Then, in a process Kukushkin described as a tedious choreography of clockwork pipetting, they exposed the cells to precisely timed bursts of chemicals that imitated bursts of neurotransmitters in the brain. Kukushkin’s team found that the both the nerve and kidney cells could finely differentiate these patterns. A steady three-minute burst activated CRE, making the cells glow for a few hours. But the same amount of chemicals, delivered as four shorter pulses spaced 10 minutes apart, lit up the petri dish for over a day, indicating a lasting imprint — a memory.
Kukushkin’s findings suggest that nonneural cells can count and detect patterns. Even though they can’t do it at the speed of a neuron, they do remember, and they appear to remember a stimulus for longer when it is delivered at spaced intervals — a hallmark of memory formation in all animals.
Intuitively, this makes sense, Gershman said. From the perspective of the cell, or any other living system that shows the spacing effect, spaced information is evidence of a fairly consistent, slow-moving environment: a steady world. Massed information, on the other hand — a singular burst of chemicals or an all-night cram session — might represent a fluky event in a more chaotic environment. “If the world is changing really fast, you should forget things [more easily], because the things that you learned are going to have a shorter shelf life,” Gershman said. “They’re not going to be as useful later on, because the world will have changed.” These dynamics are as relevant to a cell’s existence as they are to ours.
Kukushkin, who has recently taken to calling himself a “molecular philosopher,” is fairly certain his findings would have been the same regardless of the type of cell he used. “I’m accepting bets for anybody’s favorite cell line showing a spacing effect,” he said. “I think it should be the default assumption that memory is a continuous process — that all these single cells memorize, that plants memorize, that neurons and all kinds of cell types memorize in the same way. The burden of proof shouldn’t be in proving that it’s the same. The burden of proof should be in proving that it’s different.”
Gershman agrees. “In a brain, the dynamics [of memory] concern neurons signaling to each other: a multicellular phenomenon,” he said. “But in a single cell, maybe we’re talking about the dynamics within a cell of molecules at different timescales. Different physical mechanisms can give rise to a common cognitive process, similar to how I could use a pen or a pencil or typewriter or computer to write a letter.”
At the end of the day, the letter — that is, the memory — is what matters.
Structural Bias
Part of the reason that science has been hesitant to embrace cellular-scale memory is sociological, Gunawardena said. The findings of early researchers such as Jennings and Gelber were memory-holed because they didn’t resonate with the prevailing theories of their time: Jennings’ discovery of memory in Stentor went against the dogma of “tropisms,” which inspired the behaviorist psychology dominant in Gelber’s day. Both of these views presumed a living world populated by biological automata, cycling through preprogrammed responses. Cells that can learn and adapt didn’t figure into such models.
“We all have our ideologies,” said Gunawardena, who is now at Pompeu Fabra University in Barcelona. “It’s just a natural part of how humans deal with the world. … In science, we’ve really underplayed how important those biases can be in organizing scientific communities, and in setting what is considered appropriate and not appropriate science.”
It’s also an issue of semantics. Like all important terminology, “memory” is loaded, imprecise and defined variously by different disciplines. It means one thing to a computer scientist and another to a biologist — to say nothing of the rest of us. “When you ask a normal person what memory is, they think of it introspectively,” Kukushkin said. “They think, ‘Well, I close my eyes and I think back to yesterday, and that’s memory.’ But that’s not what we’re studying in science.”
In neuroscience, Kukushkin writes, the most common definition of memory is that it’s what remains after experience to change future behavior. This is a behavioral definition; the only way to measure it is to observe that future behavior. Think of S. roeselii snapping back into its holdfast, or a lab rat freezing up at the sight of an electrified maze it’s tangled with before. In these cases, how an organism reacts is a clue that prior experience left a lingering trace.
But is a memory only a memory when it’s associated with an external behavior? “It seems like an arbitrary thing to decide,” Kukushkin said. “I understand why it was historically decided to be that, because [behavior] is the thing you can measure easily when you’re working with an animal. I think what happened is that behavior started as something that you could measure, and then it ended up being the definition of memory.”
Behavior tells us that a memory has formed but says nothing about why, how or where. Further, it’s constrained by scale. Take Aplysia californica, a muscular sea slug with enormous neurons (the largest is about the size of a letter on a U.S. penny). Neuroscientists love to conduct memory experiments on Aplysia because its physical responses are easy to measure — poke it and it flinches — and they map cleanly to the handful of sensory and motor neurons involved.
The sea slug, Kukushkin said, can complicate neuroscience’s behavioral bias. Say you shock its tail, triggering a defensive reflex. If you shock it again the next day and find that the defensive reflex is stronger than it was before, that’s behavioral evidence that the slug remembers its initial shock. Any neuroscientist would associate it with a memory.
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