Overview

Our lab uses the tools of chemistry, molecular biology, and computational design to engineer proteins and nucleic acids as self-assembling nanoscale devices. Such devices include molecular barcodes for labeling, timers for kinetic analysis, rulers for measuring distances, printers for molecular manufacturing, and computers for multi-signal processing. Through the application of these tools, our goal is to define the cell-types, cell-states, and cell-cell interactions that underlie the dynamics of disease proression and drug resistance.

Our lab employs a variety of skillsets and techniques, and combines experimentation with computation. Students in the lab gain a broad spectrum of skills including molecular techniques, biochemistry, imaging, coding, device fabrication, and much more.

We are proud to be a multidisciplinary group, and welcome applicants from diverse fields including but not limited to biology, chemistry, physics, engineering, and computer science. All we require is that you’re driven, innovative, self-motivated, and curious with a passion. We also believe that an academic career should not be the only reason to pursue graduate research, and we actively work on projects that can lead to innovative careers including start-up and spin-off ventures. If you are interested in working with us, you can find the application process here!

Research Areas:

Cell-type diversity and cell-cell interactions underlie the formation of multicellular tissues and diseases such as cancer. These interactions invovlve both soluble signaling and physical contacts between cells, and together form a ‘signaling circuit’ that determines tissue-level behaviors. Many emerging cancer drugs, such as immune checkpoint inhibitors and CAR-T cells, are designed to disrupt specific nodes of the signaling circuit. Yet these drugs currently only work in a fraction of patients, suggesting that they are not targeting the most critical signaling nodes in the circuit, and/or that there exists redundant nodes which remain untargeted. Deciphering the nature of this circuit is the first and foremost challenge towards precision and personalized medicine.

The field of DNA nanotechnology has developed a suite of programmable tools for bottom-up molecular barcoding, sensing, and nanofabrication. The current focus of our lab is to use these tools for precise, multiplexed, and spatially resolved cellular analysis and manipulation. Ultimately, this will allow us to build predictive models of drug resistance and rationally designed drugs. Specific projects are detailed below:

Multi-receptor-ligand interactions at single-cell resolution

A major challenge in bio-medicine is to decipher the complex network of biomolecular interactions that give rise to a physiological or disease phenotype. These interactions are complex because they vary spatiotemporally across length scales (e.g., molecules, cells, and tissues), and involve a staggering diversity of biomolecules. We are interested in developing technologies that enable these molecular interactions (as well as their functional consequences!) to be profiled in a sensitive, quantitative, and high-throughput manner. Outcome from this research will help us better understand the molecular “interactome” within cells and tissues, and lead to the discovery of novel biomarkers for the detection and treatment of diseases.

Mapping cell states and interactions at single-cell resolution

Cells use self-assembly interactions between biomolecules to sense, compute, and integrate information about their environment. Inspired by this, we are developing DNA and protein-based computers capable of complex computation. Our approach integrates concepts from DNA nanotechnology, synthetic biology, materials chemistry, and device fabrication in an effort to make computation faster, more scalable, and more accurate. Compared to silicon circuits, these molecular computers have the advantage that they can operate in wet environments, they can directly use biomolecules and cells as inputs, and they do not need a power supply to function. We are interested in developing these capabilities for sensing and biomanufacturing applications.

Enabling molecular programming for single-cell analysis

Using the principles of synthetic biology and the tools of protein engineering and DNA nantoechnology, we aim to create artificial self-assembling machines that can perturb endogenous cellular machineries. By creating artificial nanostructures with precise shapes and dynamics, we can generate machines that perform mechanical and biochemical tasks for controlling cell fate. Ultimately, we hope our artificial molecular machines will rival the functional complexity of naturally-existing molecular machines for applications as next-generation therapeutics.

Projects

Below you will find a list of our current and past projects. These projects revolve around the themes listed above. And yes, Leo enjoys coming up with cryptic project code names, a habit he picked up from his postdoc days :-)

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Arpanet

We design nucleic acid-based transcription factors to make in vitro gene regulatory networks scalable and programmable

BubbleSort

We are using DNA-encoded molecular circuitry to rapidly sort cells. This could be useful for isolating rare cell populations or stem …

Chimera

We are creating synthetic biology methods to barcode large libraries of proteins with DNA barcodes in a parallel manner so as to enable …

picasso

We are developing DNA-based encoding schemes to enable highly-multiplexed in situ protein imaging in cells and clinical tissue …

Factory

We use a spatially programmable capsule made of DNA to organize an enzymatic cascade for coordinated RNA manufacturing

Bigfoot

We are using DNA nanotechnology to design Hi-Fi affinity reagents

Mist

We are using DNA-powered synthetic gene networks to create an in vitro operating system for molecular computing

Prospector

We are using DNA nanotechnology to explore cell surface protein complexes

Gingham

We are creating moleculars computers that can diagnose diseases without the need for instrumentation

Billboard

We are engineering DNA nanostructures to manipulate and re-wire cell receptor signaling