Recorded: 01 Jun 2003
Well, I became actually rather obsessed with genomes in the 1970s, which was before most people were thinking about whole genomes and actually Jim Watson was an indirect influence on me. I’d never met him at that time but I—like everyone of my generation I had read his book, The Molecular Biology of the Gene.
I was trained as a chemist and one of the early chapters in the Molecular Biology of the Gene was entitled “A Chemist’s View of a Bacterial Cell.” I thought this was really written for me. And at the end of that chapter Watson asked a question which I couldn’t have articulated, but I think was at the basis of my skepticism about biochemistry and biology. It all seemed doubtful that we could understand such complex processes. And he asked the question; so how do we know—I’ve painted a nice picture here about small molecules, big molecules and metabolism. But how do we know that the biochemistry that we’ve discovered so far isn’t this infinitesimal fraction of some vaster universe of more molecules and more this and more that? How do we know that there aren’t a thousand ways that cells make glucose for example? And we just happen to know about one or two of them.
Well, I said, “Now that is a good question.” We don’t know that. There’s no way of knowing that. A biochemist could never discover that. I was a chemist. That was my whole way of thinking about things. And then he said, well actually there’s an answer to that question. And it’s that genomes are finite. And his examples were all from E. coli and so he made an estimate of the size of the E. coli genome. And from that an estimate of the number of genes. I think he was right within a factor of two or three compared to current detailed knowledge. And then he looked at how many enzymes we knew about and so forth and said that, you know, the situation is not so bad. You know, we know ten percent of the title or something. And we can put this bound.
Anyway, I found this idea utterly compelling. And really as to when I really started seriously working on genomes; I think it was in 1979. I had moved to my first biology job, an independent job at Washington University in the summer of 1979. And I wrote a grant saying I was going to build a complete physical map of the yeast genome. Against all advice, everyone thought it couldn’t be done, it was a bad idea, and certainly not what a beginning assistant professor should be starting to do. It was not really respectable work. There were no journals. It wasn’t even clear that you would be able to publish a map if you actually built one. And you certainly weren’t going to get the grant anyway. This type of advice. So, actually I got the grant. It wasn’t a big grant, but it was a good grant.
It was NIH [who] funded this project. And I had enough money to hire a technician and part-time computer programmer. I brought the first computer into the genetics department. People said what are you going to do with that? This is a genetics department. And six months later I brought another computer. This was a little over the top, but we got to work. And I worked for years actually. I didn’t publish anything about this project until 1986. We worked continuously from ’79 to ’86.
Amazingly I even had the grant renewed. It was a five-year grant first of all which they never give to young people. And then at the end of five years I still hadn’t published anything and the grant was renewed. So this was the early days of genomics. And it was a period when really John Sulston and I were the two people that were doing what would now be considered genomics. I became aware through Bob Waterston, who was my next door neighbor at Washington University, a close friend and associate of John’s, became aware of this independent worm mapping project using similar but distinct technology. And John’s whole activities followed a similar course. He worked for years and years. And we actually published jointly, that is back-to-back papers, in 1986 about these two projects. And even then that was still before there was really serious activity on the genome front and the Cold Spring Harbor Symposium in the spring of 1986 was, you know, our very first discussion here. I actually was not at that meeting, but I was aware of it. In any event, we’d been working, John and I independently but with good communication have been working on that already then for seven years on these physical mapping projects.
Well, so the goal always was the human, at least for me. I remember, I actually got most of the money from the NIH. But I had a very small sort of starter grant from the March of Dimes at the same time. And I remember writing to them. Their primary interest was in birth defects and I remember writing in this 1979 application that we’ll figure out how to do this on yeast and someday we’ll be able to do it on humans. But as far as my own really more direct involvement with the human genome project, I had become aware during these long years of working on the yeast map that the methods we were using, that I was using, that John was using, weren’t going to work on humans. That they worked on paper, but they weren’t going to work in actuality. There were too many problems. And we were really going to need more powerful tools. And so already while the yeast project was finally starting to come together we thought that the single most important thing that could be done to move toward human mapping was to get larger inserts into the clones. The worm project, the yeast project and ultimately the human project were really driven by recombinant DNA clones of segments of the genome and you’d sort of get one and another and another etc. It’s a sort of tiling path as it’s called. And it makes a big difference how big the chunks are. The bigger the chunks, of course, the fewer of them you need. But in addition more importantly actually you get lost and confused and wrong less often and so forth.
So I had a lot of experience in yeast genetics and a graduate student in my lab, really two students, but David Burke really took the lead and George Carle was another student. They were working, as a side project got enthusiastic about this idea of trying to develop cloning systems that would be more equal to the task of human analysis. And so at about the same time, I think, this work was published, if I remember correctly, in early in ’87. But at about the same time as the yeast project was finally coming together we published the yeast artificial chromosome method of making very large insert clones from humans or any other organism. And the so-called YAC clones. And they did have a big impact right away because they were starting to be many of these positional cloning projects for the cystic fibrosis gene and many other examples where genetic linkage and mapping would be done to find where on the chromosome is the mutation that causes the genetic disease. But still people had these tremendous difficulties gathering up just the DNA across often a million or more base pairs. So that they could start a serious gene search. And the YAC system simplified that greatly. And had a big impact—and enjoyed a big period of intensive use in the late eighties and a lot of the early work on the Human Genome Project in St. Louis where I started to work with Bob Waterston, with David Schlesinger and with others. We had one of the earliest grants. We were using the YAC technology.
Maynard V. Olson received his Bachelor’s degree in chemistry from California Institute of Technology and Ph.D. in inorganic chemistry from Stanford University (1970). After five years on the chemistry faculty at Dartmouth College, he shifted his research efforts to molecular genetics at Washington University in St Louis and the University of Washington in Seattle. He now serves as Director of the University of Washington Human Genome Center, Professor of Genetics and Medicine, and Adjunct Professor of Computer Science & Engineering.
A pioneer in genomic research, Dr. Olson launched the ultimately successful effort to construct a detailed physical map of the yeast genome in 1979. He also led efforts to develop yeast artificial chromosomes (YACs) that allowed for the study of large portions of the human genome and proved invaluable in the tracking of disease-related genes, and he introduced STS-content mapping which led to the first physical maps of whole human chromosomes.
Dr. Olson is a member of the National Academy of Sciences and has been awarded the Genetics Society of America Medal, the City of Medicine Award, and the Gairdner Foundation International Award for his scientific contributions to the Human Genome Project.
Influenced by Watson’s book, Molecular Biology of the Gene, Olsen started working with the genome in the 1970’s. He met Jim Watson when they both served on Bruce Albert’s Committee of the National Research Council. Olsen also helped to organize several genome meetings at Cold Spring Harbor Laboratory during the 1980s.