81R, 85F-Internal Medicine/Rheumatology

Wayne M. Yokoyama, M.D. has made fundamental discoveries about how certain immune system cells, called natural killer cells, protect us from infection and cancer. He is a professor of Medicine and of Pathology and Immunology at Washington University, and a world authority on natural killer cells and their molecular biology. He was elected to the National Academy of Sciences in 2007.

What is your hometown?

I was born in Wailuku on the island of Maui in Hawaii but grew up in Honolulu on the island of Oahu. I did not have the chance to leave Hawaii until my senior year of high school when I won the state science fair and was awarded a trip to Baltimore.

What is your official title?

I am an Investigator of the Howard Hughes Medical Institute and Professor of Medicine and of Pathology and Immunology at Washington University School of Medicine in St. Louis. I also hold the Sam J. and Audrey Loew Levin Chair for Basic Research in Arthritis, and am Director of the Medical Scientist Training Program.

How/when did you become interested in science and medicine?

I grew up during the space race. I distinctly remember getting a telescope for Christmas as a boy and was then fascinated by all things related to astronomy and the physical sciences. However, when I took a course in biology during my freshman year in high school, a terrific teacher totally changed my focus. He taught a lab-based course and I thereafter became interested in biological processes.

What interested you to pursue a career in medicine?

I had envisioned a career in science and research. My high school teacher, Miles Muraoka, encouraged us to do science projects. He was very successful. Our high school won the top prize at the state science fair for 3 or 4 years in a row. A couple of years we won both top prizes. In retrospect, this was simply amazing especially when considering that we were at a public high school with less than 10% of graduates going on to 4-year colleges. He helped me win a summer fellowship from the Hawaii Heart Association as a rising high school senior to work in a research laboratory at a small hospital-based immunology research lab in Honolulu. Its Director, Dr. Mitsuo Yokoyama (no relation), sent me to work at the Blood Bank to do “tissue typing,” the predecessor to what we now call HLA typing. I learned how to collect and process blood samples to isolate the lymphocytes, then do cytotoxicity assays using antisera from multiparous women or donors who had multiple blood transfusions. We now know that these antisera had antibodies against different HLA types but they were all different, so they reacted differently with each test sample of lymphocytes. What we were able to show was that samples from donors of the same ethnic group tended to have the same antisera reactivities and that each ethnic group showed different specificities when compared to other ethnic groups. It didn’t take much to also conclude that tissue types were very complex. Even a high school student could reach that conclusion!

In the midst of all of that summer’s experience, the first renal transplant was done in Hawaii between two identical twins. The event was covered extensively by the lay media. I remember watching (on a black and white TV!) a news reporter interviewing the surgeon and asking “Why identical twins?” I knew the answer! After that, I decided that I wanted to go into biomedical research for my career. Dr. Yokoyama and later on, my other scientific mentors, were physicians and they advised me to go to medical school. I had no serious intention to enter private practice even though I was almost side-tracked a few times.

Please highlight your major career achievements, awards, discoveries, etc.

Scientifically, our laboratory is known for the discovery of inhibitory receptors on natural killer cells that recognize major histocompatibility complex (MHC) class I molecules on their cellular targets. This discovery provided the first molecular basis for how natural killer cells, a constituent of the immune system, can distinguish between targets they kill (like tumors and infected cells that lack MHC class I expression) and normal cells (that normally express MHC class I) that they spare.

These findings allowed researchers to take natural killer cells from phenomenology to the molecular level, and into the mainstream of immunology. Recently, these findings have led to observations indicating that the human versions of these receptors are important in predicting clinical outcomes from different human diseases. On the basis of our initial studies and subsequent research from our laboratory, I was awarded the 2002 Novartis Prize for Basic Research in Immunology, and was elected to the American Society for Clinical Investigation (ASCI), the Association of American Physicians (AAP), and the American Academy of Microbiology. This year, I will be inducted into the National Academy of Sciences.

However, all of these accolades are really due to outstanding work from people who work in the lab with me. I was (and still am) very fortunate to have great technicians and trainees in my lab who helped bring us international acclaim. And so, some of my proudest moments are when my technicians, students and post-doctoral fellows make advancements and receive accolades in their own careers. A number of my technicians have gone on in their own careers, receiving doctoral degrees, for example. Fifteen Ph.D. students and 36 post-doctoral fellows have trained or are training in my laboratory. Of the ones who have finished in my lab (9 and 28, respectively), many are still in training but 13 already have faculty positions in our country or abroad. One of them, Jonathan Heusel, M.D., Ph.D. is on the faculty at University of Iowa Carver College of Medicine. His work in my laboratory won him the best poster award at the annual ASCI/AAP meeting in Chicago. I was very proud of him but not as proud as when he was appointed to the faculty at the University of Iowa!

