Third year medical student Alexander Jares, PhD, tells Tyler Guinn about his motivation for getting involved with medicine and research and his experience in pediatrics.

What are some experiences that pushed you towards MD-PhD training?

“Prior to entering college, I had initially envisioned a purely clinical career, however freshman year of college I enrolled in a seminar and discussion series tailored to incoming science majors, in which senior faculty would come and give talks on their research. The scope of the topics was broad. For instance, we had a fascinating talk on how birds make iridescent colorful feathers, but also a talk on single nucleotide polymorphism (SNP) mapping in disease. Crucially, we had small discussion groups moderated by senior basic science and medical school faculty for which we had to read and present primary literature related to the talk. This experience drove home three key points: (1) there is incredible depth to any biological area of study, (2) engaging with this depth required further scientific training and (3) I wanted to have more access to that depth and scientific training in addition to a clinical career. Connecting the dots led me to MD-PhD training as a career starter.”

What was your research background before starting at Stony Brook?

“I started out in two neurobiology labs in college, with Dr. David Wells at Yale University, studying the protein changes in the brain that underpin learning in a mouse model, and then with Dr. Miguel Concha at the University of Chile as part of a Yale/HHMI program, studying the emergence of brain asymmetry in development in a zebrafish model. However, by the end of college, I was ready to explore what was at the time a fringe field: gene and cell therapy. This interest came about in a roundabout way. I had met with Dr. Joseph Piepmeier, a neurosurgeon at the Yale School of Medicine, to discuss neurosurgery as a career. We had reviewed some of his cases, and during our discussion, he mentioned gene therapy offhand. I was intrigued by the concept: curing genetic disease at its DNA source. As a result, I decided I wanted to learn more about gene and cell therapies and work in a lab full-time before starting an M.D.-Ph.D. program.

I started looking at gene therapy-related labs that did research in non-human primates and found Dr. Cynthia Dunbar’s group at the NIH. After graduating college, I joined the lab for a 2-year postbac Intramural Research Training Award (IRTA) position. I absolutely loved it. My projects spanned mapping vector integration sites, tracking of clonal hematopoiesis with DNA barcoding in a rhesus macaque model, and developing an inducible suicide gene system for induced pluripotent stem cell therapies. In short, these projects were all related to making gene or cell therapy technology safer or at the very least monitoring its safety. This is important because successful new therapies have to be demonstrated to be both safe and effective. At the time, there were no FDA-approved gene or cell therapies despite decades of efforts, largely due to concerns about safety. We’ve come a long way since – with the first three FDA approvals in the space occurring only in the past couple of years.”

How did that influence your choice of Ph.D. lab?

“I chose to work with Dr. Yupo Ma based on his extensive track record in stem cell and cell therapy research. Dr. Ma had interviewed me for the Program, and we had debated the merits of various gene therapy vectors, as well as stem cell therapy strategies. I was impressed by Dr. Ma’s vision, command of experimental details, and translational outlook. I immediately knew that Dr. Ma would provide active mentorship combined with room to experiment and take risks building experimental cell therapy systems.”

What was your work over the last few years over?

“My work was engineering stem cell lines from umbilical cord blood. The generated stem cell lines were consistent with early mesoderm, had uniform properties, were not genetically altered, and could be maintained and expanded long-term in the presence of a small molecule. Differentiation of these stem cell lines to endothelial cells may provide a safe allogeneic source of blood vessels for ischemic disease such as myocardial infarction or peripheral artery disease.”

Where do you see this work going in the future?

“There are hundreds of promising gene and cell therapy trials. The three recent FDA-approvals are only the beginning of a paradigm shift from traditional drugs to ‘living drugs’ or DNA-modifying drugs. My assessment is that, in our lifetime, new gene and cell therapies will cure many very painful and dangerous diseases. For instance, it looks like we are very close to a cure for sickle cell disease.”

Is this something you hope to continue in the future in clinical training?

“Absolutely, I remain fascinated by the scientific, manufacturing, clinical, and economic challenges of developing gene and cell therapies and making sure that they actually get to the patients in need in a manner that’s affordable to them. Making that happen is a complex endeavor with many talented people working together to find solutions. In that context, physician-scientists have an important role to play as stewards of good science, best clinical practices, and advocacy for often very sick and financially stressed patients and their families.”

How do you see research integrated into your future career after clinical training?

“There will definitely have to be research and new gene and cell therapies. Not doing research in that field for me would feel like sitting on the sidelines while others race to find cures for rare diseases. It’s a matter of personal choice. My career preference is not inherently better or worse than other choices.”

What do you feel is missing from your field currently and what is something underutilize/unexplored?

