Viruses From Structure to Biology

A Discussion with

Art Olson

Recorded and edited by
Sondra Schlesinger

January 5, 2001

SS Let's start by your telling me where you went to college and how you first got involved in science.

AO I'm from Detroit. I went to a very good public high school, Cass Technical High School. I had three years of chemistry there, was destined to go into chemistry and ended up at the University of Michigan as an undergraduate. That's where I actually got involved in crystallography. I was a physical chemistry major and did a senior project with Chris Nordman who was a crystallographer in the Chemistry Department. This was in 1967-68. He did mostly small molecules but he was also working on methods for protein structure. I did a senior thesis on a small molecule, it was an estrogen-type molecule. It was a potential drug and he made me do everything. This was all film work and we would estimate the intensities of the spots by eye on a scale of 0 to 10. You would estimate the spots and we had a little Marchant calculator where we did Fourier summations and actually I got a structure out. This was, of course, just an exercise. We did use computers, which at the time was an IBM 7090 at the University of Michigan Computing Center. The way you submitted a job was to take your stacks of punch cards, maybe two boxes which were the program and data. You would load the program in and would re-compile every time, presumably because there wasn't enough disc storage. Sometimes you would write out a compiled version on punch cards. This is a trudge through the snow story: I went from the Chemistry Department with a shopping cart filled with punch cards and submitted the punch cards and then would, hopefully, get a CalComp plot back at the end which was the electron density projection maps from which you would then identify atom positions. That was my undergraduate experience. This was in '68, I left Michigan and went into the Peace Corps.

SS Where did they send you?

AO I went to Ghana in West Africa and was a science teacher there. It was a great experience. It broadened my perceptions of the world and gave me an appreciation of the quality of life everywhere even in the poorest countries, as long as the people are nice - the Ghanians were very, very nice. But it also showed me the technological disparities. I didn't have electricity in my house, but I made a deal with a guy across the street who had a cold store and had a little generator because he was storing fish and so we ran lines and wired electricity into my house. I had a darkroom there. My motivation for getting electricity was to run my enlarger, everything else could have been done by kerosene lamp. When I returned from Ghana, I started graduate school.

SS When you went, did you know that you were going to go to graduate school?

AO I had applied to Berkeley and Cal Tech. I had never been to California but for some reason I knew that was where I wanted to be. Those were the only two schools I applied to. I was accepted to both and got deferred admission when I told them I was going into the Peace Corps. I decided I wanted to go to Berkeley.

SS Berkeley in the late '60's and '70's was a very different place.

AO I knew the difference between northern and southern California. At the time I was focused more on the culture of northern California and I don't regret the decision, going to Berkeley was great. I was in the Chemistry Graduate Program. Tom and Carol Cech were in my class. We all took quantum mechanics together from Bob Harris. I worked for David Templeton whose lab was at the Lawrence-Berkeley lab. He was a Professor in the Chemistry Department and focused on small molecule crystallography, worked mostly on the computational aspects with some experiments.

I got my Ph.D. in '75, and thatÕs when I was looking around, in '75-'76, for a postdoc. There was a fellow graduate student in the lab, Fran Jurnak, she's now a Professor at UC Irvine. She was a year ahead of me and went to Cambridge (MA) and worked in Alex Rich's lab at MIT. I kept in communication with her quite a bit during that year. She had also gone from a small molecule background to biological molecules. She was excited about some work that was going on there. Somehow, she had met Steve (Harrison), knew that he was looking for a postdoc and she told me about it. I'm trying to remember my first contact with Steve. I think I called him on the phone and talked to him. I had never met him, didn't know what he was like or how old he was. He sounded like he was interested and he said I could apply for a some fellowships, which I ended up doing. I applied for a Damon Runyon and got that. In the meantime, in order to do that, I had to read up on virus structure.

SS Let's step back a little bit because that was a big jump for you to go from small molecules to an unknown area.

AO It was an incredible jump in terms of crystallography. My whole thesis was about trying to model hydrogen electron density in crystal structures - in other words just improving the model for how you would find out exactly where the hydrogens were in a high resolution crystal structure. Then, I may have mentioned this to you, there were a series of lectures that were given at Berkeley and there were guest lectures given by Manfred Eigen and he had just published his work on self-organization in biological systems.

SS So you knew about RNA viruses. (Manfred Eigen used RNA bacteriophages as a model for his concepts on self-assembly.)

AO I considered myself a physical chemist and Eigen presented this stuff from a very physical chemical point of view in terms of reaction rates and catalytic hyper-cycles. I don't know what it was, but all of a sudden it linked what I was doing very strongly to biology. It was like physical chemistry and biology are on a continuum and structure is an important thing all the way through. Biology isn't just this "squishy stuff". It's actually atoms in space. I learned crystallography from small molecules, the size you can do by hand, write your own programs. Looking at something like a virus structure was the largest goal to which I could imagine applying some of this technology. Understanding the structural basis of self-organization is still largely a mystery. Nobody really understands all the details, but this was an opportunity, this was on the pathway to that kind of physical understanding.

SS Well at that time hemoglobin was hardly understood.

AO They're still writing papers about how hemoglobin works.

SS And also about hydrogen.

AO That's right. A crystal structure is an artifice; it's a monument, something that is produced that actually contains some relationship to the real world and it represents a landmark. At least it gives you the beginnings of understanding of how things might work.

SS Were you willing to take that jump from small molecules?

