Mining Microbial Dark Matter for Microbes that Matter

Dark Matter… a mysterious force that holds our universe together. Dark matter remains largely a mystery but is hypothesised to accounts for approximately 85% of the matter in the universe and, as far as we know, is critical to get the fundamental physics of our universe to work. At Heal Capital, we are exploring another form of ‘dark matter’ that lives in and amongst us — Microbial Dark Matter — that might be just as critical to getting our fundamental biology to function

This exciting frontier in biology refers to the exploration of microbes that cannot be cultured in a lab. Amazingly, recent estimations hypothesize that there are around one trillion species of microbes on Earth and 99% have yet to be discovered.

The key challenge is that these microbes are incredibly complex to work with in laboratory settings. This prevents us from studying microbes in a controlled environment where we could better understand how fast they grow, what metabolites they produce, and how they interact with each other. It is like trying to understand what a cake will taste like while staring at a full pantry of ingredients with a partial recipe. Within this microbial dark matter lay hidden gems, sequences of DNA that provide the blue scripts for previously unknown compounds. What is exciting is that in the 1% that we do know, we have discovered some truly amazing breakthroughs that have revolutionised our biological toolkit.

In order to mine this reservoir, we need new methods to collect and identify these microbes and pioneering companies are leading the way. Driven by key enabling technologies in sequencing and computation, we might be at an inflection point where we can capture this vast untapped opportunity and that makes us at Heal Capital incredible excited.

What is the appeal about Microbes

Since penicillin was discovered in 1928, microbes have been the largest source of novel compounds and tools with applications in healthcare, industrial manufacturing, agriculture, and scientific research. It is no surprise that the global market for microbial products is expected to reach $302.4 billion by 2023.

Crucially, these discoveries have led to the creation of entire industries in life science. However, there is likely far more to be discovered and limiting ourselves to the handful of microorganisms that we can currently culture would be a huge, missed opportunity. That brings us to the key bottleneck, finding tools to help us mine through the microbiome.

State of the Art: Tools to study Microbiome

Culturing microbes in a lab remains difficult as laboratory conditions are vastly different to the natural environment of bacteria, preventing symbiotic relationships between different strains and hampering their growth. Afterall, a petri dish is a stark change to acidic environment of your gut or the heat of a geothermal pool. Shotgun metagenomics has become a popular method by randomly shearing DNA into many short fragments and reconstructing them into separate genomes to identify the bacterial composition of the sample. The difficulty is that this method is inherently biased towards the most abundant organisms, sweeping valuable discoveries under the rug.

More recently, however, several new approaches are being developed which offer exciting potential:

• Biosynthetic gene clustering (BGCs) tries to overcome some of the bias of metagenomic approaches. The method focuses on gene clusters across different strains of bacteria that code for specialized metabolic compounds. By focusing on the end-metabolite, it aims to specifically identify high- value compounds with important roles in health and disease. For example, Lodo Therapeutics takes a BGC approach and combines computational tools with synthetic biology to identify potential new drugs. Similarly, VastBiome uses the BGC method to discover new immunomodulatory molecules with a key focus on downstream wet lab validation. Both are pioneering the exploration of the microbial dark matter within the human body.
• Culture-dependent approaches focus on making unculturable bacteria culturable by trying to replicate their natural environment and interspecies interactions. One especially interesting approach is the bacterial generation platform developed by Baccuico. They direct the evolution of bacterial communities while preserving their genetic diversity so that they evolve to become culturable and then screen them for valuable metabolites. So far, the platform has successfully boosted cultivation rates from less than 1% to an impressive 20%.

A number of other companies are also active in the space with different approaches. LifeMine was probably the first company to build a drug discovery engine mining the microbial genome. Enterome developed an EndoMimics platform to identify new drugs using compounds produced by the gut bacteria — the first two candidates that emerged from their platform target inflammatory bowel and Crohn’s diseases. Senda Biosciences takes a more holistic approach by analysing interspecies interactions to find novel medicines and Basecamp Research explores the planet’s biodiversity using a portable laboratory to screen environmental samples in search for unknown protein sequences.

What is next for the Microbial Dark Matter

All in all, it is a rapidly developing space that is briming with potential. Key enablers of these approaches are the rapid development and cost-reduction in next-generation sequencing — the Moore’s Law curve in action for synthetic biology. Furthermore, advances in computational tools have allowed us to break down massive quantities of data into useful insights and deductions. Biology is infinitely complex, perhaps too much for us to grasp, but we are entering a unique time when the above tools are becoming both economically and technically viable.

A call to arms was declared by John Cumbens, CEO of SynBioBeta, asking start-ups to fill the niche on the ‘unexplored power of microbes’, developing tools to unlock the potential of the microbiome. Novel solutions are steadily entering the microbiome space, and Heal Capital is excited to see what comes next. Breaking through frontiers is what humanity has aspired to do for millenniums, how else did we land on the moon in 1969 or planted the MARS rover in February? Now instead of looking outwards to space, we look at the microscopic universe living within and around us. Will they provide solutions to our biggest challenges, from chronic illness therapeutics to our climate crisis?