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Using Visuals to Improve Communication in Multi-disciplinary Teams

Description: Guillermo J. Tearney, MD, PhD (Professor of Pathology, Harvard Medical School) brings his expertise in research, medical imaging, and engineering to discuss how BioRender has helped his team communicate their science better within team and in all media - posters, presentations, and grants!

This webinar was recorded at VISUALIZE 2021, a virtual BioRender event dedicated to advancing communication in science.

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And it's with great pleasure that I introduce our next speaker, Dr. Guillermo Tearney. Dr. Tearney is a professor of pathology at Harvard Medical School with an amazing wide background in research, medical imaging, and engineering. Dr. Tearney has over a hundred granted patents and licenses resulting in commercial medical devices. He has served as a principal investigator on over 40 grants and published more than 150 papers in peer-reviewed interventional journals with strong standards on how he displays and communicates the science. We're excited for Dr. Tearney to speak with us today in this next session. So without further ado, Dr. Tearney over to you.

As was mentioned, I'm a pathologist and an engineer, and my career has really been in part motivated by the book and the movie called Fantastic Voyage. Right now, as pathologists, the standard of care is that tissue is taken outside of the body and we look at it under a microscope after it's been processed and stained, and that's how disease diagnosis is given to patients. But the Fantastic Voyage sort of opened up our imaginations to ask the question: what if we could miniaturize little microscopes and put them inside the body? And then we could see these microscopic structures like cells that are the hallmarks or the aberrations of which, or the hallmarks of disease. And maybe even then, we can potentially image the whole body if we can travel through it and do treatment on the cellular level, which ultimately would allow us to cure diseases at a much earlier stage and save lots of lives.

So, this vision has given rise to a field called micro-imaging. The idea is to see the unseen in living patients. Right now, you can see that the imaging comprises macroscopic. You can do x-rays or CT scans or MRI, where you see organ level disease. But what I'd like to be able to do is see disease at the microscopic scale. On this master slide, there is a scale bar that shows you different sizes going from 10 millimeters down to one angstrom. These epithelium glands, nerves, vessels, nucleus, mitochondria are different features that you can see in tissue as you go down and increase your resolution to higher and higher magnifications. The technologies that we've developed that allow you to do this in the human body and see the unseen, there is one of them called Optical Coherence Tomography, which images at about 10-micron resolution. At higher resolution, you can see individual cells. This one is called spectrally encoded confocal microscopy and oblique backscattering microscopy. And then finally, even higher resolution and dynamic information can be obtained using a technology called one-micron resolution OCT or micro OCT.

Another really big advantage of doing this in the living patient instead of taking tissue out is that you can image the whole body. You can image entire organs with these technologies. So instead of just a little snippet of tissue, which may not be representative of the patient's disease, you can actually image the whole organ and find the area of worst disease.

First, I'm going to tell you a little bit about OCT. As I mentioned, it's a 10-micron resolution imaging technology. One of the first things that we did with this was opened up the field of microscopic coronary diagnosis. So coronary arteries are the arteries that are on your heart that supply blood to your heart muscle. And when they become blocked, they can cause a heart attack. And prior to OCT, you really couldn't see the microscopic structures in the coronary arteries. And it turns out that it's those microscopic structures that are at the very root of the plaques that cause heart attacks. So we built catheters, we inserted them into patients' coronary arteries. This is actually data from the first patient ever imaged with this technology in 2007. In the lower left-hand corner is a movie of images that are grabbed as the catheter spins and pulls back within the artery. And then you can render it in 3D after you colorize the different constituents in the tissue. And you can get these virtual fly-throughs of the coronary artery as in the lower right-hand image, very similar to what was seen in the Fantastic Voyage movie.

We've also explored the use of this imaging in the gut. One of the methods that we have employed uses capsules that are on tethers. So these are capsules that you swallow. They're about the size of a large vitamin pill, and the tether allows you to both deliver the light that does the microscopy and also control the device within the body. And so here's what a typical procedure looks like. This is actually the first procedure done. It was a postdoc who looked at the capsule somewhat suspiciously but decided to swallow it. And then after a few seconds, you get these very nice cross-sectional images as the capsule travels down into the GI tract. And you can see all of the different layers with incredible clarity. Importantly, we can diagnose disease from these capsule-based images. On the left-hand side is normal esophagus, and it has a layered appearance. And on the right-hand side is a precursor to esophageal cancer called Barrett's esophagus. And you can see that you lose a lot of that layered structure, and that is the simple criteria for actually rendering a diagnosis of this premalignant condition. And so we're using this to screen for patients who might have Barrett's so that they can be monitored more closely and catch cancer at an earlier stage.

The stomach is another interesting area. This is actually that same postdoc that I showed you before, and this is digested food in the stomach. It's this beautiful swirly pattern, and you can see the stomach layer in the lower right-hand corner, as well as mucus in between the digested food in the stomach.

