Founders of "the Human Genome Project" are ready to "re-thinking it all"...

[See posting at http://www.junkdna.com/new_citations.html ]

Founders of "the Human Genome Project" are ready to "re-thinking it all"... The Uncertain Future for Central Dogma

The ScientistVol. 19. Issue 12, pp. 20.June 20th, 2005

The Uncertain Future for Central Dogma

Uncertainty serves as a bridge from determinism and reductionism to a new picture of biology
By Arnold F. Goodman, Claudia M. Bellato and Lily Khidr

Nearly two decades ago, Paul H. Silverman testified before Congress to advocate the Human Genome Project. He later became frustrated when the exceptions to genetic determinism, discovered by this project and other investigations, were not sufficiently incorporated in current research and education.

In "Rethinking Genetic Determinism,"1 Silverman questioned one of the pillars of molecular genetics and documented the need for determinism's expansion into a far more valid and reliable representation of reality. He would receive correspondence from all over the world that reinforced this vision.

Silverman firmly believed that we needed a wider-angled model, with a new framework and terminology, to display what we know and to guide future discovery. He also viewed this model as being a catalyst for exploring uncertainty, the vast universe of chance differences on a cellular and molecular level that can considerably influence organismal variability. Uncertainty not only undermines molecular genetics' primary pillars of determinism and reductionism, but also provides a bridge to future research.

PILLARS CHALLENGED
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Various commentaries detail deviation from determinism within the cellular cycle. Here we use the term cellular cycle not in the traditional sense, but rather to describe the cyclical program that starts with gene regulation through transcription, translation, post-processing and back into regulation.

Richard Strohman at UC-Berkeley describes the program in terms of a complex regulatory paradigm, which he calls "dynamic epigenetics." The program is dynamic because regulation occurs over time, and epigenetic because it is above genetics in level of organization.2 "We thought the program was in the genes, and then in the proteins encoded by genes," he wrote, but we need to know the rules governing protein networks in a cell, as well as the individual proteins themselves.

John S. Mattick at the University of Queensland focuses upon the hidden genetic program of complex organisms.3 "RNAs and proteins may communicate regulatory information in parallel," he writes. This would resemble the advanced information systems for network control in our brains and in computers. Indeed, recent demonstrations suggest that RNA might serve as a genetic backup copy superseding Mendelian inheritance.4

Gil Ast of Tel Aviv University writes: "Alternative splicing enables a minimal number of genes to produce and maintain highly complex organisms by orchestrating when, where, and what types of proteins they manufacture."5 About 5% of alternatively spliced human exons contain retrotransposon Alu sequences. These elements represent an engine for generating alternative splicing.

Thus we see a genetic control system regulated by protein products, RNAs, and interventions from DNA itself. Yet throughout, the consideration of genetic uncertainty as a bridge to cellular behavior is conspicuously absent.

Genetic reductionism, the other pillar of molecular genetics, has many challengers. Among them is Stephen S. Rothman at UC-Berkeley, who described the limits of reductionism in great detail within his comprehensive and well-constructed book.6

A more recent publication by Marc H.V. Van Regenmortel at France's National Center for Scientific Research updated this assessment by discussing not only the deficiencies of reductionism, but also current ways of overcoming them. "Biological systems are extremely complex and have emergent properties that cannot be explained, or even predicted, by studying their individual parts."7

NEW CELL MODEL

Molecular genetics appears to be at a crossroads, since neither determinism nor reductionism is capable of accurately representing cellular behavior. In order to transition from a passive awareness of this dilemma to its active resolution, we must move from simply loosening the constraints of determinism and reductionism toward a more mature and representative combination of determinism, reductionism, and uncertainty.

Helen M. Blau was a keynote speaker at the recent UC-Irvine stem-cell symposium in memory of Paul Silverman and Christopher Reeve.8 She observed: "Where we look and how we look determine what we see." Although only a brief prescription, we now propose an approach to the exploration for uncertainty that involves both where we look and how we look. We examine those cellular-cycle outputs having a relatively high likelihood of diversity and its frequent companion, uncertainty.