When Haruto Ishikawa shone a light on a flask of E. coli bacteria in a lab at Osaka University, something extraordinary happened: the solution’s pH rose, a silent but clear signal that a 700-million-year-old protein had just stirred back to life. The protein, called Anc-SzR—an ancestral schizorhodopsin resurrected from genetic shadows—was absorbing light and pumping protons into the cells, just as its modern descendants do. This wasn’t science fiction; it was meticulous molecular archaeology, bringing ancient light-sensing proteins back from evolutionary oblivion.
Understanding how proteins evolve new functions has long been a puzzle for biologists. Microbial rhodopsins, found across diverse microorganisms, all share a core structure—seven transmembrane helices—but differ wildly in their external loops, making it difficult to trace their evolutionary lineage using standard sequence alignment methods. These traditional approaches often misinterpret insertions and deletions (indels), leading to bloated, unrealistic ancestral protein models. But the Osaka team, led by Ishikawa and senior researcher Yasuhisa Mizutani, developed a smarter method: one that explicitly accounts for these genetic gaps and additions.
By analyzing sequences of schizorhodopsins and heliorhodopsins with their new pipeline, ConsistASR, the researchers reconstructed two full-length ancestral proteins. When expressed in E. coli, both folded into stable, functional forms. The ancestral schizorhodopsin not only absorbed light with a distinct spectral signature but also actively transported protons—proof of its biological activity. In contrast, the ancestral heliorhodopsin, like its modern counterparts, showed no ion-pumping ability, suggesting this trait was never part of its function.
This precision in ancestral reconstruction opens a new window into the deep past of molecular evolution. For the first time, scientists can generate ancient proteins that are not just structurally plausible but experimentally testable. The team’s decision to make ConsistASR openly available means researchers worldwide can now apply this method to other protein families, from ancient enzymes to sensory receptors, potentially unlocking how life’s molecular machinery diversified over billions of years.
"Our findings show that sequence reconstruction that takes insertions and deletions into account can successfully generate full-length ancestral rhodopsins that can be experimentally produced and tested," said Ishikawa—an understated conclusion for a breakthrough that brings us closer to reading the forgotten chapters of life’s biochemical history.