A phalanx of friends
10/11/2016 // Feature // Text: Steffan Heuer // Photo: Gutemberg Brito/IOC/Fiocruz; Andreas Fechner

The microbiome remains a largely undocumented realm although it touches virtually every aspect of human life. The MetaSUB consortium brings together researchers from around the globe to explore, map und better understand the interactions between microbes and their environments. It offers tantalizing glimpses of the next frontier of life science.

An unknown world teeming with life exists literally under our fingertips, leading a parallel existence alongside humans. Every time we shake hands, reach for an object, inhale or exhale, we make contact with an invisible world of millions of microscopic organisms. The average human sheds around 15 million microbes an hour into the environment.

Welcome to the world of the microbiome, the catch-all term to describe microscopically small organisms such as bacteria, viruses, fungi, protozoa and even algae. These organisms have colonized more or less every surface on Earth and have made a home inside our bodies as well, from our teeth and the gastro-intestinal tract to our toes. The human body, experts estimate, holds a total of 100 trillion microbial cells. That’s roughly three times as many cells as the human body consists of. If one were to put all these organisms on a scale, their weight would not amount to more than four pounds, the equivalent of a human brain.

Yet when it comes to its biological impact, the microbiome punches far above its diminutive weight. At its worst, certain notorious members of the microbiome are responsible for infectious diseases such as cholera, the avian flu or a mutated bat virus that came to be feared as SARS. That’s why many epidemiologists expect the next pandemic to arise from the microbiome. Researchers are still trying to understand what role this invisible world can play in the rise or treatment of cancers, mental illnesses and other diseases that are thought of as being caused by genes or lifestyle. Most of the time, however, this community of microorganisms acts as a symbiotic and overwhelmingly beneficial partner. Microbes act as a dynamically configurable, live shield to protect humans from pathogens, aid with digestion and further overall health and well-being.


Unlocking an exciting and dynamic research area

In short, identifying the microbiome and characterizing its interactions is considered one of the most exciting and dynamic new frontiers of life science today. Experts are certain it will provide them with valuable new insights to bolster public health defenses, develop new therapeutic applications, and even improve disciplines such as forensics, city planning and architecture.

The problem thus far has been that humans have not fully grasped the size and diversity of this parallel world, let alone been able to chart its tangled relationships. Since the term “microbiome” was coined by the late molecular biologist and Nobel Prize winner Joshua Lederberg in 2001, scientists around the world have embarked on the path of discovery. The American National Institutes of Health, for instance, launched the Human Microbiome Project in 2007, followed by the launch of the International Human Microbiome Consortium at a meeting in Heidelberg, Germany, a year later.

This initial burst of research caught the interest of Dr. Christopher Mason, Associate Professor of Physiology and Biophysics and of Computational Biomedicine at Weill Cornell Medicine in Manhattan. Six years ago, when he began dropping his six-month-old daughter at her daycare in New York, a question popped into his head: What exactly was happening when an infant explores the world by putting things in her mouth? “As a new father, I suddenly became curious to get better information about what exchange was occurring between her and the world,” recalls Mason, “and it turns out that almost nothing was known.”

Insights from mapping New York City’s metagenomic baseline

Mason turned his curiosity into a project called PathoMap that collected samples from the poles, turnstiles and other surfaces of the New York City subway. The result was the first detailed metagenomic profile of a large metropolis. “Swab by swab, we built the first baseline map of what’s present in a city. Call it genetic surveillance,” says Mason about his lab’s efforts which garnered a lot coverage when they were published in 2015.

The PathoMap project showed that humans literally don’t know the half of their world. In other words, 50 percent of the DNA collected underground didn’t match any known organism. Analyzing DNA samples from the subway also gave intriguing clues what type of information the microbiome holds. In the South Ferry station, for instance, which was heavily flooded by tropical storm Sandy in 2012, the Weill Cornell team was able to identify the remains of ocean-based bacteria swept North by the powerful hurricane.

Such “molecular echoes” can persist for months. Not only do these traces indicate what happened, but they also hint at who was there doing what. Genetic mapping allowed the researchers to reconstruct how different ethnicities flow through public transportation and match up with census data, as well as find traces of particular foods such as chickpeas or of their pets; essentially a history of who is there and what they are doing. It’s a level of detail that would be any forensic expert’s dream of, which has led to new work in this area of “metagenomic forensics.” Prior, scientists rarely had access to the technologies required to extract, amplify and analyze the metagenomic remnants of this hidden world.

MetaSUB will take microbiome sleuthing global

New York was just the opening act. In June 2016, Weill Cornell Medicine and other scientists, researchers and trained citizen scientists around the globe started to collect and analyze samples of DNA and RNA in high-traffic areas of 54 large cities around the world. The MetaSUB project, headed by Dr. Mason as principal investigator, will run for five years to not only provide geospatial but also longitudinal data, covering cities ranging from Berlin and Buenos Aires to Johannesburg, from Tehran to Shanghai and Sydney. MetaSUB will collect samples from sewer systems and beaches as well as RNA viruses such as Zika and influenza.

The consortium intentionally aims for a high number of participating locations. Once completed, researchers will be able to drill into longitudinal profiles of the world’s major cities and study how their genetic makeup, pathogen load and even antimicrobial resistance changed over time. The larger the data pool, the better the insights, particularly since urban profiles range from normal to extremely densely populated cities in temperate all the way to tropical climates. Another bonus is the inclusion of Rio and Tokyo, two Olympic host cities whose large influx of visitors promises to provide a rich tapestry of genetic material that undergoes significant change over a short period of time.

