Public Release: 

Stanford study of sea squirt provides clue to human immune system

Stanford University Medical Center

STANFORD, Calif. - "You can eat your relatives but not your friends," could be the off-kilter credo of a tiny marine invertebrate called a sea squirt that can physically merge with, and parasitize, its own kin. The trigger for this unseemly behavior has now been traced to a single gene, isolated by researchers at the Stanford University School of Medicine. That gene also points to a common origin with the vertebrate immune system, far back in animal evolution, potentially shedding light on the development of our own immune system.

The sea squirt with the questionable philosophy is Botryllus schlosseri, a colonial animal that looks deceptively like a small flower. Each of its apparent petals is actually a separate, though genetically identical, organism, linked to the others by a common blood vessel. Ringing the tiny petals are even tinier tentacle-like ampullae, the sensing organs that evaluate other sea squirts, determining who's related and who isn't.

If two adjacent squirts aren't related, their respective ampullae blacken and shrivel upon contact. But when the squirts are related, they begin to physically fuse together. Thus, the ampullae had to be able to sense genetic similarity among sea squirts, said Anthony De Tomaso, PhD, researcher in pathology and first author of a paper on the subject in the Nov. 24 issue of Nature. "We were looking for the genes which control how an individual can distinguish self from non-self," he said.

Fusing together benefits the filter-feeding squirts because they live in high-density areas such as marinas, where competition among sea life is fierce. Because adult squirts are sedentary, if the area around them is already occupied, they can only increase their feeding area by fusing.

The downside of fusing is that one sea squirt can parasitize the other, essentially taking over its body by means of mobile stem cells, which transplant themselves between the fused individuals through the shared circulatory system. Eventually one set of stem cells overpowers the other, going on to replace the tissues of the loser. It was the fusing process, body-snatching tendencies notwithstanding, that attracted De Tomaso's interest.

De Tomaso and senior author Irving Weissman, MD, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, knew that the sea squirts' ability to sense who was fusible appeared to bear strong similarities to certain cells in our own immune system, called natural killer cells. Like Botryllus, natural killer cells only recognize genetically similar material. Anything they don't recognize, they attack, as often occurs in bone marrow transplants.

Through a long process of sorting and testing, De Tomaso's team isolated the controlling gene. "We found a gene which by itself predicts whether two colonies will fuse or reject," he said, adding, "Now we have the first piece of the puzzle of understanding how this happens on a molecular level."

The gene is an immunoglobulin, the type of gene that makes up the entire human immune system. "This is the first time we've seen a connection between these two systems," said De Tomaso. Until now, no one had demonstrated any concrete similarity between the vertebrate and invertebrate immune systems. The ramifications of the finding may shed light not only on the evolution of our immune system, but also on how we might better control some aspects of it, such as our natural killer cells.

"If you could teach those natural killer cells to be tolerant, you could transplant bone marrow between any two people, a huge first step in curing diseases like leukemia," said De Tomaso. Learning how to manipulate our immune systems would also have major ramifications for treating autoimmune diseases such as multiple sclerosis, which essentially represents a breakdown of recognition by the immune system, attacking the body it should be defending.

De Tomaso's team is already working on the next step in sorting out the workings of Botryllus' immune system-deciphering the actual molecular mechanism by which the sea squirt ascertains which of its neighbors shares its urge to merge, in spite of the risks.


Also participating in the project were Stephen V. Nyholm, Karla J. Palmeri, Katherine J. Ishizuka, William B Ludington and Katrina Mitchel, all of Stanford University School of Medicine, Departments of Pathology and Developmental Biology and Hopkins Marine Station, Department of Biology.

This study was supported by grants from the National Institutes of Health and the Community Sequencing Program at the Department of Energy Joint Genome Institute.


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