The DISCOVER Interview: Francis Collins

Francis Collins is changing the way we think about DNA. First he helped decode the human genome. Now he oversees a research empire at the National Human Genome Research Institute (part of the sprawling National Institutes of Health), leading the race to find disease-causing sequences hidden in our genes, doling out hundreds of millions in grant money each year, and defending controversial science in the charged politics of Washington, D.C.

A devoted Christian, Collins defends evolution and embryonic stem cell research in his new book, The Language of God: A Scientist Presents Evidence for Belief (Free Press, 2006). He dismisses religious extremists and scientist-atheists as equally shrill and believes that both sides push their beliefs on a public who prefers that science and religion remain separate.

In college Collins found biology boring and trained as a chemist, only to become a physician and then a famed gene hunter at the University of Michigan at Ann Arbor, where he identified the gene for cystic fibrosis and helped find the gene for Huntington's disease. He blazed into the public eye in the late 1990s during the bruising competition to sequence the human genome; he ran the $3.7 billion public effort while J. Craig Venter conducted a parallel effort using private funds. After much scientific mudslinging, the two sides declared a tie in 2000 and were feted jointly at the White House.

Moving beyond mere code breaking, Collins has been focusing on the recently completed International HapMap Project, a genomic atlas of clusters of disease-causing snippets of DNA. The project catalogs human variability and identifies patterns of genes that are linked to health and disease.

DISCOVER contributing editor Duncan spent an afternoon with Collins in his offices at the NIH. Collins, a lanky man in well-worn beige jeans and a flannel shirt, has an aw-shucks breeziness about him—an ease that belies his status as one of the most powerful scientists in the world.

You're a born-again Christian who suggests that therapeutic cloning could be acceptable. Some other devout people consider it fundamentally immoral. What do you see differently?
There is a difference between doing research on an embryo that was generated by sperm and egg coming together, which is the way human beings are created, versus the very bizarre laboratory phenomenon of taking a nucleus from a skin cell or the udder cell of a sheep and putting it into an environment that takes it back in time to its stem cell state. In public discourse, they're both called embryos. Even though the somatic cell nuclear transfer approach is a very different biological phenomenon, in many people's minds it has been all blurred together. As a result, we've really missed out on a chance for a much more thoughtful, nuanced discussion, and we're still trying to recover from that.

What kind of reaction has your book provoked?
I didn't know quite what to expect, but the response has been amazing. Most of the large volume of letters and e-mails I have received have been encouraging and positive, both from the scientific community and from the religious community. A few scientists have written that it is inappropriate for a scientist to write about harmony with faith, because they think that faith already has too much power in the United States. A few conservative Christians have been stridently critical about my endorsement of theistic evolution. Most heartwarming have been a few dozen very personal messages from individuals who had been struggling with whether they were forced to make a choice between science and faith and were relieved to hear that it is possible to embrace both.

What did you think you were in for when you signed on to the Human Genome Project in 1993?
When I came here, I don't think that one person out of 10 actually believed that we would sequence the human genome by 2005. We were feeling our way in the dark—we didn't have the methods, the people, the confidence. We were really struggling.

What exactly is a gene?
That's a good question. You ask 100 molecular biologists that and you'll get 110 answers. I have a pretty classic answer—a gene is a well-defined segment of DNA that encodes for a protein. Some genes also code for segments of proteins. The key thing is for a gene to have an exon [a stretch of DNA that transcribes into RNA]. There are also pseudo-genes that encode RNA but have no apparent function. They are holdovers.

Why does the body keep those around?
It's like junk in your basement. Some of it could be thrown out, but some of it you keep around in case some day you need it.

What are you finding about the importance of known genes versus the "junk DNA" in between them?
We're learning a lot about this. At the NIH we have a project called ENCODE—Encyclopedia of DNA Elements. It's a coordinated effort among 30 labs to identify all of the parts of the human genome that have biological activity, including the so-called junk DNA. We have found that there is a lot more action. There are transcription factors happening and RNA being made. We still don't know if all of this activity is actually doing something or if it's the equivalent of background noise, but we're working to find out.

