Contributed Commentary by Peter Christey
September 13, 2019 | The microbiome is one of the most exciting new avenues for understanding human biology. With each new research study, evidence mounts for the broad involvement of our microbial communities — from the earliest discoveries about conditions of the gut, such as inflammatory bowel disease, to more recent and less obvious connections, such as autism, cancer, and Parkinson’s disease.
Despite this remarkable potential, though, microbiome research—and the diagnostics and therapeutics that will one day be developed based on these findings—is severely limited by century-old microbiology tools. Conventional culture techniques are low-throughput, taking too much time and labor to produce the quantity of results needed. They also suffer serious bias, as the more populous and fastest-growing members of a bacterial community can quickly outpace and overwhelm the slower-growing or rarer species, making them difficult or impossible to detect.
For higher-throughput results, many scientists have turned to next-generation sequencing (NGS) technologies. While this approach can yield abundant and useful data about DNA or RNA of complex microbial populations, it does not provide the breadth of information needed to elucidate cause and effect among microbial strains. DNA data can reveal the different species found in a “healthy” microbiome versus an “unhealthy” one, or how a microbiome changes over time, but tells us little about how the living microbes are interacting or the underlying physiological mechanisms driving the biology. Other ’omics analyses, including proteomics and metabolomics, have similar shortcomings.
There is tremendous promise for improved diagnostics and even therapeutics based on what we already know about the human microbiome. From diagnosing Parkinson’s through the oral microbiome to establishing a cancer patient’s prognosis from the tumor microbiome, the possibilities seem endless. But we will not achieve these things without a stronger foundation for microbiome research and analysis. We need more robust and higher-throughput methods to interrogate living microbes and to understand not just which strains are present, but also understand their physiology and the mechanisms that drive their interactions with each other and our bodies.
Current Limitations
Even in the most advanced clinical laboratories, the microbiology testing bench is stocked with materials that would not be unfamiliar to a 19th-century scientist. Agar plates have been used since the 1880s. Broth cultures and other techniques have seen no major changes in a century or more. These methods have stood the test of time because they are effective. But they cannot keep up with modern demand for microbial investigations, particularly as we increasingly recognize the importance of characterizing entire populations of microbes instead of just single strains.
Culturing microbes is currently the best approach we have for elucidating the interplay among species and predicting their effect on our own health. The ability to study living microbes is essential. Unfortunately, there is no way for conventional culturing techniques to operate at the scale needed for microbiome-based studies, which require the analysis of microbial communities that have hundreds to thousands of members. These methods are also limited by the incredibly slow growth rates of some microorganisms and by the challenge of detecting rare strains among more populous ones.
While NGS has been critical to driving our current understanding of the microbiome—most major microbiome studies have been based on sequencing technologies—it provides just one of the many dimensions of data needed to truly make sense of these complex communities. Principal component analysis and other methods of evaluating microbial sequence data provide important insights, but are insufficient for answering the most important health-related questions about how these microbes affect host biology.
Calling for Innovation
We cannot realize the promise of microbiome-based diagnostics and therapeutics without a more complete understanding of phenotypes and interplay among the many species that call our bodies home. This will require taking advantage of all the tools currently available to us, and developing creative new technologies to answer questions that cannot be addressed today.
These new tools must address the two biggest hurdles to studying microbes today: quickly and cost-effectively obtaining isolates of interest for laboratory studies, and enabling the extremely high-throughput studies necessary for microbiome scale insights. Ideally, isolation and cultivation would allow for massively parallel interrogation of many thousands of living microbes at a time. The data gathered from such an approach, combined with results from NGS, proteomics, metabolomics, and other analyses, will be invaluable for elucidating the mechanisms that drive associations between microbial populations and human health. Understanding these mechanisms is critical to developing effective diagnostics and therapeutic interventions.
Innovation is needed. Microbiome-based science must have a technology transformation — an approach that will replace the century-old microbiology tools and greatly accelerate the progress of this hugely important new field of science.
Peter Christey, PhD, is the co-founder and CEO of General Automation Lab Technologies, Inc. He has worked in the life science field for more than 20 years and holds a PhD in molecular biology as well as an MBA. Peter can be reached at peter@galt-inc.com.