VIEWPOINT • Summer 2001

By Robert H. Waterston

The publications on the human genome sequence in Nature and Scienceare major milestones in the biomedical revolution begun in 1953 with the discovery of the structure of DNA by Watson and Crick. Building on Mendel's findings that traits were inherited as units called genes, Watson and Crick showed that genetic information was stored in strings of chemical bases A, G, C, and T in much the same way that knowledge is stored in strings of letters.

The papers describe the first overview of the human genome, our genetic instruction book. Both are based on the same clone-by-clone strategy advocated and pursued by the publicly funded International Human Genome Project (I-HGP), despite assertions by the commercially funded project at Celera that such an approach would be made obsolete by their "whole genome shotgun" strategy. In the end, the whole genome shotgun method failed, and Celera retreated to the use of the public clone-by-clone sequences and public clone maps to produce a sequence that differed only in minor ways from the sequence produced by the I-HGP.

Robert H. Waterston

"Although comparative sequencing with other genomes will be needed to further explain the human sequence ... these initial views of the genome provide some fascinating insights."

Although comparative sequencing with other genomes will be needed to further explain the human sequence, and both sides agree that the present versions are incomplete, these initial views of the genome provide some fascinating insights. We have fewer genes than suspected—just two to three times as many as the much simpler worm and fly. We can begin to read our evolutionary history, as a species and beyond. Most importantly for the general public, the human genome sequence promises to accelerate the pace of discoveries of the genes behind human health and the variant forms that lead to disease, to unfavorable drug reactions, and to variation in the population.

Genes behind many diseases are already known—for example, genes leading to cystic fibrosis, to colon or breast cancer, and to Alzheimer's. But hunts for new disease genes will no longer be slowed by the search for the altered gene. Further, the studies of sequence variation will allow the discovery of genes behind complex diseases such as heart disease, diabetes, hypertension, and asthma. We will also learn about genes contributing to intelligence and behavior. The possibilities are exhilarating and seemingly endless.

This explosion of knowledge from genome research creates opportunities. Already tests are available for genes behind diseases such as cystic fibrosis, breast cancer, and Huntington's disease. With cystic fibrosis, early diagnosis can delay onset of the disease and slow its progression. Carriers of gene variants that predispose to breast cancer face an agonizing decision of whether to have a bilateral mastectomy in order to prevent it. Unfortunately, with Huntington's disease, there is no ameliorative treatment available at present. The long-term hope is that new therapies, drugs, or even corrective genes can be developed that will lead to cures.

This gap between knowledge and treatment creates new problems. One only has to look at the Burlington Northern Santa Fe Railway case, appearing in the press in the same week as the genome papers, where genetic tests were to be used to discriminate against those with predispositions to job-related disabilities, in hopes of reducing costs. This case represents both bad science and bad ethics, and vividly demonstrates the potential for abuse of genetic tests. Burlington abandoned its plans in the face of public outcry, but we should expect other cases to follow. To prevent the misuse of this powerful information, we must stand up now and demand strong laws protecting our genetic privacy.

The longer-term concerns center around whether and how this information might be used to alter our genetic makeup. Almost everyone agrees that gene therapy would be appropriate if it could rescue an infant from lifelong suffering. But what about the use of such methods to promote "desirable" traits, such as intelligence, athletic ability, or even good looks? Will altered genes be passed on to subsequent generations? These are questions that must be answered.

These complex traits are likely to involve many genes (and the environment) and require long-term study to understand them well enough to allow intelligent intervention. But this lack of clear knowledge will not stop unscrupulous practitioners in a free market from making promises to the contrary. Nor will it stop vulnerable and credulous individuals from coming under their sway. We must find ways of limiting the damage, while at the same time preventing government from becoming involved in individuals' reproductive decisions.

These publications represent a beginning, not an end. The potential benefits are enormous; bringing benefits to all as quickly as possible requires making the sequence available for all without constraint. The best way to ensure the wise use of the sequence is to include all voices in the debate. The human genome sequence is our shared inheritance. It belongs to all of us.

Robert H. Waterston is the James S. McDonnell Professor of Genetics and head of the Department of Genetics at the School of Medicine. He also directs the medical school's Genome Sequencing Center, which organized the genome map and contributed more than 20 percent of the sequence data to the publicly funded International Human Genome Project.

This article first appeared as "Part 1" of a two-part editorial, titled "Commentary: The Future at a Glance," in the St. Louis Post-Dispatchon February 18, 2001.