CONTEMPLATING THE UNTHINKABLE: REWIRING THE NERVOUS SYSTEM

Evan Snyder

Waiting for a breakthrough to halt the inexorable progress of ALS is made all the more frustrating by the gradual loss of strength and mobility that occurs on a weekly, even daily, basis. Now, new discoveries about the regenerative capacity of the nervous system may allow us to contemplate the previously unthinkable: replacing lost nerve cells.

The Old Brain Cells Theory

Why was the idea of growing new nerve cells in the brain and spinal cord unthinkable? Some tissues, like the cells that make up skin and the lining of the gut, as well as blood cells, are constantly regenerated throughout our lives. Others, like muscle and liver, have a more limited capacity for regeneration in response to injury.

But the nerve cells of the central nervous system (the brain and spinal cord) appeared not to have this regenerative capacity.

Years of experiments in spinal cord and brain injury seemed to indicate that the nerve cells of the central nervous system don't regrow after injury. Even though there are many examples of people slowly regaining some function after a traumatic brain injury, these were chalked up to different parts of the brain taking over the duties of the lost nerve cells. Also, because some researchers studying spinal cord injury noted that nerve cell extensions didn't seem to grow well on the surfaces within the central nervous system, they concluded that the environment in the adult central nervous system was "inhospitable" to new growth. Finally, scientists saw no evidence of nerve cell division beyond the early stages of infancy in nonhuman primates.

These observations fit together to reinforce the idea that the brain and spinal cord are "hard-wired" tissues and can't regenerate. This made sense to many researchers because the cells of the nervous system, unlike those of any other kind of tissue, must make many precise connections with one another. It was thought that the ability to produce new cells might upset the delicate web of connections already in place - connections that presumably store the learned information and experiences that make up our personalities.

New Theories, New Nerve Cells, New Hope....

But science isn't a static field. The first cracks in the old theory of nonregeneration in the brain began to appear more than a decade ago, when researchers discovered evidence of newly born nerve cells in the brains of adult rats.

Things really heated up two years ago when scientists led by Frank Gage of the Salk Institute in La Jolla, Calif., adapted an old technique in an innovative way to document evidence of brain cell division in tissue samples from deceased adult cancer patients. Soon after, more careful studies of the brains of adult monkeys convinced researchers that thousands of new nerve cells might be born each day, suggesting that this process probably occurs in human brains as well.

The new nerve cells found in rats and primates seemed to come from two areas of the brain: layers of cells that surround the fluid-filled spaces, or ventricles; and the hippocampus, a region involved in learning and memory. Scientists speculated that these areas must contain populations of neural stem cells - primitive cells that can divide to produce both more stem cells and new brain cells.

Although discovering potential for regeneration in the human central nervous system is exciting, the newfound neural stem cells seem to make up only a tiny percentage of the total cells in the brain. Thus, the natural process of cell replacement is probably not efficient enough to repair most brain injuries or to outpace the progress of a neurodegenerative disease like ALS.

What's needed is a way to kick the brain's repair system into high gear, either by stimulating the existing neural stem cells in the brain or by transplanting large numbers of healthy donor neural stem cells. As it turns out, progress is being made on this front, too.

At the same time that Gage published the first evidence of new nerve cells in the adult human brain, Evan Snyder of Children's Hospital in Boston published a report announcing the isolation of the first human neural stem cells. These cells could be grown in large numbers in the laboratory and, when transplanted into the brains of rodents, could migrate to appropriate brain regions and give rise to all of the major types of nerve cells.

Perhaps even better, in a later study, Snyder showed that mouse neural stem cells isolated from healthy donors could be transplanted to the brains of recipient mice to correct a neurological disease that resembled multiple sclerosis.

One of the remarkable findings from Sndyer's work is that the transplanted neural stem cells seemed to have the ability to "home in" on the areas of the brain that are damaged and then transform themselves into whatever type of cell is needed to fix the damage. "So we know that the biology is in our favor," Snyder says. This finding bodes well for diseases caused by a loss of cells over large regions of the brain and spinal cord, like ALS. Prospects for ALS

Despite this promising start, some obstacles remain to replacing cells lost to ALS. "First," Snyder says, "we need to make sure that we can deliver those stem cells efficiently and reproducibly to all of the areas that are necessary. For instance, in a disease like ALS or SMA [spinal muscular atrophy], where it's not just one segment but many segments, this would be necessary."

