Antoine Louveau was looking through his microscope at thin membranes that protect the brain when he saw something that absolutely shouldn't be there: a lymphatic vessel.
The lymphatic system is part of the circulatory system but, instead of blood, it carries lymph — a clear liquid that ferries immune cells and rids the body of toxins and waste. As a 2009 research review notes, it is "an undisputed anatomical fact" that the brain is the only major organ that lacks a direct connection to the lymphatic system.
Now that claim is disputed. If confirmed, the discovery may have huge implications for studying brain diseases like Alzheimer's and multiple sclerosis (MS).
"All the textbooks said there were not supposed to be any lymphatic vessels in that area," said Louveau, a post-doctoral researcher at the University of Virginia. But after he and UVA neuroscientist Jonathan Kipnis ran a battery of tests, they discovered Louveau had been right. "It was exactly what we thought it couldn't be," Louveau said.
The elusive lymphatic vessel hid in plain sight, throughout decades of research, because it was very small and tucked behind a major blood vessel.
Experts greeted the resulting study, published Monday in the journal Nature, with a mixture of excitement and caution. The main hurdles: Other researchers must replicate the work and confirm the vessel exists in humans, since the study primarily examined mouse brains.
The old map of the lymphatic system, left, which didn't connect to the brain, and the updated map based on the new discovery.Courtesy University of Virginia
Staci Bilbo, a Duke University neuroscientist who studies connections between the brain and the immune system, wasn't involved in the study but quickly heard about it when several colleagues emailed her. "It's generating quite a bit of excitement in the field," she said.
Maiken Nedergaard, a neuroscientist at the University of Rochester Medical Center who discovered a related system in the brain in 2012 (and also wasn't involved in the work) said she was "pretty excited" but "not awfully surprised."
Still, Nedergaard said the implications for diseases involving the brain and the immune system — not only Alzheimer's and MS, but also meningitis — could be significant. "It gives us a new tool," she said. "In biology and medicine, if you understand something, you [can start to] find new targets for treatments."
Immune system cells (T-cells) are shown in red; the lymphatic vessel is shown blue.Courtesy University of Virginia
Scientists used to think that the brain was totally cut off from the immune system and that if immune cells were found there, "something was going wrong," Kipnis told The Scientist.
Work by Nedergaard and others has changed that in recent years, but a lot of confusion about how the brain and the immune system communicated remained, since there seemed to be no direct access. How did immune cells get in, and how did they leave? No one knew.
The new study stands to resolve this and lead to new understanding of and treatments for vexing diseases.
Take multiple sclerosis, for example, a mysterious ailment that affects about 2.3 million people worldwide. Many researchers believe whatever triggers its attacks on nerves in the spine, brain, and eye starts in the body and somehow moves to the brain, Bilbo said. "This [discovery] suggests MS might actually start in the brain," she said. "It reverses our understanding of that pathology."
Then there are neurodegenerative diseases like Alzheimer's. The new vessel might be a good place to look for something going wrong. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said in a statement. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels."
That's just speculation — an intriguing possibility Kipnis, Louveau, and most likely others will explore in future studies. The brain's newfound lymphatic drainage system, and all the possible ways it can malfunction, may well be critical in these diseases. But there's also a chance at this early stage of research that it's a red herring: an interesting anatomical finding that's exciting for scientists but leads to little for patients.
For now, the researchers are hard at work on two major follow-up questions to try to figure out how the research might be relevant and useful. First, does this system definitely exist in humans? And second, what is the potential role of these vessels in Alzheimer's, MS, and meningitis?
The lymphatic vessels are shown in red, almost invisible beside the blood vessels (in green).Courtesy University of Virginia
Other scientists will scramble to replicate the results and build on the finding. If the discovery holds up, it could open a number of exciting new avenues for research.
Bilbo said, for example, there has hardly been any research on the brain's "portal areas" — those foggy zones where the brain connects to yet is shielded from the rest of the body. "[These are] really underexplored parts of neuroscience and neurology ... [These] pathways are really misunderstood. Not even misunderstood, but ignored."
The idea that an entire part of the lymphatic system was hiding in plain sight should ensure that these potentially crucial areas are ignored no longer. With any luck, this might help us solve more mysteries behind the brain — and fight some of its greatest foes.
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