Microbiome researchers, from left, Mathieu Groussin, Mathilde Poyet, and Eric Alm process a human stool sample in Malaysia.
PHOTO: CHRISTOPHER CORZETT
The villagers laughed. When they stopped laughing, they described how their toileting—which did not involve any actual toilets—took place privately, deep within the forest.
Groussin, Poyet, and MIT professor and biological engineer Eric Alm had traveled to Malaysia in March as part of a worldwide mission to preserve the biodiversity of human gut microbes. It was crucial to include hunter-gatherers like the Batek, because their diets and microbiomes are strikingly different from those of city dwellers.
But this indigenous tribe 500 kilometers from Kuala Lumpur did not routinely encounter requests for stool samples. And now their modesty was posing a dilemma to the team’s first Asian trip.
Tiny chemical factories
The human microbiome is made up of single-celled bacteria with hard-to-pronounce names like Akkermansia muciniphila, Faecalibacterium prausnitzii, and Parabacteroides goldsteinii. They live in our bodies in numbers that rival those of all our other cells combined, and they work so seamlessly with everything else that they have been likened to a separate organ. Each individual’s microbiome is unique, but researchers are becoming aware of differences among populations that appear tied to not only diet, but also to vaccinations, antibiotics, and exposure to environmental chemicals.
To researchers, some of the most interesting bacteria are the 1,000-plus species inhabiting the gut. These aid in digestion, immune function, and eradicating free radicals (atoms linked to aging and disease). There is growing evidence that the influence of gut microbiota extends as far as the brain and nervous system.
“Bacteria are tiny chemical factories that have evolved for millions of years to interface with human beings,” says Alm, co-director of MIT’s Center for Microbiome Informatics and Therapeutics (CMIT) and professor of biological engineering and civil and environmental engineering. “The likelihood that one of these bacteria in any human population, industrialized or non-industrialized, makes some compound that is important for human health is probably much higher than finding a random [therapeutic] plant in a forest.”
CMIT was launched in 2014 to explore the microbiome’s potentially life-changing effects on human health and its role in the diagnosis, treatment, and prevention of disease. The microbiome has its own physiology, which, if altered, could compromise or—researchers hope—improve the health of the host.
“It’s possible that a lot of the rapid rates of increase in diseases such as inflammatory gut disease, obesity, diabetes, and cardiovascular and autoimmune disease are associated with the microbiome,” Alm says. “Is it because our microbiome is changing? And if that’s true, what are we going to do about it?”
Research center launch
When MIT electrical engineering alumnus Neil Rasmussen ’76, SM ’80, and Anna Winter Rasmussen’s child developed ulcerative colitis at age seven, they were faced with treatments involving aggressive drugs or surgery. Anna Rasmussen was typically rebuffed when she asked physicians whether her child’s illness—an autoimmune disorder with symptoms such as bloody diarrhea and belly pain—might be meliorated through diet. Yet since the 1960s, there have been a handful of health practitioners who have reported that limiting the complex carbohydrates on which certain bacteria feed seems to help patients. “It was only in this sort of alternative medical universe that people were taking diet seriously,” Anna Rasmussen says.
Slowly, that began to change. By 2013, when Neil Rasmussen was scouting Boston hospitals for microbiome-related research that might help his child, he found himself back at his alma mater. The Broad Institute of MIT and Harvard was using cutting-edge techniques to sequence ever-increasing species of gut bacteria. And there was Alm, a civil engineer studying bacteria that ingest environmental toxins to help clean up oil spills. Alm was also deeply interested in the human microbiome, as were dozens of others in fields ranging from math to microbiology. But there was no central focus for microbiome research at MIT.
“It’s a gigantic computational and analytics problem to just understand the gene expressions between all these crazy things that live in us and on us,” Rasmussen says. “It seemed like it was a thing MIT should be doing.”
In 2014, the Neil and Anna Rasmussen Foundation funded the launch of the Center for Microbiome Informatics and Therapeutics as a partnership between MIT and Massachusetts General Hospital, which has access to patients for clinical trials. “It’s part of our goal to produce really top-level researchers,” Neil Rasmussen says. “We’re pulling brilliant people into the field.”
Fort Knox of bacteria
Soon after Groussin and Poyet completed PhDs in evolutionary biology at the same university in France (Poyet concentrated on ecology and evolution; Groussin on microbiology and genomics), they came to MIT to join Alm in investigating how human microorganisms interact with one another and with their environment.
“One of the surprising things had been that you could go anywhere in the US and compare gut bacteria to that of people living in Germany or even China who are very different genetically, very different in terms of diet, and nonetheless you’d see the same bacteria,” Alm says. “So we started to think these are the human-associated bacteria.