Getting to know the hidden world around us promises big pay-offs. First studies hint at an intricate, but not yet fully understood relationship between bacteria that colonize our bodies and conditions like obesity, metabolic syndrome or even mental disorders. 

"Understanding the various microbiomes and their impact on human health and environment is a key area of interest for our company."
Michael Kazinski, Senior Director Molecular Preanalytic Technologies QIAGEN

First studies show mind-gut connection

In one experiment, researchers from the Washington University School of Medicine in St. Louis, MO, showed that physical traits like obesity can be transmitted to mice by inoculating them with human gut microbes.

Rodents gained weight after they received intestinal microbes from an obese person, but stayed lean when they got the same “transplant” from a skinny human. Researchers now think they might be able to design probiotics that ward off obesity by manipulating the intestinal microbiome. Subsequent research by other teams has shown that the interplay between body mass index and microbiome is much more complex than initially thought and deserves further investigation.

In a similar fashion, researchers have found a gut-mind connection that may explain how our dietary habits and the microbiome can influence our mental health, affecting conditions such as anxiety and attention deficit hyperactivity disorder (ADHD). “We live as a symbiotic assembly of trillions of cells. There’s truth to the saying that you are what you eat,” says Michael Kazinski, QIAGEN’s Senior Director Molecular Preanalytic Technologies. “Understanding the various microbiomes and their impact on human health and environment is a key area of interest for our company.” Such insights, he adds, can help identify new drug targets and design novel neutraceuticals.

This kind of global sleuthing requires a standardized protocol and platform to make sure the results can be reliably gathered, interpreted and then compared. QIAGEN therefore provides the MetaSUB consortium with sample technologies and library preparation workflows to extract, purify and isolate genomic materials for analysis. Gathering and cleaning such samples poses several challenges since every swab comprises a wide range of DNA and RNA from known and unknown bacteria and viruses, as well as plenty of contaminants and artifacts that can stump or mislead researchers. The company’s MO BIO PowerSoil sample technology kits let researchers extract usable genetic material even from highly contaminated samples such as soil, dirty water or stool.

The next step involves using QIAseq FX DNA library preparation kits for next-generation sequencing that amplifies the sough-after parts while preserving the original sample for future research. Since metagenomic sampling is an open-ended exercise in hunting and gathering an unknown batch of genetic materials, the extracted information then has to be matched against a library of reference sequences. The third and final step consists of running state of the art bioinformatics analysis to turn data into insights.

"We’re embarking on a big data fishing expedition with so much new information yet to discover. We’ve opened the door just a crack, but we can already see things that are applicable to public and environmental health.”
Colin Baron, Senior Director and Head Product Management NGS Sciences QIAGEN

QIAGEN suppporting basic research

“We want to support basic research and medical development with technology that a researcher who's neither an expert in bioinformatics or genetics can use,” explains Colin Baron, Senior Director and Head Product Management NGS Sciences at QIAGEN. To be sure, studying the microbiome is still in its infancy. “We’re embarking on a big data fishing expedition with so much new information yet to discover,” he adds “We’ve opened the door just a crack, but we can already see things that are applicable to public and environmental health.”

Take contaminated soils or water. Much like the bacteria in a sewage treatment facility feast on human waste and thereby clean the water, the right mix of microbes could be put to use for environmental remediation such as dealing with a chemical spill and other environmental disasters. The same is true for agriculture. Once researchers gain a better understanding of the interaction between microorganisms in the soil and the plants that grow in it, farmers would be able to harness the positive interplay and increase yields, perhaps even give crops a microbial shield against diseases instead of using pesticides.

Urban environments offer yet another promising application. Institutions like the Alfred P. Sloan Foundation and the Bill and Melinda Gates Foundation have begun funding research into MetaSUB and related projects, aiming to understand the role microbes play in creating healthier buildings and improving public health. The tall, enclosed towers of a modern city act like semi-insulated containers that provide little air exchange and therefore have their own microbial ecosystem — with all the advantages and risks to its occupants.

While the notion of architects and city planners working with molecular biologists may still be a ways off, using the microbiome to develop personalized medicine is coming within reach. One example is the goal to develop special workflows for diagnostics and therapeutic purposes that gather and analyze the individual genetic and microbial profile of each patient.

Creating a shield of microbes for each individual

Dr. Mason, for one, has his eyes on this prize. He considers the rich yet invisible microbial world all around us a “phalanx of friends” that ought to be harnessed for precision medicine of the near future: “After our work in the subway, I’m much more at ease about touching things,” he says. “The vast majority of what we found was either inert toward human health or even beneficial.”

Mason envisions using the insights of the MetaSUB consortium to get a detailed picture of the microbial environment in any given place to design an individual medical response based on the neighborhood a person lives in. “It’s still years away, but the technologies to monitor these things already exist,” he explains. “Once we have enough information, we can make it part of your own, geospatially informed treatment plan.” Such a record could be called up, for instance, to check on any past antimicrobial resistance and implement the best antibiotic for an infection.

Such fine-grained mapping across time and space would finally shine a spotlight on the hidden world under our fingertips. In some sense, MetaSUB will rob the microbiome of some of its mysterious aura, but the trillions of invisible partners every human shares his or her body and environment with still hold plenty of secrets that await sampling, analysis and interpretation. 


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