Professor of Bioengineering at Rice University, Jeffrey Tabor, PhD talks about irritable bowel syndrome.
Interview conducted by Ivanhoe Broadcast News in 2023.
I think people are so concerned about GI and digestive issues and everything going with it. How did you get onto this to begin with and how much of a breakthrough do you see it as?
Tabor: Great question. I’ve long been interested in engineering bacteria to interact with the human body to sense when we’re sick and make drugs to make us better. But we got particularly interested in this intestinal disease space in about 2015 when I read a New York Times article about someone at Washington University who was pioneering fecal transplantation. So people who would have chronic intestinal infections or metabolic disorders like obesity. He was doing research showing that transplanting fecal material from healthy person into a diseased person could cure those illnesses and animals and the results are quite dramatic. And so that really highlighted the potential for what the bacteria inside of the gut could do to affect our health. That was the beginning of our interest in this area.
How much of these problem issues do you attribute to the Western diet being way off the path?
Tabor: I think the Western diet is obviously a major causative factor for a lot of these intestinal health issues. So the bacteria that live in our gut, our body actually nurtures them because they digest fibers from plants in our diet that we cannot digest and the digestion of those fibers actually plays a fundamental role in our metabolism, in our immune function and nervous function in other areas of our health. The Western diet largely lacks those fibers that are present in plant material. And so those good bacteria that our body nurtures basically diminish in people who eat the Western diet, and they get replaced by bacteria that really aren’t supposed to be there, who are able to digest the different types of nutrients in that diet. Those replacement bacteria don’t do the same job and just cause a spectrum of health problems.
So lets say rather than following a Mediterranean or a plant based diet – which is, of course, healthy – Joe stops by Captain D’s and gets a fish sandwich and fries and Coca Cola. What bacteria, the horrible bacteria or not so good bacteria, is a byproduct of that meal?
Tabor: So there are basically bacteria that can eat proteins instead of plant fibers. So the bacteria that are probably naturally present in the gut at low levels, but when that’s the food source that you introduced to the gut, then those not so good bacteria can expand. They can grow in numbers and they grow at the expense of the good ones.
So if you get a lot of the bad bacteria to settle in and very little of the good, assuming it’s reversible, how long would something like that take?
Tabor: That’s a great question. It’s not well understood how easy it is to go back from an unhealthy gut microbiome to a healthy one. There’s a lot of effects where once you establish an unhealthy microbiome switching your diet back to a healthy diet might not immediately reverse what that community is composed of. And so I think more work needs to be done to really figure out how to flip the switch backwards and go back to a healthy microbiome and if there’s ways that we could do that, maybe by supplementing the diet with specific food sources that healthy bacteria eat.
So in your instance, I’ve even heard of things like they’re producing toilets that monitor wastes and analyze waste and that kind of thing. In your actual dedicated efforts here, you’re actually putting sensors inside the body to signal when there’s inflammation in the gut and help the gut, what sensors are they and how do they go about doing that?
Tabor: Great question. So these are genes that have evolved inside of bacteria that sense molecules in the gut that are linked to inflammation. And so we basically find them in a wide range of different bacteria. Some of them come from the gut, some of them come from the environment. And then we put them in gut bacteria and use them to sense those molecules in the gut.
How do those bacteria sense that within the body and how do they then communicate the situation back to the person reading the situation in order to help correct it?
Tabor: Great question. So you can think of a bacteria as like a little sphere and the sensors, they have two pieces to them. So one is like an antenna that comes out of the sphere and it receives the molecule that’s in your intestine. So the molecule will float into the antenna, stick to it, and turn the antenna on. And what this does is transmits a signal across the bacterial membrane, across the sphere inside the bacteria itself. This signal is basically a chemical reaction that turns on a bacterial gene. And what we do as synthetic biologists in my lab is we put genes together that haven’t evolved to work together. So we’ll connect these bacterial sensors to say, a green fluorescent protein that makes the bacterium glow green and so that’s what we’ve done in this case. And in order to report the inflammation back to the person we currently just retrieve our little bacteria from the stool of the animal. We shine a blue light on them, and if they glow green, we know that they’ve seen inflammation.
So let’s say you tested on mice. Let’s say that you examine the waste and it’s glowing green. What exactly is that telling you about the waste?
Tabor: It’s telling us that the animal has an inflamed intestine. The specific molecule we’re sensing in the intestine of the animal is only elevated when the intestines are inflamed. And that is the only way for the bacteria to turn green. And so if the school is green, it means, it only means one thing that the intestines are inflamed.
