Chapter 09: The World's First Cancer-Directed Department of Systems Biology Emerges from a Shift in Approach to Cancer
Dr. Mills begins this chapter by explaining that as cancer research evolved in the nineties, it became clear that the usual "reductionist" approach to studying molecules was insufficient and he and others decided to found what turned out to be the world's first cancer-directed Department of Cancer Systems Biology. Dr. Mills explains the shifted mindset reflected in this department and its research.
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Tacey Ann Rosolowski, PhD:Does that make -- I don't know how to ask this question. I've been struck by how rapidly fields change. I mean as I talk to folks like you, involved so deeply in research and you know, I've been struck with the need for people to remain kind of very mentally flexible or be passed by. Is that true? How does that have an impact on departments? You kind of understand the area I'm trying to get into here.
Gordon B. Mills, MD, PhD :One of the things that you see across academia is that you have fairly rigid boundaries between different areas, and those are really detriments. So, someone who trained as an immunologist may be stuck doing immunology, even if their interests change, because they're in a department of immunology, where you have to teach immunology and you're seen as an immunologist. Similarly, molecular biology and the rest, and that can be restrictive. The MD Anderson Cancer Center, to a degree, because we don't teach undergraduate education and have to retain those particular boundaries, there is a much greater opportunity for flexibility. That flexibility on the basic science side is really quite striking. It can be a little more problematic on the clinical side, where someone for example, is in a department of breast medical oncology and their interests and concepts then change to where studying brain cancer would be most appropriate for what they're doing. You then have an intrinsic stress of where they are located, who they are working with, the potential lack of critical mass that would help them move forward, and so we have a bit of a mixture of both. The flexibility and the ability to change is critically important. Indeed, my career has changed massively. I started off as an immunologist in biochemistry and trained and worked on tumor immunology, which has now come to the fore, but that was over forty years ago now. I then evolved because of a move to Toronto, and where things were going into a joint program on the tumor biology of ovarian cancer and tumor immunology, or immunology in general. I moved here and became very much more of a molecular biologist, focused on initially, ovarian cancer, but at the request of Mickey LeMaistre saying that our ovarian cancer program has grown and matured to the degree where we had a SPORE, a P01, multiple R01s, top level investigators in the area. He asked if I could help build two different programs. One was our clinical cancer genetics program, which needed additional support and work, and the other was to help take our breast cancer program to the same level that the ovarian cancer program was, and indeed, we then took the breast cancer program to where we had a DoD program project grant, an NIH program project grant, and a SPORE grant. Again, all of those cases, in all of those cases, I was not the leader of any of those grants. My job was to help them happen, the concept of collaboration and support.
Tacey Ann Rosolowski, PhD:What was your strategy? I don't know if you want to talk about one of those programs of if you want to go back.
Gordon B. Mills, MD, PhD :Well why don't we finish off the department evolution first, and then we can go back.
Tacey Ann Rosolowski, PhD:Sure.
Gordon B. Mills, MD, PhD :So, at the time that Garth Powis arrived, the confusion that had arisen over a department of experimental therapeutics and molecular therapeutics, and how they were different, had really come to the fore. Indeed, this is a problem in many cases across MD Anderson, or a challenge perhaps. When we had a Department of Biochemistry and Genetics, if you were to ask individuals, they couldn't tell you why they were in which department. Both of them were focused primarily on genes and development, and there really wasn't much of a distinction and indeed even today, if you were to go through all of the faculty at MD Anderson, from the outside, and say why, with the work they do, are they in this department versus that department. Not are they appropriate for this department, but why specifically that department. You would have great difficulty answering that question; it's the convergence of so many different approaches. So at that time, it had become very clear that the approaches that we were using, basically reductionistic approaches of studying molecules one at a time, in depth, was not going to be sufficient to help us understand the true complexity of what was going on in cancer, and that we needed a much more integrative program. We looked aggressively across all of the different areas and groups and really decided that we needed to develop an integrative biology or a systems biology department, to capture that unique opportunity of linking an integration of information across many different areas. A mathematical model building part that comes to be integrative, or systems biology. Now, at the MD Anderson Cancer Center, integrative biology or integrative care, has really been used quite extensively to refer to alternative therapeutic approaches. Things like medicines that have come out of China, and we needed to have a title that clearly separated us from that particular area. So, of that point, it became clear that systems biology or cancer systems biology was the appropriate terminology, and so we decided again, to make sure that it was separate from some of the other groups and had a clear identity, on the term and name Systems Biology. This was the first cancer specific or cancer directed Systems Biology Department in the United States, and as far as we can tell, in the world. This really was built very much around the concept that we needed to go beyond the reductionistic, one molecule at a time, to make progress. Now, I want to emphasize systems biology builds on that reductionistic approach. It's not that that's bad. It's a great and necessary step. This is to add a layer on top of that and stand on sort of the shoulders of the incredible work that has been done elsewhere and is still being done here. And so that's what we built and I think it has been highly successful. It is recognized nationally and internationally as the first and one of the best, cancer systems biology departments.
