Dec 13, 2021 7:00 AM

A Gene-Tweaked Jellyfish Offers a Glimpse of Other Minds

Researchers have created jellyfish whose nerve cells light up when they fire, offering a tantalizing view of neurology before the rise of the brain.

We owe much of our understanding of how memory works in the brain to an unassuming sea slug called Aplysia californicus. It’s about a foot long, reddish brown, and has been favored by scientists since the 1960s because its neurons are big enough to jam an electrode into.

That wasn’t the only time researchers have plumbed the ocean depths looking for answers about our own neurology: Giant squid taught us the fundamentals of action potentials, the means by which signals propagate along nerve cells. The horseshoe crab helped to shed light on how our visual system works (despite the fact it has eight more eyes than we do). The octopus offers insights into the evolution of sleep.

“There’s this long, beautiful history of people going and finding marine invertebrates for whatever the questions were at the time,” says Brady Weissbourd, a postdoctoral scholar in biology and biological engineering at Caltech. Weissbourd is the lead author on a recent paper in Cell that brings another creature into the fold—a jellyfish that’s been genetically modified so that its neurons glow when they fire. It could give us new insight into the workings of minds quite unlike our own.

The jellyfish, specifically a species found in the Mediterranean called Clytia hemisphaerica, was the perfect candidate for scientific research. It’s about a centimeter wide when fully grown—small enough to fit on a microscope slide—and, like many jellyfish, it’s transparent. The researchers built on that potential by introducing a snippet of DNA called GCaMP, which creates a green fluorescent protein. GCaMP has been widely used in research on mice, zebrafish, and flies, but it actually originally comes from a jellyfish that’s closely related to Clytia, so Weissbourd’s team also had to knock out the genes for four other green fluorescent proteins that naturally occurred inside them.

To insert the glowing genes, they took advantage of Clytia’s unique life cycle. Its reproductive system is triggered by light. “Exactly two hours after the lights go on, the jellyfish release eggs and sperm into the water,” Weissbourd says. The researchers switched on the lights, collected the eggs, and injected them with the snippet of code for the green fluorescent trait that they wanted to insert, along with a protein that helped to splice it into the jellyfish’s DNA.

The fertilized eggs develop into larvae, which swim around looking for a hard surface to attach to—in nature, this might be a rock; in the lab a microscope slide offered a useful substitute. From there, they grow a tiny polyp that develops into a colony. These colonies are essentially immortal, and they release baby medusae—which over the course of a few weeks grow into the gelatinous, shower-cap-like creatures we call jellyfish. “They’re more like a flower or something,” says Weissbourd. “Their job is to go out and spread seeds.”

Now, researchers have a creature that they can observe under a microscope as it eats (a diet of mashed-up brine shrimp) and folds its body, while the neurons governing those behaviors glow. “You can do really high-resolution experiments, looking at every neuron’s activity over time while the animal is behaving,” says Weissbourd. They can essentially read its mind—and it’s a mind that’s very different from anything we’re familiar with.

Jellyfish belong to a group of animals called cnidarians, which also includes anemones and coral. They split off from our branch of the evolutionary tree some 600 million years ago. “We are more closely related to a squid or a worm or a fly than any of those is to jellyfish,” says Weissbourd.

They don’t have what we’d think of as a brain. Instead, Clytia has what’s called a nerve net—a network of neurons covering the underside of its “umbrella.” There’s no central control. Clytia can lose a tentacle and still search for food. The mouth can live on its own indefinitely if it’s fed. A question that has puzzled scientists is how the jellyfish is able to coordinate its movements, to fold its body to draw a piece of food toward its mouth, for instance, if there’s no organizing entity or direct communication between different parts.

That’s what Weissbourd and colleagues studied in their paper, by isolating a distributed network of neurons involved in feeding—about 10 percent of the total—and watching them activate. “One thing that jumped out is just how incredibly modular the nervous system is,” he says. Rather than the diffuse pattern of activity throughout the nerve net that they expected, they found a degree of structure: The jellyfish’s nerve net seemed to be organized into previously invisible wedges, a bit like pizza slices. “When a jellyfish snags a brine shrimp with a tentacle, the neurons in the ‘pizza slice’ nearest to that tentacle would first activate, which in turn caused that part of the umbrella to fold inward, bringing the shrimp to the mouth,” lab director David Anderson explained in a press release.

That echoes the way the nervous systems of other, more distantly related jellyfish are organized—some have nerve tracts that carry impulses from periphery to center to bring food to the mouth, a bit like the way our own spinal cord relays messages from the limbs to the brain. “Because all jellyfish have the same body plan, they have the same problems,” says Robert Meech, a research fellow at the University of Bristol who studies electrophysiology in jellyfish. “You can see how these two kinds of circuitry provide different solutions to the same problem.”

Teasing out these hidden networks is just the start. Future studies could look at other jellyfish behaviors, or attempt to map out the creature’s entire nervous system. Studying jellyfish can also improve our understanding of the historical development of the brain. By looking for shared features in distantly related creatures, we can map out when they first evolved. “We know a lot about mammals, but we don’t know much about these early emerging animals like cnidarians,” says Simon Sprecher, a professor in neurobiology at the University of Fribourg. “It’s really essential that we get to study these animals.”

Cnidarians are some of the first creatures in evolutionary history to have neurons like our own. Over time, distributed nerve nets evolved into clusters of neurons, and eventually, in some early fish-like vertebrates, a centralized clump of nerve cells with specialized regions for different tasks: a brain.

This research can also offer a glimpse at how other forms of thinking might be organized. “It lets us get at this issue of what are the options for a nervous system or behavior,” Weissbourd says. It’s hard to put yourself into the mind of a jellyfish—their life cycle of polyps and spores is utterly alien, their weird array of sensory organs have no analogues to our own. Clytia have specialized balance organs called statocysts; other species of jellyfish have sensors called rhopalia that detect light or chemical changes in the surrounding water.

Researchers have observed some things that could be thought of as akin to our emotional states; for example, Clytia display a unique set of behaviors when spawning, and they perform their feeding action more quickly when they’re hungry. “But they might have a totally different set of nervous system states,” Weissbourd says.

These gene-tweaked jellies are an exciting new platform for research, says Sprecher. Future experiments will improve our understanding of modular nervous systems, not only in jellyfish but in more complex species too. These are ancient creatures, but we know so little about how they see the world, or if it even makes sense to think of them as “seeing” in the way that mammals do. Literally peering inside them could help provide the answers.

Update 12-13-2021 1:00 ET: Research into action potentials was conducted on the squid giant axon, not the giant squid axon.