The 1st Gene-Altered Squid Has Thrilled Biologists

Jul 30, 2020
Originally published on August 11, 2020 2:29 pm

The first genetically altered squid has scientists excited about a potential new way to study marine critters that are so weird, they've sometimes been compared to alien life forms.

Scientists report this week that they have disabled a pigmentation gene in a squid called Doryteuthis pealeii. Their success shows that cephalopods — which include squid and octopuses — can finally be studied using the same kind of genetic tools that have let scientists explore the biology of more familiar lab animals like mice and fruit flies. Those are easy to keep in the laboratory, and scientists routinely modify their genes to get insights into behavior, diseases, and possible treatments.

Cephalopods may seem plenty strange enough without scientists tinkering with their genes. These tentacled beings have huge, clever brains that look nothing like our own. They travel using jet propulsion and some can change their skin color in a flash. All of this oddness is exactly why some biologists want to better understand them.

"They've evolved these big brains and this behavioral sophistication completely independently," says Joshua Rosenthal, a researcher at the Marine Biological Laboratory in Woods Hole, Massachusetts. "This provides an opportunity to compare them with us and see what elements are in common, and what elements are unique."

Until now, cephalopod research has been hindered by the fact that there's been no way to manipulate squid or octopus genes. Rosenthal is part of a group that's trying to change all that. The team is raising a wide array of exotic cephalopod species — everything from flamboyant cuttlefish to pygmy octopuses — to figure out how to keep them going in captivity and alter their DNA.

The researchers also work with a famous local squid that lives in the waters around Woods Hole. Historically, this squid has been important for neurobiologists because it has a giant, easy-to-study nerve cell. Much of what's known about how nerve cells send electrical signals comes from studies of this cell, and the research led to a Nobel prize in 1963. What's more, scientists have sequenced the DNA that makes up this squid's genetic code.

Each summer, a research boat goes out from Woods Hole and collects the squid, Doryteuthis pealeii. Karen Crawford of St. Mary's College of Maryland, a key member of the research team, had previously figured out how to take sperm and eggs from this squid and produce embryos in the lab.

Studies with the Doryteuthis pealeii squid, shown above, have led to major advances in neurobiology.
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Building upon that work, she and her colleagues figured out how to inject gene-altering materials into the fertilized egg, to disrupt a gene involved in coloring the squid's skin and eye cells. The biggest challenge was getting through a tough outer layer that surrounded the early squid embryo, says Rosenthal.

"For months, we would have needles break," he says. "So we came up with a way to get the injection needle in, finally. That turned out to be one of the biggest roadblocks in this study."

The resulting squid hatchlings had far fewer of the little dark spots that are normally characteristic of the species, because the pigmentation gene was knocked out in almost every cell.

"For me, this is game-changing. I have been interested in trying to understand how these animals work from the molecular level, and so now we actually have the ability to go in and test what an individual gene does," says Carrie Albertin, another member of the research team who also works at the Marine Biological Laboratory.

"This is something that honestly, if you asked me five years ago if we'd be able to do, I would have just giggled and said, 'I dream of it.' But, you know, I didn't think it would be possible. And yet here we are," says Albertin.

These Doryteuthis pealeii squid embryos were injected with CRISPR-Cas9 at different times before the first cell division, resulting in mosaic embryos with different characteristics.
Karen Crawford

This particular squid species isn't amenable to being raised to maturity in the lab — it's just too big. But there are plenty of other, smaller squid and octopus species, and the team is already working to transfer the technology to the ones they're cultivating in captivity. The researchers are also looking to add in genes, rather than just knocking out existing ones.

The work has thrilled other squid biologists like Sarah McAnulty of the University of Connecticut. She's studied the Hawaiian bobtail squid, and says researchers have tried to genetically alter cephalopods in the past.

"It's incredibly impressive that they've gotten it to work and this is a huge advancement for cephalopod researchers all over the world," says McAnulty. "We should all be popping bottles of champagne. This is amazing."

