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Lou Gehrig

Jeff Rothstein is directing the multimillion dollar center for ALS Research.

Cal Ripken donating $2 million dollars to ALS Research at Hopkins

In The Name of Lou Gehrig

By Joel N. Shurkin

More than 60 years after the “Iron Horse” succumbed to ALS, researchers appear at last to be making headway toward defeating the devastating neurological condition that killed him.

Among the unforgettable professional athletes of the 1930s Lou Gehrig stood out. His body was so strong and healthy that his record for consecutive games (2,130) wasn’t broken for 56 years, a feat that earned him the sobriquet the “Iron Horse.” Gehrig also was able to excel at one of the most intricate physical tasks known to humankind—hitting a baseball in the major leagues, a testament to a superbly honed nervous system.

A batter faced with a ball flying toward him at 90 miles an hour in an often-twisting arc has a fraction of a second to decide if, when and how to swing a two-pound round bat. When he makes the decision to swing, the signal goes instantly from the brain, down the nervous system to the motor neurons, which must then fire off immediately in a pattern of almost stupefying complexity to direct countless muscles. Gehrig had a lifetime batting average of .340, meaning he succeeded 34 percent of the time, splendid even by modern standards.

But at some point in his life, probably even before he put on the pinstriped uniform of the New York Yankees, Lou Gehrig’s motor neurons began to die, in the mysterious and inexorable process known as amyotrophic lateral sclerosis (ALS). First identified by the French physician Jean-Martin Charcot in 1869, ALS is a progressive and fatal neurological disease triggered by the degeneration of nerve cells in the brain and spinal column—the cells that direct muscular activity. As these motor neurons expire, the muscles they control start to falter and eventually waste away.

Gehrig’s diagnosis at 36 was young, but not rare. Hopkins has had teenage patients with the condition. More commonly, the disease hits people in their mid-50s, announcing itself with trouble opening doors or using a screwdriver. Since motor neurons are involved, there is no numbness or tingling. At onset, symptoms often are only on one side of the body.

Patients become unsteady, fatigued, lose control of the hands and arms, and can twitch and suffer agonizing leg cramps. There is no set pattern of deterioration, but even the facial muscles can fail. The deterioration process lasts two to five years, moving from one muscle group to the next. No muscles, including those that control vital functions, are immune. As one set after another succumbs, paralysis sets in. And because the mind and most of the sensory system are spared, the ALS victim finds himself awake and fully aware, trapped in a body that is dying and collapsing around him. Eventually, death occurs through asphyxiation or infection.

The exact cause of the motor-neuron massacre remains unclear. In the United States, about 20,000 people currently have a diagnosed case of ALS at any one time. The majority are men between the ages of 45 and 65. In men, one of every 800 deaths is due to ALS; for women it is one out of 1,200. More than 5,000 cases are diagnosed every year.

Images of Disease: (left to right) View of a damaged spinal cord; mouse with ALS; a motor neuron culture; embryonic stem cells growing new motor neurons.

As might be expected, Gehrig faced such a tragic end with extraordinary courage and became a symbol of grace under the pressure of the horrible disease, but following his death in 1941, decades passed without much reason for hope for anyone stricken with ALS. While palliative methods improved over the years, the outcome for patients remained unchanged. (This is the disease in Mitch Albom’s best seller, Tuesdays with Morrie.) And since there are no happy endings for ALS patients nor famous survivors, there was little public outcry for increased funding. Even drug companies largely ignored it, because the disease doesn’t affect millions of people. Today, Rilutek, the one drug that has been approved for ALS, provides, at best, a few more months of life.

This year, however, for the first time, the picture is looking a little less bleak. With Hopkins in the lead, new energy and optimism have infused the fight to find a cure for ALS. Largely motivated by patients and their families, the public has begun pouring money and interest into research. In late winter, Johns Hopkins announced the creation of a new Center for ALS Research (see page 49), the first of its kind anywhere and funded by private sources. Moreover, investigators here and elsewhere may be on the verge of answers. One product of the new drive to conquer the disease may be the first therapy that actually holds potential.

“We know a lot more about the biology than we used to,” says neurologist Jeffrey Rothstein, M.D., Ph.D., who has a picture of Gehrig on the wall near his desk. “Overall, this has probably been our most exciting year.” At 45, Rothstein has devoted his professional life to unraveling the ALS mystery. Seven years ago, he and a team of collaborators were the first to identify the role of a brain neurotransmitter called glutamate in causing the neurons to die in these patients.

Most of the impetus for the recent rush of interest in ALS has come from a young Broadway producer stricken with the disease and a Baltimore Orioles baseball player who idolizes Lou Gehrig. The producer is Jenifer Estess, who was diagnosed with ALS at the age of 35, two years ago. She formed Project ALS, which has raised more than $1 million in the last year alone for research, much of it conducted at Hopkins. The baseball player, of course, is Cal Ripken Jr., the latter-day iron man who overtook Gehrig’s estimable record for consecutive games played. He and the Orioles have created a Cal Ripken/Lou Gehrig Fund to support ALS research. The Orioles sold special seats at Ripken’s nationally heralded 2,131st game and donated that money to the fund. With these two visible organizations in the lead, other foundations have also jumped in to support the new Center for ALS.

