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‘I managed to get pretty lucky,’ student says of research, Nature paper

It was not particularly surprising to learn this fall that Tom Cech and Leslie Leinwand had found a new target for anti-cancer drug development, or that the finding was published in the prestigious journal Nature.

After all, Cech, a ��«����Ƶ distinguished professor of chemistry and biochemisty, is a Nobel laureate. Leinwand, a professor of molecular, cellular and developmental biology, has been a Howard Hughes Medical Institute investigator and an elected fellow of the American Association for the Advancement of Science.

Given these researchers’ stature—and the fact that they lead CU’s cutting-edge BioFrontiers Institute—it might come as a revelation that one of the co-authors on the Nature paper was, at the time of her participation in the project, an undergraduate student.

She is Caitlin F. Bell, now a medical student at Vanderbilt University. Recently, she talked about what it was like to work with scientists whose names are usually uttered in reverential tones.

Bell started doing “grunt work” in Cech’s lab during her freshman year. “I like to think that I just didn’t break too much stuff in the process of doing that.”

The summer after her first year, she began working with a post-doctoral researcher, Jayakrishnan Nandakumar, who was working on the project at the time and was first author on the Nature paper. She stayed on.

Nandakumar, who is a Howard Hughes Medical Institute research fellow, was an inspiration and wonderful to work with, Bell said. Nandakumar and Cech conceived of the project.

“I managed to get pretty lucky,” Bell said. She worked on the research project through the remainder of her undergraduate career at CU-��«����Ƶ. In May, she graduated with distinction with a degree in MCDB.

Her graduation roughly coincided with the time the paper was submitted to Nature, which is among the top four scientific journals (as rated by the frequency their articles are cited in subsequent research).

In the Nature paper, the scientists detailed a new target for anti-cancer drug development that sits at the ends of our DNA.

Researchers in the two laboratories collaborated to find a patch of amino acids that, if blocked by a drug docked onto the chromosome end at this location, may prevent cancerous cells from reproducing. The amino acids at this site are called the “TEL patch” and once modified, the end of the chromosome is unable to recruit the telomerase enzyme, which is necessary for growth of many cancerous cells.

“This is an exciting scientific discovery that gives us a new way of looking at the problem of cancer,” Cech said. “What is amazing is that changing a single amino acid in the TEL patch stops the growth of telomeres. We are a long way from a drug solution for cancer, but this discovery gives us a different, and hopefully more effective, target.”

Cech is the director of the BioFrontiers Institute, a Howard Hughes Medical Investigator and winner of the 1989 Nobel Prize in chemistry. Leinwand is chief scientific officer of the BioFrontiers Institute and holds a joint appointment at the CU-Denver School of Medicine; she is also the winner of the National Heart, Lung and Blood Institute MERIT Award.

Other co-authors on the study include postdoctoral fellow Ina Weidenfeld and Howard Hughes Medical Institute Senior Scientist Arthur Zaug.

Telomeres have been studied since the 1970s for their role in cancer. They are constructed of repetitive nucleotide sequences that sit at the ends of our chromosomes like the ribbon tails on a bow.

This extra material protects the ends of the chromosomes from deteriorating, or fusing with neighboring chromosome ends. Telomeres are consumed during cell division and, over time, will become shorter and provide less cover for the chromosomes they are protecting. An enzyme called telomerase replenishes telomeres throughout their lifecycles.

Telomerase is the enzyme that keeps cells young. From stem cells to germ cells, telomerase helps cells continue to live and multiply. Too little telomerase produces diseases of bone marrow, lungs and skin. Too much telomerase results in cells that over proliferate and may become “immortal.” As these immortal cells continue to divide and replenish, they build cancerous tumors. Scientists estimate that telomerase activation is a contributor in up to 90 percent of human cancers.

To date, development of cancer therapies has focused on limiting the enzymatic action of telomerase to slow the growth of cancerous cells. With their latest discovery, Cech and Leinwand envision a cancer drug that would lock into the TEL patch at chromosome ends to keep telomerase from binding there.

This approach of inhibiting the docking of telomerase may be the elegant solution to the complex problem of cancerous cells. Cech, a biochemist, and Leinwand, a biologist, joined forces to work on their latest solution.

Most of Bell’s research involved the relationship between the TEL patch and telomerase in bacteria.

“I did a lot of cloning and genetic manipulation. I was lucky enough to be trained by them to do a variety of different tests using the protein that I made.”

There were strong indications that the patch existed. “The results ended up looking a lot prettier than we expected,” Bell said.

“It was almost too pretty to be true.”

As a medical student, Bell is weighing her career options. “I really enjoyed the research that I did, and I miss it,” she said. “I’d like to find a way to combine research and clinical work.”

Cech has offered good career advice, she noted.

“He’s fantastic,” she said. “Even if I had dumb questions for him, it was always possible to get an appointment and go talk with him. He’s a very good teacher, and his love of teaching you can also see in the lab.”

Cech returned the compliment:

“Caitlin is smart, poised and very tenacious. She is talented at time-management: one moment she’s doing an experiment in the lab, the next she’s organizing a clinic in Ecuador to provide medical care in an impoverished area, all in her ‘spare time’ between classes.”

Cech also said involving undergraduate students in such research projects allows students to explore the unknown, asking real-world questions using state-of-the-art instrumentation.

He added: “This is the most engaging, most transformative, and most career-oriented education that we give our undergraduates!” It does carry a cost, given that neither the university nor the state has much support for this sort of education, Cech said. “So the individual lab heads have to write grants to get funds from national sources to pay summer student stipends and consumable supplies.”

Though she’s already been published in Nature, Bell said her fellow first-year medical students don’t comment much about it.

“I haven’t told many people.”

Emilia Costales at the BioFrontiers Institute contributed to this report.