Difference between revisions of "Team:Harvard BioDesign/Practices"

To determine the unique scrutiny which our microbial cancer therapeutic might be subjected to and address specific concerns with synthetic biology, we spoke to Dr. Stephen Sonis, a member of the Scientific Advisory Board at ActoGenix. This company is developing genetically engineered bacteria to treat diseases in the gastrointestinal tract and thus Dr. Sonis is particularly knowledgeable on this topic. We mentioned that Dr. Kronish from the Office of Human Research Services suggested that our microbial therapeutic could be difficult to get through regulatory processes because of inherent differences in its design compared to small molecule therapies. Dr. Sonis reported three major safety concerns that ActoGenix faced with development of their own microbial therapies that we have begun using to inform our design.

Firstly, ActoGenix considers public health implications of release of replicating microbial therapeutics into the broader environment. One could envision uncontrolled replication of such an organism causing release of drugs or other cytotoxic agents into waterways. Hence, he suggested that we should devise some method of controlling our bacteria such that it remains viable only in therapeutic environments. Together, we pondered methods for organism containment including active kill switches and engineered auxotrophy. We recognize that such a containment mechanism will be necessary in order to deploy this project as a cancer therapy and must be integrated once we combine BactoGrip adhesive components with cancer-fighting components.

Secondly, Dr. Sonis urged us to consider how whether a microbial therapeutic could have deleterious effects on cancer patients. Before our system could be approved for clinical trials, we would necessarily have to show that our system doesn’t make cancer patients sicker. There are complications which could arise given how a microbial therapeutics might disrupt the balance of the normal human microbiota through competition for resources in the gut. These concerns tie into what we learned about the drug development process from Dr. Kronish and Dr. Ritz. However, studying the balance various species in the overall gut microbiome could necessitate asking different research questions about microflora not typically tested in the development of traditional small molecule cancer therapeutics. Thus, we must devise tests and assays which are relevant to the specific therapeutic mechanism of BactoGrip for preclinical trials.

Finally, Dr. Sonis mentioned that we should consider whether microbial therapeutics could have deleterious consequences in immunocompromised cancer patients. He suggested that pre-clinical trials should explicitly test the therapeutic on immunocompromised mice, considering that cancer patients often have compromised immune systems. To this end, we incorporated his feedback and researched other candidate chassis organisms that would be less immunogenic compared to E. coli K12 from our proof-of-concept assays. We realized that E. coli Nissile has be used as a probiotic and is thus a more desirable chassis for our therapeutic. We transformed our system into this strain and determined that our BactoGrip pili system is compatible with the strain. In future assays, we will continue testing BactoGrip adhesion using E. coli Nissile cells. By incorporating Dr. Sonis’s feedback about immunology of microbial therapeutics in our system, we have taken the first steps to translating BactoGrip from the lab into people.