“Then we started to look at non-industrialized countries. When you get to people who are living a lifestyle that is more like the lifestyle all of our ancestors led, their microbiomes are totally different.”
Bacteria have evolved to coexist with humans. To adapt quickly to changes in their environment, gut microbiota harbor a vast number of genes they trade among themselves. The less gut bacterial diversity, Alm says, the higher the rate of gene exchange—possibly an evolutionary survival mechanism in the presence of an enemy like antibiotics, which kill off healthy microbes along with dangerous bacteria. “We don’t yet know what the implications of that are,” Alm says.
Urbanization and industrialization, Poyet says, are leading to an alarming loss of microbiome biodiversity, wiping out strains that could play crucial roles in human health. At the same time, advances in anaerobic culturing methods and gene sequencing now allow a vast majority of human gut bacterial species to be cultured, characterized, and preserved indefinitely.
What if, Poyet and Groussin wondered, they gathered up all the separate and distinct bacteria that make up colonies within the guts of different urban and rural populations around the world?
In a third-floor laboratory run by the MIT Department of Biological Engineering at 500 Technology Square, an icy mist fills the air as Poyet opens one of two industrial-sized freezers set to a chilly -80°C. She pulls out a lunch-box-sized tray packed with dozens of tiny test tubes, each labeled with a donor’s identifier. The repository is part of an ambitious, multi-location global network of similar biobanks protecting potentially useful microbes from extinction: a Fort Knox of bacteria.
Alm, Groussin, Poyet, and postdoctoral fellow Ainara Sistiaga launched the Global Microbiome Conservancy through CMIT in 2016. Over the past three years, in collaboration with scientists worldwide, they’ve collected more than 700 stool samples from different groups, including indigenous peoples: the Inuit in the Canadian Arctic; the Sami in Finland; the Beti and Baka in Cameroon; the Datoga and Hadza in Tanzania; and others in Ghana, Nigeria, and Rwanda. Participants can opt to receive an analysis of their own gut microbiome.
In the lab, Poyet slips her hands into rubber gloves in the plexiglass confines of an oxygen-free chamber—some bacteria die when exposed to oxygen—and picks up a glass petri dish. She points to dots (“This one looks like a little sun”) amid brown splotches covering the plate’s surface: colonies of different gut bacteria within the fecal sample. Painstakingly, she isolates each strain of bacteria and cultures it, maps its genomes, and fashions experiments to elucidate its unique structures and attributes. A portion of each original sample is stowed in the deep freeze.
The conservancy aims to collect 100,000 strains within the next three years from both urban and rural populations, including indigenous peoples. Alm predicts that in the coming decades, researchers will plumb these donated bacteria for hidden superpowers. A specific species might—as the Rasmussens hope—counter the effects of inflammatory bowel disease such as ulcerative colitis.
If a stool donor from Rwanda happens to have a specific bacteria or genetic component that turns out to be beneficial, the sample is traceable back to that person, who conserves ownership of donated samples and bacteria. “Discoveries may be made,” Alm says. “They may lead to therapeutics, and so could be profitable. If a company wants to make a drug by capturing one of those strains as a probiotic, a new agreement will have to be made, and those profits will have to be shared with the people who donated the materials.”
Rain forest sample
In Malaysia, collaborators from the University of Malaya helped Poyet and Groussin explain the project to the Batek villagers. They provided the big picture, and then it was time for what Poyet calls the tricky step: distributing blue plastic collection bowls. “The first day, they all said, I haven’t eaten. There’s no poop there,” Alm recalls. “Then after a while they said, ‘Well, we really don’t want to poop in the bowl.’”
“Thanks to insights from our local collaborators, we anticipated this. But it was the first time we faced a cultural barrier where we had people saying they were not very comfortable with the collection material we provided,” Groussin says. “Obviously, it’s really different from what they are used to.”
In the end, Alm, Poyet and Groussin worked it out with the tribespeople who were interested in participating. “Just do whatever you normally do and tell us where it is,” they told the villagers. When the researchers ventured out, they spotted blue bowls scattered like Easter eggs amid the dense vegetation. They adjusted their collection protocol to avoid contamination from environmental sources.
As deforestation and development eat away at the rain forest, the Batek, mainland Malaysia’s last nomadic clan, may choose to switch to “city” foods such as rice instead of forest-scavenged cassava root. Meanwhile, potentially life-enhancing bacteria associated with their age-old lifestyle will live on in tiny glass tubes.