Sofia Merajver, MD, PhD :: Profile
Professor of Internal Medicine
Co-Director Breast Oncology Program
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan
Q: Tell us about yourself as a scientist and how you became interested in breast cancer research.
A: I decided to be a scientist at the age of 5. I had asked my mother what I should be when I grow up and she told me to become a researcher. Mom was very wise in general, so I basically planned my whole life around becoming a scientist. Since a very early age, science has been my craft. Discovery is what I do.
My involvement in breast cancer is a bit of an accident. At the University of Michigan, I was completing my medical training and Dr. Barbara Weber [coincidentally a BCRF grantee for several years] was taking over as head of the breast cancer program. She called me while I was in the middle of a surgical procedure and asked me to come work with her as the junior clinician on the breast cancer unit. That's how it started; it was a good opportunity and I fell in love with every aspect of it, from the humanistic and therapeutic, to the scientific and global public health aspects. I'm very privileged to work with patients as well as pursue meaningful research.
Q: Did you ever seriously consider another kind of career than that of the sciences? If so, what?
A: Well, I've had more than one scientific career so far! Does that count? My beginnings were in physics. Again, this is attributable to my mother. I was raised in Argentina in a modest home with a vast library. When I asked my mother what kind of researcher I should become, she pulled the biography of Marie Curie off the shelf and gave it to me. From that time, I was convinced that physics would be useful for anything I would do in life. I grew up and got my Ph.D. in physics. I became head of a lab here in the United States and was very successful with grants and research. At a certain point, however, I realized that I wanted to work on scientific problems that would impact humanity in my lifetime. I had seen very clearly how the future of physics could be applied in medicine, but quantitative methods were only rarely applied in biology then. I made a radical decision to get another set of scientific credentials. I spent the next 12 years getting my medical training and specialization. It was worth it.
Q: You are known for your ongoing research on inflammatory breast cancer (IBC), both in the United States and in Africa and the Middle East. What have you and your colleagues learned about this hard-to-detect, aggressive disease?
A: The proportion of IBC relative to the total number of breast cancers is eight to ten times greater in some parts of the world, such as Egypt, for example, than it is for women in the United States. With the help of funding from BCRF, we are trying to understand the reasons that make it so much more abundant in these places. Are there inherited factors among certain ethnic populations? Is it environmental? Studying IBC now in Tunisia, Egypt, Algeria, Morocco, Tanzania, Uganda, Ghana and Zambia helps us to better understand it in American women. And just as important, having the means to study IBC in Africa and the Middle East gives us the ability to change the oftentimes meager infrastructure of treatment where women so desperately need improved care. Cancer is a painful disease to endure without treatment; in the past, I used to see too many women in Africa and the Middle East die of IBC with little to no medical intervention. We are committed to doing the work that improves outcomes in all the locations where we study the disease.
I will never forget my first trip to Egypt in 2004. My flight arrived at 2 a.m. and they took me straight to the clinic. To my complete surprise, there were 20 patients sitting on the floor drinking tea, waiting to be seen. They all had IBC, yet they were gracious and seemed happy. I was determined to help them in any way that I could. When the doctors in the clinic showed me the first slide of a very aggressive case, I realized that I had not been thinking about IBC correctly. The features of this Egyptian case sparked in my mind, for the first time, the concept that large clusters of cancer cells in the vessels of the skin (which are celled emboli) are the ones spreading to distant organs as well; they are the very culprits of why IBC moves about the body not in individual cells the way most tumors do, but in loosely bound clusters. I couldn't wait to call my lab and tell them what to work on next, while I was in Egypt.
Q: How has this discovery shaped your research goals with IBC?
A: We very quickly zeroed in on the Rho genes, genes that in 1999 were determined to be responsible for motility, or movement of cells, both normal and abnormal. Rho genes are very important in embryonic development, but afterward, they are largely turned down, probably because in our adult life tissues don't move around so much. For IBC, it will be enormously helpful to have a system of drugs that suppresses this motion. Right now, we have reached the point where we have three compounds as promising candidates. Within two to three years, if all goes well, they should be in clinical trials. We know that in several tumor types, if a lesion has hyperactive Rho genes, they are more likely to have a poorer prognosis. If we are successful with our compounds, it may lead to new interventions not only for IBC and other breast cancers, but also with pancreatic cancer and melanoma, both of which have high motility.
Q: You recently persuaded the journal Cancer Research, where you are an editorial advisor, to add a new section focused on mathematical modeling. What is mathematical modeling and why is it important in breast cancer research?
