May-June 2014, Volume 11, Issue 3
Hematology as a Journey
Published on: April 23, 2014
Awed by the physician who removed my tonsils (probably unnecessarily), I have wanted to be a doctor since the age of three. Not that there weren’t doubts along the way, as years later as a student at the University of California, Berkeley, I envisioned the road (medical school, internship, residency) that I would have to travel to reach that goal. For a time, I considered following my father’s lead, but he, a high school English teacher, straightened me out. “Don’t be stupid!” he said. “Being a teacher is fine, but you can teach at whatever you do.” Of course, he was right, and in the end, I had it both ways, as I became a physician/teacher.
When it came time to apply to medical school in 1958, there were the usual options for someone growing up in California: Stanford, the University of California, San Francisco, the University of Southern California, and the newly minted University of California, Los Angeles (UCLA). For whatever reason (likely intuitive), I chose UCLA. This decision led to my first airplane ride when I moved from Berkeley to Los Angeles. The experience at UCLA was eye-opening. Most of the lectures were given by young faculty who were deeply invested in their own research, so, predictably, part of the class complained about the emphasis on science and the others enjoyed the newness of it all.
As for internships, I didn’t apply very widely, and there wasn’t anything like today’s computerized system that “matches” applicants with a particular training program. Fortuitously, I wound up in Seattle at the University of Washington where I found myself among a group of remarkable biomedical researchers including Earl Davie, Clem Finch, and the nephrologist Belding Scribner, who was pioneering hemodialysis as an approach to treating kidney failure. Toward the end of my second year of residency in 1964, I was asked if I would be interested in becoming a hematology fellow. I don’t know why, but someone had given my name to Clem, who was head of the Division of Hematology at the time, and he approached me personally. After some thought, I accepted the invitation and “shorttracked,” entering fellowship after two years as a resident. I reasoned that if I didn’t like hematology, I would complete my third year of internal medicine training and go into practice.
Fellowship programs were so much less formulaic then. I spent most of the first two years (1964-1966) in the lab and fell in love with it. I was assigned to help develop a new assay for the elusive erythropoietic stimulating factor (i.e., erythropoietin or Epo), and I plunged in. We started with samples from normal subjects and then moved to patient samples. The bioassay wasn’t sensitive enough to reliably measure Epo activity in normal serum, so we had to concentrate urine to detect a signal. These experiments led to the discovery that Epo levels were consistently low in patients with polycythemia vera, and we went on to use the assay to analyze Epo levels in a number of polycythemic states.
Things were going smoothly until 1967, when it became clear that I was going to be drafted into the military. Coming to my support, Clem called friends at the National Institutes of Health (NIH) who informed him that there was an unexpected opening in hematology in the Clinical Pathology Department. I literally flew out that night, interviewed the next day, and, thankfully, was offered the opportunity to apply for the position. When I returned to Seattle, I found waiting for me a draft notice stating that I was to report to the Presidio of San Francisco on July 5. Now it was a race to see what would come first: the offer of a commission in the Public Health Service or July 5 and the Army. I was going somewhere, but I just didn’t know where. Mercifully, the offer to join the commissioned corps arrived about a week before July 5, and I was off to Bethesda, Maryland.
NIH was the center of biomedical research at that time, and a second postdoctoral experience there was a watershed event in my career. It was at NIH that I learned the basics of cell culture and the physical separation of cells, tools that made feasible the study of subpopulations of hematopoietic cells. And through the team of James Till and Ernie McCulloch at the Ontario Cancer Institute (OCI) in Toronto, I was exposed to novel concepts in the new world of experimental hematology, as Till and McCulloch had made seminal observations about the nature and function of stem cells and about clonality and clonal evolution. Ernie was very supportive, and I had the opportunity to visit the OCI on several occasions at a time when colony-forming assays were being developed.
When my time at NIH was up, Bob Petersdorf, chair of Medicine at Washington, offered me the opportunity to return, and I joined the faculty in 1969. I now had new tools to apply to the lines of investigation that had been started earlier. My work in the lab in Seattle linked two areas: the clonal nature of the myeloproliferative neoplasms (in collaboration with Phil Fialkow) and the potential value of Epo as a therapeutic agent (in collaboration with my close friend, Joe Eschbach). These two areas, along with ongoing studies of iron physiology led by Clem, dominated the next 20 years of my academic life in Seattle. Bev Mitchell joined the lab early on and became a good friend. It was an exciting time.
Joe and I had developed a large animal model of renal failure and convincingly demonstrated that plasma that was rich in Epo could reverse the accompanying anemia. As a result, scientists from Amgen, then a small startup company, contacted us to see if their recombinant human Epo would work in our animal model. We never got there! Rather, we quickly initiated the first clinical trials of Epo, in which we assessed response in transfusion-dependent patients on dialysis; it was amazing to see something work so well!
