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From Sample to Answer: Innovations in sample processing and CRISPR-based diagnostics facilitate clinical translation and field deployment

The recent emergence and rapid spread of several infectious disease agents underscore the urgent need for effective disease management and prevention strategies. Accurate and timely diagnostics serve as the cornerstone of effective prevention and response, enabling the rapid identification of disease outbreaks, guiding treatment decisions, and informing public health interventions. However, the global diagnostic testing capacity is currently insufficient to respond to emerging infectious disease threats, which has fueled the spread of Lassa, Ebola, SARS-CoV-2, and Zika virus in recent years. Globally, this diagnostic gap is particularly pronounced at the primary care or community level, an essential front line for initial response. Widespread, rapid, and user-friendly diagnostic tests are vital components of effective outbreak containment and response strategies, as they enable the rapid identification of new cases, thereby facilitating timely intervention and preventing further pathogen spread. Therefore, addressing the critical need in the global diagnostic testing infrastructure requires the development and deployment of diagnostic tools that are accurate, affordable, and accessible in decentralized settings.

Existing diagnostics fall short in bridging the current diagnostic gap, but recent advances in nucleic acid-based technologies, and CRISPR-based diagnostics (CRISPR-Dx) in particular, have shown significant promise in transforming infectious disease detection. CRISPR-Dx are easily programmable, robust, sensitive, isothermal, and highly specific, but further advances will be required to facilitate their use outside of centralized laboratories. This thesis aims to address this critical gap in global diagnostic testing capacity, focusing on the innovation, validation, and deployment of CRISPR-Dx for infectious diseases. We first developed SHINE, a rapid and sensitive Cas13-based nucleic acid detection platform without the need for nucleic acid extraction. In this first version (SHINEv1), we simplified the CRISPR-Dx workflow, reducing user manipulations and assay time, and enabling automated interpretation of assay results using a companion smartphone application. Next, we made further improvements and thoroughly validated this platform to create SHINEv2, a further streamlined, equipment-free, and easily deployable technology with the ability to discriminate SARS-CoV-2 variants of concern (VOCs). Given the excellent programmability of CRISPR-Dx, we expanded the use of SHINE beyond SARS-CoV-2 to other clinically relevant pathogens. We developed and validated SHINE assays to detect and discriminate species, subtypes, and variants of influenza virus, with important implications for public health and clinical care. We also designed and tested multiplexed diagnostic assays for the detection and differentiation of three tick-borne pathogens in clinical samples. Finally, given the inadequacy of existing sample processing methods – and their importance to nucleic acid test deployment – we developed a high throughput experimental workflow to analyze the effects of chemical reagents – individually and in combination – on diagnostic assay performance and nuclease activity in patient samples using a commercially available microfluidic platform. Together, the research presented in this thesis contributes to the development of more effective, accessible, and field-deployable diagnostic solutions, thereby enhancing our ability to respond to the global burden of infectious diseases.

Thesis Supervisor:
Pardis Sabeti, MD, PhD
Professor of Organismic and Evolutionary Biology, Harvard University; \Professor of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health; Howard Hughes Medical Institute Investigator

Thesis Committee Chair:
Lee Gehrke, PhD
Hermann L.F. von Helmholtz Professor, Institute for Medical Engineering & Science, MIT; Professor, Microbiology and Immunobiology and Health Science & Technology, Harvard Medical School

Thesis Readers:
Cameron A. Myhrvold, PhD
Assistant Professor of Molecular Biology, Princeton University

Ben P. Kleinstiver, PhD
Assistant Professor of Pathology, Harvard Medical School; Investigator; Kayden-Lambert MGH Research Scholar 2023-2028, Massachusetts General Hospital
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Jon Arizti Sanz is inviting you to a scheduled Zoom meeting.

Topic: Jon Arizti Sanz MEMP PhD Thesis Defense
Time: April 4, 2024, 9:45 AM (for 10 AM Start) Eastern Time (US and Canada)

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