Now that the human genome has been sequenced, what more is there to learn about genetics?
That was just the beginning. Back in 1997, two colleagues and I wrote a paper about the promise of having a really rich catalog of human genetic variation. I thought that was something we should strive for. I didn't think we'd get there this quickly! That project, called HapMap, got started in 2002 with scientists from six countries aiming to lay out how variation is organized across all the human chromosomes in four different populations.

What is a HapMap, and why is it so important?
A haplotype is a stretch of DNA with a particular combination of genetic spellings that vary among different people. Haplotypes in vulnerable gene regions can be responsible for increasing risk of disease. The idea of the HapMap Project was to define the spelling differences in the human population—there are about 10 million of these, called SNPs, or single nucleotide polymorphisms—and how they are organized into haplotype neighborhoods in the genome.

How does that help you learn about disease?
Searching for genetic variations that predict an increased risk of disease can be terribly difficult and expensive. If you had to test all 10 million SNPs in hundreds or thousands of cases and controls for a disease, it would be completely impractical and unaffordable. HapMap provides a valuable shortcut, as it defines the neighborhoods within which the SNP spellings are tightly correlated. In each neighborhood, you can identify a small number of "tag SNPs" that serve as a proxy for all the others that you didn't test. That way, instead of having 10 million things to sample, you can sample using about 300,000. That's what we're doing now, when we look for diabetes genes in my lab, and that's what the whole world is doing with this map for lots of other common diseases.

Has linking genes to diseases become easier since you began your career at the University of Michigan?
Searching for diabetes genes is much harder than anything I did in Michigan. At that time, I was looking for genes for Mendelian conditions, like cystic fibrosis and Huntington's disease: There's one single gene, and if you have the misspelled version of the gene, you are extremely likely to get the disease. Whereas for heart disease or schizophrenia or diabetes, no single gene is going to have a very large effect—these are complex diseases with many genetic and nongenetic causes.

The underlying science is also, frankly, rather tough to explain. Is there a way to describe all of this more simply?
Not really, and it hasn't helped our cause that we geneticists give inscrutable names like "haplotype" to our concepts. This really doesn't help when you're trying to explain this science to the public, or to Congress.

The race to decode the human genome sparked a lot of debate about whether public efforts or private companies are better suited for handling such huge science projects. Which side won?
The evidence is absolutely clear that large genomic data production projects should be public efforts. These data sets can stimulate research in both the public and private sectors if they are immediately made available to all scientists, without any barrier to access. This can be readily seen by the success of the Human Genome Project, and the subsequent public sequencing of more than two dozen other animal genomes, the HapMap, the Mammalian Gene Collection, and the rest. No company sees big genome data generation projects with private subscriptions as a viable business plan anymore.

Are these big biology projects increasingly international?
I think genomics has led that charge. The genome project was an international effort. Scientists from six countries agreed to the same standards and joined forces. That was unprecedented. The HapMap project was the same way.

One recent report suggested that the United States may not be the leading economy by 2050. India and China may pull ahead, and biotech will be a big part of that advance. Do you agree?
It's clearly a possibility. India's primary strength has been computation, and they've been slower to join projects in human genomics, in part because of the restriction that no samples can leave the country. That policy is understandable, because there was a time when there was a lot of "biopiracy" going on, if you want to call it that. But now, in this more open environment where international collaboration means sharing samples, they are rethinking this. We've had intense collaboration with China for six or seven years—Yang Huanming, director of the Beijing Genomics Institute, was a contributor to the sequencing of the human genome. China has quickly figured out where they want to go with this, and they've done a good job of it.

Will that be bad for science in the United States?
Not necessarily. As Americans, we have mixed reactions. It's good for us to be in a scientifically prominent role. At the same time, as a physician who wants to see advances occur, I think that if some of those breakthroughs can take place in another part of the world and they are done right . . . then it's hard to be opposed to that. Meanwhile, education in this country is going the wrong way in terms of training the talent we need for America to move forward. It's a scary scenario. I don't think people have awakened to just how serious this is. I can tell you that when I came to NIH, I primarily had American postdocs in my lab. Now almost all the postdocs are noncitizens. I can't find enough young American scientists to do this work. The pipeline has just really dwindled.

