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: 

Dr. Weinberger and colleagues pioneered the study of HIV’s decision circuit and demonstrated that stochastic ‘noise’ in gene expression—Brownian fluctuations arising from diffusion-limited reactions—can drive fate-selection decisions. The lab’s studies identified the molecular sources of noise in HIV, exposed the mechanisms regulating noise, and determined how feedback architectures tune noise for fate selection. The techniques developed for HIV also enabled the lab’s discovery of the first transcriptional accelerator circuit—a high-cooperativity feedback motif that enables signaling systems (e.g. inflammatory responses) to overcome a fundamental tradeoff wherein increased speed generates higher/toxic amplitude. These accelerator circuits in herpesviruses are being exploited for a new class of antiviral target.

Collectively, the lab’s studies overturned dogma that HIV latency was a deterministic cell-driven artifact and instead showed that HIV encodes a ‘hardwired’ latency program that is evolutionarily optimized to harness noise. Gene-expression noise is now acknowledged as a major clinical barrier to reversing HIV latency and curing HIV. These studies laid the foundation for new therapeutic strategies targeting the HIV-latency circuit, including the lab’s prediction and subsequent discovery of noise-enhancer molecules. Noise enhancers potentiate transcriptional activators, substantially increasing their efficacy and ability to activate persistent (i.e., latent) HIV.

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

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