alpha helix was like and what a beta sheet was like, and those were the elements that we needed to find out about. But we didn't really get the confirmation of that until we did these three-dimensional structures based on X-ray crystallography. So it was not very—and in fact, I was fascinated by mathematics and theory in those days when I was in graduate school, so much so that that’s what I did for a postdoc, which we may come to. But it wasn’t a driver. We weren’t looking for the theoretical underlying principles. We were out to try to just get a picture of, “What is nature?” We were trying to understand, what are the characteristics of individual protein molecules? And as I was trying to say, when I started out, there was one. When I left graduate school, there were seven, one of which was mine, I think. I mean, I'm probably wrong at the numbers, but it was—what I do know is my structure of lamprey hemoglobin was number seven in the Protein Data Bank, which now numbers 150,000 or something. And so, you know, we didn't know anything to speak of. And when we went to conferences in those early days when I was in—this is after I'm into my postdoc. I went to one conference when I was in graduate school. I can say more about that in a little bit. But afterwards, I went to lots of international conferences, and they were incredibly fascinating, because there was just this flood of new information, completely new. And it didn't really happen until somewhat later that one tried to make sense of it. And I wasn’t in that so much as some other people, but trying to understand, what are the underlying elements and principles? And most of that was really very empirical, still. It’s not first principles, trying to understand and all that happens now. But at the time, it was more trying to get just a general picture of what is it that’s out there, and what are the relationships that we can try to say are guiding some of this. And even then, it was largely empirical. There’s a sort of handedness to a beta strand, an alpha helix and a beta strand, and a beta-alpha-beta thing. And it turns out they're right-handed. It isn’t somebody went through the principles like Pauling would have and said, “Here’s how it should happen.” It just was observed. “Here’s the rule.” And then you try to figure out, what’s the basis for this rule? So it could have been done the other way if somebody smart enough had jumped into it, probably, but it’s actually pretty subtle. It’s not so clear what would have been the guiding principle of it.
Now, given the fact that you were in discovery mode, you were finding out all of these new things that had never been seen before, I wonder, how removed were you from at least thinking about the potential clinical value of these discoveries down the line? Was that, like, a totally separate world, or was that something that was apparent to you sort of right from the beginning, at least as a proposition?
It really was remote for me. And part of that was that I came into it from a very basic—the whole department that I was in, even though it had a lot of biology, muscle physiology, vision physiology, neurobiology, and those things were there, and we also had people doing molecular biology—so the idea that there was a clinical aspect—and then of course the work was supported by the National Institutes of Health. So we were not unaware that there’s a clinical realm here, but we were far removed from the possibility of doing some kind of drug development. We now—we have—we use the X-ray structures and EM structures to design compounds that are going to be agents of efficacy for therapeutics. And that was not really feasible. We hadn’t come to that. We hadn’t come to doing compounds and so on. We were just getting the very first glimmers. And the idea of applications of it to medicine were very remote. I think it became—so Max Perutz wrote a wonderful book about this, or articles about this, and talked about how one could get these molecules to be useful. He asked me to come, with five or six people, to talk at his 80th birthday party about applications that were really directly related to medicine by that point. And so it became clear that this was going to be the driver of the future. But when I was in graduate school, that was not the case. I mean, really after the basic—as you put it, the discovery of what was the underlying characteristic of life.
So I'll test your memory. What was the title of your dissertation?
[laugh] That, I don’t remember. It was prosaic. It was something like, you know, “The Structure of Lamprey Hemoglobin” [laugh] or something like that. And it might have actually had something—we did do—one of the things I did when I was—in the thesis itself was about transitions that we—we were able to see that if we took a crystal of lamprey hemoglobin that I had made, that was made without—it’s called deoxyhemoglobin, so there’s no oxygen. It’s completely oxygen-free. We had to do careful things to keep oxygen away. And when you added oxygen—but we didn't use oxygen; we used carbon monoxide instead as a sort of surrogate to oxygen. Because oxygen does another thing—it oxidizes the hemoglobin, so it’s not so easy to deal with. Carbon monoxide goes to a stable new state. And we were able to make that transformation happen within the crystal and to examine it with a microspectrophotometer that another colleague had made, another one of my graduate student colleagues had made, to do spectra of the opsins within the eye, of a goldfish in that case. And that in general is the case, by the way. It wasn’t—we were out trying to use whatever biological system we could that would substitute for what we weren’t able to do. We couldn't do experiments on humans, for example, so we did them on goldfish or whatever. So that was also part of the—that’s another heritage from Woods Hole—do everything you can on sea urchins or whatever you can find, right? And my colleague, Eric Kandel, who worked on snails and did neurobiology of snails. So it was the theme of the day that we weren’t really immediately trying to do health research, but we did understand that if we didn't understand the basics of biology for simple things, we weren’t going to understand it for humans.
And what did you see as the primary contribution of your research? The field is so brand-new at this point. What is it that you felt you were contributing to all of these discoveries that you were part of and that were happening around you?
At the time, I had no illusions that understanding lamprey hemoglobin was going to be a wonderful thing to have. It was going to help me. So my main goal at that moment in time was really to—it was to develop the technology. So I was very focused on building up capabilities in X-ray crystallography that would make it feasible to do more of it. So it was trying to do it better. And that led me to try to find ways to—and sort of the central issue—you could make measurements more quickly or something like that. You could do calculations, in principle. But one thing that we had to overcome was to figure out how to solve this phase problem that proved to be vexing. So there were ways to do that, that the Cambridge people had done—Perutz and Kendrew—to use heavy atoms. And that’s what we did, in our case. But I didn't find it very satisfying, so I was always looking for another way to do that, and that led me to much of what I've done in my life, which is to work on trying to improve the methodology for X-ray crystallography. And much of it centered—we've done many other things; refinement and so on—but the central issue has been this solving of the phase problem. We knew even the idea of it, the thought of it, was the phase problem, as the title of the monograph that Ed Lattman annotated for us that was written by Hauptman and Karle. And that spurred me on to work on that as a postdoc.
Now, when you stayed on at Hopkins from 1968 to 1969, was that standard for Hopkins students in biophysics to stay on? Or was there more work specifically that you wanted to complete at Hopkins?
So I just stayed on to complete—basically, I wasn’t very satisfied with what I had accomplished that went into my thesis. And maybe that’s what’s happening today. I did my dissertation in four-plus years, four and a half years, or not even quite four and a half. Defended in January of 1968, having come in in September of 1963. And it was an incomplete story. I hadn’t solved my crystal structure. I only had all these kinds of experiments on crystals that I had, so I still had work to do. I needed—I was determined to solve that structure, which then I ultimately did in the next year and a half, about. And so that was the motivation to continue it. Was that typical or not typical? I don’t remember exactly. I think most people we'll have gone right from their dissertation on to a postdoc or something else. In fact, of the six people in my class, I think if I'm not quite—not mistaken—only two of us went on to other things in academics.
It’s interesting—you being unsatisfied with the dissertation—you don’t hear that normally. If the committee is happy, the student is happy. I'm curious the transition from in that year going from dissatisfied with where you were to being satisfied, was that an incremental process? Was there a eureka moment at some point where you said, “I've got it!” and this is where you wanted to land? How did that process play out, and what did it mean for you to be satisfied at the end of it?
