Philip Hochendoner | Princeton University (original) (raw)

Publications by Philip Hochendoner

Research paper thumbnail of Marching along to an Offbeat Drum: Entrainment of Synthetic Gene Oscillators by a Noisy Stimulus

Modulation of biological oscillations by stimuli lies at the root of many phenomena, including ma... more Modulation of biological oscillations by stimuli lies at the root of many phenomena, including maintenance of circadian rhythms, propagation of neural signals, and somitogenesis. While it is well established that regular periodic modulation can entrain an oscillator, an aperiodic (noisy) modulation can also robustly entrain oscillations. This latter scenario may describe, for instance, the effect of irregular weather patterns on circadian rhythms, or why irregular neural stimuli can still reliably transmit information. A synthetic gene oscillator approach has already proven to be useful in understanding the entrainment of biological oscillators by periodic signaling, mimicking the entrainment of a number of noisy oscillating systems. We similarly seek to use synthetic biology as a platform to understand how aperiodic signals can strongly correlate the behavior of cells. This study should lead to a deeper understanding of how fluctuations in our environment and even within our body may promote substantial synchrony among our cells. Specifically, we investigate experimentally and theoretically the entrainment of a synthetic gene oscillator in E. coli by a noisy stimulus. This phenomenon was experimentally studied and verified by a combination of microfluidics and microscopy using the real synthetic circuit. Stochastic simulation of an associated model further supports that the synthetic gene oscillator can be strongly entrained by aperiodic signals, especially telegraph noise. Finally, widespread applicability of aperiodic entrainment beyond the synthetic gene oscillator is supported by results derived from both a model for a natural oscillator in D. discoideum and a model for predator−prey oscillations.

Research paper thumbnail of Entrainment of a Bacterial Synthetic Gene Oscillator through Proteolytic Queueing

Internal chemical oscillators (chemical clocks) direct the behavior of numerous biological system... more Internal chemical oscillators (chemical clocks) direct the behavior of numerous biological systems, and maintenance of a given period and phase between many such oscillators may be important for their proper function. However, both environmental variability and fundamental molecular noise can cause biochemical oscillators to lose coherence. One solution to maintaining coherence is entrainment, where an external signal provides a cue that resets the phase of oscillators. In this work, we study the entrainment of gene networks by a queueing interaction established by competition between proteins for a common proteolytic pathway. Principles of queueing entrainment are investigated for an established synthetic oscillator in E. coli. We first explore this theoretically using a standard chemical reaction network model and a map-based model, which both suggest that queueing entrainment can be achieved through pulsatile production of an additional protein competing for a common degradation pathway with the oscillator proteins. We then use a combination of microfluidics and fluorescence microscopy to verify that pulse trains modulating the production rate of a fluorescent protein targeted to the same protease (ClpXP) as the synthetic oscillator can entrain the oscillator.

Research paper thumbnail of A queueing approach to multi-site enzyme kinetics

Multi-site enzymes, defined as where multiple substrate molecules can bind simultaneously to the ... more Multi-site enzymes, defined as where multiple substrate molecules can bind simultaneously to the same enzyme molecule, play a key role in a number of biological networks, with the Escherichia coli protease ClpXP a well-studied example. These enzymes can form a low latency ‘waiting line’ of substrate to the enzyme’s catalytic core, such that the enzyme molecule can continue to collect substrate even when the catalytic core is occupied. To understand multi-site enzyme kinetics, we study a discrete stochastic model that includes a single catalytic core fed by a fixed number of substrate binding sites. A natural queueing systems analogy is found to provide substantial insight into the dynamics of the model. From this, we derive exact results for the probability distribution of the enzyme configuration and for the distribution of substrate departure times in the case of identical but distinguishable classes of substrate molecules. Comments are also provided for the case when different classes of substrate molecules are not processed identically.

Research paper thumbnail of Marching along to an Offbeat Drum: Entrainment of Synthetic Gene Oscillators by a Noisy Stimulus

Modulation of biological oscillations by stimuli lies at the root of many phenomena, including ma... more Modulation of biological oscillations by stimuli lies at the root of many phenomena, including maintenance of circadian rhythms, propagation of neural signals, and somitogenesis. While it is well established that regular periodic modulation can entrain an oscillator, an aperiodic (noisy) modulation can also robustly entrain oscillations. This latter scenario may describe, for instance, the effect of irregular weather patterns on circadian rhythms, or why irregular neural stimuli can still reliably transmit information. A synthetic gene oscillator approach has already proven to be useful in understanding the entrainment of biological oscillators by periodic signaling, mimicking the entrainment of a number of noisy oscillating systems. We similarly seek to use synthetic biology as a platform to understand how aperiodic signals can strongly correlate the behavior of cells. This study should lead to a deeper understanding of how fluctuations in our environment and even within our body may promote substantial synchrony among our cells. Specifically, we investigate experimentally and theoretically the entrainment of a synthetic gene oscillator in E. coli by a noisy stimulus. This phenomenon was experimentally studied and verified by a combination of microfluidics and microscopy using the real synthetic circuit. Stochastic simulation of an associated model further supports that the synthetic gene oscillator can be strongly entrained by aperiodic signals, especially telegraph noise. Finally, widespread applicability of aperiodic entrainment beyond the synthetic gene oscillator is supported by results derived from both a model for a natural oscillator in D. discoideum and a model for predator−prey oscillations.

Research paper thumbnail of Entrainment of a Bacterial Synthetic Gene Oscillator through Proteolytic Queueing

Internal chemical oscillators (chemical clocks) direct the behavior of numerous biological system... more Internal chemical oscillators (chemical clocks) direct the behavior of numerous biological systems, and maintenance of a given period and phase between many such oscillators may be important for their proper function. However, both environmental variability and fundamental molecular noise can cause biochemical oscillators to lose coherence. One solution to maintaining coherence is entrainment, where an external signal provides a cue that resets the phase of oscillators. In this work, we study the entrainment of gene networks by a queueing interaction established by competition between proteins for a common proteolytic pathway. Principles of queueing entrainment are investigated for an established synthetic oscillator in E. coli. We first explore this theoretically using a standard chemical reaction network model and a map-based model, which both suggest that queueing entrainment can be achieved through pulsatile production of an additional protein competing for a common degradation pathway with the oscillator proteins. We then use a combination of microfluidics and fluorescence microscopy to verify that pulse trains modulating the production rate of a fluorescent protein targeted to the same protease (ClpXP) as the synthetic oscillator can entrain the oscillator.

Research paper thumbnail of A queueing approach to multi-site enzyme kinetics

Multi-site enzymes, defined as where multiple substrate molecules can bind simultaneously to the ... more Multi-site enzymes, defined as where multiple substrate molecules can bind simultaneously to the same enzyme molecule, play a key role in a number of biological networks, with the Escherichia coli protease ClpXP a well-studied example. These enzymes can form a low latency ‘waiting line’ of substrate to the enzyme’s catalytic core, such that the enzyme molecule can continue to collect substrate even when the catalytic core is occupied. To understand multi-site enzyme kinetics, we study a discrete stochastic model that includes a single catalytic core fed by a fixed number of substrate binding sites. A natural queueing systems analogy is found to provide substantial insight into the dynamics of the model. From this, we derive exact results for the probability distribution of the enzyme configuration and for the distribution of substrate departure times in the case of identical but distinguishable classes of substrate molecules. Comments are also provided for the case when different classes of substrate molecules are not processed identically.