The Human Microbiome: Biomedical Implications and Birth of a Market - Executive Summary
Results from the Human Microbiome Project and other massive studies of human bacterial symbionts, which far outnumber human cells in the body, have drawn lots of attention in recent years from both the basic and applied biomedical research communities. During 2009, a PubMed search on the term ‘human microbiome’ yielded 579 citations, but for 2013 that number had increased to 3,324.
A number of new commercial ventures have sprung up in recent years to develop therapies and biomarkers for a number of common chronic conditions, notably inflammatory, metabolic, and autoimmune diseases. Most such programs are based on the notion that disruption of relatively stable microbiome ecosystems results in dysbioses, i.e., imbalances that in turn destabilize homeostasis and create the conditions for diseases to arise and flourish.
This report focuses on biomedical aspects of human microbiome research, development, and commerce. It covers necessary background material, evolution of the field, progress in basic research, activities in the developing commercial market, deal activity, interviews with experts, and trends in microbiome research and commerce. Information for the report has been drawn from the scientific literature, discussions with knowledgeable individuals, and an online survey of people working in this area.
Background and evolution
After making significant pioneering contributions to genomics, Craig Venter led an expedition to collect samples of marine bacteria and sequence them en masse using Sanger shotgun methodology. The project identified more than 1,800 species and set a precedent that established metagenomics as a viable field for investigation and commercial participation. The advent of next-generation sequencing technologies and subsequent focus on short hypervariable regions of microbial 16S rRNAs enabled the NIH-sponsored Human Microbiome Project and others of its sort to provide sufficient definition of human microbiomes to stimulate broad and accelerating participation in the field.
Early progress in the microbiome R&D led to identification of several enterotypes that may provide a basis for personalized microbial medicine. Furthermore, particular diets appear to influence individual enterotypes, which can change in accord with dietary alteration. Another provocative observation suggests that a well-behaved microbiome can serve to maintain weight, while dysbioses can result in obesity with attendant metabolic disease consequences. Early research also uncovered a likely mechanism by which dysbioses can trigger atherosclerosis.
Such early research has served to promote a view of humans as superorganisms composed not only of human cells, tissues, organs, etc., but also large numbers of bacteria, archaea, viruses, and single-celled eukaryotes living with us in symbiotic relationship. Microbiome work also has promoted an alternative to viewing the human immune system through a military metaphor in which antibodies and cells latch onto and destroy invading pathogens. A developing perspective envisions an immune system that serves to maintain equilibrium between microbes and host.
A key observation that’s triggered much of today’s commercial activity came with studies showing that patients suffering recurrent severe diarrhea-inducing C. difficile infections could be cured or improved by receiving a fecal transplant from a healthy matched individual. A common interpretation is that antibiotic treatment temporarily altered the gut microbiome and allowed normally quiescent C. difficile to overgrow and become pathogenic. Restoration of the microbiome via transplant restores balance, and the infectious agent becomes commensal once again.
Basic microbiome research
Early work in next-generation metagenomic sequencing centered on Roche 454 pyrosequencing. Speed and cost considerations later shifted attention to faster and cheaper short-fragment sequencing, a field currently dominated by Illumina’s systems. Some microbiome work continues to benefit from applying combinations of sequencing formats. A subset of researchers favors Pacific Biosciences’ technology which provides impressively long reads averaging 5,000 bases.
Data analysis remains an area of vulnerability in the microbiome space. Informatics workflows fall into two classes: gene-centric, favored when addressing high complexity microbiomes; and assembly-based, better for lower diversity applications. Either choice requires further selections downstream from the branch point. While significant improvements in data analysis have been made in recent years, the process will likely remain a bottleneck in metagenomics for some time to come. Results of metagenomic analyses must also be made consistent among laboratories and technology platforms, and early indications suggest that more work is needed in this regard.
Viewing microbiomes as ecosystems with components in dynamic equilibrium suggests that the field can benefit from adopting systems biology methods and perspectives. Leroy Hood has pointed out that the complexity of microbiomes and their interactions with each other and their host suggests that multi-omic analyses may be needed to identify subpopulations of microbes with distinct functions. The goal, as he sees it, is integration of data into metadata structures, such as a network of networks, in order to generate predictive models for use in understanding the function of microbes in communities. These in turn will enable their molecular reengineering to produce desired results. Research from Chalmers University in Denmark has identified such bacterial groups, defined ways they interact, and provided means to interpret transcriptomic data in a metabolic context. Rob Knight’s lab, which focuses in part on metabolomics of microbiomes, points out that effects of the microbiome on the whole human metabolome are only beginning to be understood, but earlier work has shown clearly that such effects do exist.