First of all, the thesis was based on this one paper that had been accepted, or maybe already published—I can’t remember—in the Journal of Molecular Biology. And it was really about these transitions. And that probably is figured into the title of it, now that I think of it. But I was already well advanced on the goal of trying to solve the structure using these heavy atoms and so forth. And I'm not sure there was a Eureka moment. There were moments when, for example, I was able to interpret the Patterson function, as it’s called, and that’s part of my legacy, basically. Patterson was the teacher of Warner Love, and so I'm a grandson of Patterson, at that level. And Patterson was trained by William H. Bragg, for example. So there’s a line that way. But anyway, I was well into that, and interpreting that Patterson function and finding out where those heavy atoms lay was crucial. So that’s a eureka moment within that little realm of crystallography for that particular problem. I had to solve that problem, and without that, I wouldn't be able to get on to the phase problem that I had to, quote, “conquer.” So that was a pivotal moment, I suppose. But I didn't see it as a eureka moment. At least I don’t think so. My point is that by the time we did the defense of the dissertation, which was all revolved around this paper that had been published. I was well advanced, and didn't put into the dissertation the work that was toward solving that structure. It was evident that it was there, and I certainly was determined to do it. And in fact, I completed some of the work that went into subsequent papers. The first paper was done with Warner before I left, or shortly after I left, perhaps. I don’t remember. But then there was another paper that we actually included Jerome Karle in the author list because I did a lot of that work while I was at the Naval Research Laboratory.
And how did that opportunity at the Naval Research Laboratory come up? What was the transition for that?
I think it’s a lot like the Argonne one that we talked about earlier. There was an announcement that they had a postdoctoral associates program or something, and I was of course interested in the work there. As I had mentioned, we had done—Ed and I had worked on it. And I had worked on the phase problem while I was—while I was at Woods Hole, in the summertime—in April, rather; not the summertime—in April of probably—I'm not quite sure. Maybe ’65 of ’66. No lampreys running, so I went to the library and studied these things and did a—was really a theoretical proposition within crystallography. No earth-shaking things, but we wrote this paper on a simplified representation of the phase probability distribution. So I was keen on that, and that led to some integrals that I wasn’t good enough to do, but Ed did. So we had this paper. And Warner, bless his heart, just let us publish this thing. So it’s Hendrickson and Lattman, and they're known as the Hendrickson-Lattman coefficients now. And Warner just said, “You guys did that, so publish it.” I'm very proud of that paper. That’s the first thing that I really did. But it gives you the background that I was keen on that problem, and I knew that Karle and Hauptman were the pivotal players in there. How it happened that I went to Karle, I can’t remember. We had something in the Washington area called the Crystal Colloquium. I think it still goes on. It meets once a month or something like that. I don’t remember. So we knew all of these people. We would go from Hopkins to these meetings in D.C. And so I knew Jerome already and made that tie-in and followed up on this opportunity to get funding to do the postdoc. Made the arrangement and pulled it off.
Now when you got to Naval Research Laboratory, was your research self-directed, or were you slotted in to ongoing projects there?
It was very self-directed. We discussed what I wanted to do. And what I wanted to do was to try to use the technology, the mathematical operations that these guys had developed. Something called the tangent formula seemed like the way to go. And I wanted to try to make that work for the protein molecules. They had developed that and implemented it for doing small molecule structures, many of them peptides or antibiotics or what have you. A lot of those experiments had been done by Isabella Karle, Jerome’s wife, who was a magician at doing it. She was wonderful at these small molecules. But I wanted to see if we could do that for these larger things, and so that’s what I set out to do. And it turned out that we did it by—the tests that we tried were by collaboration. It involved Bob Kretsinger from the University of Virginia, who was also part of this Washington-area crystallography network. And Bob actually was instrumental in setting up a whole thing on protein crystallography for that broad area, and we were involved in that as well as the Crystal Colloquium. That led me to Bob and to a structure that he did on a molecule called parvalbumin. So he had these data sets that he had available, and they weren’t—we thought we could improve them by using this tangent formula scheme. So I did a lot of calculations on that and did a lot of sort of theoretical thinking about it and so on. And a lot of the theoretical work was really just thinking about what is the implication from the calculations that Karle and Hauptman had done, or the theory that they had developed, and what was the implication of that. And basically, I was very disappointed in the applications that I made with Kretsinger’s parvalbumin problem, and so I thought it through and looked at all of the basis for it, and came to the conclusion that fundamentally, these relationships were just too weak. The power of them went down as the one over the square root of the—one over the square of the number of atoms. So if you go from a molecule that’s say, 10 or to 100 or to 10,000, which is a typical protein molecule, so it’s a big explosion from what they had been doing. And when you worked out what was the—how confining was the fundamental information from these relationships on the phases that I needed, it turns out to be way too weak individually. And it remains so. Things have improved a lot in time, but it’s still a fundamentally weak thing. So it’s not how we solve things. However, we can use—and we're delighted by these methods now, because you can solve very easily now the substructures for the heavier atoms that we put in. And for now, by now, the heavier atoms—this is stepping ahead years and years—but we now realize that we could find the sulfur atoms in the molecules quite handily if we could get enough of a signal from the anomalous scattering. That’s a big theme of my life is anomalous scattering. And those techniques that we developed along those lines made it possible to use the direct methods of Karle and Hauptman to find the positions of the sulfur atoms, and then find everything else. So it has come around to being extremely useful, but the way I was trying to do it was to use it directly to improve the phases. I didn't want to do it from scratch. I was just trying to do a simple thing—“can I improve these phases?” And it turned out that I didn't. It just didn't really work. But that led me into incessantly trying to find ways that would make it happen.
Now particularly for your first years as a postdoc at the Naval Research Laboratory, late ‘60s, early 1970s, it’s a particularly fraught time within the debates about the military and the uses of science. I'm curious if your work brushed up at all on those debates or any of those tensions, or were you so specialized or focused on your own research area that you really weren’t involved or even possibly aware of those debates that were going on at that point?
Well, no, we were aware of things along those lines, and largely, we were in our little shell, I guess, of science. But remember, I'm at the Naval Research Laboratory, after all, and I had to go through this gate every morning, and then on the weekends, I’d be protesting on the mall, the Vietnam War.
Yes. So, you know, it was a complicated time. How did I maintain sanity in that environment? It largely came from the actual mission of the Naval Research Laboratory, which is not about shooting down the Viet Cong; it’s about being prepared. You have got to remember that the Naval Research Laboratory was developed in the middle of World War II, when we realized that we were flat-footed. We had no idea how to cope. So we invented radar, for example, in those periods. The Naval Research Laboratory was instrumental in that. And they recruited Jerome Karle and Isabella Karle to that environment. Why in the world did they do that? It wasn’t to solve some military problem; it was simply that the government had decided that in order to avoid being caught flat-footed again, we had to have a broad capability within the military establishment to understand science fundamentally. So they just supported the Karles incredibly well, considering that they had no application mission – ever. Nothing they ever did was really directly implementable in any military setting. It was amazing! And there I was, in the middle of this incredibly arcane, basic thing, embedded in the U.S. Navy. It’s baffling. I don’t know why I didn't go nuts with it, but it—what my touchstone was is that we did need, and I believed in that—I believed that we needed to be prepared for the next Hitler. So I was OK. I was mentally OK with what I was doing. And I think it was morally acceptable, what I was doing.
