Microcosm Week: How E. coli Sees The Future

In my book  Microcosm  (which has just come out in paperback), I took great pleasure in all the things that something as tiny as E. coli can do. It can survive in frozen soils and stomach acid. It can can build intricate tails which it can then spin hundreds of times a second in order to swim. It can navigate away from the bad and towards the good. It can protect itself from overheating by making just enough protective proteins it needs, with thermostat-like precision. It can survive starvation by folding its DNA into a crystalline sandwich and powering down for months, even years in some cases. It can build microbial cities out of goo, and even commit suicide to help its fellow E. coli survive.

Yet I may have underestimated the brainless intelligence of E. coli. It may even be able to  predict the future.

E. coli has 4000-odd genes, which it can use in various combinations to meet the many challenges it faces. But it does not use all those genes to make proteins and RNA molecules all at once. That would not only be a spectacular waste of energy. Instead,E. coli turns some genes on and keeps others turned off, a bit like playing the keys of a piano. Proteins can clamp onto stretches of DNA near certain genes, for example, making it impossible for the microbe to read them and make the corresponding proteins. When those proteins fall off, or are pried away, the genes can be switched on. (Likewise, other proteins can clamp onto other stretches of DNA and speed up the reading of genes as well.)

One of the most important chapters in the history of modern biology was the discovery of these switches in E. coli. In later years, scientists discovered this basic on-off strategy at work (with lots of variations, of course) in the DNA of all living things.

The way in which E. coli‘s genes switch on and off is well-suited to its particular kind of life. For example, E. coli can make proteins that allow it to feed on lactose, the sugar in milk. But most of the time, it keeps the genes for those proteins shut down. If it should encounter lactose, however, the sugar molecule can pull away the repressing proteins, initiating a series of events that leads to E. coli producing a lot of lactose-digesting proteins.

In a case like this, E. coli is responding to something that’s already present in its environment. So-called “higher” species, like us, can also respond to signals of things to come. In fact, thanks to our brains, we can learn new signals. (Think of Pavlov’s dogs, drooling at the sound of the dinner bell.) That led scientists at Princeton to wonder whether E. coli can see into the future as well. It may not have a brain made up of billions of cells, but it does have a complex network of genes that might be able to use information to make predictions about things to come.

The Princeton scientists started by considering E. coli’s natural history. You get regularly infected with new E. coli carried from your hands to your mouth. (Fortunately, the vast majority of these bacteria are totally harmless. Just remember, don’t eat raw cookie dough!) For the E. coli that’s just arrived in your mouth, the world begins to change. It immediately gets a lot warmer, for one thing. Later, as it moves from your mouth down through your gut, the level of oxygen in its environment will drop to near zero. In order to survive, E. coli has to shut down the network of genes it uses to metabolize sugar with the help of oxygen, and then switch on hundreds of other genes for feeding without oxygen.

A sudden rise in temperature is a reliable signal that oxygen will start to drop over the next few hours. The Princeton scientists wondered if  E. coli might use it as a cue to start to prepare for the change. To find out, they experimented on some  E. coli, keeping careful track of which genes were turned on and off when they tweaked the temperature and oxygen levels. It turns out that when E. coli gets warm, it not only switches on heat-defense genes, but also starts making the switch to low-oxygen genes. This switch is remarkable when you consider that it can happen while  E. coli is bathing in a broth rich in oxygen. Unless the oxygen is going to drop soon, this would be a disastrous decision.

It was possible, though, that  E. coli has to switch to a low-oxygen program whenever it defends itself against high temperatures. To test that possibility, the scientists turned  E. coli‘s world upside-down. They periodically raised and lowered both the oxygen levels and the temperature in flasks of  E. coli. But now a rise in temperature was followed 40 minutes later by a rise in oxygen, not a drop.

The scientists allowed the bacteria to grow and reproduce for hundreds of generations in this bizarro world. Mutations arose, and beneficial ones spread through the population thanks to natural selection. The scientists then took a look at the bacteria after they had adapted to the new pattern of temperature and oxygen.

Now a rise in temperature prompted a far weaker response from the genes  E. coli uses to survive at low-oxygen levels. The bacteria with mutations that allowed them to continue using oxygen outcompeted the ones that automatically made the switch when the temperature rose. Their experiment suggests that the programs the bacteria use to survive high temperatures and different levels of oxygen are not inextricably linked. The link must be an adaptation, the scientists argue. At some point in the past, the ancestors of E. coli evolved the microbial wisdom that a rise in temperature foreshadows a drop in oxygen.

The Princeton scientists published the details of their experiment a year ago. Now, in the current issue of Nature, a team of Israeli scientists offer evidence that E. coli predicts the future in another way.

The Israeli scientists noted another reliable clue E. coli gets on its journy from mouth to gut. Thanks to the chemistry of our intestines, the upper part of the digestive tract has lactose on offer, but further down in the gut, another sugar called maltose is available. The Israeli scientists wondered E. coli “know” that if it encountered lactose, maltose would be coming soon.

First, they looked at which genes switched on when they fed E. coli different kinds of sugar. Feeding it maltose caused it to make a lot of proteins for digesting maltose. But feeding it lactose caused it not just to make lactose-digesting proteins, but low levels of proteins for digesting maltose too. The effect did not go in the other direction, though. Feeding E. coli maltose does not cause it to make a lot of lactose-digesting proteins.

The Israeli scientists then ran an experiment to see if there was any advantage to E. coli making the maltose proteins in response to lactose. There is indeed. Bacteria that are first exposed to lactose actually grow faster on maltose than bacteria that feed on maltose alone. Other sugars can’t give E. coli this priming advantage. Nor does the advantage work in reverse. Exposing E. coli to maltose does not speed up its growth on lactose.

Finally, the Israeli scientists ran an evolution experiment of their own. They fed E. coli high levels of lactose without any maltose. Under these conditions, making maltose-digesting proteins in response to lactose is a waste of energy. After 500 generations, the scientists found, the bacteria stopped making maltose proteins in response to lactose (although they could still make them in response to maltose itself).

E. coli does not actually learn to make associations the way Pavlov’s dogs learned. The neurons in the brains of the dogs altered their connections. E. coli evolves new connections between its genes over the course of hundreds of generations, as mutations offer up new arrangements, and natural selection favors the ones that speed up the bacteria’s growth. But these experiments do illuminate some of the interesting ways in which evolution resembles learning.

The commentary that accompanies the new paper has the clever headline, “Microbes exploit groundhog day.” In the movie Groundhog Day, you may recall, Bill Murray wakes up day after day only to find that it’s still February 2. After a while, he starts to look clairvoyant to the people around him, because he can anticipate everything that’s going to happen. In some respects, life is a lot like Groundhog Day. Things repeat themselves in a predictable order. Perhaps body temperature and low oxygen are like Groundhog Day for E. coli. Perhaps lactose and maltose are too.

But, of course, a lot of life is not like Groundhog Day. In many cases we can’t predict the future, and so we can’t know exactly what to do now to be best prepared. The same goes for E. coli. So what does E. coli do?

It pretends that it’s betting on horses.

But to find out how it does that particular trick, you’ll have to read about it in  Microcosm.

(Did I mention that it’s now out in paperback? Did I mention how the Boston Globe called it “quietly revolutionary,” and how other people have said equally nice things about it? Just asking…)