Amyotropic lateral sclerosis (ALS) and myasthenia gravis also are autoimmune diseases, in which the body produces antibodies against a part of itself.
Dr. David Richman, professor of neurology, has dedicated his career to the treatment and study of myasthenia gravis, an uncommon, chronic disease that produces muscle weakness in both arms and legs and the muscles involved in breathing, swallowing, blinking and smiling. Aristotle Onassis died from MG, and it afflicts actress Ann-Margret`s manager and husband, Roger Smith.
Richman became interested in myasthenia gravis as a medical student in the mid-1960s when much less was known about it. However, in the mid-1970s research breakthroughs led to an understanding of the disease process and development of medical treatments that can bring the majority of cases under control. And today myasthenia gravis is considered a model autoimmune disease in that information learned from it can be applied to other diseases.
In myasthenia gravis, the body makes antibodies against a chemical at the connection between nerve and muscle, thus interrupting signals. Normally, when a person thinks the thought to move and signals are transmitted from the brain down to the spinal cord and out the nerves, then acetylcholine is released across the synapse to the muscle.
”The problem in myasthenia gravis is that the chemical on the muscle
(the acetylcholine receptor) that combines with the neurotransmitter
(acetylcholine) released from the nerve is the target of the immune attack,” Richman explains. ”So it`s damaged, and not every signal sent by the nerve is properly received by the muscle. That produces the weakness.”
A number of studies are underway in Richman`s laboratory using monoclonal antibodies, which are laboratory-raised proteins used to analyze segments of the immune reaction, to try to determine how they actually block neuromuscular transmission.
In addition to supervising the research, Richman also runs the medical center`s large myasthenia gravis clinic that draws many patients from the Midwest. ”I`m in the enviable position of being able to work primarily on the clinical disease that I`m doing research on,” Richman says. ”Most of the people at the institute who are physicians are really physician-scientists.” Another neuroimmunology specialist, Dr. Raymond Roos, professor of neurology, concentrates on both ALS and MS.
ALS is a neuromuscular disease in which the motor neurons deteriorate. As a result, muscles atrophy, and the victim becomes paralyzed. It is a classic example of ”selective vulnerability” because it involves only motor neurons responsible for movement of the head, limbs and breathing, just as MS involves only the myelin that sheathes nerve cells.
One of Roos` major research interests is related to Theiler`s virus, which affects mice and causes diseases that mimic both MS and ALS, providing an ”animal model.” Experiments in his lab concentrate on determining what genes or gene products of this virus are critical for causing either disease. ”My feeling is that this is going to tell us not only about how this virus causes myelin damage or kills motor nerve cells, but we will also learn a lot about nonviral genes and the mechanism in which MS patients and ALS patients may have specific selective myelin or nerve cell damage,” says Roos, who also codirects the medical center`s ALS clinic.
While neuroanatomy is a horror of memorization for many medical students, those who end up specializing in neurological disease experience it as an awakening. Roos certainly did. He became intrigued with the ”intricacy” of the nervous system. ”When one deals with the liver, you have liver cells and other kinds of cells, but the structure of one part of the liver compared with the other is pretty similar,” he says. ”But when one deals with the brain, the structure is enormously complex.
”And I was also fascinated by the symptomatology that one sees-awed and overwhelmed by it. It`s been exciting to see the developments in neurology:
improved diagnoses and treatment of symptoms.”
Technical advances such as the computerized axial tomography scanner (CT or CAT), developed in the 1970s, revolutionized diagnostic precision. CT scanning made it possible to obtain layer-by-layer scans-sort of like slices- of the brain tissue from different angles. The subsequent development of the PET scanner, which measures metabolic activity, and MRI (magnetic resonance imaging), which provides a more high-resolution view of brain anatomy than CT, have allowed even better visualization.
At the Brain Research Institute, those tools have been combined with stunning results. Using the same type of Pixar computer that George Lucas used to create special effects in the movie ”Star Wars,” a team headed by Dr. David Levin, professor of radiology, wrote software that creates three-dimensional images of the brain from MRI and PET data. This is crucial for the neurosurgeon who must figure out where a tumor is in relation to the area of the brain that controls movement, for example, to determine whether he can remove the tumor without paralyzing the patient.
”On the basis of `slice` images, even the most experienced neuroradiologist in the world can`t say for sure where the motor strip is,”
Levin says. ”On the basis of these images we can answer that question. We`ve done this on over 20 patients now, 12 of whom have gone on to surgery, and in every case our predictions on the relationship of the tumor to speech, motor and sensory areas were correct.” Position in neurosurgery is crucial, so surgeons can ”practice” on a computer screen where they`ll open the skull to expose the brain in the operating room.
Recently, Levin and colleagues devised a way of rendering 3-D images of the blood vessels of the brain from MRI data without the invasiveness of cerebral angiography, and a way of combining MRI and PET data, which is important in planning for surgery on patients with medically intractable epilepsy.
”In the cases that we tackle, there are clues in the electroencephalogram, the MRI and occasionally in PET,” says Dr. Jean-Paul Spire, professor of neurology and neurosurgery who specializes in epilepsy surgery in which the brain tissue that is the focus of epileptic seizures is removed. ”You have to marry them to know where to go and what to do, because when you`re in the frontal lobes there`s nothing that tells you badness is here and goodness is there,” he says. ”So the (3-D image) is a very important advance.”
Spire also runs a sleep laboratory where he and his investigators are exploring narcolepsy, a condition marked by frequent and uncontrollable desire for sleep. Some evidence now suggests that it might be an immune disease.
