Dr. Clayton Yates, PhD, is a Johns Hopkins University professor of pathology and the director of Translational Health Disparities and Global Health Equity Research. He took time to sit down with WebMD and discuss the relatively new field of health disparities research and his pioneering studies into breast, pancreatic, and prostate cancers in African Americans.
This interview has been edited for length and clarity.
WebMD: Health disparities is a highly specialized field. Can you explain its importance?
Yates: If one population is disproportionately affected compared to another, the goal of health disparities research is to promote equity. While we're all trying to cure disease as a whole, particularly cancer, we also want to not have one community disproportionately affected compared to another.
WebMD: Are the disparities always driven by socioeconomic factors, or are there genetic components as well?
Yates: We as a field – and particularly my lab – have shown time and time again that there are not just social and economic factors. There are clear genomic mutational signatures and biological differences that contribute to the disparities. But I really want to emphasize the real integration, the really exciting data and where we’re headed in disparities is we're now recognizing that it’s not one or the other. We have to account for it all.
WebMD: What drew you to disparities studies?
Yates: My grandfather passed away from prostate cancer when I was around 13 years old, and I wanted to know why. I think that's also why I'm a scientist because I keep asking questions why.
When I was training, at the top of every manuscript, every grant, we would always write, “African American men are 60% more likely to get diagnosed with disease and twice as likely to die.” Then we would never think about it again. It was the first two lines of every manuscript and grant application we wrote, but no one was really doing anything about it. I said, “I have to change that.”
WebMD: Much of your research focuses on cancer in African Americans. Why is race an important variable?
Yates: When we started, we knew Black men were more likely to die from prostate cancer and we suspected race and genes played a role. Then studies from the Veterans Affairs – where everybody largely has equal access to health care – showed African American men diagnosed at the same time, same grade, same stage still had worse outcomes. That reinforced our theory, and if we were saying there were really gene differences, then it has to be associated with ancestry. And if it has to be associated with ancestry, then we should be able to trace that through the trans-Atlantic slave trade through the diaspora to Africa and to West Africa as well. If they are truly genetic, then we should find that in our native African individuals.
WebMD: What are cell line-based models, and why are they important to understanding cancer in African Americans?
Yates: We can’t observe the details of disease development in a patient. We can get a snapshot, but we can't understand the dynamic interaction – how one gene changes to another gene and how something affects it. We need human cells or “cell lines” to create models for testing. All the models that were available to study prostate cancer came from European-ancestry individuals. It never was African American.
So I created these cell lines with just cells from a patient that we grow in the lab and then we use them to test certain hypotheses and theories that will help us translate that to what would happen in a human being.
This is how you usually develop all the biology we have and the therapeutics we have currently in the world. If we don't have our models and we don't represent these populations, how can we develop?
WebMD: How do the biomarkers you’ve identified help predict cancers in African Americans?
Yates: One biomarker is that many African Americans appear to have distinctive changes in their gene structure that promote aggressive disease. We're still working on the formalization of utilizing that in the clinical setting.
A second biomarker we see, particularly in African American prostate and breast (cancer), is that people with African American-based ancestry have this sort of inflammatory response that suppresses the immune system. We believe African Americans have this heightened suppressive immunity and we found a marker, which was associated with one of these immune-type cells, that we're now utilizing for a therapeutic that we're trying to develop.
WebMD: Tell me about this novel therapeutic.
Yates: We identified an immune cell called a macrophage. Cancer cells sort of train these macrophages to turn off the other immune cells, so the immune cells can't recognize (the cancer cells). Mother Nature has these mechanisms. These macrophages are supposed to come in, and anytime you get an infection, they’re supposed to come in and gobble up any germs. But when the germ persists, they kind of go into this suppressive state and the cancer cells know how to put them in this suppressive state.
We learned how to take these macrophages and turn them back on. There are currently clinically available drugs now for different types of immunotherapy, but prostate and pancreatic cancers widely evade or resist immunotherapy, but with this new therapeutic, if we target the macrophages and turn them back on, we allow the immune system to come and do what it's supposed to.
WebMD: The novel therapeutic was slated to enter clinical trials last year. Any update?
Yates: We’re going through (the FDA’s investigational new drug process), so it's a little bit delayed. That happens in drug development. We're slated now for the end of this year or early 2025, if we stay on target.
WebMD: One of your focuses today is tumor biology in Nigerian men. How do ancestry and genetics affect tumor biology? Why is this information valuable in a clinical setting?
Yates: When I visited there for the first time, I was just drawn to the need and I felt like I could bring some of those resources there. There also was this question that if a person being an African American was associated with genetic contribution to the disease, you will see that even more pronounced in a native African individual because most African Americans are admixed, even myself. They'll have a varying level of admixture that can contribute to what genes are expressed.
If you take a homogeneous population such as native Africans, which should have over 98%, 99% African ancestry, what would be the contribution of those genes in African Americans? That's exactly what we did. We sequenced the first Nigerian prostate cancer genome, and we found all these unique mutations that were present in or more highly expressed in native Africans, compared to the European studies.
When we apply that to African Americans, we can actually see African Americans who have more West African ancestry look like native Africans. African Americans who had less African ancestry looked more like European genomic signatures. Now we can create this sort of pendulum of what a person's ancestry contributes to their genetic phenotype and their risk for prostate cancer.
WebMD: How does your research demonstrate the need for diversity in clinical trials?
Yates: We published a more recent paper showing that one of these mutations called SPOP was much higher in African American men. We also saw that SPOP created a different biology in these patients. We're seeing that African American patients that have mutations such as these will help us determine how an individual patient would respond to a particular choice of therapy. It’s really a “precision medicine” approach, where we're thinking about individuals, what constitutes and makes up that individual cancer and matching that with the right therapeutic.
In certain cases, when there is no therapeutic, that's when we go to work and try to create new ones, but there are also many cases where we have the arsenal of drugs available, we’re just not genotyping or phenotyping those individuals to make sure they're matched with their appropriate therapeutic so we can optimize their outcomes.
We're saying everybody's not the same, and if we don’t research these populations — not just African Americans, but every population — then we don't understand the contributing factors, the diet, the societal factors that could be influencing their biology.
WebMD: You once spoke to high school students about the importance of having “a career of ideas.” Can you elaborate?
Yates: I’ve been very fortunate to have a career where, over the years, I’ve had multiple ideas that have kind of panned out. There are a lot of scientists who have ideas that just don't work out. That's research. We try to go into the unknown.
As I try to mentor young people as young scientists, I like to think about it very broadly. When I say a career of ideas, you don't always have to work on everything you're thinking about. Especially as young people, as they're training, you may be in one particular area, like I was doing prostate cancer research when I was training. I wasn't focused on disparities, but I was absolutely thinking about disparities. When I got my turn to open up my own lab, then I was able to do that. But I think those foundational questions, that imagination of ideas, I was thinking about years ago before I even had the opportunity. Even the things that we're thinking about today, you may see a paper that's published from my lab tomorrow, but trust me, that idea came a long time ago.
I think a career of ideas is saying that we now know there's probably no one single magic bullet to solving cancer, and that it's going to take a body of work and a directional path in order to provide real solutions.
