Fans of the '90s cartoon "The Magic School Bus" may remember one of the show's earlier episodes, where Ms. Frizzle and her class shrink down to take a journey through a sick student's body. Along the way, they cross paths with the very bacteria responsible for the illness.
The bacteria is actually part of the microbiome, or the collection of microbes that live on or inside people.
Frizzle and her students likely never heard that term, though, because microbiome exploration started taking off only about 10 years ago, as scientists gained access to better DNA sequencing technology developed in the era of the Human Genome Project. Though nascent, the research has already provided valuable insights about the tiny organisms that call humans home and the ways they affect health.
Scientists estimate the average person has roughly 40 trillion bacteria in their bodies. Some help digest food, others break down medicines. Many remain a mystery in terms of their function and impact. Yet the promise of the microbiome as a disease-fighting tool has certainly sparked interest from academia and industry.
Launched in 2008 through funding from the National Institutes of Health, the Human Microbiome Project (HMP) has published more than 650 papers detailing the structures of various bacteria, the composition of microbial communities and what exactly makes a 'healthy' microbiome. Big pharmas, including Bristol Myers Squibb Company and Johnson & Johnson, have also pumped millions of dollars into microbiome research and investments.
The interest "is warranted, but I think some products and some hype might be ahead of the science. But [the science] will get there," said Jim Anderson, NIH deputy director for program coordination, planning, and strategic initiatives, a division that oversees NIH Common Fund, which is the major funder of the HMP.
The research focus
Drugmakers have taken two overarching approaches to developing treatments using the microbiome, according to Lita Proctor, program director for the HMP.
On the one end are companies looking to use live microbes to either prevent or treat disease. Next-generation probiotic manufacturers fit into this category. Instead of relying on the more traditional 'good' bacteria like Bifidobacterium and Lactobacillus, next-gen probiotics use less obvious — or even genetically engineered — microbes to give the microbiome a boost where it's deficient.
"You're going to start seeing products now where, as a dietary supplement or as an additive to a food product you buy, it's going to be enriched in something that will help promote a healthy microbiome," Proctor told BioPharma Dive. "Certainly fiber is one, but there's a whole suite of other compounds where experiments are showing these particular compounds seem to stimulate the beneficial members of our microbiome."
There are several biotechs with candidates in Phase 3 that would be considered live biotherapeutics, meaning they contain living organisms. Most of these companies seek to treat inflammatory diseases of the gut by replacing missing bacteria.
In that light, the Food and Drug Administration updated guidance in June 2016 for live biotherapeutic products that laid out best practices for developers conducting early clinical trials of those products.
Meanwhile, other companies are trying to use their knowledge of the microbiome to create or enhance more traditional small molecule drugs. Cancer has proven a particularly hot target among microbiome researchers, as clinical findings have suggested a relationship between immuno-oncology drug performance and the diversity of a person's gut bacteria. Roche AG, AstraZeneca plc and Bristol are each investigating the microbiome and its impact on cancer drug outcomes.
The industry is also benefiting from data collected by the larger scientific community. A series of HMP papers published back in 2012, for instance, found that the function of the human gut's microbiome is determined less by the individual bacteria present and more by how the community of microbes living there works together — similar in concept to the body's organ system, according to Proctor.
"It appears that bacteria can pinch hit for each other," Curtis Huttenhower, an associate professor of computational biology and bioinformatics at Harvard and a lead co-author for one of the papers, said in a statement. "It matters whether the metabolic function is present, not which microbial species provides it."
Not all microbes are created the same, however, especially when it comes to metabolizing medicines.
In some cases, the microbiome is actually needed to break down a drug into its active form. But in others, the microbes will deconstruct it into harmful chemicals. Recent research published in the journal Biofilms and Microbiome identified a digestive-tract bacteria that reactivates a toxic form of irinotecan, the active ingredient in Pfizer Inc.'s chemotherapy treatment Camptosar, leading some patients to experience life-threatening diarrhea.
Then there are microbes that are simply problematic. Certain assemblies of microorganisms can cause low level chronic inflammation, fatiguing the body's immune system and leaving it more vulnerable to illness.
The microbiome "can be either a help or a hindrance," Proctor said.
Determining which category it falls into has become especially important for drugmakers. Survey results from 2011 to 2014 found nearly half of all Americans used a prescription drug within the previous 30 days, according to the Centers for Disease Control and Prevention.
"What's happening in the medical field is a recognition that the dosages, the form of the medication, the frequency that you take it and so on, we're starting to really appreciate the microbiome plays a major role in those kinds of decisions — because we're realizing that microbes are playing a major role in metabolizing those drugs," Proctor said.
Have some broccoli
Unfortunately for the industry, there are still many unknowns when it comes to the microbiome.
"It's still at a learning phase, because it's complicated. We've learned that there really isn't a core microbiome, that they're similar in the same body sites from person to person, but it's not identical. So basically everyone has their own precision microbiome, and we're trying to understand what's it all about — it's probably our genetics and our diet and so on," Anderson said.
Several of the more concrete findings have involved food.
Like people, microbes need food for nutrients and overall survival. But what kind of food people eat plays a vital role in the types of microbiomes they develop.
"In terms of what is a healthy microbiome, I can't give you a definitive answer because we're still trying to come up with the right way to define that," Proctor said, "but I think that we do understand that high-fat and processed foods will nurture a different type of microbiome than a diet full of fiber and whole foods."
Microbes in the body's digestive tract operate without oxygen, meaning they ferment food. Processed foods are easier to handle, so they're digested earlier along the route. That can be problematic for microbes living in the large intestine, which can become starved if a person isn't eating enough fruits, vegetables and fiber-rich fare.
And in another troublesome turn for drugmakers, correcting the microbiome after long-term neglect may not be as simple as popping a pill.
"There is no magic bullet," Proctor said. "You can't go out and eat hamburgers and hot dogs and then take a probiotic and somehow neutralize the impact."