Microcosm_ E. Coli and the New Science of Life - Carl Zimmer [18]
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. Yet it represented a new way of thinking about life. Genes do not work in isolation. They work in circuits. Over the next few weeks, Jacob tried to explain his idea to his fellow biologists, without arousing much interest. It was not until Monod returned to Paris in the fall that Jacob found a receptive audience. The two of them began to draw circuit diagrams on a blackboard, with arrows running from inputs to outputs.
In the fall of 1958, Monod and Jacob launched a new series of experiments to test Jacob’s circuit hypothesis. The experiments produced the results Jacob expected, but it would take years of research by other scientists to work out many of the details. The lactose-digesting genes are lined up next to each other on E. coli’s chromosome. The repressor protein clamps down on a stretch of DNA at the front end of the genes, where it blocks the path of gene-reading enzymes. With the repressor in place, E. coli cannot feed on lactose.
The best way to get the repressor away from the lactose-digesting genes is to give E. coli some lactose. Once inside the microbe, the sugar changes shape so that it can grab the repressor. It drags the repressor off E. coli’s DNA, allowing the gene-reading enzymes to make their way through the lactose-digesting genes. E. coli can then make the enzymes it needs to feed on lactose.
But E. coli needs a second signal to ramp up its production of beta-galactosidase: it needs to know that its supply of glucose has run out. The signal is a protein called CRP, which builds up inside E. coli when the microbe begins to starve. CRP grabs on to another stretch of DNA, next to the lactose-digesting genes. It bends the DNA to attract the gene-reading enzymes. Once CRP clamps on, E. coli begins producing lactose-digesting enzymes at top speed. If the repressor is an off switch, CRP is an on switch.
Jacob and his colleagues christened the lactose-digesting genes the lac operon, operon meaning a set of genes that are all regulated by the same switches. As Jacob suspected, operons represent a common theme in the way genes work. Hundreds of E. coli’s genes are arrayed in operons, each controlled by switches. Some operons carry several switches, all of which must be thrown for them to make proteins. A single protein may be able to trigger a cascade of genes, switching on genes for making more switches, allowing E. coli to make hundreds of new kinds of proteins.
On-off switches are everywhere in nature. Prophages remain dormant inside E. coli thanks to repressors that keep their genes shut down. Stress causes the repressors to fall off and the prophages to make new viruses. Operons can be found in other bacteria as well. In animals like ourselves, operons appear to be much less common. But even genes that do not sit next to each other on our genome can be switched on by the same master-control protein.
It is only through the switching on and off of genes that our cells can behave differently from one another, despite carrying an identical genome. They can form liver cells or spit out bone, catch light or feel heat. By learning how E. coli drinks milk, Jacob and his colleagues opened the way to understanding why we humans are more than just amoebas.
LIVING CIRCUITS
To an engineer, a circuit is an arrangement of wires, resistors, and other parts, all laid out to produce an output from an input. Circuits in a Geiger counter create a crackle when they detect radioactivity. A room is cast in darkness when a light switch is turned off. Genes operate according to a similar logic. A genetic circuit has its own inputs and outputs. The lac operon works only if it receives two inputs: a signal that E. coli has run out of glucose and another signal that there’s lactose to eat. Its