AO I was anxious to take that kind of jump. Frankly, after 5 years of work on hydrogen, I wanted to look at things in a broader scope. The other point is that IÕve always been a fan of geometry. When domes were big in the 60's, I read up on geodesics. I read the Casper and Klug paper on quasi-equivalence in the Cold Spring Harbor Symposium. They showed Bucky's (Buckminister Fuller) domes and this was a blending of two of my interests. When I was really young I thought I would become an architect. I liked math, I liked geometry, I liked structure and it turned out I was looking at architecture, but on a very different scale. Viruses are prototypic biological architecture. The Watson-Crick paper in '56 was about why is it that you have symmetry in viruses. It's a very biological answer: efficiency.

SS It's interesting to read that paper now because the efficiency seems so obvious and yet it was a landmark at the time.

AO Oh yes, definitely, in fact, I talked to Crick about it a couple of years ago when I was writing a paper about symmetry. I did a review on symmetry in biological molecules and, according to him, it was a radical idea at the time.

SS I think one needs to know that when you read it. It seems so logical but it wasn't obvious in 1956, when the paper was published (Nature 177, 474-475,1956). But we're now talking about 1976.

AO Yes, 1976 was when I actually went to Steve's lab. I left graduate school and took a few months off. That was the centennial year and I took off about 4 or 5 months and did some bicycling along the coast of California.

SS Were you by yourself then?

AO I was living in a house in North Oakland with a number of people most of whom are still good friends and that was kind of the origin of some of these trips. There were a couple of other trips and travels during that time. It was a nice kind of transition. I had arranged the postdoc with Steve to begin in September (1976). That was when the Damon Runyon was going to start. I actually finished and defended my thesis at the end of '75 and I had a little bit of time which was nice.

SS September '76 was after the Cold Spring Harbor meeting. Steve had the 5 and a half angstrom structure (of tomato bushy stunt virus).

AO It had already been reported. The paper had not yet come out.

SS There was a meeting in Italy, at Erice.

AO That's where Fran Jurnak met Steve. That was in '75 and I think that's where she first met him.

SS Steve said that was the first time anybody paid attention to him and thought that he was doing something serious and that there was some potential in what he was trying to do.

AO Yes. Steve had been publishing papers on TBSV at 25 angstroms and you couldn't say much except for the shape, right. So the 5 and a half angstrom structure was a breakthrough; it wasn't atomic resolution and that was certainly Steve's silver chalice, that was what he was after. Also Steve and Don (Wiley) were junior faculty members at the time. They were coming up for tenure appointments. TBSV at atomic resolution was key in Steve's mind, just as the hemagglutinin was in Don's. And they were both working very hard.

SS I was impressed that Harvard had enough foresight to give both of them tenure even though neither of them had quite gotten there yet.

AO But it was clear that it wasn't going to just die, in other words that the results were going to come out.

SS You arrived in '76 and what were your impressions?

AO I remember walking into the lab, this was Gibbs, a prototypical science lab from the turn of the 19-20th century. It was a very intimate setting, there were three floors and everybody would go up and down, and then there was a basement where Bill Lipscomb had - actually he had a Richards box down there. Jim Crawford was working on the aspartate transcarbamylase structure at the time and I think I told you the story about Doug Rees.

SS Yes, but tell it again.

AO First, I want to tell you my initial impression on walking into this lab because there is a bust of this guy, Gibbs, not the famous Gibbs but Oliver Woolcott Gibbs. There was a Kendrew model of, I believe, carboxypeptidase, that Lipscomb had done. Steve's lab was just to the left as you walked in. He had a 5 and a half angstrom map stacked, plexiglass sheets, hand contoured, very nicely done on a light box and the first thing he did was to show me his map. I can't remember if Schutt was there. Both Schutt and Fritz Winkler were in the lab at the time, but I don't think they were during the first few minutes and Steve showed me the map. I was used to looking at atomic resolution, high electron density precision maps and this thing was - just so much! It was the whole asymmetric unit and I couldn't make heads or tails out of it even after Steve started pointing features out: He said: "Here are the two helices at the 2-fold axes," and I'm thinking: "What this looks like is a spaghetti explosion". It was clear that not only did Steve see it, but other people, as well.

SS So it wasn't the "Emperor's new clothes"?

AO That was my introduction to the lab - to look at the 5 and a half angstrom map of TBSV.

SS You had not met Steve before?

AO No, I had not met him. I was curious as to what he looked like. In one of the Cold Spring Harbor Symposia they had an attendees photograph and I think I had misidentified him. He was younger than I had anticipated, he's not that much older than I am. I think his first postdoc was Tony Jack, so he hadn't had many postdocs by the time I arrived. You donÕt think about that at the time, at least I didn't, in terms of where he was in his career. I was more interested in the problem. I guess it was still pretty early. When I arrived at Steve's lab, he essentially had two other people in the lab. There was Schutt who was finishing up his Ph.D. and had worked on the 5 and a half angstrom structure and Fritz Winkler, who was a postdoc at the time. They had all worked on the 5 and a half angstrom structure and Schutt and Fritz had developed a number of computational methods that enabled the structure to be solved because of the reconstruction of partially recorded spots. The unit cell of TBSV was the largest one to be solved or attempted at the time and the spots were very close to each other and with these oscillation photographs of a half degree, a lot of the spots were only partially recorded.

