The dark matter of our microbiome
Though rapid progress has been made in understanding the microbiome’s impact on human health, a fundamental issue remains largely unsolved; and it is preventing the field from making the transition from developing therapeutics based on serendipity to inventing medicine at scale using engineering principles. This issue, at its heart, is the murky understanding of the so-called “dark matter” in the human microbiome. Collectively, the dark matter refers to the vast amount of the microbial strains that remain unculturable to researchers in the lab, and for nearly any given strain, the majority of its genome that cannot be annotated. The inaccessibility issue of the microbial strains cannot be addressed by improving our methodology of isolating and cultivating them. It is because, aside from all the logistical and biological challenges, the global diversity of the human microbiome, its rate of creating new strains, and the ease of sequencing their genomes, collectively outpace such isolating and cultivating efforts by orders of magnitude. Alongside the lack of culturability, the annotation issue of a strain genome relates to our lack of mechanistic understanding of its genomic parts, which demands vigorous molecular biology work; and traditionally, it can only be achieved after the accessibility issue is addressed. The importance of tackling these issues cannot be overstated. The human microbiome represents the largest and the longest human trial ever: there are currently seven billion threads running globally and every single thread runs through the entire lifespan of the host. The microbes, living on the surface and inside of us, constantly respond to signals from our diet, medical treatments, mood, etc through two main interfaces: generating metabolites that exert local or systemic effects, and producing immunogenic components that elicit profound effects on our immune system. Both interfaces contain a large amount of modulators produced by the microbes. For instance, a conservative estimation of the number of secondary metabolites in the human microbiome pushed the number to be over one million; and the number of possible epitope peptides encoded by the human microbiome is even larger by at least one order of magnitude. Different from the other microbes that live in soil or marine environments, the human microbiota are comprised of members that have adapted to the human physiology as a result of long term cohabitation. The adaptations are in turn reflected in the components that operate on the above mentioned two interfaces: they are selected by evolutionary forces to be efficient at communicating or modulating their human host. All these characteristics and information are perfect for guiding drug design and drug development, yet they are concealed in the dark matter and are very difficult to access.