Science in the blood: Q&A with Ravi Majeti

What role do stem cells play in cancer development?

One of the most important properties of stem cells is self-renewal—the process by which they divide to make more stem cells and perpetuate the stem cell pool throughout a life. Their role in cancer is a complicated and sometimes controversial issue. Not all cancer cells are the same and within a malignant tumor or among the circulating cancerous cells of leukemia, for example, there can be cells of different function and potential. The stem cell theory of cancer proposes that among all cancerous cells, a subset act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells normally renew and sustain our organs and tissues.

What are stem cells and why are they so important?

There are two categories of stem cells. The first are adult stem cells that reside in individual tissues or organs. The blood, or hematopoietic, stem cell is perhaps the best understood and most accessible. It can differentiate into all types of blood cells—red cells, white cells, platelets—and produce all cell lineages within the adult blood system. They are also one of the few stem cell types with a long history of clinical application, in the form of bone marrow transplantation. The second type are what are called pluripotent stem cells. These include embryonic stem cells, which are derived from human embryos and induced pluripotent stem cells, a type of stem cell developed over the last decade as a major advance in the field of stem cell biology. They have enormous regenerative medicine potential because they have the ability to give rise to all the cell types in the body and can be cultured and expanded in the laboratory. But the translation of the pluripotent stem cells into clinical applications is really in its infancy and there are many basic issues that still have to be solved to bring those approaches into the clinic.

Your lab has two goals. You focus on the therapeutic targeting of leukemia stem cells, but you also focus on normal human hematopoiesis. How are these two goals related?

The overarching goal of our research is to develop new therapeutic approaches to treating leukemia and thereby treating leukemia stem cells. But in order to do that we have to know what are the vulnerabilities specific to the leukemia stem cells and, in particular, how are they different from normal blood stem cells. So understanding normal blood stem cell biology and development is critical to identifying new approaches to treating leukemia.

What’s missing from a technical perspective that will help move the field of stem cell research forward?

We can put that into two bins: the scientific questions and the regenerative medicine translational applications. What’s missing in both is not one major element but a number of smaller issues that need to be solved in order to advance the field. One critical scientific question we need to address is how do we model complex multi-factorial diseases, such as neurological or psychiatric diseases, using stem cell biology, whether they be ex vivo in the laboratory or in animal models. Modeling these complex diseases using stem cells is really key to moving the field forward. Translational regenerative medicine applications, on the other hand, include the ability to expand cells, scale the process and manufacture them under GMP (Good Manufacturing Process) conditions in order to safely administer them to individuals. Some of the challenges we face here are how to integrate cells that are engineered outside the body into an existing organ and get them to function cooperatively with the other cells that are already present and how to make an organ that could be transplanted into an individual who needs regenerative therapy.

Does treating patients have a significant influence on your work as a scientist?

I have trained extensively in the treatment of leukemia patients both with chemotherapy and bone marrow transplantation. Those experiences have really helped guide my research in many ways. Right now, I don’t take care of leukemia patients, but I’m actively participating in our clinical programs. This has an enormous impact on my research as it has allowed me to envision the big picture by asking: What are the most clinically relevant questions? And, maybe more importantly, what are not clinically relevant questions? Resources and time are limited, so you have to make those tough choices.

One of your many leadership roles at Stanford has been as co-director of the Translational Investigator Pathway (TIP) for the Internal Medicine Residency Program. What excites you about this program?

The Stanford University School of Medicine has a long, outstanding tradition of training physician-scientists who have gone on to become leaders in academic and translational medicine. I have a deep passion for mentoring physician-scientist trainees and the TIP program is an invaluable and important part of my activities here. Everyone involved seeks to link our trainees with potential mentors so they can identify areas they’d like to pursue during their research training years. Physician-scientists play a unique and critical role in medical research and a lot of translational innovation comes from this group. But they are a dying breed across the U.S. and the number of medical students interested in pursuing careers as physician-scientists has declined over the past 20 years. For the sake of medical innovation, it’s imperative we recruit and train a new crop of them. But it’s a challenge because physician-scientists often drop off the pathway towards becoming translational researchers because they don’t see very many role models or even peer models around them. Providing longitudinal mentorship and even trainee-to-trainee mentorship is invaluable. Ultimately, it’s really about building the next generation of translational investigators who will keep advancing the field.

