The work: The problem de Lange has focused on for the past two decades is a basic problem in cell biology. Chromosomes are made of protein and a single molecule of deoxyribonucleic acid (DNA) and have two ends. Our body has a vigilant surveillance system which is always looking for damage to our DNA, including breaks which can lead to various diseases, such as cancer. The ends of chromosomes are called telomeres and Dr. de Lange discovered that they are bound by a complex of proteins she named shelterin. De Lange’s work addressed the mechanism by which telomeres protect chromosome ends, an issue she refers to as the “telomere end-protection problem.” De Lange revealed that telomeres need to repress six distinct DNA damage response (DDR) pathways that threaten genome integrity. She identified the shelterin protein complex that protects telomeres and established how distinct shelterin subunits repress different DDR pathways.
The impact: Her work has solved a long-standing riddle in biology, one that has profound implications for our understanding of effective cell proliferation, chromosome integrity and a diverse array of human disorders including cancer and aging. The work on the telomere end- protection problem and the types of genome instability that result from lack of telomere function has informed scientists about the events involved in early tumorigenesis when telomeres shorten due to the lack of telomerase. De Lange’s findings argue that the genome instability in human cancer is in part due to loss of telomere function. Furthermore, understanding how telomeres solve the end-protection problem is directly relevant to the telomeropathies, which are diseases caused by compromised telomere function.
Titia de Lange received training in biochemistry at the University of Amsterdam and the Dutch Cancer Institute. As part of her undergraduate training, she worked on globin gene expression with Richard Flavell at the NIMR in Mill Hill before joining Piet Borst in 1981 at the Dutch Cancer Institute as a graduate student. In 1985, she obtained her PhD (cum laude) and joined Harold Varmus at UCSF for postdoctoral studies. With Varmus, she isolated human telomeric DNA and was the first to show that tumor telomeres shorten. In 1990, she was appointed as Assistant Professor at the Rockefeller University where she was promoted to Professor in 1997. She currently is the Leon Hess Professor, an American Cancer Society Research Professor, and the Director of the Anderson Cancer Center at the Rockefeller University. De Lange is a (foreign) member of EMBO, the US National Academy of Science, the Dutch Royal Academy of Sciences, the American Academy of Arts and Science, the American Association for Advancement of Science, the American Society for Microbiology, the New York Academy of Science, and the Institute of Medicine. De Lange was awarded the inaugural Paul Marks Prize for Cancer Research, the Massachusetts General Hospital Cancer Center Prize, the AACR’s Charlotte Friend and G.H.A. Clowes Awards, the Vilcek Prize, the Vanderbilt Prize, the Dr. H.P. Heineken Prize, and the Breakthrough Prize in Life Sciences. She holds an honorary degree from the University of Utrecht. De Lange has served on the scientific advisory boards of many US and European academic institutions, including MSKCC, CSHL, the MIT Cancer Center, the IMP in Vienna, the CRUK/LRI in London, and the Ludwig Institute for Cancer Research. De Lange also serves on several award committees, including the Lasker Jury, the Vilcek Prize selection committee, and the Pearl Meister Greengard Prize committee.