Given how broadly conceived this idea of understanding science as something that’s important for national defense, that would suggest to me that the Naval Research Laboratory would be supporting all kinds of research. So did you feel like this was a place that was extremely diverse in the kinds of experiments that were going on? Or was there a sort of natural focus on a particular branch of research or science?
That’s a good point. It’s not the place—and in fact, this is a confusion for many people when I say I was at the Naval Research Laboratory, because they immediately—the people that I know in biology immediately think it’s the Naval Research Hospital. I don’t remember the exact name, but it’s right across from NIH. Because that would be the logical thing. But the Naval Research Laboratory, number one, is really a physics-oriented laboratory, not biological at all. So there’s no biology, or, minimal biology going on. So that was a huge sacrifice that I made going there that I didn't realize I was doing at the time. And it’s because I was so focused on this very basic question of the phase problem, a sort of out-there kind of question. It doesn't really—it’s hard to explain. You know, how do you even explain that to your mother? So it had this physics mission. And certainly there was a lot of work going on at the—I don’t mean to say the whole thing was very fundamental, and it just scattered. They had lots of programs that were very mission-oriented, of course, so people were working on things. The Karles were in this sort of ivory tower at the Naval Research Laboratory. I don’t quite know how they—ultimately, Jerome wins a Nobel Prize. That’s actually immediately after I leave, 1965. Or 1975. But while they were there, they were also treated very royally, I think. And so we were in kind of a special situation, not having this sort of mission-oriented kind of [??]. So it’s very physics. But that was to my detriment, also, because there was no biology, and very little support for anything—I didn't have the tools to do anything—I could do—I was boundless in computing and things like that, but when it came to doing my research or doing what I would like to be doing, not only was I not able to do sort of state-of-the-art techniques, I didn't hear about things. So I ultimately—between Hopkins and when I went to Columbia – was 15 years in total, and during that period of time, the entirety of recombinant DNA technology evolved. So when I went back to Columbia, I had to learn all that. I knew a bit of it from reading the journals, but if you don’t listen to lectures from people on these cutting-edge things, you kind of miss it. I didn't—maybe it’s just because I'm not well-enough read, but I didn't really understand what was going on, except in very broad brushes, and so I had to relearn all of that. And when I came back to a lab at Columbia, then we're in a whole new regime. Instead of having to decide, “Where can I get an animal that I can get enough material to grow a crystal from?” which was where I had been—and I was, you know, getting blood from various sea animals and stuff like that. But we're in a new regime—or we would grind up muscles, or something like that, and get protein out of that. But then we came to the case that we could make anything we wanted, using recombinant DNA tools that evolved in that period of time. It was really incredible. It was a very big burst of [??]. And we now use those routinely, of course, and we can do anything. It’s amazing.
I'm fascinated by this idea that on the weekends, you're protesting at the mall, as a postdoc. Did you feel like you were leading a dual life? Were you open about your political views at work? Did you feel like you were leading two separate lives?
Oh, no, there’s no problem. We had lunch every day in this penthouse of this barracks-like building that we were in. And the Karles were as rabid anti-war people as I was. They just wouldn't be on the mall. [laugh]
[laugh] And that was never a problem in terms of—?
See, I'm very comfortable—they were in a very special situation. And probably there were a lot of other—I'm guessing; I don’t really know—but I'm guessing there were a lot of other people at the Naval Research Laboratory who were opposed to the Vietnam War. It was a very common thing among intellectuals of any stripe, I think, at that time. I'm sure there were conservatives there who were in step with the military concepts, but not us.
And how did this transform from a postdoc into what would ultimately be a pretty long stretch of your career at the Naval Research Laboratory? Do they have an equivalent of like a tenure track, or how did that work?
It’s not a tenure track at all. It’s just a job. So what happened is that after two—the postdoc was only a two-year span, which is a fairly short time for a postdoc. I had done reasonably well. I had done a lot of things. But they weren’t—no breakthrough kind of problem. And it was all pretty esoteric. As I said, our goal is trying to improve the methods, and this, that, and the other. We had done—we made some—I did a problem that I—it’s called hemerythrin, myohemerythrin. I struck up a collaboration with somebody who made these molecules from worm muscles. And we got a crystal structure of that, and it was published in Nature, I guess it was? Yeah, I think. Anyway, it was a nice publication. And so I did have some things to talk about. But the bottom line is, I didn't get a job. I applied to various things that were open. I didn't get jobs. I had made a bad career choice. I mean, so my colleagues at the time, both at Hopkins and many other places, the standard thing was that when you finished in this general area of protein crystallography, you went off to the Laboratory of Molecular Biology in Cambridge, England, and worked with Max Perutz or somebody else there. One of my colleagues from Hopkins went to work with Aaron Klug, and many other people worked with others there. And these people all did very well. And when they finished their postdoc, they would come back and describe their work in a little parade around the country and take their pick of whichever job was at Berkeley or at Yale or at Caltech or wherever. I hadn’t been blessed properly, I think, was part of it. Maybe it’s sour grapes, but I also hadn’t accomplished—because I had done this sort of off-the-wall kind of approach to things, I didn't have a big showy piece to show at the end of the day. Or showy enough.
So when you transition to full-time, are you a civilian employee of the Navy?
And when you said you get to Columbia in 1984 and you're sort of reemerging from the wilderness, I'm curious—were you unable to participate in conferences? Why exactly were you so cut off from academia?
Well, I was in conferences, yeah. I was a strong participant in meetings. I went to a lot of meetings, and became known as a consequence of that, within the circle. But if you're going to get a job at Berkeley or something like that, you have to be sort of mainstream, and this was a little bit off the mainstream, I think. Anyway, it worked out, and what worked out is that I ended up having a few people come to work with me, and that was very good. And the other thing is that we developed and became known for what I had set out to do—technology developments for this field. So we did some problems, some applications, but the main thing is that we—so for example, we developed—with another colleague there, John Connert [?], we developed a program for the refinement of the X-ray structures. And that had been another area like the phase problem that was clearly something that was needed. It worked extremely well for the small-molecule things that people were doing, but those techniques were just simply not, as normally practiced, applicable to these large-scale problems that we were facing. And of course the problems we have now are orders of magnitude bigger than that, but they were really big problems for the day. Big computational problems that took a lot of computer power that really didn't exist at that moment, et cetera. So we developed this program that more than—it wasn’t really about the computer power. It was really about coping with the fact that the molecules don’t diffract well enough to define the atoms very precisely in and of themselves. So we used the information that we had gained from other crystal structures of protein molecules to say, “Here’s what the characteristics—” We actually mostly used—went back to Pauling, actually, to get the atomic positions of individual elements and worked out what would be the applicable way to define the confines of bond distances and angles and other geometrical parameters of the molecules in the course of the refinement. And we called this restrained least squares refinement. And our program was the first to be really used very effectively along these lines, so it had a big reach. It has been supplanted by other things. In fact, the code has been implemented in other programs that now have other names than our name. But I'm very proud of that achievement. I think we did a lot for the field with that. And it gave me a little—gave me a name within the field, a little bit, so that helped.
