Reconstructing Genetic “Circuitry” in Cells

Professor Bernhard Palsson has created predictive models for the red blood cell, E-coli, H. influenzae, H. pylori and yeast.

In a recent study (Genome Research, November 2002) Bioengineering Professor Bernhard Palsson used his computer model of red blood cell metabolism to accurately predict which specific DNA mutations would result in chronic hemolytic anemia, and which would cause a benign form of the disease. It was the first model-based system for predicting phenotype (cell function) based on genotype (an individual’s DNA).

The work also serves as an example of the power of systems biology, and its promise for using mathematics and engineering modeling techniques to uncover new ways to diagnose and treat disease.

Palsson has been constructing cellular networks for nearly two decades, a pursuit he has dubbed “genetic circuits.”

“Every cellular function, such as metabolism, is a system requiring the coordinated interaction of dozens of gene products. Our goal is to actually map this out in a cellular wiring diagram,” says Palsson. To tackle the enormous challenge of modeling complex cellular systems, he employs a technique called constraints-based modeling, basically describing what a cell does not do in order to define what it can do through a process of elimination.

Another recent success—Palsson used his computer model of E-coli to accurately predict how the bacteria would evolve under specific conditions. The results may have applications for designing tailor-made biological materials for commercial uses or for predicting the evolution of drug-resistant bacteria.

To date, Palsson has created in silico models of metabolism for E-coli, the red blood cell, H. influenzae, H. pylori and yeast, and these models accurately predict cellular response 80 to 90 percent of the time. His San Diego-based company, Genomatica (www.genomatica.com), is now using Palsson’s patented models to create virtual laboratories for facilitating drug discovery.

Palsson is one of just a handful of people to build a complete network of the circuitry in given cells. Other researchers are describing simple control modules within the cell, as outlined by
Bioengineering Professor Jeff Hasty in the November 14 Nature Insights.

“These small mechanisms can have a big impact on cellular function. Just as in an electronic circuit, each module performs specific duties, such as generating oscillations in the amount of protein released based on the time of day,” says Hasty, who has also described a positive feedback loop, in which a gene produces a protein which in turn causes that gene to become more active. Hasty says his long-term goal is to build synthetic genetic modules which could be inserted into a patient's cells to tightly regulate the expression of a desired protein, or even to cause an undesirable cell to self-destruct.

Hasty and Xiaohua Huang, both of whom came to UCSD in 2002, join the Bioengineering Department’s growing systems biology and bioengineering group.