March 2005
Over the past decade, researchers have reported tremendous progress in studying head and neck cancer, an umbrella term for tumors of the mouth, nose, throat, larynx, and salivary glands. Much of this success owes to technological advances that have largely rendered obsolete the once familiar laboratory cliche: “One gene, one graduate student.” Today, graduate students and their mentors study the expression of thousands of genes or hundreds of proteins at a time, providing a far more detailed molecular snapshot of life inside a tumor cell. But a new and significantly more challenging scientific opportunity awaits called systems biology. It teams biologists, engineers, mathematicians, and computer scientists to tackle the next big issue in cancer research: Biocomplexity, or how the millions of molecules inside our cells are organized into vast protein networks whose collective whole is greater than the individual parts. Recently, the Inside Scoop sat down with Silvio J. Gutkind, Ph. D., an NIDCR scientist and a prominent figure in head and neck cancer research, to discuss systems biology and its likely impact on the field.
Scientific progress emerges from two main factors: a guiding vision and technological advances to pursue that vision. You started studying head and neck cancer in the mid-1990s. What was the guiding vision then?
It was a reductionist vision. The idea was the whole of a living system can be understood by studying its individual parts. That meant identifying the subset of genes and proteins that malfunction to trigger head and neck cancer. This so-called “mechanistic” approach was conceived in hopes of targeting these weak links in the system, fixing them, and eradicating the cancer. Researchers refer to this as “molecular medicine.” Technological advances over the last two decades in particular have allowed tremendous progress in pursing this dream of molecular medicine. We’ve identified many genes and proteins that clearly play a role in head and neck cancer. But it’s also become clear that this reductionist vision, while certainly vital, has its limitations. Our cells are tremendously complex, and, to truly understand their dynamic behavior, one must not only understand the workings of the individual parts that tend to malfunction but how these parts are organized into an overall system.
You're referring to systems biology, is that correct?
Right.
What is systems biology?
Well, systems biology is more a realization right now than a standard definition. As I mentioned, the last few years have seen a remarkable number of technological advances, among them the ability to read the expression of not one but thousands of genes and hundreds of proteins at a time. These comprehensive readouts of cellular activity have seeded the recognition that our cells are far more dynamic than once thought. We need to know how the parts are integrated into a system and how, in a sense, the whole becomes greater than the individual parts.
Will systems biology be the guiding vision for future research on head and neck cancer?
Systems biology certainly will be one of the guiding visions. No doubt about that. But I think we need to integrate its possibilities with the strengths of our current mechanistic approach to the problem. We know cancers arise from a series of alterations in our genes, we know these changes lead to a growth-promoting breakdown in cellular communication, and we know a fair amount about the biochemistry of some of the proteins involved. What we don’t understand well is the bigger picture. How all of these molecules fit together to form highly complex, functionally interconnected networks, with multiple inputs, outputs, and parallel processing of information. How our cells process this flow of information is extremely complex, and systems biology will allow us to begin to penetrate this complexity.
How so?
Let me give you an example. Healthy biological systems are extremely robust. By “robust,” I mean the networks within the system are adaptive to changes in their environment, allowing them to switch gears when stressed and essentially keep going. I think what happens in cancer is some of the networks in our cells lose their robustness, become unstable, and malfunction. When we get a better handle on why these protein networks might malfunction, that’s where I see our mechanistic understanding of protein interactions complementing systems biology, just as a right and left hand complement each other. The two approaches will provide the needed macro and micro-level understanding of what goes wrong and exploit this information to point the way to more effective preventive strategies and treatments modalities.
Does this mean future generations of cancer drugs will be developed to fix networks, not necessarily to kill tumor cells, as is the case now with most chemotherapy drugs?
