Working the systems

Dr. Muneesh Tewari's view of biology can be summed up with a phrase written by the 17th century poet John Donne: "No man is an island, entire of itself; every man is a piece of the continent, a part of the main."

Like other scientists who have embraced an emerging discipline known as systems biology, Tewari, a new faculty member in the Human Biology Division, believes that the whole is more than just the sum of its parts. Simply stated, the philosophy of a systems biologist is that the ultimate solution to any complex biological question — such as how cancer arises — is best addressed not by studying one discrete component of a system at a time, but by embracing the integrated web of molecules and chemical reactions to which the topic of interest is connected.

That's not to say that this increasingly popular experimental approach is an easy one, said Tewari, who joined the Center last fall. "There are still a lot of technological limitations to studying entire systems rather than individual genes or proteins, and we have and will continue to learn a great deal from studying single components of a system," he said. "But there is value in simply trying to take a systems perspective — trying to approach biological problems in their natural context. It's not much different than any social system. Life is a collection of interconnected networks."

Using a systems-biology mindset, Tewari plans to study how the interconnected networks within and among cells somehow become altered as healthy cells lose their controls on normal growth and eventually multiply to become dangerous tumors. The work may shed light on two related problems whose solutions could lead to new approaches for diagnosing, treating or preventing cancer: why tumors are so impervious to normal constraints on cell growth and how they acquire resistance to chemotherapy. Tewari's interest in these questions stems not only from his curiosity as a laboratory scientist focused on fundamental research, but also from his experience as a physician who treats cancer patients.

Dr. Barb Trask, director of the Human Biology Division, described Tewari as a "very strong addition to the Center."

"Muneesh is a medical oncologist with an innovative research program aimed at defining processes in the cell related to cancer with the ultimate goal of translating his discoveries to benefit cancer patients," she said. "His interdisciplinary focus adds great strength to the Center's research programs in genomics, solid tumors, and computational biology."

Tewari said he has already established research ties with Center investigators in each of those fields. "The collaborative environment was definitely one of the factors that drew me here. In the five months I've been here, I've begun collaborations with colleagues in each of the Center's scientific divisions."

Systems biology was a new idea when Tewari was completing his graduate work at the University of Michigan. There, as an M.D./Ph.D. student, he studied a phenomenon called programmed cell death — a chain reaction of events that causes cells to self-destruct when they either reach the end of their functional life or become abnormal. Defects in the process, which goes by the technical name of apoptosis, are common in cancer cells, which somehow manage to escape self-destruction and multiply.

A new way of thinking

"For my graduate work, I was studying one gene at time," he said. "That has been the way research has been done. But at the time, the human genome was about to be sequenced, and the genomes of some simpler organisms had just been sequenced. That opened the door to begin thinking about biology in a new way."

After finishing medical school, Tewari moved to Dana Farber Cancer Institute in Boston to complete a clinical fellowship in adult oncology. Then, he contemplated his options for beginning postdoctoral research in a Boston laboratory.

"I wanted to stay close to disease research, and I assumed that in a place like Boston I'd choose a lab with a long history of accomplishments in a particular research area," he said.

Instead, he found himself intrigued by the research of a junior faculty member, Dr. Marc Vidal, who had just joined the Harvard faculty and who was using a systems approach to study the microscopic worm Caenorhabditis elegans. With its newly sequenced genome, its many fundamental similarities to human biology and the wealth of information about how it develops from a single cell into an adult organism, the worm was an ideal model for exploring numerous questions from a systems biology approach.

In Vidal's lab, Tewari and colleagues conducted "proof-of-principle" experiments that were among the first to demonstrate the feasibility — and potential power — of simultaneously analyzing thousands of interactions among proteins in the cell. In particular, he focused on the myriad of connections around the focal point of transforming growth factor beta (TGF–), a protein that receives signals from a variety of stimuli and triggers a cascade of events required for normal development. Defects in TGF– or components of its associated chain reaction are associated with many types of cancer.

"This kind of approach offers the possibility of examining what happens to an entire system when you perturb one component," he said. "The project really got me interested in applying these kinds of experiments, combined with more conventional experiments on single genes and proteins, to study human disease."

One project he has initiated in collaboration with Drs. Beatrice Knudsen, Robert Gentleman and Charles Drescher is to catalogue hundreds of what are known as "micro-RNAs" in ovarian-cancer cells. Micro-RNAs are a newly discovered type of RNA — a molecule similar to DNA — that seems to be important for controlling when genes are turned on or off and that may act abnormally in cancer cells. By discovering micro-RNAs involved in cancer, Tewari believes it may someday be possible to create harmless analogues of these molecules and use these as drugs to swamp out the harmful effects of the micro-RNAs that cause cancer.

Tewari also plans to use a systems-biology approach to figure out why cancer cells seem to be so resistant to killing.

Medical oncology practice

"What makes the system so robust, so seemingly impervious to perturbation?" he asked. By identifying the multitude of interactions among proteins in cancer cells, and determining which interactions could be disrupted to create an "Achilles heel" or weak spot in the system, he hopes to find solutions to problems like chemotherapy resistance or to discover targets for new drugs. In a related project, he and colleagues are trying to identify defects in cancer cells that could make them extra-sensitive to killing by cisplatin, a chemotherapy drug that also damages healthy cells.

Tewari said that choice of research projects was definitely fueled in part by his experience as a medical oncologist. After he settles in to life in Seattle, he will take on clinical duties and see patients one day a week.

"That aspect of my job does inspire me," he said. "Ultimately, my goal is to study basic biology that can be translated into applications in the clinic. The Center is an ideal environment for making that possible."