Now working at the Naval Research Laboratory, I wonder if you could talk about the budgetary environment. Were you writing grants? How well were you supported in terms of the equipment that you needed, in terms of the equipment that they were able to give you? How did all of that work?
First of all, I was largely immune of it, because I didn't—I did ultimately, while I was there, get an NIH grant, and they [laugh]—they took the attitude that they didn't really—it would be like an insult or something—I'm not quite sure, but we couldn't get people supported on this NIH grant. You know, that’s the main reason we have NIH grants [laugh] is to support the people in the lab, but I couldn't support people on this thing. The Naval Research Laboratory decided they wouldn't accept money from NIH to do this. So ultimately I was able to transfer that grant to Columbia, and then I could add people and increase the budget and so on. But it was peculiar that way. So apart from my efforts of that sort to try to improve it—you know, and I was doing it so that I could hire people, then they refused to let me do that, and that of course motivated me to leave, ultimately, in part. It wasn’t that I went seeking a position. Columbia and several other places tried to recruit me. So it was the pull rather than the push, in a way, that led me to move. But I was in this cocoon that basically the Lab, called the Laboratory for the Structure of Matter, that Karle had established, was well funded, and supported all the people that were in the lab. And so I don’t know exactly how this was done, to be honest with you, but Jerome must have said to them, “I want to add Hendrickson to my cadre, and here’s what it would cost.” And so he convinced them that they should do it. And I was immune. I didn't have to do anything. So my salary support was there as a consequence of this position. And the supplies and so forth were pretty meagre. And I actually don’t remember—I didn't have an individual budget. I was within this family. And I was isolated from or protected against these pressures. We sometimes had to make pitches for it, and we would try occasionally to get other kinds of money. The Office of Naval Research had certain funds that we could apply to. But many of these organizations, unlike NIH—which I have my own problems with peer review but [laugh]—I mean, I don’t have a problem with peer review; I had problems with making it through peer review many times, but the process is excellent. Investigator-initiated research, I think, is without a doubt the way to go, whereas the Office of Naval Research, and much of the DOE as well, dictates programs and then you can apply to that program if they've decided that’s what they would like to do. The idea of investigator initiation is limited in many areas, and it was then. So we would make things and then they would say, “OK, well can’t you do something to prop up the work of Investigator X? Work on his problem, because we think he’s really great. We think he’s going to win a Nobel Prize, so you should work on that. So that you can prove that I was right in supporting him in the first place” [laugh] is kind of the theme of it. It’s really a dumb way to do things, I think.
If you could compare your prospects from the early 1970s, when you had trouble finding academic work, to the early 1980s, when you were being recruited by clearly top programs, what accounted for that transition? Was it your own research? Was it where the field was headed? Was it luck and timing? How did you make sense of experiencing this transition of your prospects from the ‘70s to the ‘80s?
I think there was an expansion during that time. It was an expansive moment for science, so that was part of it. I had gotten some visibility for the work that we were doing, even though it was still very methodology-oriented as opposed to breakthrough kind of applications, which I think we've done subsequently. But I hadn’t really done anything that was—there was one problem that was again more methodological than anything else, but the structure of crambin that we did, which was published in 1981, I think. And it was again a sort of—it’s using the anomalous scattering. It’s sort of the strongest proof of the impact of anomalous scattering, so it was really methodological, but it had an impact. So I guess it’s fair to say that the only things that I had done that were of any note of serious matter were methodological. So it took institutions who said, “OK, we think crystallography is great. We should support the things that are going to improve crystallography, and Hendrickson’s doing good work, so we'll offer him a job, or we'll at least entertain his—we'll try to get him here to talk about it.” And the bet was that I would end up doing something useful as well, perhaps, I guess. So I think that all developed. So I got some exposure. I was seen as being at the vanguard of the methodology things, if not other things. And that was good enough. [laugh]
And can you explain just the structure at Columbia? So the appointment is—so first of all, you're hired in 1984 as a full professor, so you basically leapfrog the whole tenure process. Is that right?
That’s really right. And that’s—[laugh]—it’s amusing, because I didn't realize that, you know, they don’t just hire you. They also write out to people and find out [laugh] whether you're any good and so on. I didn't even know that was happening. I was talking to them, and I thought they were just making the decision, and that was it. It was completely—I was blind to the idea that they were getting things. Subsequently, I've had people leak information about what some of the letters had said. Like one of the letters was from a very prominent crystallographer of the day, and it said nothing about Hendrickson; it just said something about the guy that was on the comparison list, and then was just blasted. [laugh]
[laugh] I wonder if you could shed some light—it seems—you know, if you look at the appointment, it’s a bit confusing. So your appointment is in the Columbia University College of Physicians and Surgeons, and your professorship is you're a professor of biochemistry and molecular biophysics. So obviously at Columbia, there’s a department of biology. There’s a department of chemistry. There’s a department of physics. Where are all of these departments in relation to your appointment, and more broadly with relation to the College of Physicians and Surgeons? How does all of that work?
Well, I'm glad you asked, because I don’t know the answer completely.
I can tell you this. There is a College of Arts and Sciences, in which the basic science departments exist, and those basic science departments would include physics, chemistry, the simple ones, biological sciences as it’s called on the main campus of Columbia University, and, as well, the basic sciences in the medical school, which includes biochemistry, physiology. Many of these have gotten new names, but the classic ones are—I think there are six of them. It’s biochemistry, pharmacology, physiology, pathology, genetics. Maybe it’s called genetics. They all have other names now like Genetics and Development, Biochemistry and Molecular Biophysics. That happened because somebody came in and wanted to add biophysics. It was going to be biochemistry and biophysics. And then the physiology department said, “Well, we do biophysics.” So then that became Physiology and Cellular Biophysics. So anyway, so these basic science departments, pre-clinical they're sometimes called in medical schools, are also part of the Arts and Sciences, and the people that are in our laboratories are people in Arts and Sciences. So their PhDs are equivalent to the PhDs in physics programs, and so on, and certainly equivalent to—easily parallel to the biological sciences one. But there are all these at the medical school. And the medical school campus is within the College of Physicians and Surgeons at some level. And at what level, I don’t really know. But the Department of Medicine and the Department of Anesthesiology and so on, these are medical departments, clinical departments, that are part of the College of Physicians and Surgeons. And we answer—in terms of the finances, our budgets are within the College of Physicians and Surgeons, so the dean I answer to is the dean of the College of Physicians and Surgeons, and vice president of something or another. I don’t know the whole thing about it. But he’s in charge of all these clinical departments as well as the basic science departments within the medical school. So it’s a little of a dual hat in that the money is handled by the medical school aspect of things, and the educational aspect of it is all within the regular Arts and Sciences. Now, I don’t know that my—I have no idea, actually—formally, my position is within the—is as an Arts and Sciences professor, but I guess the money is supplied by the Dean of Medicine. The Dean of the College of Physicians and Surgeons. It’s confusing, and I don’t know—we don’t worry about it much.