A: Amazingly, the best tools we have to study the intricate vicissitudes of biological phenomena require mathematics. Beyond accumulating a series of descriptions of phenomena, powerful as they may be, mathematics permits us to explore the patterns and principles underlying a biological phenomenon and to make predictions. We need to make these prediction tools available to clinicians and the tools themselves more widely available to cancer researchers. To succeed in this goal, we must publish understandable articles about mathematics in the journals that cancer researchers and doctors read.
With my research, for example, I realized that we must study, in real time, the dynamics of the IBC clusters. What I wanted to know about them is how they communicate, or signal, both internally and to the cells lining vessels. Learning this teaches us how to intervene and prevent the aggressive changes these cells are capable of. Based on modeling intracellular signaling pathways, we have learned something remarkable. Not only does a chemical signal move forward and backward along a pathway; in addition, when there is crosstalk among neighboring pathways, the signal crosses over the gap and transmits bidirectionally as well in the neighboring pathway. This often means, for example, that if one pathway fails or is inhibited, another pathway can pick up speed or efficiency and the biological results are the same. If you are trying to suppress certain signaling pathways, like those telling cells to move in clusters, it is vitally important to know how the pathways that direct motion are interconnected. It dictates a change in strategy!v
Q: How can laypeople better understand the significance of mathematical modeling for breast cancer outcomes?
A: Easy. If we have the ability to map the real-time activity of cancer cells taken from a patient, and aided by accurate mathematical models, we can make better decisions about a patient's treatment. Based on real time testing of a patient's live cells, you may decide to give drugs in a particular sequence in time based on a combination of actual observations and modeling: for example, while you know you can inhibit the protein causing a problem, if by a few hours later you've seen that another protein will take its place, then a different drug would be needed at that point. We have discovered that quite often crosstalk allows pathways to compensate for one another. The cells obtained from a standard breast tumor biopsy are dead, so they cannot tell us these things.
Herein lies, in my opinion, the future of personalized medicine-dynamic analyses, taking into account the major complexities of a patient's cancer. We've come very far already with targeted therapies, but we're going to go much further. Right now we have the precursor technology to look at a patient's living cancer cell that works in a few laboratories, but we need to bring this technology to the clinic, in real time, from bench top to desktop. I have seen so-called insurmountable problems in my life in physics and in medicine yield to creativity and resources: building this technology, by combining time-resolved measurements in living cells with mathematical modeling is not insurmountable!
Q: How close do you think we are to preventing or finding a cure for breast cancers?
A: An absolute cure and prevention of cancer - true eradication - is still in the future. But we are very close to turning most breast cancer into a chronic illness that affects only lightly our quality and length of life. We will do this in two ways: first, by preventing metastasis. We are close to limiting the opportunities for metastasis with breast cancer. This control will be what turns breast cancer into a more manageable, long term illness rather than a life-threatening disease; this is already occurring for many patients and we need to increase the numbers of survivors with metastatic cancer, who live well with cancer kept at bay. Second, we will become better at reducing incidence in general. We've learned so much about nutrition and lifestyle that contributes to cancer; we are on the verge better public education to greatly limit cancer occurrence. And we can and should be exporting this knowledge around the globe.
Q: How has BCRF been helpful to you?
A: The Breast Cancer Research Foundation has helped me be the kind of scientist I dreamed of being as a child. It allows me to consider all of my creative ideas in science as potential. In other words, I'm not forced to discard any potentially good ideas. I do not have to prove to BCRF that I already achieved the result in question before they fund my ideas. I can help people faster because of BCRF. This model of funding is the bridge between the safe approach to science versus the breakthrough approach to science. It allows me to mentor people and build teams. It's catalyzing. The annual meetings of BCRF grantees have often influenced what I do for the rest of the year. I learn from these colleagues and have opportunities to reach across disciplines for answers.
Q: What are the biggest challenges in cancer research today?
A: The biggest challenge in research today is how to build that bridge - the one that spans the safe approach to doing science, which is the way most funds are allocated, to the breakthrough approach to doing science, which is the way BCRF funds are allocated. We need to find ways to have more of our creativity as scientists take the lead throughout cancer research in general. The bridge has to span disciplines and teams of people and countries; the disease of cancer has no political boundaries, but cancer care and research do, and we must change that. BCRF is helping me and many others accomplish this.
Q: What advice would you give to young researchers?
I tell young people to dream big - to think about and find the answerable questions-and to build teams. It is unfortunate that we are discouraging a lot of young talent today based on how our funding in science works. Young people must not be afraid about not knowing enough mathematics, epidemiology, cell biology, clinical medicine. Have your colleagues teach you the languages you need to learn to formulate the exact question you want to answer. At the college level, pursue a broad education; take that extra math, statistics or physics course. Those are the tools of biology now.
Read more about Dr. Merajver's current research projects funded by BCRF.