Human Genome Project Completed: A Newsmaker Interview With Alan E. Guttmacher, MD

Laurie Barclay, MD

April 16, 2003

April 16, 2003 — Editor's Note: On April 14, the International Human Genome Sequencing Consortium announced the successful completion of the Human Genome Project, two and a half years ahead of schedule and $0.3 billion under budget. Although an earlier draft of the genome sequence was revealed in June 2000, this update sequences the 3 billion DNA letters in the human genome with 99.99% accuracy and with fewer than 400 gaps in structure, representing less than 1.0% of the human genome's gene-containing regions.

"The Human Genome Project has been an amazing adventure into ourselves, to understand our own DNA instruction book, the shared inheritance of all humankind," Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute (NHGRI) and leader of the Human Genome Project since 1993, says in a news release. "All of the project's goals have been completed successfully — well in advance of the original deadline and for a cost substantially less than the original estimates."

The International Human Genome Sequencing Consortium includes hundreds of scientists at 20 sequencing centers in China, France, Germany, Great Britain, Japan, and the U.S. The five institutions that sequenced the most portions of the human genome were Baylor College of Medicine in Houston, Texas; Washington University School of Medicine in St. Louis, MIssouri; Whitehead Institute/MIT Center for Genome Research in Cambridge, Massachusetts; Department of Energy (DOE)'s Joint Genome Institute in Walnut Creek, California; and The Wellcome Trust Sanger Institute near Cambridge, England, which alone generated about 30% of the entire sequence.

Bonus spinoffs from the project, also delivered with startling speed, include an advanced draft of the mouse genome sequence released in December 2002; an initial draft of the rat genome sequence in November 2002; identification of more than 3 million human single nucleotide polymorphisms (SNPs); and the generation of full-length complementary DNAs (cDNAs) for more than 70% of known human and mouse genes. All of this sequence data resides in public databases, where it is freely available to scientists around the world, without restrictions on its use or redistribution.

Despite these landmark achievements, the NHGRI and the DOE, which led the U.S. portion of the international effort, believe that the real work has only just begun. NHGRI will set forth its revolutionary vision for the future of genomic research in the April 24 issue of Nature , remarkably coinciding with the 50th anniversary of Nature 's publication of DNA's double helix structure as described by James Watson and Francis Crick.

"Never would I have dreamed in 1953 that my scientific life would encompass the path from DNA's double helix to the 3 billion steps of the human genome. But when the opportunity arose to sequence the human genome, I knew it was something that could be done — and that must be done," says Nobel Laureate James D. Watson, PhD, now president of Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y. "The completion of the Human Genome Project is a truly momentous occasion for every human being around the globe."

Now that the overall sequencing is complete, one of the next steps is to compare genetic differences among individuals and identify those associated with a specific condition, uncovering the genetic contributions to many diseases. Begun in October 2002 and slated for completion in three years, the International HapMap Project of NHGRI and its collaborators hope to produce the "next-generation" map of the human genome, identifying genes related to asthma, cancer, diabetes, heart disease, and other chronic conditions.

But has genome sequencing opened a Pandora's box of futuristic fears? To address these concerns, the Human Genome Project has devoted a significant portion of its budget to study the ethical, legal, and social implications of this research. NHGRI and DOE have also dedicated 3% to 5% of their genome budgets to examining how the exponential increase in human genetic knowledge may affect individuals, institutions, and society. Based on this work, more than 40 U.S. states have passed genetic nondiscrimination bills.

"Achieving the goals of the Human Genome Project is a historic milestone. But this is no time to rest and relax," Dr. Collins says. "With this foundation of knowledge firmly in place, the medical advances promised from the project can now be significantly accelerated."

To find out more about the significance of this monumental achievement and its implications for the future, Medscape's Laurie Barclay interviewed Alan E. Guttmacher, MD, NHGRI deputy director. As head of the Office of Policy, Planning and Communications, Dr. Guttmacher also oversees strategic planning for the NHGRI and its impact on the field of genomics. To integrate the findings of the Human Genome Project into medical practice, he will help the NHGRI develop new research tools leading to new diagnostic tests and treatments.

Medscape: Are you surprised that genomics research has advanced so quickly, and that the human genome has been sequenced nearly 50 years to the day since Watson and Crick's discovery of the double helix?

Dr. Guttmacher: In some ways I am surprised. If you had asked me half a dozen years ago, I'd have thought we'd be getting near to sequencing the human genome in the designated time, but not actually accomplishing it. I'm also surprised that we have advanced as far as we have in related areas.

Medscape: To what do you attribute this amazing progress?

Dr. Guttmacher: To collaboration among many different researchers both nationally and internationally, which has been far more efficient and effective than we would have guessed. Our ability to move ahead with the sequencing has been pretty impressive. Also, our ability to spawn other projects based on the draft sequences — essentially our ability to mine the genome before sequencing is even complete — has been very impressive. Projects which we first thought would have to await sequencing were actually started sooner, like the haplotype map and the ENCODE project, an encyclopedia of DNA elements.

