The Gene: An Intimate History - Siddhartha Mukherjee Page 0,193

have learned to coax amino acids to form chains and thus build proteins—versatile, molecular machines that could make metabolism, self-propagation, and information transfer vastly more efficient.

When, and why, did discrete “genes”—modules of information—appear on a strand of RNA? Did genes exist in their modular form at the very beginning, or was there an intermediate or alternative form of information storage? Again, these questions are fundamentally unanswerable, but perhaps information theory can provide a crucial clue. The trouble with continuous, nonmodular information is that it is notoriously hard to manage. It tends to diffuse; it tends to become corrupted; it tends to tangle, dilute, and decay. Pulling one end causes another to unspool. If information bleeds into information, it runs a much greater risk of distortion: think of a vinyl record that acquires a single dent in the middle. Information that is “digitized,” in contrast, is much easier to repair and recover. We can access and change one word in a book without having to reconfigure the entire library. Genes may have appeared for the same reason: discrete, information-bearing modules in one strand of RNA were used to encode instructions to fulfill discrete and individual functions.

The discontinuous nature of information would have carried an added benefit: a mutation could affect one gene, and only one gene, leaving the other genes unaffected. Mutations could now act on discrete modules of information rather than disrupting the function of the organism as a whole—thereby accelerating evolution. But that benefit came with a concomitant liability: too much mutation, and the information would be damaged or lost. What was needed, perhaps, was a backup copy—a mirror image to protect the original or to restore the prototype if damaged. Perhaps this was the ultimate impetus to create a double-stranded nucleic acid. The data in one strand would be perfectly reflected in the other and could be used to restore anything damaged; the yin would protect the yang. Life thus invented its own hard drive.

In time, this new copy—DNA—would become the master copy. DNA was an invention of the RNA world, but it soon overran RNA as a carrier of genes and became the dominant bearer of genetic information in living systems.IV Yet another ancient myth—of the child consuming its father, of Cronus overthrown by Zeus—is etched into the history of our genomes.

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I. Gurdon’s technique—of evacuating the egg and inserting a fully fertilized nucleus—has already found a novel clinical application. Some women carry mutations in mitochondrial genes—i.e., genes that are carried within mitochondria, the energy-producing organelles that live inside cells. All human embryos, recall, inherit their mitochondria exclusively from the female egg—i.e., from their mothers (the sperm does not contribute any mitochondria). If the mother carries a mutation in a mitochondrial gene, then all her children might be affected by that mutation; mutations in these genes, which often affect energy metabolism, can cause muscle wasting, heart abnormalities, and death. In a provocative series of experiments in 2009, geneticists and embryologists proposed a daring new method to tackle these maternal mitochondrial mutations. After the egg had been fertilized by the father’s sperm, the nucleus was injected into an egg with intact (“normal”) mitochondria from a normal donor. Since the mitochondria were derived from the donor, the maternal mitochondrial genes were intact, and the babies born would no longer carry the maternal mutations. Humans born from this procedure thus have three parents. The fertilized nucleus, formed by the union of the “mother” and “father” (parents 1 and 2), contributes virtually all the genetic material. The third parent—i.e., the egg donor—contributes only mitochondria, and the mitochondrial genes. In 2015, after a protracted national debate, Britain legalized the procedure, and the first cohorts of “three-parent children” are now being born. These children represent an unexplored frontier of human genetics (and of the future). Obviously, no comparable animals exist in the natural world.

II. The idea that histones might regulate genes had originally been proposed by Vincent Allfrey, a biochemist at Rockefeller University in the 1960s. Three decades later—and, as if to close a circle, at that very same institution—Allis’s experiments would vindicate Allfrey’s “histone hypothesis.”

III. The permanence of epigenetic marks, and the nature of memory recorded by these marks, has been questioned by the geneticist Mark Ptashne. In Ptashne’s view, shared by several other geneticists, master-regulatory proteins—previously described as molecular “on” and “off” switches—orchestrate the activation or repression of genes. Epigenetic marks are laid down as a consequence of gene activation or repression, and may play an accompanying role in regulating