[laugh] As long as the funding is there, that’s all that matters. [laugh]
Now in terms of when Columbia was recruiting you, what did you understand as the larger message of what Columbia was trying to build up at that point?
Well, that one’s pretty easy. Shortly before I was recruited—I don’t remember now exactly how much, but just a couple of years or so—the Department of Biochemistry had recruited a new chair. The man who came, he came from UCSF. His name was Isadore Adelman. And he decided to make an improvement on the department, which had gone downhill. So Adelman came in and decided that he would revamp the department and give it a much —one of the thrusts that he wanted to focus on was what we now call structural biology. It wasn’t then called that. In fact, I think Aaron Klug and I had a role in making it structural biology. But he set about doing this, and by the time that I came onto the scene, had recruited I think two or three junior people into positions in crystallography and life sciences. And they proposed that I should be recruited. He then recruited a couple of others. They ultimately didn't retain the junior people. It was kind of a sad story, but perhaps good. But we ended up having a real strength, and that has—we built on that at Columbia. We have a very strong component of structural biology including crystallography but many other aspects.
And if you compare the program and your particular research focus at Columbia, are there comparable programs elsewhere in the country? Or is what Columbia has built and what you have built, is it a truly unique focus and lab at Columbia?
I think we were in the vanguard. We did expansion of this kind of work maybe ahead of some others. But there are many other schools that have programs that are comparably broad now. I think we're still in the middle of things. We're strong. But we're not [??] by any means, no. I think I won’t get into a comparison right now, but there are [??]. I don’t think we're unique or special.
How do you divide your time between teaching undergraduate and graduate classes, and in terms of taking on new graduate students, and doing your own research? If you can give a basic understanding of how you divide your time and your responsibilities at Columbia? My question is how—and you could answer this sort of more globally, all the way from 1984 to now—basically how you divide your time between undergraduate teaching and graduate teaching. How you divide your time as a mentor between undergraduates, graduates, and postdocs, and how much of it is you just focused on your own work as an individual. If you could just sort of give a sense of your overall division of labors and resources at Columbia?
So the way it is—and this is a consequence of the medical school, and I'm not really particularly happy about it, because I think it could be improved—I have nothing to do with the undergraduates, basically. We occasionally have undergraduates in the lab, but we're on another campus, which is four or five miles away from the main campus, so it’s not a typical thing in any case. In any case, I haven't had very much to do with undergraduate education. But I've had quite a lot of graduate students and quite a lot of postdocs who have been in the laboratory. And those activities—so there’s graduate education, so I do teach courses in graduate education. At the moment, there’s a course that I teach alone, which is a little atypical. I teach a course, X-ray Diffraction, every other year that I do alone. Typically, that’s not just Columbia. There are people from all over the city that come to this. So the graduate students and the postdocs are mainly research activities. They are all doing research projects, and I'm heavily involved with their individual projects. I do teach a little bit, a little less now than I used to, actually. I used to teach more in the graduate program. The direct classroom teaching has never been a very large fraction of my time, but it is a serious part of it and remains so. But the main thrust in terms of education is the training programs in the graduate school and postdoctoral associates. So that’s mainly what I do there. It becomes an extension of your own research.
I wonder if you could talk a little bit about your style as a mentor, the way that you work with graduate students, the way that you encourage them to pursue, or as it were, perhaps not pursue particular projects, the kind of career advice that you give. Just talk a little bit about your style and philosophy as a mentor.
I have—and it’s in some ways, a failing of my approach to research—we do [??] projects, and it started out this way when I came to—it was that way before, but I started out that way at Columbia that I made alliances with many of my colleagues to do projects that were collaborative, with the idea that each of these would be a test bed for the technology that I was trying to develop. And I have become very involved in most of those projects and try to understand what is being discovered with respect to the basics of biology and hopefully applications, because we do a certain amount of medically-directed work as well. But what’s characteristic is that they're diverse. It’s not working on one thing as an experimental system, but typically have several things going at the same time. And my philosophy has been with respect to students that they should have their own projects, so that I try to have each of the people very focused on one particular project. And that’s still true today. And that’s in distinction with some other laboratories that I know, where the lab works on some problem, and everybody works on that problem. So it becomes kind of a confusion and a mess, to my taste, with respect to the educational program of the individual students. I really would like them—so I'm a little bit hands-off that way, and probably not as directive as would be useful to them, I suppose. But that’s sort of—if there’s a philosophy—I'm not sure I have a philosophy, but if there is a philosophy, it’s that people are going to need to be trained in a way that gives them a certain amount of self-reliance and independence of their own, ultimately. And I try to have them focused on a particular problem. So I have several things going on in parallel, and it does happen that people work together on problems. And I've forged those marriages in some cases, often times to my regret, as I don’t always make the right choices in how they get credit, and so on. It’s cleaner, of course, if they're working independently. And so there are a lot of papers that I—there are quite a few papers that I have that are just two authors, the student and me. There are quite a lot of other papers where there are a number of other authors. But usually that’s because we have collaborations with a bunch of other people, and it’s not a bunch of authors from my own lab, usually. Certainly there are cases like that.
The general lack of interaction with undergraduates over the course of your career at Columbia, in what ways is that beneficial, and what ways is that a detriment to your work?
We're not paid nine months of the year or something like that, as happens in the people in the main campus, in the physics department, for example. So you're paid to teach, basically. And that means that you're obliged to teach, and that means that you put a lot of effort into the teaching program. And being at the medical school and not having that—even though we have teaching, there’s no premium on teaching. We do it mainly because we think it’s good for the department to have these courses and so forth. I think it’s really self-motivated. We don’t get any benefits from it, particularly. But it is the case that people that are in the chemistry department or physics department and have these pretty heavy course loads, and I'm sure you have TAs to help you with it and all that, but you know, when you're facing classes of 500 and you have to—it’s a lot of work, and some of it’s—it’s very lovely to learn how to teach basic courses, right? You learn a lot when you do that. And I've learned a lot from teaching in general, even though they are graduate courses. But it is a relief not to have all that much effort, particularly for the junior faculty. And I missed all of that, of course. I didn't have any—I came in as a full professor, so I missed it for that reason as well. But I missed it because I wasn’t in the physics program or chemistry program. So you can do more things.
Do you see the overall trajectory of your research focus—did it change when you transferred from the Naval Research Laboratory to Columbia, or have you more or less been on the same fundamental track really ever since Hopkins to the present day? How do you see that narrative in terms of what you've been working on?
