Leor Weinberger, PhD

Director, Gladstone Center for Cell Circuitry
William and Ute Bowes Distinguished Professor
Professor
Department of Biochemistry and Biophysics
Department of Pharmaceutical Chemistry
+1 415 734-4857
Research Description: 

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.

Primary Thematic Area: 
Virology & Microbial Pathogenesis
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Regulatory Circuitry of Viruses and Engineering Novel Therapeutics
Mentorship Development: 

2022 Gladstone Outstanding Mentoring Award

Websites

Publications: 

Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents.

Cell

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

Brahma safeguards canalization of cardiac mesoderm differentiation.

Nature

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

Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance.

Cell

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

A DNA-repair pathway can affect transcriptional noise to promote cell fate transitions.

Science (New York, N.Y.)

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