There were not nearly so many hurdles to negotiate [when conducting research] in those days.… The laws today that are designed to protect patients, although made in good faith, are amazingly constrictive, making it difficult to launch innovative research efforts.
—James F. Holland, MD
James F. Holland, MD, began his journey into oncology when it was still a nascent discipline, working alongside groundbreaking pioneers in the field such as Drs. Emil “Tom” Frei and C. Gordon Zubrod. Dr. Holland recently shared a glimpse of his role in oncology’s formative years with The ASCO Post.
Please describe the scientific atmosphere when you joined the NCI in 1953.
In a word, it was exciting. B-12 had just been synthesized and found active in microgram quantities, which was new for a drug. The very day I joined the NCI they brought over artistic paintings and drawings made by volunteer sailors who had been given LSD, which was also active in microgram quantities. This program was designed to answer an array of psychiatric questions, because investigators could artificially induce psychiatric abnormalities and study them.
Up until then, the NCI had locations across the country, but when the Institute was centralized on the National Institutes of Health campus, it generated an intense atmosphere of collective scientific research. Being in the lab next to other equally enthusiastic researchers inspired many fruitful collaborative ventures that changed the course of oncology.
New Era in Chemotherapy
What led you to that early place in oncology?
When I arrived at the NCI, Dr. G. Burroughs Mider, who was the acting Clinical Director, introduced me to Lloyd Law, PhD, who had shown that in leukemic mice a combination of drugs given at the same time was better than when given in sequence. Dr. Law and I became wonderful friends, and I learned a lot about science from him. So I continued research in combination therapy, and when it became clear that mercaptopurine and methotrexate were two clinical drugs that were active in childhood leukemia, I put together a protocol with Dr. Law’s approbation.
Dr. William Newton, of the Children’s Hospital in Columbus, Ohio, and I were the first researchers to give those two drugs in combination. The strategy was based on the concept that about one-third of patients responded to methotrexate and about one-third responded to mercaptopurine, so theoretically, 1 in 9 might be sensitive to both and conceivably achieve a cure. It was the beginning of a new era in chemotherapy.
Origins of Cooperative Group Research
Please share your experience as a member of one of the country’s first collaborative trial groups.
After I left the NCI for Roswell Park, Dr. C. Gordon Zubrod recruited Dr. Emil Frei, and the three of us established a continuing collaboration. We published the first collaborative oncology paper in the United States, which appeared in Blood.1 Following that, the Cancer Chemotherapy National Service Center (CCNSC) was established under the impetus of Mary Lasker, led by Dr. Kenneth Endicott, who later became Director of the NCI. It set up a network of cooperative clinical trial groups that evolved across the country under the auspices of the NCI.
I. S. Ravdin, MD, who had operated on President Eisenhower, was appointed Chairman of the CCNSC clinical panel. He boomed, “I don’t know anything about chemotherapy, but I know how to knock men’s heads together!” And he did.
We used to meet every other month or so with Dr. Ravdin to discuss what kind of clinical research program would be best for the country. One day, Dr. Zubrod stated that the British Medical Research Council had generated a clear treatment program for tuberculosis using a collaborative clinical trial to come up with answers. Setting up cooperative clinical groups seemed like a good idea. Acute leukemia was one of the best malignancies to study because two effective drugs existed, and cancer cells in the peripheral blood and marrow gave ready access to the tumor. The emotional impact of dying children was also a factor.
At the time, Dr. Joseph Burchenal was senior to everyone us, so he got to be Acute Leukemia Group A (which became the Children’s Cancer Group) and Tom Frei and I got to be ALG-B. We recruited investigators from the United States, Canada, and Europe, making ALG-B an international organization. This brought in huge numbers of patients. The first cures of childhood leukemia in multi-institutional trials were achieved in the ALG-B using high-dose methotrexate.
Winning the Lasker Award
What was it like to accept the Lasker Award, which has become one of the nation’s most prestigious prizes in medical research?
First off, I am a strong believer that Mary Lasker was this country’s most important person in cancer research. She felt that cancer awareness needed a boost, so in 1972 the Lasker Award was given to clinicians who made progress in treating cancer. About 18 of us won the Lasker; Tom Frei won for Hodgkin disease, and I won for acute leukemia. It was a $2,000 prize, which was big-time money then.
Actually, I wasn’t there to receive the prize. During the Cold War, Richard Nixon and Leonid Brezhnev tried to put aside the notion of dropping atomic bombs on each other and agreed that finding a cure for cancer would be mutually beneficial. So Brezhnev said he would send a scientist with his family to the United States, and we, in turn, should send a counterpart family to Russia. Dr. Zubrod enlisted me and others to find a candidate, but no one wanted to go. I was leaving Roswell Park at the time, and after the third call from Dr. Zubrod, I asked my wife Jimmie, how about us? She said okay, and off we went with our six kids. I missed the Lasker ceremony, but we had an extraordinary experience for 7 months in the Soviet Union.
Then and Now
What is the central difference in the research atmosphere between the 1950s and today?
Put simply, there were not nearly so many hurdles to negotiate in those days. My colleagues and I were motivated to cure childhood leukemia, and when we had a good idea, we acted on it. We were freewheeling, but always ethical.
The same motivation exists today, but the research process has been frustrated by excessive paperwork and multilevel bureaucratic review. The laws today that are designed to protect patients, although made in good faith, are amazingly constrictive, often making it difficult to launch innovative research efforts.
Tell us about your current schedule.
I see patients all day long on Monday and Thursday. On the other 3 days, I interact with my laboratory colleagues. We are deeply engrossed in the research that I’ve pursued for 20 years, exploring a virus in human breast cancer that is a “kissing cousin” of the mouse mammary tumor virus, the causative agent for breast cancer in mice.
Forty percent of American women who present with breast cancer have this virus in their tumor, but not in the normal tissue of the same breast, which thus excludes genetic inheritance. It is acquired. We are working hard to fulfill the criteria that will prove the virus is indeed the cause of these breast cancers. It keeps me busy and out of trouble. ■
Disclosure: Dr. Holland reported no potential conflicts of interest.
1. Frei E 3rd, Holland JF, Schneiderman MA, et al: A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood 13:1126-1148, 1958.