Walter Willett, MD, Dr.PH :: Profile
Chair, Department of Nutrition
Professor of Epidemiology and Nutrition
Professor of Medicine
Harvard Medical School
Harvard School of Public Health
Q: Tell us about yourself as a scientist and how you became interested in breast cancer research. Did you ever seriously consider another kind of career than that of the sciences?
A: I trained in internal medicine at the University of Michigan but after teaching community medicine and public health in Tanzania for three years, I became interested in those fields and returned to the US to complete a doctorate in public health at Harvard School of Public Health. There I became interested in breast cancer, a topic that was being investigated by senior faculty in our department. The challenge was to understand why rates of breast cancer were so high in Western countries; if we could understand the causes, prevention might be possible.
I started college as a physics major, but when I saw what the senior people in that field were doing, it didn't look exciting to me. So I transferred to food science and then became more interested more broadly in human health. What I've done in my career is put together a lot of these pieces -- research approaches learned in physics, understanding of diets through food science, and knowledge about human health through training in medicine and internal medicine.
Q: Briefly describe your BCRF-funded research project. What are some laboratory and/or clinical experiences that inspired your work? What are your primary goals for this research?
A: My primary goal is to understand the causes of breast cancer and to find ways to prevent it. BCRF has been enormously helpful, especially by allowing us to begin research for which funding from traditional mechanisms, such as the National Institutes of Health, would have been difficult or not possible.
One of the most important ways in which BCRF has helped our research is by launching the Growing Up Today Study (GUTS), which enrolled girls and their brothers when they were 10-14 years of age. One of the challenges of breast cancer is that many of the risk factors seem to be operating before adulthood; this is not unique to breast cancer, but it is different than heart disease or diabetes where factors acting within a few years of diagnosis are most important. We know this from some several leads, such as the atomic bombing of Nagasaki and Hiroshima; for women over age 40, even big doses of radiation had limited effect on their breast cancer risk. However, if they were irradiated when they were children or young adults, several decades later, an increase in breast cancer risk was seen. We have to wait decades to see the full impact of environmental factors, such as radiation, on breast cancer. This long delay between the "cause" and actual initial effects on breast cancer creates some tremendous challenges for us as researchers of environmental risk factors for breast cancer.
Another challenge we face is that some environmental factors, such as exposure to pesticides, are difficult to measure. However, when we as epidemiologists talk about "environment," we usually are referring to pretty much everything except genetics. If we look at this very broad definition of environment, we have learned quite a bit about breast cancer.
GUTS is a good example of what BCRF has supported. The study members are the offspring of the participants in the Nurses' Health Study II, whom we started studying about 15 years ago. GUTS is the only large-scale study of diet and lifestyle factors in children; we enrolled about 25,000 individuals as young adolescents (10-14 years of age). We are repeatedly measuring diet, physical activity, and other activities of the participants by sending out questionnaires annually. Our main aim is to follow this generation until they develop breast cancer, which mostly is still several decades down the road, but already we've learned a lot about factors that influence breast cancer risk factors such as height, age at menarche, and benign breast disease (a precursor of breast cancer).
These studies are an "investment" that will pay off over decades, not the five-year window that is required by National Institutes of Health. And we've also been able to do some very interesting work looking in hormonal factors in Mongolia. Additionally, BCRF support has enabled us to pool the data from large cohort studies around the world to be able to look specifically at risk factors for estrogen receptor negative breast cancer. In many ways, BCRF has allowed us to take research directions that otherwise would not have been possible.
Q: Are there specific scientific developments and/or technologies that have made your work possible? What additional advancements can help to enhance your progress?
