Message from the Director
I can remember the many times I’ve been told how to succeed by colleagues, mentors, department chairs, etc. The common theme was pretty much what they did in their career, although the many careers they had and how they got there were different. The common part was to stay focused, which mainly was to stick with a subject and avoid distractions with other subjects. I couldn’t do it. I also didn’t have the discipline to focus on grades. I also didn’t do the standard MD, then internship, then residency, and then more fellowship. I couldn’t do any of those standard steps because I was fascinated by the research I was doing from high school on, and the flood of ideas I had when reading a paper or seeing the results of my experiments. I started to follow these ideas, even if they weren’t “focused”.
I got interested in what has largely been my career by the magic and beautiful paper by Billingham, Brent, and Medawar on experimentally inducing transplantation tolerance by injecting donor strain spleen cells into mouse fetuses. The mice, when born, could accept skin grafts from the spleen donor strain, but not from donors that were genetically different from spleen donor and fetal host. Soon after that, while I was still a high school student working with the pathologist and transplantation geneticist Ernst Eichwald, a professor from Caltech—Ray Owen—visited the lab and told us about the 1945 experiment he published that different sex cattle twins who shared a placenta made their own blood type red cells, but also made, for life, red cells from their twin. Cattle twins not sharing a placenta only had their own red cells, not the twin’s. And Burnet proposed a mechanism that allowed adult mammals to 1. mount a memory immune response to foreign antigens encountered in adulthood, 2. simultaneously to make a lower and later response to antigens upon first encounter, and 3. have no response to antigens to which they were exposed before the immune system was fully developed, as if the antigen was self rather than foreign. He called it clonal selection, and proposed each immune cell was committed to make immune receptors like antibodies of only one specificity (for example, anti-measles viral surface proteins). The cells would respond to their antigen if introduced postnatally by clonally proliferating, giving rise to both long-lived memory cells poised to respond to the same antigen if encountered and also effector cells (e.g. antibody-secreting cells) to effect removal or isolation of the antigen. However, if the antigen was encountered during fetal life, the clones of cells with receptors for the antigen would be eliminated or silenced.
These early papers, all in the 1950s or before, led me to think about how the immune system develops in fetal life, how individual cells (which we now know are T and B lymphocytes) are signaled to proliferate by engagement of their own surface antigen receptors, how blood formation of red cells and all other blood cells can be regenerated lifelong, how rare clonogenic lymphocytes meet the antigens that presumably enter the body by many different routes (by homing receptors), and how and where clonal elimination of specific lymphocytes occurs. I wondered if cancers of lymphocytes were continually triggered into proliferation using the antigen receptors, and if other cancers receive proliferative signals as well. And I wondered if the leukemia or lymphoma or other cancers were clonal—and how such clones developed. All of these questions eventually led me to search for blood-forming stem cells, then brain forming stem cells, then cancer stem cells. This in turn then lead to a search to understand the evolution of each cancer in normal stem cells. The cancer stem cells, having accumulated mutations and alterations in gene expression, emerge as a distinct cell derived from the self-renewing stem cells.
When I was about to graduate from medical school and apply for an internship, I realized that I was about to learn only what others discovered or memorized from their mentors. If I did an internship and then residency, I would not have time to explore not only the field I first focused on, but also the adjacent fields relevant to “following my nose.” As much as I enjoyed patient contact and the immediate gratification of helping them through their illness, I decided to go straight into research, while all my Stanford classmates went on to internships.
If you have read this far in this message, you are probably rebelling against my modus operandi of following my nose wherever and in whatever fields it led me. If you are trying to ‘help’ your own students or trainees by teaching them to focus rather than follow their noses and intuition, my advice should be anathema. I accept that for many, focusing on one central objective at a time does allow success also, whether in science or clinical medicine. But I followed my nose.
I still remember when my postdoc, Ravi Majeti, looked at RNA expression differences between human HSC and human AML leukemia stem cells, and declared “this is what I’ll spend the rest of my life studying.” Now he is well known for many discoveries in that field, going into great depths, yet exploring hypotheses that present themselves to him with each new discovery. He did an MD and PhD at UCSF, his clinical training at Stanford, and brings together each of these areas in his academic career. He not only makes discoveries that result in clinical trials, but in fact has several that in late-stage trials cure many patients who surely would have died from their disease without the therapies Ravi co-developed. I expect over the next 20 or so years under his leadership, he will show that one who focusses can also make and translate discoveries.
This is my penultimate message as Director. Next month I will try to imagine where the field of stem cell biology and regenerative medicine will go—at least where I hope to participate freed of administrative responsibilities. I wish to thank all my lab members over the years for using the freedom of the lab to find their own directions, and of course the faculty, students, and fellows in the institute for showing me and the world how many different ways one can make fundamental discoveries that illuminate their minds, and some of which can be translated to end some diseases.