Dr. Oliver Bögler, Vice President, Global Academic Programs, The University of Texas MD Anderson Cancer Center, and Chair of the NBTS Scientific Advisory Council conducted the below telephone interview with Dr. Brent Reynolds to discuss perspectives on the Systems Biology approach to cancer research.
Dr. Brent Reynolds received his PhD in 1994 from the University of Calgary during which time he and Dr. Sam Weiss discovered the existence of a stem cell in the adult central nervous system, challenging a century old dogma that the adult brain was unable to produce new neurons. He co-founded NeuroSpheres Ltd. where he was Vice-President of Research and in 1999 published the first report on the trans-differentiation of cells derived from one germ layer into functional cells of another germ layer.
Professor Reynolds holds 18 US patents related to neural stem cells and his lab is currently focused on the development of stem cell specific assays, in situ manipulation of neural stem cells and understanding the role that solid tissue cancer stem cells play in tumor initiation and metastasis. Recently from Australia’s Queensland Brain Institute Dr. Reynolds lab is at the William L. McKnight Brain Institute of the University of Florida.
A Conversation with Dr. Brent Reynolds
Dr. Oliver Bögler
Thanks for making time for us. I know that your background is heavily in stem cells. You were one of the co-discoverers of adult neural stem cells and you've made huge contributions in that area. Can you tell us about what kind of systems biology you've brought to this area so far?
Dr. Brent Reynolds
This is something that my lab is just getting started with and is a departure from our previous work on neural stem cells. A few years ago, we began to realize that many of the assays, methods, and technology we had developed for studying somatic neural stem cells could be used for studying “cancer stem cells.”
Our foray into systems biology is an interesting story and came about with a diversion from academic science. I had about a seven-year hiatus from doing western science, going back to school in ’97 and earning a degree in oriental medicine. For several years I practiced Chinese medicine in Canada and opened a yoga center in Thailand. Both Traditional Chinese Medicine and yoga take a global perspective of the body and view disease as a disharmony that occurs in many systems of the body. The approach to healing is highly individualized requiring treatment and balancing of multiple body systems, including those not directly affected by the disease. This is the foundation of today’s reinvention of systems biology, or personalized medicine, which borrows a lot from the principles of some of the ancient traditions, like Chinese and Ayurvedic medicine. Here a problem is viewed not from a reductionist perspective but rather from a perspective of the entire organism, because every time you poke something you're going to get a reaction to that poke. There is going to be communication between the different organ systems, feedback and some form of compensation. It was this thought pattern, together with our neural stem cell background, that started us thinking about how to look at tumors from a non-reductionist point of view and envision it as an ecosystem with many related and interconnected elements that influence each other. Basically, you cannot understand the tumor by solely understanding the individual elements, additionally you must understand how the elements work together – in other words the whole is greater than the sum of its parts.
How we started also happened in a strange way. I had just moved from Australia to the University of Florida and within the first week of arriving a 15 year old girl came to my office and said, “I have these nano particles and I want to target cancer stem cells in the brain.” She had been working at the Nano Institute for about a year and has now been in my lab for close to 3 years and is making great progress. This chance meeting however led to me meeting her father who is a faculty member in the Ecology Department. We started talking and realized that a lot of the terminology and approaches that an ecologist uses to manage wildlife populations could be used to approach tumor populations.
For example, a wildlife biologist goes to the field and collects data on birth and death rates. He measures viral loads, bacteria loads, and looks at white blood cells to see how fit that population is. He’ll look at the predators, and the food supply, and from that he is able to get an idea of how he can help manage that population, either to increase or reduce their numbers. We just started substituting the term tumor cell in place of the species he was talking about. I can look at birth and death rates. I can look at the fitness of the cells by measuring signaling pathways that are activated. I can measure and control reagents that cells use to grow and stay healthy, like growth factors or metabolic reagents. And, I can look at predators just like he looks at predators. However, in our case predators are things like radiation and chemotherapy.
So this is what started us thinking from an ecological point of view looking at tumors and asking the question, "Could we apply the principles of ecology to tumor biology? And if so, could we learn how to manage that population?"
At the end of the day, the more we understand about tumors the better we will be able to control and manage them and I am extremely optimistic that this will happen and convinced that it will come about as the result of strong molecular and cellular biology. However, when it comes to cancer and the complexity of solid tissue tumors, as well as how multifaceted they are in how they interact with the rest of the body, this is not something you and I are going to completely understand in our lifetime, our grandchildren’s or even our great-grandchildren’s. And so the question remains, “With the limited amount of information we currently have can we learn how to control cancers?” I would argue the answer is yes. If ecologists can manage or control an animal, insect or pest within a complex ecological system, even though they don't understand everything about how that system works, then we can certainly learn to control or manage a tumor population without needing to know everything about how a tumor functions.
Dr. Oliver Bögler
That's very encouraging because most of us are reductionists and feel like we need to know every little detail. So I hope you're right.
Dr. Brent Reynolds
Well, I think that approach is like anything. The more you understand, the better the chance you will get the result you want. But what frustrates me is the time it is going to take to get there, especially for those who suffer from cancer and their families. I don't think we're going to see it in a hundred years, just because of the complexity of the problem. While western science has made amazing progress in the last 50 years understanding some of the very basic subcellular elements that define abnormal proliferation, we have very little understanding on how each of these elements work together and how on a cellular level communication and adaptation occur.
Dr. Oliver Bögler
I think that's a very good point. Looking forward, are you planning on doing some systems approaches? Is that something that's on your plans?
Dr. Brent Reynolds
We’re starting to look at tumors from a complex adaptive systems approach and can draw an analogy between a tumor and a simple, yet complex society, like an anthill. For instance, you look at large anthills that are meters high and it just looks like a mass of dirt, totally unorganized. But when you look within the colony it’s highly organized. And when you look at who gave rise to that apparent mass it’s individual ants.
Now, each of these individual ants or agents work independently, yet as a group they work collaboratively. They have a simple repertoire of behaviors, but they're actually able to create a very complex bio system. And the analogy to the tumor is similar. When you look at a tumor it looks like this mass from the outside. You do histology on it and you start to see it is actually very well organized. And you look at who gives rise to the tumor; well, it’s a whole bunch of individual cells or agents. While the individual cells appear to be acting relatively independently they may very well be acting collectively. And the repertoire of behaviors that an individual cell has is, like an ant, somewhat limited.
Complex adaptive systems can be seen absolutely everywhere in the world. You see them in insect colonies, the brain, immune system, and the stock market. People are even suggesting that things like Twitter and Facebook may be developing into complex adaptive systems. A defining characteristic of a complex adaptive system is the absence of a leader. There is no master plan. There is no one directing where things go. But what emerges from the interaction and communication of a large number of individual agents is a robust complex adaptive system or society that collectively develops, in essence, intelligence.
From this perspective, we are investigating the fundamental properties of these systems, how tumors use these properties to evolve and adapt to their changing world and ultimately to short circuit the ability to adapt and evade the predators we subject them to.
NBTS would like to thank Dr. Reynolds for sharing with us his time and thoughts about systems biology and how it applies to brain tumor research.