Zachary Ryan Crook, PhD

Pronouns: He/Him/His
Zachary Ryan Crook, PhD
"Treatments for pediatric diseases tend to be opportunistically repurposed from adult therapeutics that may or may not be well-suited for the unique biology of the pediatric condition. My group's approach is to understand the underlying molecular characteristics of the pediatric condition and employ cutting-edge protein engineering tools to design molecules that selectively target these pathways, resulting in therapeutic candidates that are purpose-built from conception to be translatable, effective, and safe in a pediatric population. In doing so, we can advance novel treatments for difficult-to-treat pediatric diseases that positively impact patient lives, on timelines commensurate with the urgency of the medical need."

  • Biography

    I received a BA in Molecular, Cellular, and Developmental Biology from the University of Colorado in 2007, followed by a PhD in Biology from the Massachusetts Institute of Technology in 2013. There, I characterized mouse models of Huntington's Disease for biomarkers of neuropathology that could be precisely quantitated, permitting therapeutic candidate testing in smaller cohorts to hasten development timelines. My postdoctoral studies took place under Dr. Jim Olson, then at the Fred Hutch Cancer Center, investigating miniproteins and other protein binder modalities for therapeutic utility in pediatric brain tumors and other CNS conditions. I was recruited to Seattle Children's in 2026 to continue these studies.

    Research Description

    Research focus areas:

    1) T cell engagers (TCEs) redirect the patient's adaptive immune system to target and destroy tumor cells. We have identified a family of TCEs that target CD3 on T cells and PD-L1 on tumor cells that is highly effective against pediatric brain tumors grown in the mouse brain. This molecule uses a novel miniprotein to target PD-L1, resulting in activity superior to that of an antibody-based comparator. We are working to further characterize the family's capabilities while improving the safety profile of these molecules by incorporating features that restrict TCE activity to the tumor microenvironment.

    2) The pediatric brain tumor microenvironment often contains high amounts of immunosuppressive myeloid cells, producing signals that suppress T cell activity. This could limit immune-oncology drug efficacy in these tumors. We are using AI-driven protein design tools to engineer molecules that convert these infiltrating immunosuppressive cells into tumor-targeting cells that work alongside T cells to eliminate tumors. 

    3) Neuroinflammation is a primary contributor to neuronal damage and death in several pediatric and adult CNS conditions, including traumatic brain injury, stroke, and age-associated neurodegeneration. This is often treated with nonselective anti-inflammatory drugs (e.g., NSAIDs, steroids) that have limited efficacy and intolerable side effects (bleeding risk, systemic immunosuppression). We are developing brain-penetrant molecules that safely and selectively target pro-inflammatory mediators of neurotoxicity in these conditions, with the goal of suppressing the neuroinflammatory cascade and preserving brain function.

    Research Focus Area

    Brain Injury, Solid tumor immunotherapy, T cell immunotherapy

  • Awards and Honors

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  • Publications

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  • Clinical Trials and Research Studies

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