Wednesday, February 08, 2006


[evomech] The Human Genome Project +5 (The Scientist)

[McElheny, The Scientist, Feb '06]

Five years after publication of two drafts of the human genome, Maynard Olson of the University of Washington finds himself longing for another "lurch." To be sure, genomic scientists across the world have chalked up many achievements since 2001, but, like many of his colleagues, Olson is feeling more impatient than celebratory.

Progress has included a blizzard of comparisons between the human sequence and many others, including the chicken, the mouse, the rat, the dog, and the chimp. The flourishing of comparative genomics, says Olson, has changed the focus of genomics from a single reference sequence of genes to a rich variety of "functional elements," largely sequences that serve as ignition switches, brakes and accelerators for gene expression. And the focus on single-base changes has widened to an array of evolutionary rearrangements: insertions, deletions, reversals, and duplications. There are new tools: new global databases of all functional elements in genomes (e.g., ENCODE), small molecules for chemical genomics (e.g., PubChem), and a raft of protein structures.

And yet the last five years, in Olson's view, have been "a period of a great grinding of gears, kind of shifting of gears." In the terms of the science historian Thomas Kuhn, it's been "a period of consolidation and more normal science." Others, such as Sydney Brenner of the Salk Institute, the Nobel Prize-winning pioneer of the worm, Caenorhabditis elegans, go further, worrying that the genome sequence and the growing lists of sequences and proteins and protein interactions and functional elements don't get very deep into such core problems of biology as the operations of the cell, of development from egg to adult, or the problem of consciousness. "We've become very geno-centric," says Brenner. "The cell must become the focus."

What vexes many thousands of colleagues around the world most is that genomics hasn't yet moved into the "real world" of medical relevance. Olson led a team that sequenced the principal microbe involved in lung infections in cystic fibrosis patients, Pseudonomas aeruginosa. Referring to changes in cells of both the patient and the infecting organisms, says Olson, "it's clear that mutational cascades are a really critical aspect of disease progression, just as is the case with cancer." To build a genomics "bridge" into this area is going to call for a "very large" amount of sequencing of both patients and microbes to follow the progression of the disease. For this, the faster second-generation sequencing technologies emerging from several startup companies will be essential, Olson thinks, just as it will be for the new National Institutes of Health Cancer Genome Project, on which pilot work has begun. "They're over-promising and are trying to move too quickly, without a strong enough strategic plan," Olson argues. "Nonetheless the scientific idea is right. These policy things usually eventually fall into place as reality exerts itself."

Such issues as cheaper, faster DNA sequencing to get genomic tools into the clinic sooner will define the field for the next five years, and beyond. Echoing Olson, Cold Spring Harbor Laboratory's Lincoln Stein says the last five years have fit Kuhn's definition of 'normal science," although "the number of questions never decreases."

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Model of an Internal Evolutionary Mechanism

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