Chapter 05: From Immunology to Targeted Therapy; More Observations about Team Science; Research on Interleukin-2 About 16 minutes

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Chapter 05: From Immunology to Targeted Therapy; More Observations about Team Science; Research on Interleukin-2 About 16 minutes

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Dr. Mills talks about the evolution of his work once he took a position in the Department of Immunology (Hospital for Sick Children University of Toronto, Toronto, Canada, 1/1982- 1/1985) where he shifted his perspective from immunology to signal transduction as a therapeutic target. He describes his promotion track leading to his final role as Director of the Department of Oncology, Oncology Research (1/1990-1/1994). He talks about his relationship with Lou Siminovitch with whom he would discuss management and team building issues. He talks about team science in the biological sciences in the early nineties, explains that the system of allocating grant money influences how science took shape, and gives a definition of translational research. Next, Dr. Mills talks about research he conducted "at the interface between breast and ovarian cancer." He talks about studies he conducted during his PhD program looking at how IL-2 could regulate leukocytes, leading to clinical trials targeting pathways regulating a novel growth factor.

Identifier

Mills,GB_01_20160505_C05

Publication Date

5-23-2016

Publisher

The Historical Resources Center, The Research Medical Library, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - Professional Path; The Researcher; The Administrator; Leadership; On Leadership; Mentoring; On Mentoring; On Research and Researchers; Business of Research; Understanding Cancer, the History of Science, Cancer Research; Overview; Discovery and Success

Transcript

Gordon B. Mills, MD, PhD :

In Toronto, a number of things happened. As I mentioned, I did my postdoctoral fellowship with a wonderful group of people at the Hospital for Sick Children. I then accepted a position at the University of Western Ontario, to continue my interest in the fetuses and allograft, in a Department of Obstetrics and Gynecology, but that position never happened.

Tacey Ann Rosolowski, PhD:

Oh, okay.

Gordon B. Mills, MD, PhD :

The department chair came to me one day and said, "I need to come see you," which was a ninety mile trip for him, and that can never be good. He came in and he said, "The lab that I promised you will not be available for two years. You can do whatever you want, we'll pay you, you can do a sabbatical, but you're not going to be able to take up your position now. We still want you." So all of that was good, but in reality, one cannot take two years off, and that meant that I needed to look for a position, and I found a very nice position across the street, at the University of Toronto Hospital or University of Toronto and the Toronto Hospital, and that ended up leading much more to my interests in signal transduction as a therapeutic target and was really the beginning of a move from a strictly immunology lab, into a combined immunology, targeted therapy program.

Tacey Ann Rosolowski, PhD:

And so this was, the year was 1989?

Gordon B. Mills, MD, PhD :

No.

Tacey Ann Rosolowski, PhD:

No, 1985.

Gordon B. Mills, MD, PhD :

Eighty-four, eighty-five, in that area. And a couple of things happened in that process that also became very important for learning how to lead a group and manage people. Two things happened. The first one is, is that the group that I worked in had a completely open laboratory system, meaning that we shared everything, and I was the only essentially full-tine researcher. I actually did not see a patient for seven years, in order to get my research laboratory up and running at the level that I wanted it to be, and that meant that I became very much the de facto coordinator of how one would make an open lab team science approach work. During that time, my boss came to me and said, let's make this formal, and so I became the Head of Oncology Research at the Toronto Hospital very early on in my career, and basically had a group of nine hematologists working for me.

Tacey Ann Rosolowski, PhD:

That was 1990. Yeah, I noticed that.

Gordon B. Mills, MD, PhD :

That's fairly early.

Tacey Ann Rosolowski, PhD:

Yeah. No, I did notice that, yeah.

Gordon B. Mills, MD, PhD :

That very much continued to push my direction from pure immunology, into translational aspects of immunology, and a signal transduction program. One of the other things that happened during that time is that Lou Siminovitch, who was the head of the research institute across the street and to a degree had been the main competitor for my postdoctoral supervisor, who ended up moving out of town, took an interest and spent a lot of time talking about how to manage people, manage departments, manage groups, and I think probably did more to help me understand how one works to evaluate and build and maintain a team. He had no reason to do so. I did collaborate with his daughter, who was one of the scientists at the time, but this just became a very, I think powerful and great relationship. We met for breakfast, I would say once a month, and every time I go back to Toronto now, I still meet with him, usually for breakfast but sometimes for lunch or dinner. It just really added another level of here is why you would do things, what you would do, and again, the idea of paying forward. There was no reason for him to do anything to help me, none whatsoever. I was in a competing institution, I did not work with him, and so it was again, a very powerful learning experience.

Tacey Ann Rosolowski, PhD:

Now, let me ask you, because I mean this is quite a while ago. I imagine, you know, as team science is becoming more and more -- people are recognizing that this is the way that certain research has to happen, but I imagine there was also kind of a lack of formal information about how you make it happen. So these breakfasts and drinks in the bar and lunches, where people shared this information, was kind of the way people were figuring out how to do it. What was the state of team science at the time?

Gordon B. Mills, MD, PhD :

Very simple, there was none.

Tacey Ann Rosolowski, PhD:

There was none.

