The Ocean Within Us

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1:08The human body, they say, is around 60 % water. Did you know that? You probably did. It's one of those facts that everyone seems to have heard at some point. Actually, that 60 % figure is an average. Some of us are more watery than others. Men are more water than women, apparently. And we sort of dry out as we age, too. Older people can be closer to 50%, but a baby? A baby might be three-quarters water.

1:44But what do those numbers mean? Where is all this fluid sloshing around inside us? I want to tell you a kind of surprising story about some of the liquid that makes up so much of who you are. It is not the obvious stuff. Not the stuff flowing through your veins and arteries. And not the stuff locked up in your muscles and tissues either. Not spinal fluid, or bile, or the stuff inside your eyeballs. It's a liquid that flows around your body all the time. One that makes up around a quarter of all the fluid in your body. And until recently, it had been kind of misunderstood. It's called the interstitium.

2:30I'm Emily Knight, and I'll be your tour guide to the oceans within us. The story starts with a little anatomical mystery in around 2015 in New York. So I was working at Beth Israel Medical Center in the Department of Gastroenterology, and two colleagues of mine, two endoscopists, had gotten a new kind of endoscope. This is Neil Theis, adjunct professor of pathology at NYU Grossman School of Medicine. I'm a liver pathologist and the last few years I've been focusing on the anatomy of the human interstitium. His colleagues David Carlock and Petros Benias were using a cool new tool, probe-based confocal laser endomicroscopy.

3:14And what was new about this is that it had a fluorescent microscope at the very tip so that if you put fluorescent dye in a patient, you could actually see the living tissue at the microscopic scale. They were looking inside the wall of the bile duct. And what they were expecting to see was the dense, solid layer of collagen, which helps the bile duct keep its shape. But that's not what David and Petros were seeing through the endoscope. They saw instead of a dense layer, they saw these big, open pools of light. and didn't understand what that was. And because as a pathologist, I sort of have to begin as an expert in microanatomy, they brought it to me to look at.

3:55They thought I would know what it was. But I didn't. It didn't look like anything I had ever seen before. This supposedly dense wall was more like a mesh, porous and spongy, shot through with gaps and holes and open spaces. and those spaces were full of liquid. It turned out there were these fluid-filled spaces, more like a kind of sponge. And it didn't look like anything we'd seen on the slide. The thing is, this was living tissue they were looking at with their fancy new endoscope inside a living patient. And that's not the way anatomists usually look at tissue. When we take tissue out of a biopsy, blood and lymph and fluid flows out of it And then we fix it with something like formaldehyde to make it stiff enough to cut into a very thin section so you can see it on a slide under a microscope.

4:47And that further dehydrates it. So what we saw as a dense wall of collagen was actually the collapsed collagen that creates the structure through which these fluid-filled spaces exist. Once they'd spotted this spongy, fluid-filled layer in the bile duct, Neil began seeing it everywhere. On our slides, there are always these little cracks in the collagen. And we told ourselves the story that these cracks are artifact because collagen is so stiff that it cracks when you make it into a thin section for a slide. But then I started noticing those cracks in specimens I would get from the colon, from the stomach, in the skin of a woman who had a mastectomy.

5:28Same cracks. So we realized that everywhere in the body that looked like dense collagen with cracks was actually this expanded collagen network containing this fluid network that flows throughout the body. Okay, backtrack a second. Of course, the medical world has known for centuries that there is structural material throughout the body, networks of collagen and elastin that give shape to our tissues and organs. We call this stuff connective tissue, or fascia, or extracellular matrix. What Neil and his colleagues saw for the first time was that this connective tissue isn't just an inert scaffold.

6:07It's a dynamic, flexible system. So they hypothesised, what if these structures were less like walls, holding everything in the body apart, and more like channels, connecting everything up? They called it the interstitium. Interstitium literally means the in-between. And so these alternating layers at the microscopic level of stiff collagen and more viscous fluid flowing through it create a body-wide communication network. And there are no gaps. Everywhere you look, they're all interconnected with each other. In the skin, the organs, the coverings of the brain, the coverings around all nerves, around every vessel.

6:52It's all one continuous network. And the interstitium is actually four or five times larger than the cardiovascular system. Recently, Becky was talking about this and said, you know, we really should consider maybe it's a third circulatory system. We have the lymphatic system, we have the cardiovascular system, and we have the interstitial. I think of the lymphatic and the blood systems as tubes, But I think that the interstitium is something different. That's Becky to Neil, Dr. Rebecca Wells to us. She's a colleague of Neil's and professor of medicine and bioengineering at the University of Pennsylvania.

