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One possible research direction involves the counter-regulation of the primary, inflammatory responses to the viral infection. The body naturally makes substances that counter this process, and Sarvetnick is interested in elucidating both what these factors are and how they work.

Another direction is to study the regulation of the acquired immune cell response. Killer T cells are responsible for the immune reaction that leads to the onset of diabetes, and these are regulated in the body by cytokine molecules. Cytokines are produced by pancreatic and immune cells during infection and can regulate the immune cell response.

"They can affect the half-life of T cells and the antigen presenting cells and change the way that the killer T cells get primed," Sarvetnick explains.

Some of the basic questions are which T cells are involved, how the pancreas tries to defend itself in response to the infection, which antigens are presented by B cells, and what the exact nature of the T cell response is.

Sarvetnick's laboratory has already demonstrated that certain cytokines produced at certain times of infection can lead to the development or inhibition of diabetes in their models. For instance, the molecule Interleukin–4 has a potent inhibitory effect on the development of diabetes in pancreases with cells expressing the molecule.

The current thinking is that the interleukins interfere with the development of specific killer T cells, but the exact mechanism of this inhibition is still unknown. As are the mechanisms of other regulatory effects perpetrated by the other regulatory molecules involved.

"There are really a number of things [the cytokines] do that we are looking at," says Sarvetnick.

Other Therapeutic Implications

Another possibility for treating the disease is to understand and manipulate the growth of the pancreas. One of the great success stories in treating Type 1 diabetes in the last 35 years has been the pancreas transplant, in which a healthy organ from a donor replaces the pancreas of a diabetes patient.

However this is a major, complicated surgery, limited both by its inherent risk and the low availability of donor organs. Perhaps a better approach would be some sort of therapy that would regenerate the insulin producing islet cells in the pancreas of a person with Type 1 diabetes—to use pluripotent stem cells to replace the needed b cells within a patient's own pancreas. This may even eventually be a cure for the disease, though years away at best.

For now, the first step is the identification and isolation of pancreatic progenitor cells. These are the progenitor cells that differentiate to become insulin producing islet cells in the pancreas. They can be identified and isolated through flow cytometry through their unique cell-surface molecules—markers which are yet to be identified.

A closely related issue is the elucidation of the molecular signals that are involved in the differentiation of stem cells into the islet b cells. The ErbB receptors, for instance, seem to be implicated in this process. At the moment Sarvetnick's laboratory is busy characterizing the role of these receptors in the development and regeneration of the pancreas.

Mother of Invention

As our interview is wrapping up, the phone rings. As if by the tone of the buzz, Sarvetnick breaks off in mid-sentence and wheels around to her office door. "Is that ...?" she asks. Yes. Sorry—must take this call. Hello.... OK.... What time?.... Talk to you later then....

"That's the other side of my life," she says when she puts down the phone.

Then she tells me a story. This time it is not a story about cells and viruses but about a working scientist, her daughter, and her two sons—a tale of theatre, ballet classes, and hockey practices. The story seems even more complicated than the science she has been telling me about, involving a daily ritual of coordinating schedules, arranging for school pick-ups and drop-offs, helping with evening homework, and making sure meals are covered. She tells me about the sacrifices she has to make so that neither her children nor her research suffer. Her science and her children are her life.

"You really pare your life down to the bare necessities," she says. "And it's not easy. It's really hard and trying."

"Ok it's murder." She says. But I know that by murder she means happiness.

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Loss of insulin-producing b cells (bottom image, stained in brown) in the pancreas is the hallmark of Type 1 diabetes. Top image shows a healthy pancreas with the islet of Langerhans stained for insulin. Photo by Cecile King.











Professor of Immunology Nora Sarvetnick seen here watching birds with her children Julian (6), Estella (4), and Gabe (9). Photo by Howard Fox.