Survival of the Mutable

By Sarah Richardson|Thursday, September 01, 1994
In which the ghost of that oft-reviled ancestor, Jean-Baptiste Lamarck, returns to trouble the sleep of neo-Darwinian evolutionists.

To most evolutionary biologists, directed mutation is an oxymoron. Mutations, according to evolutionary theory, are random events-- changes in an organism’s genetic makeup that have no particular direction, and that may be harmful or beneficial. Whatever direction is to be found in evolution is put there by natural selection. When a mutation happens to be beneficial--when it improves the organism’s chances of producing offspring- -it survives, whereas harmful mutations die out. That is the essence of neo-Darwinism, a theory in which there is no room for directed mutation.

Historically, though, there was an alternative theory: Lamarckism, named for Jean-Baptiste Lamarck, the nineteenth-century Frenchman who was the first person to articulate the idea that organisms evolve. Although Lamarck knew nothing of genes or mutations, he did believe that organisms direct their own evolution--that they actively acquire the traits that help them survive and then pass those traits on to their offspring. His most famous example was giraffes. He thought they had acquired long necks after generations of straining to reach the leaves on trees.

No biologist believes that these days, so it came as quite a surprise when six years ago the eminent British biologist John Cairns made an analogous claim: that bacteria, when faced with starvation, can sometimes produce--in a directed and nonrandom way--the mutation they need to survive. Cairns’s claim was so radical that many of his colleagues questioned his data. But in the years since, a few tenacious researchers have pursued Cairns’s results and have managed to reproduce them. And just recently a group led by molecular geneticist Susan Rosenberg of the University of Alberta has given the whole line of research a large credibility boost. Rosenberg and her colleagues have found evidence for a mechanism--a set of enzymes responsible for recombining bacterial DNA--that could produce Cairns’s Lamarckian results in a neo-Darwinian way.

Cairns’s original experiment was simple. He took a strain of E. coli cells that were unable to digest lactose--because of a mutation in the gene for a crucial enzyme--and put them in a dish in which lactose was the only nutrient available. Then he waited to see how many bacteria would develop corrective mutations that permitted them to grow rather than slowly starve.

Standard evolutionary theory would predict that as the cells divided and replicated themselves, mutations would creep into their genes, and in a few cases these errors would happen to convey the ability to digest lactose. What Cairns saw, however, was radically different. To begin with, his cells couldn’t self-replicate because they were starving. Yet in spite of that fact, the E. coli colony managed to produce far more lactose- digesting mutants than evolutionary theory would predict--as many mutants as one would expect if the cells had divided 100 times. Moreover, the cells seemed to produce the mutation only when they needed it--that is, only after Cairns introduced lactose into the medium (he kept the bacteria starving on no food at all for a few days). That suggested that the cells were not mutating randomly but were responding to the presence of lactose in a directed way, like giraffes straining to reach leaves.

Cairns’s E. coli weren’t exactly like Lamarck’s giraffes, of course. Lamarck’s giraffes acquired long necks by using their necks a lot, whereas Cairns’s bacteria acquired the ability to digest lactose through a genetic mutation. The mutation didn’t even have to correct the original flaw in the lactose-enzyme gene; sometimes, Cairns and Pat Foster of Boston University found, it simply affected the way in which the gene was read by the cell’s protein-synthesis machinery so that the gene chanced to be read correctly in spite of the flaw. Nonetheless, Cairns’s E. coli appeared to be behaving in a Lamarckian way insofar as they were acquiring a characteristic and passing it on to their offspring. And by doing that, they were achieving better results than would seem possible in a purely neo-Darwinian world.

Barry Hall, a molecular evolutionist at the University of Rochester who had confirmed Cairns’s puzzling results, suggested an explanation. Little is really known about what goes on in cells that are starving, and perhaps, Hall speculated, a small group of cells in the colony might become hypermutable. They would continue to undergo mutations in an undirected and random way, as neo-Darwinism requires--but at a much faster rate. That would dramatically increase the odds that a few cells would get just the mutation they needed to survive. Those cells would then pass their success on to their offspring.

