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Pathogen Genomic Surveillance & Epidemiology

We are building and applying advanced genomic and computational technologies to study viral pathogens.

We use genomics to gain insights into the emergence, spread, and evolution of outbreaks. Over the past decade, we’ve tackled viral pathogens such as Ebola, Lassa, Zika, Mumps, and SARS-CoV-2, while fostering collaborative research programs in Nigeria, Sierra Leone, and Senegal. We support frontline responders and public health efforts through technology transfer and training. We are working to expand our genomic surveillance and epidemiology efforts, integrating sequencing with diagnostics and advanced analytics, and we’re creating a hub for diagnostics, sequencing, and analytics to support local and global public health initiatives.

Gire et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science 2014. | Metsky et al.  Zika virus evolution and spread in the Americas. Nature 2017 | Siddle et al.  Transmission from vaccinated individuals in a large SARS-CoV-2 Delta variant outbreak. Cell 2021

Pandemic Preemption and Response

We are developing technologies to identify unknown pathogens at genome centers and known pathogens anywhere they may emerge. 

To track emerging pathogen threats in real time, we are developing  a new class of diagnostics that leverage CRISPR-Cas technologies for enhanced accuracy and sensitivity combined. We are developing new machine learning methods for rapid, optimized diagnostic design across all diagnostic modalities. We are also developing experimental and computational techniques for unbiased deep sequencing-based detection of viruses and hybrid capture-based approaches for efficiently capturing numerous diverse viruses simultaneously.  These tools have been successfully used to help to discover novel viruses.

Myrhvold et al.  Field-deployable viral diagnostics using CRISPR-Cas13. Science 2018 | Ackerman et al.  Massively multiplexed nucleic acid detection with Cas13.  Nature 2020 | Arizti Sanz et al.  Simplified Cas13-based assays for the fast identification of SARS-CoV-2 and its variants. Nature 2022

Microbial Biology and Countermeasures

We are uncovering a deeper understanding of viral biology: mutations and evolution, virus-host interactions, virus-mediated gene regulation, and natural antiviral systems. 

During the 2014 West African Ebola outbreak and COVID-19, we showed how viral mutations impact the unfolding of an outbreak. We collaborated with the Jeremy Luban lab to show that mutations in receptor proteins conferred increased infectivity in human cells. We have worked with partners to conduct single-cell profiling of Ebola and other BL-4 pathogens to investigate details of gene regulation and immune responses. We have explored the therapeutic potential of CRISPR-Cas systems, showing their success in reducing viral load and infectivity in mammalian cells. We have created massively parallel technologies to identify the wide range of peptides viruses produce and studying which of these they present to our immune systems. 

Diehl et al. Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic. Cell 2016 | Kotliar et al.  Single-Cell Profiling of Ebola Virus Disease In Vivo Reveals Viral and Host Dynamics. Cell 2020 |  Weingarten-Gabbay et al.  Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell 2021

Human Genetic Variation and Disease

We are identifying associations between genomic loci and human diseases, characterizing the consequences of genetic variants, and leveraging variation to improve human health.

Most disease-associated and evolutionarily adaptive mutations occur in non-coding regions, which are difficult to study through conventional means. We developed a massively parallel reporter assay to investigate differences in expression between alleles at thousands of sites in non-coding regions. Our lab has leveraged our cross-disciplinary work in human disease and viral evolution, to discover viral capsids that target specific cell types for precise gene delivery. Finally, we continue to study human evolution around the world, characterizing background patterns of variation, developing neutral demographic models and simulations, and constructing machine learning approaches to localize signals of selection. 

 

Grossman et al. Identifying Recent Adaptations in Large-Scale Genomic Data. Cell 2013 | Tewhey, et al. Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay. Cell 2016 | Tabebordbar et al. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell 2021

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  • Dr. Sabeti announced as HHMI investigator
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