Snyder says the second obstacle is making sure that the cell not only becomes a motor neuron, but sends its connections in the right direction, out the right tracks, and makes contact with the right muscles, "and that those contacts are efficient, effective and appropriate." Already, Snyder's lab has begun to chip away at some of these obstacles. He reports that his group has preliminary evidence that mouse neural stem cells will become motor neurons when transplanted into mice whose own motor neurons have been made to degenerate. The group also has some early evidence that human neural stem cells may be able to become at least a few motor neurons in a primate model of motor neuron degeneration.

Now Snyder's group is trying to determine if the cell replacement process is efficient enough to allow experimental animals to regain lost functions or if it will be necessary to find some way to "rev up" the natural system even more.

"We're definitely looking for signals that might make the process more efficient," he says. "Fortunately, the phenomenon takes place even in the midst of our ignorance about what the signals are. The cells seem to do it [migrate to damaged areas and replace lost cells] on their own. Or, at least, the environment seems to instruct them on its own."

One concern about "rewiring" the human nervous system is that some motor neurons with very long extensions, or axons, would need to travel a great distance to be reconnected to the appropriate target muscles. For muscles that are farthest away from the spinal cord, like those of the foot, the process of reconnection could take months or years.

Snyder points out, however, that not all target organs are that far away. For example, to regain control of the bulbar muscles, which are responsible for swallowing, replacement axons would only need to travel a short distance. He suggests that just getting control of these muscles could make a great difference in the life of someone with ALS.

"I think there are gradations, too," Snyder says, "as to how long the regrowth process would take and what muscles would be effective - which muscles are most important. It might certainly prevent a person with ALS from getting worse."

Now that it has been demonstrated that our nervous systems do hold the ability to regenerate, and lost cells can be replaced by new cells, scientists are racing to do the fundamental groundwork to exploit this new knowledge in the repair of nervous systems damaged by trauma or disease. "This is a pretty exciting period of time," Snyder predicts. "I think the field of stem cell research in general and neural stem cell research in particular is going to make a major impact over the next decade, or certainly the next quarter century, on what happens with nervous system diseases."  

To read more about the potential of stem cells to repair damaged tissues, see "Renewing Muscles and Nerve," in MDA's national magazine, Quest, vol. 7, no. 2.

Return to Top

Maintaining Function, Modifying Environment are Key in ALS Physical Therapy Programs

A walker can help compensate for weakness in the pelvic and leg muscles in ALS.

Physical therapist Sheila Hayes sees ALS patients at the Eleanor and Lou Gehrig MDA/ALS Center at Columbia-Presbyterian Medical Center in New York. Hayes was recently interviewed by The ALS Newsletter about physical therapy in ALS.

Q: What are the goals of physical therapy in ALS? How are they different from goals in other kinds of physical therapy?

A: In the old way of looking at things, rehabilitation meant you were going to get better. In neuromuscular disorders, people often stay the same or lose ground.

Recently, there's been a lot more interest in doing rehabilitation with this group of patients, because there are many ways physical therapy can help maintain function and enhance mobility in people with neuromuscular diseases. In fact, the American Physical Therapy Association now has a special interest group on degenerative diseases.

Q: Let's talk about the specific goals for PT in ALS.

Flexibility
A: There are actually several goals for PT in ALS. One is to maintain flexibility. It makes mobility so much easier if flexibility - what we call range of motion - is maintained. If you lose range of motion, which means the normal way that a joint can move, it's going to be harder to walk, to transfer, to get in and out of a chair, even to move around in bed. Another reason to maintain flexibility and range of motion is to prevent pain from developing. When joints are immobile they become tight, and when a person tries to move the joint, it creates pain. That pain usually causes a person to splint themselves [protect the joint by not moving it]. The joint is then moved even less. If you stop moving a limb, there will be less circulation and nutrition to the joint, and the joint will become even more stiff and painful. So, it just becomes a vicious circle.

