Much of human physiology is controlled by electrical stimulation of and by the nerves. Although electronic implants that replace natural stimulation of muscles and nerves, such as the cardiac pacemaker and vagus nerve stimulator, offer a unique means for treating certain diseases for which no other effective therapy exists, many of their complications, such as harmful immune responses and unsustainable power requirements, preclude the development of a lifetime solution. To radically resolve the debilitating issues associated with these electronic neural implants, this CAREER project proposes a new neural implant technology using the patient's own cells. As a proof of concept, this project will create an entirely new type of circuit design, called a multicellular biological neural pacemaker (BNP). The BNP will use cardiomyocytes, the muscle cells that control the beating properties of the heart, as the power source and signal generator. The "generator" will stimulate motor neurons, which in turn can excite muscle cells. The core problem of this design is obtaining synchronized rhythmic activity between the motor neurons and the cardiomyocytes. To establish feasibility, this "wiring" problem will be addressed by genetically engineering functional channels, called gap junctions, between the cell types while they are cultured together. If successful, this transformative technology can be extended broadly to applications ranging from the development of a biological heart pacemaker, to treatment for Parkinson's disease, and to muscle stimulation. Complementary to the research goal, this project will carry out a diversified series of educational activities, including building a competitive interdisciplinary research team, organizing a campuswide Neuroengineering Journal Club and a Neurotechnology Seminar Series, and organizing an annual symposium on biocircuits at the Materials Research Society Spring Meetings.
As part of the long-term career goal to establish a research program on the science and engineering of autologous neural implant technology toward the ultimate substitution for electronic neural implants, the focus of this project is to prove this concept through an example biocircuit design of multicellular biological neural pacemaker (BNP). The feasibility for such a design will be investigated using an in vitro coculture system designed to validate the hypothesis that motor neurons can be electrically synchronized to cardiomyocytes via genetically engineered gap junctions. Specifically, this project will: (1) study how cardiomyocytes and motor neurons adapt to a coculture; (2) form functional gap junctions among motor neurons and cardiomyocytes using lentiviral transduction; and (3) recapitulate the results with hiPSC-derived motor neurons and cardiomyocytes. This work will lay the foundation for building this multicellular BNP. Here, in vitro demonstration of intercellular functional wiring for the design of the BNP as an example living implant suggests the possible application of autologous neural implants for medical treatment. Furthermore, this approach of engineering cellular inputs/outputs (I/Os) for wiring atypical heterogeneous biocircuits will spark great interests in the scientific community for cellular I/O engineering and development of application-specific integrated biocircuits. With synthetic cells and specifically designed intercellular I/Os, it will be possible to build, from bottom up, more complex heterogeneous biocircuits of advanced functionalities, thus greatly expanding the engineering capability of biology for a variety of exciting applications.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
