Chapter 05: An Overview of a Research Career
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Description
Here Dr. Mendelsohn provides a synopsis of his work on epidermal growth factor (EGF) and the discovery of monoclonal antibodies up to the point of joining MD Anderson. “Things fell into place between 1964 and 1974,” he says, noting as well that at the beginning of that period, there were no medical oncologists. By 1970, there was a greater understanding of cancer. From research focused on the mechanisms of cell division, some scientists were beginning to think about cancer as a loss of control over cell division. In 1980, during the period when Dr. Mendelsohn was at the University of California-San Diego, he became interested in epidermal growth factors and, in partnership with Gordon Soto, began to see if blocking the binding site for EGF would influence cancer. He explains the mechanism of EGF in tumors and describes the role of tyrosine kinases (one kind of protein that stimulates growth and can become stuck in the “on” position) and how understanding of these processes let to the discovery of monoclonal antibodies that would block the sites where growth factors could bind and stimulate tumor growth. He talks about the first grant proposal he submitted –and how it was turned down (and eventually funded by private money), noting that public grantors are often risk averse and wait until an experimental theory shows promising results. This work was eventually lavishly funded. Dr. Mendelsohn ends this Chapter by explaining that he came to MD Anderson with a laboratory and four grants. However he had to devote all his efforts to the institution and so closed his laboratory –a very difficult action to take.
Identifier
MendelsohnJ_01_20120926_C05
Publication Date
9-26-2012
City
Houston, Texas
Interview Session
John Mendelsohn, MD, Oral History Interview, September 26, 2012
Topics Covered
The Interview Subject's Story - The ResearcherProfessional Path The Researcher Contributions Discovery and Success Discovery, Creativity and Innovation Professional Practice The Professional at Work Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care Cancer and Disease Overview Definitions, Explanations, Translations Business of Research
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
John Mendelsohn, MD:
Between 1963 and 1970 when I was offered a faculty position things fell in place. There were no medical oncologists in 1963. We didn’t understand cancer very well at all. If you wanted to use molecular biology to study cancer, you probably weren’t going to work in a lab of a cancer person. You worked in the lab of a molecular biologist, and I did that. I went to the NIH and worked in a very basic science laboratory in Bethesda. Terrific training. I didn’t know I wanted to be an oncologist then. I knew I was interested in medicine, and I was interested in science. I originally thought I would be a hematologist, because a lot of the laboratory work that was leading to understanding science was going on in hematology at that time.
Tacey Ann Rosolowski, PhD:
You did a fellowship in hematology oncology ’68-’78 at Washington University in St. Louis.
John Mendelsohn, MD:
The main emphasis was on hematology. The solid tumor cancer part was felt to be a trade more than a science.
Tacey Ann Rosolowski, PhD:
Where did that cancer piece come in?
John Mendelsohn, MD:
Around 1970, we began to understand more about cancer. My research at Wash U and my research on my Fulbright Scholarship to Scotland for a year and my research during medical school in the laboratory of Byron Watson, another mentor and role model, was all about what controls whether cells divide properly or not. Just around 1970, people were beginning to think about cancer as a disease where the biochemical mechanisms that control whether a cell divides properly or not were important.
Tacey Ann Rosolowski, PhD:
You said that in 1970 people were beginning to think about cancer as a disease. How did they think about it before then?
John Mendelsohn, MD:
It was a disease where the issue was a loss of the proper controls over whether a cell is dividing by the rules or not. This was thought about before, but it was beginning to be converted into experimental action, and actually that really took off in 1970. In 1970, when I began my own research, it was with white blood cells. It was with lymphocytes. It carried over into my interest in hematology. But again, I made a big career decision change in 1980. I was studying what controls the growth of lymphocytes, and I got very interested in Epidermal Growth Factor and the EGF receptor, which I talked about in length, I think, in that other interview with Dr. Olsen. Lymphocytes don’t respond to Epidermal Growth Factor. But I was working with another wonderful person, who I learned a great deal from; my collaborator in this case, Gordon Sato at UCSD. We generated the hypothesis that if we could block the binding of Epidermal Growth Factor to its receptor on the surface of tumor cells, we might be able to inhibit the growth of those tumor cells, which was a novel hypothesis and really exciting for me and for him.
Tacey Ann Rosolowski, PhD:
How did you come up with that idea?
