Noise Enhancer & Suppressor Molecules

Long ago, chemists realized that chemical-reaction efficiency could be enhanced not only by catalysts but also by increasing the thermal energy (i.e. kT in the Arrhenius equation).  In other words, catalysts deterministically lower activation-energy barriers on potential-energy landscapes (below) but when such deterministic drivers are insufficient to cross the barrier, amplifying thermal fluctuations (e.g. via a Bunsen burner) provides an added perturbation for crossing activation-energy barriers.

Remarkably, this physical-chemistry concept also applies to gene regulation in cell-fate decisions (Dar et al., 2014).  Roughly, the chemical potential-energy landscape can be compared to a Waddington-epigenetic landscape, where transcriptional activators are essentially catalysts and we have identified a class of noise-enhancer compounds that act like biological Bunsen burners.  As a model system, we focus on HIV, where achieving a cure will require latent virus be reactivated and purged.  Unfortunately, current reactivation schemes are ineffective.  Through screening a small-molecule library for compounds that enhance stochastic gene-expression noise.  These noise-enhancer compounds (already FDA approved) act like Bunsen burners, potentiating transcriptional activators to greatly enhance HIV reactivation.  Moreover, noise-suppressor compounds—effectively equivalent to ‘ice packs’—inhibit reactivation.

Since molecular noise is a fundamental biophysical phenomenon—influencing phenotypes from antibiotic persistence to cellular reprogramming and cancer—noise-modulating molecules could provide a general tool to manipulate diverse cell-fate decisions.

Papers of note: Dar et al. Science 2014. (linked above)