“Gene and cell therapies are underweighted in medical school curricula and are not that well known outside the field. This is partly due to the newness of the field, its relatively small size, and 30 years of hype that is only now coming to fruition. I sense that that’s changing, and that awareness is expanding, and I am trying to do my very small part to help.”

MSTP Training:

What scientists or physicians have been role models over the years and what were aspects that you admired about these people? How did you find them?

“There were so many role models, many of which I encountered through classes or via lab. I admired people who were kind, but direct, and who saw their role as making sure the right decision was made and not that they came across as always right.”

 

What were important activities or habits that helped you with the training so far?

“Engaging with researchers in my field outside my home institution. Speaking with as many people as is reasonable and soliciting their opinions. A leadership position in a national society. Physicians and scientists, and people in general, love giving their opinions, and that’s a fantastic opportunity for learning.”

 

What are important activities or habits you wish someone would have told you earlier?

“Keep a journal.”

What activities outside of the MSTP were important to you throughout the program?

“I started martial arts training during my Ph.D. The activity taught me the importance of learning from everyone and treating everyone inherently with respect. Also, if you didn’t know what you were doing, it was immediately obvious, and you had to work on fixing it. Notably, I made friends with fantastic people in the community and learned a lot not only about my community but also about how the public processes scientific breakthroughs and how they experience the medical system from the patient side.”

 

What does it feel like to be on the last ‘leg of the race’ for MSTP training?

“It feels good. If the Ph.D. felt like meandering through the woods foraging for berries, then going back to the clinic is like being part of a huge machine that’s relentlessly moving forward – I think of Charlie Chaplin’s Modern Times. You just have to keep up with a fast-moving conveyor belt. I am also enjoying the social nature of medicine, meeting and working with many different people continuously.”

 

How has getting the Ph.D. has helped you in the clinic and why is it important to you?

“It’s taught me that biology is very complicated and doesn’t always make sense. No one sat down and rationally designed the DNA code and epigenetics to run like a well-written computer program. I concluded that some things are so hard to figure out that it’s not realistic for medicine to be perfect. For that reason, paradoxically, the Ph.D. has taught me to accept some of the non-evidence-based aspects of medicine and get with the program, because it’s not realistic for medicine to have all the mechanistic answers and the data to back-up every decision, although of course, that’s the goal that we are aspiring to.”

 

What rotation are you on now? How is it going? Why did you start with this one?

“Pediatrics. I am actually truly enjoying it. The quality of the medical education has been excellent. On a day to day basis, I find getting the history & physical examination from the family and the patient very rewarding. In pediatrics, there is also a wide-range of physical exams spanning many ages. Notably, I was surprised at how fast some of the pediatric patients recovered. One day my patient is on 12 liters of oxygen, and a few days later, she’s breathing on room air overnight. Those positive experiences are, of course, tempered by occasional losses of young patients. It’s important to take the time to process these losses and grieve appropriately.”

 

Have you found any residents, attendings, or others that helped you with the transition?

“Yes, I found all of the above to help me. 4th year medical students are a fantastic resource on the floors too. They are far more knowledgeable than you, but also can vaguely remember their start on the floors too, and they have plenty of good advice that’s highly relevant to you. Otherwise, I didn’t advertise the transition specifically, because I didn’t assess the need to. I just mentioned that it was my first clerkship and that I was coming in a block later than my colleagues because of research.”

 

What was the easiest/hardest thing to adjust to going back to the wards?

“Hardest thing was the anticipation of going back. We tend to predict and run worst-case scenarios in our heads when we anticipate something unknown. Once I actually started and got into a routine, it became much easier because there were specific, actionable things I could do to improve my performance on the floors. The easiest thing was actually the early wake-up times, I am a lark and don’t mind waking up at 3:30am. On the flipside, I don’t care much for being at work in the evenings.”

What would you say to students a few years earlier, looking ahead on what to expect?

“#1 Don’t worry about going back to clerkships, the Program chose you because they believe in you, and so you will very likely be fine. The only way you get a 100% chance of failure is if you give up. If you keep on moving, you have an excellent chance of making it through. And then all the standard advice. There are no shortcuts or magic secrets that I am aware of. Show up early, introduce yourself to the team and when you see patients, treat everyone respectfully and with consideration, be willing to learn and appreciate advice from your superiors – which is basically everyone. Notably, it’s important to understand that you are there to learn for your future patients. Your current patients are probably going to be OK without you on the team. Embracing that reality is very freeing and motivated me to take every opportunity to see more patients, spend time with them, and learn from them. As a medical student, you have the luxury of time to observe, listen, and learn. On the flipside, it’s important to learn to build trust fast with the team and when interacting with patients. My approach is to listen well and summarize back key points to ensure that people know that you heard them.”

(Written by Tyler Guinn)