Phsical therapists help keep joints moving, to help prevent pain and stiffness.

Strength
Maintaining strength for as long as possible is always a goal in the progressive neuromuscular disorders. But how you do that varies, and people have different ideas. The theory that's pretty much accepted now is that, when you have dying motor neurons [muscle-controlling nerve cells], as you do in ALS, the surviving motor neurons send out new "sprouts" to muscle cells that have lost their motor neurons. These newly innervated muscle cells and their nerve cells are called giant motor units. They work, but they're more susceptible to fatigue than the original motor units. They're not as efficient. They can only compensate for so long, because ALS is a progressive disease.

So, if you stress them too much, you're going to overstrain them. You'll overfatigue yourself and make it more difficult to do a functional activity, such as using your computer, putting on your shoes or feeding yourself. If the point of doing exercise is to maintain function, then it doesn't make sense to do something that's going to interfere with function. I don't think you'll hasten disease progression by doing too much in the way of strengthening exercises, but there are people who disagree with me on that. You do risk straining muscles, which can cause a temporary decrease in strength and jeopardize safety.

Neck supports can keep the head in a functional position despite weakness. Photo courtesy of USMC/Sinco, Pasadena, Calif.

Function
In addition to maintaining strength and range of motion, there are other ways that physical therapists can help people maintain function.

These are orthotic devices - formerly called braces - and assistive devices. They include things like ankle-foot orthoses, which keep the foot in a functional position for walking; canes and walkers; neck supports; and any kind of modification that's needed, such as adapting a favorite armchair so that the forearms are better supported.

Sometimes, just following some simple advice like, "If you're reading, prop the book at eye level," can take an incredible amount of strain off certain muscles. It's not always easy to see this for yourself.

Decreasing Pain
I think the main way to decrease pain is to prevent it in the first place. Range-of-motion exercise plays a really important part in that. The pain that people with ALS have is usually related to orthopedic problems - joint restrictions, tendon irritation and so forth, which are caused by lack of movement.

For existing pain, the standard treatments used by therapists may be helpful. These include moist heat, ice, massage or sometimes a TENS - transcutaneous electrical neuromuscular stimulation - unit. [This unit is thought to interfere with the transmission of pain signals by overriding them through mild electrical stimulation.] The therapist can discuss options with the client's physician.

Q: How do you know how much exercise is too much, or the wrong kind?

A: I went to a physical therapy convention last June where six people did a presentation on ALS and came up with these general guidelines:

It's OK to do mild to moderate strengthening exercises for muscles that are so far uninvolved, that show no overt weakness. But once a person is starting to exhibit weakness, it's best to stay away from weight machines, free weights or any type of resistance exercises.

The reason is that, when there's overt weakness, it's an indication that a fair number of motor units are no longer functioning, and you'll strain them with this kind of work.

Once a person starts to have weakness, active range-of-motion exercises become the emphasis of the exercise program. Then, if weakness progresses so that he or she is having trouble with functional activities like getting dressed or hair combing, assistance may be needed to do the range of motion.

Eventually, the person may need complete assistance, what we call "passive" range-of-motion exercises, in which a family member or health care professional is moving the limb for them.

You can tell if you've overdone it if later in the day, or the day after exercising, you feel weaker. The next time, cut back on the amount of exercise or the time spent exercising. Cramps or muscle fatigue during exercise mean stop and rest.

A - Normally, each motor neuron controls a group of muscle fibers. B - when a motor neuron dies, a neighboring motor neuron can "sprout" new nerve endings to control the muscle fibers "orphaned" by the dying neuron, but these new connections aren't as strong as the original ones.

Q: How often should someone with ALS see a physical therapist?

A: In chronic illnesses like ALS, a lot of emphasis is placed on home exercise programs. I usually see ALS patients once or twice at the beginning and make recommendations for them and for the family. Then, I try to see them about every two to three months. Some people will want to go to a therapist nearer their home as well, for ongoing therapy, and I will then consult with that therapist on the exercise prescription.

It's important in ALS for a person to get follow-up consultations as things change. The goals that the therapist sets have to be somewhat short-term because of the progressive nature of the disease. Goals have to be modified as weakness progresses.

