No part of our body is more vulnerable than the brain. Within minutes of losing blood and oxygen supply, our delicate nervous system begins to suffer irreversible damage. The brain is our most energy-hungry organ, and brain enzymes typically devour it from the inside within hours of death. When cell membranes rupture, the brain liquefies. Within a few days, microorganisms can eat up the leftovers in the rancid process of decay. After a few years, the skull becomes just a hollow cavity.
However, in some cases, the brain outlasts all other soft tissue, remaining intact for hundreds or even thousands of years. Archaeologists have wondered as they discovered naturally preserved brains in ancient cemeteries, tombs, necropolises, and even shipwrecks. Scientists at the University of Oxford published research earlier this year revealing that such brains are more common than previously realized. Researchers examined centuries of scientific literature and counted more than 4,400 cases of preserved brains dating back up to 12,000 years.
Alexandra Morton-Hayward, a molecular scientist at the University of Oxford and lead author of the new study, said: “The brain decays so quickly, so it’s really strange to find that it’s preserved. ” he says. “My most important question is how on earth is this possible? Why does it happen in the brain and not in other organs?”
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Such aberrant storage involves the ‘misfolding’ of proteins, which are the building blocks of cells, and has interesting similarities to the pathologies that cause some neurodegenerative conditions.
As all biology students learn, proteins are formed by chains of amino acids strung together like beads on a necklace. Every protein has a unique amino acid sequence, and there are 20 common types in the human body. This determines how the protein folds into its proper three-dimensional structure. However, perturbations in the cellular environment can cause folding failure.
Misfolding and aggregation of brain proteins is linked to dozens of neurological diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and bovine spongiform encephalopathy (BSE), a disease of cattle also known as mad cow disease. It is the root cause of degenerative diseases. Scientists are now discovering that some misfolded proteins can form clumps after death, persisting for hundreds or even thousands of years.
It is only in recent years that scientists have begun to seriously investigate these strange incidents. A major breakthrough was made in 2008 when archaeologists discovered the 2,500-year-old skull of a man who had been hanged, decapitated and dumped in an irrigation canal in Heslington, England. Although all other soft tissue had long since disappeared, researchers were stunned to discover that the skull still contained a shrunken brain.
A team of neuroscientists from University College London used a chemical analysis technique known as liquid chromatography-mass spectrometry to analyze ancient brains and found that they are among the most ancient brains ever discovered in an archaeological specimen. They identified nearly 800 conserved proteins. They concluded that the ancient brain was preserved by protein clumps.
When protein folding goes wrong
In living organisms, protein folding is highly context-dependent, and perturbations in the cellular environment can lead to misfolding.
A typical example is egg white. It is normally a clear liquid, but when conditions change, such as when eggs are fried or boiled, the proteins loosen and intertwine, forming clumps. “It’s a collection,” says Ulrich Hartl, a leading researcher in protein folding diseases at the Max Planck Institute for Biochemistry in Martinsried, Germany. “The same thing is happening in the brain at a microscopic level.” Many diseases share similar underlying mechanisms. That is, the protein abandons its healthy native state, spreads out, and becomes entangled in a jumbled mass with other misfolded proteins.
In disease, the misfolded version becomes the thermodynamically most stable state of the protein and aggregation is often irreversible. Hartl says he wouldn’t be surprised if similar mechanisms were behind the preservation of ancient brains. “It’s interesting that the brain can be preserved for such a long time after death,” he says. “The interesting question for me is: Does this somehow reflect what is happening during neurodegeneration?”
permanent brain
The discovery of Heslington’s brain has stimulated new research into brain preservation. The effort is centered at the University of Oxford, and its lead researcher is Morton Hayward, a former mortician turned molecular scientist. Currently pursuing a Ph.D. She has assembled the world’s largest collection of ancient brains, with more than 600 specimens dating back 8,000 years, from regions including Britain, Belgium, Sweden, the United States and Peru, and analyzes how they were preserved. I am doing it. (Specimens were collected in accordance with Oxford research ethics guidelines.)
To understand why these brains did not decay, Morton-Hayward used a powerful microscope to examine ancient brain tissue. She placed mouse brains in jars of water and sediment and measured how they degraded over time. She used mass spectrometry to identify the remaining proteins and amino acids in ancient brains. She identified more than 400 conserved proteins. (The most abundant of these is myelin basic protein, which helps form the insulating sheath over nerve wiring.) She sliced the ancient brain tissue and placed the sample in a diamond-light synchrotron (UK). They brought it to the state-run particle accelerator) and attacked them. The movement of electrons at nearly the speed of light allows us to understand the metals, minerals, and molecules involved in the preservation process.
