By Bernat Olle, PureTech Ventures
The last few years have seen an explosion of academic work in the field of the human microbiome and the National Institutes of Health has made a big bet that this field can transform medicine. To make a long story short, scientists are finding that the bugs that colonize your gut, airways, skin, etc., do a whole lot of good things without which human life would be pretty miserable (see for example the collection of articles in the most recent issue of Science Translational Medicine, or the flood of articles in Nature and PLoS), including protecting us from opportunistic infections, keeping allergies and autoimmune diseases at bay or supplying key nutrients. The tricks that our microbes use to make all this goodness happen and the chaos that results from messing with them hold critical clues for developing a whole new class of therapies. Future microbiome modulators could be (among others) orally administered commensal microbes, or natural or synthetic molecules that mimic their effects. For full disclosure, at PureTech Ventures we strongly believe in this field, too, and have started new company initiatives to mine this space including this company.
Other promising therapeutic modalities that captured the public's imagination at the time they emerged, such as recombinant DNA (rDNA) and RNAi, have taken a long time to materialize (or have not been translated into products yet, in the case of RNAi). Given all the attention the microbiome field is getting now, and the lessons of the past, striking a note of caution when considering translation of microbiome therapies to the clinic seems wise.
Not your average new therapeutic modality
However, there are several reasons why drugs that modulate the microbiome could be translated to the clinic significantly faster than other new therapeutic modalities such as rDNA and RNAi:
No fundamental technological barrier: Notwithstanding the technical complexity of the microbiome field, which requires integration of many technologies from genome sequencing, new bioinformatics tools, unique animal models, and metabolite profiling tools (more on this later), there isn't one fundamental technological barrier that needs to be resolved to enable clinical translation. That was not the case for rDNA and RNAi therapeutics. Manufacturing stood in the way of translating rDNA drugs to the clinic. Delivery stands in the way of RNAi drugs. Initially, protein products were only available in miniscule quantities or were very costly to produce in large-scale. MAbs were not feasible until hybridoma technologies came around. Early pioneers of the rDNA industry had to figure out ways to express protein products in recombinants hosts, at high yields, with correct folding, with the right glycosylation patterns, at large scales, and with the right purity. That took time. Similarly, delivering RNAi therapies systemically to where they are needed in the body remains stubbornly complicated, despite some progress in using lipids and nanoparticles to address targets in the liver.
In contrast, the technology needed to manufacture products based on live microbes already exists. With some tweaks, essentially the same cell banking, fermentation and analytical methods already in use to manufacture biologics can be applied to manufacture live organisms. Purifying a microbe from a fermentation broth is trivial in comparison to purifying a protein. And over millions of years of evolution, our microbes have evolved intelligent ways of delivering themselves into our gut via the oral route and without the need for fancy delivery systems. Humans are born sterile, and we get colonized by microbes that use a number of strategies to reach their natural niche in the human body, such as forming spores.
Established proof of principle that the microbiome can be modulated and that this is of value to patients: OK, so there is exciting data coming out of microbiome research projects--but are there any simple applications of this therapeutic modality that have worked in the clinic? RNAi, stem cells, and genomics companies did not have a satisfactory answer to this question. In contrast, transplantation of the microbiota in humans ("fecal transplantation" … yep, eating somebody else's poop) has been performed for decades with very promising results. At present, it is only used to treat refractory patients with selected conditions such as C. difficile infections or IBD. Whether the procedure is repulsive is beside the point. It works, and it establishes proof of principle that manipulating the microbiome (1) can be done and (2) is of clinical value.
You can't change your "human" genome, but you can change your microbiome: In fact, it happens all the time. It changes depending on what you eat, your hygiene, your age, or what drugs you take (particularly antibiotics). This provides much more flexibility for intervening. Identification of microbiome anomalies points to alterable fates.
Safety: Humans have lifelong exposure to massive amounts of commensal microbes (we have on the order of a hundred trillion microbes in our gut). So you'd think we have evolved to tolerate a wide range of doses of certain live organisms. Yes, rDNA drugs too were expected to be safer than small molecules because they are more "natural" but they proved to be immunogenic sometimes. That has not been a problem with probiotics used as supplements and food ingredients, which have an extremely safe track record of human use.
It can't possibly be that simple
Sure, it probably will not be simple. Some notes of caution often heard these days merit attention:
"Mapping out the biological pathways is a scientific process that takes a long time." True, no matter what therapeutic modality is being used. But has this been the rate limiting step for RNAi therapies to make it to the clinic? And while mapping what role our microbiome plays in a highly complex disease like cancer will take time, there is low hanging fruit to go after in other therapeutic areas in infectious disease and inflammation, just as certain hormones and growth factors were a logical starting point for rDNA therapies.
"It is not always clear if microbiome changes are cause or effect, or what caused the microbiome changes in the first place." While often it is not known whether microbiome alterations were caused by hygiene, diet, antibiotic use, genotype, immune responses, enteric infections, or combinations of the above, this has not stopped clinicians from intervening and shifting the microbiome of patients back to a "healthy state" (See fecal transplantation comments above). Surely, some of the correlative connections coming up in the literature will prove to have no role in driving disease (they may still lead to very useful biomarkers). But there already is very compelling evidence that in other cases alterations of the microbiome are a driver in pathology, regardless of whether they were the initial disease trigger. Numerous experiments have demonstrated that transplanting the microbiota of diseased animals into healthy hosts transfers disease phenotypes and influences onset and/or progression of obesity and chronic inflammatory diseases such as allergies and autoimmune diseases. It is also well accepted among clinicians, and supported by animal experiments, that microbial communities promote pathology in IBD.
"We don't know how much variation there is in the human microbiome across individuals and within individuals." Actually we are starting to get a good sense of this variation thanks to $140 million from the NIH and a growing suite of open source tools (bottom line: yes, there is variation in species but their functions, e.g. metabolic pathways, vary little across individuals). In certain instances, this variation will uncover subtypes of individuals within a complex disease spectrum, improving the odds of success in clinical trials.
"Probiotics in foods and supplements have shown little to substantiate their health claims and don't even colonize the gut." Again, true in most cases. In making probiotics, just as in making antibodies, you get what you select for. And food companies have focused on selecting strains based on their technological properties (manufacturability, ability to formulate in food matrixes, acid tolerance, shelf live, etc.), not based on their functions in human biology, which is a theme for a whole separate blog entry, coming up soon.
Dr. Bernat Olle is a principal at PureTech Ventures. He has been a member of the founding teams of Follica, Vedanta Biosciences and Enlight Biosciences. He serves as the chief operating officer and a member of the board of directors of Vedanta Biosciences. He completed his doctoral work at the Chemical Engineering Department at MIT, where he co-developed a novel method to increase oxygen transfer in bioreactors by using colloidal nanoparticles.
Editor's note: This piece originally appeared June 15 on Giving Life to Science: The Official Blog of PureTech Ventures.