They were both great guys and I really enjoyed talking with them and they both gave me both scientific and social grounding in the lab. But both of them were about to leave. There were other people around because there was Don Wiley's group. Judy (White) was in his lab at the time. She was Don's first graduate student. Ian (Wilson) hadn't arrived yet. Bill Lipscomb had a number of graduate students and among them were two first year graduate students, one was Doug Rees and the other was Paul Kuttner. They talked to me early on. They told me they had originally signed up to work with Steve, but Steve was going on a mini-sabbatical to the MRC (the Medical Research Council) in Cambridge, England and he had just hired a postdoc, Gerald Stubbs, who had come from Australia and since Gerald was going to be the only Ph.D, he was going to rule the roost as far as the graduate students were concerned and neither Doug or Paul were interested in that situation. It turned out that Gerald went over to Brandeis and worked with Don Casper on TMV fiber diffraction. I don't know the full history but Gerald came to work in Steve's lab and ended up working with Don (Caspar). When I came, they (Doug and Paul) were happy to see someone else there. Shortly after I arrived, Bill Lipscomb was awarded the Nobel prize. Doug and Paul had already moved over to his lab and were very happy that they had made the move before, as opposed to after the award, because of the appearance of intention.

When Lipscomb won the prize, he decided that he wanted to redecorate Gibbs and one of the things he did was to change the lighting from mostly soft incandescent to bright fluorescent. It was an intimate three story building and there were two landings. On each one of these landings there were these really nice blown glass globes covering the incandescent light bulbs. One day I came in and the workmen had taken them down and had put up fluorescent lights. I've been a fan of glass, a friend of mine is a glass artist, and I asked: "What did you do with those globes?" They said that they were about to toss them out. So I rescued them from a trash heap. There were two of them. Steve was away, he was at the MRC when this happened, and when he returned he asked: "What happened to those glass globes?". I said: "Steve, you're lucky, I saved them". He said: "I've had my eye on them ever since I came to Gibbs." And I said: "You can have one and I'll take one."

SS Do you still have it?

AO It's a sad story, a relatively recent one. The two globes looked the same, but they weren't. One was a hand blown piece and the other was a mold-blown piece, you could see the seam in it. Steve ended up with the molded one. The one that I had broke about two years ago. I should have given it to Steve. Just an interesting side story about Gibbs.

SS How long did you and Steve overlap before he went off to Cambridge?

AO Probably not more than a month because I don't think he was around when the Nobel Prize was announced in October.

SS Did you have a project that you could do without him?

AO Basically the 2.8 angstrom data collection had already begun. The X-ray machines were at Harvard and the computing was going on pretty much at Columbia (in New York). There was some preprocessing that was done at Harvard. We got the photographs, we had an Optronics scanner hooked to a DEC PDP20 so the first bit of processing was done on the PDP20. These minicomputers had just come in the past few years and they revolutionized crystallography. It had what was called DEC-tape and a paper tape reader on it and it was hooked up to the Optronics scanner which, I think, had 50 micron resolution. There was plenty for me to do at that point because we had to process all these films by hand. Basically my function when I got there was to process the films. I think the first time I ever made Steve happy was when I found a bug in the code for reconstructing the partial spots. You make these measurements and if you screw up the estimates of the partials, you aren't going to get a structure out at the end.

SS Was this a direction that was OK for you? Did you feel that this was what you had expected to do when you got there?

AO Crystallographers are by their nature accustomed to deferred gratification and I was no exception. I was willing to learn about the system and learn about the computing and do what was essentially rote work but you had to be very careful. A lot of science is just turning the crank in some sense to get the results. But then at the end, we would have a structure and that's what drives all crystallographers, I think. So I was happy doing it. I loved Cambridge. I had this great apartment that Schutt had left when he went to the MRC. He sublet it to me, furniture and all. It then went on through several generations before he ever reclaimed it because he stayed in England longer than he originally anticipated. It was a great time. I really enjoyed the environment and the people. And the kind of carrot - Steve would come back periodically and at one point he told me, I think it was at the end of February or March, that there was would be a workshop in Paris. By that time we should have processed all the films and would start in earnest on the structure solution. The whole point of this workshop was that Gerard Bricogne had developed phasing methods based on non-crystallographic symmetry and they seemed to be working, they worked for TMV structure, and we could apply them to tomato bushy stunt virus.

SS I didn't realize it was a workshop. I thought from what Steve said that it was a period of time when the computer was available.

AO No, it was actually a formalized workshop. I can't remember what it was called but basically it was about phasing using non-crystallographic symmetry and the application of that. It was a very computer intensive procedure and I don't know how the workshop evolved. The head of CECAM, Carl Moser, was an American expatriate who lived in Paris, he was a real Parisian. Somehow Steve and maybe a couple of other people persuaded him to organize this workshop. Their IBM 370 was much more powerful than what was available to us. We were using an IBM, probably a 360, but not a very big one, that was at Columbia University. The way we would submit jobs was that there was a little card reader in Malinkrodt in the Chemistry Computing Center there. These were just job control cards. By that time the executables were resident on the computer and we didn't have to read those in. The job control language was fed into processing jobs to get the data. You wouldn't have anticipated doing very large non-crystallographic symmetry phasing calculations on that machine. The one in Paris was much faster and there were a number of people at the workshop who had problems that required this kind of technology.

Roger Burnett was working on the hexon structure for adenovirus at the time, they were still working on the TMV structure at Cambridge, Michael (Rossmann) was working on SBMV and Bror Strandberg was working on satellite tobacco necrosis virus.