Q: How does someone with ALS find a therapist with expertise in this disorder?

A: If you go to an MDA clinic, you're going to find a therapist who's familiar with neuromuscular diseases. At an MDA/ALS center, the physical therapists should have expertise in ALS. The exercise guidelines in the various neuromuscular conditions aren't that different from each other, though; you want to avoid overexercising muscles that are still functioning.

Out in the general community, you need to ask specific questions. Most therapists have general information about all aspects of physical therapy, but things have gotten so specialized that you can have therapists who mostly focus on things like sports injuries, orthopedics or cardiopulmonary rehab. You need to go to a therapist who has a background in neurological rehab, including neuromuscular disorders.

Fortunately, in the physical therapy profession, there's now much interest, knowledge and participation in the management of degenerative diseases, such as ALS and Parkinson's and Huntington's diseases. 

Return to Top

Cell Death Blockers Join Growing Arsenal Against ALS

MDA researchers have found that a compound that blocks enzymes involved in a specific type of cell death delays the onset of ALS by 20 days and increases life span by 22 percent in mice engineered to have the disease. The results were announced in the April 14 issue of the journal Science.

The muscle-controlling nerve cells (motor neurons) lost in ALS are thought to die through a deliberate mechanism called apoptosis, or programmed cell death. This cellular death mechanism depends on the activation of a series of enzymes known as caspases.

Robert Friedlander

Now, MDA-funded researchers Robert Friedlander of Brigham and Women's Hospital and Harvard Medical School in Boston, and Serge Przedborski of Columbia University in New York, and colleagues, have used a pharmacological caspase blocker called zVAD-fmk to prevent the motor neurons of mice with ALS from dying.

Although not directly comparable to other compounds tested in the same mice, the new drug appears to be at least as effective as creatine and coenzyme Q10, and more effective than the Food and Drug Administration-approved drug riluzole, in protecting the mice against the effects of ALS. These four compounds may slow the progress of the disease through separate mechanisms, leaving open the possibility of achieving additive effects by combining medications.

Serge Przedborski

"I think any kind of pharmacologic treatment that works in ALS is going to be similar to what happens in HIV [the AIDS-causing virus]: With only AZT you didn't see too much of an effect, but now there's a whole cocktail of drugs that work in different ways and patients are getting better," says Friedlander.

The group also found evidence for increased caspase activity in the donated spinal cord samples of people who died of ALS, indicating that caspases probably play a similar role in cell death in humans.

Unfortunately, zVAD-fmk (manufactured by a company called Enzyme Systems) may not be useful in humans because of some associated toxicities and is still only experimental. However, Friedlander and colleagues hope their work will serve to stimulate pharmaceutical companies to develop less toxic caspase inhibitors.  

Return to Top

Government to Explore Potential Link Between ALS
and Gulf War

For some, the recent announcement by the Department of Veteran Affairs (VA) and the Department of Defense (DOD) of a one-year epidemiological study to determine the rates of ALS among Gulf War veterans is late, but still welcome.

Although the conflict between the United States and Iraq known as the Persian Gulf War ended in 1991, some of its veterans have experienced ongoing medical problems that they believe are caused by duty-related chemical exposures. Collectively, these symptoms are dubbed Gulf War Syndrome, and have since been recognized by the U.S. government as legitimate illnesses incurred in the line of duty.

Many veterans have speculated that the number of cases of ALS among the relatively young population that served in the Gulf War is higher than that among the general population (see The ALS Newsletter, vol. 4, nos. 2 and 4). Several private groups have collected the names of Gulf War vets with ALS, but the government has been slow to release an official count.

Now, the VA and the DOD have initiated a $1.3 million study to determine whether the incidence of ALS among Gulf War vets is, indeed, higher than would be expected. So far, the government has counted 28 cases among the 697,000 men and women who were deployed to the Gulf between August 1990 and August 1991, a number not out of line with the occurrence of ALS in the general population. In order to complete their count as accurately as possible, researchers associated with the study would like to hear from veterans who have received diagnoses of motor neuron diseases (including ALS) and who were on active duty between Aug. 2, 1990, and July 31, 1991, regardless of whether they served in the Gulf theater. Veterans or family members and friends may call toll-free at (877) DIAL-ALS (342-5257).

