The Flaws That Made Us Complex


An enzyme from three different species is compared, with structural "flaws" shown in green. (From Fernández & Lynch, Nature, 2011)

One common misconception about evolution is that it produces “better” organisms with time – a seductive opinion to humans who would like to think of themselves as the pinnacle of natural selection. In a way, it’s an easy error to make, for who would look at a single-celled bacterium next to a human and think that the four billion years of evolution between the two species hadn’t produced some improvements? But when Ariel Fernández and Michael Lynch compared the proteins that bacteria and humans share, they found that the unicellular organisms held a surprising advantage. Though the overall shape of the proteins were the same, the human proteins were leakier, more vulnerable to the destabilizing effects of water than those of the bacteria.

But according to the paper published yesterday by Fernández and Lynch in Nature, those protein flaws may have been the key spark that led to the evolution of complex organisms.

“We hate to hear that our structures are actually lousier,” said Fernández, a visiting scholar at the University of Chicago and senior researcher at the Mathematics Institute of Argentina (IAM) in Buenos Aires . “But that has a good side to it. Because they are lousier, they are more likely to participate in complexes, and we have a much better chance of achieving more sophisticated function through teamwork. Instead of being a loner, the protein is a team player.”

The engineering advantage of bacteria over humans boils down to one simple fact: they will always far outnumber us. Billions of bacterial organisms can fit into a single Petri dish, and in a single human body there are over 100 times more bacterial cells than there are humans on Earth . When a genetic mutation with a negative effect pops into existence in these huge populations, natural selection quickly disposes of it, preserving the integrity of the protein that gene encodes. But when a mildly negative mutation appears in a relatively small population, such as that of humans or elephants or pine trees, selection is less efficient and the mutation may spread – a phenomenon called genetic drift.

The direct effect of these mild mutations would be to introduce minor flaws into the structure of proteins. If the change in protein function was too severe, it would cease to function and likely kill the organism. But if the change was just a small nick in the armor of the protein, making it chemically more vulnerable to water, the mutation might stick around long enough to be passed on to offspring. That theory informed Fernández and Lynch’s hypothesis: proteins from species with small population sizes would contain more of these flaws than those from species with large populations.

Their idea was proven true: compare the same protein between, say, humans, flatworms, and bacteria, and you’ll find a descending frequency of protein flaws. Even within a single species, the difference can be measured. Some bacteria have both endosymbiotic populations that live inside other organisms and larger, free-living populations, and the proteins from the endosymbiotes were found to contain more structural errors than their free-living peers.

But the exciting part is what happens after those errors accumulate. A protein more vulnerable to chemically reacting with water wants to protect those flaws as well as possible. One easy way to do this is to cover up those flaws, by becoming “sticky” and binding with another protein. These interactions create new possibilities for biology – suddenly a simple protein becomes a multi-protein complex that can be regulated and modified in new ways. And if those new complexes work better than than the protein by itself, natural selection can take over and spread the mutated gene for the flawed-but-useful protein through the population.

“It’s not an argument against selection, it’s an argument for non-adaptive mechanisms opening up new evolutionary pathways that wouldn’t have been there before,” said Lynch, professor of biology at Indiana University. “It’s those first little nicks getting into the protein armor that essentially open up a new selective environment.”

That’s a provocative idea in evolutionary biology – instead of natural selection producing ever greater complexity, the random appearance of protein errors and stickiness may have jump-started the journey from microbe to man. However, this strategy could go wrong, the authors warned. If too many errors are introduced into a protein, it can become too reactive, a phenomenon seen with prions, amyloid-beta, and tau proteins which form dangerous aggregates underlying encephalopathy and Alzheimer’s disease. The sweet spot is the “twilight between order and disorder,” Fernández said.

“This is a novel bridge between protein chemistry and evolutionary biology,” Lynch said.  “I hope that it causes us to pause and think about how evolution operates in new ways that we haven’t thought about before.”

The idea could also be useful for scientists in the growing field of bioengineering. Researchers are trying to use the tools of natural selection to “evolve” better materials that self-assemble or self-repair. But the history of life on Earth suggests that introducing a little imperfection and randomness into the process might be the secret to creating complex results.

“Natural designs are often one notch more sophisticated than the best engineering,” Fernández said. “This is another example: Nature doesn’t change the molecular machinery, but somehow it tinkers with it in subtle ways through the wrapping.”

[More coverage of this research can be found at the BBC and Nature News.]


Fernández, A., & Lynch, M. (2011). Non-adaptive origins of interactome complexity Nature DOI: 10.1038/nature09992

About Rob Mitchum (525 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
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