Is there a teacher, mentor or University of Iowa Carver College of Medicine faculty member who has helped shape your education?

I had many great mentors at the University of Iowa. One was Dr. Robert Ashman, who until recently was Chief of Rheumatology. Dr. Ashman gave me a chance to get back into the basic immunology research laboratory after I finally finished clinical training. I found that I loved being back at the lab bench, and the experience rekindled my interest in a basic research career. He gave me a chance to develop my own ideas in his lab, and with that experience, I gained more confidence that I really could be successful in science. It’s a long road towards becoming a physician-scientist and there was much to learn. I learned a lot from Bob Ashman.

Clinically, I was inspired by Dr. M. Paul Strottmann (58MD, 62R-Internal Medicine), who got me interested in rheumatology. His approach to the patient in helping them deal with seemingly minor things (but really important to the patient), such as buttoning a shirt or walking across the room, was quite a contrast to our dealings with patients as residents up on the medicine wards. As a clinician, I wanted to help patients in the same way.

The environment was also important. Dr. Francois Abboud (61R-Internal Medicine) led a department of physician-scientists so I had a lot of role models to follow. I had many other mentors, on the medicine floors and clinics, and in the research labs. I am afraid of trying to list them for fear of forgetting to acknowledge any one. So I hope they will forgive me and I also hope that they know that each one of them impacted me as a physician and scientist.

How or why did you choose the University of Iowa for your education and medical training?

As a member of the 4th M.D. graduating class at my state medical school, the University of Hawaii, I didn’t have a lot to go on to make a decision for where to do an internal medicine residency. Most of my classmates were interested in primary care or practice since that was the focus of our medical school. Also, most prior graduates went to programs on the West Coast for obvious reasons. However, I had heard that the University of Iowa had an outstanding internal medicine residency program. Since I was interested in a research and academic career, I knew I wanted an outstanding university-based internal medicine program so I applied to Iowa and was invited for an interview!

I was awestruck when I visited the campus. In addition to its physical size, even back then, one memorable experience was learning that University of Iowa Hospitals and Clinics had 3 CT scanners at a time when the entire state of Hawaii had only one! The Chief Resident at the time, Dr. Lynell Klassen (78R-Internal Medicine), now Chairman of Internal Medicine at the University of Nebraska, spoke with me about my prior research experiences and I learned that he had even worked on the same strain of autoimmune mice as I had. No other program asked me about my research work so specifically. I thought Iowa would be a great place to get clinical training and further develop an investigative career in basic research.

I am still grateful to the Department of Internal Medicine for taking a big chance with me and entrusting care of their patients to me. They had no experience with University of Hawaii M.D. graduates and therefore had no idea if I would turn out all right.

What kind of professional opportunities or advantages has your University of Iowa medical training provided?

I received great training at the University of Iowa as well as outstanding mentorship as I mentioned above. In addition, there are many great scientists and physicians at Iowa. They are known all over the world and in turn they know many, many others in academic medicine. When it was time for me to move on, they were all very supportive and helpful in opening doors for me. And then when I had to prove myself at the next stages in my career, I was able to rely on what I had learned at the UI Carver College of Medicine to succeed.

As a graduate of the University of Iowa Carver College of Medicine, what does being the recipient of the Distinguished Alumni Award mean to you?

Iowa has so many outstanding alumni in all aspects of medicine, from practitioners to policy makers, from investigators to industry leaders, from diagnosticians to deans of medical schools, in academia, government, and industry. Just the other day, I was watching a presentation on the web from the Chief Scientific Officer of a prominent biotech company, and I realized that he was a resident with me at the University of Iowa! Thus, I am deeply honored to be considered among the outstanding alumni of the University of Iowa Carver College of Medicine.

Please describe your professional interests.

Scientifically, I have had almost a lifelong interest in the immune system. I retain that interest today, with a focus on understanding how the innate immune system contributes to the immune response to tumors and infections.

