HEALTHGreat minds: Mapping genomesTwo men with very different approaches have been instrumental in the Human Genome Project.By Victoria Stagg Elliott, amednews staff. May 21, 2001.
Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future. Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute, and J. Craig Venter, PhD, president of Celera Genomics, are two men aiming for the same target: the decoding of the human genome. Their means, styles, philosophies and uses for the completed project, however, are very different. The government's Human Genome Project started in 1990 as a joint effort between the Dept. of Energy and the National Institutes of Health. Originally a 15-year initiative, it has accelerated significantly over the years with the advent of new technology and a competitor in the private sector -- Celera Genomics. Dr. Venter, a former NIH researcher, founded Celera in 1998 to utilize his method of "shotgun sequencing" to complete the work in less than a year. Despite months of public acrimony, last summer, the two former colleagues announced jointly that they had completed sequencing the 3.1 billion base pairs of the human genome. Dr. Collins, the gentleman scholar who has directed the federal effort since 1992, is a deeply religious man. His office on the NIH campus is decorated with the covers of medical journals such as Nature Genetics and JAMA. It reflects a hybrid style of academe and government issue. Celera Genomics, farther out on the fringes of the Washington, D.C., suburbs, has the same medical journals decorating its offices, but also Forbes and Business Week. There are visible signs warning against the use of recording devices on the premises and high security doors blocking entry beyond the lobby. Behind those doors are large labs with more computers than people. It is in this high-tech labyrinth that Dr. Venter, the businessman and maverick of genetic science, goes to work. Dr. Collins Dr. Venter
Question: How will a physician integrate genetics into his or her practice? Answer: Any physician who's seeing patients with heart disease or hypertension or diabetes is seeing genetics. [But so far], it hasn't mattered very much for clinical management. That's all going to change in the next five to seven years. We will likely uncover the genetic contributions to the major common illnesses that fill up our clinics and hospital wards. Question: What about the cost-benefit analysis of genetically testing patients for diseases when they don't have symptoms and there might not be a treatment? Answer: Genetic information without an intervention will have limited value to people, and physicians won't get particularly excited about offering it. For example, we can test right now for future risk of Alzheimer's, but it's not being offered because there's no intervention available for people at high risk. The sea change here is that an [increasing] amount of genetic information will lead to an intervention. If we all believe in preventive medicine, then genetics is a very powerful strategy, allowing prevention to be individualized. Question: Any other thoughts on how genetics will affect scope of medical practice by 2010? Answer: I think we will see at least some examples of the pharmacogenomic approach coming into reality, where a genetic test will be used to predict the correct drug to use for an illness. There's a very impressive example that's almost now become the standard of care for childhood leukemia. If you're going to give 6-mercaptopurine, you want to know whether [your patient] is the one in 300 kids who is going to have a violent or even fatal reaction to [it] because of a genetic glitch. Perhaps even more significantly, we will begin to see the introduction of designer drugs based on a molecular understanding of disease, as has recently happened with the drug Glivec and chronic myelogenous leukemia. Question: Do you think the genetic age could lead to a reallocation of resources from the treatment of end-stage disease to prevention? Answer: I hope health care financing shifts to more preventive strategies. It certainly is more appropriate if what we are trying to achieve here is high-quality, long life. The laboratory part of genetic testing is not going to be that expensive. More of the cost, though, will come from the need for information exchange and counseling. I have very significant concerns about how we're going to handle that part, given the way managed care is driving interactions between patients and physicians into smaller and smaller time intervals. That doesn't seem like a good setting for effective exchange of fairly sophisticated statistical risk information. Question: How can an individual's genetic information be safeguarded? Answer: We have to solve this problem, and it is increasingly urgent to do so. Already in genetic testing research, fully a third of people who otherwise would qualify opt out because of fear that the genetic information will fall into the hands of insurers or employers and do them harm. The same will undoubtedly be true in clinical implications, unless we can provide assurances that legal protections will prevent misuses. Question: What about concern regarding the uses of genetic information and who benefits? Answer: That gets into the very complicated area of when licenses and patents should apply to genes. Clearly patents on genes can be justifiable in circumstances where [the gene] leads directly to the development of a therapeutic product. When it comes to diagnostics, it's a little less clear that having very exclusive rights on a particular gene is in the public's best interest. Question: What do you think of the failure-to-warn issue that recently came up in several lawsuits where family members sued physicians because they were not told about the hereditary diseases that their relatives had been treated for and that they were later diagnosed with? Answer: This is a potential collision between important principles, the duty to warn and the duty to maintain physician-patient confidentiality. My own personal experience is that [this scenario] is a wonderful ethical argument for the classroom but in reality virtually never happens. If there is a condition that places other family members at high risk, some patients may initially feel discomfort about contacting their family members. But after they give it some thought, they almost invariably do. Question: What drives you to do this work? Answer: I am driven by a sense of responsibility to try to reach out to people who are sick and a sense of frustration that many of the tools we have to accomplish that goal are far more limited than they ought to be. I am driven by the conviction that genetics holds the best promise that we've ever had to shine a light into those dark places and illuminate the mechanism of illness in a way that will lead us to a better outcome. Furthermore, as a person of faith, I can't help but look at this as a unique and remarkable opportunity to appreciate God's creation. ADDITIONAL INFORMATION:Francis S. Collins, MD, PhDBorn: April 14, 1950, Staunton, Va.