SS Steve was telling me not about the workshop, but using the computer to get data.

AO There were lectures and there was plenty of time to run calculations. Truthfully, most of the calculations that were done were probably focused on TBSV, although I know other people did calculations. There was a Dutch woman there who was working on lobster hemocyanin. I know Shoshona Wodak was there and Joel Janin was there, but I don't believe they had structural problems they were trying to solve. They were interested in the computational methods.

SS. This must have been way before you were beginning to think that you would be going in the direction of computers rather than in the direction of structure.

AO That's true. It was influential in some sense because the focus was on the computing and I have always been more focused from the technology point of view on the computing rather than on crystal growth end of crystallography.

SS Steve described being there one night when they were running the programs and could actually see that things were working. Were you there too?

AO Yes

SS Would you like to tell me your remembrances?

AO I'm trying to remember. Steve and Gerard spent very long nights there; they were essentially running these calculations. Steve was very hands on at that point. Gerard was the one who wrote the program. He knew the program. Steve knew what he wanted to do and Gerard knew how to do it using the code. So I wasn't there for all the nights but I do remember one night where the code actually worked and there was great excitement the next day. I was only aware of it the next day. I don't think I was there the night the code actually ran and gave believable results.

Everybody lived in different places. Gerard had a little garret-type apartment he was renting near the Bastille. Steve, Fritz (Winkler) and Roger were sharing an apartment. This was in the 14th arrondisement. I was staying very close to there, a couple of blocks away at Cite' Universitaire in a dorm. I spent a lot of time up at the Bastille with Gerard. We had a fun time together that summer and that's where we got chased by the gendarmes out of the Centre George Pompadieu, but that's another story.

I don't know whether Steve told you this story but actually after the phasing was done and the electron density map was calculated, we had to visualize the map. Maybe I'm wrong but my recollection is that they wrote the map out on magnetic tape and someone, I can't remember who, took it to the MRC. They had a plotter there. It was basically a minimap. Then that was sent back to Paris and it arrived at the apartment that was shared by Fritz, Steve and Roger. I believe Steve wasn't there at the time so Fritz took the map out and stacked it and started to put down little round stickers where the alpha carbons were in the structure and Steve came in and he was crestfallen. This was his "baby", and I think just this moment of being able to put the first marks on the map was kind of lost to him. Fritz was just as curious as any of us would be and he had worked so hard on this. It was a very interesting moment. The glory wasn't dissipated in any sense, it was just a personal moment. It had nothing to do with priority or anything because everybody that worked on the structure knew that Steve was the driving force on it; it was clearly his structure. It was one of these moments - all of a sudden you are going from some fuzzy image to something where you can actually trace the protein chain.

SS It must have been an incredible moment.

AO And you look at it and all of a sudden you see - It's not like everything comes at once, things kind of go in jumps. Every once in awhile you realize something else about the structure.

SS Is it because of the non-crystallographic symmetry that you didn't need the heavy atom derivatives?

AO Let's put it this way, the non-crystallographic symmetry allows you to extract more phase information from any single structure, but you still need some kind of phasing model to start out with and there were heavy atom derivatives for TBSV. But basically you have a lot of data to fit and so the non-crystallographic symmetry puts constraints on that fitting process and makes it more accurate and that was a major breakthrough for virus crystallography in particular because of the large amount of non-crystallographic symmetry. It's being used for lots of structures now that larger subunits are being solved. Yes, I think that was the major technical breakthrough that pushed it over so we could actually get a good three-dimensional atomic resolution structure. Gerard Bricogne is an amazing person and he is very, very focused and is very mathematical.

SS I've been thinking about writing him but it would be hard because we have wanted to emphasize the biological aspects, not the ones in which he is more expert. I have heard so many great things about him that I really feel he should be part of this.

AO We have had very interesting discussions over the years. I remember, I think it was at a Gordon Conference after the structure came out, maybe in the summer of '78, we were talking about computing and he posed the question: when would there be a mole of computing cycles - an Avogadro's number of computing cycles having being expended in the Universe? I mean Avogadro's number of 10 raised to the 23rd power is a very large number and I don't remember what our estimates were, but it turns out that about now is the answer.

SS Art, how involved were you in interpreting the structure from the biological standpoint? Steve made two points that he thought changed his thinking completely; one had to do with the arms in the protein and the other had to do with not being able to see any RNA. Before we talk more about the aspects that you followed, were you involved in any of those aspects?

AO At two levels. One of them was that I built the original model into the electron density map. This was using brass parts in a Richards box. I didn't know that much protein chemistry at the time. So we needed to build the model and I had to design the Richards box and have it constructed. It's not something you can order from a catalog. There were three different subunits, the A, B and C subunits, that were structurally different. In fact, the A and the B subunits were sufficiently similar that we didn't build both of them, but we knew that we had to build at least the C subunit and the A or B subunit. So I devised this docking station where you could bring in maps from one and bring in maps from the other and so forth.

SS It must have taken an incredible amount of time to do this.

AO It took a long time to actually build a model. We got back from the Paris Workshop and the first thing we had to do was to design the Richards box and find some undergraduates that would contour. Basically what we did was we printed out the electron density maps with numbers on computer printout and we would lay that down on a table, put a piece of acetate over it and then by hand with a magic marker draw contours around equal numbered values. That is how you create sections of the map and then you would mount those on thicker pieces of acetate and stack them up. So just getting the map computed, contoured, and up so that you could start to interpret them, it wasnÕt an insignificant amount of work and then building the model - these Kendrew models - was one bond at a time. At this point we weren't building the virus structure, we were only building a single subunit so we contoured the area of the subunit.