The field of psychiatry, while long dominated by Freudian psychology, now operates in the border area between neurology and psychology and has become increasingly biological.
”We are very much on the brink of a major revolution in our ability to use science in the assessment and treatments of many of the psychiatric disorders that have ravaged mankind for centuries,” says Dr. Stuart Yudofsky, the recently appointed chairman of psychiatry. ”I believe schizophrenia and manic-depressive illness are brain disorders (rather than purely
psychological). We`re understanding the neurochemistry and neurophysiology of the full range of psychiatric disorders and therefore we can design specific biological interventions.”
Yudofsky`s major interest is aggressive disorders. In his former position as director of the Neurological Institute at Columbia-Presbyteri an Medical Center in New York, he noticed that among patients who had brain lesions of various sorts-stroke, head injury, Parkinson`s disease, Huntington`s chorea, etc.-severe irritability, agitation and even violence were common. Yudofsky wants to develop better drug treatments for these patients, but he also wants to explore the question of whether some people without obvious neurological illness or injury are neurologically predisposed to violence.
Last year, the neurobiologists at the university`s Joseph P. Kennedy Jr. Mental Retardation Research Center also became members of the Brain Research Institute. Understanding the biochemical actions of neurotransmitters, growth factors and hormones on nerve cells normally is what interests Dr. Robert L. Perlman, Kennedy center director who is both a pediatrician and
neurobiologist.
”These chemicals act over a long time period to support the survival and health of brain cells,” Perlman says. ”What we`re learning about the brain now is that many of the processes that are important during brain development remain important throughout life and become impaired during senility.
”The divisions between development and degeneration are really very arbitrary. The processes that go on in development are the same processes that may go awry in aging. So the degenerative diseases of the nervous system are just the other side of the coin of what goes on during normal development.”
Dr. Richard J. Miller, professor of pharmacology and physiology, studies the process that causes cells to die in stroke, producing paralysis and other aftereffects.
In stroke, blood flow to nerve cells is interrupted, depriving them of oxygen.
Then, too much of a neurotransmitter called glutamate is released into the fluid surrounding those cells, causing them to take in too much calcium. The excess calcium causes the cells to die.
”If you could block the calcium influx into nerve cells during this period of time, the cells would not die, and the patient would be okay,”
Miller says. ”One of the things we do is try to find out what are the pathways by which calcium normally goes into nerve cells. How do they work?
How are they regulated? What drugs can we find that can block them and so might be effective in stroke and also in epilepsy?
”It turns out that there are several different types of calcium channels that may be of importance in this particular process. We study this by culturing cells from different parts of the brain (and measuring) calcium ion fluctuation in single nerve cells and (studying) how these processes lead to death of nerve cells.”
Dr. Clifford B. Saper, professor of neurology and neuroscience, studies neurotransmitters. In the last year his laboratory discovered four new substances that had not previously been thought of as neurotransmitters.
”We`re interested in how those systems of nerve cells in the brain that use those neurotransmitters are involved in normal control of a whole range of behaviors-hormonal changes, autonomic changes that occur in the body,” says Saper, who also is head of the Committee of Neurobiology, the university`s program for training Ph.D.s in neurobiology.
”And we`re also interested in how these things break down in certain diseases. We look at these neurotransmitters in normal brains and in the brains of persons who died with Parkinson`s disease and Alzheimer`s disease to see what the specific alterations of specific neurotransmitters can tell us about how the disease originates and spreads in the brain.
”We also are interested in the abnormal proteins that are made in the brain in Alzheimer`s disease and we`ve done some fundamental studies mapping out these proteins. They point out that Alzheimer`s disease is incredibly specific. It picks up just those areas of highest intellectual activity in the cerebral cortex and leaves the rest alone until later in the disease process. ”Our latest work has been using a special antibody called ALZ-50 that recognizes a protein that`s made in Alzheimer`s brains but not in normal brains. Using this antibody we are able to identify neurons in the brain that we think are targeted for death in Alzheimer`s but still are not yet involved in the disease process.
”We`re able to identify very early cases of Alzheimer`s. We find that it comes into the brain apparently through the hippocampal formation-the focal point for all of the intellectual systems in the cortex to feed their information into the memory system-and spreads out through its connections across synapses into the cerebral cortex.”
Although Alfred Heller`s laboratory does work similar to that done in Bruce Wainer`s lab, its secondary interest is neurotoxicity. One research aspect looks at the effect of drugs-both drugs of abuse and therapeutic agents-on the microbrains in culture. And another aspect explores the hypothesis that Parkinson`s disease, which is marked by tremors and muscle weakness, might be caused, in part, by industrial hazards.
The central nervous system is so enormously complicated that it supplies more than enough fodder for thousands of scientists around the world. The founders and trustees of the Brain Research Foundation hope that the facility they spawned might one day achieve world-class status.
Dr. John Mullan, chairman of the neurosurgery section and a pioneer in developing techniques for vascular surgery, believes the institute has failed to live up to its early promise in one aspect. (Mullan was appointed the first director of the institute in 1967 when it was still in the planning stages and remained director until 1985.)
Asked if he is satisfied with the way the institute has turned out in terms of research, Mullan replies: ”In terms of research, yes. But in terms of the clinical input that should have been put into it, no. We should be working on basic research and its application at the clinical level, but (the latter) was never extended the way the original planners intended.”
Still, the future bodes well for the Brain Research Institute with members who are as enthusiastic as Clifford Saper.
”When I wake up in the morning,” Saper says, ”I want to tear the door off the lab to get in there and see something that nobody`s ever seen before. That is the biggest kick-to find something new and have the potential that it might even help somebody. That`s what keeps me in this business.”
