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[From NYT] Humbled by the genome`s mysteries

Posted February. 21, 2001 14:17,   


Two groups of researchers released the formal report of data for the human genome last Monday — on the birthday of Charles Darwin, who jump-started our biological understanding of life`s nature and evolution when he published "The Origin of Species" in 1859. On Tuesday, and for only the second time in 35 years of teaching, I dropped my intended schedule — to discuss the importance of this work with my undergraduate course on the history of life. (The only other case, in a distant age of the late 60`s, fell a half-hour after radical students had seized University Hall and physically ejected the deans; this time at least, I told my students, the reason for the change lay squarely within the subject matter of the course!)

I am no lover, or master, of sound bites or epitomes, but I began by telling my students that we were sharing a great day in the history of science and of human understanding in general.

The fruit fly Drosophila, the staple of laboratory genetics, possesses between 13,000 and 14,000 genes. The roundworm C. elegans, the staple of laboratory studies in development, contains only 959 cells, looks like a tiny formless squib with virtually no complex anatomy beyond its genitalia, and possesses just over 19,000 genes.

The general estimate for Homo sapiens — sufficiently large to account for the vastly greater complexity of humans under conventional views — had stood at well over 100,000, with a more precise figure of 142,634 widely advertised and considered well within the range of reasonable expectation. Homo sapiens possesses between 30,000 and 40,000 genes, with the final tally almost sure to lie nearer the lower figure. In other words, our bodies develop under the directing influence of only half again as many genes as the tiny roundworm needs to manufacture its utter, if elegant, outward simplicity.

Human complexity cannot be generated by 30,000 genes under the old view of life embodied in what geneticists literally called (admittedly with a sense of whimsy) their "central dogma": DNA makes RNA makes protein — in other words, one direction of causal flow from code to message to assembly of substance, with one item of code (a gene) ultimately making one item of substance (a protein), and the congeries of proteins making a body. Those 142,000 messages no doubt exist, as they must to build our bodies` complexity, with our previous error now exposed as the assumption that each message came from a distinct gene.

We may envision several kinds of solutions for generating many times more messages (and proteins) than genes, and future research will target this issue. In the most reasonable and widely discussed mechanism, a single gene can make several messages because genes of multicellular organisms are not discrete strings, but composed of coding segments (exons) separated by noncoding regions (introns). The resulting signal that eventually assembles the protein consists only of exons spliced together after elimination of introns. If some exons are omitted, or if the order of splicing changes, then several distinct messages can be generated by each gene.

The implications of this finding cascade across several realms. The commercial effects will be obvious, as so much biotechnology, including the rush to patent genes, has assumed the old view that "fixing" an aberrant gene would cure a specific human ailment. The social meaning may finally liberate us from the simplistic and harmful idea, false for many other reasons as well, that each aspect of our being, either physical or behavioral, may be ascribed to the action of a particular gene "for" the trait in question.

But the deepest ramifications will be scientific or philosophical in the largest sense. From its late 17th century inception in modern form, science has strongly privileged the reductionist mode of thought that breaks overt complexity into constituent parts and then tries to explain the totality by the properties of these parts and simple interactions fully predictable from the parts. ("Analysis" literally means to dissolve into basic parts). The reductionist method works triumphantly for simple systems — predicting eclipses or the motion of planets (but not the histories of their complex surfaces), for example. But once again — and when will we ever learn? — we fell victim to hubris, as we imagined that, in discovering how to unlock some systems, we had found the key for the conquest of all natural phenomena. Will Parsifal ever learn that only humility (and a plurality of strategies for explanation) can locate the Holy Grail?

The collapse of the doctrine of one gene for one protein, and one direction of causal flow from basic codes to elaborate totality, marks the failure of reductionism for the complex system that we call biology — and for two major reasons.

First, the key to complexity is not more genes, but more combinations and interactions generated by fewer units of code — and many of these interactions (as emergent properties, to use the technical jargon) must be explained at the level of their appearance, for they cannot be predicted from the separate underlying parts alone. So organisms must be explained as organisms, and not as a summation of genes.

Second, the unique contingencies of history, not the laws of physics, set many properties of complex biological systems. Our 30,000 genes make up only 1 percent or so of our total genome. The rest — including bacterial immigrants and other pieces that can replicate and move — originate more as accidents of history than as predictable necessities of physical laws. Moreover, these noncoding regions, disrespectfully called "junk DNA," also build a pool of potential for future use that, more than any other factor, may establish any lineage`s capacity for further evolutionary increase in complexity.

The deflation of hubris is blessedly positive, not cynically disabling. The failure of reductionism doesn`t mark the failure of science, but only the replacement of an ultimately unworkable set of assumptions by more appropriate styles of explanation that study complexity at its own level and respect the influences of unique histories. Yes, the task will be much harder than reductionistic science imagined. But our 30,000 genes — in the glorious ramifications of their irreducible interactions — have made us sufficiently complex and at least potentially adequate for the task ahead.

We may best succeed in this effort if we can heed some memorable words spoken by that other great historical figure born on Feb. 12 — on the very same day as Darwin, in 1809. Abraham Lincoln, in his first Inaugural Address, urged us to heal division and seek unity by marshaling the "better angels of our nature" — yet another irreducible and emergent property of our historically unique mentality, but inherent and invokable all the same, even though not resident within, say, gene 26 on chromosome number 12.


Stephen Jay Gould, a professor of zoology at Harvard, is the author of "Questioning the Millennium."