We are a platform innovation lab

We expand the platforms at hand to build with biology and, in the process, expand what they can do to unlock new biotechnology.

Cell-free gene expression systems recreate the same gene transcription and translation in an open test tube reaction. By removing constraints such as cell growth and survival in a living cell, cell-free systems let us design and engineer biological systems that are difficult, and sometimes impossible, to work on.

For decades, the E. coli lysate-based cell-free system has been the workhorse powering biotechnology innovations, but it also set an inconvenient ceiling. Crude lysate carries thousands of native enzymes and regulatory molecules that interfere with engineered systems, and E. coli’s own biochemistry cannot support the growing diversity of designs people want to build.

Sooner or later, the limit isn't what biology can do, it's what the platform can support.

We are now facing this ceiling. Our ability to design and build with biology is advancing faster than ever, but the platform can no longer support our endeavors. So we build better platforms.

Expanding the Platforms We Work On

Most cell-free platforms are built from the lysate of a single host, and the composition of that lysate is a black box.

We characterize the proteome, RNA pool, and metabolome in detail to understand how the reaction chemistry actually comes together to support gene expression. This has already pinpointed concrete, fixable bottlenecks, from a missing cofactor to mismatched tRNA usage and availability. Diagnosing a bottleneck lets us engineer the host and the reaction conditions against it, arriving at reaction environments that are simpler to assemble and more reliably productive.

Reconstituted systems use purified components rather than crude extract, trading yield and cost for control over composition.

We develop custom reconstituted platforms for sensing tasks that will not work in a crude lysate background at all. Stripping away the murky background chemistry creates a clean reaction environment in which a sensor responds only to its intended signal. The longer goal is a design-build-test workflow where every element’s purpose and activity is known, so reaction rate and yield are set deliberately rather than discovered by trial and error.

Relevant Works

What New Platforms Open Up

A platform is only as interesting as what it lets someone build. Each capability we add opens applications that were previously out of reach, and each application we chase exposes the next platform limitation. Two directions currently drive the work.

Traditional phage work requires propagating a susceptible host. A cell-free platform removes that requirement so we can build better phages.

As antibiotic resistance spreads, bacteriophages, the natural predators of bacteria, are drawing renewed attention as antimicrobials against multidrug-resistant infections. We reboot phage directly from genome sequence, assembling and recovering infectious particles without a host, which makes production and engineering far faster. We are building this capability out across diverse phage and engineering them against ESKAPE pathogens.

Swap the genetic program, and the same reaction detects a different target.

Cell-free reactions are unusually well suited to diagnostics: one reaction can be retargeted from ions and small molecules to nucleic acids and proteins just by changing the sensor and reporter it expresses. For point-of-need use, these reactions can be freeze-dried for ambient-temperature storage and shipping, then activated by adding the sample itself. We build toward diagnostics that are fast, low-cost, and field-deployable while still meeting the sensitivity and specificity that real clinical and environmental samples demand.

Relevant Works

Shipping the Program

Building outside the cell, in an open tube, lets us see and control every variable. Shipping is where we give that control up and test whether we’ve got it right.

A phage rebooted in a tube has to go on to infect a live pathogen. A sensor built in a clean reconstituted reaction has to return a true answer in serum, in an environmental sample, in whatever someone actually hands us. Both are the same test in different form: the program has to hold true in the wild.

That trip is the hardest test we can give our own work, and it is where our funded projects point: engineering rebooted phage against live ESKAPE pathogens, and detecting, eliminating, and reprogramming the oncogenic bacteria implicated in colorectal cancer.

More detail on the adaptive phage framework and the oncogenic bacteria project.