To extend our work on clonal disorders, we developed a model of G-6-PD heterozygosity in the cat – a model that Jan Abkowitz, then a fellow and currently ASH’s immediate past president – exploited brilliantly. Ken Kaushansky, also a fellow at the time, introduced molecular biology to the division in studies of hematopoietic growth factors, their receptors, and their biology. Ken’s work in this area culminated in his cloning and expression of the gene that encodes thrombopoietin (Tpo), Epo’s little sister.
My years in Seattle were interrupted by another important event — a year on sabbatical with (now) Sir David Weatherall at Oxford. The Weatherall lab was studying the regulation of globin chain synthesis in an attempt to better understand the pathophysiology of hemoglobinopathies. While I probably disappointed David in how little I accomplished, living abroad and watching really good minds in action in a resource-restricted environment was revelatory. Through that experience, I made many friends and adopted a view of the world that I don’t believe I would have had it not been for the experience of living outside of the United States. I also came to like football, as it’s defined on the rest of the planet.
In 1989, I accepted a new challenge, moving to New York City and the New York Blood Center with a goal of expanding the research programs there. Fortunately, a very talented husband-and-wife team of scientists, Anna Rita and Giovanni Migliaccio, accompanied me, and they sustained and grew the laboratory by encouraging and supporting the work of visiting fellows and scientists. New York was a challenge, but very exciting.
In 1998, I was recruited to the Blood Research Institute of the BloodCenter of Wisconsin in Milwaukee, which Dick Aster had led for many years. The Institute was home to a group of extremely bright scientists including Dick, Peter Newman, Bob Montgomery, and Hardy Weiler. My time at the BloodCenter provided one of the best experiences of my life, and with the support of the scientists and the Institute’s Board, we were able to recruit a number of outstanding young investigators who have gone on to success in their own right.
The final move, in 2007, completed the circle, bringing me back to California and to the University of California, San Diego (UCSD), where I rejoined Ken Kaushansky. At that time, Ken was chair of the Department of Medicine and (with some irony) my ultimate boss. The move to UCSD was in support of my wife’s career, and she now heads the Center for Hemophilia and Thrombosis here. With Sandy Shattil’s support, I try to do what I can to remind people (especially the fellows) that there is such a thing as benign hematology and that the study of blood should be a passion, not a pothole on the road to board certification.
As I look back, I don’t have enough fingers and toes to count all the good things that have happened to me, starting with Clem, my most influential mentor. Through hematology, I have had the opportunity to meet countless people brighter than me and to work with outstanding fellows and young scientists both here and abroad. And ASH became, and remains, an enormous part of my life.
Hematology has been a marvelous journey, and I count myself most fortunate to have been able to make the trip.
Thoughts From a Former Protégé
Kenneth Kaushansky, MD
Senior Vice President for Health Sciences, Dean School of Medicine, Stony Brook University
In 1996, Hilary Clinton penned the book It Takes a Village to Raise a Child, based on an ancient African parable. I have often hijacked that title to claim, “It takes a village to raise a physician-scientist.” While I do believe that most successful physician-scientists can name multiple mentors, there is almost always, as John puts it, a “most important mentor.” Most scholarly articles on mentorship list at least six roles a successful mentor fills: teacher, sponsor, advisor, agent, role model, and confidante. Most would also agree that the successful mentor does not have the role of cloning oneself, but rather, he/she should be an astute enough listener to help the protégé pursue their own dreams – a seventh role. There is little doubt that John Adamson is my most important mentor, as he was able to fulfill each of these roles. It is no wonder that he was the 2013 recipient of the ASH Mentor Award.
John taught me how to pen a scientific paper. When he revised and then handed back to me my very first scientific manuscript, I noticed it weighed about twice what it had when I handed it to him a few days earlier: the weight difference, of course, being that of the red ink. “Not bad for an author for whom English is a second language,” he quipped. But the weight of the red ink became less and less as time went on, as I learned not only science from John, but also how to communicate science. One of the critical junctures in my career came when I proudly pronounced that, despite not knowing which end of the pipette to use, I wanted to become a hematologic molecular biologist.
John was a terrific sponsor; he made sure I had ample protected time for research, suggesting that purifying hematopoietic growth factors would help achieve my career goals and introducing me to another mentor, Earl Davie, who greatly enhanced my scientific toolbox. John has served as a primary advisor and academic confidante throughout my career, epitomizing the principle that mentorship does not end when the student leaves the lab. John was also a terrific agent. Shortly after we cloned human GM-CSF, John was invited to present his work on erythropoietin at a Gordon Research Conference (GRC). He suggested to the meeting organizers that I present in his place. It was my very first GRC. And John epitomizes the quintessential role model, constantly exuding scientific integrity, service to one’s community, and excellence in clinical care, educational endeavors, and scholarship.
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