So what hasn’t changed is that I still maintain a strong devotion to technology development, but it has gone to a smaller and smaller fraction as time has gone on, and I've become more and more engaged in the projects that we are developing. So I'm becoming much more conventional as a biophysical scientist in the sense that I'm now working on research projects that are related to the molecule and not the method in a large measure. But I guess to my mind is a little exceptional and I think has been not the best choice of my life, but I have maintained strong efforts in several projects. It might have been wiser to have focused attention on a few of them rather than several. So that hasn’t changed. But my devotion to the science that I'm working on, on the individual projects, as opposed to the techniques by which we can answer questions, is a big change, a big shift. And that happened because it was feasible to do it that way. I really had no choice but to work on methods when I was at the Naval Research Laboratory. That’s what I went there for, so it’s not really a complaint, but I really didn't have the resources to do other things, nor the personnel. Moving to Columbia has been wonderful, because I have a lot of really good people. I have a lot of really great collaborators. Apart from the people in my own—in Jerry Karle’s operation—I really had no other comradeship in biology at the Naval Research Laboratory. It was just simply not a focus of the place. And so it has been a complete revolution as far as my career is concerned, to be at Columbia.
Your involvement over all of these years in the technology—I wonder if you can talk a little bit about—how does that play out? Do you work with engineers, or do you work with companies that produce the instrumentation to get you what you need? How do these instruments come about and what is your role in that?
So no, I haven't worked with any companies on them. We work with companies, but hire them in, basically. We haven't really collaborated that way. So the technology that I've had to do when it comes into instrumentation has largely been in synchrotron radiation. And so we've built synchrotron beamlines and that happened because I needed capabilities that didn't exist in conventional sources that we were using. I had ideas on having to do with, again, anomalous scattering and the way we do those experiments that then became fruitful when I was asked to join the Howard Hughes Medical Institute, I think it was 1986. And as a consequence of that, I suggested that what would be great is if we could parlay that into building a synchrotron beamline at Brookhaven National Laboratory. And they agreed to that program, and so that led me into embarking on that aspect of things. So we built up a team at Brookhaven, employed by the Howard Hughes Medical Institute at the team, and we built a beamline to do the experiments that I wanted to do. And that became a very successful venture. Then ultimately Howard Hughes decided to discontinue support of that. It has been taken over by their structural biology center. And then the Department of Energy decided to build a new synchrotron at Brookhaven, which meant that the old one would be closed down, and we decided to build a new beamline there, which we are now operating. Well, not today, because it’s all closed down, but—
How do you integrate your work—from Columbia, Howard Hughes, Brookhaven—is it all part of one seamless whole, or do you tend to stovepipe your projects based on institution?
All of the research projects, or almost all of the research projects, are done at Columbia, and the people there make use of the facilities at Brookhaven, and also at the New York Structural Biology Center. We haven't talked much about that, but I have a job there as the director of research. And I'm there one day a week, and we have another project there that is supported by NIH at NYSBC on memory protein work. And we have a team of people from Columbia that oversee some of that, but the people that are employed by this grant are all at the New York Structural Biology Center, and in some ways they're an extension of my scientific family, but in a way that part is really distinct, and they're doing research projects that we tap into, but they're not the research—it’s not my laboratory’s research, per se. It’s another technology development kind of aspect, really. But there are several of us at Columbia that are engaged in that, so that’s a big thing. And then there’s the overall project at the New York Structural Biology Center, which allows—and that’s why—the synchrotron fits into that. We also have very large-scale resources in NMR spectroscopy and also in electron microscopy.
That is something that I wanted to get to. You’re named scientific director in 2010. What were the circumstances that led to that appointment?
Well, I knew that I was being discontinued by the Howard Hughes Medical Institute, so I was seeking—I was happy to do this. I didn't seek the job; they came after me to do it, and I took it. They had changed the way they were organizing the facility and wanted a new director of research. And I agreed to do it in part because it gave me another source of funding that I was going to be losing from the Howard Hughes Medical Institute. So that was sort of the motivation to do it. And I like doing it, and I think it’s a very strong resource. It’s an important extension for us at Columbia to have the New York Structural Biology Center. And it has evolved into a really major program that’s very important.
And infrastructurally, the New York Structural Biology Center, is it attached to a larger institution, or it’s a self-contained organization?
It’s self-contained. It’s a consortium of nine institutions in New York City, including Columbia, and including CUNY, the City University of New York, which is on—and it is situated on the campus of City College, which itself is a venerable institution. And there we have this facility that includes NMR and electron microscopy as well as some other research laboratories that we have. And then we have this out-station at Brookhaven as well. So it includes all of the major scientific institutions in New York, and everybody pitches in, gets advantages from this equipment, as well as the [??].
I want to transfer a little bit now to sort of broader questions that sort of tie together the whole of your career. And I want to return to this very interesting comment you made about—you know, in the late 1960s, when—you were explaining how crystallography was able to basically image things at resolution that was unachievable before. And so my question is, fast forwarding to the present day, has crystallography maintained that capacity vis-à-vis other technologies? Is it still ahead of the pack in the way that it was in the late 1960s in terms of the things that you can see at a given resolution?
It is not light years ahead of every other technique now, and other techniques have come in the meantime. So NMR spectroscopy became capable to do measurements that could be interpreted in terms of atomic structure. That’s largely due to the work of Kurt Wüthrich. And so that became very useful technology and was competitive in some regions with crystallography. But ultimately it has faded away as not being really truly competitive. What has really become highly competitive right today, as of five years ago, is cryo-electron microscopy. And we and many of my colleagues also do electron microscopy. And the ACA, the American Crystallographic Association, has welcomed the cryoEM people into the fold as practitioners of science that is able to do atomic-level analyses. And the thing that was the breakthrough for EM was the development of new detectors that allow one to get rid of some [??] that was happening due to damage that happens from the electron beams. And it has been marvelous. I mean, we are really able to do some things that we couldn't have done. Now that said, and I have talked about this at various meetings and so forth, there are things that are clearly now better done by EM, I think, than there are by X-rays. There are things that are better done by X-rays than by EM. And there are some things that are sort of competitive between the two. Where things are certainly better done by X-rays is when one has a relatively small molecule. By relatively small, I mean 50,000 Daltons. So that’s not small, but it is very difficult to do those kinds of problems, if at all achievable, by cryo-electron microscopy, A. B, if you want—if you do do them—and it has gotten better and better, and will continue to get better, but it will reach a limit, I think, that will be not as good in resolution as is achievable in the best of cases by X-ray crystallography. So X-ray crystallography I think is going to remain the on-parallel leader with respect to high resolution imaging an [??] very advantageous for certain kinds of systems, is one thing. And the second thing is that when it comes to using structure as a way to develop molecules that could be therapeutically interesting, crystallography has the possibility for higher throughput, trying to examine many different possible compounds, as happens when doing structure-based drug development, for example, in companies. It’s very common. And they do crystallography a lot, and do many, many crystal structures as a consequence. And to do that many things by EM would be difficult because there would be a need to use so much EM time that it becomes more or less impractical. And the information that one gets from it is often times not as decisive as you would really like to do the chemistry. To get the chemistry right, you really need to be at pretty high resolution. So in favorable cases, anyway, the crystallography is a better bet for that.
The other question that I want to ask—comparing your examples as a graduate student to today is—when you were saying as a graduate student that you were pretty aloof from thinking about the clinical or therapeutic value of your research, to what extent has that changed for you? Not just for your field, but you personally. Are you more involved in those questions, in particular with your appointment at Columbia? Do you see where or are you motivated by how the research that you do does have or could have potential to advance health science research generally?
