The “interstitium”: Interesting science versus PR spin and pseudoscience

If there’s one thing I’ve learned over the years, it’s that quacks are adept at co-opting pretty much any scientific finding in medicine and using it to justify whatever pseudoscientific treatment that they’re offering. Antivaxers are particularly adept at this, having tried to use science such as MTHFR mutations, mitochondrial disorders, and just about every discovery about autism other than genetic links to it to bolster their fixed belief that vaccines cause autism. They are, however, not alone. Quacks of all varieties love to invoke quantum theory, new findings in cancer research (such as the rediscovery of the importance of the Warburg effect), and a variety of new scientific discoveries as “mechanisms” for their woo.

This brings me to a new scientific finding that’s been discussed a lot in the press. Somehow, I didn’t get around to discussing it, even though the study reporting the finding provides several issues, including how eagerly a questionable narrative about the study was accepted by the science press as valid, as grist for Oracian Insolence. Fortunately (or unfortunately), I’ve been informed by readers about a recent episode of Science Friday that is likely to lead to quacks invoking these new scientific findings as a basis for the mechanism of their quackery even faster than I would have predicted. Even worse, the investigators themselves were the first to make the link.

I’m referring to the interstitium, which numerous news reports were portraying as a newly discovered “organ.” There were a number of headlines that made me grit my teeth, like this:

That last one, by the way, is last week’s Science Friday, which featured an interview with Neil Theise, a professor of Pathology at the NYU School of Medicine, and Rebecca Wells, a professor of Medicine and Bioengineering in the Faculty of the Center for Engineering Mechanobiology at UPenn, two of the authors of the study above. In the interview, they imply that the interstitium could explain how acupuncture works, but more on that later. First, let’s look at the study.

I note that study itself was published in Scientific Reports (which is not, as it is sometimes misrepresented, Nature, but rather an open access journal published by Nature Publishing Group). The reason I bring this up is that this is not the first study published in Scientific Reports that I’ve discussed. In fact, a mere two weeks ago, I discussed a particularly dodgy study published in Scientific Reports that claimed to have found that human heart rate variation (HRV) measured by EKG, responds to changes in geomagnetic and solar activity, indicating that the earth’s electromagnetic field controls our autonomic nervous system. Before that, I discussed a study published in Scientific Reports in which mice were tortured in the name of antivaccine pseudoscience. When I last mentioned a Scientific Reports study, the study’s defects led me to make an analogy that was most definitely not flattering to Scientific Reports. Basically, I said that Scientific Reports was Nature’s answer to PLoS but in reality was increasingly striking me as Nature’s answer to Medical Hypotheses, the journal long famous for publishing “speculative” papers on how vaccines cause autism and a number of other scientifically dubious topics.

In fairness, I am not saying that this study on the interstitium is anywhere near that level. Quite the contrary. I find it intriguing, even if the way its findings were communicated to the press were a masterpiece of PR, with the promotion of the narrative that a “new organ” had been found when in fact the study didn’t really show that. I’ll tell you what I mean, and then I’ll discuss the claim that somehow this “new organ” can provide a mechanism by which acupuncture “works.” I also can’t help but wonder why this study was published in Scientific Reports, instead of a pathology, anatomy, or surgery journal, if the discovery is indeed as novel and potentially transformative as the schools’ PR blitz claims. I also note that it appears not to have been the authors who originated the “new organ” narrative.

Based on an observation while investigating a patient’s bile duct for signs of cancer in which Mount Sinai Beth Israel Medical Center medics Dr David Carr-Locke and Dr Petros Benias noted cavities that did not appear to match any previously known human anatomy. They therefore approached New York University pathologist Dr Neil Theise to ask for his expertise. Together they used a technique known as confocal laser endomicroscopy (pCLE) to examine extrahepatic (outside the liver) bile ducts. This technique can provide real-time histologic imaging of human tissues at a depth of 60–70 μm during endoscopy. using this technique, the investigators examined extrahepatic bile duct tissue taken at endoscopic biopsies looking for pancreatic or bile duct cancer after injection of fluorescein, a fluorescent dye commonly used in medicine. They noted a reticular pattern within fluid-filled sinuses that, according to them, had no anatomic correlate. Freezing the biopsy tissue before fixation preserved this structure, demonstrating that it was part of the submucosa. (The submucosa is a thin layer of tissue in various organs of the gastrointestinal, respiratory, and urinary tract underlying the mucosa, the layer containing the epithelial cells and the membrane upon which they sit, to the smooth muscle surrounding the tubular structures of the organ). In addition, specimens were obtained from twelve pancreatico-biliary surgeries, with the patient being injected with fluorescein a few minutes before the blood vessels to the organ were tied off and divided to resect the organ, and the tissue subjected to various immunohistochemical studies.

