Manipulating Microbes: New Toolbox for Better Health?

Bacteroides thetaiotaomicron

Caption: Bacteroides thetaiotaomicron (white) living on mammalian cells in the gut (large pink cells coated in microvilli) and being activated by exogenously added compounds (small green dots) to express specific genes, such as those encoding light-generating luciferase proteins (glowing bacteria).
Credit: Janet Iwasa, Broad Visualization Group, MIT Media Lab

When you think about the cells that make up your body, you probably think about the cells in your skin, blood, heart, and other tissues and organs. But the one-celled microbes that live in and on the human body actually outnumber your own cells by a factor of about 10 to 1. Such microbes are especially abundant in the human gut, where some of them play essential roles in digestion, metabolism, immunity, and maybe even your mood and mental health. You are not just an organism. You are a superorganism!

Now imagine for a moment if the microbes that live inside our guts could be engineered to keep tabs on our health, sounding the alarm if something goes wrong and perhaps even acting to fix the problem. Though that may sound like science fiction, an NIH-funded team from the Massachusetts Institute of Technology (MIT) in Cambridge, MA, is already working to realize this goal. Most recently, they’ve developed a toolbox of genetic parts that make it possible to program precisely one of the most common bacteria found in the human gut—an achievement that provides a foundation for engineering our collection of microbes, or microbiome, in ways that may treat or prevent disease.

In a paper published in the journal Cell Systems [1], the MIT researchers used an innovative genome editing system called CRISPR-Cas (see Copy-Editing the Genome) to insert specially designed genetic circuits into the common human gut bacteria, Bacteroides thetaiotaomicron (B. theta).These engineered bacteria were then successfully introduced into the intestines of laboratory mice, where they were able to sense particular molecules delivered via drinking water and to respond to those molecules by turning certain genes in the circuit on or off.

In one experiment, led by Timothy Lu and Christopher Voigt, the team used their new toolbox to program B. theta to turn on a light-producing protein called luciferase when they sensed a compound called arabinogalactan. Within a day of the mice drinking water that contained arabinogalactan, luciferase activity increased about 75-fold in animals with engineered gut microbes. Similar activity was seen in the animals’ microbe-laden feces, providing glowing evidence that the circuit was indeed working as intended!

The researchers tested more complex genetic circuits, too. For example, when the mice were fed a form of sugar called rhamnose, it activated an enzyme in engineered B. theta that permanently reverses the order of the DNA letters in a short section of the bacteria’s genetic instruction book. The researchers were then able to detect whether mice had been exposed to that sugar through a simple DNA test.

In principle, the new toolkit makes it possible for scientists to manipulate the activity of any gene in B. theta on demand. While it has become very clear in recent years that the microbiome is integral to our health and well-being, there is still much that scientists don’t know about the precise roles of specific microbial species. These new tools can now be used to engineer the microbiome in ways that serve to answer those questions.

Furthermore, given Homo sapiens’ intimate association with B. theta (it is present in at least half of people and abundant in their stool), this toolbox may help to tackle some major human health problems. In patients with inflammatory bowel disease, for instance, it might be possible to engineer B. theta to detect a flare-up early and respond by delivering an anti-inflammatory agent right where it’s needed. In fact, the researchers say they are already working on a circuit to do just that. They will study it first in mice, but tests in humans could be coming relatively soon.

The research described in the new study took place at one of three new NIH-funded National Centers for Systems Biology focused on human health [2]. The MIT-based center, led by Ron Weiss, is also working toward engineered approaches to target antibiotic-resistant bacteria, RNA-based circuits to sense and destroy cancerous cells, and more.

References:

[1] Programming a human commensal bacterium, Bacteroides thetaiotaomicron, to sense and respond to stimuli in the murine gut microbiota. M Mimee, A C Tucker, C A Voigt, T K Lu. Cell Systems. 2015 July 9. [Epub ahead of print]

[2] New National Centers for Systems Biology focus on fundamental processes that influence health. National Institute of General Medical Sciences (NIGMS) News Announcement. November 26, 2013.

Links:

Timothy Lu (Massachusetts Institute of Technology, Cambridge, MA)

Voigt Lab (MIT)

The MIT Center for Integrative Synthetic Biology

Human Microbiome Project (NIH)

NIH Support: National Institute of General Medical Sciences

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