In his lab at Rice University synthetic biologist Jeff Tabor is creating a kind of Lilliputian naval academy. The midshipmen are so small they can’t be seen with the naked eye. But they’re part of a vital mission to protect U.S. naval forces from internal enemies, ranging from metabolic disorders to anxiety and depression.
In 2014 Tabor received a three-year grant from the U.S. Office of Naval Research (ONR) to genetically modify a harmless species of Escherichia coli bacteria normally found in the human gut. The goal is to create an edible probiotic organism that can hone in on developing disease and stave it off, even before symptoms take hold. He has recently succeeded in engineering E. coli with sensors that can detect the presence of chemicals signaling disease—at least in the mouse gut.
His ultimate aim is to design “a precision gut bacterium that manipulates the intestinal environment in humans to keep it healthy,” he says. This involves rewiring the genes of E. coli to transform the cells into predictable and reliable microbial medics loaded with engineered genetic circuits that can sense specific chemical disturbances and fire off a battery of molecules to neutralize them. The cells would live only a short time in the gut, perhaps six hours or so, “just long enough to do their job,” Tabor says. Then they would die naturally or self-destruct.
Tabor’s initial target: obesity and related metabolic issues. “We want to use a genetically engineered E. coli cell to sense the chemicals that signal gut disturbances linked with obesity,” Tabor says, “and then deliver beneficial molecules to prevent weight gain.”
Tabor’s work represents the fruitful collision of two hot fields: synthetic biology, the engineering of microorganisms to make useful products; and microbiomics, the study of the microbes living on and inside humans and other animals, collectively known as the microbiome. "There's great potential in this area because there are so many widespread chronic diseases associated with the gut," says Pamela Silver of the Wyss Institute for Biologically Inspired Engineering at Harvard University, which published report of the first synthetic engineered gut microbe in 2014.
The 100 trillion bacterial cells that reside in our guts play a major role in nearly every aspect of human biology—digesting food, guiding the immune system, even dictating mental health by sending signals to the brain that affect mood, cognition and behavior. It’s not surprising, then, that disruption of these gut microbial communities can lead to disease, including obesity and related problems.
Tabor’s project is part of a larger program on the microbiome funded by the ONR to help U.S. naval forces be more robust in the face of stressors—changes in diet or environment, fearful situations, sleep loss or disrupted circadian rhythms from shifting time zones or living in a submarine. “We’re interested in how gut microbiota respond to these stresses,” says Linda Chrisey, program officer in the ONR’s Warfighter Protection and Application Division. “Are they contributing to the host’s response? If so, can we tweak the microbiota to insulate the host from the stress?”
Tabor chose to focus on obesity “because we already know a lot about it at the molecular level,” he says, “so it’s a good model to test the concept.” Our microbiota act like a kind of metabolic ‘organ,’ that affects calorie and nutrient absorption, manages energy balance and controls body weight. (Scientists aren't sure what shapes microbiomic composition. Increasing evidence suggests that it’s determined before birth and has to do with genetics, maternal diet and mode of delivery.) It’s clear that some bacteria make molecules that disrupt the balance within, causing obesity and other disorders. Studies have shown that the gut bacteria of healthy people churn out compounds that strengthen the intestinal wall but those of obese people make compounds that weaken the wall. This allows bacterial molecules to pass into the bloodstream where they do not belong, triggering an immune response. The resulting chronic inflammation is correlated with a laundry list of ailments, from inflammatory bowel disease to mental health disorders, such as anxiety and depression.
It’s still early in the game, but Tabor has already isolated several sensors, reengineered them and put them into a single E. coli bacterium. He has fed the modified cells to mice and shown that the sensors have been activated inside the mouse gut, suggesting they have detected the target chemicals.
Tabor plans to have a single E. coli bacterium carry up to a dozen sensors so it can detect multiple signals at one time for a more accurate diagnosis. Ultimately, he plans to engineer these cells to produce drugs when and where they’re called for—highly targeted antibiotics designed to bind with and deactivate those bacterial chemicals that might otherwise leak into the blood from the intestine—thereby preventing the changes that lead to obesity, inflammation and associated ills. Delivering these drugs to the exact tissue in the body where they’re needed and nowhere else would both decrease side effects and increase efficacy.
However, "these are genetically engineered organisms, so there will be a long debate about them," Silver says. "We'll have to weigh the risks versus the potential benefits. But we're working to develop ways to make these organisms inherently safe. And I think the concern over risks will be neutralized by the benefits, especially for people who suffer from chronic disease.”
So far, Tabor has altered only mouse microbiota. But, he says, “it’s hard to imagine a future where we aren’t diagnosing and treating, possibly curing, many diseases in humans by manipulating gut bacteria in this way—diabetes, autoimmune disorders, cancer, neurological disorders,” and, yes, weight issues.
In fact, the Navy may find creative ways to deploy these synthetic probiotics not just to avoid obesity and its attendant problems but to quickly shift body weight and metabolism as necessary, Tabor suggests. “Imagine you have a team of marines going from a temperate environment, say, at sea level, to a really cold environment, like up on top of a mountain, in a short period of time. You want them to be able to put on some fat quickly to be more robust in the cold environment.”
The solution? A dose of yogurt laced with synthetic probiotics that change warfighters’ metabolism to increase fat for a couple of weeks—and after that another dose to take it off when they return to sea level.