Before we went to Paris, I spent two weeks with Steve at the MRC. I was sitting with Tony Crowther and John Finch in their shared office and my job was essentially to determine from the five and one-half angstrom map, subunit boundaries which was one thing that you could do pretty well. So I was there with a compass and a ruler and defining circles because the way we were defining the boundary was by the overlay of circles on sections. Everything outside of that was solvent flattened.

SS I just wanted to emphasize here that you didn't have the sequence.

AO Right, we didn't know the sequence. Steve was much more astute than I was in terms of deciding what amino acid was appropriate at a given spot. He did a lot of tweaking after I built parts of the model to get the geometry more reasonable from a hydrogen bonding point of view. Back to the question about interpretation; one level of interpretation was invovled in building the map, and the other one was trying to understand the biology.

My background was not in biology, but there is one story and I don't think I ever told it to anybody. Once we got this structure out, I was working with a pen plotter just doing some diagrams of how things fit together. Steve had sketched out the original diagrams in the paper and then I had done it on the computer Š the subunits represented as trapezoidal shapes. One night I was at home and I was trying to work out a color scheme. We were focused mainly on the trimer, since the "interdigitated arms" were novel in terms of structure, so I colored in just the C subunits on this virus particle. At this point we already knew about the trimeric association at the three-fold axes, that these arms intertwine. We also knew that there was a very strong two-fold interaction across the helices that were apposed at the two-fold axis. After I colored this in, I saw what was essentially obvious, but if you are focused on the small piece you donÕt see it, that is that the C subunits alone formed a structural scaffold. In other words, because of the interactions at the three-fold and the two-fold, this made a T=1 particle from just the C subunits that could, in fact, be on the pathway to assembly. I was very excited by this because I hadn't thought about it before. The next day I took this colored drawing in and showed it to Steve. I don't know whether he had conceived of this scaffold independently before that, he had never mentioned it to me, but this was something I felt I had discovered independently about the structure. Obviously the interaction at the three-fold, the arm interactions, is a key concept because before that we had no idea of what may possibly pre-assemble and so that was very recent knowledge at that point and was key to this T=1 scaffold idea.

But to continue, this was the Fall, we had the electron density map and we were building the model and starting to interpret the model. I'm kind of fuzzy about the exact timing of these things. This was '77. I can't remember when we wrote the paper. It didn't come out until '78, but I always consider the structure to be in 1977 because that's when we got a good picture of it. Later I'll tell the story of where the structure actually resided. Steve had secured some space temporarily on the top floor of Mallinckrodt and that's where we built the Richards box and built both the C and the B subunit models.

SS It must have been a very exciting time. There are only a few times in science when you know you have a lot of work but you know you are okay.

AO Exactly. That's right, this is the deferred gratification that drives us, I guess. There were some other experiments going on at the time. Ian Robinson was a graduate student. You know if you add EDTA and raise the pH, the particle swells by about 10% and he was doing some small angle scattering experiments on the swollen particle at the time and all of a sudden you had this actual model. One thing we did do, I did it at least a couple of times, was to make a physical model of the subunit. Do you know what a Byron bender is? Byron Rubin is a crystallographer who devised this. You essentially feed in a stock of wire and dial the phi-psi angles of the backbone. If you are very careful and do it in strict order, you end up with a three-dimensional "tube" diagram of the backbone of the protein. I made one of those. Because the TBSV subunit has two domains and there is a hinge between them, I essentially made them as two separate parts and put them together with these little Kendrew couplers so that you could move one to the other so you can show the difference. There is a major rearrangement of the two domains between the C and the A and B subunits. That was one of the early 3-D graphics that I could actually take around and show to people.

SS Were you traveling around to give talks?

AO I went to the Gordon Conference in the summer of '78 and I also went back to Berkeley and gave a talk on the TBSV structure. It was before I actually moved back to Berkeley. That's where I went after I left Steve's lab. That was really kind of the beginning of my new career in graphics. Steve had purchased an Evans and Sutherland graphics system. This was after we had built the brass model, but you can't see anything with just a single model if you want to look at protein-protein interactions. What are the interactions at the quasi-three fold? This is where the transition for the swelling was taking place. There were all these questions about the interactions between protein subunits that you can't visualize with a single subunit which is all we had in the Richards box. It may be that Steve and Don together bought the Evans and Sutherland picture system and this would have been in late '77 or early '78 and I was like a kid in a candy store.

SS It's hard to remember back then but did you have enough experience in programming?

AO I've always been interested in graphics. I have an avocation in art and photography and I've always been interested in graphics. Back when I was an undergraduate at Michigan, using a CalComp pen plotter was a revelation to me. At the time we were using a program called ORTEP (Oak Ridge thermal ellipsoid plot) which is still used today. Carol Johnson at Oak Ridge developed it. Basically it depicts the atoms and it represents their temperature factors by plotting them as thermal ellipsoids. When I was a graduate student at Berkeley I used the plotters there all the time. There were some tektronics, what they called green flash screens, where you could plot a picture on a screen instead of on paper and, if you were really ambitious, you might even start to think about taking a picture of many, many plots and doing an animation of something like that. So these were the things that were rolling around in my head. Before I even got to Steve's lab, I was very, very interested in the possibilities of computer graphics.

