Johns Hopkins Gazette: June 10, 1996

On Research:
Young Scientist
Earns Honor For
Yeast Cell

Emil Venere
News and Information
When Kyle Cunningham began studying a mysterious process in yeast cells six years ago, he had no idea his work eventually would have important implications for human organ transplantation.

A few years ago, other scientists discovered why the drugs used in transplants are so effective: they inactivate a single biological component in cells of the immune system--an enzyme that is essential for the cells to destroy foreign tissue. The enzyme operates at only one step in a complex mechanism that, as Cunningham discovered, also exists in the simple yeast cell.

It now seems likely that the entire mechanism is present in yeast, said Cunningham, an assistant professor of biology.

That's important because scientists can more effectively study the process in yeast by exploiting powerful genetic technology. All of yeast's genes are known in fine details and are easy to modify. So, it should be possible to identify other key factors in the immune-cell mechanism, possibly leading to new and improved drugs for organ transplants.

Cunningham, who is pursuing that goal, has earned a rare honor for his work. He was one of 15 young scientists recently named a Searle Scholar, earning a three-year, $180,000 grant to further his research. More than 160 scientists, from 86 universities, had been nominated by their universities for the award, which is given only to recently appointed assistant professors.

Of the 15 winners, two were from Hopkins. Alex L. Kolodkin, an assistant professor of neuroscience in the School of Medicine, also was selected as a Searle Scholar. The funding comes from a trust established by John G. Searle, who was president of G.D. Searle & Co., a pharmaceutical company.

Cunningham, who came to Hopkins in 1994, specializes in genetics and cell biology. His work focuses on a cellular process known as calcium signaling, which plays a vital role in the activation of human immune cells called T-cells.

The immune cells can be inactive for years or even decades. But when the right foreign invader--usually a protein or carbohydrate--called an antigen enters the body, it triggers the T-cells into action. The immune cells then reproduce, with the sole mission of killing the foreign agent.

Scientists recently have discovered that, immediately after the antigen binds to the T-cell's surface, a "calcium signal" is generated; the cell's interior is flooded with calcium, which in turn prompts a series of reactions, including various genetic responses essential for the immune cell's activation.

The immunosuppressive drugs work by blocking a key step in that calcium signaling pathway.

In the T-cell, the calcium comes from two places. It is first released by an internal structure called the endoplasmic reticulum. But much more calcium is needed to activate the T-cell; it also enters the cell from the outside, through channels in the cell membrane.

After flooding into the cell, the calcium attaches to a protein "sensor" called cal-modulin, which then activates an enzyme called calcineurin. The calcineurin modifies another protein, which moves into the cell's nucleus and switches on a number of genes used for the T-cell's activation.

Although doctors have been using anti-rejection drugs for 20 years, until recently scientists did not know how they worked. It is now known that the drugs, cyclosporin and a new compound called FK506, work by binding to calcineurin, inactivating the enzyme and preventing the immune cells from springing into action.

Unfortunately, both those drugs can have toxic side effects in the brain and kidneys. Because calcineurin probably is performing some unknown functions in cells of those organs, and the drugs may be interfering with the normal functions, scientists are trying to identify new drugs that lack the harmful side effects.

"But we need to know more about the basic biology of it all," Cunningham said. "We want to know, biologically, what else is calcineurin doing?"

"This is a tremendous biological question; what does calcineurin do in life, not just in a T-cell?" Cunningham said.

Most of the steps in the mechanism surrounding calcineurin still are largely unknown. A key mystery is how the cell knows when it's time to open channels in the membrane letting the calcium flow into the cell. Somehow the endoplasmic reticulum sends a message to the cell membrane, prompting the channels to open.

The messengers, channels and other factors are not yet known.

If that signaling mechanism were understood in more detail, more effective anti-rejection drugs could potentially be discovered.

"The channel and all of the things that activate it are potential targets for new immunosuppressive drugs," Cunningham said. "The Holy Grail of this field is to figure out what's going on there."

In work to be published soon, he will report the identification of the first known components of the process in yeast: a messenger molecule and a channel. Together with biologists in other laboratories, Cunningham suggests that similar factors might be acting just the same way in T-cells, and perhaps in other types of human cells.

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