Gordon B. Mills, MD, PhD :

Everybody was recognized for what they did in their lab as a group and really, the concept of doing more and going beyond that, was something that really was not happening at that time. It just was not something in the biological sciences that was really even being discussed at all. However, there was a component in the Canadian system that is important, and that is, is that the grants and the amount of money that was available is much less than that in the American system, and that meant in order to bring projects to completion, you had to interact and collaborate with others. There were no labs with fifty and sixty people, which I saw almost in shock, when I came to the American system, and further that again with spreading money around, which is how the Canadian system worked, forced collaborations and interactions. We weren't calling them team science, we were calling them collaborations. To a degree, it was a variant on team science, but not really quite there. It's a transition where you would have two or three labs work together, that would change, and you might alternate who was last author or first author, but it was not really a formal building of teams that would cross boundaries. I think that started in my career, through interactions with Joe Gray, after I moved to the MD Anderson Cancer Center. I would say that he is probably even more of a proponent for the concept of team science than I have been, but this is someone whom I collaborated with when he was in San Francisco, Berkeley, and now in Portland. It didn't matter that he wasn't here physically. We built a collaboration where we would alternate papers, where we would share concepts, postdocs, ideas, and started the concept that you really do need to have broad teams to make progress as efficiently as we can in the current environment. I think the team science concepts are much more driven by translational research and patient care, where you are trying to say my goal is to make a difference for patients and patient outcome, in the near future. That really does require a much more team orientation than, I'm trying to improve basic science knowledge, which can really be done in a different environment. And I do not want to imply that one is better than the other. The individual who builds that knowledge base by deep, consistent study of a specific area, is what the team science builds on. These are not diametrically opposed, it's not that one is better than the other; it is that certain people are ideally suited to one, certain people to the other, but that translational area, I think really demands the team science concepts much more broadly than some of the basic science areas.

Tacey Ann Rosolowski, PhD:

Just for the record, how do you define translational science or translational research, because I've gotten a lot of answers to that question.

Gordon B. Mills, MD, PhD :

People have asked me, how do you define systems biology, and I will say that it's a little bit like one of our Supreme Court judges, "I don't know how to define pornography, but I know it when I see it." And I think that that is very much where we are in a definition of translational science. I think it really is a concept that says the direct goal, not the long-term goal, of the program, is to change patient outcomes. So, a basic science program that discovers a new area such as the identification of CRISPR as a new tool, is not designed to directly impact patient outcomes, but is going to have an incredible impact on how we do that. That's the type of research where you say curiosity research eventually could have an incredible impact, but it's not directly aimed at altering patient outcomes. Translational research says the goal of this project is, within a reasonable period of time, to change how we manage patients.

Tacey Ann Rosolowski, PhD:

I like that. So, Toronto Hospital, and the evolution of your research with signal transduction.

Gordon B. Mills, MD, PhD :

My interest, as an obstetrician and gynecologist, in cancer, had always been ovarian cancer. It became clear, during some of that process, that ovarian cancer and breast cancer were related, and that by studying one and comparing to the other, you could learn a lot more. And so I became more and more at that interface and further, with my interest in immunology and being head of what in essence here, would be a department of hematology, that continued my interest in liquid tumors and in the immune aspects. But it came to the point where we were doing more and more around ovarian cancer, the immune system and ovarian cancer, and how those worked together to result in what was happening to patients.

Tacey Ann Rosolowski, PhD:

What kinds of studies and what were the impacts on patients?

Gordon B. Mills, MD, PhD :

Well, so one of the things that I did very early in my career was to identify interleukin-2, LAKs, and TILs, which very much, through development by others, became a method of management of melanoma, renal cell carcinoma, and is still beginning to see its major application in terms of tumor immunology and immunotherapy.

Tacey Ann Rosolowski, PhD:

You mentioned two terms there. You said identifying interleukin-w, LAKs and TILs.

Gordon B. Mills, MD, PhD :

L-A-K-s, and T-I-L-s.

Tacey Ann Rosolowski, PhD:

And just, can you give me the layperson’s definitions of those?

Gordon B. Mills, MD, PhD :

These are tumor infiltration lymphocytes and lymphokine activated killer cells, which is where the interleukin-2 came from. There were many people involved in this and in no way would my name be attributed to that, other than by a few in the field, but it was something that we had done.

Tacey Ann Rosolowski, PhD:

[01:-07:15] What was the piece that you contributed to this work?

Gordon B. Mills, MD, PhD :

We worked on what became one of the key regulators in the immune system inerleukin-2, before it was even called interleukin-2, and identified, along with others, its ability to activate and promulgate the growth of lymphocytes, and that it was a key regulator. There are now many other interleukins, but the fact that this was number two meant it was very early on in the process. That was when I was a graduate student, and continued to characterize how interleukin2 worked, how it stimulated the T-cells and how they perceive their environment, and to a degree that continues to be used in how we now are attempting to trick the immune system into attacking tumor cells. And then the other aspects of what I did was identification of a novel series of growth factors that play a major role in progression and growth of tumor cells, and those have now led to criminal trials, targeting those pathways both in cancer and in acute macular degeneration, which is a related disease, because both require angiogenesis and new blood vessels. Those trials are still ongoing and that, I think linking all of that to ovarian cancer came to the point of where I was recruited here.

Tacey Ann Rosolowski, PhD:

Tell me about that.

Chapter 05: From Immunology to Targeted Therapy; More Observations about Team Science; Research on Interleukin-2 About 16 minutes

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