The Gene: An Intimate History - Siddhartha Mukherjee Page 0,85

twentieth-century medicine, the anatomy and physiology of genes would lay the foundation for a powerful new biological science. In the decades to come, this revolutionary science would extend its domain from simple organisms to complex ones. Its conceptual vocabulary—gene regulation, recombination, mutation, DNA repair—would vault out of basic science journals into medical textbooks, and then permeate wider debates in society and culture (the word race, as we shall see, cannot be understood meaningfully without first understanding recombination and mutation). The new science would seek to explain how genes build, maintain, repair, and reproduce humans—and how variations in the anatomy and physiology of genes might contribute to the observed variations in human identity, fate, health, and disease.

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I. Monod and Jacob knew each other distantly; both were close associates of the microbial geneticist André Lwoff. Jacob worked at the other end of the attic, experimenting with a virus that infected E. coli. Although their experimental strategies were superficially dissimilar, both were studying gene regulation. Monod and Jacob had compared notes and found, to their astonishment, that both were working on two aspects of the same general problem, and they had combined some parts of their work in the 1950s.

II. In 1957, Pardee, Monod, and Jacob discovered that the lactose operon was controlled by a single master switch—a protein eventually called the repressor. The repressor functioned like a molecular lock. When lactose was added to the growth medium, the repressor protein sensed the lactose, altered its molecular structure, and “unlocked” the lactose-digesting and lactose-transporting genes (i.e., allowed the genes to be activated), thereby enabling a cell to metabolize lactose. When another sugar, such as glucose, was present, the lock remained intact, and no lactose-digesting genes were allowed to be activated. In 1966, Walter Gilbert and Benno Muller-Hill isolated the repressor protein from bacterial cells—thereby proving Monod’s operon hypothesis beyond doubt. Another repressor, from a virus, was isolated by Mark Ptashne and Nancy Hopkins in 1966.

III. Unlike cosmological turtles, this view is not absurd. In principle, the single-celled embryo does possess all the genetic information to specify a full organism. The question of how sequential genetic circuits can “actualize” the development of an organism is addressed in a subsequent chapter.

IV. DNA replication requires many more proteins than just DNA polymerase to unfold the twisted double helix and to ensure that the genetic information is copied accurately. And there are multiple DNA polymerases, with slightly different functions, found in cells.

V. The fact that the genome also encodes genes to repair damage to the genome was discovered by several geneticists, including Evelyn Witkin and Steve Elledge. Witkin and Elledge, working independently, identified an entire cascade of proteins that sensed DNA damage, and activated a cellular response to repair or temporize the damage (if the damage was catastrophic, it would halt cell division). Mutations in these genes can lead to the accumulation of DNA damage—and thus, more mutations—ultimately leading to cancer. The fourth R of gene physiology, essential to both the survival and mutability of organisms, might be “repair.”

From Genes to Genesis

In the beginning, there was simplicity.

—Richard Dawkins, The Selfish Gene

Am not I

A fly like thee?

Or art not thou

A man like me?

—William Blake, “The Fly”

While the molecular description of the gene clarified the mechanism of the transmission of heredity, it only deepened the puzzle that had preoccupied Thomas Morgan in the 1920s. For Morgan, the principal mystery of organismal biology was not the gene but genesis: How did “units of heredity” enable the formation of animals and maintain the functions of organs and organisms? (“Excuse my big yawn,” he once told a student, “but I just came from my own lecture [on genetics].”)

A gene, Morgan had noted, was an extraordinary solution to an extraordinary problem. Sexual reproduction demands the collapse of an organism into a single cell, but then requires that single cell to expand back into an organism. The gene, Morgan realized, solves one problem—the transmission of heredity—but creates another: the development of organisms. A single cell must be capable of carrying the entire set of instructions to build an organism from scratch—hence genes. But how do genes make a whole organism grow back out of a single cell?

It might seem intuitive for an embryologist to approach the problem of genesis forward—from the earliest events in the embryo to the development of a body plan of a full-fledged organism. But for necessary reasons, as we shall see, the understanding of organismal development emerged like a film run in reverse. The mechanism by which genes