John Mendelsohn, MD:
I had to change my whole research lab. We came up with the idea by thinking about and looking at new data that was coming out of the journals over a period of about 2 years and integrating that into the background that he had. He was a world expert on growth factors and how they stimulate the proliferation of cells. I’d done a lot of research on lymphocytes, what stimulates them to grow and what stops them from growing, and what are the chemical pathways involved. Today they’re called signal transduction pathways. In the 1970s, the only one that was known was something called cyclic AMP, and I was working on that. There were data that cancer cells expressed high levels of EGF receptors, sometimes a million instead of 10,000. That’s a whole lot more. There were data that cancer cells could make their own EGF and autostimulate themselves. The hypothesis was published in 1980 that cancer cells had uncontrolled growth, because they made their own growth factors and stimulated themselves. In 1979 and ’80, there were publications showing that the Epidermal Growth Factor receptor had in itself a tyrosine kinase, which is an enzyme that phosphorylates tyrosine. In 1980, there were only 2 other tyrosine kinases known. Now there are 500 and many of the new drugs are against tyrosine kinases; back then, one was called SRC, and we knew that SRC could cause cancer in animals, and the other was called a platelet-derived growth factor receptor. Then we put together; okay, there’s this new chemical pathway that involves tyrosine kinases. It’s rare, but one of them, SRC, can cause cancer in mice and Epidermal Growth Factor seems to be a very prominent feature in human cancer, because that receptor is overexpressed on many cancer cells. By the way, cancer cells can make their own growth factor and autostimulate themselves. Maybe this would be a good target. We said, “Let’s target the EGF receptor now.” Neither of us were chemists. We were molecular biologists who knew some immunology. This is where new technology comes in. I was head of the new UCSD Cancer Center, and Gordon Sato and a man named Nathan Kaplan were my 2 chief advisors in science. They were both in the biology department at UCSD, which is fabulous, but they both were passionately interested in cancer, and they worked with me. So there were 2 new technologies. One was making monoclonal antibodies and the other was growing human tumors in mice that are hairless that have an immune problem. Well, we decided we wanted those technologies for our cancer center, so they helped me set this up. Then we decided we’d use those technologies, and we would try to find an antibody that would bind to the receptor for Epidermal Growth Factor. There were other antibodies available that did that, but we wanted to find one that bound at the EGF binding site and prevented the growth factor from reaching the receptor. So we essentially put chewing gum in the lock so the key couldn’t get in. That’s the way we thought about it. We wrote a grant to do that. It was turned down, but we did it with other money and some very hardworking post docs and collaborators.
Tacey Ann Rosolowski, PhD:
Why do you think it was turned down at that time?
John Mendelsohn, MD:
It was felt it wouldn’t work. Once we wrote the 1st paper, the research was well funded by the National Cancer Institute for 15 years, but that 1st grant was turned down. That is not unusual, incidentally. A lot of the pilot work that goes on is done with smaller grants and philanthropy, and the National Institutes of Health, for the main part, are a little risk averse in that they want to see the preliminary data, and they want to know that this isn’t just a wonderful idea but that there’s really some scientific evidence that it will work, which we provided with our first couple of publications. It turned out that we had a good idea and we were lucky. It was luck that Dr. Watson’s lab was opening up and was available to an undergraduate. Everybody else in that lab were grad students and post docs. When I walked in, he was unpacking the boxes. It was luck that my training set me up in a field that was ready to open up, experimental oncology. There was fit. The specialty of oncology first was announced in 1970, right when I finished my training. There were no specialists in oncology then. There were only hematologists. It was luck that I met Gordon and we talked and that we had these resources so we could study the human tumors growing in the mice and show that the antibody retarded their growth. The technology for making monoclonal antibodies was there. But maybe it wasn’t all luck. Luck helps the prepared mind in somebody that’s willing to take advantage of it and work hard.
Tacey Ann Rosolowski, PhD:
Do you have more elements of that story you’d like to put in place at this point?
John Mendelsohn, MD:
A few years later, Gordon Sato went into another field. He wanted to solve the world’s food problems and began to work in that area. I had the fun of continuing working on blocking the Epidermal Growth Factor receptor, the idea that you could target a therapy against the product of a gene that was causing cancer, and that turned out to be a good field to be in. I came to MD Anderson with a lab, 4 grants, planning to continue this research, and I walked into a place that had been told to cut back 50% of its hospital beds and had already cut its budget over $90 million on a base of around $600-$650 million. I didn’t want to do this. Following up another question you asked, I decided, okay, I’ve had a great time being a physician. As my other responsibilities grew, I had to do less and less doctoring. I had a great time doing research and running a department at Sloan-Kettering. Now it was time for me to put fulltime into the institution and work to make other people famous and to make this institution a success, so I closed my lab. That was hard. I brought researchers with me. I handed them my grants. I wrote the NIH and said, “So-and-so is taking over this grant, and so-and-so is taking over that grant.” I wished them well and turned my attention to MD Anderson.
Recommended Citation
Mendelsohn, John MD and Rosolowski, Tacey A. PhD, "Chapter 05: An Overview of a Research Career" (2012). Interview Chapters. 1421.
https://openworks.mdanderson.org/mchv_interviewchapters/1421
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