In its 13-year history, the National Human Genome Research Institute has had three directors. The first was James D. Watson, who had the small résumé advantage of being the co-discoverer of DNA. Watson was replaced by Francis Collins, who merely led the Human Genome Project effort to determine the first complete sequence of human DNA. When Collins went on to become director of the National Institutes of Health in 2008, he was succeeded by Eric Green, another leading scientist in the Human Genome Project.
Friday, the first and third names in that list were both at the University of Chicago for this year’s Jean Mitchell Watson lecture, an annual event named for Watson’s late mother. In his brief introduction, the 82-year-old Watson reminisced about growing up on the South Side of Chicago, birdwatching with his father, and how his undergraduate education at the University set him apart when he went on to graduate school. “My Chicago education really showed, because Chicago taught me how to think, whereas the other students had been taught to remember,” Watson said.
But the main event was Green, who has taken the baton from Watson and Collins in the race to maximize the benefits of genetic research. This year’s tenth anniversary of the Human Genome Project’s first milestone – the completion of the genome’s first draft – received mixed publicity, including a high-profile critique by the New York Times on the project’s lack of immediate medical impact. In his talk, Green laid out a rebuttal to those criticisms, arguing that the Human Genome Project was the beginning, not the end of the genomic revolution in medicine.
“Effective advances in health care sometimes take decades. We shouldn’t think it’s going to be any simpler just by bringing genomics to the table,” Green said.
The structure of Green’s talk was therefore about the bottlenecks that yet needed to be broken in order to realize the potential of genetic-based personalized medicine. In a sense, Green said, the Human Genome Project was just the first bottleneck-breaker, giving scientists a publicly-accessible reference genome to use for their own research. But in true scientific fashion, completing the initial challenge only created several more:
1. How Does This Thing Work?
As Green demonstrated with a slide full of tiny As, Cs, Ts, and Gs, just knowing the content of the human genome is far from enough. Only 1.5 percent of the 3 billion base pairs are in genes that code for proteins, the primary purpose of DNA. Another 3.5 percent is under evolutionary pressure – which means it’s biologically important – but scientists don’t know why. Understanding how DNA regulates itself, a field called epigenetics, will be an important step toward resolving this mystery and gaining more control over genetic function. The University of Chicago and Argonne National Laboratory are heavily involved in one such effort, called the ENCODE project.
2. Variation Matters
Of course, we don’t all share the same 3 billion base pairs, and our unique combination of genetic variation has a lot to do with who we are, for better or worse. Understanding those variations and their role in human disease and development will be crucial in turning science-fiction genetic promises into reality. Two major efforts already underway, the International HapMap Project and the 1000 Genomes Project, have begun cataloging the millions of variants present in populations around the world for future use in predicting and treating disease.
3. Finding the Causes of Disease
Since the release of the first genome sequence, thousands of disease-associated genes and mutations have been identified. However, most of these associations were for monogenic disorders – errors in a single gene that typically produce only very rare diseases. The source of common diseases such as diabetes, heart disease, and depression are likely due to complex mixtures of multiple genes that have so far largely eluded scientific efforts, Green said. That may be because many of the key variants for such conditions are located in those mysterious non-coding regions.
“It’s the part of the genome that we don’t understand as well,” Green said. “This really shows us that we have a lot of work ahead of us for what turn out to be the variants that are most medically important.”
4. Gene Sequencing at Discount Prices
Knowledge about the genes and variants important for human disease will only be useful if it is possible to routinely scan people for that information, Green reminded the audience. Here, amazing strides have been made since the Human Genome Project, where the first complete genome cost roughly $1 billion to sequence. Next-generation technologies recently unveiled by several different companies have brought that cost down to approximately $20,000 per genome, and Green is optimistic that his institute’s 2003 goal of a $1,000 genome is within reach. The impact may be best described by the recent publicity trick of the “vanity genome,” with companies hyping sequences of figures such as Glenn Close and Ozzy Osbourne in recent months.
5. Oh Yeah, That Nurture Thing
Important as they are, genes can’t explain everything. Genetic variation may tip a person toward a particular fate, but environmental factors – where they live, what they eat, whether they smoke – can dramatically change those odds. What’s more, the human genome is not the only resident of the human body; genes from the wide variety of bacterial species living in the gut and other place outnumber human genes by 25 to 1. “You are a minority owner of your ecosystem,” Green said. Thus, efforts such as the Human Microbiome Project seek to characterize those genes as well, which may be of equal influence upon our health.
6. What to Do With All That Data
Scientists are already working to break the previous five bottlenecks down by collecting more and more data. But the mother of all bottlenecks, according to Green, is what scientists do with all that data, an unfamiliar problem for biologists. More than any other area, the infrastructure and analytic techniques created to wrangle all that data into useful form will set the pace for genetic medicine.
“We’re facing big data as a biomedical research community for the first time. Physicists and planetary scientists, they’ve faced this for a long time,” Green said. “We’ve never been big data people in biology, and we are now. Genomics is one of the fields that’s really driving that.”
Hearing all those challenges back-to-back (plus several more that Green only touched on), might seem dispiriting. But rather than taking them on one-by-one, all the major challenges are being worked on simultaneously, with backing from the NHGRI. Returning to the metaphor of a race, Green agreed with The Economist’s Geoffrey Carr in his 30,000-foot view of genomic science after the “race to the starting line” which was the Human Genome Project.
“Everything I’ve been talking about with respect to genomic medicine is a marathon,” Green said. “But it’s a compelling marathon, and it’s going to be an exciting run.”