Sources: National Human Genome Research Institute, World Book Encyclopedia WeblinkNational Human Genome Research Institute (http://www.nhgri.nih.gov/) JAMA abstract, "Implications of the Human Genome Project for Medical Science," Feb. 7 (vol. 285, issue 5) (http://jama.ama-assn.org/issues/v285n5/abs/jsc00413.html) The businessman: J. Craig Venter, PhDQuestion: How do you think your work is going to impact medical practice? Answer: There's probably no part of medical practice that won't be impacted by sequencing the human genome. At a basic science level, things are now going at a magnitude faster than anybody might have ever imagined. That has changed the time course for new diagnostic and therapeutic discoveries. It's now not a question of if. It's a question of when. Question: What's the answer to the question of when? Answer: It's impossible to predict because of all this work going on across the board. For new diagnostics, there are things that are already in clinical medicine from genomic efforts. Some things are already starting to find their way through. There are two new antimicrobial vaccines in clinical trials from genomic work. One of the genomes we sequenced at the Institute for Genomic Research was the malaria genome. Steve Hoffman [MD], who was head of malaria research in the Navy and now head of immunotherapeutics here at Celera, developed some new malaria vaccines that are actually in clinical trials in the Navy. But the first things to reach the market will be new diagnostics and predictors of disease outcome. Question: What can be done to close the gap between the discovery of disease genes and new treatments? Answer: What the genome is going to give us is an understanding of how cells work. I absolutely believe that if we understand how biology works, we will understand how cancer develops and we will understand where to intervene in those cellular pathways to dramatically change those outcomes. The biggest discovery to come out of our sequencing [thus far] is that there are only 26,000 genes. It's not enough to have [discovered] one gene, one protein, one function, one disease. It's understanding the complex interaction between genes and proteins and protein interaction that will provide the understanding of biology. Question: What about the cost-benefit analysis of genetically testing patients for diseases when they don't have symptoms and there might not be a treatment? Answer: If we can predict whether somebody has increased risk of getting colon cancer and we know that when they're 20, we can give tremendous power to that person by not having them wait until they're 50 to have their first colonoscopy. We can, by using this information in the future, have lower medical costs by understanding the likelihood of disease and how to do something about it in advance. Question: How do you think genomics is going to affect drug development? Answer: That's what Celera is trying to do: Change the entire paradigm of drug development based on our sequencing and analysis of the human genome. We're trying to change the entire process based on high throughput, scientific approaches. For example, the public human genome project consumed somewhere between $3 billion and $5 billion, and it's still not done yet. That money was consumed over a 15-year period and involved over 3,000 scientists. Because we used new computers and new methods, we had 50 people at Celera who sequenced the human genome in nine months. We're using those same new technology approaches to have an equally dramatic effect on the next stages. We're building the world's largest laboratory dedicated to sequencing proteins. Our goal is a million protein sequences a day -- which is probably more than have been done to date in history -- to understand the changes in protein expression associated with different diseases. That will give us new early diagnostics. It'll give us new early validated targets for both immunotherapeutics and for small molecules. Question: What is your position on gene patenting? Answer: It's only been controversial because people want to make it controversial. Physicians would not have any new medical treatments or diagnostic tools, if they were not patented first. But fortunately, the patent office has raised the bar substantially so that companies can't just patent random pieces of DNA without knowing a lot more about their role in biology and medicine. Question: What motivates you do to this kind of work? Answer: Very few scientists have had the privilege that I've had in making basic science discoveries. But at the same time, I'm too impatient to wait for others to try and turn those into things that change the outcome of disease. I would like to see in my lifetime major diseases changed dramatically as a result of the science that my colleagues and I have done.
J. Craig Venter, PhDBorn: Oct. 14, 1946, Salt Lake City
Sources: Celera Genomics, Britannica.com WeblinkCelera Genomics (http://www.celera.com/) Science article, "The Sequence of the Human Genome," February (vol. 291, issue 5507) (http://www.sciencemag.org/cgi/content/full/291/5507/1304) Copyright 2001 American Medical Association. All rights reserved.
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