Juggling your work as a physician-scientist, you must have met challenges along the way. Do you have any advice for junior scientists facing challenges?

I have the great privilege of mentoring lots of junior scientists and junior physician-scientists. There will always be personal and professional challenges in any career, and my advice is to focus and commit yourself to doing what is most interesting and important to you. Take on those activities that will sustain you intellectually for your whole career. Too often we focus on the short-term, which is often based on real-world issues like family and finances. But it’s really important to think about the big picture in the arc of a career. At the beginning of their training, physician-scientists are presented with a number of amazing opportunities—research, teaching, clinical practice. It’s okay to prioritize them in different ways. They just don’t need to be prioritized equally. And I think it’s very difficult to pursue them all at the highest level. That’s a trap that some junior scientists fall into. Finding the right mentor—or I should say mentors—is key because you need multiple types of mentorship. My final piece of advice is: life intervenes. That’s OK. Sometimes people feel that they’ve lost out or they’re not succeeding because they can’t handle everything all at once. No one can.

How do you think we can reach out to the younger generation and encourage more young, bright minds into science?

Outreach is key, especially in the middle schools and high schools. That’s where you can really hook young people on the excitement of science and scientific inquiry. They need role models to give them real-world examples of what a career in science is really like. Otherwise, the only examples they’re exposed to are from the movies or from television. As scientists, we need to be able to convey complex scientific projects and principles in a way that young people can understand them. That means we need to get out of our offices and ivory towers and speak clearly and coherently about what we are doing, why it’s important, what the problems are that we are trying to solve and how science is the pathway to solving them.

Does Stanford have any youth science programs?

We have a number of great programs for middle school and high school students. Some are targeted toward underrepresented minority students and others toward any student who applies. We have short-term weekend opportunities that expose kids to biomedicine and biomedical sciences and summer programs where high school students can spend eight weeks in a laboratory learning some of the basics of scientific research along with a classroom-based curriculum. The problem is that there are way more students interested in participating than we can host. We should never turn away a student who wants to participate in one of our programs. Everyone should be given an opportunity to test-drive a career in science.

Why do you think Acute Myeloid Leukemia (AML) is the cancer with the strongest evidence for the critical involvement of cancer stem cells?

The biology of AML is different than that of other tumors because the leukemia cells are liquid and circulating so they are less dependent on interactions with other cells. The cancers that occur in solid organs are more dependent on their microenvironment, which is a biologic distinction that also contributes to different interpretations of the cancer stem cell model. The stem cell hierarchy and blood development has been clearly elucidated and the assays for normal blood stem cells have been applied to the investigation of AML. And it’s the presence of those assays that has propelled AML to the forefront of the cancer stem cell research field. I also think that AML is really just hijacking aspects of this normal blood stem cell hierarchy and so it’s been easier to ascertain the experimental evidence for the critical involvement of cancer stem cells in AML. Since the blood system is liquid and moves around the body, it’s not set in a physical location or in a physical structure. It’s unlike a solid organ where there are multiple cellular subtypes that are physically linked, which makes the experimental process of isolating individual cells and studying them potentially a confounder in the interpretation of the experiments. This means that the cells in contact with other cells and components in an organ may have different properties and behave differently after you have dissected the tissue, digested it and prepared single cells for study.

You have a number of academic and administrative appointments in addition to your clinical work. What do you do to relax and have fun?

I’ve always made it a high priority to spend time with my family. I have two sons who are in high school but over the ten-year arc of my career, they went from little boys to young men. We like to travel and my wife has been the key in insisting that I unplug when we go on vacation instead of sitting and looking at my computer in the evenings when we come back to the hotel. I’m also a basketball junkie. I’ve played basketball all my life. I’ve coached my sons’ basketball teams, I watch basketball, I talk about basketball, it’s hard to find somebody who’s more into basketball than me. When I was in medical and graduate school, before I met my wife and had kids, I played every day. I still play full court basketball once a week even though I probably should stop because I’m getting too old for all the contact.

And your favorite team?

Golden State Warriors— I’m a Bay Area guy through and through. How can you not love Steph Curry? Come on now!