MIT-OpenBiome Translational Microbiome Workshop
Select one or more prompts to discuss and brainstorm around with teams of 3-6. Each team should contain at least one member from MIT, OpenBiome and a non-MIT/OpenBiome member at large.
- What degree of phylogenetic resolution is clinically relevant and/or desirable for microbial associations or interventions?
- How can we effectively deliver intact microbial strains and communities?
- How can we select donors to maximize clinical efficacy of FMT in new indications beyond FMT?
- How can OpenBiome safely and sustainably increase the quantity of stool collected to meet the growing clinical need?
- How should fecal microbiota for transplantation be regulated?
1. What degree of phylogenetic resolution is clinically relevant and/or desirable for microbial associations or interventions?
Microbiome studies are usually conducted using one of three approaches: qPCR, 16S rRNA and Whole Genome Shotgun (WGS) sequencing. qPCR is cheap and quantitative, but limits itself to a pre-specified set of microbes for which specific primers were designed. 16S rRNA is of medium cost, and is good for identifying the presence and abundance of different taxa, but is limited to the region of the 16S gene being amplified and thus cannot detect differences at the genomic level or minor strain-differences not visible in that sequence. WGS is more expensive, but sequences everything in the sample and therefore yields more information about genomic contents and sequences outside of the 16S gene, while giving a slightly lower but similar level of community coverage to 16S. Alternate approaches can include designing primers for sequence amplicons other than the 16S gene, that allows for more precise identification and quantification of specific strains or specific gene isoforms (e.g. MLST).
- Do clinical microbiome applications benefit from identification of specific strains at a higher resolution than is available with 16S sequencing? Is there evidence for this?
- Do clinical microbiome applications benefit from identification of specific genes and/or gene isoforms in the microbial metagenome?
- Are there hybrid forms of these technologies or other ‘middle ground’ approaches that could enhance the ability of clinical researchers to identify associations between the microbiome and disease?
- Are there faster or lower cost tools for achieving these objectives?
2. How can we effectively deliver intact microbial strains and communities?
The efficacy of microbial therapeutics implicitly relies on the delivery of viable cells to their site of action. Current methods in FMT are either invasive or poorly targeted and are likely to compromise the viability of oxygen-sensitive strains. Long term storage is likely to further compromise viability. Furthermore, existing delivery techniques are either highly invasive (e.g. colonoscopy) or poorly targeted (e.g. current capsules/enema). Existing coating technologies rely on a thermo-stable active pharmaceutical ingredients (API). Beyond simply processing samples in an anaerobic chamber and using acid-resistant capsules, what can we do to facilitate the delivery of intact microbial communities?
People: Elaine Vo, Gina Mendolia, Mark Smith
3. How can we select donors to maximize clinical efficacy of FMT in new indications beyond FMT?
Although FMT from healthy donors is highly effective for the treatment of recurrent C difficile infections, regardless of the healthy donor used, this may not be the case for other indications. In particular, a recent study investigating FMT in UC (Moayeddi, 2015) found that a single donor achieved a 39% efficacy (7/18) while four other donors achieved an aggregate efficacy of 10% (2/20). This suggests that there could be significant heterogeneity in donor efficacy. Given this potential for heterogeneity, we are eager to define best practices in donor selection. Specific clinically desirable components could be metabolites, microbial profiles, or a desirable level of community diversity. There are many open questions regarding best practices in trial design and donor selection.
- Does it make sense to combine material from multiple donors into a single FMT treatment?
- How should we select donors for indications for which microbial associations are poorly understood?
- What type of experimental and/or computational data should we include in this donor selection process?
- People: Mark Smith, Zain Kassam, Thomas Gurry, Scott Oleson
- Papers: Heterogeneity of FMT in UC
4. How can OpenBiome safely and sustainably increase the quantity of stool collected to meet the growing clinical need?
OpenBiome’s operations hinge upon receiving regular stool donations from healthy donors. As demand for fecal preparations grows, so too must the amount of stool collected. However, finding eligible donors can be challenging due to OpenBiome’s stringent screening criteria. Of those who expressed interest via the online stool donor registry, the vast majority (97%) were excluded from participation. Once recruited, donating on a regular base can also be challenging, as donors must drop off samples at OpenBiome within 45 minutes of passage.
- How can OpenBiome increase the number of donors without compromising safety?
- How can OpenBiome encourage current donors to increase the number of donations?
5. How should fecal microbiota for transplantation be regulated?
The regulation of fecal microbiota for transplantation poses a unique challenge, as stool is a complex and variable substance which does not fall neatly into traditional regulatory categories. In the United States, the FDA has chosen to define FMT as an “investigational new drug.” This designation typically requires that physicians file an investigational new drug application if they intend to use fecal microbiota for treatment or research. However, the FDA has issued “enforcement discretion,” allowing physicians to use FMT without an IND for “C. difficile infection not responding to standard therapy,” while continuing to require that physicians file an IND for use in all other indications.
The current regulatory paradigm in the US poses several challenges. First, it creates uncertainty for practitioners, stool banks and industry, as the future of enforcement discretion remains uncertain. Second, it does not elegantly handle uses for FMT beyond recurrent C. difficile infections. Third, the drug paradigm regulates the stool preparation process, but not the highly variable stool contents.
Internationally, stool is typically regulated as a drug or not regulated at all. Alternative frameworks that have been advanced include regulating stool as a biologic product or a tissue, or creating a hybrid model unique to stool.
- What regulatory paradigm should be adopted for FMT in the United States to maximize both safety and access?
- How should the safety of stool contents be assessed?
- How should the regulatory paradigm vary for different indications, if at all?
- How should fecal microbiota be regulated at the international level?
- People: Carolyn Edelstein, Rachel Sachs