Marti Davidson Sichel Assistant Editor Genetic Engineering & Biotechnology News
In Terms of Genes, the Human Microbiome Outnumbers the Human Genome 100 To 1, but It Is Just Starting To Win Recognition
The microbiome has become the hot new area of discovery in recent years thanks to emerging therapies for everything from obesity and depression to cancer and inflammatory disorders. According to a January 2016 report issued by MarketsandMarkets, the human microbiome is expected to account for a $658 million market by 2023. With hopes of cashing in on this market, which is expected to grow 22.3% between 2019 and 2023, developers are taking a close look at the science of this once-underappreciated area of biology. It has been called the symbiome, the universe of host-microbiome interactions—at least among those who don’t mind liberal use of the suffix –ome. In this article, however, we’ll be more conservative and simply refer to the microbiome.
A few years ago, basic microbiome treatments such as fecal replacement therapy (FRT) seemed less like the future of medicine and more the fodder of hospital dramas. The microbiome wasn’t as well understood as it has become, nor was its potential recognized across therapeutic specialties. As they become more familiar with the terrain, scientists are exploring ways to resolve outbreaks of dysbiosis, microbial imbalances on or inside the body. For example, scientists are trying to engineer specialized microbes that could launch targeted attacks on gastrointestinal invaders. The idea is to eliminate microbial subpopulations that would cause disease if they were given a chance to thrive.
The new weapon against dysbiosis is the microbial gene database. Until recently, reference databases were few and far between. They were created using samples from a limited number of people and geographical origins. Now databases are being combined and expanded. For example, scientists based at the Institut National de la Recherche Agronomique (INRA) assembled an integrated catalog of about 10 million reference genes in the human gut microbiome. “This expanded catalogue,” the scientists reported in 2014 in Nature, “should facilitate quantitative characterization of metagenomic, metatranscriptomic, and metaproteomic data from the gut microbiome to understand its variation across populations in human health and disease.”
The creation of comprehensive microbial catalogues reflects not only the spirit of cooperation, but also the rapid development of metagenomic sequencing technology. Without this technology, many microbes would remain unknown simply because they cannot be cultured.
Although whole-community profiling is still in its infancy, databases are quickly filling up with information about the most prominent and promising candidates. One of the main bacterial phyla that dominates the gut is Proteobacteria, in which resides the Escherichia coli family. E. coli Nissle (EcN) is a bacterium that has already been noted for its usefulness as a probiotic in treating inflammatory bowel disease and as a treatment for ulcerative colitis, a painful and potentially deadly disease.
EcN has also been recognized as a good starting point for genetic engineers and synthetic biologists interested in creating helpful microbes. Back in 2008, Michael Schultz, Ph.D., writing in the journal Inflammatory Bowel Disease, emphasized EcN’s potential: “The unique combination of fitness and survival factors to support intestinal survival, the lack of virulence, and obvious probiotic properties make this microorganism a safe and effective candidate in the treatment of chronic inflammatory bowel diseases.”
Later, in 2015, researchers citing Schultz’ paper described using EcN to develop an orally administered diagnostic. These researchers, who were based at MIT and the University of California, San Diego, reported in Science Translational Medicine that they were able to engineer bacteria that could noninvasively indicate the presence of liver metastasis by producing easily detectable signals in urine.
Diagnostic applications that would make use of synthetic biology at the microbiome level were also cited in a review that appeared 2015 in PLoS Biology (“Where Next for Microbiome Research?”). In addition, this review considered therapeutic interventions that would make use of synthetic biology. Admittedly, development here is less advanced. Nonetheless, contributors to the review such as the J. Craig Venter Institute’s Karen E. Nelson, Ph.D., saw possibilities in more refined versions of FRT. “The field of synthetic genomics,” the review stated, “creates novel opportunities for synthetic human microbiomes or their synthetic products, which can be used for modulating human health.”
Instead of the many thousands of dollars a patient could spend on repeated attempts at only possibly successful treatments for ulcerative colitis, a targeted EcN therapy could, in theory, act in the place of a time-consuming FRT regimen, producing positive results after just one (relatively cost-effective) treatment.
On a humanitarian level, some have imagined developing microbiome-modifying treatments to “inoculate” children of famine, creating a hostile environment for certain kinds of harmful microbes while simultaneously introducing beneficial strains that could repair or even prevent the intestinal degeneration that occurs when microbial communities become dysfunctional due to a lack of safe, clean water and food. It wouldn’t solve the issues of poverty and deprivation, but it would improve the situation enough to give recipients a fighting chance.
A “Normal” Microbiome?
High-throughput sequencing is providing new tools that enhance culture-based approaches to the study of microbiomes. These tools have been described in the journal Molecular Systems Biology, in an article (“Computational meta’omics for microbial community studies”) contributed by a scientific team at the Harvard School of Public Health. According to this team, metagenomic and metatransgenomic assays allow scientists to evaluate whole communities, separating hosts from pathogens from environmental factors and then facilitating the study of host-pathogen interactions.
The next step is figuring out how to distinguish ideal microbiomes from those that could use some work—and structuring databases accordingly. These current approaches depend on reference genome catalogs, which will need to be more comprehensive if they are to offer up the keys to good health. A database of more than just model organisms and pathogens potentially could be used to build a pipeline to enrichment, using translation mapping and functional annotations to pinpoint microbes with therapeutic potential.
To counteract that fact, some large-scale efforts are taking advantage of innovative isolation approaches such as culture-independent techniques and single-cell sequencing to fill in the gaps in sequenced portions of the microbiome phylogeny. In the PLoS Biology review, the University of Washington’s Elhanan Borenstein, Ph.D., suggested that “mechanistic and phenomenological models that could provide a predictive understanding of the microbiome’s function and dynamics are an especially promising route, paving the way to rational microbiome design and personalized microbiome-based intervention.”
Approaches like this could be used to identify thousands of species at a time. Once the functions of these species are better understood, scientists will be better able to identify dysbiosis caused by specific diseases—and better able to create personalized microme-based interventions.
Whole-metagenome shotgun sequencing uses short, random fragments of extracted DNA and RNA from whole communities to break down and reassemble markers for specific organisms and their function. It’s a technique that offers a lot of insight into microbe function and processes, but currently comes at a great cost. That will likely change, however, as science progresses and whole-metagenome sequencing becomes more common.
Synthetic Form, Natural Function
We still don’t yet know the full potential microbiome treatment holds, but we also don’t know the efficacy of these treatments in the long term. That’s where synthetic production comes into play. Advances in next-generation sequencing should open up the field of synthetic genomics and create more opportunities to apply genetically modified biologics and other medically valuable synthetic products.
Synthetic biology has already provided successful yeast-based malarial therapeutics as well as those that have been helpful in influenza vaccine production. There may be scores of applications waiting to be discovered. Some suggest that engineered bacterial strains or super-efficient synthetic probiotics may act as vehicles for bioactive delivery to specific sites of infection, both internally and on surface regions. One trial is even underway in which genetically engineered bacteria are being used to compensate for diminished liver enzyme production. After these bacteria are ingested in pill form, they remove harmful excess metabolites in the bloodstream.
These curated collections of microbes would, in theory, contain only desired bacterial strains, perhaps even winnowed down to just a few specific species. This kind of synthetic colony would bear none of the risks that exist when working with harvested samples and all of the benefits. We may soon see unique, designed colonies, purpose-bred for targeted deployment. So while concept of microbiome makeup as intellectual property is a debate for another time, that time may come sooner than later.