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Francis Collins
On Deciphering the Human Genome, The Future of Genetics, and Life Post-NHGRI

When Francis Collins, MD, accepted the post as the director of the National Human Genome Research Institute (NHGRI) in 1993, he had no idea that part of his legacy would be deciphering the whole human genome and discovering that humans have about as many genes as ground worms and fruit flies. Nor did he envision that he would be as deeply entrenched in a scientific pursuit that has led to new understanding of a myriad of human conditions — offering future generations a chance to identify risk genes. Dr. Collins Dr. Collins stepped down as NHGRI director on Aug. 1 and will see what life has planned for him. [Alan E. Guttmacher, MD, is Acting Director of the NIHGRI.] “I am feeling restless,” he said, adding: “It has been a glorious and exhausting ride.” Dr. Collins talked to Neurology Today about his plans and his hopes for the future of genetics, which ushers in new strategies for personalized medicine.

WHAT WILL LIFE LOOK LIKE FOR YOU AFTER THE NHGRI?

For a year or so I have been restless. The time was right to move. The first thing I am going to do is write a book on personalized medicine that is accessible to the public. I am also interested in global health and maybe I will go do missionary work in Africa. I don't really know.

WHEN YOU BEGAN AT THE NHGRI DID YOU IMAGINE THAT TECHNOLOGY WOULD HAVE ADVANCED SO FAR?

The technology to do this genetics work was not in existence. It is amazing. The whole network was nowhere in view. The skepticism was huge. It was a wonderful opportunity to have the ability to bring scientists together from multiple disciplines in multiple countries and agree that the vision was so compelling that we just had to work together in this and not worry too much about giving the data away. [The complete sequence of the human genome is available on the institute's web site at www.genome.gov.]

WHAT WAS THE BIGGEST SURPRISE?

We had a sweepstakes to guess how many genes were in the human genome. Boy, were we surprised. The original prediction was not based on something we could quantify. We had a bit of human hubris, I suppose. We knew ground worms and fruit flies only had 15,000 to 20,000 genes and we were quite sure we were more made up of so much more. We were quite sure we were special. Of course, we are special. Ground worms and fruit flies have not sequenced their own genome. We learned that gene count is not the way to rest your confidence in your specialness. The human genome was thought to have at least 100,000 genes. At the end of the sequencing of the human genome it was determined that there are about 20,000 to 25,000.

HOW MANY GENES ARE INVOLVED IN THE BRAIN?

The brain is a big deal. About a third of the human genome is active in the brain. An awful lot of the fanciness is what these genes do in the brain. It is not just the genes but the regulatory pathways that decides whether the genes are on or off and this is far more complicated than we realized. A lot of genes that we thought were “filler” are critical for these regulatory signals. When it comes to the brain, the marriage between genetics and imaging and disease is turning out to be very exciting. We now know that genes are at work in schizophrenia, Alzheimer, Parkinson, Huntington, autism, and other brain diseases. I take great delight in the fact that genomics is turning out to be the engine of discovery for many of these developments.

HOW DO YOU FEEL ABOUT THE LATEST DEVELOPMENT IN GENETICS: DIRECT-TO-CONSUMER GENETIC TESTING?

I am torn about this development. On the one hand it is exciting to see that these clinically validated discoveries are embraced by the public and the market picked it up. On the other hand, we don't have the data to know what interventions will be successful for people at high risk. The risk factors are pretty small, and there is a danger that people will be turned off when they realize the information is not helping them. We need to think about the regulatory systems for this direct-to-consumer testing. There are truly some snake-oil opportunities on the Web. We have to find the right balance to give people accessible information on what they want — quality information and what it means and what they should do about it — but it is not there yet.

I am the representative to the Secretary's Advisory Committee on Genetics, Health and Society that has spent nine months grappling with this issue. At a minimum, we need a well-developed, user-friendly Web site where anyone can go and find the scientific data behind any of the 1,600 genetic tests now available. Now you have to depend on the company marketing the test to tell you what it's good for. That is not good if you want the consumer to have the chance to make rational decisions.

WHAT TYPE OF GENETIC INFORMATION ARE PEOPLE GIVEN?

There are three different kinds of tests that are available. The majority of tests now available are for rare, highly-penetrable single mutation conditions. It is usually ordered only when there is a high suspicion that the gene is present. Many of the tests being marketed direct-to-consumer by and large offer information on predisposition. These are tests that provide information on highly penetrable genes for common conditions like BRCA1 and BRCA2. But then there is a growth of genetic tests being offered that are based on scientific findings on hereditary factors for common diseases that may have a small effect on a given disease. All of us are likely to carry a few of these.

WHAT ABOUT GENETIC RISK FACTORS FOR COMMON DISEASES?

The number of new genetic risk factors linked to common diseases like diabetes and hypertension grows by the day. What we have learned about hereditary factors is just scratching the surface. Most of the heredity factors have not been discovered. With these discoveries the ability to make predictions about risk will get stronger. The environment plays a critical part in disease. I think it will get to a point where lots of people are interested in having their genetic information, and we will also come to a point when there will be validated interventions so that people can lower their risk of disease. And that is a good thing. It is a vision of individualized prevention and personalized medicine to get us to a place we would really like to get to. We spend so much of our health care dollars to treat far-advanced disease. Wouldn't it be good to shift some of that emphasis towards preventing the disease? And doing that as a ‘one-sized-fits-all’ would not be ideal. You want to make the intervention specific for that individual.

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DR. FRANCIS COLLINS: “…When it comes to the brain, the marriage between genetics and imaging and disease is turning out to be very exciting. We now know that genes are at work in schizophrenia, Alzheimer, Parkinson, Huntington, autism, and other brain diseases. I take great delight in the fact that genomics is turning out to be the engine of discovery for many of these developments.”

Scientists are identifying these genetic risks through genome-wide association studies. The technology has led to the offering of these tests sometimes weeks after they were published. I am not sure anyone was prepared for this. Some people think it's great and others think it is jumping the gun. Companies are developing applications before we know enough about these modest risks.

WHAT DO YOU THINK OF JAMES WATSON ALLOWING HIS GENOME TO BE SCANNED AND MADE AVAILABLE TO THE PUBLIC?

I am not a fan of celebrity genomes. We are seeing a growing number of people having their genetic sequence determined and putting the gene out there. It is good because we need to study human genomes. The fact that it is Jim Watson and Craig Venter seems to send a signal that this is for the scientific elite. I think we should do a better job of carrying out the activities in a way that is well represented. The Genome Institute, the Sanger Institute, and the Beijing Genome Center in China are now studying 1,000 genomes.

THIS YEAR, AFTER A 13-YEAR BATTLE, THE PRESIDENT SIGNED THE GENOMICS NON-DISCRIMINATION ACT OR GINA. HOW WILL IT AFFECT GENETICS RESEARCH?

The passing of GINA is a wonderful milestone. The goal of the bill is to make it safe for people to have genetic testing without fear that it will affect their health insurance or employment. When I came to the NIH in 1993, there were no protections in place. Many states began creating laws and Congresswoman Louise Slaughter (D-NY) wrote the first statute 13 years ago. It got very little attention. Many people have been afraid to take genetic tests, as we learned from our experience with BRCA genes. Mutations in the BRCA genes can significantly increase a woman's risk of breast cancer but many women have not taken advantage of screening. Or they use a different name for testing. Or ask their doctors not to put it in the medical chart. This bill frees up physicians to practice good medicine. On the research side, people have been fearful of joining a genetic study because they worry that it will somehow get into their medical record and it would affect their health insurance.

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