When Cindy Hahn was a young girl, her father, a virologist, used to let her sit at his microscope and look at immune cells fighting a pig virus. The pig virus sticks in her memory; it sparked a passion for science she is now pursuing as an MD-PhD student at Dartmouth's Geisel School of Medicine.
After majoring in chemistry at Amherst College, Hahn wanted to find out if she was genuinely committed to a career in biomedical research. The best way to do that, she felt, was to jump in full force working in a top-notch research institution. She applied and was accepted as a research associate in pediatric oncology at Dana-Farber Cancer Institute. She spent three years studying acute leukemia and found she had "a real affinity for blood cells and blood diseases. . . . That's where I realized that scientific investigation could really make a difference in people's lives," she says. "It was where I found my real passion for research and why I wanted to apply to MD-PhD programs."
Her time at Dana-Farber solidified Hahn's desire to be a physician-scientist. "It is a really nice marriage between being able to see patients and then go back to the lab and ask specific questions that relate to those patients, and then bring the scientific findings back to the clinic," she says. "MD-PhD training enables you to do that the best." Hahn is completing her PhD on sickle cell disease and will start her third year of medical school at Geisel in the fall of 2014.
Through her hard work she has gained impressive honors. She received a Ruth L. Kirschstein National Research Service Award from the National Institutes of Health (NIH), which offers funding for both her PhD and the final two years of medical school. She also received the American Society of Hematology Abstract Achievement Award, and her latest paper on a new pathway with potential to treat sickle cell disease was named a plenary paper (honored for definitive, original research) by the journal Blood.
For her PhD, working in the lab of Christopher Lowrey, a professor of medicine and of pharmacology and toxicology, she has been researching new therapeutic strategies for blood diseases such as sickle cell. Sickle cell disease is an inherited red blood disorder in which the body distorts red blood cells into a sickle or crescent shape. Sickle cells are fragile and break down prematurely, which can lead to anemia. They can also get stuck when they travel through small blood vessels, reducing blood flow and causing chest pain and stroke. The disease affects millions of people throughout the world, including about 95,000 people in the U.S. It is especially prevalent among people of African descent; about 1 in 12 African Americans in the U.S. carry at least one copy of the genetic variation that can cause the disease.
People with sickle cell disease have a mutated version of a gene, called the HBB gene. HBB produces an abnormal form of beta-globin (a protein in hemoglobin) which then distorts normal red blood cells into a sickle shape. In a quirk of biology, people are actually born with an alternative fetal globin gene which is turned off at birth. If it is turned on, it can serve as a suitable replacement for mutated HBB. The alternative gene increases levels of the protein gamma-globin, which leads to the synthesis of healthy red blood cells and helps reduce disease severity. Much research has therefore focused on finding drugs that increase gamma-globin RNA levels.
Currently there is one FDA-approved drug for sickle cell disease that does this, hydroxyurea. However, it is only effective in about 50% of patients. Also because it is used as a cancer chemotherapeutic and has strong side effects, it is not the most ideal for long-term treatment. So researchers, including Hahn, are working to understand the mechanisms of increasing fetal hemoglobin in order to develop a more effective therapy.
Hahn has identified a unique cell stress signaling pathway that controls the synthesis of gamma-globin protein. When this pathway is activated by salubrinal, an experimental lab drug, it specifically increases only the gamma-globin protein without changing the gamma-globin RNA levels. This is an entirely new molecular mechanism to increase gamma-globin. Additionally, enhancing gamma-globin protein synthesis complements drugs that increase gamma-globin RNA, such as hydroxyurea. Combining drugs that use different mechanisms (including the new pathway) could increase gamma-globin levels at reduced drug concentrations, thus lowering unwanted drug toxicities.
Since Hahn is studying human blood stem cells in a lab using experimental drugs, it will be some time before her findings result in actual treatments for patients. Yet the fact that cells from multiple human donors respond to drugs that activate the pathway is "very promising", says Hahn, and hopefully will guide new treatments.
Discovering this pathway was slow and difficult for Hahn and her colleagues. Then something "just clicked," she says. "I started to think about this pathway in a different way and that different approach panned out. That opened up a door to discovering that this pathway was involved. It was thinking about how in different creative ways you can ask a certain scientific question."
Next steps will be to figure out how gamma-globin protein is selectively increased. These are "deep mechanistic studies," says Hahn, that look at how proteins are synthesized by ribosomes in the cell. "That can get into very technically challenging experiments," she says. And more creative thinking.