In a statement issued by the two departments, VA Chief Research and Development Officer John Fuessner said, "If we do find an elevated risk for development of ALS, the finding will have broad implications for veterans, VA and the DOD alike."

For more information about the study, see the VA's Epidemiologic Research and Information Center Web site at http://hsrd.durham.med.va.gov/ERIC/ALS/ALS.htm; e-mail Study Coordinator Dawn Howard at dawnhoward@mindspring.com; or write: ALS Study (152), VA Medical Center, 508 Fulton St., Durham, NC 27705. 

Return to Top

Still Kicking: ALS Hasn't Put Football Coach Ray Dorr Out of the Game

Coach Ray Dorr

Touchdowns, completed passes and first downs have always been a huge part of Ray Dorr's life. As a well-known assistant football coach who has coached at seven major universities across the country, football has remained central to his life.

So it's no surprise that since Dorr, 58, announced last June that he has ALS, support has come from virtually every corner of the country and from some of college football's more notable figures.

A coach for the last 33 years, Dorr has helped shape the careers of several NFL standout quarterbacks, including Warren Moon, Rodney Peete and Chris Chandler. His coaching highlights include 15 trips to post-season bowls, including five times in the Rose Bowl.

Dorr himself was a four-sport athlete in high school, and played college football at West Virginia Wesleyan College where he was a three-year starting quarterback.

He began coaching as a graduate assistant in Akron, Ohio, in 1967 and worked his way through assignments at Kent State, Washington, Southern Illinois, Southern California and Kentucky before arriving at Texas A&M University in College Station in 1997.

Another career highlight came last December when he received the Frank Broyles Lifetime Achievement Award, presented to assistant coaches who have made significant contributions during their college coaching careers.

Dorr coached the Texas A&M quarterbacks through last season when, remarkably, he never missed a meeting or practice despite his illness.

Although ALS quickly affected his speech, Dorr and his players communicated without a hitch, Dorr's wife, Karen, said.

"It was amazing how the players could understand him," she said.

And along the way, he has taught his players a lot more than football.

"Sometimes it's easy to give lip service as a coach and tell the players to do the right thing and be courageous and be all you can be. It's not that easy to do, but Ray puts that into practice," Aggies' Head Coach R.C. Slocum told local media last fall. "The players see him talking with the quarterbacks, being courageous. They are getting a learning experience." Dorr is able to walk, and continues to drive himself to work every day. A feeding tube has allowed him to gain back some weight he had lost in previous months, Karen Dorr said.

He stepped down from an official coaching job at the end of last season, but remains on the job, now officially listed as a special assistant to Slocum.

Actually, he has joked that his position should be called "quality control," Karen said. His wide-ranging tasks include analyzing films, writing reports, helping manage practices and organizing other day-to-day details. The team began its spring practices last month.

The people at Texas A&M have been especially helpful, Karen said, with endless support and encouragement. "The whole staff just really loves him," she said.

In addition to visits and phone calls from football associates, Ray Dorr's adult sons, Stephen and David, visit and call whenever they can. Karen said the family also finds strength in their religious faith. The Dorrs take part in Fellowship of Christian Athletes activities and host weekly Bible study groups at their home.

Above all, Dorr fights ALS with a positive attitude and remarkable courage, his wife said. The key is having a reason to live, and never, ever giving up, she said.

"I think he's really an inspiration to everybody," she said.  

Return to Top

MDA/ALS Center Director Engel Honored by Former Students

W. King Engel, director of the Jerry Lewis MDA/ALS Clinical and Research Center at the University of Southern California School of Medicine in Los Angeles, will be honored this month by more than 200 of his former students.

Engel, a longtime MDA research grantee who has studied ALS and other neuromuscular diseases, will be feted for his contributions to science and for training physicians who specialize in neuromuscular disorders.

At USC, Engel is director of the Neuromuscular Center and a professor of neurology and pathology. He's also director of MDA's clinic at L.A.'s Hospital of the Good Samaritan. The reunion to celebrate Engel's achievements will be held during the American Academy of Neurology's meeting in San Diego April 29-30.

