David Botstein on Conceiving of the HGP: Mapping Development
  David Botstein     Biography    
Recorded: 28 May 2003

I have told that story many times. It’s been written down many times. Indeed, I was with Ron Davis and John Roth. We taught a Cold Spring Harbor course together. And in those days Cold Spring Harbor—I might even say Jim [Watson]—was too cheap to give us the plane fare for all of us to get together to plan the course. We were just supposed to come and teach it. You know____________?? deliver the goods, and on the day before the course somehow magically we’ll all get together. And at that time the instructors, Roth was in Utah, Davis was in California and I was in Boston. So this was not—and there’s no Internet. So this was not a trivial undertaking.

So Roth conceived a scheme that we would be invited as reviewers of their genetics training grant in Utah. And we would be—travel at the NIH’s [National Institute of Health] expense to Utah. And we spent a couple of extra days doing the planning for the Cold Spring Harbor course. And we’d would review these graduate students who were being educated at the governments’ expense on the Utah training grant. The thing that was interesting about this was that the training grant included the entire University of Utah campus and that included the medical school and in the medical school there was a department of human genetics. And in the department of human genetics was Mark Skolnik and Mark Skolnik had a student named Kravitz. And Kravitz and Skolnik had been laboring away trying to understand the mode of inheritance of an inherited human disease called hemochromatosis. And Kravitz gave a talk at this review and in the talk he said he was been able to distinguish between the then current hypothesis that hemochromatosis is a simple dominant and another idea that it was a recessive. And he was able to do that because of its linkage on Chromosome 6 to HLA [Human Leckocyte Antigen.] And he was able to do that because HLA is very polymorphic and no matter who he—which families he looked at he could follow the inheritance. And this was, of course, came with the then apparatus of human genetics. It was serology for the HLA types, some kind of diagnostics for the hemochromatosis and, of course, LOD [logarithm of odds] scores and all the mathematical things that become familiar.

And the molecular biologists on the review panel were having none of this. They thought that if you needed statistics you obviously didn’t have enough data. And they basically thought that Kravitz and Skolnik by extension were some kind of charlatans.

Now it just so happened that I have a degree in human genetics and my minor was in the mathematics including the aforementioned LOD score. And I understood perfectly that Skolnik was not a charlatan, that Kravitz was not making this up, and that the statistics were not optional and in fact they were probably right about all of this. And so I found myself as a molecular biologist trying to explain this to the other guys. And I remember saying very clearly, I remember saying, “There’s nothing special about HLA. “ The argument from the molecular biologist was “oh, HLA because HLA has something to do with the cell surface and the hemochromatosis and they made all types of molecular conclusions.” And I said, “No, the only thing that’s important about HLA is that it’s polymorphic. And if you had polymorphism all over the genome you could map anything.” And as soon as the words were out of my mouth I said, “We do have polymorphisms all over the genome and we can map anything.” And that was the light bulb, as you say, that went off because we knew that there were transposable elements. That there were what are now called restriction fragment length polymorphisms. Because in my lab we had, in fact, mapped the gene which is the ribosome—repeated ribosomal DNA of yeast by exactly this method. Joe Sambrook et. al had mapped a few genes here at Cold Spring Harbor using restriction fragment differences and Maynard Olson had mapped a few tRNAs in yeast. All of this was—we were very familiar with. And I was looking at Davis and Davis got it right away. Sure we had polymorphisms all over the genome and we spent the rest of the day thinking about what this all would mean. And most of that thinking was right. I mean we figured out what was going to happen and it happened—faster than we expected.

David Botstein is a prominent geneticist whose advocacy for gene mapping was crucial in laying the groundwork for the Human Genome Project. Botstein received his Ph.D. from the University of Michigan for his research on bacteriophage synthesis. As a member of the MIT faculty he continued working with phage P22 DNA and discovered many bacterial and yeast genes. He served as Vice President of Science at Genentech before becoming professor at the Stanford School of Medicine where he led in sequencing the first large eucaryotic genome.

On July 1, 2003 he was appointed as Director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University. At Princeton he will continue to expound upon genome projects, explore the relationship between genes within the genome, and uncover how diseases like cancer alter the expression of genes.

Botstein researched at the CSHL while on sabbatical from 1974-1975. At the 1986 CSHL symposium on Human Genetics he played a crucial role in advocating for the Human Genome Project. While serving on the National Research Council Committee he emphasized that money be laid aside to fund the sequencing of other simpler organisms with which the human genome can be compared. Like Jim Watson, he has passionately supported the Human Genome Project since its inception.