For most of human history, the inner workings of the human body remained a secret. The microscope was invented and many other scientific methods have allowed scientists to study the anatomy and its structure over the past few centuries. Just in the past decade, researchers perfected the art of imaging microstructures while highlighting different cell types with fluorescent colors. In some cases, it helps make it possible to see the glow with the naked eye.
That’s what happened when Kjeld Mollgard, an 80-year old neuroscientist, was dissecting mice to study the structure of microscopic tunnels surrounding the brain–and spotted something unexpected.
This was part of a research study led by Maiken Nedergaard, a professor of neurology at the University of Rochester Medical Center in New York, who was looking to uncover the secrets behind the brain’s glial cells and its waste disposal systems. Glia make up about half of the brain, and they do almost everything from supporting neurons to recycling brain signaling chemicals to providing immune support.
“[Møllgård] is probably one of the few people in the world who would be able to actually see something we didn’t know existed,” Nedergaard told The Daily Beast.
Mollgard noticed something unusual while dissecting the mouse to study it. It was a unique body part. In the past, neuroscientists had established that there were three protective membranes between the brain and the skull. However, in this mouse, he spotted a fourth: a very thin membrane sitting just atop the brain. Later, they verified its existence in humans. Subarachnoid lymphatic like membrane (SLYM) is the new membrane. It is fragile and would easily be damaged during routine dissections. This is why its existence has been overlooked until now.
Nedergaard believes that the SLYM is an important structure that works as a protective barrier and a filter for waste disposal. The cerebrospinal fluid, a liquid that surrounds the brain and spinal chord, is responsible for all brain waste. It’s a clear watery solution. Here the membrane plays an essential role.
“I think it [the SLYM] has a barrier function that separates clean and dirty CSF,” Nedergaard said. It may help collect, sort, and flush waste from brain cells–including debris, toxins, misfolded proteins, and byproducts of metabolism–separating waste and toxins from nutrients that can be reused or recycled.
The SLYM is also home to plenty of immune cells that can patrol and defend the brain, responding to infection or damage. Nedergaard posits that if there is a problem with the membrane, it could lead to further brain damage and neurodegenerative conditions like Alzheimer’s.
With scientists dissecting and studying brains every single day, why has it taken so long to spot the SLYM? It is because any fluid-filled spaces within our bodies collapse shortly after death. Nedergaard stated that CSF is almost gone five minutes after our death. It is absorbed by the brain, expanded, and then ruptured any fragile structures.
Luckily, Mollgard was doing a careful dissection of the mouse brain as he was searching for another type of delicate structure. Nedergaard’s lab had developed a mouse model to study a series of tunnels surrounding the brain called lymphatic vessels which are lined by immune cells called lymphocytes. These vessels are involved in transporting waste and other molecules out of the brain.
In their mouse model, the lymphocytes were marked with a fluorescent green protein which would make these tunnels visible after careful dissection. The team discovered that a layer fluorescing green cells was covering the top layer of the brain when they looked.
“I believe there is a great deal to discover about the microanatomy of the human body,” Paul Neumann, professor of medical neuroscience at Dalhousie University in Nova Scotia, Canada who was not involved in this study, told The Daily Beast. As we develop new microscopes and techniques for studying the human body, it is possible to find these tiny structures more often.
“A function makes it, in my mind, super exciting. Something that can lead us to revise a textbook.”
— Paul Neumann, Dalhousie University
“We can now do in vivo microscopy,” Nedergaard said. This technique allows scientists to image humans and other animals while they’re alive, and visualize a group of cells–sometimes even watching them in action–by adding genes into the animals that tag a group of cells with fluorescent proteins. Scientists are excited by new discoveries such as these, which can help us understand the structure of our bodies.
“A function makes it, in my mind, super exciting. Nedergaard stated that such a function could lead to the revision of a textbook.
Now her team is looking to understand the consequences of SLYM breakages as a result of disease or or traumatic brain injury. She said, “I have no doubt you will discover more secrets about your body because the techniques are better and we’re asking more complex questions.”
In fact, there may be an anatomical Renaissance where important new structures are discovered unintentionally or rediscovered every few year.
Five years ago, surgeons were using an endoscope–a kind of snake-like camera–to look for cancer inside a patient’s bile duct. Instead of cancer, they found a series of pockets that no one had reported seeing before. After taking a closer look, they realized that these were collapsed structures–connected pockets below the skin and in the gut, lung, and urinary systems–and called it the interstitium.
“That was actually a major discovery,” Nedergaard recalled. “All the fluid is taken up by cells that swell up and that means that all fluid filled spaces disappear.” It turns out that the interstitium is important for regulating the immune system, and may be an important way that cancer cells spread through the body.
Sometimes what appears to be a new structure or organ in the body has been characterized decades or even centuries before, albeit with less sophisticated careful techniques. Neumann stated that one of his colleagues loves to tell the truth: “If you want make a discovery, then read an old book.” In 1508, Leonard Da Vinci first characterized the mesentery, what appeared to be small membranes that helped the small intestine stick to the abdomen–think separate pieces of duct tape holding the gut in place.
For most of medical history anatomists believed that the mesentery was just another part of the gut because it wasn’t one continuous structure. But after careful examination in 2016, surgeons Calvin Coffey and Peter O’Leary from the University of Limerick discovered that the mesentery was one continuous membrane, a structure separate from the intestines. Treating it as its own organ opened up new insights into chronic gut disorders. For example, researchers discovered that cutting out the mesentery alongside diseased parts of the gut increases remission rates for Crohn’s disease.
Still, sometimes these structures are properly identified but disregarded by other scientists in the field. In 2012, the glymphatic system–large tunnels surrounding the brain’s blood vessels that carry waste molecules toward the lymph nodes–gained recognition as an important part of the brain’s immune system. It was discovered many decades ago.
“The discovery a decade ago of the ‘glymphatic system’ provided an explanation for observations reported by Helen Cserr in the late 1970s of clearance of material from the brain into lymph nodes,” Neumann said.
Cserr was a young researcher who wasn’t taken seriously, in part because no one thought the immune system affected the brain. “She produced a beautiful set of data in the 1980s showing the glymphatic system.” Nedergaard said. However, other scientists were skeptical and could not replicate her results. “This big prominent lab published a couple of papers saying that she was wrong. She actually had to leave research.”
Cserr died in 1994 due to a brain tumor. Three decades and many paradigm shifts in neuroscience, such as the idea that the brain doesn’t connect to the rest of our immune system took place before her discoveries were confirmed.
Mollgard had the past expertise to spot the new membrane. In many cases however, it is possible for young researchers to discover unexpected information that will eventually be discarded. Nedergaard urges her students to look closely at unexpected results because these are learning opportunities, even if they prove to be wrong.
“And you also in some cases, when you can’t explain the finding, you keep it in the back of your mind,” she said. “Then maybe, it’s always a mystery, and maybe 10 years later, you have another observation, and you can put it together.”
The influx of advanced molecular biology, microscopic techniques, and inquiry will help us understand the minutiae within our bodies. This means that scientists will continue to accidentally discover, rediscover, and revise what we know about anatomy. Along the way, this may lead us to a few new avenues for better treatments for diseases alongside even more questions about our bodies.
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