by Sheldon Teitelbaum
These debilitating maladies strike the young, the middle-aged and the old, the famous and the unknown, without respect for sex, race or heredity. W. King Engel and Valerie Askanas of the USC Neuromuscular Center are determined to find a way to beat them.
Amyotrophic lateral sclerosis, or ALS, better known as Lou Gehrig’s disease—after the famous baseball player who suffered from it—has afflicted clock-wise from center front Senator Jacob Javits, musician Charlie Mingus, character actor David Niven and boxer Ezzard Charles.
If neuromuscular diseases weren’t so dreadful, and if medicine weren’t so hard pressed to respond to them effectively, the story of the Kentuckian with dysimmune dysschwannian neuropathy might actually be funny.
He turned up at the USC Neuromuscular Center in 1981 in a wheelchair, in which he'd lived for the last 10 of his 27 years. The disease had made his hands and feet virtually useless, and he was too weak to stand unaided or even to raise his arms. Conventional corticosteroid and azathioprine treatment hadn't helped at all.
But in the course of a discussion with W. King Engel, director of the center, the Kentuckian mentioned that his condition had, on several occasions, improved after a bout of the flu.
Engel proposed treating him with PolyICLC, a drug that he was using for another purpose and one which produced as a side effect a sort of artificial flu, complete with the familiar symptoms of fever, chills and aches.
The Kentuckian agreed to give the treatment a chance. After the first dose he grew stronger, and he continued to do so with repeated doses.
Now he walks about eight miles a day and can hold a chair over his head. In fact, he became well enough to work and holds down a job as a computer programmer. He owes his health to the fact that every six to eight weeks, for an extended period of treatment, Engel made him slightly sick, curing him, it would seem, with the common cold.
The Kentuckian was lucky. For many of the people who come to USC’s six-year-old Neuromuscular Center, betterment is strictly a long shot. But they come anyway, driven in part by desperation and also by the realization that Engel’s unusual research and clinical orientation seems to offer some of the best odds in the world. Neuromuscular diseases—of which scientists have identified about 100— strike about 1 percent of the population. Sometimes the disorder stems from the faulty metabolism of a nerve cell or of a muscle cell. Or, for any number of reasons, messages from the brain to the muscles fail to inspire movement, Normally such commands would activate upper motor neurons in the brain, which would in turn transmit them to lower motor neurons in the spinal cord and then out the peripheral nerves to the muscles. Neuromuscular diseases occur when there is a breakdown somewhere along the way.
These diseases are not choosy. They can strike early, producing “floppy” babies who die scant days after birth. Children are frequent victims. Young and middle-aged adults, elderly persons, both sexes, all races—virtually anyone is vulnerable. And only 20 percent of all neuromuscular disorders are hereditary.
Because of their particularly distressing quality, these diseases have a habit of making news, especially when they affect someone who is well known. The most familiar example of this is amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease. One of the most virulent of the neuromuscular diseases, it gained public attention when it struck former vice president Henry Wallace, actor David Niven, senator Jacob Javits, jazz musician Charlie Mingus, boxer Ezzard Charles and, of course, Gehrig himself.
ALS is fatal within five years for some 80 percent of those afflicted. The disease essentially destroys the upper and lower nerve cells, resulting in powerless muscles. Victims face an insidiously debilitating process as they lose their mobility and, eventually, their ability to speak, eat or even breathe. Yet their intelligence remains intact throughout, making them continually aware of the tragedy engulfing them. There is virtually nothing that can be done to hold the degenerative process in check, much less reverse it.
Another well-known disorder, Duchenne muscular dystrophy, has the same result, though it is slower to run its course. It can be particularly heartrending because it strikes at children.
Engel's strategy against these and other neuromuscular diseases is to treat them directly as they occur in people rather than approaching them only in more controlled experiments with in vitro phenomena.
He admits that this approach is often more difficult. But he believes that bringing both clinical and laboratory approaches to bear directly on the patients themselves often produces the best results.
Of the 300 scientists worldwide whose research is most often cited by other researchers, Engel is the only one in the neurology category who actually takes care of patients on a regular basis.
A graduate of Johns Hopkins University and McGill University’s Faculty of Medicine, he came to USC in 1981 from Bethesda, Maryland, where he had been chief of the Medical Neurology Branch and in charge of neuromuscular diseases at the National Institute of Neurological and Communicative Diseases and Stroke.
He brought with him his wife and colleague, USC professor of neurology and pathology Valerie Askanas, a graduate of the Warsaw University School of Medicine in Poland, who serves as co-director of the center.
