As a medical student in Germany, Stefan Feske studied two Turkish brothers born with severe combined immunodeficiency syndrome, or SCIDS, a rare, life-threatening genetic disease characterized by a seriously debilitated immune system. Because the boys' T cells could not take up calcium, their immune systems would not work. These siblings provided Feske and his collaborators with a unique opportunity to track down a key protein involved in this process by studying human cells in which it was already dysfunctional. "You cannot do this for every gene hunt," says Feske, now an assistant professor of pediatrics at Harvard Medical School.
That search ended recently with the discovery by Feske and his Harvard collaborators, Anjana Rao and Yousang Gwack, of Orai 1, a protein that may be part of the ion channel that admits calcium into T cells, a step required to set the body's immune response in motion. The group's endeavors, reported in the May 11 issue of Nature, represent several years of investigations that were part of a larger 20-year effort to track down this critical cog in immune functioning.
Because the pathway that this channel participates in has been conserved throughout evolution, fruit flies and humans still make and use many of the proteins involved in much the same way. Recognizing this similarity, Gwack, now a research associate in pathology at Harvard, developed a genetic screen in fruit flies that complemented Feske's patient studies. By expressing a key human protein in fruit fly cells, Gwack was able to search for the elusive calcium channel in the fly's smaller genome. His data, combined with a genetic analysis of the siblings' extended family, led the team to a single gene that was mutated in both patients. Gwack named the new protein encoded by the gene Orai 1, after the keeper of heaven's gate in Greek mythology.
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Ion channels facilitate the movement of specific molecules, such as calcium or potassium, into and out of cells. Because these proteins span the cell membrane, they make a particularly appealing target for finding new drugs. "The problem for most drugs is that they have to get into the cell," Feske says. Getting into a cell means getting past its membrane, something ion channels were made to accomplish.
Drug companies around the world have been searching for ion channels specific to the immune system, especially a particular calcium channel, whose genetic identity has evaded researchers for two decades. The discovery of Orai 1, which may be a subunit of the immune system's calcium channel, represents a major breakthrough in that initiative. "The impact is going to be huge," says Michael Xie, director of ion-channel research at Synta Pharmaceuticals in Lexington, Mass., which is developing drugs that interact with this calcium channel. "Inhibition of this immune channel could provide one of the most direct means of manipulating the immune response."
Because drugs that block this passageway would stifle the body's immune response, they could be useful in treating a variety of autoimmune disorders, such as allergies and rheumatoid arthritis, which occur when the body's immune system turns against itself. Scientists also hope further research on Orai 1 will lead to better drugs for preventing transplant rejection, which occurs when the immune system attacks a donor organ. Drugs that home in on this apparently immune-specific calcium channel could avoid side effects, such as kidney impairment and neurotoxicity, caused by other transplant drugs, which interact with molecules found in several types of cells.
Still, more work remains before scientists can be certain of the role that Orai 1 plays. It is possible, for example, that the newly discovered protein is not a component of the channel itself but rather a modulator, or key, that opens and closes the channel like a doorway. And even if Orai 1 turns out to be a channel protein, it may be only one of the components that makes up the channel. "It's not the end of the story," Gwack says. "But the whole field is getting very, very hot now."
