Research reveals even single-cell organisms exhibit habituation, a simple form of learning

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Microscopy image of the single-celled ciliate Stentor roeseli. Credit: Joseph Dexter

A dog learns to sit on command, a person hears and eventually tunes out the hum of a washing machine while reading … The capacity to learn and adapt is central to evolution and, indeed, survival.

Habituation—adaptation's less-glamorous sibling—involves the lessening response to a stimulus after repeated exposure. Think the need for a third espresso to maintain the same level of concentration you once achieved with a single shot.

Up until recently, habituation—a simple form of learning—was deemed the exclusive domain of complex organisms with brains and nervous systems, such as worms, insects, birds, and mammals.

But a new study, published Nov. 19 in Current Biology, offers compelling evidence that even tiny single-cell creatures such as ciliates and amoebae, as well as the cells in our own bodies, could exhibit habituation akin to that seen in more complex organisms with brains.

The work, led by scientists at Harvard Medical School and the Center for Genomic Regulation (CRG) in Barcelona, suggests that single cells are capable of behaviors more complex than currently appreciated.

"This finding opens up an exciting new mystery for us: How do cells without brains manage something so complex?" said study senior author Jeremy Gunawardena, associate professor of systems biology at the Blavatnik Institute at HMS. He co-led the study with Rosa Martinez Corral, a former post-doctoral researcher in his lab who now leads a research group in systems and synthetic biology at CRG.

In this video, a single-cell pond dweller called Stentor roeselii exhibits markers of avoidance behavior, as reported in earlier research led by Gunawardena. The new study suggests this organism is also capable of habituation. Credit: Harvard Medical School

The results add to a small but growing body of work on this subject. Earlier work led by Gunawardena found that a single-cell ciliate showed avoidance behavior, not unlike the actions observed in animals that encounter unpleasant stimuli.

What the researchers discovered

Instead of studying cells in a lab dish, the scientists used advanced computer modeling to analyze how molecular networks inside ciliate and mammalian cells respond to different patterns of stimulation. They found four networks that exhibit hallmarks of habituation present in animal brains.

These networks shared a common feature: Each molecular network had two forms of "memory" storage that captured information learned from the environment. One memory decayed much faster than the other—a form of memory loss necessary for habituation, the researchers noted. This finding suggests that single cells process and remember information over different time spans.

Studying habituation in single cells could help propel understanding of how learning in general works, the researchers said. The findings also cast the humble single-cell creatures in a new, more tantalizing light: They are not merely molecular machines packed in microscopic bodies, but they are also agents that can learn.

But what about more practical applications?

The researchers caution that these remain purely speculative for now. Yet one daring idea would be to apply the concept of habituation to the relationship between cancer and immunity.

Tumors are notoriously good evaders of immune surveillance because they trick immune cells into viewing them as innocent bystanders. In other words, the immune cells responsible for recognizing cancer may get somehow habituated to the presence of a cancer cell—the immune cell gets used to the stimulus and no longer responds to it.

"It's akin to delusion. If we knew how these false perceptions get encoded in immune cells, we may be able to re-engineer them so that immune cells begin to perceive their environments correctly, the tumor becomes visible as malign, and they get to work," Gunawardena said.

"It is a fantasy right now, but it is a direction I would love to explore down the road."

More information: Biochemically-plausible models of habituation for single-cell learning, Current Biology (2024). DOI: 10.1016/j.cub.2024.10.041. www.cell.com/current-biology/f … 0960-9822(24)01430-1

Journal information: Current Biology

Provided by Harvard Medical School