Tacey Ann Rosolowski, PhD:Can you give me a window into that process, because I mean, so you're looking around and what are you seeing in terms of the landscape? Is it a mixture of people taking a more reductive approach and people experimenting with other things? How did you begin to bring together this new approach?
Gordon B. Mills, MD, PhD :So, if we were to perhaps give you a little flow to this, I had spent years and as many of my colleagues had spent years, what we call drawing arrows. Molecular A affects molecule B, molecule C is affected by both A and B. That is necessary and it's critical, but it becomes clear, when you start adding three or four of these, that you simply can't understand that by drawing arrows. Linear arrows are not how biology works. Biology works by some key pathways, no question, but with massive amounts of modifiers, feed forward, feedback regulatory loops that allow the cell to perceive its environment, and then to process an incredibly complex amount of information and give the appropriate functional outcome. That integrative process of all of these things coming in, really was not understood and when I started basically --and I use this slide still when I teach this to students-- we had this idea that cells perceive their environment and they had an outcome of what they would do. We simply, at that point in time, drew what was called a black box in the middle. That black box was clearly perception, integration output, but we had no idea what went on in that box. For many times we thought, in again a reductionistic manner, that it was one or two key events. Whether it was calcium changes, which I studied for years, protein kinase-C, that was thought to be the key integrative molecule of this process, and clearly, that's too simplistic. No one thing can allow interpretation of a complex environment. And about that time, we developed the pathways and the processes that integrate that information, but when you draw them, there are so many arrows and diagrams that it's again, back to being a black box, because it is incomprehensible. There's just too many things that the human mind cannot deal with all of them at once, and how that integrates. So, about that time, we decided we needed to do something different, and the goal is, is can you then build mathematical models of those processes that allow you to understand how that information is integrated into the appropriate response. The piece behind that is, if I can understand that, and I can understand how it went wrong in cancer, we have the potential then, to target the processes in a much better way of saying I love this molecule because I've studied it for my whole life, it must be the target that is critically important, and maybe it's not because it's not the key integration point or it's not rate limiting. So the idea was to get away from our favorite molecule, to a process oriented concept. There's another way to describe systems biology. What we do most of the time in reductionist science could be alluded to as studying the brick, a brick in great detail. Is it red, is it heavy, is it light, is it porous, and understanding every possible aspect of a brick. But by understanding that, how do you understand what a house looks like, and even more importantly, how a house is a house or whether a house is a home. Take this a little further along and perhaps even the better way of dealing with this, where it is very challenging, is to say well, go to a Roman ruin, when you have a pile of rubble, and that's our understanding of how the cell is and what it works. So we've got this pile of rubble. Now how do you take that and put it back together to get a building? This is what Schliemann tried to do and in some of the things he built, where they were just completely wrong. It is absolutely clear now that what came out of this had nothing to do with what was there. But the real challenge is, is not to reconstruct the building, but from that pile of rubble, figure out what the culture was, and that's what we're trying to do in systems biology. By having enough information on the pieces, those little blocks and bricks, to start to understand not just how they come together physically, but how they interact conceptually to go from the bad illusion here, a house to a home, which is a totally different process, but that's where as good a description as I can come up of, of what systems biology is.
Mills, Gordon B. M.D., Ph.D. and Rosolowski, Tacey A. Ph.D., "Chapter 09: The World's First Cancer-Directed Department of Systems Biology Emerges from a Shift in Approach to Cancer" (2016). Interview Chapters. 68.