For more than 50 years scientists have operated under a set of seemingly incontrovertible assumptions about genes, gene expression, and the consequences thereof. Their mantra: One gene yields one protein; genes beget messenger RNA, which in turn begets protein; and most critically, the gene is deterministic in gene expression and can therefore predict disease propensities.
Yet during the last five years, data have revealed inadequacies in this theory. Unsettling results from the Human Genome Project (HGP) in particular have thrown the deficiencies into sharp relief. Some genes encode more than one protein; others don't encode proteins at all. These findings help refine evolutionary theory by explaining an explosion of diversity from relatively little starting material. We therefore need to rethink our long-held beliefs: A reevaluation of the genetic determinism doctrine, coupled with a new systems biology mentality, could help consolidate and clarify genome-scale data, enabling us finally to reap the rewards of the genome sequencing projects.
UNEXPECTED RESULTS In the mid- and late 1980s, our testimony before the congressional committees controlling HGP purse strings relied upon our old assumptions. (1) In describing the genome's potential medical value, we elevated the status of the gene in human development and by extension, human health. At the same time, the deterministic nature of the gene entered the social consciousness with talk of "designer" babies and DNA police that could detect future criminals.
Armed with DNA determinism, scientific entrepreneurs convinced venture capitalists and the lay public to invest in multibillion-dollar enterprises whose aim was to identify the anticipated 100,000-plus genes in the human genome, patent the nucleotide sequences, and then lease or sell that information to pharmaceutical companies for use in drug discovery. Prominent among these were two Rockville, Md.-based companies, Celera, under the leadership of J. Craig Venter, and Human Genome Sciences, led by William Haseltine.
But when the first draft of the human genome sequence was published in the spring of 2001, the unexpectedly low gene count (less than 30,000) elicited a hasty reevaluation of this business model. On a genetic level, humans, it seems, are not all that different from flies and worms.
Or maybe they are, if we can assume that genes are not strictly deterministic....