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Kathleen Gabrielson on the toxic effects of stress


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Kathleen Gabrielson on the toxic effects of stress

Interviewed by Shawna Williams

Kathleen Gabrielson on the toxic effects of stress

Kathleen Gabrielson with a portrait of Anna, an early test subject for the “blue baby operation” that has saved the lives of many children with congenital heart defects.

Kathleen Gabrielson is an associate professor of molecular and comparative pathobiology. She investigates the side effects of cancer drugs and the impact of stress on the body.

What drew you to veterinary pathology?

Gabrielson: In high school, my family had a horse, which led me to an interest in animals and medicine. I worked for a bit at the San Diego Zoo and thought seriously about being a large-animal vet. In vet school, I met some veterinary pathologists and did summer programs in pathology, including one at Johns Hopkins, and I loved medical research — the whole process of coming up with a hypothesis and validating it (or not). After vet school, I returned to Johns Hopkins, did a postdoctoral fellowship in comparative pathology and then completed a Ph.D. in toxicology at the school of public health.
One thing I really enjoy about being a veterinary pathologist at Johns Hopkins is working with people from different departments on a range of projects that involve research animals. Vets tend to have a really broad view because of our training, where we learn about many different species and diseases, and this makes us very good collaborators.

What do you work on?

Gabrielson: One of my interests is off-target effects of the cancer drug trastuzumab on the heart. Trastuzumab is a monoclonal antibody and, unlike chemotherapy, it works by binding to a receptor called HER2 (also called ErbB2) that’s overproduced by some tumors. HER2 makes cells grow, divide and resist cell death, and when trastuzumab binds to it, it causes cancer cells to either die or slow their growth. But the downside of trastuzumab is that it can interact with other drugs to become toxic to the heart, and we aren’t able to predict in advance which patients will develop this toxicity. 
One question we’re looking at in my lab is what causes certain cells in the adult heart to ramp up HER2 production, making them targets of trastuzumab. Stress is one factor we’re testing — it’s a powerful thing. We’re also investigating what happens in mice when heart cells are temporarily making more HER2 early in the animal’s life. HER2 may be involved in cardiac muscle cell division when the time is right. My idea is that the cells are supercharging HER2 production for a reason, and maybe artificially tamping it down makes the heart more susceptible to toxicity. If that turns out to be true, maybe we could avoid the problem by knowing the risk factors for HER2 receptor elevation and, if needed, wait to begin trastuzumab treatment until levels return to baseline. Or, if heart toxicity was detected and the patient had to go off trastuzumab, physicians would be able to identify when it was safe for her to go back on the drug.

You mentioned the power of stress. Are you looking at other effects it might have?

Gabrielson: I’m working with Malcolm Brock in the Department of Surgery and colleagues in Japan on a project studying the effects of maternal stress on the next generation. It’s funded by the Japanese government through Juntendo University, which is interested in the long-term health effects of events like the 2011 tsunami. There have been some human epidemiology studies on this, like the effect on adult disease among children born soon after the Dutch famine of the 1940s. We want to go further.
We’re planning to expose mice to stress during the equivalent of their second to third trimester by isolating them for a few hours each day when mice would rather be sleeping. Our day is mice’s night — they like to sleep then. Then, we’ll test whether their offspring, and even their offspring’s offspring, respond differently to stress compared to offspring of unstressed mice. Our collaborators will be comparing umbilical cord blood from babies whose moms were or weren’t exposed to very stressful events during pregnancy to see if they can detect changes in the epigenome — that is, the proteins and chemical groups that attach to DNA and affect whether genes are turned on or off — and we’ll also look at this in our mouse studies. We may find that there are biomarkers for this stress and also a remedy for the children of stressed-out moms, like raising them in a certain environment.