We also have imaged inside the small intestine which is the next segment of the gut. The small intestine is lined with finger-like projections called Villi that help in the absorption of food. You can see the dynamics of the Villi incredibly as the capsule is traversing down the small intestine. It's amazing that this kind of image can even be grabbed, but it can be grabbed with a tiny little capsule. This is a 3D fly-through, taking that data and then rendering it in 3D and virtually flying through it. It looks very spongy because of all of those Villi. If you look over here, you can actually see bile, which is a fluid in the intestine that is built up. If we render underneath that, we see this opening in the small intestine called the ampulla Vater, and this is where the bile actually comes out into the small intestine and also pancreatic fluids. Like I said, this is all grabbed with a capsule after it was swallowed, and the procedure just took a few minutes. There are so many applications of this in terms of diagnosing disease, diagnosing a disease called celiac disease, screening for pancreatic cancer, and it can all be done in patients. It doesn't require sedation, and the patients far prefer swallowing this capsule than undergoing a more extensive endoscopic procedure.

Moving to higher resolution technology, I'm going to talk about spectrally encoded confocal microscopy which actually sees individual cells. This is a typical specially encoded confocal microscope image, and it's an enormous image. It's a hundred thousand by a hundred thousand pixels, so you can actually, like Google Earth, pan and zoom into it. You're looking now at the nucleus of all of these cells and you can see the nucleus and the cell membranes. It's sort of like Google Earth, but for your body. You can look at a very low magnification and then you can zoom in to an individual house, which is a nucleus in this case, and zoom and pan and zoom throughout the tissue. One of the areas that this is promising is in a condition called eosinophilic esophagitis. This is inflammation of the esophagus that's caused by food allergies. So you eat a certain food that you're allergic to, and these inflammatory cells, called the eosinophils, come into the esophagus and create damage. Right now, patients that have this have to have many, many endoscopies. It's a big pain, it's very time-consuming, and a lot of these patients are children. What we've been trying to do is develop a capsule instead that you can swallow, and that grabs the same types of images that I showed you before, but not needing a biopsy. So you just swallow the capsule, you get the images of the cells, and you can figure out whether or not the treatment is working or not. Here's a patient swallowing the capsule. It's a pretty simple procedure, and what we end up grabbing is this enormous microscopic image of this person's esophagus, in this case, spanning 20 centimeters all the way from the stomach on the right up to the throat on the left. Again, if you zoom in on any given spot, you can see different cells of the stomach. You can see an area here that has normal esophagus and looks pretty gray and unremarkable, and then an area where these inflammatory cells are there, and you can see these white dots that characterize that this is actually a diseased area where there's inflammation.

Another technology that we've been developing tries to untether the capsule. This is a completely wireless microscope that uses a technology called OBM that essentially is a phase contrast microscopy technology that works in human tissue. This is the postdoc actually showing that there are no wires. It's all battery-powered and it wirelessly transmits data. It's magnetically activated, so it's put near this metal disc, which is a magnet and it's now sitting on top of a phantom containing beads. You can turn it over and these are 10-micron beads, the size of a cell, and we're wirelessly transmitting images of those beads in the phantom onto the computer monitor. This kind of technology potentially allows us to make the Fantastic Voyage a reality. We can take these wireless microscopes, we can control their position within the body, and this is an example of a magnetic control system that can move it around the body. Then, we can get 3D images that we can put into virtual reality systems that will allow us to move the capsule around and also provide surgical lasers that can do treatment but not macroscopic treatment, but treatment on the cellular level. The big vision is that someday, this will come true, and we will have these micro robots moving around our body and not have to open people up to do surgery.

Now, I'm going to talk a little bit about the highest resolution technology that we have, which is called micro OCT. It's an advanced form of the OCT here in the blue area. If we compare the micro OCT images to the standard OCT images, we can see the incredible increase in image quality and resolution afforded by this new technology. Here, we're seeing individual nuclei. Here, we're seeing cell borders, and this is a case where we're looking at inflammatory cells. As you can see, with standard OCT, it just looks kind of like a washout. You don't see any of these features. We've been exploring micro OCT and the cardiovascular system, so instead of just looking at 10-micron resolution images, we can get one-micron resolution images and see all of these cells that contribute to atherosclerosis like smooth muscle cells, macrophages, which are a type of inflammatory cell, the endothelium, which is the cells that cover the surface of the arteries, and other structures like crystals that form in your artery and platelets. We can get incredible detail on the stent implants that they put in the arteries to keep the arteries open and see how cells respond to them.

We've also developed a catheter that does this. It has a special beam that produces a bunch of rings that allows you to get this high resolution. This is a part of the coronary artery that has been imaged by the catheter and you can see in the 3D perspective that it has a very rough surface. The roughness is because these are cells that are adhering to the surface attacking the artery wall. You can actually, if you look at the cross-sectional image, see these cells, which are macrophages communicating with one another. Then, here's another cell, for example, that is another macrophage which is actually going after crystals that are sitting in the artery wall.

