England is currently in the middle of a heatwave (if you’re from a tropical country, try not to laugh). The air is hot, still and oppressive, and I feel like I’m stuck in a Tennessee Williams play. I wish I had a fan but, of course, all of the shops are out of fans. The smart move would have been to buy a fan in the middle of winter, when they were readily available. The fan would have been useless for months, neither giving me benefits not inconveniencing me. But when the environment changed and a cooling device suddenly became useful, I’d be laughing.
A lot of evolutionary biologists are coming round to the same idea. We’re used to the idea that living things pick up changes (mutations) in their genes. Some of these benefit their owners and spread through the population thanks to natural selection; others are harmful, and get weeded out. But many mutations don’t seem to do anything at all. They don’t change any proteins. They don’t influence the success of their owners. They’re called “neutral”.
But these neutral mutations might not be so innocuous after all. Some, like my imagined fan, suddenly become useful when the environment changes. Others lay the groundwork for further mutations that would otherwise do nothing (or be harmful) on their own—in other words, they make organisms better at evolving.
These “cryptic mutations” turn out to be a powerful force in evolution. They’ve been discussed since the 1930s, when eminent biologists talked about unimportant genetic changes that could later give rise to valuable ones, or stores of “concealed potential variability.” But it’s only now that we have the tools and techniques to find concrete and convincing case studies.
I’ve written about these discoveries in a new feature for Scientific American. The lead story is one of the best examples of how important cryptic mutations can be, and how they are relevant to our health. But do head over there for the full story.
When Jesse Bloom heard in 2009 that Tamiflu, once the world’s best treatment for flu, had inexplicably lost its punch, he thought he knew why. Sitting in his lab at the California Institute of Technology, the biologist listened to a spokesperson from the World Health Organization recount the tale of the drug’s fall from grace. Introduced in 1999, the compound was the first line of defense against the various strains of flu virus that circulate around the world every year. It did not just treat symptoms; it slowed the replication of the virus in the body, and it did its job well for a time. But in 2007 strains worldwide started shrugging off the drug. Within a year Tamiflu was almost completely useless against seasonal influenza.
The WHO spokesperson explained that the sweeping resistance came about through the tiniest of changes in the flu’s genetic material. All flu viruses have a protein on their surface called neuraminidase—the “N” in such designations as H1N1—which helps the viruses to break out of one cell and infect another. Tamiflu is meant to stick to this protein and gum it up, trapping the viruses and curtailing their spread. But flu viruses can escape the drug’s attention through a single change in the gene encoding the neuraminidase protein. A mutation called H274Y subtly alters neuraminidase’s shape and prevents Tamiflu from sticking to it.
Most public health experts had assumed that flu viruses would eventually evolve resistance to Tamiflu. But no one anticipated it would happen via H274Y, a mutation first identified in 1999 and originally thought to be of little concern. Although it allows flu viruses to evade Tamiflu, it also hampers their ability to infect other cells. Based on studies in mice and ferrets, scientists concluded that the mutation was “unlikely to be of clinical consequence.” They were very wrong. The global spread of viruses bearing H274Y proved as much.
That spread “sounded alarm bells to me,” Bloom says. Something else had changed to let the virus use the mutant neuraminidase without losing the ability to spread efficiently. He soon found that certain strains of H1N1 had two other mutations that compensated for H274Y’s debilitating effects on the virus’s ability to spread from cell to cell. Neither of the pair had any effect on their own. In the lingo of biologists they were “neutral.” But viruses that carried both of them could pick up H274Y, gaining resistance to Tamiflu without losing their infectivity. Both mutations looked innocuous individually, but together they made the virus more adaptable in the face of a challenge. To put it another way, they made it better at evolving.