Sea urchins made to order: Scripps scientists make transgenic breakthrough

Consider the sea urchin. Specifically, a painted hedgehog: Lytechinus pictusa spiky ping pong ball from the eastern Pacific Ocean.

This species is the smaller and shorter spiny cousin of the purple hedgehog devouring kelp forests. They produce huge amounts of sperm and eggs that are fertilized outside their bodies, allowing scientists to observe the process of hedgehog formation up close and on a large scale. One generation gives rise to another in four to six months. They share more genetic material with humans than fruit flies and can’t fly—in short, the perfect lab animal for a developmental biologist.

Scientists have been using sea urchins to study cell development for about 150 years. Despite hedgehogs’ status as super-reproducers, practical concerns often force scientists to focus their work on more readily available animals: mice, fruit flies, worms.

For example, mice scientists can order online animals with specific genetic traits they hope to study — transgenic animals whose genes have been engineered to express or suppress certain traits.

Researchers working with urchins usually have to spend part of the year collecting them from the ocean.

“Can you imagine mouse researchers setting a mouse trap every night and whatever they catch is what they’re studying?” he said Amro Hamdounprofessor at UC San Diego’s Scripps Institution of Oceanography.

Marine invertebrates represent about 40% of the biodiversity of the animal world, yet appear in a tiny fraction of the percentage of animal studies. What if researchers could get to sea urchins as easily as mice? What if lines of transgenic hedgehogs could be created and raised?

How much more can we learn about how life works?

“You know how everyone was making sourdough during the pandemic? I’m not good at making sourdough,” Hamdoun said recently in his office in Scripps’ Hubbs Hall. Instead, he focused on a project of a different kind: a new transgenic laboratory animal, the “fruit fly of the sea.”

In March, Hamdoun’s lab published a paper on the bioRxiv preprint server, demonstrating the successful insertion of a piece of foreign DNA—specifically, a fluorescent protein from a jellyfish—into the genome of a painted hedgehog, which passed the change on to its offspring.

The result is the first transgenic sea urchin that happens to glow like a Christmas bulb under fluorescent light. (The paper has been submitted for review.)

The animals are the first transgenic echinoderms, a phylum that includes starfish, sea cucumbers and other marine animals. Hamdoun’s mission is to make genetically modified hedgehogs available to researchers anywhere, not just those who happen to work in research facilities on the edge of the Pacific Ocean.

“When you look at some other model organisms like Drosophila.” [fruit flies], zebrafish and mice, there are well-established resource centers,” said Elliot Jackson, a postdoctoral researcher at Scripps and lead author of the paper. “If you want a transgenic line that marks the nervous system, you could probably get that.” You could have ordered it. And with that, we hope we can be for sea urchins.”

The ability to genetically modify an animal trumps what scientists can learn from it, with implications far beyond any single species.

“It will change sea urchins as a model for understanding neurobiology, for understanding developmental biology, for understanding toxicology,” he said Christopher LoweA Stanford biology professor who was not involved in the research.

The lab’s breakthrough and its focus on making animals freely available to fellow scientists “will allow us to explore how evolution has solved a lot of really complicated problems in life,” he said.

Researchers tend to study mice, flies, and the like not because animal biology is best suited to answering their questions, but because “all the tools that were necessary to get to your questions were developed in just a few species, he said. Deirdre Lyonsassociate professor of biology at Scripps, who collaborated with Hamdoun on early research related to the project.

Expanding the range of animals available for sophisticated lab work is like adding colors to an artist’s palette, Lyons said: “Now you can get the color you really want, the one that best fits your vision, instead of sticking with a few models. “

On the ground floor of Hamdoun’s office building is Hubbs Hall Experimental Aquarium, a garage-like space overflowing with tanks filled with recirculating seawater and a diverse assortment of marine life.

On a recent visit, Hamdoun reached into the tank and gently dislodged a painted hedgehog. With surprising speed, he ran across the outstretched palm as if exploring foreign terrain.

