Dr. Titia de Lange: Telomere Function and Cancer ▲ NCI Cancer Bulletin for December 11, 2012 - National Cancer Institute

NCI Cancer Bulletin for December 11, 2012 - National Cancer Institute

Dr. Titia de Lange: Telomere Function and Cancer

Leon Hess Professor 
Director, Anderson Center for Cancer Research
Rockefeller University

Dr. Titia de Lange

When Titia de Lange was about 16 years old and living in Holland, she saw an electron microscope image of a chromosome in a Dutch newspaper that changed her life.
"I remember being completely struck by it," said Dr. de Lange. "Massive amounts of DNA were packaged in all of these endless loops. And our genetic information had to function within this element; that is how it has to work.
"But how could it work?" she said. "Everything I've done in my career goes back to that image and to that question."
Dr. de Lange began pursuing the answer as an undergraduate student. Organic chemistry was what she really wanted to focus on, but because there weren't many women in the field, and perhaps also because her grandmother was a biologist (who earned a Ph.D. in 1911), she chose biology instead.
Eventually, she found her way back to the molecular realm, first working with Dr. Richard Flavell, her undergraduate advisor at the National Institute for Medical Research in Mill Hill, London, and then with Dr. Piet Borst, her thesis advisor at the University of Amsterdam, who showed her how to manipulate DNA and to clone genes.
She then accepted a postdoctoral position in Dr. Harold Varmus' laboratory at the University of California, San Francisco, to learn more about genome instability in cancer. It was there that Dr. de Lange eventually focused her work on telomeres, which are long stretches of repeated nucleotide sequences that are found at the ends of linear chromosomes.
The End-Protection Problem
When a cell divides, it must copy its genetic information so that each daughter cell has its own set of instructions. But a small amount of DNA is lost from the ends of a chromosome each time it is replicated. The bits that are left off are part of the telomeres, which protect the chromosomes themselves from being degraded. Telomeres also prevent the ends of different chromosomes from fusing with each other.
In most normal cells, telomere degradation continues for 20 or 30 cell divisions until they become too short, at which point the cell stops dividing and eventually dies. In this sense, telomeres limit the lifespan of cells. In embryonic and adult stem cells, as well as many cancer cells, an enzyme called telomerase replenishes the telomere repeats lost during replication, keeping the cells alive indefinitely.
If telomeres don't work correctly, the chromosome becomes unstable, which can lead to DNA mutations, wholesale losses, and rearrangement of chromosomes that are characteristic of some cancers.

The telomeres at the ends of normal chromosomes (left) are protected by a protein complex called shelterin, which helps chromosomes remain stable. When any of the proteins that compose shelterin are missing (right), the ends of telomeres can become fused or experience other changes that disrupt the normal growth cycle of the cell, in some cases leading to cancer.

Dr. de Lange studies the molecular and cell biology of telomeres and how telomere function is altered in cancer. In the early 1990s, after joining the faculty at Rockefeller University, she identified a binding factor on telomeres that she called TRF. Over the next 10 years, she and others isolated five more proteins that work together with this binding factor to form a complex named shelterin.
DNA has magnet-like stickiness and recombines easily when one end gets close to the end of a neighboring chromosome, which can cause structural rearrangements such as fusions and translocations. By protecting chromosome ends, shelterin prevents such rearrangements. It also keeps telomeres safely hidden from the machinery in the cell that would otherwise mistake them for chromosome breaks that need to be repaired.
The need to keep telomeres hidden so that chromosomes remain stable is known as the end-protection problem, and work in Dr. de Lange's laboratory has made substantial progress in terms of describing it.
"Now the question," she said, "is how does the [shelterin] complex do this? It's not trivial. Six proteins and six pathways mean six tricks. We think one trick is the t-loop"—physically, the telomere end is tucked back into itself as a loop, a finding that she and her collaborator, Dr. Jack Griffith at the University of North Carolina, Chapel Hill, first published in 1999—"but that would only take care of two pathways, and we still need to understand the other four. We have a big task ahead of us to figure out mechanistically how this complex does such a clever job."