Yeah. So we're definitely motivated by the implications for health, and the problems that we work on are problems that are in the mainstream. This really came to focus for me 20 years ago or so, when we worked on the structure—this is a little bit reminiscent of today, because when I moved to New York from Washington, D.C. was about the same time that AIDS had struck. I so remember—I was moved, because I would read the obituary lists, and, “So-and-so, 42 years old.” “So-and-so, 38 years old.” And it’s very sobering. And we worked on the structure of a molecule called CD4, which is the site of the binding of the HIV virus, which had been worked out by my colleague Richard Axel. And we did a collaboration on this, and we solved the structure of CD4 and published it, and it received some attention. It was on the front page of The New York Times. And I get a call from some guy who says, “I see in your structure that there’s this phenylalanine that is sticking out, and that makes me think that maybe aspartame”—which is a sweetener, artificial sweetener that has aspartic acid—and phenylalanine—will have that phenylalanine—maybe that would actually bind and block the entry of the virus. And I said, “Wow.” [laugh] You know? Here’s—"I guess your work has some relevance, Wayne.” But the problem is, the guy is impatient, right? And that was a characteristic of the ACT-UPkind of time of AIDS research. I mean, these people were desperate, and they felt—they didn't have the luxury of the—they had the luxury, in a way, that the current people under attack by this COVID virus—they had time to think about what was going on, and they did think, and they came trying to diagnose what would—trying to figure out ways to help. So actually that then—this is a long-winded story, but maybe this is, you know, important, what you try to contribute to that. And I ultimately concluded—maybe it’s just out of laziness; I don’t know—but I really concluded that that would be a misdirection. That I really don’t think I have the right background to do the medical application work, and that it would be smarter of me to continue to do work that was very basic and to contribute—even to continue diverse projects to hope that some of them—and I still think that’s true, and I think the projects that—I'm working on papers right now on molecules called Hsp70s that are protective against neurodegenerative diseases. I think this could be an incredibly important thing, also, but it’s probably going to be for others to see how you can make a difference in the clinic. So we think about it all the time.
When you decide to take on a new project—so there’s always limitations of time and resources and things like that, and obviously all of those things are very valuable. What are the factors that go into your decision-making when you commit to a new project? What are the things that make you say, “I'm going to work on this, and I'm not going to work on that”? Do you have basic parameters that you apply to new possible endeavors?
Not really, I guess. Not in a very thoughtful way. Increasingly—so resources are a major factor, so if we don’t have the resources for it, we can’t take on a new project very well. So that’s a major factor. Can we get support for it? And I have less support now than I had when I was supported by the Howard Hughes Medical Institute, so I don’t have the luxury of sort of having a kitty to do whatever thing I might want to do. But it’s still the case that I'm pretty much buffeted by the winds of the day, I guess, and I choose things according to what I think are the—what’s interesting about it. Is it a project that fits some of the themes that I have? And my themes are fairly broad, but there are a few themes, and so I try to keep within that, and within the capabilities of the expertise that we have. So those are major factors. And I haven't made any new choices in the last two years or so, so we're working on more or less the same problems but different—they're similar problems. So we work on membrane proteins, ion channels largely, and we have a few of those kinds of problems going on, and I've added—for example, I'm supported on a new problem that has to do with ion channels. We're writing a paper on it right now. But it’s another ion channel. We've done other ion channels. And it’s one that I've known about for a while. It’s a new project. And so we do do new projects, but they're usually related thematically to something that we've been working on.
I want to ask you—throughout your career, you have been recognized by your peers and by scientific organizations with many awards and honors. And I'm curious, what among them stand out for you personally and professionally? In other words, were there awards that gave you sort of personal satisfaction, and are there awards that stick out that really helped advance your career either in terms of opening doors with new colleagues or funding prospects? Or do you see those things as one and the same in terms of the personal satisfaction and the professional recognition?
Yeah, I can’t think of—maybe I'm just blind to it, but I don’t see anything about awards and—I haven't had so many awards, but I don’t see that the awards have really advanced my life. I don’t believe they've opened doors or something like that, so much. I suppose in terms of the award—a very meaningful recognition is to become a member of the National Academy of Sciences, and I appreciate that, and that happened some time ago, so it was a—it’s wonderful that it happens when you have a lot of career ahead of you. But the one that was really fun for me was the recognition from the American Crystallographic Association as the first recipient of the Patterson Award. So there was double connection, you know? I felt really proud that I was, in some ways, a scientific descendent of Patterson. So it was recognizing the things that we had done on this crambin structure with anomalous scattering [??] sulfur [??] so I was very proud of that achievement. And that was sort of an early recognition as well, and it was from my fellows at the ACA, so that was fun, too. So that was, I suppose, very meaningful to me.
That gets me to my next question, which is because you have your hand in so many different disciplines, do you see yourself as fundamentally x? Are you fundamentally a physicist, a biophysicist, a biologist, a chemist, a crystallographer? If you had to limit yourself to sort of one moniker or title, what would it be? At the end of the day, what are you?
I would say biophysicist, and I think that would be the closest to come to it. I don’t really see myself truly as a physicist. Yeah, biophysicist I think is as good as I can get. Although I will say that in many cases I do—when introduced to somebody in a more social setting, I will say I'm a biochemist, in part because I'm in a biochemistry department, or classically biochemistry department. It has now got a biophysics element in it. Another browning out. And I think it’s more accessible to people to say biochemist than biophysicist perhaps, but maybe that’s not even true.
And in what fields do you see your research having the largest impact or the greatest contribution? Does that naturally align with how you see your own work? Do you see the greatest contributions in the field of biophysics, or how do you view that?
Yeah, I guess I would say that. It’s true. I would like to think that ultimately—and I am a great believer that medical advances that are really important usually have their foundation in some very fundamental work— to health research even if it’s not the direct bedside applications of what we do today, but that what we do today may well have a very important impact into the future. And I think it is through medicine that I would hope that our work will have its greatest overall impact. So biophysics isn’t a discipline that has that kind of impact per se , but it is one of the foundations that can be very fundamental to developments in that kind of direction, and it’s going to be there and not in materials research or something [laugh]. It’s not fundamental physics. We're not doing things in cosmology or what have you. But it’s [??] medicine [??].
Are there concepts or laws in science that you feel strong affinity to, that really shape the way you see the world, the way that you conduct your research, that are just stuck with you from your education, that remain relevant to you, day in and day out?
Hmm. Not really. I don’t think in such profound ways, I guess. I can’t help on that one. I'm sorry.
What about mysteries? The idea—things personally to you or in your field that were fundamentally mysterious to you at the beginning of your career, that through advances in your own research and in your field at large, you now have a much greater understanding of and are basically no longer mysterious?
