Medical Genetics, Molecular Biology, and the Human Genome Project, 1980-2008

Mendelian Inheritance in Man (MIM), in its successive editions, chronicled the expanding realm of genetic knowledge, especially regarding disease-related genes. But mapping the location of specific genes on specific chromosomes was still slow, laborious work. Writing in 1971, McKusick noted "Identifying the gene responsible for a particular human trait and finding its locus, or site, on one of the 23 pairs of chromosomes of man is a labor a little like hunting in a cluster of mazes for an invisible animal identifiable only by its odor." Finding such quarry required tracking indirect clues, constructing family pedigrees, linking unusual traits, and applying sophisticated probability theory. Nevertheless, gene mapping enthusiasts, including McKusick, believed that a complete map of all the possible gene segments in chromosomal DNA would be a useful reference work for genetic medicine and science. McKusick boldly suggested in 1980 that it might be possible to do this by the year 2000, though it was not clear how this could be achieved, nor precisely how this complete information would aid the study of birth defects.

McKusick's statement was prescient: human gene mapping accelerated after 1980, aided by new molecular techniques such as DNA probes and markers. By 1990 over 2,000 genes had been mapped to specific chromosomes, many of them to specific chromosomal regions. The advanced DNA sequencing techniques developed during the late 1970s made it possible to consider analyzing all 3 billion base pairs in the human genome. The Human Genome Project (HGP), a large-scale effort to carry out a complete sequencing of human DNA, was formally proposed in 1985, and hotly debated for the next few years. Which government agencies would fund and oversee such a massive project? (The Department of Energy (DOE) had long done research on the biologic effects of radiation, but many argued that the National Institutes of Health (NIH) should serve as the base agency.) How much would it cost? How would the results further scientific knowledge? What benefits would the project generate for the public? Given that only some segments of DNA seemed to function as genes, was it even good science to sequence the entire genome?

To assess these questions, in late 1986, the National Research Council organized a committee on mapping and sequencing the human genome. The committee, which included McKusick, Sydney Brenner, James Watson, and other eminent scientists, concluded in their 1988 report that the project should be done, that it could be completed in 15 years at an annual budget of $200 million, and that mapping of DNA markers should be done first, to provide a scaffolding for the sequencing. The committee also recommended that the sequence of the genomes of other species should be determined in parallel with that of the human. The project funding was approved by Congress, and work began officially in October 1990, with both the DOE and NIH taking a part.

The Human Genome Project had been discussed and planned by scientists in other countries as well, and in 1988, the Human Genome Organization (HUGO) was founded as a non-governmental coordinating agency for the global effort. McKusick, because of his leadership in many areas of medical genetics, particularly the international Human Gene Mapping workshops, was asked to serve as founding president of HUGO. The organization was to be "a U.N. [United Nations] for the human genome," as Norton Zinder put it. Rather than serving as a funding agency, it has been a coordinating agency for the various genome projects funded by national governments, fostering scientific collaborations, coordinating and facilitating the exchange of data and materials, and encouraging public discussion on various aspects of the global genome project.

From the start, the HGP raised a number of ethical, legal, and social issues. Would the ability to "read" an individual's genes for potential health or behavioral problems result in a "new eugenics," and legitimize discrimination by schools, employers, insurance companies, or the criminal justice system, for example? How would the privacy of individual genetic information be safeguarded? McKusick participated in many of the discussions on these topics, chairing the HUGO ethics committee, and also serving as a member of the ethics committee for the National Center for Human Genome Research. By the early 1990s, law enforcement agencies increasingly used DNA technology to assess forensic evidence, and at the request of FBI director William Sessions, McKusick was part of the group that formulated standards for DNA forensics.

As one colleague commented, McKusick lived and breathed medical genetics. He never really retired, but continued to teach, write, and edit the Online Mendelian Inheritance in Man, serve on committees, and attend conferences in his later years. Only his final illness kept him from attending the 2008 annual Bar Harbor course; even so, he watched the proceedings on streaming video the day before his death on July 22, 2008.