UCSB materials and chemical engineering professors have found a unique way to apply their expertise toward understanding a chronic neurological disease, multiple sclerosis.
By applying basic physical analysis to biology – a process becoming increasingly popular among researchers – scientists are making gains toward understanding diseases outside of the usual medical and clinical approaches. UCSB has been a major source of this work and has recently published a study that could have implications for the treatment of MS. The study, titled “Synergistic Interactions of Lipids and Myelin Basic Protein,” was printed in the Proceedings of the National Academy of Sciences on Sept. 14. It has already generated interest from the medical community and will very likely lead to a host of new studies.
UCSB professors of chemical engineering and materials Joe Zasadzinski and Jacob Israelachvili teamed up with the director of the Center for the Study of Neurodegenerative Disorders, Cynthia Husted, to write the study. The combination of medical and engineering approaches has yielded some novel results.
“Joe and I have had bio-oriented grants from the [National Institutes of Health] for many years,” Israelachvili said. “But this was actually an interesting thing because it wasn’t a [project] we were funded to do. We just did it.”
Husted said she was anxious to bring MS research to UCSB and has been encouraging molecular researchers to work on biological systems for a decade.
“I came to Santa Barbara in 1994 on my own money deliberately to work with [Zasadzinski] and [Israelachvili],” Husted said. “I wanted to get back to molecular-level tools.”
Husted had been pursuing MS research through typical medical and clinical channels, but said she thought the molecular-level research could be a valuable tool. Israelachvili said he agreed the approach is valuable.
“It looks very nice, and one of the nicest things about it is that if it turns out to be true, here is something very physical; a very basic fundamental physical principle applied to a very complex medical problem,” Israelachvili said. “It would be very nice if it could actually help.”
The new method involves the use of a specialized microscope to inspect the tiny biological components that comprise the covering of a nerve. By closely inspecting the molecular damage that MS causes to the nerve, researchers can better understand the disease and work toward developing a cure.
In addition, a chemical substance has been identified that was observed repairing damaged areas of a simulated nerve covering in the laboratory. This breakthrough finding will likely lead researchers to conduct clinical trials on lab animals.
Multiple sclerosis affects about 400,000 Americans, according to the National MS Society. The disease is not contagious, is not inherited directly and occurs in women twice as often as in men. No specific environmental factors have been found that are known to cause MS, but it has been suspected that the disease may result as a combination of genetic and environmental variables.
There are a few forms of the disease; the most common is called relapsing-remitting. The National MS Society says that about 85 percent of people diagnosed with MS have this type, which causes brief spells of worsening symptoms followed by periods of remission.
A less common form of the disease is called primary-progressive and accounts for about 10 percent of people diagnosed. This type of MS is characterized by a steady worsening of symptoms, with no remissions. About half of people diagnosed with relapsing-remitting MS show signs of progressive-like symptoms within 10 years and are said to have secondary-progressive MS. Zasadzinski said that the disease is usually not severe enough to cause death but that death is possible.
MS is a neurological disease, which means that the symptoms are caused by damage to the body’s nerves. Most scientists agree that the damage is caused by the body’s own immune system, but the cause and exact mechanism is still unknown.
Because the nerves are affected, the symptoms of MS range widely. Nearly every bodily function requires nerves to exchange signals between the brain and the body, so damaging a random group of nerves could cause unpredictable symptoms. Commonly, these symptoms include difficulty walking, numbness, vision problems and cognitive disorders.
Nerves in the body are often compared to metal wires in an electric circuit. Both wires and nerves carry electrical impulses over a long distance, and both require a sort of insulation to keep the electrical signal inside the wire.
“Your nerves consist of basically the wires, which are called the axons, and the myelin is the insulation,” Zasadzinski said. “If you have a wire that’s insulated, it works a lot better than if it’s not insulated.”
The danger of having an uninsulated wire in a house is an electric shock, but the danger of having an uninsulated nerve is that the nerve’s weak electrical signal will be lost.
