MD-PhD Student Research Aimed at Improving Patient Care

Graduate student Ben Schrank’s paper in Nature started with a hunch. Schrank, a student in Columbia’s MD-PhD program, and his mentor Jean Gautier, PhD, were looking for new proteins that might be involved in DNA repair. “If you’re able to inhibit DNA repair, you could make cancer treatments more effective,” Schrank explains.

A mass spectrometry machine analyzed a batch of frog DNA and produced a long list of more than 100 proteins that could potentially play a role. Two possibilities—Arp2/3 and actin—stood out to Schrank and Gautier, professor of genetics & development in the Institute for Cancer Genetics at the Vagelos College of Physicians and Surgeons, who has studied DNA repair for years.

“Our project was high risk, high reward,” says Schrank. “There was no precedent in the scientific literature that explained active roles for Arp2/3 and actin. It was a gamble on my part. Jean and I talked and he encouraged me to do the experiments.”

Those experiments revealed that Arp2/3 and actin are critical conductors of DNA repair. The proteins push the ends of broken DNA into clusters where repairs are made, and repair falters when damaged DNA can’t be moved.

Discoveries like this underscore the mission of Columbia’s MD-PhD program. Student trainees hone their research skills in the labs of faculty mentors, pursuing scientific findings that may be translated into clinical practice. The program matriculates 12 to 15 students per year, and the program currently has 104 MD-PhD students, from those in their first year to those in their final year of the program.

“The goal of the MD-PhD program is to train the next generation of biomedical leaders,” says Steven L. Reiner, MD, director of the MD-PhD program. “The curriculum emphasizes both clinical and scientific education, enabling our graduates to become research innovators and play a key role in the translation of scientific findings to clinical practice.”

Schrank submitted his research to Cell and spent eight months interacting with the journal’s editors and revising the draft before the paper was turned down. Rejection stung, but Schrank pressed on. The paper was stronger thanks to multiple revisions and was ultimately accepted by Nature with Schrank earning a first author credit.

For the future, Schrank is pursuing a career in radiation oncology, an area closely tied to the research he has conducted. Since completing his clinical clerkships, he’s come to fully appreciate the thoughtful discussions happening at Columbia around patient care and research. “The conversations are not just about how we should treat patients,” he says. “They’re about why we’re providing this treatment for a patient. What’s the evidence for this treatment?” He believes the MD-PhD program is preparing him to go beyond practicing medicine to bring change to the field—and that change comes from knowing how to ask the right questions and find the answers in science.  

“The beauty of research is it’s very autonomous,” says Schrank. “I came into the lab day and night. I had a list of experiments and ran them simultaneously. All of my experiments went into the paper.”

Building Resilience as a Research Scientist

MD-PhD students are expected to publish their work. The process can be grueling. There are no guarantees when conducting research. Aha moments are few and far between. 

“The process of conducting research and turning it into a paper is long and a lot of it is out of your control,” says Matthew Decker, an MD-PhD student in the lab of Lei Ding, PhD, assistant professor of rehabilitation & regenerative medicine and of microbiology & immunology. “There are many ups and downs, but they’re also a valuable part of your training.”

In addition to publishing their research, MD-PhD students have to navigate a program that starts with medical school, then moves to the laboratory, and then back to medical school. 

“MD to PhD is like switching to a different part of the brain but in an enjoyable way. As a PhD student, you are creating new knowledge in a narrow field. As a medical student, you’re learning an incredible amount from a huge field. These are two different modes of learning but doing both gives you a great combination of skills invaluable to a doctor and research scientist.”

During the initial MD portion, students follow the same curriculum as traditional medical students but also rotate in labs to find the right research mentor. “I wanted to work with an investigator beginning his career,” Decker explains, “someone who would trust me with big ideas and projects.”
 
Decker studied how the body supports production of hematopoietic stem cells (HSCs), which give rise to all blood cells. With the help of machinery that can sort through tens of millions of cells, Decker discovered that a growth factor that keeps HSCs healthy is supplied by a surprising source, the liver. These findings could inform how HSCs are stimulated for therapeutic use and lead to improvements in bone marrow transplantation. 
 
After 18 months of research, Decker began preparing a manuscript, which took another month. In the weeks after he submitted the manuscript to Nature and waited for feedback, he continued to conduct experiments and gather more data. The manuscript was turned down, so he submitted it again, this time to Cell, and received another rejection. 

