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Genome Engineering Stem Cells

What if we could radically alter the configuration and placement of genes, redesigning the chromosomes themselves? We are developing approaches to assemble large designer segments of DNA and then write them into/over any region of the human genome. It can be repeated, thereby enabling the writing of millions of base pairs of DNA. We focus on engineering human induced pluripotent stem cells (hiPSCs) and mouse embryonic stem cells (mESCs) because they can become any cell in the body.

 

In our first project, we are building "personalized" universal human stem cells, as an off-the-shelf cellular platform. This opens up new ways to build smarter, safer, and more efficacious cell therapies and regenerative medicines.

 

We also focus on understanding the information contained within gene regulatory information and other intergenic DNA. The eventual goal is an integrative framework for programming cellular processes, such as transcription, cell fate decisions, and cell-to-cell communication.

Finally, we also build better humanized mouse models by writing in larger segments of DNA. Those interested in collaborating in new mouse models or NK-cells should please reach out!

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Programmable off-the-shelf Dendritic Cells
as a Cancer Immunotherapy Discovery Platform

Cell immunotherapies, like CAR-T, have revolutionized the treatment of cancers. However, CAR-T can only recognize proteins already found on the surface of cancer cells. This limits the number of addressable cancers to those with common surface epitopes like HER2 or CD19. The majority of cancer mutations are not found externally, but internally within the cell. This means there are limited potential targets for CAR-T.

However, the natural targeting protein used by T-cells, the T-cell Receptor, recognizes targets from within cells. Our goal is to identify new universal cancer targets from within cancer cells, and discover new T-cell Receptors against these targets. The T-cell Receptors can then be genetically introduced to T-cells to redirect them towards untreatable cancers.

To do so, we are building programmable Dendritic Cells from human iPSCs as a new platform technology. Dendritic Cells mediate the innate and adaptive immune responses and activate immature T-cells. We will use these programmable Dendritic Cells to find new T-cell receptors from the blood of cancer patients. In addition, Dendritic Cells can also be used as a cellular platform for cancer vaccination, reducing autoimmune responses, or tolerizing the body to cell/tissue transplants.

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Sentinel cells and cell programming

How do cells interpret signals from each other? What is the language by which cells communicate? Using our universal iPSCs, we are developing new types of synthetic cells that can decode the internal workings, physiological status, and identity of any cell in the body. We call this process "cellular decryption". Our ability to write large genetic circuits into any cell type enables us to program these cells to one day recognize different cell types, diseased cells, and then respond therapeutically within the body.

In addition to performing cellular decryption, these cells will respond to endocrine signals within our own physiology, making them akin to an orthogonal immune system. We will program these cells to perform new functions such as emitting signals for blood diagnostics, interface with natural innate immune responses, and even perform tissue repair by transforming into healthy new cell types. The cells, for instance, could be used to regenerate fresh neurons upon recognizing diseased brain tissue. The eventually goal of this program is to build a language and grammar for how cells communicate with each other, perform functions, and change and respond over time.