Yes. Let me give you another example. Molecular biologists often talk about “signaling pathways.” They’re referring to multiple proteins aligned in a theoretical row that produce a sequential set of linked chemical reactions that process and propel a signal from the surface of the cell to its nucleus. From this perspective, the imperative is to understand the mechanistic breakdown. Why does the signal not get through? Which proteins are the guilty parties? From the perspective of a system’s biologist, it’s not that simple. Pathways exist but they are relatively short units, or modules, within a greater interconnected network. Getting back to the idea that the sum is greater than the individual parts, a systems biologist would posit that by virtue of a network’s interconnectedness, or strength in numbers, the whole possesses “emergent qualities” that none of the connected modules have in isolation, such as robustness. Thus, one must factor in how these emergent qualities influence the behavior of pathways.
So, back to your question. We already have uncovered key pathways that are involved in various head and neck cancers. We’ve seen in preclinical models that these pathways can be targeted rapidly and lead to the collapse of experimental tumors. Why? Tumor cells seem to become addicted to certain pathways to fuel their aberrant growth. But it’s also clear that systems biologists are correct - it’s not that simple. The network influences its constituent pathways.
But if we're talking about cells as complex systems, how much of the complexity must be known before researchers can attempt to repair, say, a single defective network?
That’s actually a critical point. You don’t have to wait until the perfect blueprint of each and every cellular network has been completed to help people with cancer. Even as these processes emerge, one by one, you can begin to look at the network and try to determine the key events that drive the cancer process. What do these networks become dependent on? Then you can ask the simple question: Can I interfere with that? Of course, you can use drugs initially, assuming you have them. But now, using new technologies - the revolution of the RNA interference technologies to block gene expression - you can quickly validate some of these pathways. Then, if you have a drug, you can go and interfere with the process.
Systems biology studies are performed now in less complex, single-celled organisms such as brewer's yeast. As the research progresses and new technological tools emerge, systems biology one day will be applied to cancer. Do you see head and neck cancer playing a prominent role in forwarding this research?
Definitely. Obviously, I have a bias as someone who studies head and neck cancer, but there are practical reasons to suggest these tumors will play a prominent role. First, because of their locations in the throat, mouth, nose, and neck, they are some of the few cancers in which you can readily access and monitor them over time. Of course, there is a huge potential for imaging these tumors, which has not been adequately explored. Just as importantly, for the vast majority of head and neck cancers, the carcinogens are relatively well known.
Right, the tumors are exposure driven.
They are exposure driven. Most of these cancers are linked to smoking, chewing tobacco, alcohol consumption, and some other well-characterized factors. The point is: Systems biology will be challenging enough for cancer researchers. Problems with accessing, imaging, or characterizing tumors shouldn’t limit the research, and these are largely non-issues in head and neck cancer.
And yet, what you learn in head and neck cancer is very applicable to cancer in general.
Good point. One of the key issues in drug development now is what’s called surrogate markers, or molecules that you can monitor in a cancerous tissue to evaluate the effectiveness of a treatment. If you try to look for surrogate markers in other tumor types, it’s relatively difficult to obtain tissues that you can monitor over time to evaluate how a pathway or gene is affected. In head and neck cancer, it is possible. This concept also is true when searching for new preventive modalities to intervene earlier, at the precancerous stage. But we need to get the dental community more involved in identifying these early lesions in their patients. Right now, there is a desperate research need for more tissue samples.
Why's that?
Because there are very few that have been collected. There is a real need for more dentists to team with the scientific community. We desperately need dentists to provide tumor samples to their nearest oncology center and, in essence, help us discover new ways to benefit their patients. Our current samples are from just a small percentage of patients, which limits the necessary breadth of the research.
So now, with all of the new technologies and new information about head and neck cancer, it's a great time to create those teams to really fuel the research.
Exactly. One lab, one institution can’t do it alone. It requires a team effort. You can’t spend your career in your own lab, focusing on a single pathway or molecule. It can only be done on the basis of true collaboration. Scientists can no longer afford to be self-centered or isolated. Indeed, it will take a concerted effort from educators and the scientific and health professional communities to prevent this disease, as well as to take full advantage of the emerging scientific opportunities to battle its ravaging consequences.