Microbial ecology and systems biology, two symbiotic subject areas as it were, are keys to elucidating the role of human microbiomes in health and disease. To paraphrase a recent workshop report on the subject, microorganisms shape their host environments and are, in turned, shaped by it. Microbiomes ideally exist in stable equilibrium with their environment. They gain benefits from the host, while providing useful ‘goods and services.’ Disruption of these equilibria based on perturbation of hosts, microbes, or environmental niches due to changes in diet, use of antibiotics, et al. can result in dysbiosis with consequences for health that microbiome research has only begun to uncover. Microbiome researchers have established associations between dysbiosis and numerous chronic diseases, but have yet to establish whether these relationships are also causal. Still, the dramatic growth in incidence of many such diseases since the start of the antibiotics era combined with observations on geographic variation are highly suggestive of causation in certain instances. Two recent studies in microbial ecology, one for environmental microbiomes in homes and the other in hospitals, provide provocative and surprising insights into how our individual microbiomes affect and are affected by these environments.
Microbiome research has much to say about obesity, inflammation, and insulin resistance, which increase in association with decreases in gut bacterial diversity. Many studies report associations between diet, weight, dysbiosis, and disease, but at present evidence for causation remains largely circumstantial. Observers indicate a need for more longitudinal studies in which large numbers of affected and control individuals have their microbiomes monitored over extended time periods. A recent study showed that antibiotic-induced dysbioses in young mice reversed when the drug was withdrawn. Yet mice so-treated gained weight much more rapidly than controls when put on high-fat diets. Transplanting their microbiota to germ-free mice also transferred the weight gain phenotype so that this study appears to establish causation.
Research activity in pursuit of diagnostic assays is at present largely confined to population studies. At least one private and another public program collect fecal samples from individuals who pay a fee, and in return get results telling how their microbiome data appears in comparison to other populations with and without particular disease phenotypes.
Commercial activity in the microbiome space
Projects now in various stages of commercial development cover a broad spectrum of applications. This report covers descriptions and activities of 23 microbiome companies. The most prevalent applications fall in the category of live biotherapeutic agents (probiotics to some) that deal with various diseases and disorders. These include Crohn’s disease, skin ulcers, acne, diabetes, inflammatory bowel disease, and C. difficile gastroenteritis. Some programs in this category address broader disease or health maintenance issues including: autoimmune disease, cholesterol reduction, metabolic diseases, the immune system, and infectious disease. Two companies work to engineer commensal bacteria that can enter the microbiome and generate therapeutic molecules in situ for treatment of inflammatory bowel disease, mucositis, and infectious diseases. Several organizations are developing microbiome-based diagnostic products, which include biomarkers for Crohn’s disease, colon cancer, and pre-term labor risk.
The report also describes 12 recent microbiome-related deals. Of these, five involve research collaborations between small companies and big pharmas. J&J’s Janssen Biotech unit is active in three of these deals, Pfizer in one, and Merck in another. The Mayo Clinic Center for Personalized Medicine has been active in the microbiome space, providing funds and collaborative support to three small companies. In two instances large companies have provided research funds to academic groups. Other arrangements include small companies working together, another collaborating with a large clinical lab services firm, and another which has been granted a technology license.
Our online survey of 63 people active in microbiome work divides about evenly between those in commerce and academia. About three-quarters of respondents are managers or principal investigators. Nearly half are connected to work on inflammation, and a third are involved with metabolic diseases. About three-quarters of respondents feel that levels of microbiome-related activities in their organization would stay about the same or increase during the next two years. Two-thirds of respondents felt that sufficient microbiome-related information is now available to justify translational efforts, while one-third disagreed. Two-thirds felt optimistic that microbiome work will provide major contributions to healthcare, while nearly a third said it’s too early to tell. Nearly two-thirds agreed that big pharma will become heavily involved in microbiome work over the next decade, and only 15% disagreed.
Trends and conclusions
Based on our interviews and survey results, it seems clear that people working in the field are highly bullish about the importance and future success of microbiome R&D in diagnostics and therapeutics, quite possibly with a personalized twist. Nonetheless, it is still early days for the field, and it may be well to remember that many veterans of post-genomic wars can relate tales of great promise with results that fell short of expectations. Still, the microbiome space has a certain compelling air to it that suggests warranted optimism. The C. difficile fecal transplant example alone seems emblematic.
Regarding commercial potential in the microbiome space, the market size is at present negligibly small, and we expect it will take a couple of years more work on products currently in development before estimates can be made with any reasonable degree of confidence. However, it seems also fair to predict that the market size at the end of a decade will likely be well up in the billions of dollars in annual sales if only some of the products in development accomplish their aims.
A subject of great interest to participants and observers in the space is whether big pharma will embrace the microbiome in a big way. Early participation as evidenced by the level of dealing-making at such an early stage in the field’s development supports optimism. In this regard, our interview with James Brown, the head of GlaxoSmithKline’s Microbiome Matrix Team reveals further reason for optimism. The very existence of such a team and GSK’s willingness to commit resources in that way reveals serious interest. Regulatory policy in the U.S. and Europe will no doubt play an important role in the future of microbiome-related commerce. The FDA’s behavior in the fecal transplant matter may be instructive in this regard. Initial concern over pathogenic microbes in transplant material led the agency initially to require an IND for each instance of that activity. Very recently, the FDA changed direction and now allows physicians to do the procedure without need for an IND.