SS Even before you went to Steve's lab and then when you were doing the Richards box, could you imagine that this could all be done by computer?

AO This was a very interesting transition period from the mid - to the late '70's, there were a lot of systems, so-called electronic Richards boxes, that were being developed. Bob Diamond at the MRC was developing Bilder (the German word for pictures); the group at the University of North Carolina was developing GRIP (graphical interaction with proteins), and Dave Barry at Washington University was developing what was called the MMS-X (molecular modeling system). All of these were using the vector graphic scopes. The vector graphics developed in research labs in the mid-to late '60's and by the early '70's there were probably two or three companies, Evans and Sutherland, Vector General, that were starting to sell commercial vector graphic systems for three-dimensional graphics. They were very expensive. At the time that I was building things in the Richards box, there were 3D computer graphics systems available at academic sites that you could visit and try to fit your molecules. That would have involved a lot. You would have practically had to live there for several months to do the building at that time. The programs weren't great by today's standards. You could actually get the work done, but it was questionable as to whether it was more or less work than building in the Richards box at the time. This was a transition time but just parenthetically I believe that the electronic Richards box ended up being a strong driving force for three dimensional vector graphics in science. It was really the first 3-D graphics that was used for production purposes, at least in molecular science.

SS Tell me about your transition.

AO I had written code to plot stuff when I was a graduate student and when I was an undergraduate. When Steve got the Evans and Sutherland, I read over the instruction manual. I was more interested in trying to get the molecule up on the screen and rotating it around. There were some demo programs that came with the Evans and Sutherland and one was called Architecture. It was written by a guy named Mickey Mantle, (no relation to the baseball player). It had geometric objects that you could build into scenes and then you could manipulate the scenes. Basically it was a little 3-D viewer and the objects that he had were buildings and other architectural elements. You could manipulate them independently to place them in the scene and then you could navigate around the scene. I figured that all I had to do was to replace these building with molecules; all I had to do was to take a look at the formats he was using to get his data in. The first thing that I did was to use the geometric co-ordinates of the protein subunits instead of the coordinates of some architectural elements.

SS That must have required writing fairly sophisticated programs.

AO Basically it required taking apart the existing program. I did learn a fair amount about the 3-D graphics methods that existed at that point which is mostly called display list architecture. I didn't spend months programming. The interesting thing was that probably within a week or so of getting the machine up and running, I had a picture of the individual subunit and then I could bring in more subunits so we could see the structure and its interactions with the other subunits in the virus.

SS Did you find it better to look two-dimensionally on the screen? Which did you find more useful?

AO We could not look at multiple subunits with the physical model. We couldn't look at relationships between the subunits in the assembled structure. It's clear that if you were looking very closely and you were sure that the model was accurate and it hadn't sagged or anything like that, looking at a physical model is very compelling. That's one of the reasons I'm very interested in exploring physical models now because I think it uses more perceptual apparatus than just the sight and interpretation of the 2-D, even a moving 2-D image. But from the point of view of being able to understand the relationships of multiple proteins in the architecture of the virus, we couldn't have done it in a Richards box.

SS I think what I am imagining is you didn't even know how to think about it because no one had ever done it before. It's like looking at something no one has ever looked at before. Is it a revelation or do you have to learn how to look?

AO I think the human brain is very good at interpreting relationships. Conceptually, there is no difference between looking at relationships of structures in a single molecule in a Richards box or between multiple molecules on a computer screen. The physical and psychological processes are very similar, just that this has enabled us to build structures and examine structures that we couldn't do very easily from the physical point of view. There weren't any perceptional surprises, but there were revelations about the orientations of the N-terminal subunits and how the arms folded over one and another that you could see. We had plotted them out as stereo images before we got the Evans and Sutherland, but moving them around and showing relationships dynamically is very instructive.

SS So you didn't have to be very clever to understand this was the wave of the future.

AO It seemed pretty obvious to me. I remember staying up all night trying to make a video of what I was getting on the screen. That's what started me on this story because I took that video when I gave my presentation at Berkeley.

SS When you gave your presentation at Berkeley were you also talking to the plant virologists?

AO It was in the Chemistry Department. I don't recall that there were any plant virologists.

SS One of the things that was clear to Steve, and also to me, was that the structure didn't have a large impact on the virology community at the time and in part I wanted to try to understand why. I think it was just because the virologists were so far removed from thinking about structure.

AO I think so. This also speaks to what I was most interested in next - communicating this structure. I gave a couple of presentations and I had heard Steve's presentations at the time. Even with pictures, it's not that easy for somebody who isn't used to thinking spatially about molecular structure and molecular assembly to understand. That was my motivation initially for looking at it on the Evans and Sutherland, for making this kind of video, and then later on, when I was at Berkeley making the film about TBSV.

SS Before we jump to Berkeley, how much longer did you stay in Steve's lab and how did you begin to switch into this other field?

AO I stayed in Steve's lab through about February of '79. I had a Damon Runyon/Walter Winchell Fellowship for cancer research.

SS You must have had a hard time explaining how this was related to cancer.

AO I had to and at the time there were theories of viral cause of cancer and that's how I tied it in - at Steve's suggestion.

SS I have to admit that until recombinant DNA technology came on the scene, if anybody had said that bacterial genetics was going to revolutionize cancer biology, people would have thought they were crazy.