A visitor to their domain, which occupies a floor of Los Angeles’ Good Samaritan Hospital, will discover a staff of four faculty, numerous clinical and laboratory fellows drawn from all over the world and a team of highly skilled technicians.
Engel and Askanas employ various lab techniques, all making use of human tissues or fluids—and occasionally of animal tissues—to study basic mechanisms such as drug actions before the drug is applied to patients.
Engel and Askanas: “We're frequently asked when someone is going to come up with a cure for ALS. We wouldn't be working as hard as we do if we didn’t think it was going to be sooner rather than later.”
Laboratory techniques used in the center include histochemistry, tissue culture, biochemistry, autoradiography, pharmacology, electronmicroscopy and immunology.
For example, human muscle tissue culture, a technique highly developed by Askanas, enables them to focus on how neuromuscular diseases manifest themselves in people.
Askanas’ technique, the fruit of some 15 years’ work—which is correlated with pioneering histochemistry done by Engel during his early training—involves culturing human muscles obtained during a diagnostic biopsy.
In her earlier studies, when human muscle was cultured alone, it developed only to a limited degree, resembling the immature muscles of a human embryo that had not yet received a nerve supply from spinal cord nerve cells and therefore was unable to contract.
Askanas discovered, however, that these tissues could be “innervated” by merging them with motor nerve cells. In this instance, embryonic rats proved to be of value, as their nerve cells closely approximated the functions of their human counterparts and were also immediately available.
This system also avoids the problem of tissue rejection because muscle tissue grown in a petri dish lacks an immunological system that might otherwise dispatch killer T-cells to wipe out the foreign rat neurons.
The rat-charged human muscle fibers don’t merely contract. They also exhibit some of the characteristics of mature human muscle. This maturation process can be further enhanced by treating the tissues with certain hormones essential for growth.
EEngel's strategy is to treat neuromuscular diseases directly as they occur in people rather than only in the controlled setting of the laboratory.
The object of this merging of rat and man is to identify the biochemical cause of, as well as the steps in, muscle cell deterioration in the abnormal muscles of patients referred to the center. And, possibly, to test an experimental treatment of their actual living, contracting muscle in the controlled and safe microcosm of the plastic petri dish.
Sometimes it isn’t otherwise possible to determine if a particular disease is intrinsic to the muscle cell itself or whether it originates in a failure outside of that cell.
But if the disease shows up in the tissue culture, that indicates that it is inherent within the muscle cell.
Previously, Askanas had found that some key muscle disorders—such as Duchenne muscular dystrophy and myotonic atrophy—which should have proved to be intrinsic to the muscle cells, nevertheless failed to turn up in the cultures grown without nerve cell innervation,
In her current research, Askanas hopes to demonstrate that in some instances, the greater human muscle maturity achieved by co-culturing with the rat spinal nerve cells will allow such diseases to ‘“‘declare”’ themselves biochemically and ultrastructurally in the petri dishes.
“If she does,” explains Engel, “it will follow that the cultures can, if sufficiently refined, provide a microcosm, an arena or an exercise pool, in which a disease can be observed from the moment of its onslaught until it has destroyed the tissue. This technique can ultimately be used to figure out the actual pathogenesis and pin point the exact biochemical cause of these diseases.”
Also, these little universes within a petri dish can become a safe environment in which to try various treatments without endangering or causing discomfort to patients.
“It’s a trendy technique,” Askanas says.
Trend-setting isn’t merely a matter of methodical research, though careful attention to detail is invariably crucial. Creativity is involved, and it is often expressed in conceptual leaps forward that owe as much to instinct as to the accomplishments of other researchers.
Take, for instance, Engel’s treatment of one particular neuromuscular disorder caused by faulty metabolic processes rather than by neural breakdown:
In 1981, a 16-year-old Spanish boy came to the Center unable to lift his arms or legs, walk, swallow or even breathe. He was kept alive only by a respirator and feeding tube.
Engel had previously diagnosed the boy as having muscle carnitine deficiency, a muscle disease caused by a lipid metabolism defect which often responds to treatment with carnitine. But in this instance, carnitine didn’t prevent severe muscle weakness.
Examining muscle biopsy material, Engel found that the muscle cell membranes were badly damaged. He postulated that the cause of this damage was not the lack of long-chain fatty acids as fuel; but, rather, that an excess of them was virtually wrecking the boy’s muscle cells via a detergent-like action on the membranes.
Engel decided he would ‘‘defat” the boy. He prescribed a liquid-nutrient diet, based upon a commercially available dietary supplement called Portagen, that contained no “poisonous” long-chain fatty acids.
He also required that the boy stay away from paella and other fatty foods and reduce his weight from 154 to 116 pounds.