Medscape: What are the therapeutic implications of sequencing of the human genome? On which diseases or categories of disease do you think there will be the greatest impact?

Dr. Guttmacher: The sequencing itself has no impact, but the use of sequencing information has a very broad impact throughout the spectrum of diseases. It will help us redefine categories of disease. Before, we have categorized diseases based on their symptomatology, but now we can group them genetically, which should be more meaningful in terms of underlying biology, pathways and mechanisms of disease, and ultimately causation. This will lead in and of itself to better treatment and prevention strategies.

The first and most dramatic inroads may be in cancer, but genome sequencing should ultimately have a profound impact across all diseases, including infectious disease, cardiovascular disease, neurodegenerative disease, and others.

Medscape: Will genome sequencing facilitate diagnosis of genetic conditions and even discovery of new diseases?

Dr. Guttmacher: Genome sequencing offers ways to diagnose earlier in the disease process, as well as more precisely. We may even be able to diagnose pre-disease conditions by identifying genetic risk factors for certain diseases while individuals are still healthy.

Medscape: Are there dangers in that approach, for example, by creating a self-fulfilling prophecy of illness, or by opening the door to discrimination on the basis of risk factors for disease?

Dr. Guttmacher: This type of information does carry with it risks to society, with potential impact on insurability and employability, for example. So we have to manage this information much as we do standard medical information. The problem of coming up with information is usually less than the problem of what we do with it once we have it, and certainly genomics will add to that dilemma. If we do identify individuals who are genetically at risk for certain diseases, the best management may be to fiddle with the environment, not to fiddle with their genetic structure. With cancer, for example, it's much easier and cheaper to manipulate environmental factors, like secondhand smoke, and we have much more experience doing that. Increased genetic risk needs to be interpreted in the context of everything else we know about an individual.

Medscape: Does genomic sequencing offer insight into biological clocks involved in aging? Are there any implications for life extension, or conversely, for accelerating development of a clone into an adult, if that were theoretically possible?

Dr. Guttmacher: Information was released today and will appear online in Nature next week that Dr. Collins' group has discovered the gene responsible for progeria, a disease of premature aging, based on the human genome sequence. This is the first of many such steps to identify the biological basis of aging. Certainly we will all continue to age, but now we may begin to understand the steps involved.

Medscape: Do you think that this information will lead to genetic engineering or "designer babies"? How can unethical applications be avoided?

Dr. Guttmacher: Designer babies are not on our doorstep, but we need to consider this down the road. It's not an immediate risk, but certainly a risk we need to be concerned with some years from now. We need a much broader and deeper discussion of how to govern these issues. Committees will certainly be set up to deal with the scientific and larger societal implications. They may involve elected government leaders, groups specifically formed to lead these discussions, and members from academia or from nonprofit organizations. As with any major change in life, this change in science needs to be addressed in terms of its much larger ramifications.

Medscape: Does genome sequencing threaten individual privacy, for example, if sociopathic or other undesirable personality traits are identified with specific gene sequences? Are ethical safeguards in place to prevent misuse of genetic information and/or discrimination on the basis of genotype?

Dr. Guttmacher: Threats to individual privacy are more immediate than the issue of designer babies. Already more than 40 states have legislation limiting employers' access to genetic information. We need effective federal legislation — we're close to passing a bill, but we need to complete this. We also need to develop standards of practice concerning this. In some ways, genetic information is no different than other medical information, but in other ways, it is; it speaks more to who we are. Because this information may be particularly charged, it may need more protection. We're just beginning to grapple effectively with this.

Medscape: In this era of bioterrorism, are there any dangers of having all the sequence data freely accessible to scientists all over the world?

Dr. Guttmacher: It's less of a danger than it is a protection. Dealing with SARS [severe acute respiratory syndrome], for example, although that's not bioterror-related as far as we know, it is a good model for dealing with a new infectious agent. The first real steps came through using the genetic identity of the virus. When dealing with possible bioterror agents, having genetic knowledge of differentagents will be helpful. Any kind of information can be used for good or ill. It's not the information, but how we use it that's important.

Medscape: What is the next step for research laboratories that have been heavily involved in this project?

Dr. Guttmacher: There's a number of next steps that we've already alluded to. The haplotype map will make further genetic research much easier. The ENCODE project is looking at what's hidden in the genome, and the exact mechanism by which it functions. The major research, now that we have the genomic sequence in hand, is to figure out what it says and what it means. The techniques learned in human genomic sequencing are also applicable to sequencing other organisms, and comparative genomics will help us understand even more about the human genome.

Medscape: Overall, what do you see as the greatest significance of this project?

Dr. Guttmacher: I'm not sure that there is a single greatest significance. But if I had to pick just one, I'd say it's the way this knowledge will change our approach to health and to healthcare. We don't have that in hand yet, but there is a promise of that. If we looked back centuries from now, we'd see that this was an important first step. It's a wonderfully exciting time, this beginning of the genome era, with much potential benefit for biology, for health, and for society.

Reviewed by Gary D. Vogin, MD

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