The discovery process is illustrated in Figure 1 of the paper:

Interstitium

How the “interstitium” was discovered

The authors started recognizing this structure in other organs as well:

The characteristic histological features of this bile duct submucosa structure (spaces filled with fluid and with collagen bundles lined asymmetrically by flat cells) are readily visualized in other tissues. The structure was recognized consistently in the dermis in clinical resection specimens of skin (Fig. 3A), and pCLE applied to thin regions of skin in vivo after fluorescein injection showed the same reticular pattern in the dermis as in the bile duct. Fluid-filled spaces and collagen bundles lined by cells staining for CD34 are seen on histology in multiple organs and tissues, including in the submucosa of the entire digestive tract, the urinary bladder, peribronchial tissue, fascia, and stroma of arteries and veins of all sizes (Fig. 3B and Supplemental Fig. 1).

The existence and nature of these spaces have implications for medicine, as they could potentially better explain the phenomenon of “third spacing,” in which fluid moves from the vascular space to the interstitial “third space,” resulting in edema, too little intravascular fluid, and decreased cardiac output. It might also explain why gastrointestinal tumors are much more likely to metastasize to regional lymph nodes once they reach the submucosa, particularly given that the interstitium appears to be connected to the lymphatic system.

Now here’s the interesting thing. Nowhere in the paper do the authors propose that this new network of spaces is actually a new organ. For instance, here is the conclusion:

In sum, while typical descriptions of the interstitium suggest spaces between cells, we describe macroscopically visible spaces within tissues – dynamically compressible and distensible sinuses through which interstitial fluid flows around the body. Our findings necessitate reconsideration of many of the normal functional activities of different organs and of disordered fluid dynamics in the setting of disease, including fibrosis and metastasis. A submucosa subjected to directional, peristaltic flow is not the previously envisaged wall of dense connective tissue, but a potential conduit for movement of injurious agents, pro-fibrogenic signaling molecules, and tumor cells. This raises the possibility that direct sampling of the interstitial fluid could be a diagnostic tool. Finally, our study demonstrates the power of in vivo microscopy to generate fresh insights into the anatomy and physiology of normal and diseased tissues.

That is basically a fairly conservative view of the finding. It’s interesting. It suggests further areas for research. It validates the usefulness of their technique. It contributes to our knowledge. But identify a new organ? I’m with Anirban Maitra, a pathologist at the University of Texas MD Anderson Cancer Center, who observed:

News reports have suggested that this interstitium could represent a widespread organ in the body, whose connections with the lymphatic system might be involved in cancer metastasis. While researchers not involved in the study agree that the interstitium likely plays diverse roles in the human body, they are reticent to call it a new organ.

“It is fair to say that histologists [and] pathologists have long known that there is an interstitial space and that it contains fluid,” Anirban Maitra, a pathologist at the University of Texas MD Anderson Cancer Center who did not participate in the work, writes in an email to The Scientist. “The claim that it is a hitherto undiscovered organ, and the largest one ever at that, seems a stretch,” he cautions.

“Most biologists would be reticent to put the moniker of an ‘organ’ on microscopic uneven spaces between tissues that contain fluid. By this definition, the abdominal cavity and pleural spaces should be discrete organs” too, says Maitra.

Quite right. What appears to have happened is that the NYU Langone medical center press release described the finding as a “new organ,” and that characterization stuck in every news report I’ve seen about this finding. The authors are not blameless, though. The press release states that the “current study is the first to define the interstitium as an organ in its own right, and as one of the largest of the body, say the authors.” Whether they said that or not to the university PR person who composed the press release, I don’t know, but I do know that they’re cited as having said this.

The authors are also far from blameless when it comes to their Science Friday appearance. In it, they didn’t really push back against Ira Flatow’s use of the narrative that the interstitium is a new “organ,” although I must admit that most of the conversation about the finding (at least the first half) was pretty interesting, including the unanswered questions about this space.

As is often the case in live radio, things started to go south when Flatow started taking phone calls. The first call was from an osteopath, who started pontificating about how, for over a hundred years, osteopaths have had literature about the importance of the lymphatics and fascia in health and disease and how osteopathic manipulation can impact both. Dr. Theise, unfortunately, fed into this narrative by saying that the fascia really is this space (something that I as a surgeon, having actually seen these dense bands of fascian in vivo during operations, have a hard time believing) and basically buttered up the osteopath regarding how he had hoped that the osteopathic community would look at his study and go, “Aha!”

