The twins looked identical, with one immediately visible exception. One twin was fat, the other thin.
The adult, human siblings may have had differences in diet and behavior, but deep inside them something else was playing a surprising role: their gut bacteria.
Our bacterial cells outnumber our human cells 10-to-1, and scientists have increasingly discovered that the varied microbial populations of these foreign colonies — collectively called the microbiome — can have profound effects on our health, mood, and, yes, weight.
With increased understanding of these tiny organisms, we might just be able to coax them to do our bidding, giving us unprecedented control over human health.Twin Mysteries
To find out what was going on in the microbiomes of four sets of differently shaped identical twins, researchers transferred some gut bacteria from a lean (human) twin to a sterile mouse: one with no foreign bacteria at all. The mouse stayed lean, even when they later added some bacteria from the obese twin.
But when that bacteria from an obese twin was added to a sterile mouse, it quickly gained weight. Something in the gut bacteria must have changed the mouse's metabolism, the way it processed food or burned calories or ... the scientists couldn't be sure.
The good news? Mixing in some of the skinny twin's gut bacteria seemed to help the fattened mouse slim down after the initial weight gain.
The scientists suspected that something that had been living inside the lean twin protected that sibling from getting fat — and might even be a key component of warding off or curing obesity.
But what was it? And would it have the same effect on humans?Probiotic Power
Modern medicine is great at fixing a wide range of acute infections. Strep throat, for example, is usually cured quickly and easily with a course of antibiotics.
Yet, we're increasingly plagued by problems like obesity, diabetes, depression, and anxiety, which slowly impinge on the quality and length of our lives.
While we can't use sterile mice to make any definitive conclusions about humans, the twins study, published in the journal Science last year, provided clear evidence that the microbiome is involved in weight gain — something earlier research had only suggested.
It turns out that the trillions of bacteria in your gut do more than just help you digest food and produce vitamins. They have strong connections to obesity and metabolism, and maybe even to whether you are depressed or happy, healthy, or sick.
There's still much more research we need to do to understand the intricacies of our own microbiome. But we may well find that when it comes to our health, antibiotics that fight off infections — as miraculous as they are — are just half of the equation. To treat some of humanity's most nuanced and chronic conditions, we may have to harness another piece of the puzzle: probiotics.
Probiotics have become a big business with a market of about $23.1 billion in 2012. They are defined as bacteria, often found in fermented foods, that are believed to have a beneficial effect on health. People eat "good bacteria" all the time, hoping a few spoonfuls of yogurt might help with digestive issues, for example.Beyond Yogurt
That approach, while cheap and tasty, is imprecise and not usually effective. Humans are not sterile mice, after all, and we all start with our own unique mix of bacteria swirling around. Stirring a few new microbes into the already-colonized pot doesn't always have the desired effect, making it difficult to use them to our advantage.
"Probiotics are bacteria that we've taken from nature and put in a pill, saying 'these bacteria seem to have some beneficial effects,'" said Jeff Tabor of Rice University in an interview with Business Insider. "But they have minds of their own. They might have beneficial effects in certain environments [but not in others] ... and we have zero control."
Such erratic behavior means that probiotics in their current state are of little use to doctors. "Imagine taking an antibiotic where half the time it decided not to work because — we don't know why," said Tabor.
If we can learn to control probiotics, we can make them useful and maybe even essential.
That's why researchers are now actively working to alter bacteria from nature so that their behavior is reliable and, ultimately, helpful. In biologist John March's lab at Cornell, for example, they have armed probiotic bacteria with tools to make an intestinal cell act like more like a pancreatic cell. "This gives the diabetic a way to make insulin in response to glucose and potentially would obviate (or at least reduce) the need for insulin injection," March explained in an email.
As it turns out, the next phase of probiotics cannot be found in the yogurt section of your local supermarket. Instead, we should look to synthetic biologists like Tabor and March. They are working to design something better than anything we could find in nature: engineered probiotics that will be able to read their environment, detect a problem, and then act.Enter The Tiny Doctors
Bacteria already "know" when we suffer from problems like obesity and diabetes — they experience the wide range of physiological changes that happen inside our bodies. The next step, then, is to create bacteria that can fix these changes, before a doctor would even notice something wrong.
"Organisms that detect changes in biochemistry (like those of the microbiome) are able to tell when we are sick," March explained. "The trick is getting them to respond to us being sick (or about to be sick) in a way that we can detect or that has meaning to us (by making us better, for example)."
These armies of tiny biological robot doctors are not science fiction: March has already developed probiotics that protect mice against cholera.
If we can manipulate gut bacteria, we might be able to find new ways to treat some of the most intractable human diseases, even surprising ones like depression and anxiety.
Tabor is working to do just that for a U.S. Navy-funded project called "Engineering Probiotics that Improve Warfighter Performance by Maintaining Lean Body Mass and Inhibiting Anxiety."
"The goal of the grant is to engineer bacteria that are both diagnostics and therapeutics, that produce protective molecules when they detect you need them," he explained. "We want to tailor-make bacteria to act like little doctors in your gut."
The results will be interesting not just to war fighters but to anyone who has struggled with weight or mental health.
Still, thinking of your mental health and obesity status as closely tied to the tiny creatures flourishing inside you may seem like a stretch. It's anything but.The Gut Wars
Much of our knowledge about the importance of the microbiome comes from animal models, but we do know a few things about its importance in humans. In healthy people, gut bacteria strengthen the intestinal wall. But in obese people it seems the opposite is happening.
"Obese people appear to have a compromised intestinal barrier," said Tabor, and molecules that originate in gut bacteria, that have no place in the bloodstream, seem to be finding their way there.
To understand why this is problematic, think about what happens to your body if bacteria get through your skin and into your bloodstream: Your immune system goes on the offensive. It's ready to fight off an infection — and that's a good thing.
When the bacterial molecules floating around in your blood are coming from your own intestine, your body still recognizes them as foreign and mounts an immune response. But unlike an ordinary pathogen that can be fought off, these false enemies are always there, sending your immune system into overdrive and prompting widespread inflammation.
Such chronic inflammation amounts to a never-ending civil war inside your body and is associated with a long list of ills.
It "can cause lots of metabolic diseases — and even cancers and disorders like depression and liver disease," said Tabor. (Note that this is not "leaky gut syndrome," a disease popular in the alternative medicine community despite a lack of scientific evidence supporting its existence.)
When this low-grade inflammation burns on unabated, it has also been show to cause behavioral changes in mice, inducing conditions similar to anxiety and depression. That's one reason researchers think the microbiome might be a crucial part of not only obesity and diabetes, but also some of society's most pervasive mental health problems — the very illnesses that, too often, leave doctors stuck and patients frustrated.'A Brand-New Frontier'
The idea that a specially engineered yogurt could help us manage some of our most difficult and common problems — obesity, diabetes, and mental illness — is certainly exciting. But it's important to stress that this research is in its infancy. "There may be some pretty substantial limits to what we can do with probiotics," said March.
Scientists are beginning to catalog and understand the tiny organisms crowding our gut, but with the exception of some very specific applications, most of that research so far has changed the lives (and bodies) of mice, not people.
Still, Tabor is hopeful that engineering the microbiome will yield clinical applications soon. He refers to the whole enterprise as "a brand-new frontier," but is confident that his research, and other research like it, will eventually change how we treat and understand disease.
"In the future, it does seem like we will transition to a period where engineered organisms are acting as drugs and diagnostics in our bodies," he said. "That seems like an inevitability to me."
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GAME CHANGERS: Read more in this series.