Last common ancestor L. pictus and Homo sapiens lived at least 550 million years ago. Despite the different evolutionary paths we have taken since then, our genomes reveal a common biological heritage.

The genetic instructions that govern the transformation of a single zygote into a living body are strikingly similar in our two species. Specialized systems distinct from a single fertilized egg and the translation of a jumble of proteins into a unique living creature—at the cellular level, it all happens in essentially the same way in hedgehogs and humans.

These animals are “really fundamental to our understanding of all life,” Hamdoun said, placing the hedgehog back in the tank. “And historically very inaccessible genetically.

The experimental aquarium was built in the 1970s, when the only way to obtain research specimens was by collecting life from the sea. A few floors up in Hubbs Hall, Hamdoun led the way to a hedgehog nursery—the first large-scale effort to raise successive generations of animals in a laboratory. At any given time, the team has between 1,000 and 2,000 sea urchins in various stages of development.

Against the wall stood row after row of small plastic tanks, each containing a juvenile hedgehog the size of a lentil. A strip of tape on each tank recorded the genetic modification of the animal and the date of insemination. On some, the second piece of tape marked animals that had a modification in the DNA of their gametes, meaning they could be passed on to offspring. (For this reason, the lab keeps its hedgehogs carefully separated from the wild population.)

“One of the big questions in all of biology is understanding how a series of instructions in a genome gives you whatever phenotype you want to study,” Hamdoun said — basically, how the chain of amino acids that is an animal’s genetic code gives rise to the characteristics of a living, breathing creature. “One of the basic things you have to do is be able to edit that genome and then study what the result is.”

He pointed to a tank with a small hedgehog that had had the ABCD1 protein excised from its genetic code.

ABCD1 acts as a bouncer, Hamdoun explained, parking along the cell membrane and ejecting foreign molecules. The action of the protein can protect the cell from harmful substances, but sometimes it can work against the best interest of the organism, for example, when it prevents the cell from absorbing necessary drugs.

Researchers using hedgehogs in which this protein no longer functions can study the movement of the molecule through the organism – For example, DDT — and measure how much of the substance ends up in the cell without the confounding interference of ABCD1. They can back-analyze how much of a role ABCD1 plays in preventing the cell from absorbing the drug.

And then there are fluorescent hedgehogs.

“The magic happens in this room,” Jackson said, walking into a narrow office with $1 million worth of microscopes at one end and a decades-old hand crank bolted to a desk at the other.

He placed a petri dish containing three pencil-sized transgenic urchins under the microscope. At 120 times its size, each one looked like a Times Square New Year’s Eve ball come to life—a glowing, wiggling creature of five-fold radial symmetry.

Fluorescence isn’t just an echinoderm party trick. Lighting up cells makes it easier for researchers to track their movement in a developing organism. Researchers can watch the early blastula cells divide and reorganize into nerve or heart tissue. Eventually, scientists will be able to turn off individual genes and see how this affects development. It will help us understand how our own species evolves and why that evolution doesn’t always go according to plan.

The lab “did a great job. The community has really embraced it,” he said Marko Horbsenior scientist and director of the National Xenopus Resource at the University of Chicago’s Marine Biological Laboratory.

Horb operates a national center for genetically modified species of Xenopus, clawed frogs used in laboratory research. Funded in part by the National Institutes of Health, the center develops lines of transgenic frogs for scientific use and distributes them to researchers.

Hamdoun envisions a similar resource center for the street people of his lab. They have already begun sending small vials of transgenic hedgehog sperm to interested scientists, who can custom-breed the hedgehogs with eggs obtained from Hamdoun’s lab or another source.

Hamdoun vividly recalls the time he spent earlier in his career trying to track down the random snippets of DNA necessary for his research, the disappointment and frustration of writing to professors and former postdocs only to find that the material was long lost. He would prefer that future generations of scientists spend their time exploring.

“Biology is really interesting,” he said. “The more people have access to it, the more we’ll learn.”