The Gene: An Intimate History - Siddhartha Mukherjee Page 0,81

could be regulated by metabolic inputs. If enzymes—i.e., proteins—were being induced to appear and disappear in a cell, then genes must be being turned on and off, like molecular switches (enzymes, after all, are encoded by genes). In the early 1950s, Monod, joined by François Jacob in Paris, began to systematically explore the regulation of genes by E. coli by making mutants—the method used with such spectacular success by Morgan with fruit flies.I

As with flies, the bacterial mutants proved revealing. Monod and Jacob, working with Arthur Pardee, a microbial geneticist from America, discovered three cardinal principles that governed the regulation of genes. First, when a gene was turned on or off, the DNA master copy was always kept intact in a cell. The real action was in RNA: when a gene was turned on, it was induced to make more RNA messages and thereby produce more sugar-digesting enzymes. A cell’s metabolic identity—i.e., whether it was consuming lactose or glucose—could be ascertained not by the sequence of its genes, which was always constant, but by the amount of RNA that a gene was producing. During lactose metabolism, the RNAs for lactose-digesting enzymes were abundant. During glucose metabolism, those messages were repressed, and the RNAs for glucose-digesting enzymes became abundant.

Second, the production of RNA messages was coordinately regulated. When the sugar source was switched to lactose, the bacteria turned on an entire module of genes—several lactose-metabolizing genes—to digest lactose. One of the genes in the module specified a “transporter protein” that allowed lactose to enter the bacterial cell. Another gene encoded an enzyme that was needed to break down lactose into parts. Yet another specified an enzyme to break those chemical parts into subparts. Surprisingly, all the genes dedicated to a particular metabolic pathway were physically present next to each other on the bacterial chromosome—like library books stacked by subject—and they were induced simultaneously in cells. The metabolic alteration produced a profound genetic alteration in a cell. It wasn’t just a cutlery switch; the whole dinner service was altered in a single swoop. A functional circuit of genes was switched on and off, as if operated by a common spool or a master switch. Monod called one such gene module an operon.II

The genesis of proteins was thus perfectly synchronized with the requirements of the environment: supply the correct sugar, and a set of sugar-metabolizing genes would be turned on together. The terrifying economy of evolution had again produced the most elegant solution to gene regulation. No gene, no message, and no protein labored in vain.

How did a lactose-sensing protein recognize and regulate only a lactose-digesting gene—and not the thousands of other genes in a cell? The third cardinal feature of gene regulation, Monod and Jacob discovered, was that every gene had specific regulatory DNA sequences appended to it that acted like recognition tags. Once a sugar-sensing protein had detected sugar in the environment, it would recognize one such tag and turn the target genes on or off. That was a gene’s signal to make more RNA messages and thereby generate the relevant enzyme to digest the sugar.

A gene, in short, possessed not just information to encode a protein, but also information about when and where to make that protein. All that data was encrypted in DNA, typically appended to the front of every gene (although regulatory sequences can also be appended to the ends and middles of genes). The combination of regulatory sequences and the protein-encoding sequence defined a gene.

Once again, we might return to our analogy to an English sentence. When Morgan had discovered gene linkage in 1910, he had found no seeming logic to why one gene was physically strung with another on a chromosome: the sable-colored and the white-eyed genes seemed to have no common functional connection, yet sat, cheek by jowl, on the same chromosome. In Jacob and Monod’s model, in contrast, bacterial genes were strung together for a reason. Genes that operated on the same metabolic pathway were physically linked to each other: if you worked together, then you lived together in the genome. Specific sequences of DNA were appended to a gene that provided context for its activity—its “work.” These sequences, meant to turn genes on and off, might be likened to punctuation marks and annotations—inverted quotes, a comma, a capitalized letter—in a sentence: they provide context, emphasis, and meaning, informing a reader what parts are to be read together, and when to pause for the next sentence:

“This is the structure of your genome. It contains,