AO That's right, it's true you don't know what the impact of the work you are doing is going to have. It can be arbitrary how you frame the work. I had anticipated that I would do a two year postdoc in Steve's lab and then move on, hopefully to a more permanent academic position. An organization was formed at the Lawrence Berkeley Laboratory, called the National Resource for Computational Chemistry. David Templeton may have told me about it because I think he was on one of its advisory panels. They were looking for people in different branches of chemistry, at the staff scientist level, to spearhead different sections of this resource. The goal of the resource was to aid computational tasks in various aspects of chemistry and there was an opening for a person in crystallography. The risky thing about it was there would not be any experimental crystallography at this Center; it would be purely computational. I remember conversations with some colleagues as to whether I should move away from the experimental into the strictly computational. I think what enticed me in that direction was a talk with Bill Lester, who was director of the NRCC. He said they were very interested in getting into 3-D computer graphics and that would fall under my domain. I was willing to make the jump at that point.

SS This is the late '70's. I'm trying to think of what the computers were like then.

AO This was a very interesting time in terms of computing technology because the NRCC had its genesis in a series of workshops starting in '72 or '73 and going through to '76. The model for scientific computing at that time was the computing center. There would be a computing resource that scientists would come to use. In the late '70's, while I was at Harvard, the Digital Equipment VAX came out. This machine revolutionized scientific computing because all of a sudden there was a computer that a laboratory, or a smaller group, could control on its own. We were no longer under the tyranny - and this was the way it was always looked at - of the computing center. You had your own computer and you could do with it as you wanted. This was very, very appealing. It was just after I left Harvard that they got their first VAX. I remember going to Digital Equipment in Marlboro, NH. Craig Steele was the computer technician in Steve's lab. He and several others from the lab went up there to take a look at this new VAX780 which was the first of the series to come out.

The reason this has impact - I'm getting a little bit ahead of the story, but the NRCC, where I went after Steve's lab, bought a VAX. Originally, when the NRCC was founded, the idea was that it was going to be at Lawrence Berkeley Laboratory. It was going to use the CDC7600, this was the supercomputer of the day. NRCC would make it available to the chemical community for different computations. That was the central computing model. By the time the NRCC actually got going, the minicomputer had revolutionized scientific computing. Chemists were buying their own VAXes, free of the tyranny of the centralized computer system. From the NRCC point of view, it ultimately meant the death knell of that program because at the time, we were judged on the criteria of supplying CDC time to the computing community. We actually ended up doing something that I think was much more important: there is a legacy of software that came out of that group that is still being used in the chemistry community today. There's a quantum code called GAMMES that is used and a number of other codes. There was a postdoc who came to work with me at the NRCC, T.J. O'Donnell. He was into computer graphics as well and what attracted him was that we had bought the same Evans and Sutherland picture system. He got his degree in chemistry at University of Illinois at Chicago Circle. He came and showed a scene from Star Wars that he had worked on, doing the computer graphics. This was the late '70's and what we did was we designed a little computer language that we called GRAMPS. It didn't do what the electronic Richards boxes did but rather provided a more generic language for looking at chemical models at different levels, all the way from the reaction dynamics of water up through virus structure. I was very interested in virus structure. T.J. did the programming, and I was involved in the design.

SS And is he now working for Spielberg?

AO No, no, he actually worked for Abbott Laboratories for a number of years and is now doing private consulting. He was a "died-in-the-wool" Chicagoan, but he moved out to San Diego recently. We ended up with a language that I could now use to do the communication of the virus structure that I tried to do the year before with jerry-rigged software in Steve's lab with a video camera pointing at the screen. I bought a little Bolex 16 mm movie camera and hooked it up through the keyboard so that I could trigger it from the software and we started to make movies. I made a movie that I called TBSV and put a Scott Joplin ragtime piano sound track to it.

SS I wonder if we have that?

AO You may have the polio virus movie. The TBSV film was originally done in black and white, because it was just a monochrome screen at the time, and once we did that, we convinced Evans and Sutherland to loan us a color system. They had just come out with a color Picture System. They loaned it to us, we redid the movie in color, and then showed it all around. We've had requests for that movie for years and years. I think probably five or six years after that movie was made, when I would give talks, people would come up to me and say: "I saw that movie and it changed the way I thought about biology" or "it made me interested in crystallography". That is really the most rewarding thing that you can hear - something that you had done has inspired other people to work in a field that you think is worthwhile and interesting. That was a real boost.

But it was the motivation from the virus structure that led directly to the kinds of features we put into this graphics environment. What we did, and a number of people have done similar things, is expand the repertoire of what you can use the 3-D graphics for, what kind of representations are possible. That's been a strong component of what I have been doing ever since. When the NRCC ended, I was given a position at LBL (Lawrence Berkeley Laboratories), but Richard Lerner was just starting up the effort in structural biology here at Scripps. For biologists, this was very visionary. There weren't any molecular biology departments that focused on structure at the time. Lerner contacted me because he was working on influenza. He was looking at peptide immunogens and the peptide information that he was using was from Don Wiley's and Ian Wilson's hemagglutinin structure. He got to know (and hired) Ian Wilson who was just finishing his postdoc with Don Wiley. Ian said that Lerner had crystallography and now he wanted computing. I was at Berkeley and Ian knew I might be interested.

SS Lerner really was ahead of his time.

