Leor Weinberger, PhD

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Leor Weinberger, PhD

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Director, Gladstone Center for Cell Circuitry
Professor, School of Medicine
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Biography

Weinberger and colleagues discovered the HIV latency circuit (Weinberger* et al. Cell 2005), which provided the first experimental evidence that stochastic fluctuations (‘noise’) in gene expression drive biological fate decisions. Noise-driven decisions were then found in systems ranging from bacteria to cancer. The lab's studies overturned dogma in the field by showing that HIV latency was a ‘hardwired’ virus program (Razooky et al. Cell 2015; Rouzine et al. Cell 2015) and discovered stochastic latency programs in other viruses (Chaturvedi et al. PNAS 2020). For these contributions, Weinberger received the NIH Avant-Garde award for HIV research and an NIH Merit Award. The lab discovered noise-enhancer molecules (Dar et al. Science 2014), now used by numerous other labs—e.g., to modulate circadian rhythms (Li et al. PNAS 2020)—and discovered a cellular noise-control pathway that potentiates embryonic cell-fate transitions (Desai et al. Science 2021). These studies demonstrated that transcriptional noise can be a ‘feature not a bug’ of cellular systems and play a functional, physiological role. On the therapeutic front, the lab conceptualized and forwarded Therapeutic Interfering Particles (TIPs) (Weinberger et al. J Virol. 2003)—a first-in-class antiviral countermeasure that is single-dose and escape-resistant (see TED talk, below). The lab's initial work led to the DARPA INTERCEPT program (a $40M initiative that funded dozens of virology labs worldwide from 2015–20). In 2020, the lab discovered TIPs for SARS-CoV-2 (Chaturvedi et al. Cell 2021)—the first TIP reported for any virus—and provided long-sought evidence for the therapeutic effect of the TIP mechanism of action. Following FDA reviews, the DoD and NIH funded TIP clinical trials for HIV and SARS-CoV-2.
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  1. Chaturvedi S, Beutler N, Vasen G, Pablo M, Chen X, Calia G, Buie L, Rodick R, Smith D, Rogers T, Weinberger LS. A single-administration therapeutic interfering particle reduces SARS-CoV-2 viral shedding and pathogenesis in hamsters. Proc Natl Acad Sci U S A. 2022 09 27; 119(39):e2204624119.
  2. Chaturvedi S, Beutler N, Pablo M, Vasen G, Chen X, Calia G, Buie L, Rodick R, Smith D, Rogers T, Weinberger LS. A single-administration therapeutic interfering particle reduces SARS-CoV-2 viral shedding and pathogenesis in hamsters. bioRxiv. 2022 Aug 11.
  3. Chaturvedi S, Pablo M, Wolf M, Rosas-Rivera D, Calia G, Kumar AJ, Vardi N, Du K, Glazier J, Ke R, Chan MF, Perelson AS, Weinberger LS. Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents. Cell. 2022 06 09; 185(12):2086-2102.e22.
  4. Leor S. Weinberger. A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Biophysical Journal. 2022 Feb 1; 121(3):447a.
  5. Hota SK, Rao KS, Blair AP, Khalilimeybodi A, Hu KM, Thomas R, So K, Kameswaran V, Xu J, Polacco BJ, Desai RV, Chatterjee N, Hsu A, Muncie JM, Blotnick AM, Winchester SAB, Weinberger LS, Hüttenhain R, Kathiriya IS, Krogan NJ, Saucerman JJ, Bruneau BG. Brahma safeguards canalization of cardiac mesoderm differentiation. Nature. 2022 02; 602(7895):129-134.
  6. Chaturvedi S, Vasen G, Pablo M, Chen X, Beutler N, Kumar A, Tanner E, Illouz S, Rahgoshay D, Burnett J, Holguin L, Chen PY, Ndjamen B, Ott M, Rodick R, Rogers T, Smith DM, Weinberger LS. Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance. Cell. 2021 12 09; 184(25):6022-6036.e18.
