The Gene: An Intimate History - Siddhartha Mukherjee Page 0,77

a poem to the Tie Club, although he never sent it out:

What are the properties of Genetic RNA

Is he in heaven, is he in hell?

That damned, elusive Pimpernel.

In the early spring of 1960, Jacob flew to Caltech to work with Matthew Meselson to trap the “damned, elusive Pimpernel.” Brenner arrived in early June, a few weeks later.

Proteins, Brenner and Jacob knew, are synthesized within a cell by a specialized cellular component called the ribosome. The surest means to purify the messenger intermediate was to halt protein synthesis abruptly—using a biochemical equivalent of a cold shower—and purify the shivering molecules associated with the ribosomes, thereby trapping the elusive Pimpernel.

The principle seemed obvious, but the actual experiment proved mysteriously daunting. At first, Brenner reported, all he could see in the experiment was the chemical equivalent of thick “California fog—wet, cold, silent.” The fussy biochemical setup had taken weeks to perfect—except each time the ribosomes were caught, they crumbled and fell apart. Inside cells, ribosomes seemed to stay glued together with absolute equanimity. Why, then, did they degenerate outside cells, like fog slipping through fingers?

The answer appeared out of the fog—literally. Brenner and Jacob were sitting on the beach one morning when Brenner, ruminating on his basic biochemistry lessons, realized a profoundly simple fact: their solutions must be missing an essential chemical factor that kept ribosomes intact within cells. But what factor? It had to be something small, common, and ubiquitous—a tiny dab of molecular glue. He shot up from the sand, his hair flying, sand dribbling from his pockets, screaming, “It’s the magnesium. It’s the magnesium.”

It was the magnesium. The addition of the ion was critical: with the solution supplemented with magnesium, the ribosome remained glued together, and Brenner and Jacob finally purified a minuscule amount of the messenger molecule out of bacterial cells. It was RNA, as expected—but RNA of a special kind.I The messenger was generated afresh when a gene was translated. Like DNA, these RNA molecules were built by stringing together four bases—A, G, C, and U (in the RNA copy of a gene, remember, the T found in DNA is substituted for U). Notably, Brenner and Jacob later discovered the messenger RNA was a facsimile of the DNA chain—a copy made from the original. The RNA copy of a gene then moved from the nucleus to the cytosol, where its message was decoded to build a protein. The messenger RNA was neither an inhabitant of heaven nor of hell—but a professional go-between. The generation of an RNA copy of a gene was termed transcription—referring to the rewriting of a word or sentence in a language close to the original. A gene’s code (ATGGGCC . . .) was transcribed into an RNA code (AUGGGCC . . .).

The process was akin to a library of rare books that is accessed for translation. The master copy of information—i.e., the gene—was stored permanently in a deep repository or vault. When a “translation request” was generated by a cell, a photocopy of the original was summoned from the vault of the nucleus. This facsimile of a gene (i.e., RNA) was used as a working source for translation into a protein. The process allowed multiple copies of a gene to be in circulation at the same time, and for the RNA copies to be increased or decreased on demand—facts that would soon prove to be crucial to the understanding of a gene’s activity and function.

But transcription solved only half the problem of protein synthesis. The other half remained: How was the RNA “message” decoded into a protein? To make an RNA copy of a gene, the cell used a rather simple transposition: every A,C,T, and G in a gene was copied to an A, C, U, and G in the messenger RNA (i.e., ACT CCT GGG→ACU CCU GGG). The only difference in code between the gene’s original and the RNA copy was the substitution of the thymine to a uracil (T→U). But once transposed into RNA, how was a gene’s “message” decoded into a protein?

To Watson and Crick, it was immediately clear that no single base—A, C, T, or G—could carry sufficient genetic message to build any part of a protein. There are twenty amino acids in all, and four letters could not specify twenty alternative states by themselves. The secret had to be in the combination of bases. “It seems likely,” they wrote, “that the precise sequence of the bases is the code that carries the genetical information.”

An analogy to natural language illustrates