Reconfiguring probiotics as recombinant therapeutics
This research involves the development of modular expression cassettes that will re-configure target organisms for safe and effective therapeutic synthesis within a mammalian host. We are engineering enteric bacteria into effective in vivo cellular factories, responding to a specific molecular imbalance by synthesizing an appropriate corrective therapeutic. Cellular therapies share a need for accurate detection of target molecule levels, benign coexistence within the host, and a sufficient level of tunable gene expression.
As an example, we engineer bacteria to reprogram intestinal cells into glucose-responsive, insulin-secreting cells. In this work, bacteria secrete human signals that bind to outer membrane proteins in intestinal epithelia, thereby transforming them into a “pancreatic-like” cell that can replace lost pancreatic functionality in a host. See the “Cool Stuff” tab for a video of the approach.
Synthetic Intestines and In vitro models
We are developing synthetic intestinal scaffolds that are capable of housing both human epithelia and bacteria for several applications in (1) regenerative medicine, (2) in vitro drug design and (3) reducing the need for animal models of disease. See the “Cool Stuff” tab for a video of the approach.
We are also exploring nematode models of disease that include both human and rodent components.
Controlled in vivo mutagenesis
Bacteria have evolved systems that can allow for continued gene transcription in times of stress. We are using these systems and combining them with genes from various organisms to allow for targeted, in vivo mutagenesis that can be screened in real time.
Adaptive gene silencing
Microorganisms have several mechanisms for sensing and responding to their environments. We want to learn more about these mechanisms (such as promoters, enhancers, and inhibitors), and incorporate them into biotechnological solutions to a wide variety of problems. By using tunable gene silencing via RNA interference (RNAi), short RNAs (sRNA), or micro RNA, we can study the dynamics of signaling cascades that are controlled by sensing mechanisms. From here we use cell signaling and tunable gene expression to correct and enhance target organisms so they can more effectively adapt to environments that we define.
Join Us! We are looking for a few talented and energetic researchers to join our team. If you’re interested in any of these project areas and have some ideas you’d like to put to the test, contact Professor March at the following email address: jcm224@cornell.edu. If you’re sending blanket emails to nearly everyone in the academic universe, please don’t reply.