Consider the sea urchin. In particular, the painted hedgehog: Lytechinus pictus, a spiky ping-pong ball from the eastern Pacific Ocean.
The species is a smaller and shorter cousin of the purple urchins that devour kelp forests. They produce enormous numbers of sperm and eggs that are fertilized outside their bodies, allowing scientists to view the process of sea urchin creation up close and on a large scale. One generation leads to the next within four to six months. They share more genetic material with humans than fruit flies and cannot fly away – in short, an ideal laboratory animal for the developmental biologist.
Scientists have been using sea urchins to study cell development for about 150 years. Despite the status of sea urchins as super-reproducers, practical problems often force scientists to concentrate their work on more easily accessible animals: mice, fruit flies, worms.
For example, scientists working with mice can order online animals with the specific genetic traits they hope to study: transgenic animals, whose genes have been artificially manipulated to express or suppress certain traits.
Researchers who work with sea urchins typically spend part of their year collecting them from the ocean.
“Can you imagine if mouse researchers set a mousetrap every night, and whatever they caught, they would study?” said Amro Hamdoun, a professor at UC San Diego’s Scripps Institution of Oceanography.
Marine invertebrates represent approximately 40% of the animal world’s biological diversity, yet appear in a meager fraction of a percentage of animal studies. What if researchers could access sea urchins as easily as mice? What if it were possible to create and raise lines of transgenic hedgehogs?
How much more can we learn about how life works?
“You know how everyone made sourdough during the pandemic? I’m not good at making sourdough,” Hamdoun said recently at his office in Scripps’ Hubbs Hall. Instead, he set his sights on a different kind of project: a new transgenic laboratory animal, “a fruit fly from 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 sea urchin that passed the change on to his descendants.
The result is the first transgenic sea urchin, a sea urchin that glows like a Christmas light under fluorescent lights. (The article has been submitted for peer review.)
The animals are the first transgenic echinoderms, the phylum that includes starfish, sea cucumbers and other marine animals. Hamdoun’s mission is to make genetically modified hedgehogs available to researchers everywhere, not just those who happen to work in research facilities on the edge of the Pacific Ocean.
“If you look at some of the other model organisms, like Drosophila [fruit flies], zebrafish and mice, there are established resource centers,” said Elliot Jackson, a postdoctoral researcher at Scripps and lead author of the paper. “If you want a transgenic line that labels the nervous system, you can probably get it. You could order it. And that’s what we hope we can be for sea urchins.”
The ability to genetically modify an animal expands what scientists can learn from it, with implications far beyond any individual species.
“It will transform sea urchins as a model for understanding neurobiology, for understanding developmental biology, for understanding toxicology,” said Christopher Lowe, a Stanford professor of biology who was not involved in the study.
The lab’s breakthrough, and its focus on making the animals freely available to fellow scientists, will “allow us to explore how evolution has solved a lot of really complicated life problems,” he said.
Researchers tend to study mice, flies, and the like not because the animals’ biology is best suited to answer their questions, but because “all the tools needed to answer your questions were built up in just a few species said Deirdre Lyons. , an associate professor of biology at Scripps who worked with Hamdoun on early research related to the project.
Expanding the range of animals available for advanced laboratory work is like adding colors to an artist’s palette, Lyons said: “Now you can start to get the color that you really want, that best suits your vision, rather than being stuck with a few models.”
On the ground floor of Hamdoun’s office building is the experimental aquarium Hubbs Hall, a garage-like space filled with tanks full of recirculating seawater and a colorful assortment of marine life.
During a recent visit, Hamdoun reached into a tank and carefully released a painted sea urchin. It zoomed across an outstretched palm with surprising speed, as if exploring alien terrain.
The last common ancestor of 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 shared biological heritage.
The genetic instructions that direct the transformation of a single zygote into a living body are strikingly similar in our two species. Specialized systems that differentiate from a single fertilized egg and the translation of a tangle of proteins into a single living thing – at the cellular level, it all happens in much the same way for sea urchins and humans.
These animals are “really fundamental to our understanding of all life,” Hamdoun said, as he placed the boy back in his tank. “And historically very inaccessible genetically.”
The experimental aquarium was built in the 1970s, when scooping up life from the sea was the only way to obtain research specimens. A few floors up in Hubbs Hall, Hamdoun led the way to the hedgehog farm – the first large-scale attempt to raise successive generations of animals in a laboratory. At any given time, the team has 1,000 to 2,000 sea urchins in various stages of development.
Row after row of small plastic containers lined one wall, each containing a young hedgehog the size of a lentil. A strip of tape on each tank noted the animal’s genetic modification and the date of conception. In some, a second piece of tape indicated animals that had the change in the DNA of their sex cells, meaning it could be passed on to offspring. (For this reason, the laboratory keeps its hedgehogs closely separated from the wild population.)
“One of the big questions in all of biology is understanding how the sequence of instructions in the genome gives you the phenotype you want to study,” Hamdoun said — essentially how the sequence of amino acids that is an animal’s genetic code gives rise to to the characteristics of the living, breathing being. “One of the fundamental things you have to do is be able to edit that genome and then study what the outcome is.”
He pointed to a tank containing a small sea urchin whose genetic code is the ABCD1 protein cut off.
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 against harmful substances, but can sometimes be against the interests of an organism, for example when it prevents the cell from absorbing a necessary drug.
Researchers using sea urchins in which that protein no longer works can study the movement of a molecule through an organism – DDT, for example – and measure how much of the substance gets into the cell without the disruptive interference of ABCD1. They can reverse engineer how big a role ABCD1 plays in preventing a cell from absorbing a drug.
And then there are the fluorescent hedgehogs.
“The magic happens in this room,” Jackson said, walking into a narrow office with $1 million worth of microscopes on one side and a decades-old hand-cranked centrifuge bolted to a table on the other.
He placed a petri dish containing three transgenic sea urchins the size of a pencil eraser under a microscope. They were 120 times larger and each resembled a New Year’s Eve ball in Times Square come to life: a glowing, wiggling creature with pentameric radial symmetry.
Fluorescence isn’t just an echinoderm party trick. By illuminating the cells, researchers can more easily track their movements in a developing organism. Researchers can watch as the early cells of a blastula divide and reorganize into neural or cardiac tissue. Eventually, scientists will be able to switch off individual genes and see how that affects development. It will help us understand how our own species develops, and why that development does not always go according to plan.
The lab has “done a great job. It’s been very welcomed by the community,” said Marko Horb, senior scientist and director of the National Xenopus Resource at the University of Chicago Marine Biological Laboratory.
Horb heads the national clearinghouse for genetically modified species of Xenopus, a clawed frog 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 his lab’s hedgehogs. They have already started sending small vials of sperm from transgenic sea urchins to interested scientists, who can grow custom-made urchins using eggs obtained from Hamdoun’s lab or another source.
Hamdoun vividly remembers the time he spent earlier in his career tracking down random pieces of DNA needed for his research, the disappointment and frustration of writing to professors and former postdocs only to discover the material had long been lost gone. He would prefer that future generations of scientists spend their time making discoveries.
“Biology is really interesting,” he said. “The more people get access to it, the more we’re going to learn.”
