By tinkering with a few of the parts in a vital signaling circuit found in human cells, UCSF scientists have demonstrated the possibility of an entirely new technology: developing new devices or therapies by mixing and matching sub-cellular signaling components.
Like modern-day high performance machines, cells are constantly monitoring signals in their environment in order to “decide” on a course of action such as growth or movement. The signals are transmitted and processed by groups of proteins linked in specific circuits. Focusing on a protein that directs cell movement, the researchers were able to substitute key parts of the protein so that the reaction driving cell movement came under the control of new signals. Their study demonstrates that the signaling proteins are made of highly interchangeable “modules,” the scientists report. This interchangeability may allow engineering of cells with new decision-making circuits, the scientists say.
“Signaling proteins and other molecules in cells talk to one another by touching or binding one another,” says Wendell Lim, PhD, UCSF associate professor of cellular and molecular pharmacology. “When you look at different signaling systems in cells, you can recognize many of the same components—the same subfragments of proteins—linked together in different ways. We showed that the components are modular—the equivalent of electronic components. By mixing and matching components we can generate novel and diverse circuits and behavior.
“It may be possible to use this technology to engineer cells that can act as cheap and robust sensors or computers, for example. You might be able to engineer cells that act like an artificial pancreas. In principle it may be possible to combat cancer by designing a signaling switch that promotes cell death only when triggered by proteins found in tumor cells.”
Lim is senior author on a paper reporting this research in the September 26 issue of the journal SCIENCE.
Lim’s laboratory, at UCSF’s Mission Bay campus, is interested in how the enormous diversity of signaling circuits observed in living cells have evolved. His research team and others have come to understand that like much in evolution, nature has repeatedly used the same or similar modular components for different functions.
“If you build some machine that is perfectly engineered for one function but it’s not modular, it is inflexible—it can only perform that one function,” Lim says. “But if it’s modular, you can replace one module and that can create a new function. That’s apparently how many new cellular signaling proteins and circuits have evolved. It’s very similar to how an engineer can make many different circuits from the same types of modular electronic components “
Over the course of evolution, Lim explains, cells have apparently gained new circuits—say, a new way to respond to a hormone—by re-mixing their modules of signaling proteins. The new research shows that it is possible to mimic what nature has done repeatedly.
Lim and his colleagues manipulated a naturally occurring signaling protein, known as N-WASP, which normally directs cells to move by promoting the build-up, or polymerization, of the protein actin. When the actin buildup pushes one edge of a cell, the cell moves in that direction.
Actin polymerization is normally controlled in the cell by two signals “upstream” of the N-WASP protein.
“We simply replaced the regions of the protein that detect the normal upstream inputs with novel protein modules that detect two unrelated inputs,” Lim says. “We could show that the ‘decision’ to polymerize actin remained intact, but now under the control of these new input signals.”
To accomplish the replacement, the scientists spliced together the genes that encode the new modules and those that encode the output module—the module that drives actin polymerization—into one composite gene. They then tested the protein encoded by the composite gene and for its responsiveness to novel inputs.
Other attempts to engineer proteins have relied on making many specific mutations in proteins—changing their sequence—a much more difficult undertaking, says Lim, than the modular replacement his lab accomplished.
“Not only is the modular approach easier, but it can also yield proteins capable of integrating multiple signals, mimicking the sophisticated behavior required for cell functions,” Lim says. “With that integration, unlike a simple light switch, you can do more complex things.”
Switches that can integrate multiple signals also form the backbone of modern electronic circuits, he points out.
“Cells do computations and process information in much the same way computers do, so maybe we can ‘reprogram’ cells the way we can reprogram computers.”
John Dueber, BS, and Brian Yeh, BS, two of Lim’s graduate students, are finalists in the Collegiate Inventors Competition (sponsored by the National Inventor’s Hall of Fame) based on this work. UCSF and Lim have applied for a patent on this technology.
Co-authors on the study, along with Lim, are Dueber, Yeh and postgraduate researcher Ka-Yam Chak, BS.
Lim’s UCSF laboratory is part of the Institute for Quantitative Biomedical Research, or QB3, a partnership of UCSF, UC Berkeley and UC Santa Cruz.
The research is funded by the Sandler Foundation, the Packard Foundation, the National Science Foundation, and the National Institutes of Health.