Finding the Needle in the Cellular Haystack

In the final analysis, our cells are just microscopic protein factories. Working with just 20 different amino acids, cells knit these building blocks into more than 20,000 different proteins that help them do everything from produce energy to communicate with other cells. Cells also post a fragment of each of these proteins, called a peptide, on the cell’s surface. There it is inspected by the cytotoxic T lymphocytes (CTLs) in a particularly draconian quality control exercise. If the CTLs believe that the peptide is produced by disease-causing agents, such as a virus or a bacterium, they kill the infected cell.

In 1990, Victor Engelhard, a professor of immunology; and Dr. Craig Slingluff, a professor of surgery, made an interesting proposal to Don Hunt, the University Professor of Chemistry. At the time, it was not obvious that CTLs would react to cancer cells because they are not foreign to the body. Engelhard and Slingluff knew, however, that a small percentage of people with melanoma, a particularly deadly form of skin cancer, recovered on their own. They hypothesized that the CTLs of these lucky few had become sensitized to peptides uniquely presented on the surface of their cancer cells. If these peptides could be identified, they realized that they might be able to use them to train the immune systems of other melanoma sufferers to attack the cancer cells in their bodies.

Hunt, a world-class expert in mass spectrometry, seemed to be the most likely person to help them find these elusive peptides. Hunt had previously shown that peptides can be volatilized into a mass spectrometer and fragmented into their constituent building blocks, which are then weighed by the instrument. Because each of our 20 amino acids has a unique mass, a scientist with a mass spectrometer can identify a peptide by reading its sequence of amino acids. The challenge, however, was daunting. Hunt had to develop methods to sift through the 10,000 peptides on the cell surface to find the few that the immune system recognizes as foreign. “Instrumentation drives cutting-edge biomedical research,” Hunt says, “which then stimulates the development of new instrumentation.”

To date, Hunt has identified a number of peptides that are unique to melanoma cells. These are presently being used in clinical trials run by Dr. Slingluff here at U.Va. Hunt has now extended the range of his research to include the identification of unique peptides on the surface of leukemia, colon, ovarian, and breast cancer cells as well as the peptides that cause rejection of organ transplants and that trigger such autoimmune diseases as diabetes, arthritis, and multiple sclerosis.