Well, there are lots of things along that line. I've become educated throughout my life. I'll give you one example, which is as a consequence of the work that we did in developing the beamline—when we developed the beamline, we had a team of people that met with us every other month or something like that. We had physicists—real physicists. They were experts in X-ray optics, we call it, and so forth. And there are fundamentals in X-ray diffraction from perfect crystals that I actually had not understood. I had done a lot of reading and teaching, even, of X-ray diffraction, and I hadn’t really grasped it. So I didn't thereby really understand how the monochromators worked. And these guys educated me on it. And this is kind of a trivial example that I should of—it’s like a gap in my understanding. But it was eye-opening, and it really helped. And then years later—so that then pushed me to understand the fundamentals of diffraction from a crystal in a way that wasn’t necessary to understand X-ray diffraction for my biological applications but is necessary to understand it from the point of view of the technology that we need to make a monochromator out of a crystal. So I learned that. And then it came back because that forced me to understand the X-ray diffraction problem in a more fundamental way. And people then started to do these experiments a few years ago, 2009 I think is the paper, at using the free electron laser at Stanford. And the very first application was on a crystal that wasn’t even—it was just the very first use of this facility, and it was done on a very large protein molecule, photosystem 1 [?], and got X-ray diffraction that showed all of the little beats in between the diffraction maxima, which was just thrilling, to see the fundamentals of the physics laid out in front of you that way. And I don’t think I would have been able to even fully grasp that, had I not been pushed to do it in order to make the monochromator for our beamline. Anyway, you probably wanted a more profound example than that, but that’s—[laugh]
No, that’s what came to mind; that’s what came to mind. So that really is a question about your own personal education—things that were mysterious to you that you learned about. What about more broadly in terms of your field? Not just you, but your colleagues, your mentors—things that in the late 1960s simply were not understood by anybody, and now are understood.
Yeah, and I think this is relevant to the current day. We didn't understand HIV infections. It became a really imperative thing that we should understand it well enough to be able to control it. And we contributed in this area. A lot of other people did as well. And so there were a lot of mysteries about it that are less of a mystery now. The overall scheme of the idea of the virus coming in and being able to essentially hijack equipment from the host cell and to subvert the real activities of different molecules—in the case of HIV, the immune system molecules were subverted to the replication of the virus. And many of those principles of how viruses interact with hosts of various kinds—us, people—I think had been very mysterious. There were people ahead of me who under…got it in a way that I didn't. But I think the world as a whole didn't get it. And we of course don’t really get it with COVID-19, completely, but we are better prepared now to understand that. And as with HIV—this is a little off that particular topic, I guess, but with HIV, I think with structural biology, we contributed enormously. We learned how to inhibit the replication machinery, how to inhibit the protease and those—the combination of those leads us to be able to control it, from the work that we were doing that had to do with the entry of the virus in the first place. That’s one thing, and that’s another direction for [??]. But where I think we have a real leg up and which we've been working on since day one with the HIV problem—we did this coprotein [?] and the first structure we did of the virtual protein together with the CD4 molecule that I mentioned earlier gave us a hint of how to handle that. And Peter Kwong, who did that work with me, is now at the NIH in the Vaccine Research Center, and has developed whole procedures on being able to do drug development that will—I mean, to do vaccine development, to try to design a vaccine to control AIDS. An HIV-directed vaccine. And that hasn’t happened. HIV mutates very rapidly. The immune system response is complicated. We know in principle it can be done, but we don’t know how to elicit it right now. But what Peter and his colleagues did on that problem has worked. It worked with human respiratory—RSV—respiratory syncytial virus—and that work was done by a guy named Jason McLellan. And Jason McLellan has now got a job at the University of Texas Austin, and already, a month or two ago, he published the structure of the spi [?] protein, the trimer, of COVID—of I guess a SARS-Cov-2. And another colleague of mine, a couple of colleagues of mine at Columbia, are using it to develop—to find out where the antibodies bind that are elicited by patients from our hospital. It’s marvelous! And I just—somebody sent me a paper of the replication enzyme that is from SARS-Cov-2, together with a compound that is in clinical trials at Columbia and other places to control this virus. And these developments are happening pretty rapidly. We're talking about two months, an incredible—incredibly encouraging, I think, that we can attack problems of this magnitude that quickly. It’s not quickly enough, you know? I'm going to start crying, you know, because people are dying.
Yeah, yeah. Well, I think—I have a final question, and that’s looking to the future. And that is, what are the things that you're excited about, either personally, for your own work, or for your field? And you can think in terms of a timeline within your own lifetime, or where your field is headed for the next generation. What are the things that excite you or fill you with a sense of wonder and might make you proud of your contributions as a building block to where things are headed?
That’s a tough question. Some of it is—the first answer is to sort of carry on from what I was just saying about the prowess of our technology now having come to a state where we can actually imagine addressing really difficult problems. And no doubt there will be future problems of that kind, and I would hope we’d be better able to cope in a quick way, or that we can think ahead a little bit. It’s a little bit—I feel like we've been limited. We should have been able to cope with SARS-2 better than we are, given that there was—that it’s related to SARS. And did we not learn our lesson from that well enough, or couldn't we have been smart enough to have figured out that maybe we need a thrust on something like that problem to be prepared for another virus of that kind? And of course, now we're smart enough to know that coronaviruses are a real threat, and we'll probably be smarter about that for the future. But I would like to think that maybe we can become as a people foresightful enough to anticipate where these problems are going to be. But I'm also hugely pessimistic on that question, not on health issues but on environment issues. I just read a book on Greenland that is extremely sobering. I was telling my daughter, my high school daughter about this. And one of the things that is in that book is the threat of the ice caps melting, and Greenland melting, Antarctica melting, and that the people that are being born now in 2020 will be only 80 years old at 2100, and the estimates are that the seas will be a meter higher or more. And there are other estimates. And my daughter is completely convinced that her life is screwed by the environment. Completely screwed. That she is suffering in her lifetime because of climate change. And we have such Neanderthals in charge of things [laugh] that we throw out the possibility of coping with this. This has nothing to do with my research, per se, but it is I think overall a very disturbing phenomenon, that we have so much power to understand and cope with things, and we have so little ability to look forward and think through the consequences of actions that we have today.
But you're saying that’s a political problem. That’s not a sci…
That’s a political factor. On the question of climate change, I have no doubt that heroic things will happen to cope with the consequences. But it’s insane that we're not doing something meaningful now. Things that are within our capability to do today that are really essential to do before—like the ice cap melting is—it’s going to go critical. [laugh] And at that point, it’s going to be almost impossible to stop. But we can anticipate now what the likelihood is going to be. Just as we anti…some people anticipated with COVID-19 that it’s going to get bad. We have to do something now or it’s going to be seriously bad. So these are political decisions, but they have to be informed by science. And science is a crucial component of the whole societal picture. You asked big questions. The big questions, I think, are that science is a part of society, and has an important role.
And you as an individual scientist, where do you see your own role in these issues?
I think I can hope to contribute some to some of these directions, and we will try to do that. I have a guy in the lab who has worked on the X-ray beamlines, and in this period, he has invented an economical ventilator. It’s not implemented yet. He has built it, and it’s a prototype that can be implemented. So I think we have, all of us, an ability to do something that’s going to be impactful in the moment, and I think—I guess generally what I was trying to say earlier is that we all have a responsibility to be part of the solutions of the big picture questions also.
Well, Dr. Hendrickson, I want to thank you so much for your time. This has been an absolute delight and an honor to be with you, so I really appreciate it.
It has been fun! It’s too bad we weren’t together personally, but maybe we can do that, too.