Some argue that six (or more) bases could in fact be less optimal: Mutations might become too common and cells would have difficulty doing damage control. Simulations have suggested that populations of organisms that use two base pairs would not only have optimal replication accuracy but would evolve most efficiently and reach the highest levels of fitness, according to one study.
But that argument comes with a caveat, according to Romesberg: Without knowledge of the selective pressures that existed billions of years ago when the code would have been evolving—without a clear picture of how rapidly the environment was changing or what competition looked like—it’s impossible to make such judgments about mutation rate. The same general argument could apply to whether three is the best number of letters for constituting a codon. “When you don’t understand the problem, it’s very hard to theorize about it,” he wrote in an email.
Ultimately, then, the argument comes down to whether the observed number of amino acids—20 in most organisms, although some organisms code for 21 or 22—is optimal. At the very least, 20 is “good enough,” Freeland says. That number enabled the emergence of all living organisms, and their adaptation to every extreme environment thrown their way. The 20 naturally occurring amino acids are ideally and evenly spread over a wide range of hydrophobicity, size, and electronegativity values.
But would adding more colors to the palette improve anything? Some say no—that having 20, 21, or 22 is a “Goldilocks” scenario, and that their properties are already spread out enough to allow proteins to be fantastically varied while also evolving efficiently.
Others disagree, and are holding out for evidence that they hope is soon to arrive. According to Benner, our DNA’s nucleotides are not as stable as they could be, and having an expanded alphabet could very well have a positive effect if the additions are well chosen.
“It’s conceivable that on a long evolutionary timescale, having additional amino acids would be advantageous, allowing the host to adapt in new ways,” Liu says. “But it would be an entirely new chemistry that’s difficult to predict.”
Freeland agrees, noting that evidence suggests life began with a smaller handful of amino acids and gradually enlarged its inventory. “There’s nothing magic about 20 amino acids,” he says. “It’s not clear to me what advantage there would be to going beyond that, though. I’m not saying it couldn’t get more optimal. It’s just that it’s already good enough.”
Major innovations in the genetic code might also have difficulty taking hold because many researchers describe its rules as effectively “frozen.” Once organisms began to flourish with three-letter codons, Benner says, it became hard for anything that deviated from that system to compete.