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UNRAVELING THE SECRET OF LIFE: DNA self-duplication, the basic precept of biotechnology, is denied

by Barry Commoner
GeneWatch
May-June 2003

References

Unraveling the DNA Myth: The Spurious Foundation of Genetic Engineering

by Barry Commoner
Harper's Magazine
February 2002

Synopsis
References

The Real Central Dogma

What can account for this universal disregard of the Central Dogma proper? Crick's formulation of that hypothesis is typically simple, direct and authoritative: "Once (sequential) information has passed into protein it cannot get out again." Even a casual reader who ventured into his 1970 paper¹, a brief but pungent review of his theory's status, might notice that Crick regarded his second hypothesis so critical to the viability of the whole science that he closed the paper with an ominous warning: If, contrary to the Central Dogma hypothesis, experimental evidence showed that genetic information could flow from protein to DNA, to RNA, or to protein, it "would shake the whole intellectual basis of molecular biology."

The reason why this vibrant new science might totter if proteins not only receive genetic information but contribute to it as well, can be visualized in a simple diagram. The Sequence Hypothesis is neatly symbolized by a straight line with arrows depicting the flow of genetic information from DNA to RNA and from RNA to protein, where, according to the Central Dogma, it stops. DNA is then the sole source of the protein's genetic information and hence of the inherited trait that the protein engenders. If, in defiance of Crick's warning, we extend the diagram to show that the protein's genetic information is transferred to DNA (or RNA), the original line loops back from protein to DNA and the genetic flow is no longer linear but circular. No one component of that circle can be the singular source of genetic information; both DNA and proteins (and perhaps some RNAs as well) contribute to the overall commingled flow of genetic information.

As the article points out, there is direct experimental evidence to show that a protein, DNA polymerase, that catalyzes the synthesis of DNA (by linking together free nucleotides that are attracted to a "primer" strand of DNA) influences the nucleotides' linear order and therefore the newly made molecule's genetic information. Indeed, a battery of different protein enzymes is needed to assure that the newly synthesized DNA faithfully replicates the nucleotide sequence of the original primer DNA. This means that the genetic information embodied in the new DNA strand is the commingled product of genetic information supplied by the original DNA primer and by the various participating DNA polymerase enzymes. Similarly, the proteins that catalyze the processes that lead from DNA through RNA to protein synthesis (such as alternative splicing) contribute, together with DNA, to the genetic information that is commingled in these final protein products.

Clearly, Crick's second hypothesis, the Central Dogma proper, is crucial to the explanatory power of the theory of molecular genetics. By forbidding the circular flow of genetic information, it gives the DNA gene exclusive control over the genetic specificity of proteins and the inherited traits that they create. It is this negative mandate that establishes DNA as the unique molecular agent of biological inheritance, possessing an absolute power that transcends the natural genetic barrier between species and that justifies its elevation to a cultural icon. The dire prophesy that Crick attached to the breaking of this taboo warns of the profound impact of depriving DNA of its genetic sovereignty. DNA then becomes but one of the participants in an inherently complex molecular system of inheritance - but it is a system that, unique to the living cell, rises to the level of biology.

Indeed, it is the very ability of proteins to transmit genetic information that enables them to produce a specific inherited trait. Even before the discovery of the DNA double helix, it was known that it is the biochemical specificity of protein enzymes that gives rise to inherited traits such as Drosophila eye colors. That specificity - the enzymes' ability to catalyze a particular chemical reaction - resides in a localized configuration on the surface of the protein's three-dimensional structure. Crick was aware that the nascent protein, a linear structure, had to be folded up in a particular way to create the catalytic "active site" on its surface, and he assumed that this was automatically determined by the protein's amino acid sequence - that is, its genetic information. So, despite Crick's dictum that the protein's genetic information "cannot get out again," in fact in an enzyme it resurfaces, so to speak, in the active site from which it is finally transmitted to specific inherited traits such as eye-color pigment.

The editors of Nature Genetics provide us with a direct, if bizarre, confirmation that, in its current truncated usage, the central dogma has been distanced from its relation to inheritance. But their assertion that Crick's theory "had nothing to do with the relationship between an organism's genome and its inherited traits" is also an astonishing misstatement of historical fact. At the time of Crick's 1958 paper², it was known not only that protein enzymes engender inherited traits, but also that DNA is a major component of the gene-bearing chromosome, serves as a transmissible agent of bacterial inheritance, and is endowed with a molecular structure that facilitates its replication. But without a biochemical link between the gene's DNA and the enzyme's protein, the sought-for molecular explanation of biological inheritance remained out of reach. By proposing how the gene's DNA could govern protein specificity, Crick's Sequence Hypothesis deftly filled this gap.

Seen in this historical context, Crick's theory clearly postulated a molecular explanation of inheritance precisely because, as the editorial, unblushing, says, "it simply stated that information flow in the cell goes from nucleic acid to proteins." It was this newly forged link, for which Crick deserves most of the credit, that triggered the explosive growth in molecular genetics and the widespread view that biological inheritance - not merely the protein's amino acid sequence - is governed by the flow of genetic information originating, exclusively, in DNA.

Since then, however, researchers have observed numerous experimental results that do not fit into the simple DNA-RNA-protein pattern of what they regarded as the central dogma. The infidelity of DNA replication, the existence of alternative splicing, not to speak of the shortfall in the human gene count - all of them "unexpected" because they failed to fit even this truncated form of Crick's theory - were nevertheless seen only as more detailed versions of the Sequence Hypothesis, albeit now disguised as the central dogma.

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