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Cellular Control: Synthetic Signaling and Motility Systems

 
2010 Progress Report – Executive Summary

Vision: Engineering Cells and Cell-Like Devices as Next Generation Therapeutic Agents
Our long-term goal is to use synthetic biology approaches to engineer cells or artificial cell-like devices that can be flexibly programmed to carry out a wide range of specific therapeutic tasks. Such cellular “nanorobots” would in principle be able to carry out combined diagnostic (sensing) and therapeutic (delivery) functions in a patient – long a dream of medical research. Looking forward, we have chosen to focus on engineering therapeutic cells and cell-like assemblies that can be used to detect and treat cancer. Cancer cells present a difficult challenge because they can evade efficient immune responses through many mechanisms such as loss of surface markers, production of immune inhibitory factors, and local reshaping of the tumor environment to achieve a physiological niche that supports tumor growth and metastasis. Thus we hope to develop custom therapeutic cells or smart cell-like devices designed with enhanced tumor target detection, resistance to tumor inhibitory signals, and the ability to evoke spatially and temporally controlled responses that either kill tumor cells or reshape the tumor environment, allowing for a highly effective anti-tumor therapeutic response.

These molecular and cellular engineering approaches will build upon, complement, and synergize with other cutting edge therapeutic strategies, such as adoptive cell-based therapies and gene therapy. Whereas gene therapy has traditionally been focused on replacing missing or damaged genes, we are working on the development of novel application-specific synthetic cell or cell-like systems, custom engineered for a complex therapeutic task. These therapeutic goals build upon our increasingly deep molecular and systems-level understanding of how cells carryout complex signal processing and sensor/actuator tasks. Such approaches, should ultimately be applicable to treatment of a wide range of diseases beyond cancer.

Current Progress: Laying the Foundation for Engineering Cellular Control
For the first five years of this center, our focus has been to develop the tools and strategies for engineering cellular control systems, including those involved in signaling and motility. These synthetic biology approaches will form the foundation for achieving our translational goals of constructing and engineering therapeutic cells with designed behaviors. Our major five advances are summarized below.

We have made significant advances in learning how to engineer cell signaling and motility pathways in systematic ways:

  1. Developed strategies for placing cell motility under control of diverse novel input signals.
  2. Developed strategies for rewiring kinase pathways in living cells, and for systematically tuning their dose-response and dynamic behavior
  3. Developed computational methods to guide biological design at the levels of: a) redesigning protein- protein interactions optimized for cellular engineering, and b) of functional circuit modules

    We have made significant advances in understanding how force generating polymer systems, like actin, are harnessed by cell signaling pathways to bring about diverse and complex morphological changes:
     

  4. Elucidation of the diverse mechanisms by which actin-related polymers, including those from prokaryotes, can perform mechanical work to spatially organize and reshape cells.

    We have also made significant advances in developing novel technologies for constructing/reconstitutiing complex cell-like assemblies that could be a platform for constructing smart therapeutic devices

  5. Developed novel microfluidic encapsulation method to generate vesicles with complex and well-defined molecular content, organization and component orientation.
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