  7. Desai RV, Chen X, Martin B, Chaturvedi S, Hwang DW, Li W, Yu C, Ding S, Thomson M, Singer RH, Coleman RA, Hansen MMK, Weinberger LS. A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Science. 2021 08 20; 373(6557).
  8. Chen X, Pablo M, Weinberger L. Evaluation of Singer et al.: Technical points on analyzing viral replication kinetics in single cells. Cell Syst. 2021 03 17; 12(3):205-206.
  9. Notton T, Glazier JJ, Saykally VR, Thompson CE, Weinberger LS. RanDeL-Seq: a High-Throughput Method to Map Viral cis- and trans-Acting Elements. mBio. 2021 01 19; 12(1).
  10. Chaturvedi S, Klein J, Vardi N, Bolovan-Fritts C, Wolf M, Du K, Mlera L, Calvert M, Moorman NJ, Goodrum F, Huang B, Weinberger LS. A molecular mechanism for probabilistic bet hedging and its role in viral latency. Proc Natl Acad Sci U S A. 2020 07 21; 117(29):17240-17248.
  11. Chaturvedi S, Engel R, Weinberger L. The HSV-1 ICP4 Transcriptional Auto-Repression Circuit Functions as a Transcriptional "Accelerator" Circuit. Front Cell Infect Microbiol. 2020; 10:265.
  12. Li Y, Shan Y, Desai RV, Cox KH, Weinberger LS, Takahashi JS. Noise-driven cellular heterogeneity in circadian periodicity. Proc Natl Acad Sci U S A. 2020 05 12; 117(19):10350-10356.
  13. Hansen MMK, Martin B, Weinberger LS. HIV Latency: Stochastic across Multiple Scales. . 2019 12 11; 26(6):703-705.
  14. Herzig E, Kim KC, Packard TA, Vardi N, Schwarzer R, Gramatica A, Deeks SG, Williams SR, Landgraf K, Killeen N, Martin DW, Weinberger LS, Greene WC. Attacking Latent HIV with convertibleCAR-T Cells, a Highly Adaptable Killing Platform. Cell. 2019 10 31; 179(4):880-894.e10.
  15. Hansen MMK, Weinberger LS. Post-Transcriptional Noise Control. Bioessays. 2019 07; 41(7):e1900044.
  16. Hansen MMK, Desai RV, Simpson ML, Weinberger LS. Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability. Cell Syst. 2018 10 24; 7(4):384-397.e6.
  17. Vardi N, Chaturvedi S, Weinberger LS. Feedback-mediated signal conversion promotes viral fitness. Proc Natl Acad Sci U S A. 2018 09 11; 115(37):E8803-E8810.
  18. Hansen MMK, Wen WY, Ingerman E, Razooky BS, Thompson CE, Dar RD, Chin CW, Simpson ML, Weinberger LS. A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. Cell. 2018 06 14; 173(7):1609-1621.e15.
  19. Saykally VR, Rast LI, Sasaki J, Jung SY, Bolovan-Fritts C, Weinberger LS. A Bioreactor Method to Generate High-titer, Genetically Stable, Clinical-isolate Human Cytomegalovirus. Bio Protoc. 2017 Nov 05; 7(21).
  20. Razooky BS, Cao Y, Hansen MMK, Perelson AS, Simpson ML, Weinberger LS. Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean. PLoS Biol. 2017 Oct; 15(10):e2000841.
  21. Pai A, Weinberger LS. Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets. Annu Rev Virol. 2017 09 29; 4(1):469-490.
  22. Aull KH, Tanner EJ, Thomson M, Weinberger LS. Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch. Biophys J. 2017 Jun 06; 112(11):2428-2438.
  23. Dar RD, Shaffer SM, Singh A, Razooky BS, Simpson ML, Raj A, Weinberger LS. Transcriptional Bursting Explains the Noise-Versus-Mean Relationship in mRNA and Protein Levels. PLoS One. 2016; 11(7):e0158298.
  24. Ali I, Ramage H, Boehm D, Dirk LM, Sakane N, Hanada K, Pagans S, Kaehlcke K, Aull K, Weinberger L, Trievel R, Schnoelzer M, Kamada M, Houtz R, Ott M. The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7. J Biol Chem. 2016 07 29; 291(31):16240-8.
  25. Rast LI, Rouzine IM, Rozhnova G, Bishop L, Weinberger AD, Weinberger LS. Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals. PLoS Comput Biol. 2016 05; 12(5):e1004799.