Engineering Probiotics to Sense and Treat Gut Disease

A Conversation with Dr. David Riglar

By Ryan L. Cross

Inflammatory bowel disease affects over one million Americans and directly costs patients over six billion dollars a year. Current treatments manage the disease with variable success, and diagnosis requires invasive and sometimes inaccurate procedures like colonoscopies.  But David Riglar, a postdoctoral research fellow at Harvard Medical School has a better idea: probiotics.

Probiotics are microorganisms like bacteria that are ingested intentionally for health benefits. Riglar is genetically engineering multiple bacterial species for a single probiotic to diagnose and treat inflammatory bowel diseases.

We spoke for an hour by phone and another hour in person while touring Dr. Pamela Silver’s synthetic biology labs that David works in at the Harvard Medical School and the Wyss Institute. A condensed and edited combination of those conversations follows:

Do I hear an Australian accent?

Yes, I grew up and did my PhD in Melbourne, Australia.

The gut microbiome, the collection of organisms that live naturally in the digestive tract, has received more attention lately. What drew you to this field?

A lot of new research is showing that more and more diseases have a correlation with the gut microbiome. We already know that bacteria are sensing these things in some way.

What exactly are the bacteria sensing?

If there is a molecule present in the surrounding environment then there are likely bacteria able to use it or sense it. Bacteria are amazingly good at that. This study hasn’t been published yet so I would prefer not to mention the specific molecule.

So you engineer bacteria to sense a molecule that indicates gut disease. Then what?

Basically we take our bacteria, grow them up, put them in the mouse, and then take the mouse poo and just spread it out onto these plates for screening purposes. The non-colored bacterial colonies are negative and the colonies that are changing blue are positive for the disease.

Sounds like a straightforward diagnostic, but what’s wrong with current tests for inflammatory bowel disease?

Current diagnoses are reliant on invasive procedures, particularly colonoscopies, which are unpleasant enough that some patients will just refuse them, so they are not getting the care or the sort of monitoring that they need. And they also cost a lot of money, about ten billion dollars in the US per year.

Your diagnostic would be cheaper and less unpleasant, but what else?

Inflammatory bowel disease is actually an umbrella for two diseases: ulcerative colitis and Chron’s disease. Differentiating between them is not always straightforward, even with a colonoscopy. So we are interested in having our consortium of bacteria sense particular markers produced by the inflamed gut to differentially diagnose these two diseases.

Why are you engineering a whole “consortium” of bacterial species for the probiotic? Wouldn’t one species be easier?

The consortia idea is about being able to share the burden. For example, bacteria live in different areas of the gut, so the idea is to potentially have a consortium where one type of bacteria is sensing the disease, and then it sends a signal to another species with a higher abundance in the gut to release a therapeutic, and another species to act as the diagnostic that gets represented very highly in the feces. But there is no final product at this point to say this is exactly how it will work. Engineering a lot of these bacteria and then getting them to act together is not a trivial task.

Are synthetic probiotics safe? Can the engineered bacteria survive outside the gut?

We don’t want them to get into waterways and pass between different humans. So the idea is that we engineer the bacteria to sense when they are in the correct environment, which in this case is the gut. By creating safeguards to have a bacterial community shut itself down and basically kill itself when it is outside the gut we can prevent propagation between people.

This large, sealed chamber in your lab with the rubber gloves built into the plastic window looks like something out of a movie. What is it for?

This is an anaerobic chamber, and we basically grow anaerobic bacteria that can’t live in oxygen in here. The majority of gut bacteria will only grow in anaerobic conditions. It takes extra time and infrastructure, so there aren’t that many species of gut bacteria that have been extensively studied.

Are the built-in rubber gloves as annoying to use as they look?

You can put your hands in them if you want. Imagine doing this for a couple of hours. The chamber is maintained at 37 °C, so the whole plastic bag is just like hugging a warm…moist…person. It is what it is. I feel like if there are important questions to ask, let’s do it.

Sources:

Phone Interview with Dr. David Riglar on September 15, 2015

In-person interview with Dr. David Riglar at the Warren Alpert Building, Harvard Medical School, and the Wyss Institute on September 22, 2015

Background Sources:

http://www.ccfa.org/

http://www.cdc.gov/ibd/index.htm

Note: David wished for me to note that the lab he works in is a dynamic, interdisciplinary group, whose projects require the work of multiple participants. To learn more about the other scientists on the team, visit their lab website, they have some fantastic work on the radar.

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