Systems Biology: Creating the Circuits of Life

CAMBRIDGE, Mass.  — Whitehead Fellow Trey Ideker often thinks of himself as an engineer and the cell as a circuit. “I see myself looking at all the wires at once to understand how they work with each other and then making the wiring diagrams,” he says. “I want to know which wires are used for what–for example, which wires short-circuit to cause cancer and which need to stay active to keep the body healthy.” Ideker’s approach to understanding cell circuitry, an approach known as systems biology, is part of a new research initiative that is shifting biological science from the local to the global, from the parts to the whole.

“Systems biology goes beyond merely defining the parts, in this case, genes and proteins, and looks at how the parts fit and act together,” he says. “By integrating multiple levels of biological activity, including information generated by genome sequencing, proteomic analysis, and microarrays we can gain a global perspective of how a system works. We can then build a computational model of the system.”

According to Ideker, such models will not only enhance our understanding of how the body works, they will revolutionize contemporary approaches to drug development. For example, scientists can use system models to test drugs comprehensively on a computer before testing them in the lab or clinic.

A Global Perspective

A human cell’s wiring consists of myriad protein-to-protein, protein-to-gene, and other biomolecular interactions. It is this wiring that switches genes on or off, controls which proteins are produced and correctly processed, and, at a higher level, determines how the cell responds to signals from its environment and to various threats. As a result, even small malfunctions in any of these interactions can become a catalyst for disease.

Because there are approximately 40,000 genes and potentially millions of proteins that make up the circuitry of the cell, many researchers narrow their focus to a regulatory subsystem linked to a particular disease, such as the molecular interactions that cause breast cancer or Alzheimer’s disease. In contrast, Ideker’s lab has taken on the daunting task of creating a computer model that encompasses every protein-to-gene and protein-to-protein interaction in the cell. To manage this complexity, his lab is also developing software to sift through the entire circuit to extract just those interactions relevant to a disease process.

In collaboration with the Institute of Systems Biology in Seattle, Ideker has created a software package called Cytoscape, scheduled for public release this summer, to help build and analyze such models. The lab is currently piloting this software on the yeast cell, which is similar in structure but somewhat simpler than the human cell. To create their model, Ideker and his colleagues feed massive amounts of data, including information gleaned through their own discovery efforts and that which is available in public databases, into a computer. Using Cytoscape, the team then builds and constantly refines the model of the cell, making it possible for them to simulate thousands of interaction scenarios.

The Future is Now

Ten years ago, Ideker’s research would not have been possible. This is in part because the systems biology approach draws heavily on information and technologies generated by the Human Genome Project, the world’s first global effort to define all of the elements of a system and create a database to contain its findings. “The concept of systems biology is not new, but its time has come. It’s popular because it is finally possible,” says Ideker.

While a beneficiary of the Human Genome Project, systems biology takes genome sequencing to the next logical level. To date, Ideker’s wiring diagram is able to predict 15 to 40% of the genes affected when an yeast cell is perturbed or stimulated in lab. He believes that it is only a matter of time before further technological developments make it possible for the team to tackle the human cell.

Ideker hopes the work in his lab will create a strong foundation for scientists working on subsystems of the cell. “When it all comes together, we will have a very powerful tool to share with the research community,” he says.

But to succeed, systems biology will need to overcome some challenges, says Ideker. He sees a pressing need for technologies able to more completely characterize all the elements in the cell (such as metabolites and drugs), the cross education of scientists in key systems biology disciplines, and for academic institutions to make a strong commitment to supporting the field.

But he adds, “No matter what the current obstacles, systems biology is here to stay. It is just a matter of time before computerized systems models become as common in the molecular biology lab as the pipette or the centrifuge are today.”