Martin Fussenegger - Biotechnology and Bioengineering

Gene Control: From Biotechnology to Human Therapy

From a systems perspective, human disease originates from spontaneous, environmentally triggered or pathogen-induced perturbations of endogenous expression or signaling networks, and often results in disabling or fatal pathologies. Currently available therapeutic strategies include administration of small-molecule drugs or biopharmaceuticals, reprogramming of genetic deficiencies using gene-transfer technologies, and implantation of engineered cells or synthetic tissues. Focusing on mammalian cells and capitalizing on an integrated interdisciplinary systems approach we are implementing progress in basic research to achieve generic and prototypic advances in human therapy. Our current research initiatives include several programs interfacing with biopharmaceutical manufacturing, gene therapy and tissue engineering:

• Design of prototype biopharmaceutical manufacturing strategies by integrating engineering of mammalian production cell lines for increased secretion of high-quality biologics with upstream process development.

• Design of novel trigger-inducible transgene expression systems for pharmacological dosing of in-situ-produced protein therapeutics as well as therapeutic reprogramming of endogenous gene networks.

• Development of safe, efficient and affordable gene and protein transfer technologies with a focus on engineering of attenuated viral delivery systems.

• Controlled transdifferentiation of mammalian cells by ectopic expression of different transgenes with precise dosing and timing enabling production of therapeutically relevant cell phenotypes.

• Design of complex synthetic gene networks with digital expression logic allowing construction of prosthetic transcription circuits for seamless integration into host physiological networks.

• Evaluation of prototype gene therapy applications using mouse disease models.

• Epigenetic reprogramming of mammalian cells to improve transgene control modalities and lock cells into a desired phenotype.

• Design of scaffold-free microtissues to study vascularization, transdifferentiation, intercellular crosstalk, tissue-implant fusion and electrogenic characteristics in a multicellular three-dimensional configuration.

• Discovery of novel cytostatic, immunosuppressive and anti-infective drugs using engineered mammalian sensor proteins and tissue culture systems.