Diversity Makes a Difference: Q&A With Brian Estevez, PhD, New Diversity Fellow

Looking at a scientific problem from new and different perspectives is what research is all about, which is why Children’s Hospital of Philadelphia’s Research Institute is dedicated to cultivating a more diverse workforce.

“We value diversity within our research community and it is undoubtedly part of what makes us successful,” wrote Bryan Wolf, MD, PhD, Chief Scientific Officer and Director of the Research Institute, in a Cornerstone blog post. “Individual differences in race, ethnicity, genetic makeup, gender, age, religion, language, abilities/disabilities, sexual orientation, gender identity or expression, and socioeconomic status are an integral part of what makes us great.”

Last year, the Research Institute launched the Postdoctoral Research Fellowship for Academic Diversity in partnership with Penn. The new opportunity was designed to enhance the recruitment of a diverse population of postdoctoral fellows whose life experience, research experience, and employment background could contribute significantly to their academic missions. Two new CHOP diversity fellows began the program at the end of August, sharing their unique points of view as they tackle pressing pediatric research questions.

In this Q&A, we got to know Brian Estevez, PhD, a new diversity scholar who is working in the lab of Mortimer Poncz, MD, chief of the division of Hematology at CHOP. The edited conversation follows below.

We’re excited that you’re getting started on some ambitious research projects here at the Research Institute. But first, tell us a little bit about your background and your family.

I was born and brought up in Brooklyn, New York, where there is a strong bottleneck in some of the not-so-friendly areas. There are many poor people and no extracurricular activities. Kids just play on the streets where there are a lot of bad influences. It was a blessing that I had a big, gigantic family because a lot of my real friends growing up were my cousins, so there weren’t any openings for outside influences. That protected me during the sensitive years in my life, and I never felt the need to get too involved in my immediate inner city environment. If I didn’t have such a strong family connection, I don’t know if I would have made it through any of those tough times. Once you get out of the bottleneck, though, you can take advantage of a lot of things.

How did you become interested in learning about pediatric research?

I did my undergraduate work at Queens College and majored in biology, and I had my first research experience as a sophomore. I realized that I liked to do the experiments, I think because I’ve always learned better by doing. I decided to apply to graduate schools that do more research. I ended up at the University of Illinois at Chicago where my mentor was a platelet biologist, and I got my PhD in cellular and molecular pharmacology. My ultimate goal is to have a lab of my own.

What attracted you to apply for the Postdoctoral Research Fellowship for Academic Diversity?

I interviewed all over the United States, and what I found that was different about CHOP is that we’re good at research, but we’re also good at a lot of other things. What enticed me about this place is the substructure of the program was very rich. I have interests in research and teaching as well. Not all programs let you be so flexible about having these other ventures besides your primary appointment to do research. Here at CHOP and Penn, a lot of options are available.

How do you plan to pursue both research and teaching?

I’m also part of the PENN-PORT Program (Postdoctoral Opportunities in Research and Teaching), which is sponsored by NIH. It combines a traditional mentored postdoctoral research experience with a mentored teaching experience for postdocs who are interested in teaching at undergraduate colleges and universities that are minority-serving institutions. I thought it would be great to circle back and help people who are going through similar things that I went through. Maybe they’ll see my face and think about doing research too — it’s good positive reinforcement to see yourself represented in the system. I also thought teaching would revitalize me because on some days research can be cut and dry: You try an experiment, and if it doesn’t work, you go home and try again the next day. So I wanted to mix things up and get renewed energy from the students.

What research projects do you have underway with your mentor, Dr. Poncz, that you’re the most enthusiastic about?  

Well, I’ll tell you the patient story that sold me to join his lab. Morty has a patient with a bleeding disorder who he has seen since he was 3 years old, which was in the early 1980s. At that time, they didn’t know why he had such low platelet counts. Eventually, they sequenced his genome and found he has a mutation in a protein called RUNX1, a transcription factor that is absolutely essential for blood cell development. But while they knew what his mutation was, they didn’t know a way to help him.

Fast-forward to what we’re doing today. The patient is now in his late 30s, and he donated his stem cells through a skin biopsy, and then the iPSC Core Facility at Penn took that skin biopsy and pushed it into becoming induced pluripotent stem cells. The concept of induced pluripotent stem cells is based on the fact that when a specific set of critical transcription factors, sometimes called Yamanaka factors, are added into adult cells they can be genetically reprogrammed all the way back to before they were terminally differentiated into their mature state. All of us started out as a single cell, and that single cell had totipotency, meaning it could be anything that it wanted to be. However, as that cell divides it also terminally differentiates into tissues and specialized cells and during that process many genes are turned off. Reprogramming patient cells into iPSCs provides an almost unlimited source of embryonic-like cells, which can then be differentiated into any cell type.

Morty’s lab has developed a system where we can use this patient’s stem cells and push them into becoming megakaryocytes, which are the cells that produce the platelets in your bloodstream. Right now, this patent’s megakaryocytes don’t work well. I found that, similar to what has been shown for other patients with RUNX1 mutation, they’re more immature compared to normal megakaryocytes, and they don’t produce many platelets. They’re not developing as they should because they’re missing the activity of the RUNX1 protein since his cells only have one good copy.

It sounds like you’ve made quite a bit of progress in only a few months. What are the next steps?

I’m trying different combinations of drugs to see if I can increase the activity of his RUNX1, so that his megakaryocytes can develop and work better. I’ll test those megakaryocytes by injecting them into mice to see if they produce normal amounts of platelets. Basically, we want to recapitulate his thrombocytopenia in an in vitro culture and find a way to rescue his platelet production.

The other thing that is special about this RUNX1 mutation is that it increases your chance of getting leukemia by 50 percent. That is part of the big picture here. What we propose is that if we can correct his platelet production deficiency, we also might reduce his chance of getting cancer later on in his life. Many people in his family have inherited thrombocytopenia, and some have already gotten leukemia and passed away.

When you do research, you can be in the background and never know where you’re findings are going to go, so I’m really excited about working on a project that I know could benefit an actual family.

Editor’s Note: Stay tuned for another Q&A with Amy Lavery, PhD, a diversity scholar who is working with Amy Waldman, MD, a pediatric neurologist and medical director of the Leukodystrophy Center at CHOP. In the meantime, explore the Diversity and Inclusion section of the Research Institute’s website.