Thirty years ago, in December, 1984, Richard Myers was battling a nasty case of altitude sickness. At the time a young postdoctoral scholar, Myers, had 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 HudsonAlpha Institute for Biotechnology in Huntsville, Ala., he and other young researchers played a pivotal role in the subsequent sequencing effort. Myers co-led one of the first human genome centers in the United States, and his lab, together with the newly formed Joint Genome Institute in Walnut Creek, California, was eventually responsible for sequencing about 11 percent of the genome, including all of chromosomes 5, 16 and 19.
In the 30 years since the meeting, researchers not only learned the entire sequence of the three billion nucleotides that make up the human genome, but they’ve also sequenced thousands of other species. They’ve learned to compare and contrast genome sequences among and within species to trace evolution’s winding path, and they’ve begun to shine a light on what has been called the “dark matter” of human DNA. They’ve compared populations from around the globe to discover ethnic and racial differences critical to the success of personalized medicine, and they’ve learned new ways to improve crop productivity to feed an ever-growing world.
They’ve also increasingly relied on large national and international collaborations to tackle unwieldy projects that would be impossible for any one lab or private company to complete alone. It also set new standards for data sharing and paved the way for public and private research partnerships.
“The HudsonAlpha Institute rests on the foundation established by the Human Genome Project,” said Myers. “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. Last year alone we analyzed over 2,500 whole human genomes. We collaborate with hundreds of scientists around the world, and have launched more than 2000 projects with groups around the world. All this was unthinkable 30 years ago.”
Human Genome Project conceived
In short, the speed of discovery in genes and genomics in the past three decades has been unprecedented. And it all started with an off-hand suggestion.
“When someone at the meeting commented that the only way to approach the problem of identifying individual mutations would be to sequence the entire human genome, everyone in the room laughed,” recalled Myers. But without knowing the natural rate of mutations in humans over time, it would be impossible to know whether the bombs’ radiation had truly affected the DNA of the survivors’ descendants.
The idea was laughable at the time because DNA sequencing itself was in its infancy. Sanger sequencing, a method of determining the sequence of nucleotides in a short piece of DNA, had been developed only seven years earlier. The manual labor and time required to sequence just a few thousand nucleotides made the three billion nucleotides in the entire genome unreachable with the technology that existed at the time.
Myers was one of the youngest participants at the meeting, trained in biochemistry rather than human biology. He’d been encouraged to go to the five-day meeting by his postdoctoral advisor at Harvard University, Tom Maniatis, Ph.D., who recognized that Myers’ work in identifying point mutations in short stretches of DNA could be of interest to the other participants.
“I’m not a shy person, but I was a little intimidated,” said Myers. “I didn’t know anything about human genetics. I gave my talk about half way through the meeting, describing the two methods I’d worked on to detect DNA mutations, 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.”
The Alta Summit was sponsored by the United States Department of Energy and the International Commission for Protection Against Environmental Mutagens and Carcinogens. One year after the meeting, in 1986, the Department of Energy proposed what was to become the Human Genome Project, which was officially launched in the United States in 1990. The first draft of the three billion nucleotides that make up the human genome was released in February 2001, and the final sequence was delivered in 2003. The project was completed earlier than expected due to advances in technology and competition between the publicly funded Human Genome Project and a private company, Celera, headed by biochemist Craig Venter.
Decision to make data publicly available
A glaring difference between the public and private efforts was the availability of data generated. In 1996, researchers involved in the Human Genome Project from around the world met in Bermuda to discuss how best to release the massive amounts of data, which they had previously agreed should be publicly available.
“A hallmark of the public effort is that we pledged to distribute the data right away,” said Myers. “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.”
This open collaboration and sharing of ideas was evident during the snowy days at Alta.
“We spent a lot of time talking and bouncing ideas off one another during the days of the meeting,” said Myers. “Being snowed in probably helped, and we had no Internet or cell phones to distract us. My roommate was Maynard Olson, from St. Louis, whom I had never met. His Salt Lake City-bound flight had been delayed by fog, and I was in bed when he arrived in the middle of the night. He switched the light on, started talking, and never stopped. I didn’t sleep much for the next three days.”
At the meeting, Myers had described a way to detect single nucleotide mutations by hybridizing a segment of RNA to genomic DNA from different individuals. If the genomic DNA contained a mutation or polymorphism, there would be a mismatched base pair between the RNA probe and the genomic copy. Like a faulty zipper, the mismatch would fail to pair correctly, creating a tiny, single stranded bump in the otherwise seamless double-stranded hybrid of DNA and RNA. This bump would then be recognized and cut by an enzyme called RNAse I, which specifically cleaves single-stranded RNA.
The work sprang from a previous study in which Myers and Maniatis developed a way to study individual point mutations in the promoter of the beta-globin gene in red blood cells by exposing the DNA to very low levels of a mutagen, and then isolating the resulting mutant DNA fragments on a denaturing electrophoresis gel. The location and nature of the individual point mutations affected how the DNA migrated through the gel and allowed Myers to isolate each version for further study. The participants at the meeting immediately realized that both techniques could be helpful in their quest to identify radiation-induced mutations, and Olson and others were enthusiastic about its potential to identify naturally occurring human genetic variation called polymorphisms.
“Maynard is one of the most brilliant people I know, and he and Jim Neel, from the University of Michigan, encouraged me to keep working in human genomics even though I didn’t even know what a polymorphism was,” said Myers. “I was trained as a biochemist, purifying proteins and trying to understand how they worked.”
Neel had an ongoing interest in the effect of radiation on the human genome. He was one of the first researchers in Hiroshima and Nagasaki after the bomb had exploded, and he had launched one of the nation’s first departments of human genetics in 1956.
Other researchers at the meeting, including George Church, who had recently received a Ph.D. from Harvard University, and David Botstein, from the Massachusetts Institute of Technology, explored pulsed-field gel electrophoresis, restriction fragment length polymorphism, flow cytometry and immunofluorescence as ways to parse the location and effect of mutations in the human genome.
“Our conclusions, at the end of the meeting, were sobering,” said Myers. “We were excited about the potential inherent in the technologies we had discussed, but even then realized that this was going to be a very long haul. But we knew it was going to be worthwhile.”
How far the technology has come
The scale of possibility at the HudsonAlpha Institute shows how far the technology has come. The institute recently purchased 10 ultra-high-throughput sequencers from Illumina, Inc. Together, the sequencers can sequence an entire human genome for about $1,500, and about 18,000 genomes per year. It’s likely that the next three decades will yield discoveries we can hardly conceptualize.
“As always, HudsonAlpha is focused on collaboration and data sharing,” said Myers. “We don’t function as a silo; we spread the information around. We’re also heavily committed to the idea of public and private collaboration. HudsonAlpha presents a unique model of a nonprofit research institute. We actively recruit private companies to share our space, 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.
“I can’t believe how much faster and easier it’s been in 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 am eager to see what the next decades will bring.”