Hall had a modest bit of experimental evidence to back up his idea that the bacterial survivors were hypermutable: he found that in addition to the beneficial mutation, they also had a slightly higher incidence of useless ones. But he could not say what molecular mechanism might cause the cells to become hypermutable when they were not even dividing. The absence of a mechanism limited the impact of Hall’s theory. Unless scientists have a mechanism to explain a phenomenon, says Rosenberg, they won’t believe it exists.

Building on work done earlier by Cairns and Foster, Rosenberg and her colleagues have now identified a possible mechanism. Cairns and Foster had discovered that an enzyme called Rec A was crucial to forming these puzzling mutations. Rosenberg has found that another enzyme, Rec BCD, is also essential. Together the Rec enzymes make it possible for one bacterium to swap genes with another in what passes for bacterial sex. The same enzymes also enable an individual bacterium to repair serious damage to its DNA--such as breaks in both strands of the double helix.

That is one way, Rosenberg proposes, that a cell could become hypermutable. A normal bacterial chromosome is circular, she explains. We know that the biochemistry of Rec BCD is such that it can’t do anything to a circular DNA molecule, she says, because it loads onto DNA at double- strand breaks. So we’re suggesting that double-strand breakage could be the molecular basis of this hypermutable state.

Double-strand breaks might form, for example, when a starving cell stops replicating in midoperation, leaving its DNA unzipped--with the two strands pulled apart for copying--in various places. Those places would be more susceptible to breaking. The Rec enzymes would patch up the breaks by bringing in pieces of DNA from elsewhere in the cell. But in repairing the bacterial DNA they could make mistakes and mutate it. And in a few cases these mutations might change the DNA in such a way that the bacterium could digest lactose. At that point the bacterium would start eating and replicating again, and stop being hypermutable.

Rosenberg’s scenario is neat, but it is already clear that it cannot explain all the observed instances of directed mutation. Barry Hall has found that under a different set of experimental conditions--in which E. coli cells must mutate to be able to make an amino acid they need to grow--the organisms do not rely on the Rec enzymes to get them out of their fix. Thus it seems that bacteria may have more than one way of making directed mutations.

One way would be enough, though, to fundamentally alter our understanding of how single-celled organisms evolve. In standard evolutionary theory, individual organisms do not adapt to changes in their environment; it is the population that adapts. When a change occurs--for instance, when suddenly the only food around is lactose--those cells that happen to be already equipped to deal with the change are the only cells that survive, and from then on the population consists of their offspring. If bacteria can become hypermutable, however, it means that an individual cell has a chance to adapt to a change after it occurs and thus to save itself. And it means that the population as a whole becomes more adaptable, too--which, according to Hall, may help explain how single-celled microbes were able to survive and prosper in the harsh environment of the early Earth, when they were the only life around.

Directed mutations aren’t likely to occur in the same way in higher organisms. Lamarck’s notion that acquired characteristics can be inherited may work in bacteria, but it cannot work in humans or giraffes. Even if it were possible (which it isn’t) for the cells in a giraffe’s neck to mutate in such a way as to allow the animal to reach higher for leaves, the change would not be passed on to its offspring. The only genetic mutations that survive into the next generation are those that occur in sperm or egg cells, and they don’t change the characteristics of the parents.

Yet that does not mean directed mutation cannot occur at all in higher organisms. Cancer researchers have long puzzled over how a noncancerous cell might undergo the numerous mutations it takes to become cancerous. Cairns and others now think that hypermutability--induced not by starvation but by the benefits that can accrue to a cell if it becomes cancerous--might help explain the transformation. To see why, you have to think of a human cell as an entity with independent interests that don’t necessarily coincide with those of the whole human. Normal cells behave in a very disciplined way, Cairns explains. They are allowed to multiply under certain conditions and not under others. You can say, if you like, that all the time they’re under selection pressures to evade those rules. Because if they could evade them, they would be able to multiply, and from their point of view, that might seem a great idea.

Rosenberg thinks the phenomenon of directed mutation may shed light on human biology in ways that can’t be foreseen. What happens in starving, nondividing E. coli might be a model for understanding how mutations occur in cells that don’t divide--such as brain cells. E. coli is just a bacterium, says Rosenberg, but it’s a system in which you can really learn how things work. So far, the DNA of E. coli has behaved like the DNA of every other creature that people have looked at. It will change people’s ideas about what can happen in big, multicellular creatures like us.
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