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Postdoctoral Scholar position at the Gladstone Institutes:
Harnessing the RNA-binding properties of Cas13a for HIV-1 self-testing
The Laboratory of Professor Jennifer Doudna at the Gladstone Institutes in San Francisco invites applications for a Postdoctoral Scholar position. Professor Doudna’s laboratory is within the Gladstone Institute of Data Science and Biotechnology and is funded in part by an NIH collaborative R33/R61 grant entitled “Harnessing the RNA-binding properties of Cas13a for HIV-1 self-testing”. The focus of this program is to develop a qualitative (yes/no) technology to enable patients to test themselves for the presence of HIV using their cell phones as a reader of a fluorescent signal. The project has three aims: 1) optimize crRNA and Cas13a for increased sensitivity; 2) develop enhanced read-out technology for mobile phones; and 3) apply the optimized assay to clinical samples. The Doudna Lab will be work closely on this project with the laboratory of Dr. Melanie Ott at Gladstone, and with the laboratories of Drs. Dan Fletcher and Steven Deeks at the affiliated UC San Francisco. The collaboration with the Ott laboratory will have a specific focus on assay development.
Our long-term goal is to contribute necessary biomedical knowledge and technology to enable clinical HIV-1 cure strategies. Our recent discovery that Cas13a binds RNA in a sequence-specific manner and subsequently exerts a general RNase activity that can be exploited for specific RNA detection (Abudayyeh et al., 2016, PMCID: PMC5127784; East-Seletsky, et all, PMCID: PMC5576363) suggests that this protein is suitable for sensitive detection of HIV RNA in biological samples without employing RT or amplification steps. This RNase behavior has recently been adapted for detection of Zika and Dengue virus RNAs (Gootenberg et al., 2017, PMCID: PMC5526198). Our own preliminary results show that recombinant Cas13a in combination with HIV-1-specific guide RNAs (crRNAs) leads to sensitive detection of HIV-1 RNAs. Our rationale is that the systematic and comprehensive exploration of the biological properties of the Cas13a system will lead to a fundamentally new approach to HIV RNA detection with unique advantages for self-testing: a single-step procedure, straight-forward detection technology, no RT and amplification steps.
We need to optimize three components: first, both guide and homolog selection; second, the RNase Alert assay for sensitive and convenient self-testing; and third, for to achieve the necessary sensitivity and specificity for at-home use. We anticipate these studies will lead to paradigm-shifting new technology to enable early and frequent monitoring of HIV infection. This postdoctoral scholar will develop and optimize a reporter assay using Cas13a to detect clinically relevant titers of HIV and to distinguish between viral serotypes. They will screen Cas13a homologues for sensitivity of on-target and off-target binding and will define optimal substrates of nuclease binding and testing orthogonality of crRNA individually and in a multiplexed environment. Additionally, the postdoctoral scholar will complete chemical analysis to optimize the readout system.
A Ph.D. with a strong background in biochemistry and genetics (or related disciplines) is required. Experience with working in teams, as well as an ability to work independently, is essential. Applicants should submit a cover letter, CV, and a summary of research experience. Three (3) confidential letters of reference will be requested. Minorities and women are especially encouraged to apply.
HHMI is an Equal Opportunity Employer