The meeting will include a scientific program called "Neuromuscular Panorama: The Past, Present and Prologue to the Future," for which all of the world-class speakers will be former students of Engel. 

Return to Top

NEW RESPIRATORY CARE VIDEOS AVAILABLE FROM MDA

New Respiratory Care Videos Available from MDA

MDA's Television Production Division has produced two new videos about respiratory care that will soon be available through local MDA offices.

Both videos feature people with ALS, as well as those with other neuromuscular disorders, and contain valuable information a person might need in order to make an informed choice about assisted breathing.

"Breathe Easy: A Respiratory Guide for People With Neuromuscular Diseases" illustrates options and devices for people who require breathing assistance due to the effects of ALS or other neuromuscular diseases. The 25-minute video explains equipment, techniques, and advantages and disadvantages of different ventilation options, including coughing assistance, suctioning, noninvasive assisted ventilation and tracheostomy.

"Breathe Easy" will be available from MDA program service coordinators for use by support groups, seminars and individuals.

Another version of the video, "Breath of Life," is geared for use by physicians, respiratory therapists and other medical professionals. It will also be available for use through MDA offices and clinics.

The pharmaceutical company Amgen underwrote the cost of producing the respiratory care videos. 

Return to Top

ALS FIGURES IN NEW THRILLER

Scott Turow's latest legal thriller, Personal Injuries, has the usual elements of the author's blockbuster stories: compelling characters, an exciting and inventive tale, and plenty of surprising twists in the action.

But throughout the novel there also winds a poignant story of how ALS affects Lorraine "Rainey" Feaver, wife of Robbie Feaver, an unsavory and gregarious lawyer who is best known for his womanizing.

Feaver has been caught making payoffs to a handful of judges who decide his cases. To save his own hide, he takes part in an FBI operation to gather evidence against the judges, all while coping with his wife's decline and his elderly, dying mother.

Feaver's tortured soul and regrettable past add dimension to the action, especially when he's paired with Evon Miller, alias of the agent who's assigned to supervise him. Miller, who forms a fascinating bond with Lorraine, has her own hefty set of emotional baggage that lends further drama.

While ALS isn't the main focus of the novel, Turow carefully handles the disease and its effects with an obvious concern for details and a respect for people who are affected by it. The novel artfully portrays the challenges and harsh realities im-posed by ALS, and is sure to raise awareness in Turow's huge audience.

Those with ALS, and families and friends, might find the novel thought-provoking, but should also be aware that the ultimate end could be a bit discomforting. Lorraine's struggle probes sensitive issues such as choices about ventilation and assisted suicide.

Turow, a former assistant U.S. attorney in Chicago, is now a partner in a private practice. He's also the author of best sellers Presumed Innocent, The Laws of Our Fathers and The Burden of Proof. Personal Injuries, published by Farrar, Straus and Giroux, is available in most bookstores in hardback for $27. Read the book's first chapter at www.turowpersonalinjuries.com on the Internet.  

Return to Top

20TH MDA/ALS Center Designated in Kansas

The University of Kansas Medical Center (KUMC) in Kansas City was recently chosen as the latest site for an MDA/ALS research and clinical center. It is the 20th such multidisciplinary facility in the United States maintained by MDA to serve people with ALS.

The center will operate under the direction of Arthur R. Dick, professor of neurology at KUMC. Dick has co-directed the MDA clinic at KUMC since 1991. The center can be contacted by calling (913) 588-6997 or e-mailing to Kpeters@KUMC.edu.

The 20 MDA/ALS centers across the country are focal points of MDA's ALS research and services program. An up-to-date list can also be found in the March 2000 issue of The ALS Newsletter (Vol. 5, No. 1).

Individuals with ALS who are registered with MDA receive services at the 20 MDA/ALS centers as well as at the 230 hospital-affiliated MDA clinics located nationwide. 

Return to Top

The Association welcomes gifts for ALS research honoring significant occasions of achievement. These gifts may be made in tribute to special people or to mark such events as anniversaries, birthdays, weddings, graduations or retirements.

THE ALS NEWSLETTER
Muscular Dystrophy Association
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718-3208

Return to Issues Index