Research Overview

Technology is driving revolutionary changes in biology. What began as the sequencing era has led to methods for deducing the network architecture that defines gene regulation and cellular signaling. Systems Biology can be viewed as the generation of such networks, along with the development of computational models to describe how they mitigate cellular behavior. Likewise, DNA synthesis technologies are driving the development of Synthetic Biology, whereby genomes can be reconstituted from chemical building blocks. This could lead to cells with highly reduced genomic complexity, as genes that govern the ability to adapt to multiple environments are eliminated to construct specialized organisms for biotechnology and basic research. Finally, imaging technologies that span many length scales, from tissues to single molecules, are catalyzing the development of Quantitative Biology. A central goal of Q-Bio is the deduction of the fundamental equations that can be used to describe biology.

The Biodynamics Laboratory (BDL) seeks to understand the network interactions that mediate gene regulation and cellular signaling. Since behavior arising from these complex interactions is difficult to predict with qualitative reasoning, we employ experimentally validated computational modeling approaches. We design and construct de novo synthetic gene circuits, which provide a natural framework for reducing the complexity of gene regulatory networks. We use tools from physics and engineering to study such simplified systems and to dissect, analyze, and control the modular components that govern the dynamics of gene regulation and cellular signaling.

Synthetic Biology

Quorum-triggered oscillations in a growing population
The engineering of genetic circuits with predictive functionality in living cells is a defining focus of synthetic biology. What started with the design and construction of a genetic toggle switch and an oscillator a decade ago, has led to circuits capable of pattern generation, edge detection and event counting. We have sucessfully engineered a gene network with global intercellular coupling which can generate synchronized oscillations in a growing population of cells- using microfluidic devices tailored for cellular populations at differing length scales, we investigate synchronization properties and spatiotemporal waves. Our synchronized genetic clock sets the stage for the use of microbes in the creation of a macroscopic biosensor with an oscillatory output, and provides a specific model system for the generation of a mechanistic description of emergent coordinated behaviour at the colony level.

Systems Biology

Single-cell gene response in a changing environment
Natural selection dictates that cells respond optimally to environmental changes. The nature of such an optimal response is likely to depend on the specifics of the dynamically changing environment. For example, a rapid response may be optimal when environmental changes are slow, whereas a slow response may be necessary to effectively filter undesirable environmental fluctuations. While this assumption of a context-dependent cellular response is perhaps natural, the current understanding of the regulation of most cellular processes has relied on data generated from static or semi-static environments. We focus on systems biology approaches aimed at transforming our understanding of cellular response from the realm of tightly controlled batch experiments to that of dynamically changing environmental conditions.

Mammalian Cell Signaling

Dynamic macrophage response to lipopolysaccharide (24hrs)
The tools we use to construct and explore synthetic systems can also be used in larger-scale networks. Mammalian cells are capable of undergoing extreme changes in transcription and behavior in response to single signals at nanomolar concentrations. Intrinsic and extrinsic noise play a large role in this process- cells exposed to the same signal behave extremely heterogeneously. As a result, many large-scale responses have been notoriously difficult to even define with traditional static and population-level studies. We take a new approach to these systems, describing changes in expression and behavior using newly-developed automated tracking techniques. We use this approach to study responses in dynamic signaling environments which more accurately replicate in vivo conditions.

Rational Design and Evolution

A competitive growth advantage in a natural environment is a key to survival, as the ability to consume available nutrients and grow faster than competing organisms ensures the propagation of a species. Therefore, organisms have evolved complex metabolic networks to confer the optimal growth characteristics in their most common environments. We combine microfluidic technology and synthetic biology with quantitative modeling to engineer competitive growth advantages in dynamic environments through both a natural evolutionary process as well as synthetic network construction.

Microfluidics Design

Microfluidics chip loaded with E. Coli
The use of microfluidic technology has become widely popular in the field of synthetic biology and beyond. Microfluidics facilitates the study of cellular behavior because it provides the necessary tools for recreating in vivo-like cellular microenvironments. We use microfluidic devices to observe cellular development within dynamic microenvironments, and design devices to generate thermal or chemical gradients or incorporate large-scale networks of fluidic channels for high-throughput cellular analysis. With these devices, we can generate single-cell expression profiles for a large number of cells, which is essential to understanding the roles of regulatory motifs within native and synthetic gene networks.