New technology enables predictive design of engineered human cells

Significance 

One of the most exciting frontiers in medicine is the use of living cells as therapies. Using this approach to treat cancer, for example, many patients have been cured of previously untreatable disease. These advances employ the approaches of synthetic biology, a growing field that blends tools and concepts from biology and engineering. The new Northwestern technology uses computational modeling to more efficiently identify useful genetic designs before building them in the lab. Faced with myriad possibilities, modeling points researchers to designs that offer real opportunity.

Northwestern University scientists led by Dr. Josh Leonard together with Dr. Neda Bagheri from the University of Washington built a new cell therapies by engineering cells that can activate immune system. To engineer a cell, the authors first encoded the desired biological functions in a piece of DNA, and that DNA program is then delivered to a human cell to guide its execution of the desired function, such as activating a gene only in response to certain signals in the cell’s environment. Dr. Josh Leonard is an associate professor of chemical and biological engineering in the McCormick School of Engineering and a leading faculty member within Northwestern’s Center for Synthetic Biology. His lab is focused on using this kind of programming capability to build therapies such as engineered cells that activate the immune system, to treat cancer. Bagheri is an associate professor of biology and chemical engineering and a Washington Research Foundation Investigator at the University of Washington Seattle. Her lab uses computational models to better understand—and subsequently control—cell decisions.

The study, in which dozens of genetic circuits were designed and tested, is published in the journal Science Advances. Like other synthetic biology technologies, a key feature of this approach is that it is intended to be readily adopted by other bioengineering groups.

To date, it remains difficult and time-consuming to develop genetic programs when relying upon trial and error. It is also challenging to implement biological functions beyond relatively simple ones. The research team used a “toolkit” of genetic parts invented in Leonard’s lab and paired these parts with computational tools for simulating many potential genetic programs before conducting experiments. They found that a wide variety of genetic programs, each of which carries out a desired and useful function in a human cell, can be constructed such that each program works as predicted. Not only that, but the designs worked the first time.

The genetic circuits developed and implemented in this study are also more complex than the previous state of the art. This advance creates the opportunity to engineer cells to perform more sophisticated functions and to make therapies safer and more effective. With this new capability, we have taken a big step in being able to truly engineer biology.

New technology enables predictive design of engineered human cells - Medicine Innovates
FIGURE: Synthetic biologists achieve a breakthrough in the design of living cells. Credit: Justin Muir

About the author

Josh Leonard

His research group works at the interface of systems biology and synthetic biology in order to probe and program the function of complex, multicellular systems to develop transformative biotechnologies and enable a new paradigm of design-driven medicine. Using the tools of synthetic biology, biomolecular engineering, computational systems biology, and gene therapy, the group develops technologies including programmable cell-based “devices,” immune therapies for cancer and chronic disease, smart vaccines, biosensors for global health applications, and tools for advanced metabolic engineering.

By bringing an engineering approach to the investigation, design, and construction of biological systems, the Leonard group is advancing the frontiers of design-driven medicine to address unmet medical needs and create safe, effective, and long-lasting treatment options that improve both quantity and quality of life.

Reference

J. J. Muldoon, V. Kandula, Hong, P. S. Donahue, J. D. Boucher, N. Bagheri and J. N. Leonard. Model-guided design of mammalian genetic programs, Science Advances (2021)

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