“One thing I’ve learned is that sometimes people will not be interested in the things you’re interested in and that’s not a reflection of the worth of your research,” says Decker. 

He used the comments from the journals, as well as data from ongoing experiments, to improve the paper. Next time he submitted the research, it was accepted by Science. 

Feeling of Freedom 

Heather Lee, like Decker, is an MD-PhD student in Ding’s lab, where she has room to branch out. She is the only one in the lab investigating the behavior of genes within HSCs instead of examining their environment. 

“It’s a great feeling to come to the lab and have your own project, decide the research questions, and then figure out how to answer them,” says Lee. “You can’t find these answers on the Internet.”

What Lee studies may one day impact treatments for leukemia and other types of blood diseases. Lee studies the factors that control HSCs: what causes them to generate more stem cells or go on a different path and develop into more mature cells. These processes often go awry in blood cancers.

In her paper in Nature Cell Biology, Lee identified a new factor—called m6a methylation—that pushes HSCs to become mature cells but is not needed once cells have matured. “Our study and others suggest it may be possible to develop m6A-targeted therapies against leukemia cells without damaging HSC function,” Lee says.

Though she’s excited by the findings, they also caused Lee some uncertainty. Her research contradicted a long-held assumption among scientists that removing m6A alters gene expression; Lee found no such change.

“I had a moment of doubt,” says Lee, whose paper was rejected by two other journals before it was accepted for publication. “I questioned my research at first but ultimately I had to trust myself.”

Trusting her gut led Lee to science in the first place, combined with the example of her parents who were graduate students when they met. In college, Lee conducted research for three years in an immunology lab, where her faculty mentor encouraged her to pursue graduate school in an MD-PhD program, something she had not known existed, though she was planning to apply to medical school. Going through the program has only solidified her interest in a career as a medical scientist.     

“My goal is to have a career combining research and medicine,” says Lee. “The training in Columbia’s MD-PhD program opens a lot of doors to ask clinical and translational questions and those are skills that a lot of other people don’t have.”

Lee adds: “Conducting biomedical scientific research provides useful information. What you find will help people in some way and you’re adding to this scientific community that’s trying to understand things better.”

Research Tips for MD-PhD Students

Finding a research mentor, applying for grants, and publishing papers are among the demands of Columbia’s MD-PhD program—not to mention finding time to step back and recharge outside of the classroom, hospital, and the lab. Decker, Lee, and Schrank share advice based on their experiences. 

Applying for Grants: “It’s helpful to look at other grant applications that have been funded,” says Decker, who applied for an NIH research training grant for students to conduct his research. “Columbia’s MD-PhD program maintains archives of funded grant applications and documents with instructions and advice. Ask your mentor for help accessing these files.”

Choosing a Lab, Finding a Mentor: “Students have a lot of anxiety about finding the right lab and mentor,” says Schrank. “It’s important to have a good rapport with the faculty member you’re working with in the lab. At some point, though, you have to commit. You’re here to train. The area of research is less important. The sooner you can settle into the lab and start working, the better it is for you.”

Lee adds: “I’ve benefited from being in a small lab with an accessible faculty mentor. Having my own project from start to finish, instead of inheriting someone else’s project, has been the best way for me to train.”

Seeking Inspiration, Overcoming Challenges: “Having good relationships with the grad students, postdocs, and faculty mentor in the lab can help you to deal with challenges,” says Lee. “My mentor talks about what makes great science, why we do what we do, and how to distinguish ourselves as emerging scientists. These things can keep you stay motivated during down times.”

Achieving Balance: “The time you spend in the lab will go quickly and months will pass and no one will tell you to take a break and disconnect,” says Schrank. “I forced myself every few months to be out of the lab, either to go on a trip with my partner or to Wisconsin to visit family. Spending some time away enabled me to come back and look at my project with fresh eyes. It helped me to refocus and set deadlines.” 

Managing the MD-PhD Transition: “Going from medical school to grad school is a tough transition,” says Lee. “Medical school is about absorbing as much information as possible. In grad school you’re asking: What information do I want? It’s a total shift. As a PhD student, no one is telling you what to do. You have to decide what to do and set your own deadlines. Remember your time is under your control and your personal wellness should be among your priorities.”