So I know this is a long way off, but it eventually reaches human beings. What do you, other than signaling the inflammation? What would be the next step in that process for the human and the doctors to actually fix those directions?
Tabor: Great question. Instead of having the bacteria glow green, there’s actually two directions. One is we’d like the bacteria to produce a dye that’s visible at home without a special toilet. So instead of green fluorescence, which is hard to see, we’d like to put, say, a blue dye which would dye your toilet water blue. And so you might ingest these bacteria each morning if you have inflammatory bowel disease. And if your toilet water turns blue that day, you know that you’re having an inflammatory flap and you might call your doctor. The second direction we want to take it, is eliminate the diagnostic aspect of the, of the bacteria and replace it with a therapeutic. So instead of making a blue dye, we can engineer the bacteria to secrete an anti inflammatory drug, similar to the types of drugs that you see advertised on TV all the time to treat Crohn’s disease, or ulcerative colitis. These could be antibodies, or other types of protein drugs. We can engineer bacteria to secrete those and actually treat the inflammation in the intestine when they see that the inflammation is happening. We think that this would be a way to make those drugs more potent by delivering them to the tissue that’s inflamed. And actually reduce the side effects of those drugs because you’re not having to inject them in the bloodstream. And they’re not having to travel throughout the body in order to get to the site of the disease.
Do you envision in the future that this is going to be some a diagnostic tool for let’s say colon cancer or intestinal cancer?
Tabor: We hope that it will be. And I think the major challenge we currently face is the bacterial sensing element. How do you engineer bacteria to sense colon cancer? Colon cancer looks much like healthy tissue, though there are some differences. What are the right bacterial sensors and genes we need to find to have a bacteria be able to discriminate a cancer from a healthy tissue. So that’s an ongoing area of research. And I think once that problem is addressed, we’ll be able to adapt the technology to sense colon cancer, or other types of diseases.
Can you walk us through a timeline of the first germination of this idea? In other words, you’re reading about the fecal injection, ecole injections and where you are now and then also in the future when people see this, they automatically think they call their doctor to go get it, you know what I mean.
Tabor: Great question. So the first time we read about how effective fecal transplants were, we were motivated to take a slightly different approach, so instead of just doing a fecal transplant, which is you’re transplanting a complex material from one person into another. And you don’t totally understand what’s in that material and there could be viruses and other things in there that are bad. We wanted to take a different approach. We wanted to make a precision fecal transplant, as it were, to take a specific strain of gut bacteria that we understood very well, engineer it to carry out very specific diagnostic and therapeutic functions and then reintroduce it into a person in order to have high effectiveness for the disease we’re treating, and low side effects. And so that was a big difference from the fecal transplant idea. And so there was some basic research that needed to happen. The first disease we got interested in was inflammatory bowel disease. There was a lot known about it and there were a lot of potential solutions we could, we could take. It took us about two years to find the first bacterial sensor of inflammatory bowel disease. And this was because we had to do some basic scientific discovery. We were searching in bacterial genomes, analyzing their genes, discovering sensors of inflammation, biomarkers, and then putting them back in bacteria and back in animals. And so that took several years. Since that time, we’ve focused our efforts on what I’d call increasingly clinically relevant biomarkers. So when you’re sensing inflammation in a mouse, mouse inflammation isn’t exactly the same as human inflammation. The early inflammation sensors we developed, we think they’re going to work better in the mouse than the human. So we spent the last three years, I think finding sensors that we think will work in people and in the last couple of years, we’ve also focused on, on these types of biomaterial delivery systems to deliver the bacteria to the body, to protect them as they’re entering the body, to make them easier to detect in the stool samples. And ultimately, we think that those materials that we’re using to protect our bacteria are going to allow them to be more effective therapeutics when we begin producing therapeutics.
And how long do you anticipate that will objective?
Tabor: I think we could have a bacterial therapeutic in clinical trials within three years.
And after the clinical trials, what’s the year? What’s the time period to market?
Tabor: It’s unclear to me. I think it depends on the disease. Frankly, what the economy is doing and what the appetite for venture capital investment in biotechnology companies, is at that time. I think that could have a major effect on how fast the technology can be advanced to the market. But my general educated guess on answer to your question would be a year to market after a clinical trial.
I agree that’s quick. I don’t need to infer anything, but I had inferred from the last comment that if you’re looking for VC funding, Big Pharma is do they look at this as a competitor, or what’s the situation there?
Tabor: No I think Big Pharma would look at this as a new technology that they might be interested in acquiring and developing with their resources.
END OF INTERVIEW
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