UCSF Researchers Engineer Cells to Change Shape and Movement

By Wallace Ravven Scientists have carried out a bioengineering feat that advances the possibility of "reassembling" and reprogramming living cells to serve as mini-robots in the body to treat disease. In two papers published May 21, researchers in the UCSF lab of Wendell Lim, PhD, showed that they could reprogram biochemical circuits in living cells to control cell shape and movement in very precise, intended ways. Lim is a professor of cellular and molecular pharmacology and an investigator in QB3, the California Institute for Quantitative Biomedical Research, based at UCSF Mission Bay. "These papers provide some of the first steps towards the ability to engineer cells that can be custom-programmed to adopt a specific shape or function," Lim said. These reprogrammed cells could have many diverse therapeutic functions. It may be possible, for example, to program cells to act like miniature robots that can transform into a neuron or repair a wound on demand. The work is part of the emerging field of synthetic biology, which aims to understand the engineering principles of living cells and apply them to build useful functions. The cells in our bodies are complex machines that take on different shapes and structures, depending on their task. A neuron has to form long axonal processes that make connections over great distances, while a white blood cell has to maintain a more variable, amoeba-like shape that allows it to pursue and devour infectious bacteria. As complex and puzzling as these shapes and movements appear, all cells contain biochemical circuits "similar to those in a computer," Lim said, and they control the cells' shapes and movements. The different shapes found in different cell types are the result of differences in how these biochemical circuits are "wired."
The foreground of this image is a model of a switch protein that UCSF scientists have engineered to control change in cell shape. The ON state is shown on the left, while the OFF state is on the right.

The new field of synthetic biology aims to understand the "engineering principles" of living cells and apply them to build living cells with new abilities to aid medical treatments of other applications. The foreground of this image is a model of a "switch protein" that UCSF scientists have engineered to control change in cell shape. The ON state is shown on the left, while the OFF state is on the right. The research is led by UCSF professor Wendell Lim.

In the first paper, published in the journal Nature, the researchers show that by engineering designer proteins that integrate into the circuits of certain cells, those cells can be reprogrammed so that they form a particular desired shape in response to novel biochemical signals. They were able to induce the cells to form either long, spiked structures called filopodia or flat, extended sheets called lamellipodia. In the engineered circuits, the change into these shapes was triggered by activating a very common signaling molecule known as protein kinase. The protein in turn transferred a common activating chemical - a phosphate group - to the engineered switch protein to turn it on. This is not a normal role for the kinase. In the second paper, published in Nature Biotechnology, the scientists show that these engineered circuit proteins can be designed to show digital behavior - all-or-none activation - like that of the core elements found in computer circuits. In this case, the authors were able to engineer a protein that digitally switches on and off its ability to activate the biochemical reactions that drive cell shape change. "The research shows the possibility of reprogramming complex cellular circuits with the flexibility and diversity found in modern electronic circuits," Lim said. Lim is the senior author of both papers. Lead authors of the Nature paper are Brian J. Yeh, a graduate student in the Chemistry and Chemical Biology program and in the Cellular and Molecular Pharmacology department at UCSF; and Robert Rutigliano, PhD, in the Molecular Genetics and Microbiology department in the School of Medicine at State University of New York, Stony Brook. Co-authors are Anrica Deb in UCSF's Cellular and Molecular Pharmacology department and Dafna Bar-Sagi, PhD, in the Biochemistry department at New York University School of Medicine. John E. Dueber, PhD, is lead author of the Nature Biotechnology paper. He was a UCSF biochemistry graduate student and is now a fellow in the Synthetic Biology department at the Berkeley campus of QB3. Ethan Mirsky, co-author, is a UCSF biophysics graduate student. The research is supported by the Rogers Family Foundation, the National Institutes of Health Nanomedicine Development Center and the National Science Foundation Synthetic Biology Engineering Research Center. Bringing synthetic biology to a new generation of budding bioengineers, UCSF is sponsoring a team of San Francisco high school students this summer to work on reprogramming cells as part of the International Genetically Engineered Machine competition, or iGEM, to be held at MIT in the fall. The summer program aims to introduce promising young students to this new field of cellular engineering.
Rewiring Cellular Morphology Pathways with Synthetic Guanine Nucleotide Exchange Factors Brian J. Yeh, Robert J. Rutigliano, Anrica Deb, Dafna Bar-Sagi, Wendell A. Lim Nature, advance online publication May 21, 2007 Abstract | Full Text | Full Text (PDF)
Engineering Synthetic Signaling Proteins with Ultrasensitive Input/Output Control John E. Dueber, Ethan A. Mirsky, Wendell A. Lim Nature Biotechnology, advance online publication May 21, 2007 Abstract | Full Text | Full Text (PDF)
Related Links: Synthetic Biology: Divining and Designing New Biological "Components" UCSF Today, August 8, 2006 International Genetically Engineered Machine Competition MIT Lim Lab