“In MS the insulator is attacked and destroyed by the [immune system],” Husted said. “It’s considered an autoimmune disease.”
The process of losing the nerve’s insulation is called demyelination and accounts for all of the lost nerve impulses and subsequent symptoms a person with MS may experience. The production of myelin appears to function normally in people with MS, but the myelin sheath does not stay in place around the nerve.
“The myelin gets produced by cells near the axons; it sort of oozes out and wraps around [the nerve],” Zasadzinski said.
The myelin winds around many times, creating a tightly layered coil of myelin membrane around the nerve.
“With [MS], what appears to happen is that the layers start to separate,” Zasadzinski said. “In advanced stages, the sheath just breaks apart completely.”
Looking at Molecules
Even though no one knows why MS occurs, it may seem that the process by which MS damages the body is well understood. However, by looking in a novel way at the myelin’s molecular structure, this new research from UCSB has added to the overall understanding of the disease.
“If you get down to the molecular view, which is where we come in, each [myelin] membrane has two sides to it,” Zasadzinski said.
These two sides form an entity called a lipid bilayer. Lipid bilayers are very abundant throughout the whole body because they are versatile barriers the body uses to enclose microscopic parts, like cells.
“Seventy to 80 percent of myelin is lipids,” Husted said. “The brain is mostly lipids; about 50 percent of its dry weight is lipids.”
A lipid is a molecule that has a head and one or more tails – they often look like tadpoles in schematic diagrams. The head is hydrophilic, which means it is attracted to water, and the tails are hydrophobic, which means they are repelled by water. When a large quantity of lipids is put into water, the lipids naturally form structures that allow the tails to avoid touching the water. The bilayer is one of these structures, with each layer of heads keeping the water away from the tails.
In the case of the myelin bilayer, there is also glue that helps hold two adjacent bilayers together.
“The myelin basic protein, which is the glue that cements these two [layers] together, goes in between [the lipid bilayers],” Zasadzinski said.
The reason that the protein helps bond the lipids together is that it has a positive electrical charge. The lipid heads are negatively charged, and because opposite charges attract each other, the protein serves as a junction between bilayer heads.
“You basically have two negatively charged surfaces with a positive molecule in between,” Zasadzinski said. “If you have just the right amount of negative lipids to balance the positive, you get the strongest bond.”
Lab animals with a disease similar to MS have an imbalance of charges in their lipid bilayers that causes problems and may be responsible for the ultimate demyelination.
“We know that the membranes get farther apart; that is usually the first sign before there are even any symptoms,” Israelachvili said.
u have too many negatives and not enough positives, then that is not only going to decrease the binding, it’s going to push it apart,” Zasadzinski said. “You wind up with a fairly narrow sweet spot. If it goes too far either way, it’s going to push things apart.”
This discovery marks one of the key points of the recent UCSB research. These observations were made with a specialized device called an atomic force microscope. This instrument allows extremely small depth variations to be seen in a bilayer made in the laboratory.
Holes in the Bilayer
In addition to the electrical charge findings, UCSB researchers also found that the sticky myelin basic protein can repair damaged myelin.
“If you have the myelin membrane sitting in salt water, little holes in the membrane – instead of sealing themselves – have the tendency to grow bigger,” Zasadzinski said.
The fact that the membrane cannot repair itself may explain how some of the small defects become major problems in people with MS. In the laboratory, adding the protein to a membrane with holes causes the holes to close. The membrane is fluid so it is able to spread out when displaced.
“The protein will partially insert into the membrane so that it pushes things away, and if you have a place where nothing is pushing back, that’s where [the membrane] is going to go,” Zasadzinski said. “The holes actually start to fill in, and that is quite weird.”
This could be a very important finding because it shows how damaged myelin could be repaired.
“It has been thought that once the damage is done, it cannot be undone,” Husted said. “It’s promising new technology, but it’s important not to get hung up on one hypothesis.”