His condition improved slightly within a few weeks on this regimen. Within a year of the boy’s return home, he was walking two miles a day and playing golf. He is still required to maintain himself on a liquid prepared from the powder he receives from the U.S. as well as some raw fruits and vegetables. The boy, now a law student, says giving up most regular food has been a small price to pay for his life.
Engel finds it difficult to account for the knack he and Askanas seem to have for developing unconventional treatments for various conditions. He admits that serendipity plays a part, and he is also quick to acknowledge the importance of the knowledge base created by others. Certainly by concentrating only on neuromuscular diseases, they are able to focus their efforts, and by doing both clinical and lab work, they find it easy to transfer from one aspect to the other. But basically, he says, success is often a matter of being prepared to try out new methods and ideas. “It’s a kind of opportunism that we follow here,” he says. ‘We go after an idea or hunch and sometimes it works.”
He offers an illustration of his own: Some years ago, a 60-year-old Pennsylvania woman came to the center suffering from polymyositis, a neuromuscular disease which, like myasthenia gravis, is capable of inducing varying degrees of weakness and paralysis. She too could neither move nor breathe, and she suffered from numerous secondary infections as well.
Polymyositis and myasthenia gravis are termed “‘dysimmune diseases” because they occur when the body’s immune system begins to attack its own normal tissues as it might ravage a foreign invader.
It has been thought for some time that lymphocytes are the primary perpetrators of such attacks. Therefore, in such cases, a number of drugs have been used to hinder these offending, misdirected lymphocytes. However, the drugs all have side effects, many of them significant, and in some patients the usual drugs don’t work.
The Pennsylvania woman had been treated with two such drugs—prednisone and azathioprine—to no avail. Casting about for an alternate treatment, Engel learned that Stanford researchers had developed a technique for treating Hodgkin’s disease that required focusing radiation exclusively on the lymph nodes. But his patient was too weak to be positioned for the process.
He then learned that radiation therapists had discovered that a very light dose of radiation showered all over a lymphocytic leukemia patient’s body often reduced the lymphocyte count preferentially. So he tried that totalbody irradiation on his patient.
After one six-week course of such treatments, she improved rather impressively. Within two months, she was off the respirator and, within a year, walking, cleaning house and driving a car. Now, six years later, she is, according to a letter from her husband, “leading a healthy and happy life.”
He adds that “the amazing thing in my mind is that for the past four years she has not suffered a single illness, such as a flu, cold or upset stomach.””
Engel has subsequently found totalbody irradiation to be beneficial in patients with other neuromuscular diseases, such as myasthenia gravis and dysimmune peripheral neuropathy, when drug treatments have failed.
“In fact,” he says, “I think treatment with total-body irradiation or total-nodal irradiation—which we are now doing in less-advanced cases— may be safer than some of the drugs currently in long-term use for these dysimmune diseases.”
Despite such dramatic successes, Engel says he could write a couple of books on the things he's tried that have not panned out.
About three years ago, he made headlines throughout the world when he reported at a scientific meeting that he had found that a drug called thyrotropin-releasing hormone, or TRH, had proved helpful in counteracting symptoms of muscle weakness or spasticity (stiffness) in amyotrophic lateral sclerosis, the dreaded Lou Gehrig's disease.
Engel had initially hoped that TRH would halt the deterioration of the nerve cells affected by ALS and was surprised that it provided symptomatic relief for weakness and spasticity. But he has been disappointed by its apparent failure to preserve the motor nerve cells from deterioration.
An example of normal human neuromuscular junctions (left), where neurons interact with muscle fiber; and (below) a portion of human muscle obtained from diagnostic muscle biopsies in which co-cultured rodent motor neurons have established junctions of their own. These connections result in more mature growth of cultured human muscles and open entirely new approaches to the study of various neuromuscular diseases.
“So we're back on that trail again,” he says. Finding a cure for ALS is one of the center’s top priorities.
Meanwhile, he and Askanas are also intent upon “‘getting a handle on some of the hereditary and metabolic diseases, and on improving anti-dysimmune treatment for the difficult cases of myasthenia gravis, polymyositis and certain peripheral neuropathies.”
Is his research, and the field as a whole, proceeding apace? It depends whose pace, says Engel.
“It's never fast enough for the patients who have these diseases or for those of us concerned for them.
“But yes, the pace seems to be accelerating. As the knowledge base continues to expand, the likelihood of breakthroughs increases.
“I’m frequently asked when someone is going to come up with a cure for ALS. I have to say that it can be tomorrow or in two years, maybe a lot longer. It’s impossible to know.
“But we wouldn’t be working as hard as we do if we didn’t think it was going to be sooner rather than later.”