7:32Neil wondered if he could bring some of his tissue specimens and look at them with the microscopy that we have at the University of Pennsylvania to see if the structure would be consistent with what Neil was proposing. We were in a dark room looking at samples, and when the first images came up, we realized that, yes, in fact, the hypothesis that collagen surrounded spaces through which fluid flowed, that was in fact true. And so we were just in the dark kind of yelling, you know, this is great. We could see it right in front of us that this was what was happening. So the idea that fluid moves through the body via the interstitium, why was that an important discovery?

8:14It suggests there's a way of fluid moving around the body other than through the lymphatics and the vasculature. I think one way of thinking about it is as the groundwater into which the body's organs are lying. It's fairly easy to imagine our cardiovascular system, the blood flowing in our veins and arteries, as kind of like a network of rivers and streams. Fast-flowing, dynamic, bringing valuable nutrients downstream. Then there's the lymphatic system, which directs our immune response. Perhaps that's a little more like an estuary, with milky lymph fluid draining from vessels into nodes, transporting the flotsam of pathogens away and out to sea.

8:57Rebecca thinks of the interstitium as something a bit more placid, but just as important. Is it more of groundwater or an ocean than a system of rivers and streams? I mean, I love that idea because groundwater doesn't flow quite as much as the way we think about a river does, but it is sort of ever present and it sort of swells to where it's needed and then it flows away and drains away. This fluid that's sort of partially just there in our body, but it's also moving around in a way we don't quite understand. I think that's beautiful and you've said it much better than I did, but I love this concept.

9:31But these three water bodies, as they interact with each other, they flow into each other a little bit? unquestionably in interstitial spaces, we can see the openings to lymphatics. And we can also see capillaries. So capillaries definitely drain into the interstitium and interstitial fluid flows into lymphatics. So there's no question that all three systems are connected. So I think just in terms of basic anatomical knowledge of the body, this is incredibly important. You know, it would be like thinking about the earth without groundwater. I mean, it would just be, it would be impossible. Neil and Rebecca and their collaborators wrote up their findings into a paper.

10:12And in March 2018, it was published. And immediately, it went extraordinarily viral. A fascinating discovery. New research suggests scientists found a newly identified organ in the human body. That makes up a previously unknown organ called the interstitium. That might play a critical role in how other tissues and organs do it. Search dubs it, our body's brand new organ. It's news to me. To target this new organ, the opportunities could be endless. There was the scientific headline in the paper itself, which was there's a form of interstitium that we hadn't really recognized before. And that's what we said in the paper.

10:50Where did the line about the new organ come from? How did that happen? So it was the press team for NYU. They asked me, so this is really large. Could this be an organ? And I said, well, honestly, I hadn't really thought about it in those terms. But depending on how you define an organ, and there are several different ways to define it, I said, yeah, perhaps this could be considered an organ. And then the press release went out saying a new human organ was found. By the end, my institution estimated that there were 4.2 billion people in the world who had seen this news. What was it like for you after that?

11:25It was crazy. I had people come up to me on the street and say, I saw you on the news. That was exciting. In the scientific world, it was much more fraught. And Becky and I both had experiences of being at meetings and people sort of mocking us. So that was off-putting. As a scientist, you want things being considered on their merits, not because of the advertising and marketing. I was not happy that it had gone viral in that way. I don't actually think it matters if it's an organ or not. But I thought that at the stage of research that we were at, that was an overstatement. And unfortunately, the scientific field responded that way.

12:05Most people read only the publicity, but had not read the actual paper, which was very carefully written. I received some flack. And I think it hurt my scientific credibility for a while. It was rather a painful period of my life. And what was the nature of the pushback that you got? I mean, was it just that that's a sort of an arrogant claim that you didn't have the evidence for? What was the pushback? The pushback was that that was arrogant, there was no basis for it, that we hadn't adequately taken into account that people had known that structures like this had existed for a long time. And that is absolutely true.

12:40But I take my scientific reputation very seriously. and I was not so happy about being associated with something that legitimately was said to have been overstated. We'll put it that way. So their paper didn't actually make that headline grabbing claim of the discovery of a brand new organ but they did make a few hypotheses about what this biological entity might be for. Their biggest idea was that it connects up distant tissues and organs in a body-wide communication network. The connection between the interstitium in any one tissue or organ is the interesting idea that this paper provoked. There are channels that potentially help those organs to communicate and I think that's a really interesting concept.

13:35I've come to visit a place where the gaps and spaces in between our body tissues take centre stage. This is the Cell Matrix Centre in Manchester. Rachel Lennon is its director. I'm a paediatric kidney doctor here in Manchester at the Children's Hospital and I'm also director of the Manchester Cell Matrix Centre and the Cell Matrix Centre here has been going for over 30 years now. So the Cell Matrix Centre, what is the Cell Matrix? Cell matrix. So matrix is the proteins like collagens, but actually give the structural support to many of our tissues. And matrix can be very dense and stiff, like the matrix in our bones and our tendons, but it can also be very soft and suited for supporting the cells in our brain, which is a very different type of tissue.

