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Human Practices: Transitioning From the Bench to the Bedside

Many previous iGEM teams have tried to implement a bacterial therapeutic as part of their project. Outside of iGEM, there has been a steady interest in engineering bacteria to become therapeutic vectors as well. However, the question that guided our human practices project was essentially: Why aren't bacterial therapeutics transitioning into clinical practice or even clinical trials?

While there are certainly many barriers to bacterial therapeutics such as time and money, we hypothesize that iGEM teams, as a result of their unique positions as research and educational institutions, are positioned to address two major barriers to the adoption of bacterial therapeutics: biological barriers and perception barriers.

Biological Barriers to Bacterial Therapeutics

From a technological standpoint, there is a great deal of work that remains to be done before a bacterial therapeutic can enter the drug development pipeline. While many iGEM teams, including us, have helped set the groundwork for bacterial therapeutics, there are still some biological barriers to a bacterial therapeutic. We identified the immunogenicity of laboratory strains of E. coli. as a major biological barrier. We then investigated methods to decrease the immunogenicity of E. coli., eventually choosing to port modules of our target drug delivery system into a non-immunogenic strain of E. coli., Nissle 1917.

The 2012 Penn iGEM team has engineered a novel platform for targeted therapeutics which employs simultaneous spatial and cellular targeting. We have achieved spatial (and temporal) targeting with a blue light-switchable transgene expression system, and cellular targeting through display of an antibody-mimetic protein on the surface of E. coli for the first time.

As a proof of concept, we applied our system to the treatment of cancer, a disease in which spatial and cellular targeting are of utmost importance. We displayed a high-affinity antibody-mimetic protein which targets Human Epidermal Growth Factor Receptor 2 (HER2), a protein commonly overexpressed in cancer cells. We combined this cellular targeting with a light-activated cytotoxic protein delivery system to successfully target and kill breast cancer cells.

Human Practices

Upon conception of this project, we realized that although hundreds of academic research projects and iGEM projects have been conducted in the realm of Health and Medicine, almost no engineered bacterial therapeutics have been brought to the clinic. We analyzed the hurdles and road ahead for bacterial synthetic biology-enabled therapeutics, compiling a thorough report with specific actions which iGEM teams in Health/Medicine can take to make their therapies more clinically tractable. This project directly informed our wet lab work, causing us to port our therapeutic system into a non-pathogenic, probiotic bacterial strain which is already used in human therapies today.

We hope our targeted therapeutic platform will allow other scientists and iGEM teams to target any cells they choose. In the near term, we are planning to test our cancer cell targeting/killing bacterial system in a mouse model and make a real impact on cancer research and therapy.