One of the most exciting studies under way through the center is the possibility of using stem cells—primordial cells taken from fetuses in the earliest stages of life—to support or possibly even replace dying nerve cells. Hopkins’ John Gearhart and colleagues elsewhere have demonstrated that stem cells injected into mice have migrated to the animals’ spinal column and apparently transformed themselves into nerve cells. Gearhart, in fact, has 12 lines of cloned neural stem cells in his lab. Using this new knowledge, Rothstein and his lab are planning clinical trials in the next 12 months.

One key to defeating ALS, researchers say, is understanding glutamate, a major and widely dispersed neurotransmitter. “Glutamate has to be controlled. If there’s too much around it kills neurons,” Rothstein says. ALS may be a glutamate management problem, although how the substance kills neurons still is a mystery. A hint that glutamate is crucial to the pathology of ALS is that the only drug that has any effect on ALS, Riluzole (or Rilutek), is an anti-glutamate substance. “We know the glutamate story is relevant, but it is not the whole story,” Rothstein says.

Also exciting the experts is a technique involving the protein EAAT2, which is deficient in ALS patients’ brains and spinal cords. EAAT2 protects nerve cells against glutamate toxicity. In collaboration with clinicians at Thomas Jefferson University in Philadelphia, Rothstein’s group is preparing gene therapy trials to induce production of more of the substance.

Five years ago, neuropathologist Donald Price, M.D., Ph.D., created a group of mice that developed ALS. Since then, by studying subsequent crops of Price’s mice, Rothstein has learned that ALS begins well before symptoms become apparent. The average normal mouse lives three years. Mice bred with ALS are lucky to make it to four months, or 120 days. Using the best treatment currently available, researchers can extend the rodents’ lives for another 20 to 24 days. Yet preliminary experiments using gene therapy to induce EAAT2 proteins have yielded ALS mice that are still alive a year later.

It’s a small number of mice, and the experiment needs to be repeated with more animals, but there are enough similarities between human ALS and the ALS bred into the mice to cause considerable excitement. The experiments were publicized in a long article in the Feb. 7 issue of The New Yorker about 30-year-old Stephen Heywood of Newton, Mass., who has ALS, and his brother, Jamie, who has given his life over to finding a cure. Again, the impetus for the gene work came from a patient (Heywood) and his kin. The family refused to accept the status quo, put Rothstein together with the team at Jefferson and raised the necessary money for the studies.

There’s more promising news. Science has come up with new ways to put human genes on computerlike chips that could allow researchers to identify multiple genes responsible for neuron death. There are essentially two forms of ALS, hereditary and non-genetic. Only 5 to 10 percent of patients have the familial form, but this group has given researchers insight into the pathogenesis of the disease.

There’s an excitement about ALS work today because there are so many interesting questions and so many unknown answers. Scientists want to know why, out of the billions of neurons in the brain, are motor neurons selected? What are the key elements that allow certain motor neurons to survive and others to die? It is the richness of the questions that makes this research a frontier era for young neuroscientists.

The Lou Gehrig metaphor is valuable for understanding ALS. So is the irony, in the sense that Gehrig was such an unusual physical specimen. Iron Horse or not, he was struck with the same muscle weakness that all patients feel first. In Gehrig’s case, he began to make errors he normally would not have made. His batting average declined, and he even tripped on the bases. When it was obvious something was wrong, he took himself out of the lineup—ending his streak—and went to see a doctor.

Gehrig’s motor neurons may well have begun dying while he was still a child. He only noticed the onset when enough neurons had succumbed to interfere with his baseball prowess. He died almost two years to the day after he made his historic farewell speech to thousands of adoring admirers at Yankee Stadium in 1939, declaring: “Fans, for the past two weeks you have been reading about the bad break I got. Yet today I consider myself the luckiest man on the face of the earth.”

When he died, one sportswriter wrote: “There was no reason to dislike him. And nobody did.” In that way, perhaps he truly was “the luckiest man on the face of the earth.” No doubt few would agree, given the conditions and age of his death.

Today, more than 60 years after Gehrig succumbed to the affliction now known by his name—Lou Gehrig’s disease—what is finally changing, Rothstein says, is the time line projected for combating ALS. Normally, researchers do one experiment. If it works, the study is replicated. If it works again, they move to the next step. Rothstein says that’s too slow. Now experiments are being done parallel to each other, not serially. The two groups of investigators can compare notes. Moreover, researchers at Hopkins from across disciplines meet regularly to discuss their work. Neuroscience researchers from Rothstein’s lab, the lab of Ted and Valina Dawson and Don Price’s group have formed a consortium, putting basic scientists in close collaboration with clinicians. Rothstein calls it the “Hopkins way.”

What may account for the ALS group’s unusual enthusiasm and energy, in fact, is that so many of the researchers studying the disease are clinicians. Rothstein has no doubt that all his studies on mice to understand the mysterious killer have been heightened by also being a physician. “This has been my plan all along,” he says, “to understand the mechanisms of a disease—and then apply what I learn to developing new therapies for treating my patients. In my case, that disease is ALS.”