“I Think I’ve Just Thought Up Something Important”–Francois Jacob (1920-2013)

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Francois Jacob. Image from http://www.nobelprize.org

I just learned the sad news that the great biologist Francois Jacob has died. He won the Nobel Prize for his work in the 1950s that showed how cells switch genes off–the first crucial step to understanding how life can use the genome like a piano, to make a beautiful melody instead of a blaring cacophony.

Jacob was also a wonderful writer, and so I had enormous pleasure mining his memoirs for my book Microcosm: E. coli and the New Science of Life. I hope this passage gives a sense of what he was like–

One day in July 1958, François Jacob squirmed in a Paris movie theater. His wife, Lise, could tell that an idea was struggling to come out. The two of them walked out of the theater and headed for home.

“I think I’ve just thought up something important,” François said to Lise.

“Tell!” she said.

Her husband believed, as he later wrote, that he had reached “the very essence of things.” He had gotten a glimpse of how genes work together to make life possible.

Jacob had been hoping for a moment like this for a long time. Originally trained as a surgeon, he had fled Paris when the Nazis swept across France. For the next four years he served in a medical company in the Allied campaigns, mostly in North Africa. Wounds from a bomb blast ended his plans of becoming a surgeon, and after the war he wandered Paris unsure of what to do with his life. Working in an antibiotics lab, Jacob became enchanted with scientific research. But he did not simply want to find a new drug. Jacob decided he would try to understand “the core of life.” In 1950, he joined a team of biologists at the Pasteur Institute who were toiling away on E. coli and other bacteria in the institute’s attic.

Jacob did not have a particular plan for his research when he ascended into the attic, but he ended up studying two examples of one major bio- logical puzzle: why genes sometimes make proteins and sometimes don’t. For several years, Jacob investigated prophages, the viruses that disappear into their E. coli host, only to reappear generations later. Working with Élie Wollman, Jacob demonstrated that prophages actually insert their genes into E. coli’s own DNA. They allowed prophage-infected bacteria to mate with uninfected ones and then spun them apart. If the microbes stopped mating too soon, they could not transfer the prophage. The experiments revealed that the prophage consistently inserts itself in one spot in E. coli’s chromosome. The virus’s genes are nestled in among those of its host, and yet they remain silent for generations.

E. coli offered Jacob another opportunity to study genes that some- times make proteins and sometimes don’t. To eat a particular kind of sugar, E. coli needs to make the right enzymes. In order to eat lactose, the sugar in milk, E. coli needs an enzyme called beta-galactosidase, which can cut lactose into pieces. Jacob’s colleague at the Pasteur Institute, Jacques Monod, found that if he fed E. coli glucose—a much better source of energy for E. coli than lactose—it made only a tiny amount of beta- galactosidase. If he added lactose to the bacteria, it still didn’t make much of the enzyme. Only after the bacteria had eaten all the glucose did it start to produce beta-galactosidase in earnest.

No one at the time had a good explanation for how genes in E. coli or its prophages could be quiet one moment and busy the next. Many scientists had assumed that cells simply churned out a steady supply of all their proteins all the time. To explain E. coli’s reaction to lactose, they suggested that the microbe actually made a steady stream of beta-galactosidase. Only when E. coli came into contact with lactose did the enzymes change their shape so that they could begin to break the sugar down.

Jacob, Monod, and their colleagues at the Pasteur Institute began a series of experiments to figure out the truth. They isolated mutant E. coli that failed to eat lactose in interesting ways. One mutant could not digest lactose, despite having a normal gene for beta-galactosidase. The scientists realized that E. coli used more than one gene to eat lactose. One of those genes encoded a channel in the microbe’s membranes that could suck in the sugar.

Strangest of all the mutants Jacob and Monod discovered were ones that produced beta-galactosidase and permease all the time, regardless of whether there was any lactose to digest. The scientists reasoned that E. coli carries some other molecule that normally prevents the genes for beta- galactosidase and permease from becoming active. It became known as the repressor. But Jacob and his colleagues had not been able say how the repressor keeps genes quiet.

In the darkness of the Paris movie theater, Jacob hit on an answer. The repressor is a protein that clamps on to E. coli’s DNA, blocking the production of proteins from the genes for beta-galactosidase and the other genes involved in feeding on lactose. A signal, like a switch on a circuit, causes the repressor to stop shutting down the genes.

Another similar repressor might keep the genes of prophages silent as well, Jacob thought. Perhaps these circuits are common in all living things. “I no longer feel mediocre or even mortal,” he wrote.

But when François tried to sketch out his ideas for his wife, he was disappointed.

“You’ve already told me that,” Lise said. “It’s been known for a long time, hasn’t it?”

Jacob’s idea was so elegantly simple that it seemed obvious to anyone other than a biologist.