Thirty years ago, in December, 1984, Richard Myers — at the time a young postdoctoral scholar — joined 18 other researchers at a gathering 8,500 feet above sea level, at the Alta ski resort near Salt Lake City, Utah.
The weather outside was stormy, and the scientists spent much of the five days of the meeting snowed inside discussing the repercussions of an event that had occurred nearly 40 years earlier: Was it possible to track radiation-induced mutations in the DNA of the descendants of those exposed to the atomic bombs in Hiroshima and Nagasaki?
At the height of the cold war, the question was pressing. For how many generations did the echo of such radiation exposure linger?
The answer, unfortunately, was elusive. Technology at the time was too limited to accomplish such a task. But discussions at the small meeting, which came to be known as the Alta Summit, sparked one of the most massive, most successful, and most expensive biological research endeavors in human history — the Human Genome Project.
It also changed the course of Myers’ career, from biochemistry to human genetics. Now the director and president of the non-profit HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, he and other young researchers played a pivotal role in the subsequent sequencing effort. Here he answers questions about the summit, its lasting influence on what was to become the field of genomics, and how HudsonAlpha extends that legacy to advance human health and crop science.
What was the purpose of the Alta Summit? How did you come to be involved?
I was one of the youngest of the 19 participants at the meeting, and I was a little intimidated. The meeting was sponsored by the Department of Energy and the International Commission for Protection Against Environmental Mutagens and Carcinogens. The organizers wanted to know if it was possible to track the effect of radiation from the atomic bomb in Hiroshima and Nagasaki on the DNA of survivors and their children. We knew from the many cases of leukemia in those that survived the initial blast that the radiation had a damaging effect on the cells of the body. But did the children of those survivors who didn’t develop cancer also have an increased prevalence of mutations due to changes in their parents’ sperm or egg cells? Did the atomic bomb change your germ cells in a way that was heritable?
I went to the meeting at the suggestion of my post-doctoral advisor, Tom Maniatis at Harvard. He was invited, but encouraged me to go in his place because I had been working on techniques isolate point mutations in the promoter region of the gene for beta-globin, which is expressed in red blood cells, which led us also to develop methods to detect mutations. But I didn’t really know anything about human genetics.
What happened at the meeting? What was the atmosphere?
The meeting was held at the ski resort at Alta, Utah, which is about 8,500 feet above sea level. I had terrible altitude sickness, and didn’t ski. I don’t like having a frictionless surface under my feet! (Once I was asked to leave an ice skating rink because I kept knocking the other skaters down when I fell.) Other researchers, like George Church, who had just completed graduate school at Harvard, did do some skiing, but mostly we all sat and talked. We had no Internet or cell phones then to distract us, and the weather was quite stormy.
My roommate was Maynard Olson, whom I had never met. He flew in to Salt Lake City in the middle of the night, and I was asleep when he arrived. He walked in the room, switched on the light, and started talking. I didn’t sleep much for the next three days because we didn’t stop talking the whole time. He’s one of the most brilliant people I know. He and Jim Neel (who had been one of the first researchers to arrive at Hiroshima after the bomb was dropped), encouraged me to pursue my research and start working on human genetics.
I knew only a couple of the other participants when I arrived, but I came to know each person quite well during the course of the meeting. Although I didn’t even know what a polymorphism was, and barely understood what germ cells were, I knew by the end of the five days that I wanted to be a human geneticist.
What research did you present at the meeting? How was it received?
I had been trained as a biochemist, purifying proteins and trying to understand how they worked. I had been working on understanding the promoter region of the beta-globin gene, to better understand how the beta-globin protein functioned in red blood cells. So I decided I needed to mutate each nucleotide in the promoter to see how it affected the expression of the gene. There was no efficient way to make mutations in vitro efficiently at the time. So we treated the promoter DNA with very low levels of a mutagen, so that only about one nucleotide was changed per 10-20 promoter molecules (to ensure that we had only one mutation per promoter), and then to find some way to isolate the mutants from the wildtype fragments. We figured that we could separate the mutant from the wildtype DNA molecules based on their melting behavior by using denaturing gradient gels, a magical system that had been developed by Tom Maniatis’s dissertation advisor, Leonard Lerman.
So I took a pool of these mutant molecules and ran them together with the unmutated version. Some ran above the wildtype, and some below. I cut each of those bands out, purified, cloned and sequenced them with radioactive Sanger sequencing . I sequenced more than 300 DNA pieces in this manner, and compared their ability to regulate the expression of the beta-globin gene. This was all new at the time, and we eventually published our work in Science in 1986. We also used a similar technique to identify changes in the beta-globin promoter associated with the blood disease beta thalassaemia in the genomes of patients, which we published in Nature in 1985.
