Genomic Science and Society

Francis Collins, the home-schooled director of the National Human Genome Research Institute, visited Harvard Medical School on February 20, one...

Francis Collins, the home-schooled director of the National Human Genome Research Institute, visited Harvard Medical School on February 20, one week after publication of the public and private drafts of the human genome in the competing journals Science and Nature. He came at the invitation of the student-organized Harvard Health Caucus to kick off a lecture series that will explore the impact of the human genome project from a variety of disciplinary perspectives.

Sequencing is just one of eight goals of the human genome project, Collins said, but tremendous progress has been made in that arena. At full tilt, the project was sequencing a thousand base pairs a second to meet its deadline. "Twenty years ago," Collins said, "a thousand base pairs was about enough to get a Ph.D.!" He then launched into a presentation of the genome's top 10 surprises--"a format familiar to those of you who stay up too late at night":

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10. "The genome is lumpy. It is a landscape of mountain ranges and deserts, and deep valleys." Some areas have many genes, others have very few. It is heterogenous and variation is not randomly distributed.

9. "We don't have as many genes as we thought we did." Worms have 19,000 genes, we have "about 31 to 32,000" he estimates--not much more than mustardweed, which has 25,000. Yet we are fairly complex, leading to the conclusion that "our genes must be elegant in some way."

8. Human genes can make more proteins than the genes of simpler organisms. One human gene routinely makes several proteins, and those proteins are elaborate.

7. Human proteins are more architecturally complex than the genes of simpler organisms. "If we look at gene homologues [a genetic analogue] from other species, and then look at their protein products, it looks as if we tend to have more domains that make a protein more flexible or able to multitask. Each domain is a fold in the protein that carries out a particular function. Even though mammals seem to have only 7 percent more kinds of domains, they are put together in interesting ways."

6. There are at least 200 genes that weren't inherited lineally from our ancestors. These genes have no homologues in worms or flies or yeast, but they do have homologues in bacteria. "DNA from bacteria got into one of our ancestors--and that DNA has helped us." We don't know how this happened. "Perhaps a retrovirus of some sort has been capable of making these transfers."

5. "All those repetitive sequences that we call 'junk DNA' turn out to be some of the most fascinating parts, because they provide an historical record of where our genome comes from that has more specificity and detail than any of us had imagined." Pieces of the human genome date back 800 million years to an ancestor common to us and much of the biological kingdom. These "repeats" function like geological strata, recording events that happened to us a very long time ago. Because they can be dated, they can tell a lot about mutation rates and also evolution. "Now that was a surprise."

4. Much of the "junk DNA" appears not to be junk after all. Evolutionary forces seem to select for some of it, though we still don't know what advantages it confers.

3. The male mutation rate is twice the female rate--males account for the majority of disease-causing mutations but also for the majority of evolutionary progress. "We didn't know that."

2. All humans are 99.9 percent the same at the genetic level. "And most of the 0.1 percent differences pre-existed when we were all black Africans 100,000 years ago, and there were only about 10,000 of us." As such, we are more alike than the vast majority of species because we are young from an evolutionary standpoint.

1. The genome tells us more about human biology, health, and disease than we ever expected. Already, free access to the genome has led to the discovery of dozens of disease genes and drug targets providing tremendous public benefit.

Collins praised the caucus program, which was organized by students from several graduate and professional schools, for modeling "what needs to happen across disciplines and sometimes doesn't, if we're going to tackle some of these very challenging and difficult issues that are part medicine, part science, part public policy, part ethics, and part religion."

By 2010, he predicted, we'll understand the genetic basis of most diseases, but providing access to all people will be ever more challenging. By 2020 we'll have gene-based designer drugs tailored to individuals and we'll be able to pinpoint the biological basis of many mental illnesses; we may even be smart enough to do responsible germline gene therapy by 2020, but there are a host of ethical questions and issues surrounding that, he warned. "By 2030, we might have comprehensive, genomics-based health care with individualized preventive medicine based on genotyping to tell you what your risks are." In labs, "more people will work at computers because we'll have computer models of the human cell and maybe even entire human tissues; and the human life span ought to increase."

But Collins also sounded a cautionary note. "If we can change the germline, what is to prevent us from changing, in a systematic way, the very nature of human biology, not to fix a gene here and there, but to actually take charge of our own evolution and try to improve ourselves?" asked Collins. "I find this a chilling scenario, because it implies that we could know what an improvement is, and that someone would be making that kind of determination." He ended his talk with poetry, recalling T.S. Eliot's Four Quartets: "'We must never cease from exploration. The end of all our exploring will be to arrive where we began, and to know the place for the first time.' I don't know the place Eliot was talking about," he said, "but in this case I think he was talking about ourselves."


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