14:27If Neil and Rebecca's idea of the interstitium is like a sponge full of liquid, then you could think of the extracellular matrix as the fibrous material of the sponge itself, the thing that the interstitium sits in and flows through. It's really dynamic. I think of it a bit like a coral reef, if you like. And if you were to kind of jump in and look around you, you would be in this thick forest, almost, of collagens and laminins and fibulins and all of these different components. this kind of very delicate kind of wavering forest of trees that are kind of just moving in response to the flow of the blood.

15:07Here in Manchester, they've been studying these spaces for decades. I mean, I guess going back to the early days of microscopy were when these structures were first appreciated and it's the 1850s where actually William Bowman found these under the microscope And as technology has moved along over two centuries almost, we've been able to build up that picture. And in Manchester, we're over 30 research groups now connected by this need to understand more about matrix in their different settings. There was a paper that came out in 2018 which proposed a sort of a new understanding of this space in between our organs.

15:47They coined this term interstitium. how much been impacted that paper have over here where you've been studying this space for like you say decades yeah so all papers that kind of get us to think about our tissues in different ways are well received they get us thinking and I think this paper in particular grabbed attention was it surprising was it kind of unexpected no but I think the really interesting concept was to then think about the interstitium as this conduit for communication across tissues. Right, that's a big thing, isn't it? Communication and the interconnectedness of the whole body.

16:26Do you think the understanding of the human body as this sort of holistic entire thing which communicates internally, has that been underestimated over the years? Yes, I would say so. And I think to some extent that's because it's difficult to study. But we are now in a position with the amazing technology that we have to understand what is that level of communication? What are the signals? Where do they go wrong? And what could we potentially do to intervene? Are there signals from that matrix, from that interstitium that alert other tissues in the body? so the function therefore of perhaps the interstitium is to make sure that those alert signals are delivered.

17:14At the Cell Matrix Centre they have a bunch of different research groups teasing out what this structure is doing in our body. Some look at the mechanics of how it moves or helps tissues to move. Others look at how it might contribute to the spread of disease from one organ to the next. Some even look at the role it has in keeping our body clocks ticking along. Judy Allen is more interested in giant, invasive, parasitic worms. Hi, I'm Judy Allen. I'm a professor of immunobiology at the University of Manchester. I study the immune response to infection, and particularly infection with parasitic worms, but I also have become very interested in the extracellular matrix and wound repair.

17:56As an immunobiologist, Judy's route into this world was through the immune system, And that operates through one of the other fluid networks in the body, the lymphatics. The lymphatic system is at least as complex as the blood vascular system. And they really go side by side. These very tiny lymphatic vessels reach into every one of your tissues. So it is a really extensive system that's moving fluid and cells around your body with a very different purpose than the blood system. But as we've seen, all the three fluid systems in the body, The rivers of the blood, the draining estuary of the lymph and the bubbling, shifting groundwater of the interstitium, all of them flow into and drain out of each other all the time.

18:41And so the fluid in the interstitium plays a huge role here too. It's part of a natural inflammatory response is that you get a buildup of fluid in those interstitial spaces. Those interstitial spaces have very small lymphatic vessels. when they feel that fluid pressure, those valves open, and into those valves goes the fluid from the interstitial spaces, but also the immune cells. That lymph node begins to really swell, full of the immune cells that are now really specific for that infection. They move in through this thing called the thoracic duct, where they then get dumped into your regular bloodstream, and then from there, it'll go right back into the tissue where it needs to fight that infection.

19:24So you've got interstitium to lymphatic vessel to lymph node, back into blood, back into the original tissue. So it is all deeply interconnected. Back to the parasitic worms then. I was studying worms, particularly filarial nematodes, things that cause diseases like elephantiasis or river blindness. And these are big. I mean, you can see them with the naked eye and they migrate through our tissues and they can do a lot of physical damage. Judy was studying what the body does in response to a burrowing nematode working its way through your flesh. It's called a type 2 immune response. And the first step is to flood the site with a very particular fluid called hyaluronin.

20:05And the interstitial spaces are packed with hyaluronin. Fall flavours are waiting for you at Whole Foods Market. Cozy pics all through the store. like maple leaf cookies from 365 brand. Swing by the bakery for pumpkin cheesecake, here for a limited time, and pumpkin turmeric bread freshly baked every single day. Sip the season with 365 brand cinnamon spice coffee and pumpkin spice creamer while you still can. Spice up fall at Whole Foods Market. At QVC, shopping is more than just checking out. It's discovering something new every day. Start with today's special value. Then explore exciting finds across the brands and categories you love.

