Evolving attitudes

Just as the ancient Greeks centered their understanding of the human body on its four humors, and later eras separately proclaimed the heart, the brain, and even the genome as the leading player, the microbiome is now taking center stage. This superorganism, as it has come to be known, has become a major force in the biomedical research marketplace, attracting substantial financial investment and taking up more and more column inches in publication space. It is also becoming equally clear that this young field still has a long way to go before it truly shifts the paradigm for understanding disease.

“There are a lot of microbiome evangelists out there who would tell you this has changed our world; it’s changed it already and will continue to change it,” says Noah Palm, PhD ’11, FW ’15, assistant professor of immunobiology. Palm heads the lab that seeks to understand the mechanisms by which the microbiome interacts with the human hosts’ immune system, with the ultimate goal of using these interactions to combat disease. However, “so much is still in question, at a basic science level, that must be understood before research addresses how the microbiome can be used in therapies.”

The impatience and an eagerness to take advantage of the resources brought by hype surrounding the microbiome, says Palm, means that there is pressure to fulfill the great promise of the microbiome too hastily. “You have one or two failures and everyone gives up on the whole thing. That’s actually one of my major fears in terms of the whole field of biotech. I do believe there will be transformative, paradigm-shifting therapies that target the microbiome. But it’s not going to be next year.”

Rather than evangelism, Palm says a common view at Yale is a more “conservative, data-driven kind of perspective,” he says. More conservative scientists say microbiome research must focus on establishing cause-and-effect evidence that the microbiome impacts disease on a molecular level, rather than just inferring causality through observation. According to Eduardo Groisman, PhD, the Waldemar Von Zedtwitz Professor of Microbial Pathogenesis, it is very difficult to locate a sure causal relationship between a microbe in the gut microbiota and a function in its host, but there are many undeniable correlations. “The underlying assumption of all these correlations, which is very intuitive, is that if you have an abundance of a particular type of bacteria from the microbiome, then that organism is responsible for a particular behavior,” he says. Groisman studies bacteria, such as the gut-symbiotic Bacteroides thetaiotaomicron, in an attempt to find the mechanism behind how organisms know when and how to shut particular genes on and off.

“To a lot of scientists in mature fields, it’s not causation until you have a level of molecular insight that makes you comfortable with how it’s really working, not just that it works,” says Palm. To them, causation means more than a presence or absence of particular microbes or groups of microbes in the gut that cause disease, proof of their function, and how they exert that function. The challenge of causation is further confounded by the vast diversity in the microbiome, which varies widely among both individuals and populations. “If you compare it to understanding, say, the function of human genes, it’s of an intractable magnitude. There are 150 times more genes in your microbiome than in your own genome,” says Palm. The microbiome is also intensely sensitive and can change within an individual even within a day.

Further, the expense of experimentation influences the research. Because of this, “there is a temptation to generate a lot of data,” says Groisman. “What these correlations are providing is information. But one cannot equate information with knowledge.”

In the past 10 years, major strides have occurred in moving from correlation to causation in microbiome research, with investigators using animal models, particularly gnotobiotic, or germ-free mice, for proof. Palm’s postdoctoral work with Sterling Professor of Immunobiology Richard Flavell, PhD, used immunoglobulin A to identify the bacteria in the microbiome that affect irritable bowel disease (IBD). Using these mice, who are born completely sterile, the team was able to isolate and identify a particular microbe that drives the disease. “To me that’s causation,” Palm says. “This bug is causing this disease.”

Groisman points to the most established use of the microbiome in therapy as an example: fecal material transfer, an FDA-approved treatment for the stubborn and potentially deadly Clostridium difficile infection, or C. diff. The science behind this therapy, which has been shown to work in the vast majority of C. diff cases and even save lives, is based on an observed correlation, not causal effect, says Groisman. It is a very recent development, with the long-term effects still unstudied. “How many of these correlations will hold over time? We will see.”

When it comes to the microbiome, “there are still massive gaps in our fundamental knowledge,” says Palm. Despite these growing pains, the field is making progress toward maturity, balancing the excitement over the potential of the microbiome with rigorous study. “I think we have at least the beginnings of this tool set to do the correlation-to-causation transition,” says Palm. The tool set includes increasing improved DNA sequencing, as well as culturing techniques that allow annotation of the vast number of microbes that make up the microbiome. “The hope is that by leveraging cutting-edge tools and feeding the data we get into computational pipelines, you start to take bigger bites of the apple, even though the problem seems intractable at this time,” says Palm. With careful use of the resources available, the hope is that all this information will eventually turn to true knowledge.

This young field is not just a flash in the pan. “The microbiome is not going away,” says Palm. “Just like neurobiology is not going away. Nobody is going to stop studying the brain. Same thing with the microbiome.”