Then, near the end of the interview, Flatow asked whether this discovery lends any sort of explanation for how acupuncture or acupressure works. I groaned. I groaned even more as Rebecca Wells went off the rails by agreeing that, yes, she thought that it could explain acupuncture. She asserted that acupuncture definitely does work. (No, it does not. It is a theatrical placebo.) Theise then joined in, citing work that claims that, when you stick a needle into the skin, sound waves go 1 cm in all directions detectable on ultrasound but that if you put it in an acupuncture point it travels all the way up the meridian. Yes, he went there. He speculated that these interstitial fluid channels could be explain acupuncture meridians and provide a way for messages to travel along them. Wells then speculated about the electrical properties of collagen and how their discovery could suggest ways for signals to be transmitted. I dearly wanted to find the specific study to which Theise referred, but there wasn’t enough information for me to do so, other than that it’s probably at least ten to fifteen years old and one of its coauthors is named Yang. Given that there is such a thing called Yang acupuncture points, trying to narrow down the many hits on searches was taking way more time than I was willing to devote to the task.

Elsewhere, in another interview published in The Science of Us:

“Acupuncture has no anatomical correlate,” says Theise. “There’s no vein; there’s no artery; there’s no nerve corresponding to the meridian [the map of acupuncture points on the body].” Without any anatomical correlate, it’s been difficult for researchers to explain why a localized therapy like acupuncture could have such far-reaching effects. Knowing that the interstitium is filled with fluid could change that. “This is the layer of skin the acupuncture needle goes into,” says Theise. “There’s fluid in there. When you put the needle [into an accu-point], maybe the collagen bundles are arranged into a channel through which fluid can flow.” Studies show that “sham” acupuncture, or acupuncture in which needles are placed a centimeter off the meridian, doesn’t provide the same kind of pain relief that true acupuncture does: Sham accu-points may reduce pain in the immediate, local vicinity, but won’t have the widespread effects that true accu-points do. If accessing true accu-points allows interstitial fluids to travel throughout the body, that might account for the difference.

Not surprisingly, “integrative medicine” specialists are all over this finding too:

Dr. Shaista Malik, director of the Susan Samueli Center for Integrative Medicine at UC Irvine, says that in the cardiovascular world, specialists have long been aware of this “third space” (the circulatory system being the first, and the lymphatic the second), but agrees that the new research provides a deeper understanding of what it looks like, and what it does. “[The third space] was very elegantly described in this paper, because it’s showing that there’s organization and structure to this, while previously it was considered unstructured,” says Malik. “This is a really interesting finding that could go a long way in explaining why local therapy, stimulating only certain acupuncture points, could produce systemic effects.

We’ve met Dr. Malik before in my discussion of the quackery promoted by the Samueli Center at UC-Irvine and how the $200 million gift to the university will transform it into a center for quackademic medicine. You can see from her quote the direction that we’ll hear apologists for quackery taking this research and how they will use it.

Dr. Theise is also wrong on so many levels, and his contributing to the narrative that quacks will use to justify acupuncture is infuriating. As I like to say, it doesn’t matter where the needles are placed. It doesn’t even matter if the needles are placed. Indeed, twirling toothpicks against the skin produces the same effect. Basically, acupuncture is nothing more than a theatrical placebo. It does not work any more than placebo. The author of the article Katie Heaney asks Do We Finally Understand How Acupuncture Works? The answer is most definitely no, because acupuncture doesn’t work. Steve Novella recently reviewed why again while discussing Theise’s and Wells’ study, noting:

We have had over 40 years and thousands of studies, and still researchers are unable to show that acupuncture is a real thing. The simplest explanation for this fact is that acupuncture is not a real thing. This also conforms nicely to everything we know about biology and physiology – magical meridian lines do not exist.

Unfortunately, thanks to an overeager PR department at NYU, coupled with investigators who mistakenly believe that acupuncture works and have been willing to shoehorn their discovery into the narrative promoted by quacks, I foresee a whole lot of “interstitium” quackery and use of Theise’s and Wells’ discovery by quacks to “explain” their quackery coming. It won’t just be acupuncture, either. Indeed, Malik went beyond acupuncture to claim that this discovery suggests how Tai Chi and yoga supposedly “work,” too. Chiropractors will soon be all over the interstitium because anything involving fascia and the lymphatics is catnip to them. Soon we’ll see regimens designed to “detox” your interstitium or to use your interstitium to “detox.”” We’ll learn from antivaxers that vaccines are so harmful because the evil “toxins” get into the interstitium. I guarantee it. (I’m guessing some antivaxer somewhere has already done this.)

This is the harm that poor science communication can cause. Not only did PR department spin vastly overinflate the importance of a study with an interesting finding beyond what that finding warrants, but the investigators themselves have provided a narrative custom-made to promote quackery.