Another technique I discussed involved the use of an enzyme called RNAse I, which specifically cuts single-stranded RNA. I found that it was possible to detect point mutations in total genomic DNA by hybridizing an unmutated (wild type) RNA probe molecule to genomic DNA from individuals with just a single base pair mutation. That section of the resulting double stranded molecule would not pair correctly and would stick out like a tiny bump, which would be recognized and cleaved by the RNAse.
I gave my talk about half way through the meeting, describing these techniques, and they all got very excited. The veterans at the meeting thought that this might be the best way of monitoring small changes in the genome. However, although it was much more efficient than previous methods, it still wasn’t a practical way to scan the entire genome. Furthermore, we realized that no one knew what the base rate of mutations was in humans. And someone, I don’t remember who, said “The only way we are going to figure this out is if we sequence the entire human genome.”
What was the response to that realization?
Well, everyone laughed. It was a ridiculous idea at the time. But then we started thinking about the implications of having such a sequence. Within two years, in 1986, Charles DeLisi, then the director of the DOE’s Health and Environmental Research Programs, proposed to Congress what was to become the Human Genome Project, and the project was formally launched in 1990. It was a huge, collaborative, international effort that was projected to take about 15 years and cost about $3 billion; in reality it was completed in 2003 (two years early) and cost about $2.7 billion. Recent reports estimating the economic impact of the completed project suggest a multiplier of about 141. That is, we’ve realized $141 in benefit for every one dollar the project cost.
What was the mood when the meeting ended? You had, after all, failed to accomplish the stated goal.
Well, our conclusions were sobering. We were excited about the potential inherent in the technologies we had discussed, and many of us had begun to conceive of other possible strategies. George Church, for instance, had begun to formulate ideas for what would lead to multiplex sequencing. But even then we realized that this was going to be a really long haul. We also realized that it was going to be worthwhile. Personally, I knew without a doubt that I wanted to become a human geneticist.
So, how did you get formally involved in the Human Genome Project?
In 1984, I was a postdoc, and about to start looking for a job. I knew I wanted to study human genetics, and the University of California, San Francisco had the program I was most interested in. I started there as a faculty member at the end of 1985 in the Departments of Physiology and of Biochemistry and Biophysics. I met David Cox there in 1986, and together (at the urging of James Watson, whom I had known since graduate school) we applied for and received one of the first grants to establish a human genome center in 1990 as part of the Human Genome Project. At the time we were using radiation hybrid mapping to establish the locations of DNA markers in the genome, which was necessary to be able to correctly assemble the DNA sequences generated by the project. In 1993, David and I moved to Stanford, where we began collaborating with the Joint Genome Institute in Walnut Creek to sequence the genome. In the end we, together with the JGI, were responsible for sequencing about 11 percent of the human genome, including the entire sequences of chromosomes 5, 16 and 19.
How did the private sequencing effort announced by Celera in May of 1998 affect the public research effort? How was it received in the media and the public arena?
Celera’s founder, Craig Venter, promoted the idea that the public effort was slow and cumbersome, and resistant to technological changes that occurred during the course of the project. This mantra was embraced by some large media outlets like the New York Times, which really tried to play us off against one another. And in some ways the competition was good—we finished the public Human Genome Project two years earlier than expected.
A hallmark of the public effort is that we pledged to distribute the data right away. In contrast, Celera did not have any obligation to release their data. This was before the Internet, so we released information on floppy discs — on a nightly basis for a while. We were committed to this because genome projects are expensive, community projects and the public deserves to have access to the outcome. I’m very proud to have participated in an effort that said from day one ‘these data are for everyone.’ It would have been terrible to allow a kind of data land grab, where individual labs withheld information on particular sequences.
Conversely, this approach didn’t preclude individual labs making discoveries by studying the data within the sequences and even patenting them if they wished. That was what we hoped would happen, and it worked beautifully.
How did this set the stage for institutes like HudsonAlpha?
The HudsonAlpha Institute for Biotechnology rests on the foundation established by the Human Genome Project. A major focus of the institute is to use the subsequent advances in sequencing technology to make a difference in human health and disease, including brain diseases, cancer, autoimmune conditions and heart disease. We collaborate with hundreds of scientists around the world, and have launched more than 2000 projects with groups around the world.
We also have a unique model. We actively recruit private companies to share our space as tenants (and collaborators), and we now have 27 here with us. There’s a lot of cross pollination that occurs, when our faculty members interact with the company researchers.
We’re also always looking forward. We recently purchased ten ultra-high-throughput sequencers from Illumina, Inc. These new sequencers can sequence an entire human genome for about $1500, and about 18,000 genomes per year.
I can’t believe how much faster and easier sequencing has become even in just the six years that I’ve been a part of HudsonAlpha. We’re extremely excited at the potential to transform human health and crop biology. We are still growing and working to be on the front of the discovery wave. I’m eager to see what the coming decades hold.