We are a synthetic biology lab in a department of biomedical engineering. Our work utilizes principles from multiple fields such as genomics, immunology, stem cell biology, regenerative medicine, and neuroscience. Our modus operandi is to use DNA technologies to program stem cells to become neuro-immune cell types that can act as “smart” therapeutic cells with abilities beyond that found in nature. Our work primarily focuses on addressing cancers, neurodegenerative diseases (specifically Alzheimer’s), autoimmune disorders, and tissue degeneration.
REWRITE: REcombinase WRiting of Iterated DNA and Trap Excision
We develop genome writing approaches for genetically engineering large sections of the human genome at 100+ kb. These technologies combine advances in CRISPR/Cas9, recombinases, and synthetic DNA assembly to generate novel “designer” segments of the human genome as well as synthetic gene circuits. We do this in human induced pluripotent stem cells (iPSCs), which have the potential to become any cell type in the body. Our key focus has been to “REWRITE” the polymorphic HLA/MHC (human leukocyte antigen/major histocompatibility complex) locus, which spans 6 megabases, in order to match any person’s personal HLA “fingerprint”. These “immune-matched” human iPSCs would free us from relying on patient-derived cells, and could be used as an “off-the-shelf” cellular platform to build smarter, safer, and more effective cell therapies and regenerative medicines.
DESTROI: Dendritic cells for Eliminating Solid Tumors from Reprogrammable Off-the-shelf IPSCs
Leveraging our immune-matched human iPSCs and REWRITE, we develop programmable dendritic cells as a modular platform for addressing solid cancers and adaptive immune responses. Dendritic cells are the most effective professional antigen presenting cell, utilizing the complete repertoire of HLAs to display mutated as well as foreign peptides to educate adaptive immune cells (T- and B-cells). Dendritic cells also have the ability to enter “cold” solid tumors, which have become invisible to the immune system. A major goal is to generate scalable amounts of dendritic cells of defined states. Programmable dendritic cells have multiple applications including homing to solid tumors, cancer vaccination, identifying orphan T-cell Receptors, reducing autoimmune responses, or tolerizing the body to tissue transplantation.
REPHRESH: REgenerative PHagocytes genetically REwritten for Self-Healing
We also leverage our human iPSCs to develop programmable macrophages, the other professional antigen presenting cell of the body. Macrophages are professional phagocytes (“eating” cells) that transform to specialized states that can promote tissue repair or recruit immune responses. Macrophages are found all over the body and have the unique ability to cross the blood-brain-barrier and become microglial cells (brain macrophages), cells which are central to the clearing of neurotoxic molecules like β-amyloid. We are developing synthetic genetic switches to control the behavior of the cells, enhance their surveillance of different parts of the body, and even release therapeutic cargo in response to specific cell types. The central goal is to use our macrophages as a “trojan horse” for regenerating damaged brain regions but also other tissues in the body.