A: One of the most important technological advances has been modern computing. We sometimes overlook that, but the ability to collect a large amount of data and analyze it underlies every bit of our research. Modern genetic analysis, genome-wide association studies, and whole genome sequencing technologies have yet to reach their full potential in revealing information about breast cancer and our genetic makeup. In some ways, we have known all along that the non-genetic factors are the most important for breast cancer. We have clues from studies that compare breast cancer rates in different countries where there may be an eight-fold difference among them. Also we know from long-term epidemiologic studies that when people move from low-risk countries to the United States, a high-risk country, they develop high rates of breast cancer. Obviously, it was not their genetics that were changing over time. It was something about the non-genetic factors that was very important.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: Much of our research is looking at earlier periods in life. We now have added a younger cohort of women, the Nurses' Health Study II, whom we purposely enrolled as young adults, 25 to 43 of age. They have provided many new insights on factors related to breast cancer. We have collected data on their diets during high school, as well as information from their mothers, who are able to describe their pregnancies, including information on diet and breast-feeding. We are able to put together the lifetime experience pretty well for our cohort members, and much of our work will be focused on those early-life factors and the same factors operating at different periods across the lifespan.
BCRF funding has also enabled us to collect mammograms of women in Nurses' Health Study II. The mammograms allow us to look at changes in the breast well before a diagnosis of breast cancer. We are also incorporating new genetic information, gene expression and DNA methylation data. We are putting together all these pieces of what happens throughout a lifetime for the same individuals. These pieces have been looked at one at a time, but I think that it is important to incorporate all this information on the same people to get the most complete picture of the precursors of breast cancer.
Also, it is now clear that breast cancer is not a single disease, and that we are increasingly being able to define it by molecular characteristics. It is clear that different forms of breast cancer have different causes, and being able to define cases more specifically will assist our efforts to find strategies for prevention.
Q: What other projects are you currently working on?
A: There are many different elements to the Nurses' Health studies in addition to breast cancer, such as other major health outcomes including cardiovascular disease, diabetes, dementia, and Parkinson's disease. We are learning a lot from looking at mechanisms leading to a variety of diseases and we are applying that knowledge to cancer. For example, inflammation, which is one of the underlying pathways thought to lead to breast cancer, is also implicated in heart disease, diabetes, and other cancers. Looking at only one disease at a time predates modern biology.
We are also doing a study on men, where we are examining conditions of prostate cancer and also other major cancers that occur in both men and women. Again, we gain insights from different populations. Pulling together data on diet and lifestyle from populations all around the world, which we're able to do for the first time, is turning out to be very valuable as well. So, opportunities for research at this point in time are almost endless. It's a very exciting time in science.
Q: How close are we to preventing and curing all forms of breast cancer?
A: With regard to prevention, progress has been more challenging and slower for breast cancer than for diabetes and heart disease. We have identified fairly simple diet and lifestyle ways to prevent over 90% of diabetes and over 80% of heart disease. But, we know how to prevent only around about half of breast cancer. For example, avoiding weight gain during adult life, not using hormone replacement therapy, and keeping alcohol consumption quite low could prevent about 50% of breast cancer deaths that occur after menopause. We still know less about pre-menopausal breast cancer but we have found some factors that are related to risk and are avoidable, such as high consumption of meat and alcohol.
We are a long way from being able to prevent all breast cancers. And I think one of the realizations, as the result of research, has been that some of it is built into our way of life in ways that we don't want to change. For example, we know now that if women start having children immediately after the onset of menstruation and have one child every year or two, which is what traditional populations did, that would dramatically reduce breast cancer incidence. But, that would also lead to over-population, affect a woman's ability to go to school, and have many undesired consequences. Because some of the reasons for our high rates of breast cancer are due to factors that we don't want to change, I think we will probably need to use some pharmacologic means to reduce breast cancer rates to the point that it is a rare disease. For example, designer types of oral contraceptives will probably eventually play an important role in helping to reduce breast cancer risk. While we have made progress, there is still a long way to go.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: BCRF has impacted breast cancer research in many different ways. I can't begin to describe all the ways that other investigators use this support -- research on the underlying biology, early treatment, and early diagnosis are all very strongly supported by BCRF. In our own work, BCRF has been enormously important in allowing us to prepare the platform to study breast cancer from early adolescence onward. That has not yet happened anywhere else in the world, and it would not have happened in our work had it not been for BCRF.