AO Very much so. From our point of view, it was called a "no brainer" but again this is all with hindsight. When I came to Scripps at the end of 1981, there was only one computer being used in the Institute and that was to drive a cell sorter. There was nobody doing computational modeling or anything like that here at that time. I couldn't afford a VAX11/780 so I bought an 11/750 when I got here and I bought an Evans and Sutherland colorgraphic system. That was my start-up equipment and I called my lab the Molecular Graphics Laboratory. It was in the basement over at Stein at the time, this building (the Molecular Biology Building) hadn't been built yet.

You probably know the Lawrence Berkeley Lab, it's up on the hill overlooking the campus. The view from my office was of the Golden Gate Bridge and when Richard Lerner came up and saw the view from my office, he said: "we'll give you as good a view".

SS He did pretty well. (I said this as Art and I took a look at the wonderful view of the sea that he has from his office.)

This is probably a good time to tell the story about the painting (and I will insert the parallel story of the drawing that Picasso did on the wall of Bernal's home).

AO I was spending a lot of time up in Mallinckrodt building the TBSV model in the Richards box. A friend of mine who I had known from Berkeley, Bruce Carter, came to visit. He had been one of my house mates in North Oakland. He was traveling with his father, and while they were in Boston, his father had an attack of phlebitis and was hospitalized. Bruce had to spend a couple of weeks in Boston instead of a couple of days. I was building the model and couldn't take time off so he would come and visit me. It was a hand-type operation and it was nice to have company. He was itching to do something so we decided he could paint a mural on a wall in the room we were in. There was a blank wall. I think it was painted but it may have been just drywall.

I generated a computer plot, just an abstract triangular shape, and replicated it with icosahedral symmetry. I did it originally on the Evans and Sutherland and then plotted it out. Then we projected the image on the wall. Bruce painted it and put some artistic touches into it in terms of color choices and how he represented the lines and so forth. It was up there at least through the time that I left Harvard and probably longer. My recollection is that it was Chris Dobson who took over that space and had it remodeled.

Steve decided that he wanted to preserve that painting so he had them cut out that piece of the wall. When Fairchild was being built, he had it framed and hung in Fairchild. I was here at the time. He called me up, asked me for a title and said: "make it pretentious". There was a Richard Serra sculpture outside of Fairchild called "Composition Number Two" or something. Steve didn't like it and wanted to parody it. I said: "call it 'Variations on a Virus Blue' ". They put that on the plaque and put Bruce and my names as the creators and as far as I know it's now in the permanent collection of Harvard University. The plaque says:

Bruce Carter and Arthur Olson
Variations on a Virus Blue (1978)
Donation of the artists

SS I wanted to record that because there are many stories of names like "amber" and the explanations of how they originated get lost. The best are the northern and western blots which are derived from the Southern blot. These names are often in the newspapers, but not that Southern is the name of the scientist who developed that blotting method.

AO The "Variations" was pretty funny. I'm glad that it's there. It's not a great work of art but it is a nice piece of history.

Richard Lerner was aware of the movies I had done and he got me in touch with somebody from Disney because they were developing the EpCot Center in Orlando at the time. There was a producer in Los Angeles, Eddie Garrick, who was in charge of a movie, an Omnimax film. The film was going to be in the General Electric Pavilion that was called Horizons. Somebody from Disney and Eddie contacted me and asked if I would be interested in doing some computer animations for this project. I said: "sure". OmniMax is a hemispherical large format projection and at the Horizon Pavilion, you watched it while you were riding in a car. You were actually going through two of these domes where there is a film loop that is being played. Eddie Garrick was responsible for the production of a two minute Omnimax film and our component of it was going to be a computer graphic molecular modeling of DNA and I agreed to do it. It was actually very challenging work because the resolution that they needed to write this was very high resolution on this film. I ended up sending reels and reels of magnetic tape to DICOMED, a company in Minnesota with a film writer, that wrote the final film, large format film.

I completed the DNA segment which was basically a ride down the major groove. I have had people come into the lab and tell me that it made them sick. At the end of the segment, after you got off the groove, what I decided to do was to take an assembly scene from the virus movie and recast it so that on the dome coming down from outside were the TBSV subunits. The C subunits would come down and make the cage and the A and B subunits would come in and fill out the content of the dome. They kept that in and since we had already developed the software for it, I did another sequence that had to do with the space station. They had some data that had a mock-up of the shuttle and I made a space station based on some figures and put that in. TBSV was at EpCot. This was in 1983 and I didn't get a chance to see the film in the Pavilion until about three or four years ago. I went to a conference in Orlando and I took my two sons. For the first time I went to Epcot, and it was still playing. As far as I know it's still there and everybody's that been through that pavilion has seen TBSV.

SS Do they know what it is?

AO No, unfortunately not, it isn't explained at all. It's just part of a visual journey. I hadn't realized this until I went there. The Pavilion presents a view of how society has looked at the future through the ages and our segment is supposed to represent the future as we look at it today. They are still using the same view of the future from 1983 in this Pavilion, which looks pretty dated if you think about what has happened to computer graphics in the meantime. This is from the 18th century to the current views of the future and TBSV is part of that vision for society.


| Introduction | Some historical highlights: structural virology and virology |
| Solving the Structure of Icosahedral Plant Viruses | Picornavirus Structure | Poliovirus | Polio
The Influenza Virus Hemagglutinin
| The Influenza Virus Neuraminidase | Issues of Science and Society |
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