Targeting Telomeres in Oncology: NCI's Investment
In principle, the telomeres of cancer cells should be an ideal target for cancer treatment. The enzyme telomerase is inactive in most adult cells, aside from stem cells, but about 80 to 95 percent of cancer cells use telomerase to extend their telomeres and to attain immortality. Other cancer cells use something called the ALT pathway to attain immortality.
"If we can selectively figure out how to block the mechanisms by which cancer cells overcome their natural limits, that would be almost like a magic bullet," said Dr. Richard Pelroy, program director in NCI's Division of Cancer Biology.
Several agents that target the enzyme telomerase are being tested in clinical trials, including small-molecule inhibitors, immunotherapies, and viral therapies. So far, none has shown the level of effectiveness that is hoped for, Dr. Pelroy said. "We need more-detailed molecular and mechanistic knowledge of what is happening at the telomeres during normal division and abnormal division."
To that end, NCI is funding basic research grants in this area, hoping to learn more about the risk factors that are associated with telomere dysfunction and cancer, as well as to refine the approach for targeting this potentially vulnerable feature of cancer cells.

Her recent work has described cellular features that may one day be used to home in on cells that use something other than expression of telomerase—namely, a process called the alternative lengthening of telomeres, or ALT, pathway—to prevent their own death. (See the sidebar.)
Science for the Right Reasons
Dr. de Lange's research has brought her accolades and wide recognition. During the last 12 or so years, "she's virtually defined the field of telomere protection," said Dr. Richard Pelroy, program director in the DNA and Chromosome Aberrations Branch of NCI's Division of Cancer Biology. "It was known that cells must be able to detect telomere dysfunction and deal with it in order to have normal cell division," he explained, "but the discussion was merely conceptual before her work."
For Dr. de Lange, life as a scientist is much easier now than it was when she first started down the path. As a young scientist, she had very little money and no laboratory assistance. "Nobody cared about telomeres," she said. "It was backwater research. We had meetings on telomeres in the early '90s—unofficial meetings, of course—and there were literally fewer than a dozen people who attended them."
What she did have, she said, was intuition and enthusiasm. "I loved telomeres," she said. "This is very important, to love something to death and be willing to do something important for it." That is the message that she tries to impress on everyone who works with her: Find your love in science first, and then good things will follow.
"She is 100 percent, fully dedicated," said Dr. Dirk Hockemeyer, an assistant professor at the University of California, Berkeley, who first worked with Dr. de Lange as an undergraduate exchange student from Germany and returned to earn his Ph.D. under her mentorship. "She's interested in really understanding how things work, and she won't let go until she's figured them out," he said. Dr. Hockemeyer recalled an example from 2006, when Dr. de Lange took a sabbatical from teaching so that she could work at the bench in her own laboratory and continue experiments that she had started 10 years earlier.
"She taught me to be happy with science for the right reasons," said Dr. Nadya Dimitrova, who did her Ph.D. work with Dr. de Lange. Dr. Dimitrova recalled that when she was writing her graduate thesis, Dr. de Lange "returned the draft to me and said that my conclusion and discussion weren't brave enough. 'You need to take this opportunity to say everything that you think…your whole model and hypothesis that goes even beyond your findings.' So, I started it all over and wrote a discussion that was far reaching and even prescient in some ways, and I'm very proud of that to this day."
Dr. de Lange doesn't believe that science has to be high risk in order to be satisfying, and she's careful not to pontificate about what one must do to attain success. But she does have one bit of advice for people who are considering careers in basic research.
"If you do a project just because you anticipate a high payoff, and you don't love the underlying science," she said, "I don't think you'll be able to sustain it. My advice is to find your own niche, one that you truly like, and then it doesn't matter so much. You'll do high-risk stuff, you'll do low-risk stuff, whatever is needed."
Which is exactly what happened in her case.
"I thought there would be bigger things to pursue eventually, but we're still working on telomeres," she said. "It's a much more complex and interesting subject than I ever could have anticipated."
—Brittany Moya del Pino