One of the neat things about microCT is that it provides insight not just on tissue structure but also dynamics. This is an example where we're looking at little structures on top of the airway cells called cilia. These cilia are like little rowing ores that are beating back and forth. Their purpose is to propel mucus out of our lungs. You can actually see the cilia in micro OCT. This is not possible to see with any other technology. This is in cell culture. You can see the cilia and the mucous mode but you can also see it in human tissue culture. You can see the cilia beading and the mucus moving.

We've recently started doing this in the nose because the cilia in the nose tell you something about the cilia in the lung. This is one of our procedures where we have a little probe that we put into the nose and you can get these images of people's noses in vivo where you can actually see these little cilia flickering on the top of the tissue. We can look at disease states, for example, cystic fibrosis where the cilia become abnormal and the mucus becomes abnormal. You can see all kinds of findings like in this lower left-hand image. You can see the cilia are gone and the mucus really isn't moving around. In some of the lower images on the right, you can see inflammatory cells there and you can see other abnormalities in the mucus which is much more highly reflective and the surface is kind of jagged and eaten away.

Another advantage of micro CT is that you can actually look at how molecules and organelles move inside cells and characterize and change image contrast based on the speed of the motion of those structures inside the cells. So, if we take a micro OCT movie of a piece of tissue and we grab many frames over time, we can see that there's some modulation. The image changes differently and at different speeds at different portions of this image. If we color code that, for example, red is slow motion or no motion, blue is medium motion, and green is fast motion, we get this composite image that actually has much greater contrast than the original grayscale image but also the contrast is meaningful. In other words, it tells you what's going on inside the cell. It turns out that this blue and green motion corresponds to metabolic-like activity. So, when cells are metabolically active, they're blue and also green. But, when cells are static or portions of them are dead, then they show up as red in the image.

This is an example of that. This is the standard grayscale micro OCT image on the top. Then, you can see the dynamic micro SD image. So, much more structure is visible and it looks almost exactly like the conventional histology that we use. If we zoom in on it a little bit more, you can see that the bottom layer is very blue which means it's metabolically active which is actually true. Then, it's still somewhat blue in the intermediate layer and the blue sort of goes away at the top layer. That tells us about how this tissue grows. The cells divide at the bottom and they mature and they die and slough off the top. We're actually seeing this with the dynamic micro OCT technology. It's really exciting and it will open up new opportunities for cancer diagnosis and other diagnosis of abnormality of the inner linings of the organs of our body.

So, this is kind of a summary of what we've been doing. We have been trying to make the "Fantastic Voyage" a reality. We've developed all of these imaging technologies, made probes and capsules that allow them to go into patients. We're even working on wireless capsules that will allow us to see these cells. I would say that it's all enabled through the pipeline that exists in our lab where we invent these microscopes. They're huge and on a big table with lasers running all around. We figure out how to miniaturize them and then we make these miniaturized components in a shop that has all kinds of advanced equipment including many different 3D printers and computer-controlled lathes and mills. Then, those parts are fabricated into final clinical devices in clean rooms. Finally, we test those devices in patients here at Mass General Hospital. This is a great pipeline that we've been using in our lab. It has the advantage that we can learn from the patient and then bring it back through the invention process and continue on this in a circle.

So, we have been using BioRender a lot and we're really excited about the program. This slide tells us a little bit about what Biorender is useful to us. First, it's got a simple interface to create professional, rapidly created professional quality conceptual figures. It allows us to communicate science with minimal text. It's easily accessible to a wide audience and it minimizes discipline-specific jargon and makes it easy to add your images and data. We're really high on this tool. It really fits well within the way we like to visualize things. We're a very visual group and we work with images a lot. This is an example in a publication of how we've used Biorender where we've shown one of our micro OCT probes, how it's inserted into the inner ear through this so-called round window to visualize the cochlea and the organ of corti within the inner ear. It's been a very effective way for us to use the templates and to edit them so that we can show our concept in a simple fashion. It also helps in grant writing. We've used this in many, many grants where we've used BioRender templates, showed our endoscopes going inside the anatomical body and were able to really describe processes in a single figure. When you're writing grants, it's hard. It's not like a presentation or a movie where you can show a process. But, Biorender has visualization tools and the way it's laid out allows us to really show processes. In this case we're showing you how to develop a new technology and use it to visualize inside the lung with some of our Advanced Imaging Technologies. So with that, I'd like to thank everybody who works in my lab, my collaborators, and all of our funding sources that have funded this work. This is a photograph of a recent zoom photograph of our lab. Thank you very much for listening to my talk, and here's my contact information if you want to follow up and get additional information. I'm happy at this point to answer any questions.

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