I did not always want to become a scientist! Growing up in Germany, I was interested in many things, including literature and physics, so molecular biology and genetics are relatively new fields for me. After completing my undergraduate degree, I decided to go to medical school, first, because I had to do something, and, second, because medicine seemed an interesting and varied profession.
Hot Springs, Fledging Soccer Team & Charlemagne
I enrolled in medical school in Aachen, Germany, which is famous for its hot springs, fledgling soccer team, and Charlemagne. During this time, I became interested in physiology and biochemistry. For my clinical training, I went to the University of Edinburgh, in Scotland. This was a great experience -- I indulged in the Edinburgh Festival and delivered babies in the Scottish countryside. On the wards of the Royal Infirmary, where I also treated cancer patients, I was struck by the limited options we, as physicians, had to offer them. In addition, I was intrigued by the biology of cancer, in particular the way some cells could escape their normal growth controls and the "social" context of their environment, giving rise to a tumor.
Back in Germany, I chose to do a residency in Clinical Hematology and Oncology and started a research project on the mechanisms of drug resistance in cancer cell lines for my doctoral dissertation. At the same time, the field of hematologic oncology experienced a tremendous success story when it became clear that a type of leukemia, acute promyelocytic leukemia (APL), was caused by a translocation between two chromosomes, 15 and 17, involving the receptor for retinoic acid (Vitamin A). With an understanding of the genetic basis of APL, scientists explored using a derivative of vitamin A to drive the leukemia into remission. Amazingly, it worked!
Understanding The Genetics Meant Immediate Results
Practically speaking, this meant that instead of giving my patients intensive chemotherapy, I would give them vitamin A tablets in the morning and by the evening I could look at the patients and their blood smears and see an immediate effect. Clearly, understanding the genetics of the disease had made all the difference.
Hooked on the science of cancer and its therapy, I decided to come to Memorial Sloan-Kettering to do a fellowship. In my mind, I was testing myself to see if I liked research science enough to stay in the field. I joined the lab of Francis Sirotnak, who was using molecular pharmacology to develop new antifolate drugs -- one of which turned out to be a great success against T-cell lymphoma. I was impressed by the quality of science here and was also exposed to a variety of different approaches pursued by guest speakers, such as Scott Lowe, of Cold Spring Harbor Laboratory, Frank McCormick of University of California, San Francisco, and Ronald A. DePinho, of Harvard University. It became clear that research science was what I wanted to do.
In considering where to pursue my postdoctoral fellowship, I decided to join Scott Lowe's lab at Cold Spring Harbor. Scott had made the interesting observation that oncogenes -- genes that, when mutated, lead normal cells to become cancerous -- directly activate those genetic programs which oppose tumor formation, such as cell death and growth arrest. Consequently, a given tumor had to disrupt these mechanisms of growth control and Scott and his team had learned that the path a given tumor takes to escape tumor suppression could alter its sensitivity to cancer drugs, often resulting in drug resistance.
Working in Scott's lab, I wondered if the genetic changes occurring in tumor evolution might also result in specific vulnerabilities, which one could exploit with specifically 'tailored' treatment approaches. For instance, we used the drug rapamycin as an adjunct to standard chemotherapy for the treatment of a particular type of B-cell lymphoma normally resistant to conventional anti-cancer drugs. Using this combined approach in mouse models, we were able to prevent some tumors from building up resistance to the standard drugs. Only effective in lymphomas with an activated Akt signaling pathway, rapamycin reverses drug resistance by disrupting Akt signaling, which would otherwise disrupt apoptosis. (Akt in humans is a family of enzymes involved in cellular survival pathways and activated in many cancers.) Altogether, it was fulfilling work with important translational potential.
Follow the Journal Articles
When it was time for me to decide where to start my own lab, Scott's advice was to go where the people worked whose journal articles I found interesting. I looked through my stack of papers and things were pretty clear: Memorial Sloan-Kettering's Charles Sawyers, Harold Varmus, Joan Massague, Pier Paolo Pandolfi, Eric Holland, and Neal Rosen were the recurrent names. As a result, I applied for a faculty position at the Sloan-Kettering Institute (SKI). For comparison, I also looked at other research institutions in the US, England, and Germany. While each had its specific advantages, the focus on cancer genetics and its translation into new therapies in the Cancer Biology & Genetics Program at SKI was unique and exactly what I was looking for.
In the time since I had gone to Cold Spring Harbor, SKI has built a very nice, modern research tower, the Zuckerman Research Center, where my lab is now located. Also, I received a lot of expert help in setting up my lab. In fact, within a few weeks we went from empty shelves to a working lab.
Research Goals
My research goals involve gaining a better understanding of the genetics of cancer, and translating that understanding into new therapies. Conceivably, if genetic changes incurred in tumor evolution could cause resistance to chemotherapeutic drugs, on the flip side, they might also result in specific sensitivities. Using targeted approaches, we might be able to exploit these dependencies. What this means on a practical level is that we model relevant genetic changes found in human cancer specimens in cell cultures and accurate mouse models. Using these cultures and models, our aim is to better understand the interaction of genetics and treatment, which will in turn hopefully optimize existing therapies and lead to novel approaches.
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