While bodies can avoid decomposition through embalming, freezing, sunburn, and dehydration, Morton-Hayward focuses on cases in which the brain causes decomposition. only Soft tissue remains. Preserved brains are typically collected from waterlogged, low-oxygen burial environments, such as low-lying cemeteries or, in the case of Heslington’s brain, irrigation canals. The human brain is made up of approximately 80 percent water, with the remainder divided into proteins and lipids (fatty, waxy, or oily compounds that are insoluble in water). Oxford researchers believe that this unique chemical reaction may make nerve tissue particularly easy to preserve.
A photo of a brain stored at the University of Oxford.
Morton Hayward believes that the brain is preserved by a process called molecular cross-linking. In other words, brain protein debris and degraded lipids form a sponge-like polymer that resists decay. This process can be catalyzed by metals, especially iron. The strong covalent bonds (electrons are shared) and high molecular weight of these cross-linked molecules make the shrunken brain extremely durable, chemically resistant, and thus able to resist decomposition for centuries. It may be possible.
Morton-Hayward did not find thread-like fibrils known as amyloids, which are characteristic of other protein folds in Alzheimer’s and Parkinson’s diseases, in ancient brains. “When we set out on this journey, we wondered if we would ever find amyloid,” she says. “But we don’t seem to be able to do that.” Instead, amino acids from other degraded proteins “are cross-linked by the same kind of mechanism. And that’s why we found that in these ancient brains. “It’s like what you’re looking at. It’s a collection, but it’s a different kind,” she says.
Nevertheless, some aspects of brain preservation “closely parallel neurodegeneration,” she says. She found evidence of oxidative damage that produces precursor components for cross-linking, both in ancient brain tissue and in mouse brain decomposition experiments. Such damage caused by iron dysregulation is thought to be involved in brain aging and a range of neurodegenerative diseases.
“Perhaps these processes occur throughout life as we age naturally, and they may simply continue after death,” Morton-Hayward suggests.
New research shows that the brain turns into fat selem, or “grave wax,” which is formed when body fat turns into a tallow-colored, soap-like substance (often when a corpse is submerged in water). We have overturned the old assumption that it is preserved by Although the brain is rich in lipids, it usually contains only small amounts of triglyceride fats, which are the tomb wax. “Adipose tissue forms in areas such as the buttocks, arms and cheeks,” says Sonia O’Connor, an archaeologist and pioneer in ancient brain research at the University of Bradford in the UK. “There’s no fatty tissue in the brain. It’s a wrong chemistry.”
But new research shows that the brain has chemistry suitable for postmortem cross-linking and protein aggregation, paradoxically making our most perishable organ the most commonly It is also preserved soft tissue.
eternal disorder
Why are these protein aggregates so durable? Part of the answer may stem from an essential ability of the human brain: its plasticity.
Until the beginning of this century, proteins were often described as binding together in a predictable “lock-and-key” manner, but over the past two decades it has become clear that some proteins are much more versatile. Proteins with intrinsically disordered regions, including intrinsically disordered proteins (IDPs), make up approximately one-third of all human proteins and can adopt many conformations and binding partners . This is an important property for proteins to adapt their structure and function. Myelin basic protein is a prime example of a disordered protein. This “molecular glue” in the fatty insulating sheath around neurons can adapt to the formation of neural circuits that are unique to every individual and must change throughout life.
Unlike regular proteins, IDPs do not have a stable three-dimensional structure and can assume various shapes. They are famous for their ability to bond with many partners. Unfortunately, this versatility makes disordered proteins susceptible to misfolding, which plays an important role in pathological conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, prion disease in humans, and BSE in cattle. I am.
When Vladimir Uversky, a biophysicist at the University of South Florida and a leading researcher on disordered proteins, read about the Heslington brain, he immediately wondered if IDPs might play a role. I doubted it. His analysis of protein datasets extracted from ancient brains confirmed that the most abundantly conserved proteins were characterized by high levels of disorder.
He hypothesizes that IDP acts as a “molecular mortar” by gluing molecules into rigid aggregates that act like “long-term preservatives.” Ubersky calls this phenomenon “stability of instability,” and it helps explain why protein aggregation persists so much in neurodegenerative conditions and even in the dead. Like the Oxford researchers, he believes molecular cross-linking enhances the durability of these remains.
Another dangerous property of protein aggregation is that it can become a seed for growing disease states. “It sucks everything in,” Ubersky said. “That material would act as a black hole.”
While we are alive, we have defenses against protein misfolding, but these defenses weaken as we age and stop completely after death. In the postmortem brain, cross-linking and aggregation can run out of control, limited only by the laws of chemistry and physics.
Indeed, the stubborn molecules in ancient brains differ from the protein pathology seen in living patients. Still, researchers are intrigued by the eerie similarities. Many of the preserved brains come from what Morton-Hayward calls “scenes of suffering,” such as mass graves, Victorian workhouse and asylum cemeteries, and sites of violent death. She suspects that oxidative stress during life unleashes molecular processes that continue in the grave.
“In that case, we could study aging on a much larger trajectory than just the human lifespan,” she says.
