Daniel Brat, MD, PhD, serves as chair and Magerstadt Professor of Pathology. A neuropathologist and scientist, Brat has spent nearly two decades studying diffuse gliomas — the most common type of brain tumor — and the mechanisms that drive their progression. His basic and translational research has led to a number of breakthrough findings, including the identification of a novel way of classifying gliomas based on their genetic makeup, published in the New England Journal of Medicine in 2015.
Brat, who joined Northwestern Medicine in September 2017, is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Listen to Brat talk about his findings in the most recent episode of the Breakthroughs podcast.
What are your research interests?
I am interested in a group of neoplastic diseases that affect the brains of children and adults called the diffuse gliomas. These are all relatively resistant to current therapies and are ultimately fatal, but have highly variable times to malignant progression. My main interest is in determining the mechanisms by which these become high grade and rapidly progressive. As a part of these investigations, we study how brain tumors become hypoxic (low in oxygen), since this is important to rapid growth, and how they become enriched in stem cells, new blood vessels and immune cells.
We use many approaches for these studies, including Drosophila (fly) models to study stem cell biology; mouse models where we microscopically visualize the tumor through a skull window as it undergoes malignant transition; and large molecular databases of the human diseases using bioinformatics techniques.
What is the ultimate goal of your research?
Those of us who went into pathology are intrigued by disease and want to know how they arise at the cellular and molecular levels. Ultimately, we believe that if we can uncover the forces that lead to the development and progression of a disease, we can devise better approaches for targeted therapies. Viewed from a different angle, some of the properties that drive diseases can be recognized as vulnerabilities that can be exploited therapeutically. In the diffuse gliomas, it is not possible to completely resect all of the tumor cells neurosurgically, so we would like to target specific cell populations that might more fully eradicate the disease, including brain tumor stem cells that replenish the tumor population, or the immune cell population to help suppress its growth.
How does your research advance medical science and knowledge?
The most recent significant advances of my work are related to the understanding of the diffuse gliomas as molecular diseases, rather than histologic diseases as they appear under the microscope. Interobserver variability using microscopic methods was unacceptably high and did not predict the clinical behavior of disease, leading to problems in clinical management. Studies that I led with the Cancer Genome Atlas (TCGA) brought a new understanding of diffuse gliomas as discrete genetic entities and led to a molecular classification that is more reproducible, biologically meaningful and clinically relevant. The TCGA-based results pointed toward a new classification system by the World Health Organization and represented a substantial advancement in precision and reproducibility of diagnosis. We are now developing diagnostic and testing guidelines by the College of American Pathologists and American Society for Clinical Oncology, which will close the circle on the discovery-to-clinic journey.
How did you become interested in this area of research?
From my earliest days in medical school, I was fascinated by the brain — mostly because it seemed to be an organ above the rest in terms of its complexity and direct relation to human behavior. I knew I wanted to focus on diseases that affected the brain, but didn’t know exactly which ones.
My interest in brain tumors came about during my residency in pathology, since I saw the central importance of establishing the correct diagnoses for patients and also recognized the need for better understanding of the cellular and molecular mechanisms that cause them to develop and progress.
Like many people, I think the mentors I had as a student and a trainee played critical roles in shaping my interests, and I gravitated toward people who studied brain tumors who had positive attitudes and a passion for their work.
Which honors are you most proud of and why?
Prior to joining Northwestern this past year, I received two awards in the same period of time that were very meaningful to me and stood out for the feeling of pride and accomplishment that came along with them. One was the award for Outstanding Support of Residency Training in Pathology and the other was Outstanding Mentor for Post-doctoral Research from Emory University School of Medicine.
These awards meant that someone noticed and appreciated the efforts that I placed on the training of the next generation of physicians and scientists, which has much more impact on the future than individual accomplishments.
What do you enjoy about teaching/mentoring young scientists in the lab?
Most students begin their journey of education passively as consumers of knowledge. Yet for a subset, there comes a point during undergraduate, medical and graduate school when they begin to understand that they can actually contribute to biomedical advances by participating in investigation.
Witnessing the first time the light bulb goes on with the realization that they have created something new that didn’t exist before, but could someday be important, is very gratifying. It doesn’t happen to everyone, but the act of discovery can rapidly transition a student from reader to writer, from reciter to creator, and ultimately from pupil to teacher.