Robert Negrin Is Having Quite a Year

Seeking the interface between science and medicine

These noteworthy events underscore the illustrious career of a physician scientist who says he “wasn’t very interested in medicine” when he found himself studying biochemistry at UC Berkeley. While attending graduate school at the University of Wisconsin, he realized that working in basic science, although incredibly important, just wasn’t fulfilling for him, and he thought he “needed to do something more directly linked to people and the human condition.” That led him to Harvard Medical School, where he worked with Robert Weinberg, PhD, whose lab cloned the first human oncogene.

After earning his MD, Negrin began an Internal Medicine internship and residency at Stanford in 1984, which made him aware that “what I really wanted to do was be at the interface between science and medicine,” and hematology was one place he thought science and medicine were best aligned.

“I met wonderful people in hematology, including Drs. Stanley Shrier and Karl Blume, who was starting the bone marrow transplant program at Stanford. And I thought that was pretty interesting. What I liked the most about those individuals and a number of other hematologists that I met was how they thought about things, their passion for their patients, for the field, for science, and applying discovery to a human problem. And that, for me, was fascinating, and ultimately something I could do for 30 or 40 years,” he says.

Advancing careers

In the 40-plus years since Negrin came to Stanford, he’s had opportunities to collaborate with many other physician scientists who have helped advance his career and whose careers he has helped advance.

“I had a very important collaboration with Chris Contag, PhD, emeritus professor of Neonatology in the Department of Pediatrics at Stanford and who is now leading the Institute for Quantitative Health Science & Engineering at Michigan State University. He developed bioluminescent imaging, a system that emits light when a gene gets turned on that can be captured with a sensitive camera system. We collaborated for over 15 years using that system to study how different populations of cells, including T cells, function in the setting of transplantation because of their importance in graft versus host disease (GVHD),” he says.

“Another really important person to me was Peter Greenberg, MD, emeritus professor of Hematology. He introduced me to clinical research. We did some very early studies on growth factors, and that was a really fun experience to understand what it takes to do clinical research, and how to move a concept forward,” he says.

Among those whose careers Negrin helped advance is David Miklos, MD, PhD, James and Katherine Lau Professor and chief of BMT-CT.

“Rob’s amazing preclinical Treg [regulatory T cell] work and national BMT leadership attracted me to Stanford. He wisely recruited me from my Dana-Farber instructorship in the depths of winter to sunny California, and his support has never faltered. Rob has provided me continuous opportunities, has always been my friend, and funny, now I’m his chief,” Miklos says.

Negrin confesses his distaste for the term “mentor, because it feels like it’s such a unidirectional kind of word. I always found that in the people I’ve mentored, I’ve learned a lot from them, and so those people were very, very important in my life and helped guide me in very important times.”

Blood & Marrow Transplantation: Robert Negrin, MD, physicians, and staff attend patient reunion, 2022. 

Paying it forward

Recalling how Randy Schekman, PhD, a future Nobel laureate, made time to help him while he was an unfocused UC Berkeley undergraduate, Negrin today likes paying it forward in hopes of “helping somebody launch their career and then watching that career really unfold in beautiful ways.

“I’ve had the privilege of helping to educate or launch the scientific and medical careers of extraordinary, gifted trainees from all over the world. Many of them are now in leadership roles at their various institutions. 

“And that’s what we get to do. We get to interact with young people. They’ve had an incredible impact on my life and my science, and we built something together. To me, that’s the essence of what academia is about,” he says.

Whether working with junior or senior colleagues, Negrin is passionate about science and has led a program project grant titled “Bone Marrow Grafting and Cellular Therapy for Leukemia and Lymphoma,” a program that Blume started and that Negrin has directed since 2000. Recognizing the program’s importance, the National Cancer Institute recently renewed it for another five years.

“That funding has been the engine of our science, providing resources for our division,” says Negrin, who was chief of BMT-CT from 2000 to 2020.

“It allows us to bring a number of investigators together to work on common problems from different angles. And many things have come out of that program project grant, including a deeper understanding of the biology of transplantation and cellular therapy and practical applications for overcoming some of the challenges of treatment.

“A major focus of my laboratory has been the study of the biology of GVHD, a terrible problem resulting from a bone marrow transplant. However, the major benefit of the transplant is that the immune system from the donor can reject the underlying cancer — something we call the graft versus tumor (GVT) effect that is also a result of donor T cells among other cell populations. So the fundamental question that my laboratory has been focused on for a long time is how do you get this beneficial GVT effect without the harmful GVHD,” he explains.

The Negrin laboratory has been building off the work of Japanese Nobel laureate Shimon Sakaguchi, MD, PhD, and Stanford colleague Samuel Strober, MD, who identified specific populations of cells called regulatory T cells that help regulate human immune systems. Negrin’s team demonstrated that GVHD can be avoided while retaining the graft versus tumor effect by giving the right combination of cells with the right timing.

Collaborating with industry

The team developed the idea in the laboratory based on fundamental biological principles. Fortunately, the Negrin lab was able to collaborate with a company called Orca Biosystems to move the concept forward. Orca Bio brought resources to perfect the process and to export it to multiple sites around the country. The collaboration with Orca Bio resulted in a number of important studies that were led by Everett Meyer, MD, PhD, associate professor of Blood and Marrow Transplantation and Cellular Therapy in the Department of Medicine and of Stem Cell Transplantation in the Department of Pediatrics. Orca Bio recently completed a phase III registrational trial that will be published this year.

“That trial really validates this whole concept and led Orca Bio to apply to the FDA for product licensing. In a crazy turn of fate, the day the Nobel Prize was awarded to Shimon Sakaguchi was the same day that Orca Bio received their PDUFA (Prescription Drug User Fee Act) date, which is the date that the FDA will decide on product licensing,” Negrin says.

Relying on fate for one’s success violates a crucial tenet of Negrin’s work ethic. Asked what advice he would offer to those who are early in their careers, the veteran physician scientist talks about persistence.

“If you think an idea has merit, keep at it and try to overcome all the disappointments that will come, all the papers that will be rejected, and all the grants that aren’t going to get funded. That’s just part of the process, and you have to have a long view and a bit of a thick skin to learn from those experiences.”

Taking the long view has clearly worked out for Negrin, who is relishing his annus mirabilis.