Curled tentacle of the longfin inshore squid, D. pealeii.
Karen Crawford

When biologists study natural squid, eventually they "hit something of a wall of understanding," because they can't play around with the animal's genetics to explore how its systems work at the most basic level, says McAnulty. She believes the ability to genetically modify cephalopods should make all kinds of novel experiments possible.

"If I could do anything, I would totally start playing around with the immune system of the squid," says McAnulty, to try to figure out how, say, the Hawaiian bobtail squid knows not to attack a kind of glowing, symbiotic bacteria that lives inside it.

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Some of the weirdest creatures on the planet are cephalopods, animals like squids and octopuses. Now in the journal Current Biology, scientists say they've managed to tinker with the genes of a cephalopod in the lab. NPR's Nell Greenfieldboyce reports on why a gene-altered squid is such a big deal.

NELL GREENFIELDBOYCE, BYLINE: Bret Grasse's official job title is manager of cephalopod operations. When I recently visited the Marine Biological Laboratory in Woods Hole, Mass., he showed me around a room full of burbling tanks.

BRET GRASSE: So we've got our beautiful, flamboyant cuttlefish. We've got our striped pyjama squids. These ones are native to Australia. We've got our Octopus chierchiae, which is the pygmy zebra octopus. They're native to Nicaragua - a very small octopus species that doesn't get much larger than a table grape.

GREENFIELDBOYCE: The work here involves everything from the very latest high-tech gene-editing tools to a bucket of rocks sitting on the floor. The rocks are used to make habitats in the tanks and to weigh down the lids.

GRASSE: So, you know, octopuses are notorious for being able to kind of escape out of their enclosures.

GREENFIELDBOYCE: These critters have sophisticated brains that look nothing like our own. They can solve puzzles, change their skin color in a flash and travel using jet propulsion. Josh Rosenthal is a researcher at the Marine Biological Laboratory. He says these animals evolved completely independently from us. Their relatives are things like clams.

JOSH ROSENTHAL: And this provides an opportunity to compare them with us and see what elements are in common and what elements are unique.

GREENFIELDBOYCE: The problem is there has been no way to modify their genes, and being able to do that is really important. Most lab biologists study just a few species, like mice and fruit flies, because the gene-editing technologies for them have been all worked out. This makes it easy to study a gene's role in behavior, disease and treatments. But none of that was available for cephalopods. So Rosenthal and his colleagues have been building those tools, first using a squid that lives in the waters around Woods Hole. A researcher named Karen Crawford had figured out how to fertilize its eggs in the lab. So the team did that and then injected gene-altering materials. It wasn't easy. The fertilized egg is surrounded by a tough, almost rubbery coating.

ROSENTHAL: For months, we would have needles break. We couldn't figure out how to get it.

GREENFIELDBOYCE: But they finally did it and turned off a pigmentation gene that normally makes small, dark spots on the squid's skin. Those spots are missing on the altered baby squid.

ROSENTHAL: Pigment genes are easy because you can see them, right? You can see if it's working as the things develop.

GREENFIELDBOYCE: Carrie Albertin is a member of the research team. She says, for her, this is a game-changer.

CARRIE ALBERTIN: This is something that, honestly, if you asked me five years ago if we'd be able to do, I would have just giggled and said, I'd dream of it. But, you know, I didn't think it would be possible, and yet here we are.

GREENFIELDBOYCE: Other squid biologists are equally thrilled. Sarah McAnulty is with the University of Connecticut. She says it's incredibly impressive that they've gotten this to work.

SARAH MCANULTY: This is, like, a huge advancement for cephalopod researchers all over the world. We should all be popping bottles of champagne. This is amazing.

GREENFIELDBOYCE: She says this particular squid can't live long term in a lab; it just gets too big. But she says it's proof of what's possible. And the researchers are already working with smaller creatures they have in those tanks to alter genes in them, too.

Nell Greenfieldboyce, NPR News.

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