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Westerhoff engineers his way to systems biology

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At the ninth annual HUGO conference in Berlin last April, Hans Westerhoff’s talk showed just how far the field has traveled since the flurry of publicity surrounding the sequencing of the human genome. The Dutch professor of molecular cell physiology and mathematical biochemistry, with a dual appointment at the Free University of Amsterdam and the University of Amsterdam, hopes to use the genome to help identify the causes and mechanisms of biological processes. His approach to systems biology, he thinks, can accomplish this.

Westerhoff’s most direct involvement in systems biology takes the form of the Silicon Cell (http://www.siliconcell.net), a project he leads to create a “live” database that replicates the behavior of a human cell. By “live,” he means that collaborating researchers can log on to the database to perform in silico experiments of their own, changing inputs and constants regulating the metabolism and gene expression to calculate the cell’s appropriate response. His own research interests with the Silicon Cell center around the study of glycolysis in an effort to better understand how the pathogen Trypanosoma bruscei interacts with the human body.

In his approach to systems biology, Westerhoff takes a surprisingly engineering-based bent. The regulation of genes, proteins, and metabolism all contribute to how a cell responds to a given stimulus, he says, but not equally so under any specific set of circumstances. Westerhoff’s group has developed equations that he uses to assign values to the relative contributions of various regulatory interactions, and the model provides a framework for figuring out which actors in the cell matter the most when the cell reacts to specific events. Westerhoff also introduced the idea of “vertical genomics,” whereby researchers simultaneously study the regulation of genes, proteins, and the metabolism for a particular stimulus, as opposed to investigating just gene regulation, or just the metabolism, for example, under many types of conditions.

Westerhoff is also indirectly involved in an ambitious German project to model hepatocyte cells, which are closely associated with liver function. The “Hepatocon,” as this initiative is known, received its first €20 million ($24 million) in funding in January, and involves several groups across Germany experimenting with hepatocyte signal transduction and blood detoxification pathways, as well as additional groups responsible for developing theoretical models that fit the experimental data. “The problem is that there’s a high failure rate for making good models of human cells,” Westerhoff says, but at the very least he’s hopeful that the project will lead to a better understanding of drug toxicology.

— John S. MacNeil

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