Current technologies for designing multi-functional biologics with predictable therapeutic properties are limited. I will describe the design and construction of next-gen genomically recoded organisms (GROs), in which multiple codons have been eliminated from the genome of E. coli to enhance the genetic encoding of synthetic amino acids (sAAs) at monomeric precision. Genetically encoded synthetic chemistries serve as attachment sites for modalities to tune therapeutic properties of protein or peptide therapeutics. Next-gen GROs establish a new paradigm for producing entirely new classes of multi-functional ‘smart biologics’ comprising diverse chemistries.

My laboratory approaches fundamental questions in virology through the lens of systems biology. We recently discovered thousands of 'hidden' viral proteins across ~700 viral genomes by developing Massively Parallel Ribosome Profiling (MPRP). This new universe of proteins includes immune targets for vaccine design and genomic elements that regulate viral protein expression, offering fresh insights into the complexity of viral gene regulation.

Our genomes encode the re-use of elements (signaling pathways, transcription factors, etc.) in multiple distinct contexts to achieve remarkably organized processes during embryogenesis. Here we will discuss (1) how the sequential order of activities can be essential for stem cell differentiations and (2) the development of Syntax's synthetic biology system (the Cellgorithm platform), which was built to control stem cell differentiations via pre-programmed, CRISPR-based, step-wise endogenous gene regulations.

Site-specific incorporation of noncanonical amino acids (ncAAs) into proteins expressed in living cells by reprogramming the genetic code offers powerful new ways to probe and engineer protein structure and function. In this presentation, I will describe our recent work on expanding the scope of this technology and its application to develop next-generation biotherapeutics such as antibody-drug conjugates and enhanced AAV vectors for gene therapy.

Nature has inspired the development of half of all oral medicines, making natural products a rich source for novel drug candidates. But nature only makes minute quantities of the world’s most critical molecules, and only rarely are they safe and efficient for human healthcare. This presentation will showcase how Biomia uniquely facilitates access, expansion, and exploration of nature-inspired molecules, by combining innovative manufacturing and AI-assisted drug discovery of novel, safe, and efficient therapies in one platform.

The programmability of mRNA therapeutics makes them amenable to synthetic biology approaches for drugging previously undruggable targets. By utilizing synthetic genetic circuits, we have developed STX-003, an mRNA that expresses IL-12 specifically in tumors. Recombinant IL-12 has potent antitumor effects but is prohibitively toxic. Through the power of synthetic biology, STX-003 leverages the antitumor activity of IL-12 while minimizing its toxicity, improving tolerability while effectively controlling tumors.

Tissue targeting remains a grand challenge for engineering—hindered by the low throughput and high cost of in vivo testing. Manifold Bio has built a state-of-the-art in vivo Multiplexed Protein Screening Platform, powered by a protein barcoding technology called mCodes. In this work, we screen thousands of nanobody shuttles against 59 unique BBB receptors in mice to identify a novel portal, PX1. In the first ever multiplexed NHP study, we screened 38 lead shuttles to identify ones engineered at Manifold Bio within the past two years on par with benchmarks, highlighting the impact in vivo screening can have on antibody design.