The Gene: An Intimate History - Siddhartha Mukherjee Page 0,83

set out to isolate the DNA-copying enzyme. If such an enzyme existed, Kornberg reasoned, the easiest place to find it would be in an organism that was dividing rapidly—E. coli during its furious phase of growth.

By 1958, Kornberg had distilled and redistilled the bacterial sludge into a nearly pure enzyme preparation (“A geneticist counts; a biochemist cleans,” he once told me). He called it DNA polymerase (DNA is a polymer of A, C, G, and T, and this was the polymer-making enzyme). When he added the purified enzyme to DNA, supplied a source of energy and a reservoir of fresh nucleotide bases—A, T, G, and C—he could witness the formation of new strands of nucleic acid in a test tube: DNA made DNA in its own image.

“Five years ago,” Kornberg wrote in 1960, “the synthesis of DNA was also regarded as a ‘vital’ process”—a mystical reaction that could not be reproduced in a test tube by the addition or subtraction of mere chemicals. “Tampering with the very genetic apparatus [of life] itself,” this theory ran, “would surely produce nothing but disorder.” But Kornberg’s synthesis of DNA had created order out of disorder—a gene out of its chemical subunits. The unassailability of genes was no longer a barrier.

There is a recursion here that is worth noting: like all proteins, DNA polymerase, the enzyme that enables DNA to replicate, is itself the product of a gene.IV Built into every genome, then, are the codes for proteins that will allow that genome to reproduce. This additional layer of complexity—that DNA encodes a protein that allows DNA to replicate—is important because it provides a critical node for regulation. DNA replication can be turned on and turned off by other signals and regulators, such as the age or the nutritional status of a cell, thus allowing cells to make DNA copies only when they are ready to divide. This scheme has a collateral rub: when the regulators themselves go rogue, nothing can stop a cell from replicating continuously. That, as we will soon learn, is the ultimate disease of malfunctioning genes—cancer.

Genes make proteins that regulate genes. Genes make proteins that replicate genes. The third R of the physiology of genes is a word that lies outside common human vocabulary, but is essential to the survival of our species: recombination—the ability to generate new combinations of genes.

To understand recombination, we might, yet again, begin with Mendel and Darwin. A century of exploration of genetics illuminated how organisms transmit “likeness” to each other. Units of hereditary information, encoded in DNA and packaged on chromosomes, are transmitted through sperm and egg into an embryo, and from the embryo to every living cell in an organism’s body. These units encode messages to build proteins—and the messages and proteins, in turn, enable the form and function of a living organism.

But while this description of the mechanism of heredity solved Mendel’s question—how does like beget like?—it failed to solve Darwin’s converse riddle: How does like beget unlike? For evolution to occur, an organism must be able to generate genetic variation—i.e., it must produce descendants that are genetically different from either parent. If genes typically transmit likeness, then how can they transmit “unlikeness”?

One mechanism of generating variation in nature is mutation—i.e., alterations in the sequence of DNA (an A switched to a T) that may change the structure of a protein and thereby alter its function. Mutations occur when DNA is damaged by chemicals or X-rays, or when the DNA replication enzyme makes a spontaneous error in copying genes. But a second mechanism of generating genetic diversity exists: genetic information can be swapped between chromosomes. DNA from the maternal chromosome can exchange positions with DNA from the paternal chromosome—potentially generating a gene hybrid of maternal and paternal genes. Recombination is also a form of “mutation”—except whole chunks of genetic material are swapped between chromosomes.

The movement of genetic information from one chromosome to another occurs only under extremely special circumstances. The first occurs when sperm and eggs are generated for reproduction. Just before the spermiogenesis and oogenesis, the cell turns briefly into a playpen for genes. The paired maternal and paternal chromosomes hug each other and readily swap genetic information. The swapping of genetic information between paired chromosomes is crucial to the mixing and matching of hereditary information between parents. Morgan called this phenomenon crossing over (his students had used crossing over to map genes in flies). The more contemporary term is recombination—the ability to generate combinations of combinations of genes.

The second circumstance