TITIA DE LANGE, an Ellison Medical Foundation Senior Scholar, ranks among those who pioneered in the study of telomeres, small stretches of repeating DNA that cap off and protect the ends of chromosomes. Telomeres’ stability – and the enzyme, telomerase, that can keep them whole – are now seen as key elements in the normal aging process. They are also deeply involved in the abnormal puzzle called cancer. Dr. de Lange, who is Dutch, came to telomeres by proximity. While earning her doctorate in Professor Piet Borst’s laboratory at the University of Amsterdam in 1984, Dr. de Lange worked on trypanosomes – the protozoans that cause sleeping sickness. She discovered that the genes that allow trypanosomes to escape their host’s defenses sit very near the ends of chromosomes, adjacent to these strange things, the telomeres. Very little was then known about telomeres, other than that they existed, as reported by Nobel Prize winner Barbara McClintock in the 1940s. Indeed, when Dr. de Lange searched the literature in 1981, she found only five papers on the subject. By contrast, a recent Medline search turned up 2,356 papers with “telomeres” in the title. “There was nothing known about how they are made and what their function is,” Dr. de Lange said. “The mitotic clock was known, but the mechanistic basis for that wasn’t known.” At Stanford University, Dr. Leonard Hayflick had shown that normal cells can divide about 50 times before they go into senescense and stop, a phenomenon known as the mitotic clock or the Hayflick limit. After moving to San Francisco to work on oncogenes with Dr. Harold Varmus, Dr. de Lange soon resumed work on telomeres, trying to isolate them from human cells. “I was very interested in genomic instability at that time,” she said. Across the bay, at the University of California at Berkeley, Elizabeth Blackburn was working on the telomerase enzyme found in ciliates, and a graduate student in her laboratory, Carol W. Greider, discovered the first half of that molecule. Also active in unraveling telomerase’s makeup were Dr. Thomas R. Cech, a Nobel Prize winner at the University of Colorado, and Victoria Lundblad, now at the Salk Institute in California. Both Dr. Greider and Dr. Lundblad are also Ellison Medical Foundation Senior Scholars. Scientists have since learned that telomeres gradually shrink, shortening slightly with each round of cell division. Once they get too short, the chromosomes begin falling apart, sometimes joining loose ends, causing the cells to stop dividing and die. This is seen as one defense against cancer, since cells that are growing out of control soon commit suicide by shortening telomeres too far. Unfortunately, cancer cells overcome that problem, immortalizing themselves by turning on production of telomerase, which rebuilds the shortened telomeres. Thus cancer cells avoid senescence, and keep on dividing to form tumors. Dr. de Lange, who is now Leon Hess Professor and head of the laboratory of cell biology and genetics at The Rockefeller University, has contributed much to the accumulating knowledge. She cloned and characterized two key telomere-binding proteins, TRF1 and TRF2, and described how they regulate telomere structure. She showed that a checkpoint mechanism involving the tumor suppressor gene p53 is involved in the cell’s response to altered telomere structure. She was among the first to see how telomere dysfunction could promote cancer. In 1999, Dr. de Lange and Dr. Jack Griffith at the University of North Carolina, another Ellison Senior Scholar, made a major structural discovery, showing that loops exist at the ends of normal telomeres. So far, the loop “is thought to have two functions – it protects the telomere, and it regulates telomerase,” Dr. de Lange said. The data suggest that a chromosome can turn its telomerase off to avoid having telomeres that are too long. Each chromosome, she said, controls its own telomerase. The next goal, she said, is to understand how the loop arrangement works. “It is like a molecular machine,” she said. “We have the nuts and bolts but don’t yet know how they work together.”