A time to sequence.

My views on the Human Genome Project first appeared in Science in 1987 in the form of a one-word quotation: "Huge" (1). Eight years later, in deference to the size and complexity of the current program, I have been allotted more space. I use it here to examine the state of the project and to suggest a path forward. The basic game plan for an organized Human Genome Project in the United States was established by a National Research Council committee, chaired by Bruce Alberts (2). Indeed, I was testifying before this committee in 1987 when my assessment of the project's scale caught a Science reporter's attention. The Alberts Committee recommended an early emphasis on genetic linkage mapping and clone-based physical mapping of human DNA. In parallel, the committee recommended research on the technology of DNA sequencing, as well as pilot-scale sequencing of the genomes of model organisms. This approach was viewed as the best way to improve the reliability of DNA sequencing--and to drive down its cost--while simultaneously gathering data of immediate biological value. To a remarkable degree, the Alberts Committee read the historical and technical trends correctly. It now appears that even its estimates of time scale and cost-15 years at $200 million per year--were about right. In 1987, skeptics could still argue about basic feasibility with some force. Conversely, many of the project's proponents lacked a realistic sense of the diversity of problems that had to be solved before mammalian-scale sequencing would become practical. Even the Alberts Committee's middle-of-the-road recommendations would likely have proven to be overambitious if it were not for several unforeseen developments. Technically, the most important of these has been the emergence of the polymerase chain reaction (PCR) as a primary tool for DNA analysis. Rapid advances in computer technology have also been significant, particularly because they have allowed most of the project's dataanalysis and data-management needs to be met by the distributed efforts of small groups of programmers working in close collaboration with experimentalists. Finally, vigorous international participation in the project has materialized, a development that the Alberts Committee strongly en: