When the body attacks the mind: myelin and multiple sclerosis

Multiple sclerosis damages the nerves, and especially their sheath - the myelin. Second article in the series

For the previous episode: Electricity, nerves and the ethnobiology of zombies

"He was happy to share in the sadness in the world. We cannot heal the sadness in the world, but we can choose to live happily." Joseph Campbell, 1904-1987

"Why did the soul of man have to be placed in such a close, sad, full of feeling and incomprehensible relationship, with a bone so vulnerable as his own body?" asked Thomas Hardy at the beginning of the 20th century, reflecting the eternal frustration that people felt when their bodies betrayed them while their souls were at their peak. Hardy was born in the 19s, but when he reached the age of eight, the life of another person, who suffered all his life from the painful relationship between the body and the soul, came to an end. This man was Augustus Dasta, who, had his fortune been somewhat different, might have been crowned King of England.

Augustus was born in 1794, the illegitimate grandson of King George III. His father, the royal prince, married without receiving official permission from the king, and therefore George decided that the marriage was null and void and that the offspring would have no right of claim to the monarchy. The infant Augustus was transferred to his mother's custody in England, and grew up to be a young, handsome and disillusioned Elam. He longed to be part of the royal house that rejected him, and sought, to no avail, recognition from his father and grandfather. To get the same recognition, Augustus petitioned many times to the members of the royal house and parliament, but to no avail. Such was the situation for the first twenty-eight years of Augustus' life.

Between petitions, Augustus decided to spend a few days with a beloved relative in Scotland. The journey took many days, as was the way of journeys at that time, and when Augustus arrived in Scotland he discovered to his regret that the relative had died unexpectedly, and that he had arrived just in time to attend the funeral. While standing, surrounded by a storm of emotions, over the fresh grave, Augustus could not stifle his tears. The tears blurred his vision, but he wiped his eyes and returned to his temporary home. It was only there that he discovered that although the tears had dried, his vision had not returned to its strength. In all practical respects, Augustus lost his sight. [1]

If young Augustus were alive today, he would surely have immediately gone to see a doctor. It would give him a series of tests, including a magnetic resonance imaging (MRI) test [2], during which his brain was mapped using a powerful magnetic field, and photographed slice by slice. Since the nobleman was not physically injured, most likely the doctor would have looked for a brain tumor that could have disrupted the activity of the visual center, or the activity of the nerves that carry the information from the eyes to the brain. That hypothetical doctor, had he examined Augustus, would not have encountered evidence of a tumor, but would have discovered another strange sign: a scar in the center of the brain, marking the area where the nerves were damaged. But how does that scar appear in the brain, as if an invisible knife penetrated through the skull and left without leaving a mark on the outside?

Augustus continued to live his life, unaware of the mystery hidden within his mind. His servants and friends read letters to him, and he began to write a diary by dictation. Although he tried to treat the visual impairment as only temporary, he feared that his eyes would remain damaged forever. It is said that the child becomes an adult when he realizes that he will not live forever. Here, at the age of 28, Augustus' childhood ended.

To the tormented young man's relief, after several weeks his vision returned to normal, without any medical treatment. If the doctor had re-examined Augustus' brain, he would have found that the scar had almost disappeared, replaced by normal nerve tissue. But in the 19th century, the device for magnetic resonance imaging had not yet been dreamed of, and in any case, despite the momentary recovery, the dispossessed heir to the throne was not expected to live a life of honey.

It was not a knife that injured Augustus' brain, nor was a bacteria or virus responsible for destroying the tissue. In fact, there was no foreign entity behind the attack at all. The nerve cells, the source of the soul, were attacked in this case by the body.

the isolation of the nerves

in the previous chapter (Electricity, nerves and the ethnobiology of zombies), we saw how the nerves transmit an electrical signal along their long branches. The transmission of the signal begins when the cell membrane in the 'yes' area changes its surface tension, leading to the opening of the sodium channels that allow positive ions to flow into the cell and turn the membrane tension positive. As a result of the change in voltage, the adjacent sodium channels are also opened, and thus the information can progress in leaps and bounds along the long nerve extension, when each new channel that opens leads to the opening of another channel down the nerve extension.

Although each channel opens in less than a thousandth of a second, the signal transfer speed is not great and reaches a speed of 25 meters per second, at most. This speed is sufficient for small creatures, such as most invertebrates, in which the neural processes do not extend to a great distance. But in the animals that belong to the group of vertebrates, many nerve processes extend to a length of millimeters and centimeters, and in humans one can find processes that reach a length of a meter or more. This is why the vertebrates underwent an evolution that perfected their nervous system and added a new component to it, which allowed them to reach a signal transfer speed of up to 100 meters per second.

If we cut a human nerve across it, we can see that the nerve branch is surrounded by many skins, which are tightened around it similar to the skin of an onion. The layers of the sheath are formed by unique cells, whose entire function is to wrap around the nerve extensions again and again and again, and keep them isolated from the environment. Their role can be compared to that of the black rubber that wraps telephone lines in the depths of the sea. The many layers of membranes surrounding the extension isolate the nerve membrane from the environment and thus allow the voltage change to 'jump' for a distance of several millimeters along the extension, at the speed of an electromagnetic wave, and without delaying the opening of each sodium channel in turn.

The insulating sheath around the nerves is called 'myelin', and the cells that sacrifice their bodies to produce it are called Schwann cells in the peripheral nervous system, or oligodendrocytes in the central nervous system. Despite its great effectiveness, it is clearly not sufficient for nerves that exceed a millimeter or two in length. It does provide excellent insulating conditions, but even these do not allow the voltage change to survive more than a few millimeters along the nerve. Because of this, a mechanism is needed to recreate the electrical signal along the nerve, before the voltage change finally dies out.

If we walk along the nerve branch, like surveying an underwater telephone line, we will discover a strange phenomenon. Although the entire extension is coated with an insulating layer, there are still bald areas, where the sheath is cut and exposes the nerve to the environment outside the cell. If some engineer designed a telephone line this way, we would certainly want to hospitalize him. But in nerves, those areas exposed to the environment are necessary to amplify the electrical signal.

The electrical signal - the change in cell membrane voltage - jumps from one ice to another, as it is driven at a speed close to the speed of light in transparent materials. In each of the bald spots there are thousands of voltage-dependent sodium channels, which open when they sense the voltage changing, and allow the positive sodium ions to flow into the cell in the bald area. The flow leads to a strong change in the membrane voltage in that area, and to a renewed creation of the electrical signal. The new signal skips to the next bald spot, where it is amplified again, and again and again, until it reaches the end of the nerve and successfully transmits the message. Those bald areas were already discovered at the end of the 19th century by the famous French researcher Louis Antoine Ranvier, and to this day they are named after him - nodes of Ranvier.

Although invertebrates manage to function well without the insulating myelin sheath, we vertebrates have long adapted to its existence. If it weren't for its presence, the speed of signal transmission would be slowed to an impossible rate, the nerves could fire electrical signals inadvertantly and adjacent nerves could leak information to each other.

The scar that appeared in the brain of the unfortunate Augustus is now well known to modern doctors, and it practically indicates a battle area, full of cavities. This is where the immune system declared war on the myelin sheath, and tried to erode it down to its last fatty acid. And like the most common ways to hell, everything is done with the best of intentions: to protect the body.

The role of the immune system is to protect the body from foreign agents. The process by which the immune system decides that one of the proteins in the body is a threat is not fully understood yet, but it is clear that it is very common. The immune system is constantly in a delicate balance between the body and the environment. It must be sensitive enough to detect foreign agents and keep them away from the body, but not be too sensitive, because then you will start attacking the body itself. When the immune system becomes too sensitive to the body's own factors, an autoimmune disease breaks out, during which the immune system mobilizes its many cells, and all its forces in an attempt to destroy self cells and tissues, which it has inadvertently marked as foreign factors.

The scar in the brain is a sign of the place where macrophages - phagocytic giant cells, in the service of the immune system - attacked the myelin sheath. The macrophages settle on the sheath, crumble and digest it, leaving the nerve extension exposed and unable to function properly. In this area, where the myelin was almost completely worn away, the scar appeared in Augustus' brain.

How, then, was Augustus' eyesight restored? The reason lies in the ability of the oligo-dendrocytes to regenerate the myelin sheath in the brain. When the sheath was damaged, the oligodendrocytes rewrapped themselves around the nerve and restored the branch's ability to transmit signals. This disease, in which the victim suffers from repeated neurological attacks, which fully or partially recover between attacks, is the most common type of multiple sclerosis. In Hebrew the name 'sclerosis' describes the degeneration of the brain. In English, the name refers to the many scars that appear in the brains of patients with the disease.

The next years of Augustus did not pass pleasantly for him. The experience he went through, which forced him to rely on his servants and friends, matured him overnight. He concentrated less on his efforts to get into the royal house, paid more attention to his family and friends and concentrated on the small joys in life rather than sadness. But autoimmune diseases do not disappear by themselves, and the macrophages did not rest on their laurels and continued to gnaw at his brain without hesitation. In the four years since the first attack, Augustus suffered from additional attacks that damaged his vision. All recovered in turn, but each added to his anxiety.

At the age of 33, Augustus visited his mother in Lausanne, Switzerland, during the hottest period of the summer. We find evidence in his diary that the severe heat worsened his vision problems and his general feeling. This fact corresponds to the 'Ohtoff symptom', which describes the onset of new neurological attacks under heat stress and the increase in temperature, due to the erosion of the thickness of the myelin sheath and its inability to provide the necessary insulation for the nerves. Augustus and his mother left Lausanne in favor of a trip to Italy, but the neurological attacks did not stop appearing. In Florence, Augustus began to suffer from double vision, when the ability to coordinate between the optic nerves was cut off and each of them transmitted an image separately to the brain. As with the other symptoms up to that time, this time too his sight returned to normal, but never strength.

During multiple sclerosis, each attack marks the erosion of the myelin sheath in different nerves. Each separate attack comes to an end when progenitor cells arrive at the erosion area, divide and differentiate into mature oligodendrocytes that repair the mantle. In 2007, the brains of two multiple sclerosis patients, who suffered from the disease for 21 and 22 years, were studied, and it was shown that approximately 47% of the scar surface is re-wrapped in myelin [3]. This fact indicates that the restoration of myelin occurs continuously, even in old age, but we know that the restoration process can deteriorate in its efficiency with age. The reason for this is still unclear. Some believe that the oligodendrocyte progenitor cell pool is depleting, but this does not seem likely, because such progenitor cells can also be found in areas of old chronic scars, which do not heal. The most likely hypothesis today is that the repetitive scarring causes the nerve branch to lose the signals that attract the oligodendrocytes and their progenitor cells, thus preventing the healing process. The more scars accumulate that do not fully heal, the more the patient's control over his body deteriorates.

Augustus' nerves continued to scar, but the healing process was slow. The neurological symptoms began to manifest themselves in new ways: he lost control of his legs, and reached the point where he was unable to even get out of bed for three weeks. At this time Augustus changed his medical advisor and sought the help of Doctor Kent. Kent recommended eating beef guts twice a day and drinking quality wines, and within a few weeks Augustus' legs returned to full function. Despite the temptation of financing steaks and wines at the expense of the health insurance fund, it is hard to believe that the expensive treatment helped by itself. It is more likely that the nerves were simply recoated with the myelin sheath they needed. Nevertheless, Augustus was never able to dance again, or run fast.

The source and cure for multiple sclerosis

Augustus lived in the first half of the 19th century, when doctors were unaware of the existence of multiple sclerosis. The disease was first systematically described in 1868 by the French neurology giant Jean-Martin Charcot, who earned the dubious nickname "Napoleon of the neuroses", and one of his students was Sigmund Freud. Although Charcot described the scars he found in the brains of his patients, medical science had to advance another hundred years to reach a basic understanding of disease progression.

The source of the disease has not yet been definitively determined, but it is clear that it is a combination of genetic and environmental factors. It is known that patients with multiple sclerosis tend to be infected with the measles, mumps, rubella and Epstein-Barr virus at later ages than usual. This phenomenon may imply that MS is related to the 'hygiene hypothesis', according to which children who are kept in a hygienic environment during their childhood, do not develop a stable immune system. The destabilized immune system may erupt in action against the body and damage the myelin.

The genetic causes of the disease have not yet been determined, but it is known that if one of the children in the family is sick with multiple sclerosis, each of his siblings has a 5% chance of getting sick as well. If it is identical twins, the chance increases to 25%. The chances remain the same even if the babies were separated from each other and adopted immediately after their birth. These data clearly indicate that the disease does have a genetic basis - but that the environment also has a decisive influence on the development of the disease.

If Augustus had lived in our time, it would certainly have been possible to characterize his illness even at the time of the first attacks. But similar to the 19th century, and despite the basic understanding we have acquired about the treatment of the disease, the treatment options available to us today are still terribly limited, and do not constitute a real cure.
In the XNUMXs, the treatment with interferons was introduced for the first time - molecules that are secreted by some cells and transmit instructions to other cells.

Interferon-beta, which is still used to treat multiple sclerosis, is apparently capable of dampening part of the inflammatory response in the patient's brain. Studies conducted over a period of two to three years have shown that the frequency of seizures decreases by about 30% as a result of taking the drug. The negative side of interferons is their flu-like side effects, which last about half a day from the time of injection, and the fact that between five and thirty percent of patients develop antibodies against the interferons in the first year of treatment, stopping their effect.

The second drug used today came from an unexpected source, demonstrating the importance of basic animal research. Many laboratories around the world focus on drug development, by treating animals suffering from various specific diseases. In order to study multiple sclerosis in animals, it is necessary to make them develop the disease and for this they use special proteins that stimulate the immune system and cause it to go out of control and attack the myelin. In the XNUMXs, researchers from the Weizmann Institute tried to produce an artificial polymer that would be similar to the disease-causing proteins in its physical and immune properties, and hoped to obtain a research tool that would cure the disease in experimental animals cheaply and efficiently, thus increasing the ability to research the disease. But the synthetic protein they produced lied badly.

"We tried for a whole year, but we failed to cause the disease with the help of the synthetic protein we created." According to Prof. Ruth Arnon from the Weizmann Institute [4]. The surprising turn came when the researchers tried to inject the experimental animals with both the new synthetic polymer and the proteins that cause the disease. But instead of the injected animals contracting multiple sclerosis, the researchers discovered that the polymer may actually be used as a vaccine against the disease. "We did the first experiments on guinea pigs and got surprising results. In the control group, nearly 80% contracted the disease, compared to the group that was injected with the polymer, in which only 20% contracted the disease. The severity of the disease in the control animals was also much more severe than the disease that broke out in the 'vaccinated' groups."

After four more years of successful tests in other experimental animals such as rabbits, mice, rhesus monkeys and beavers, the synthetic material was transferred to clinical tests in humans, which it also passed successfully. Copaxone, the product of the invention of Prof. Michael Sela, Prof. Ruth Arnon and Dr. Deborah Titelbaum from the Weizmann Institute, was marketed in the United States in 1996 on behalf of the Teva company, and is currently one of the most popular and effective treatments for the disease. Its level of effectiveness has been proven in clinical studies, which have shown that it is able to reduce the frequency of attacks fourfold, over a period of two years. As another advantage, Copaxone causes almost no side effects, and the most common side effect is redness and slight swelling in the injection area.

Copaxone's mode of action is still unknown. Studies in animals and in vitro systems (experiments outside the body, in test tubes and plates for growing cells) imply that copaxone stimulates specific T cells of the immune system, which are capable of suppressing the immune response [5]. Another suggestion, which is still not supported by actual findings, is that copaxone is similar to one of the proteins that appear in the myelin sheath, and therefore serves to 'distract' the immune system, which concentrates on it instead of the real myelin.

The two drugs - interferon beta and Copaxone - do offer relief in the frequency of attacks, but cannot completely stop the disease. The multiple sclerosis patient continues to deteriorate over the years, although at a slower rate as a result of the inhibitory drugs. Many researchers are trying to find drugs that can help patients with the disease to restore their brains. One of the most promising directions today focuses precisely on oligodendrocytes in the brain. If a way is found to increase the activity of the oligo-dendrocytes, it is possible that the myelin sheaths will be restored very quickly as needed, to the extent that neurological attacks will not occur.

Augustus Dasta himself died at the age of 54, with his central nervous system full of patches, old and new scars. Until his death in 1848, he suffered from many neurological attacks, among other things, he completely lost his strength and suffered from frequent constipation. His legs failed him completely, and he suffered from uncontrollable spasms that prevented him from sleeping comfortably at night. Despite all these, he did not lose his optimism until his last day. Life taught Augustus that one must look for the good in every bad. The last paragraph in his diary, two years before his death, corresponds to the mindset he acquired since the onset of the disease in his youth, in which he describes his happiness for the small grace he found that day: the restoration of his ability to limp across the room on one leg.

"...I received Indian moccasins as a gift, I put them on:- and I walk in them without my left foot, which some time ago was crooked at the ankle and is not ready to straighten unless it is supported by an iron. Surely this is a clear improvement. Thanks to the Almighty!"

Sources

1. The Case of Augustus d'Este (1794-1848): the First Account of Disseminated Sclerosis

2. Multiple Sclerosis, Lancet 2008; 372: 1502–17

3. Remyelination can be extensive in multiple sclerosis despite a long disease course, (2007) Neuropathology and Applied Neurobiology 33, 277-287

FDA:

4. Ilanit Conference 2008 http://www.fda.gov/cder/foi/label/2001/20622s15lbl.pdf

More on the subject on the science website

• Experiments on animals - the story of Copaxone, the important drug for multiple sclerosis developed in Israel
• Embryonic stem cells inhibited the development of multiple sclerosis