zach charlop-powers

Notes from the Galien Forum Microbiome Panel

Sun Nov 18, 2018

The Galien Forum is a yearly event that mixes biomedical science and business. I attended this year for the first time and was impressed by the buzzing of people - the sort of business-heavy sound and feel that I imagine is not unlike the famed J.P.Morgan Healthcare Conference. Although I wasn’t able to attend most of the day but I did make it to the Microbiome section.

The Microbiome panel started off in an interesting way. The previous panel, on gene editing, went over time. And after a few minutes of waiting, the standing-room only crowd emptied out to leave a room that was at least half empty. The gene editing section had, among others, executives from Pfizer and Bluebird and the scientific and venture-based interest was strong. When the Microbiome panel convened, the chair, Nancy Thornberry, acknowledged this juxtaposition, noting that among the panelists there were no members of Big Pharma, and that the attitude of Big Pharma seemed to be “wait and see.” This was a bit surprising because the intense scientific and popular interest in the human microbiome has led to a field that to me gives the impression of an overheated bubble. I wrongly assumed that this was the same on the business side. Financiers, in this case at least, remain cautious.

My general concern about hype was assuaged during Sarkis Mazmanian’s introduction. His slides covered the current state of affairs in microbiome research - that all of our surfaces are covered with bacteria, that there can be important physiological consequences of changes in bacterial composition, and that there are exciting areas of research in the microbiome space: the possibility to make probiotics to treat various bowel afflictions or the possibility of using the human microbiome to identify targeted metabolites that may affect immune function or neurological behavior - and perhaps other things as well.

The rest of the panel, composed of scientists or scientist-entrepreneurs, was led by Nancy through a series of questions about what they see as the successes and prospects of microbiome science, with an emphasis on translational therapies. The general consensus was that we are in early days of understanding the mechanistic, causal events of the human-microbiome interface. Insofar as diseases go, there is currently only a single unequivocal win in microbiome research - the treatment of C. Difficile infection by fecal transplant (90% successful). Here, the replacement of C.Diff bacteria by the infusion of new, “healthy” bacteria can eliminate the infection. This observation is the basis of the current lead compound of panelist Bernat Ollie’s Vedanta Biosciences, a company attempting to formulate a standardized medication that would yield the same result. Bernat mentioned that Vedanta was struggling with the scaling requirements of the various probiotic components in their lead formulation - suggesting that it was quite an engineering and formulation challenge to handle a mixture of bacterial components - especially since many (most? all?) are anaerobes.

Similarly, as befits scientists, both Dan Littman and Michael Fischbach expressed caution that to develop effective treatments we need to understand causality, but that we don’t understand causality. However, there are promising suggestions that the microbiome is altered in IBD as well as in NASH. More mechanistic studies are needed they say, and I couldn’t have agreed more. It was discussed that bacterial metabolism of gut metabolites could be an interesting avenue of study - for example as a chemotherapy adjuvant to reduce loss of active drug to the gut (its not uncommon for metabolic processing to annihilate the bioavailability of drugs, rendering them ineffective). Nancy Thornberry and Michael Fishbach were both positive about the possibility of identifying bacterial-derived metabolites that modulate human cells in useful ways. Fischbach pointed to possibility of bacteria to modify bile salts into signaling compounds.

NF wondered how we could get all of the various stakeholders and scientists into the same room in order to discuss, for example, the gut-brain axis. How can you get methods developers, sequencers, IBD specialists, neuroendocrinologists, vagus nerve specialists and so on to get into the room together? The scope of the problem is part of the experimental/operational challenge and part of what they are hoping to achieve, presumably, within Kallyope. Michael Fishbach’s partial response is to “democratize” the microbiome sciences - to make the experimental and analytical tools sufficiently easy so that they can be used by a larger cohort of investigators.

To the question of “what is holding us up” from making therapies, the panelists returned to a common theme: NL & MF brought up the lack of mechanistic understanding. SM mentioned that full metagenomic sequencing would improve the analysis and understanding of microbiomes and is currently a roadblock. NT: we are working on very cool [gut-brain] circuits.

In the Q&A a few questions were asked that underscore the interest and potential of the microbiome: how are satiety responses governed? Can fecal transplants effect weight gain in humans (supposedly there is a study of obese/thin mice fecal transplant affecting obesity of the recipients)? Why/how are antibiotics used for weight gain in livestock - an interesting phenomena that is well known and utilized by the big ag companies. (Maybe Vedanta should develop a cow-fattening microbiome chow :) )

One final point that was made and that I agree with is that the science of the microbiome may simply allow us to better understand how the microbiome affects us, but that this may be the value, not the small molecules or probiotics that we are currently thinking about. If one can use the microbiome to understand circuits or targets, we can use classic target-based pharmacology+med-chem to make drugs. This was a comment that resonated with me and with which I wholeheartedly agree.

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