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A project by Stephen L. Talbott

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Getting Over the Code Delusion


IT IS NOW WIDELY RECOGNIZED that the Human Genome Project (HGP) failed to yield anything like a DNA “Book of Life”. As molecular biologist Tom Misteli wrote in the journal Cell, the project “shed little light onto the Holy Grail of genome biology, namely the question of how genomes actually work”. It did not reveal the immaculate, computer-like logic that was supposed to give organisms their marching orders. Instead, it has shown DNA inextricably woven into, and regulated by, virtually all the processes — all the life — of the cell.

The HGP brought vivid attention to paradoxes both old and new. First, it turned out that we share between 98 and 99 percent of our protein-coding genes with chimpanzees, leaving many to wonder how to explain our differences — or even whether there were any very significant differences. Second, it now became indisputable that humans have no more genes than some much simpler organisms. (The water flea has more than one and a half times the number of our genes.) Third, some 95 - 98 percent of the human genome does not bear the protein-specifying genetic “code” at all, but was dismissed at first as “junk DNA”.

And all this brought renewed confrontation with a fourth, long-perplexing truth: cells originally possessing the same genome in our developing, embryonic bodies eventually differentiate into hundreds of distinct cell types, suitable for lungs, livers, bones, blood, retinas, and so on. If DNA makes us what we are, how can the same DNA produce such radically different cellular features?

Part of the answer is now often said to be that the so-called junk DNA actually performs vital regulatory functions to help make the differentiation of cells possible. But, of course, the junk DNA is also the same in the different cell types, so that doesn’t get us very far. The more profound answer is that gene regulation in general is distributed throughout the cell and organism. Cells with the same DNA can become very different because the organism directs the functioning of its DNA at least as much as the DNA directs the functioning of the organism. The power of being what it is lies with the organism as a whole, not with one of its parts — hardly a huge surprise for anyone who has actually observed the integral unity of living creatures.

Central to the new understanding is the fact that chromatin — the DNA/RNA/protein complex comprising our chromosomes — is organized by the cell in extraordinarily complex ways. Wrapped around millions of “spools”, compacted more here and less there, joined by a huge and still not fully catalogued array of auxiliary molecules that shape its form and functionality, chromatin participates in a dynamic spatial and temporal “dance” in the nucleus — a choreography that is at the same time a choreography of gene expression. In sum, how genes are employed by the body is less a matter of fixed code than of a living performance that looks more like an athletic or artistic production than an exercise in computer logic.

The nucleosome — that DNA-enwrapped “spool” — seems to play a central role in the overall drama of the cell. In part via its plastic, mobile tails and the many chemical modifications they undergo, the protein core of the nucleosome mediates between the wider environment on the one hand, and the DNA it is intimately bound up with on the other. It is a focus for countless external gene regulatory factors while at the same time it is always responding to the dynamically changing structure of DNA. It participates in rhythms and transformations that feed into the movements and mutual engagements of chromosomes within the three-dimensional nuclear space. From its position as mediator between DNA and the cellular environment, it plays a key role in orchestrating gene expression.

The central truth arising from genetic research today is that the hope of finding an adequate explanation of life in terms of inanimate, molecular-level machinery was misconceived. There are no such mechanisms in the living organism at any level. One by one every reliable and predictable “molecular mechanism” has been caught deviating from its program and submitting instead to the fluid life of its larger context. And chief among the deviants is that supposed First Cause, the gene itself.

Trying to define the chromatin complex that makes up our chromosomes, according to geneticists Shiv Grewal and Sarah Elgin writing in Nature, "is like trying to define life itself".

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Selected excerpts from the chapter
bullet Are chimps human?
bullet The Human Genome Project: Did the revolution happen? (1)
bullet The Human Genome Project: Did the revolution happen? (2)
bullet A curious detachment from materiality
bullet The code versus the whole organism
bullet Chromosomes are dynamic
bullet Chromosomes interacting with chromosomes
bullet Even the DNA sequence is dynamic
bullet DNA is not a one-dimensional sequence
bullet Does code trump form and rhythm?
bullet The language of histone tail modifications
bullet The nucleosome’s plastic form and fluid movement
bullet It’s life all the way down