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21:13So hyaluronin is a really, really, really huge, long polysaccharide. The sort of dogma is that it can hold a thousand times its own weight in water. So it's incredibly hydrophilic. Hyaluronin is an essential part of just initial tissue repair. So when you first get wounded, you begin to fill in with this provisional matrix, which is mainly hyaluronin, and then you can begin to lay down sort of collagen fibres and other things. When everything goes well, that is an absolutely perfect, essential part of it. It's amazing how we can heal our wounds. But sometimes the hyaluronin can build up and be very, very damaging.

21:51An example of this came in an unexpected way for Judy back in 2020. A colleague of mine contacted me during the pandemic and said that we've noticed that in our patients who are having very severe COVID-19, that they have a higher immune signature for this kind of type 2 response, which was really, really not expected because this is a wound repair, anti-worm response. And one of the things they saw that was really being regulated by this type 2 immune response was hyaluronin. To bring hyaluronin to the site of an injury is not unusual at all. That would be a completely normal response for the body.

22:27That would be not only normal, almost universal. Yes. But to bring hyaluronin into the lung in response to infection, is that a good thing or is that a problem? The answer is both, right? So anytime you inhale something, whether it be pollution or smoke a cigarette or you get a viral infection, your lung will start making hyaluronin. All immune cells have receptors for it. So it also holds immune cells. So it really helps promote that original inflammatory response potentially. Normally, it just turns over very quickly. But for reasons that we study and don't fully understand yet, in diseases like COVID-19, it builds up and doesn't necessarily go away.

23:12And we think that in COVID-19, it's a major cause of death. They simply can't breathe. Okay. So this same substance, which makes the space in between your tissues plump and moist, is also the thing that's thick and sticky and can fill up your lungs with the flu or with COVID. Absolutely. Yeah. You look at the people who've died of COVID-19 and the lungs are just packed with hyaluronin and it's full of water and those things are contributing to the failure of the lungs to function. The interconnected fluid network of the interstitium allows the body to transport the things it needs from where they're made to where they need to be.

23:49But this feature also means it's vulnerable to hijack by things we really don't want traveling around our body. Looking at cancer under the microscope is something I've spent a tremendous amount of time doing. And the classical ways we think of cancer spreading in the body are getting into the blood vessel walls and spreading through the cardiovascular system, getting into nerves and spreading along nerve tracts, and getting into lymphatics to get to lymph nodes. What we now understand is that for many tumors, maybe most, perhaps all, in order to get to these other structures to spread, it first spreads through the interstitium.

24:27So all these years we've been missing a primary pathway for cancer getting out from its primary site and invading the rest of the tissue. We have these beautiful images, beautiful for a pathologist, it's cancer. And you see the cancer cells just moving through these pre-existing spaces like they're just going out for a picnic. How could we use that knowledge to treat cancer differently? I mean, what can we do with that in terms of stopping it spreading? I don't know. I mean, this is one of the wonderful things here. It opens up all these questions like how does tumor move along these spaces? If we understand what the mechanics are, maybe we'll devise interventions to inhibit that from happening.

25:08It must be a pretty eerie experience watching a cancer cell move through the body in the way it does, knowing what that cell can do to us. Oh, yeah. As a pathologist, you sort of lead this double life where you're looking at these images under your microscope. They're very pretty. There are lots of colours. But you know that down the hall, up a floor, or in a clinic somewhere, there's a person, a family, dealing with something really horrendous. Back when they first published, when that claim about a new organ was made, Neil and Rebecca weren't just getting flack from fellow anatomists. Neil also had a lot of pushback from a place he wasn't expecting, from practitioners of alternative medicine.

25:53The folks in fascia world, the osteopaths, the craniosacral folks, the Rolfers, etc. They said, we've known there's fluid there. This is not news. We've known it for 70 or 80 years. And I wasn't aware that they knew that. And what became clear to me is that they had, in fact, been recognizing this all the way along. But the orthodox Western medical biomedical community wasn't really allowing them to publish in the medical literature. So it wasn't there for me to find in my searches. I was invited to China. They said, oh, we see it in the news about this interstitium stuff. Could you give us a talk on it?

26:31And one of the first questions I got after from someone very high up in the traditional Chinese medicine world said, so how have people responded to this? And I told them about, you know, how fascia world had been affronted at first because they'd known about it for 70 or 80 years. And he laughed and he said, yes, and we've known about it for 4 ,000 years. And that's when I started to become aware that this anatomy was actually a conceptual bridge as well as a physical bridge between structures. That what in Chinese medicine they talk about meridians and acupoints relates to this anatomy. And then when I speak to practitioners of Tibetan medicine where they practice pulse diagnosis and they go, yes, we're feeling the interstitial fluid.