Dr. John Pandolfino jokes that he comes from a long line of electricians and plumbers – and that as a gastroenterologist he has stayed in the family business.
That’s because the esophagus, the organ that brings food from your mouth to your stomach, is basically a tube with some electrical wires, he said.
Tia Ghose: You use a digital twin in a condition called achalasia. Can you tell me more about what this condition is?
John Pandolfino: The esophagus, you know, its main job is to push things down into the stomach when it enters the esophagus. And then when something refluxes up, the esophagus also has to push it down to protect you from aspirating and getting it into your lungs. What happens in achalasia is that the lower esophageal sphincter, which is a kind of barrier that separates the esophagus and the stomach, does not open. It doesn’t relax. Achalasia actually means failure to relax. When that muscle doesn’t relax and open up, the food just builds up in the esophagus and you start to literally, almost, drown in your own saliva and food. So it can be a fatal disease.
What was interesting was that we noticed after treating patients that they developed this diverticulum (a weakening and ballooning of the wall), and we didn’t really understand why this happened. So we asked the mathematical model, the virtual esophagus – we actually gave it a bunch of options. We changed a lot of the variables, like what type of operation do they have? How long did they cut the muscle? Did they include something called an anti-reflux procedure, where you kind of take a piece of your stomach and wrap it around the esophagus so you don’t get reflux? Would it matter what kind of motility problem they had? There are different subtypes of achalasia. So would some subtypes be better than others? We went through this whole process. How deep would you cut the muscle? And we just ran simulations.
So it took a couple of months of training this and running it through millions and millions of scenarios to show what would happen. And finally, the model actually predicted what would be the best surgery, and it also predicted which patients would be most at risk of developing the complication.
So with that information, we submitted an NIH grant that focused on looking at two different types of surgery: the standard approach versus one that’s modified by the virtual esophagus, so what the virtual esophagus chose. So we’re going to test this default approach, which works pretty well, versus this other approach. And we think we’ve modeled the study so that they look equivalent, but we think the new one will have less reflux and less diverticula development.
TG: What you describe seems like a far cry from what people describe as a canonical digital twin, where you integrate all the important chemicals and signal processing involved, all the mechanical forces and all the real-time data from wearables and medical imaging. How far away do you think we are from that kind of digital twin?
JP: From a mechanical point of view, I think it’s pretty good already.
In terms of getting into the molecular structure and the actin (muscle filaments) and how the muscles contract and the calcium influx, I think we are very far away. We have just learned how proteins fold; developing a mathematical model of the cell is going to take quite a long time.
But I think, mechanically, we can do this, and the great thing is that this approach can be used across all organ systems—the bladder, the aorta, the left ventricle. These processes where you rely completely on the transport mechanics – now we can take this and apply it across these (systems).
TG: So what you’re envisioning right now is pretty close, is mainly for pump-and-pipe systems and largely for operations. Do you see it as having prognostic or diagnostic value?
JP: It will certainly have prognostic value because you will get to the point where you can pick up scenarios where medication will no longer have any effect, right? So if someone gets to a point where they’ve deformed the wall, that wall is gone. No medicine you give them will make them better.
TG: People have floated the idea that a digital twin could be used to replace some animal research and clinical trial data.
JP: Yes.
What it will do is it will take us away from using animals for surgery.
John Pandolfino, chief of gastroenterology and hepatology and director of the Northwestern Medicine Digestive Health Institute
TG: Do you actually think that is realistic?
JP: If you look at surgeries, you don’t have to do this on animals. You would do this on a simulation, like we have, to see what the effects are, and then you can actually go from that to different changes in people. That’s exactly what happened here: Our virtual esophagus proved what we thought would probably be the right way to do this. So that proved our hypothesis mathematically and now we embark on a human trial.
TG: But most animal research, I’d guess, is focused on testing new compounds that might have therapeutic potential, right? So, do you think it has a lot of potential there?
JP: Those studies where they give a mouse 50 times the dose that a human would see, is that going to kill it? I don’t think (digital twin technology will) affect that. What it will do is it will take us away from using animals for surgery.
In addition, I believe that this will lead us to an area where we will be able to create much better models for simulation. So we want to understand a lot more about the material properties of the organs, how they respond to stress and strain, and develop simulations that don’t just run in the virtual world, but actually have tactile twins, right? So something that’s actually made of a material that simulates the esophagus or simulates an organ almost perfectly so that when you cut it, it’s the same feel.
TG: You can exercise on it and you can pour goop down it and see how it expands or something?
JP: Exact. But you know, there’s only so much you can learn from understanding one part of human anatomy and function, because the body doesn’t come up with completely different ways of doing things. It repeats it and it can just make it bigger or smaller, use a slightly different length. (Organs like the bladder and the heart) all work pretty much the same. They have a tube that has some contraction. There are sphincters that open and close. If you even look at the esophagastric junction, the valve that’s at the anti-reflux barrier, it’s very similar to the ano-rectal junction where you have a bowel movement. And actually, if you look at the physiology of how you defecate and how you swallow and protect yourself from having reflux, they’re literally just reversed.
TG: Nature just copies itself.
JP: Yes.
TG: So you think this has much more applicability across the body?
JP: Yes, even in the esophagus. I mean reflux heartburn affects like a fifth of the country. And really, reflux isn’t a problem with too much acid. Most people with reflux have normal acid.
It’s more of an anatomy and physiology issue. So, you know, our approach will allow us to hopefully modify many of the surgeries that are done for reflux and even maybe help create less invasive approaches that work. So, just in the GI (gastrointestinal tract) in general, in the esophagus, it’s going to have a lot more use. And so even in people who may have bladder problems, an overactive bladder or maybe a hypoactive bladder, how do you assess that in terms of bladder flow and emptying? (It is) similar in aortic aneurysms. Aortic aneurysm is basically a diverticulum. It’s just a pressure-related change in anatomy where it basically balloons out. And when it balloons out, because it balloons, it loses its function, and then the blood doesn’t pump properly.
This article is for informational purposes only and is not intended to provide medical advice.
