The genes for apoptosis reminded Kaczanowski and Zielenkiewicz of an arms race between a predator and its prey. In their new paper, they speculated that they might be holdovers from the tools evolved by a prey organism, presumably the original mitochondrial bacterium, to defend itself.

Maybe, once caught inside our ancient ancestor, apoptotic proteins became a way for the mitochondrion to stress the host into changing its behavior, goes a hypothesis collected by Durand and Grant Ramsey, a philosopher of science, in a review they published last June. Or maybe they are the remnants of a way the mitochondrion ensured that the host could not get rid of it — a poison for which only the mitochondria possessed the antidote. Somewhere along the way, the process was captured or transformed by the host, and a variant evolved into apoptosis proper.

The search for answers about the origin of eukaryotic apoptosis seems to be drawing researchers deeper into the bacterial world. In fact, some wonder whether the answers may lie in why single-celled organisms take their own lives. If some form of programmed cell death is older than multicellular life — older even than eukaryotes — then perhaps understanding why it happens in organisms with no bodies to benefit and no mitochondria to speed the process can explain how this all got started.

For the Good of Some Whole

Here’s one reason a single-celled organism might choose to die: to help its neighbors.

In the 2000s, when Durand was a postdoctoral researcher at the University of Arizona, he discovered something intriguing during an experiment with single-celled eukaryotic algae. When he fed algae the remains of their kin who had died by programmed cell death, the living cells flourished. But when he fed them the remains of kin killed violently, the algae’s growth slowed.

Programmed cell death appeared to create usable resources from dead parts. However, this process could only benefit relatives of the dead algae, he found. “It was actually harmful to those of a different species,” Durand said. In 2022, another research group confirmed the finding in another algae.

The results possibly explain how cell death can evolve in single-celled creatures. If an organism is surrounded by kin, then its death can provide nutrition and therefore further its relatives’ survival. That creates an opening for natural selection to select for the tools for self-induced death.

Bacteria, too, are single-celled, and may live among their kin. Can they also die for some greater good? There are hints that under the right conditions, bacteria infected with a virus may kill themselves to arrest the spread of disease. These revelations have reshaped how researchers think about programmed cell death, and Aravind recently discovered another piece of the puzzle.

It involves protein regions called NACHT domains, which appear in some animal apoptosis proteins. NACHT domains also exist in bacteria. In fact, in the wild, the microbes that have the most NACHT domains sometimes partake of what looks very much like multicellular living, Aravind said. They grow in colonies, which makes them especially vulnerable to contagion and especially likely to benefit from each other’s self-sacrifice.

Aravind’s colleague Aaron Whiteley and his lab at University of Colorado and his lab equipped E. coli with NACHT domains and grew them in test tubes. Then they infected the cells with viruses. Strikingly, they found that NACHT-bearing proteins were required to trigger a form of programmed cell death, with infected cells killing themselves so swiftly that the viruses were unable to replicate. Their sacrifice could protect others around them from infection, Aravind said.