Cell biologists at UCSF have received $15.4 million from the National Institutes of Health to set up one of two new National Centers for Systems Biology, to study how cells respond to their environment – an emerging field of research that could revolutionize medicine by creating “smart cells” to deliver medications and other therapeutics more effectively.
Wendell A. Lim, Ph.D., a Howard Hughes Medical Institute investigator and UCSF professor of cellular and molecular pharmacology, will lead the UCSF center, which is being funded for five years under the NIH program. Researchers at the center will work in collaboration with colleagues at the second center, led by Alexander Hoffmann, PhD, at UC San Diego. Results will shed light on ways cells adapt and protect themselves and may lead to new therapeutic tools.
The UCSF initiative is heralded as a possible means of engineering a patient’s own cells for therapeutic uses, according to Paul Brazhnik, PhD, who oversees systems biology center grants at NIH’s National Institute of General Medical Sciences (NIGMS).
“By developing an understanding of the design rules that govern biological circuits, particularly those involved in adaptation, Lim’s center could help steer a revolutionary direction in medicine – the engineering of ‘smart cells’ that can carry out therapeutic or biotechnologically useful tasks,” Brazhnik said.
The UCSF Center for Systems and Synthetic Biology will build on previous research by Lim and his colleagues into understanding how cells use biological circuits to sense and adjust to their surroundings.
Living cells use molecular control circuits to achieve complex behaviors, such as homeostasis – the cell’s ability to regulate its internal environment to maintain constant conditions – and adaptation, the process by which cells adjust to become better suited to their environment, Lim explained. Typically, such systems are studied on a case-by-case basis, using reverse engineering to dissect the structure of individual regulatory networks. However, that approach often fails to reveal what’s occurring behind the function.
This project, he said, will apply a proactive approach, known as forward engineering, as well as comparative genomics to understand the fundamental design principles of adaptation. It will ask not how any one particular system works, but rather, which core network structures are required to achieve adaptation and which synthetic adaptation circuits can be developed.
“This engineering-inspired approach has the potential to transform medicine,” Lim said. “The fundamental understanding of circuit structure and function that emerges will allow us to recognize core circuit architectures in natural systems, how these are perturbed in disease states, and how they can be engineered to carry out therapeutic or biotechnologically useful target functions.”
The group will integrate approaches from engineering, genomics, proteomics, systems biology and synthetic biology to identify principles and architectural features involved in common cellular behaviors and will examine these circuits across different species. That information will allow the center to engineer synthetic circuits that can trigger desired cellular responses to external cues, making them potentially useful in biotechnology and biomedicine.
NIGMS provided the support for both of the new centers, which join 10 others that had been set up in previous years.
The funding will enable UCSF to expand its research and start a fellowship program in systems biology aimed at attracting talented young scientists from areas outside UCSF’s traditional strengths in the biological sciences, including from engineering, math and information technology.
Those efforts are part of a larger effort under way in the UCSF schools of Medicine and Pharmacy, and the University of California institute for quantitative biosciences, known as QB3, headquartered at UCSF.
“Modern Biology and Medicine are becoming increasingly dependent on the quantitative sciences,” Lim said. “It is critical that here at UCSF we build up a strong foundation in these areas.”
The UCSF team includes Chao Tang, PhD, professor of Bioengineering and Therapeutic Sciences; Nevan Krogan, PhD, associate professor of Cellular and Molecular Pharmacology; Hana El-Samad, PhD, assistant professor, and Hao Li, PhD, professor, of Biochemistry and Biophysics; Chris Voigt, PhD, associate professor, and Alma Burlingame, PhD, professor, of Pharmaceutical Chemistry; as well as Jasper Rine, PhD, professor of Genetics, Genomics and Development at UC Berkeley.
Hoffmann’s San Diego Center for Systems Biology of Cellular Stress Responses will also receive $15.4 million and will investigate how cells respond to stress, including pathogens, toxins and metabolic imbalances. That team will use genomics, proteomics and synthetic biology techniques to understand the signaling pathways involved in normal stress responses and how these responses protect cells. Results will provide clinically relevant insights into a range of human health problems.
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