The Gene: An Intimate History - Siddhartha Mukherjee Page 0,84

is more portentous. When DNA is damaged by a mutagen, such as X-rays, genetic information is obviously threatened. When such damage occurs, the gene can be recopied from the “twin” copy on the paired chromosome: part of the maternal copy may be redrafted from the paternal copy, again resulting in the creation of hybrid genes.

Once again, the pairing of bases is used to build the gene back. The yin fixes the yang, the image restores the original: with DNA, as with Dorian Gray, the prototype is constantly reinvigorated by its portrait. Proteins chaperone and coordinate the entire process—guiding the damaged strand to the intact gene, copying and correcting the lost information, and stitching the breaks together—ultimately resulting in the transfer of information from the undamaged strand to the damaged strand.

Regulation. Replication. Recombination. Remarkably, the three R’s of gene physiology are acutely dependent on the molecular structure of DNA—on the Watson-Crick base pairing of the double helix.

Gene regulation works through the transcription of DNA into RNA—which depends on base pairing. When a strand of DNA is used to build the RNA message, it is the pairing of bases between DNA and RNA that allows a gene to generate its RNA copy. During replication, DNA is, once again, copied using its image as a guide. Each strand is used to generate a complementary version of itself, resulting in one double helix that splits into two double helices. And during the recombination of DNA, the strategy of interposing base against base is deployed yet again to restore damaged DNA. The damaged copy of a gene is reconstructed using the complementary strand, or the second copy of the gene, as its guide.V

The double helix has solved all three of the major challenges of genetic physiology using ingenious variations on the same theme. Mirror-image chemicals are used to generate mirror-image chemicals, reflections used to reconstruct the original. Pairs used to maintain the fidelity and fixity of information. “Monet is but an eye,” Cézanne once said of his friend, “but, God, what an eye.” DNA, by that same logic, is but a chemical—but, God, what a chemical.

In biology, there is an old distinction between two camps of scientists—anatomists, and physiologists. Anatomists describe the nature of materials, structures, and body parts: they describe how things are. Physiologists concentrate, instead, on the mechanisms by which these structures and parts interact to enable the functions of living organisms; they concern themselves with how things work.

This distinction also marks a seminal transition in the story of the gene. Mendel, perhaps, was the original “anatomist” of the gene: in capturing the movement of information across generations of peas, he had described the essential structure of the gene as an indivisible corpuscle of information. Morgan and Sturtevant extended that anatomical strand in the 1920s, demonstrating that genes were material units, spread linearly along chromosomes. In the 1940s and 1950s, Avery, Watson, and Crick identified DNA as the gene molecule, and described its structure as a double helix—thereby bringing the anatomical conception of the gene to its natural culmination.

Between the late 1950s and the 1970s, however, it was the physiology of genes that dominated scientific inquiry. That genes could be regulated—i.e., turned “on” and “off” by particular cues—deepened the understanding of how genes function in time and space to specify the unique features of distinct cells. That genes could also be reproduced, recombined between chromosomes, and repaired by specific proteins, explained how cells and organisms manage to conserve, copy, and reshuffle genetic information across generations.

For human biologists, each of these discoveries came with enormous payoffs. As genetics moved from a material to a mechanistic conception of genes—from what genes are to what they do—human biologists began to perceive long-sought connections between genes, human physiology, and pathology. A disease might arise not just from an alteration in the genetic code for a protein (e.g., hemoglobin in the case of sickle-cell disease), but as a consequence of gene regulation—the inability to turn the right gene “on” or “off” in the appropriate cell at the right time. Gene replication must explain how a multicellular organism emerges from a single cell—and errors in replication might elucidate how a spontaneous metabolic illness, or a devastating mental disease, might arise in a previously unaffected family. The similarities between genomes must explain the likeness between parents and their children, and mutations and recombination might explain their differences. Families must share not just social and cultural networks—but networks of active genes.

Just as nineteenth-century human anatomy and physiology laid the foundation for