Industrial Scale Microbiome Mining is a New Drug Discovery Toolbox

The vast majority of the critically essential secrets in biology are hidden from researchers. The human microbiome is now considered a human organ, yet the word “microbiome” was not in the research lexicon as recently as 20 years ago. Science missed this human organ because the tools to understand the human body are still emerging for science to uncover new secrets. Without genomics technologies, the human microbiome may have gone undiscovered for decades. New groundbreaking tools are rare in research, but one of the newest tools to understand the hidden secrets of biology and human health is the emerging technologies of industrial scale microbiome mining with potentially a humanity-changing impact.

What is microbiome mining

Mining the microbiome is discovering new small molecules that are relevant to the signaling in our cells. To quantify the opportunity to uncover critically important biological secrets, there are nearly 250,000 human metabolites listed in the Human Metabolome Data Base (HMDB total), yet only about 150 metabolites have shown a microbial origin (HMDB microbial).

Metabolites are small molecules that are drug-like and interact with other molecules, like proteins most can pass through the blood-brain barrier, penetrate cell walls, and even disrupt DNA. Small molecules make up 90% of the drugs on the shelf. There could be tens of thousands, potentially hundreds of thousands of microbial metabolites to uncover and understand these drug-like small molecules that interact with human biology by turning on, off, up, or down biological activities.These microbial metabolites enter the bloodstream and are responsible for the cascade of chemical activity not directly associated with the microbe but with the interaction in a human.

The microbiome drives most human health activity in combination with genes and lifestyle factors from conception to death and every illness or disease in between. An interesting fact that should be contemplated is that all microbiome genes and metabolic pathways have substantial overlap, and the human microbiome overlaps with the marine microbiome by 73%.

The slow evolution of microbiome mining and research approaches

What is well established in the few short years of human microbiome research is that nearly 2,400 years ago, Hippocrates had insight into gut health and food dynamics that researchers today are enumerating. Many diseases or drugs’ effectiveness in treating various diseases has been linked to the human microbiome. The knowledge connection between microbiome and health is in its infancy. Uncovering microbiome secrets should lead to new targets, new markers, and new drugs. The complexity is the challenge, so using the existing tools in combination with current knowledge can permit a focus on creating new actionable activities leading to therapeutic advancements.

The human microbiome is complex and virtually unknown, based on the simple fact that human microbes outnumber human cells by nearly 40 trillion to 30 trillion. The more than 25 million genes in the human microbiome outnumber the less than 25 thousand human genes. Each day we are still learning new information about the human genome, which is 1/1,000 the data of our human microbiome.

The tools to research microbes and microbiomes are well established, but each is insufficient and inefficient as a stand-alone. Researchers have studied microbes for nearly 100 years, and certainly, the pharmaceutical products that emerged from microbial sources outnumber all other drug sources combined, including plants, when considering microbes in plants are being annotated as the real source.

Culturing microbes has led to most actionable activities leading to drugs or small molecule knowledge but is handicapped for two major reasons. The first impediment is that less than one percent of the globes microbes would grow and scale in culture, thus no way to understand the drug-like metabolites within the microbe. The second big issue is that even if a microbe grows in culture, many metabolic pathways to create a metabolite are not activated because of the unnatural growth conditions.

Omics approaches such as genomics, metabolomics, proteomics, lipidomics, etc., and technologies like combinatorial or computational chemistry, synthetic biology, machine learning, or artificial intelligence are great tools but have not delivered on the promise because of an indirect focus and lack of meaningful data. The initial costs and lack of meaningful results from the fairly new indirect omics, along with other factors, have contributed to about a 200% increase in inflation-adjusted costs of new drugs while, at the same time, a shrinking approval rate of new structurally different drugs.

Researchers have praised the biosynthetic potential of microbes for decades, with a focus on culturing or indirect omics as key to delivering on the prospect. The new mining tool can stand alone but will complement the other discovery approaches, filling in data gaps and accelerate new drug starting points. Early opportunities for microbiome-based discoveries will likely fall into several therapeutic categories, including immunomodulation, neuro/CNS, infectious disease, and oncology.

How industrial scale microbiome technology works

Industrial scale microbiome mining is a new technology that allows access to the other 99% and shows promise for discovering new therapeutic opportunities. The technology was first shown to obtain unknown natural small molecules from aquatic microbiomes that had therapeutic equivalents in use as drugs.

The industrial scale microbiome mining technology depends on taking environmentally responsible large samples of aquatic habitat and removing the microbiome from that sample without damaging the microbes. The microbes are then processed to remove the proteins and lipids, leaving a batch of small molecules. The small molecules are sorted via various analytical equipment processes to present the small molecules for further testing and interrogation.

The technology is in the early execution phase, as it was not taught in academia or practiced by any industry. The breakthrough initially occurred due to looking for a better natural source of bioplastics, and the Department of Energy’s Advanced Research Projects Agency (ARPA-E) funded a generation one technology. Today’s technology is at full scale and capable of typically creating 1 million grams dry weight of high-quality microbiome with tens of thousands of addressable novel small molecules for research teams to test.

A microbiome mining future will uncover opportunities

Looking at the history of drug discovery, it is feasible to extrapolate that 1% culturing of microbes led to more than 50% of the drugs on the shelf. Logic would dictate the hypothesis that if researchers had access to the other 99% of actual small molecule chemistry of unculturable microbes and natural microbiomes, these currently inaccessible molecules would create massive opportunities for discovering new targets, markers, cures, and treatments.

The new mining toolbox will start slow worldwide, but as the pipelines fill with new opportunities that microbial access facilitates adoption, and technology advances will accelerate. It is likely, in short order, 3-5 years, that new opportunities in therapeutics will impact rare and orphan diseases as well. Other life science areas will also benefit, including agrochemicals, sustainability, remediation, carbon capture, advanced energy, and cosmetics. Within ten years of execution and widespread adoption, most pipelines will be traced to the opportunity of untapped microbes of the earth.

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