Studying alternate realities has traditionally been the purview of physicists, cosmologists, and philosophers. Maybe theologians. But at the University of Chicago, biochemists, molecular biologists, and geneticists in Joseph Thornton’s lab are examining why things in biology have turned out as they have and not some other way. They note that “history leaves no trace of the roads it did not take” and ask: is the current state of things inevitable?

And, if it's not, it’s worth figuring out why things aren’t different—and whether the outcome could have been better than the solution life on Earth ended up with.

Remaking the past

By “things” here I mean proteins. For Thornton’s lab, this means the estrogen receptor and a related receptor that handles other steroid hormones like androgens, progestogens, and corticosteroids. These receptors bind their preferred steroid, then bind to specific DNA sequences and control the activity of a particular suite of genes. The DNA sequence that the estrogen receptor binds—called the estrogen response element—differs from the DNA sequence that the more generic steroid receptor sticks to, though only in two locations.

Previously, the authors used evolutionary analysis to figure out what the ancestor of these receptors looked like. When they engineered DNA to produce this ancestral receptor, they found it stuck to the estrogen response element. So, the changes on the pathway to the generic steroid receptor involved a series of mutations that changed the DNA it stuck to.

Thornton and his group subjected this ancestral protein to some alternative evolutionary paths—160,000 of them—to assess how, and if, any other steroid receptors could have arisen from the ancestral version.

They found 828 variants of the steroid receptor that could bind its preferred DNA sequence just as well as, or even better than, the receptor we have. These alternate, nonexistent steroid receptors don’t all work the same way: they have different methods of contacting the relevant parts of the DNA.

So the version we have is not the optimal one. Did we end up with it because it was the easiest version to evolve? The answer here is “no.” It is not uniquely accessible from the ancestral protein; other equally good versions could have arisen in just as few mutational steps. So the need to bind steroids limits it, but not to a single sequence.

History also provides a limit, since the modern receptor is based on the sequence of the ancestral one. Even though the functionality of the ultimate version is not dictated by the starting DNA sequence of the ancestral gene—it could have evolved to bind some unrelated chemical, for example—the sequence of the ultimate version is. If the ancestral gene sequence had happened to be different, the steroid receptor we ended up with would probably look different, too. But it would probably work just as well.

Chance or fate

Natural selection drives evolutionary processes by favoring mutations that optimize fitness. But chance plays a huge role in evolution, too, and this study highlights two distinct ways in which it does so.

The first is contingency: the future depends upon random events that occurred in the past, like the sequence of our current steroid receptor being contingent upon the ancestral gene. And that ancestral gene isn’t predetermined, since a number of possible versions could have done the trick.

The second is stochasticity: since a number of equally capable steroid receptors could have evolved from the ancestral version, the one we ended up with is essentially random.

The sequence for the steroid receptor is conserved among current species; once it evolved, it became locked in place. This could trick us into thinking it is the best one that could ever have been, that this sequence was specifically selected and optimized for its function. But it’s not so, as any one of the 828 possible receptors that could have evolved might have gotten locked in, too, tricking us into thinking that that version was the best one that could ever have been.

The authors of this work conclude by noting that “the singularity of the present seems to rationalize the past.” But they followed 160,000 evolutionary paths not taken by the steroid receptor protein to warn us away from the illusion that things are the way they are because they couldn’t possibly have been otherwise. If only reconstructing counterfactual occurrences, as these scientists did for this protein, were as easy to do for other aspects of human history.

Nature, 2017. DOI: 10.1038/nature23902 (About DOIs).