Many people say that science has become more politicized under President Bush. Has that added to the problem?
Clearly there has been tension. Perhaps we haven't done enough to try to understand each other. But when I speak to a member of Congress or the administration, that conversation almost always goes well. I think if we had done that early on, there would be less digging in of positions. A major problem is the general lack of scientific familiarity across the whole population. After all, politicians are supposed to be representative of the people who elect them. If we've done a poor job of explaining science to the public, is it any surprise that it has political consequences?

Do you hope that the Democratic-controlled Congress will lift restrictions on stem cell research?
I hope it's a discussion that gets beyond the rhetoric and into some of the scientific detail. If we're going to have a meaningful discussion about ethics, we will really have to understand the science behind a particular dilemma. That was the whole intention of the Ethical, Legal, and Social Issues program of the Human Genome Project—to try to elevate the somewhat nutty depictions of possibly bad scientific outcomes and ask, "What have we just learned, what is realistically around the corner, and how can we have a reasonable, high-level public debate about where the boundaries should be?"

The media often portray the religious right in the United States as antiscience. Is that a fair characterization?
I don't think it's fair to blame believers for getting defensive about attacks on the Bible when they see their whole belief system is under attack from some members of the scientific community who are using the platform of science to say, "We don't need God anymore, that was all superstition, and you guys should get over it." Believers then feel some requirement to respond, and this has led to an unfortunate escalation of charges and countercharges. As a result of the tensions over evolution, I think we see an increasing tendency for believers to dig in about things like Genesis 1 and 2, claiming that there is just one acceptable interpretation. That's not a strong position. St. Augustine, for example, came to the conclusion that we really don't know what the writer of Genesis was trying to describe in the creation story, and we should be careful about drawing conclusions about the nature of the world based on what those verses say. He was concerned that science would ultimately prove specific narrow interpretations to be incorrect, and then faith would be put up to scorn. It was as if he was sending us a warning 16 centuries ago, saying, "Guys, watch out for this."

What motivates those who polarize the debate?
I think the people who are most fervently opposed to evolution are not doing so on a political basis. I think that many of those folks have been brought up to believe that if you accept evolution, you lose your faith. If you're presented with only that option, then as a believer you have to resist Darwin with every fiber of your being. You'll congregate with people who believe as you do, you'll listen to radio shows that agree with you, and you'll try to hold it together against what's perceived as an onslaught of Godless, secularized science that threatens your core beliefs.

Do you believe that personhood begins at conception?
You mean, is that when we get a soul? Now we're into theology, and it's an area where science isn't really going to give you an answer. The only thing that science can say is that whatever line you draw between the fusion of sperm and egg and the birth of the baby is somewhat arbitrary. On the other hand, that doesn't prove that the soul exists right at that moment of fusion. Identical twins do not have the same soul, yet they started out as the same union of sperm and egg.

We keep hearing that the middle ground between science and faith is increasingly difficult to maintain. Do you feel that your position is precarious?
I think it's rock solid. If God chose to use the mechanism of evolution to create human beings, who are we to say He wouldn't have done it that way? It's unfortunate that this potential harmony between worldviews is perceived by some as delicate or fragile. Much of what seems to threaten this view are the ultraliteral interpretations of Genesis 1 and 2, as I mentioned, which are fairly recent arrivals on the scene and which many other theologians down through the centuries have not been comfortable accepting anyway.

Doesn't Scripture sometimes explicitly contradict science?
I don't find any troubling examples of that in the Bible, as long as you recognize that the point of Scripture was not to teach science. Can you imagine God lecturing to his chosen people about radioactive decay?

And yet people have been burned at the stake over this issue.
Before we start trashing religion, we should recognize that religion down through history has been misused by lots of people in terrible ways. But it's also done some profoundly good things. What has atheism done to help people? The worst examples of human carnage in the 20th century came from the atheist regimes of Stalin and Mao. The principles of faith are generally altruistic, gentle, and loving. The problem is when someone takes those principles and twists them to suit their own purposes—that was the Inquisition, and that is suicide bombers.

So what would you say to the scientists who are fervently opposed to religious thought and practice?
Is there any dogma more unsupported by the facts than from the scientist who stands up and says, "I know there is no God"? Science is woefully unsuited to ask the question of God in the first place. So give the religious folks a break. They are seeking the kind of spiritual truths that have always interested humankind but that science cannot really address.