We are a synthetic biology / bioengineering lab in a diverse and collaborative scientific community, with the broader goal of impacting human health. 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.
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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.
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We also have a long-standing interest in Genome Organization, which is the study of how the arrangement and architecture of elements (such as super-enhancers) within the genome lead to transcription and ultimately cellular function. On top of this, we are interested in how this interfaces with epigenetic machinery to confer stable cellular identities. The long-term impact of these studies is to provide a language by which we can program new cellular functions into cells.
DESTROI: Dendritic cells for Eliminating Solid Tumors from Re-programmable
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 RE-engineered 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 novel biologic delivery vector for regenerating damaged brain regions but also other tissues in the body.