As a clinician, I still attend on the medicine service and the rheumatology consultation team. It’s been especially great to see how basic science has impacted clinical rheumatology, particularly since most of the advances have come from the immunology research laboratory.

As an educator, I am particularly interested in training the next generation of physician-scientists. I learned a lot from my mentors at Iowa and elsewhere, and I want to pass my knowledge to budding physician-scientists. And I want to be a good role model for them. I am very pleased that I seem to have inspired my own trainees to pursue rheumatology, do basic research, or enter other areas that I find to be professionally rewarding.

You have been a pioneer in research on natural killer cells and their role in protecting the body from cancer and infections. Your research on the subject has spanned many years. What has kept your passion alive during your research?

It’s actually pretty simple. I find the topic to be very interesting. It might not be that interesting to many others, even other immunologists, but I still find it fascinating. In addition, science is a funny thing. When you think you have the answer, you realize that there are more questions that arise. Other times, you learn something and then realize that it’s the answer to a question you hadn’t yet asked, so then you need to figure out what the question was. It’s akin to the quiz show Jeopardy. It is never ending puzzle.

You have made seminal discoveries in the molecular biology of natural killer cells, have been a Howard Hughes Medical Institute investigator, have published extensively, and were recently elected to the National Academy of Sciences. What would you say your greatest achievement has been?

Certainly, getting into the National Academy of Sciences is probably the most notable since there are only 75 members in the immunology section of NAS. The Novartis Prize is also a great achievement since it is the only immunology-specific prize and is only given once every 3 years at the International Congress of Immunology. I am one of only a couple of investigators who won a Howard Hughes Medical Institute appointment after a national competition then resigned (because I changed institutions) and had to recompete at the national level to get it back! During that time, I questioned my sanity. On the other hand, renewing a Howard Hughes Medical Institute appointment is probably the most daunting challenge, even for Nobel Laureates! Hopefully, I will remain in the Howard Hughes Medical Institute because my colleagues there have inspired me as well. Scientifically, however, I am most proud of my trainees, as mentioned above, and that I seem to have inspired them as well.

But I think my greatest achievement is the success of our own children, Christine and Reid. My wife, Lynn, should get most of the credit but I did contribute 50% of their genes! Christine is a graduate of Harvard University and is now doing post-baccalaureate work at Columbia University. She will be applying to medical school this summer. Reid is a graduate of Stanford University and is now working at Google. Both are native Iowans and were born at University of Iowa Hospitals and Clinics.

What are some of your outside interests?

I have loved photography for almost as long as I have had an interest in immunology. I developed an interest in wildflower photography after taking a class on wildflower identification while I was a resident. More recently, I developed a passion for bird photography; especially trying to capture birds in flight. I am the weekend cook at our home, so I like to try different recipes and dishes, then try to find the wines to go with them. I first learned about wines also while I was at the University of Iowa. Now that we are empty-nesters, my wife and I also like to travel.

Do you have an insight or philosophy that guides you in your professional work?

Actually two simple things. 1) Figure out what you really like to do and are really interested in working on. It’s really hard, maybe impossible, to do very high quality work if you aren’t seriously interested in your work. 2) Figure out what is expected of you. By definition, if you continually exceed those expectations, you will be successful.

What is the biggest change you've experienced in medicine since you were a student?

There are many issues that others have written about, from change in reimbursement to regulatory concerns. However, I find that residents today rely a lot more on imaging and blood tests, and less on information gathered directly from the patient, as compared to what I did as a resident. At our institution, patients often have a CT scan in their chart before they reach the medical floors from the ER! I still think it is vital to make sure that you get a really good history and physical. I learned that at Iowa.

What do you see as "the future" of the medicine?

Clearly, there will be more and more advances in imaging and blood tests; the horizon of gene-based diagnosis and treatments is certainly in sight. Biologic therapies will become more important. We will see more computers in the clinic and improvements in artificial organs, prosthetic devices, and instrumentation for surgical intervention are coming. Some of these things will even be done remotely.

However, I still believe that a physician, a human being, has to speak with the patient, understand their problems, and have the compassion and commitment to advocate on their behalf. And that physician needs an outstanding, fundamental understanding of basic science in order to make sense of the new approaches in the future to help the patient deal with his or her situation. These are the skills and know how that I learned at the University of Iowa, that I use today, and that will never be replaced by better scanners, machines, or DNA tests.