In 1938, Lou Gehrig was diagnosed with the degenerative nerve disease ALS. He would lose his capacity to walk, talk and swallow. He would die choking as the disease followed its normal, horrific course.
His physicians could scarcely imagine what caused it.
Now, researchers speak of progress - hints that they can slow the disease's destruction. They do not, however, speak of cures.
Lou Gehrig's disease, or amyotrophic lateral sclerosis, causes the atrophy and death of specialized nerve cells in the spinal cord that control virtually all the muscles that enable us to move.
Researchers are piecing together theories that might explain why the nerve cells suddenly die. They have genetically manipulated mice so that the mice develop ALS, turning them into living laboratories that can do much to advance therapies. And they are testing three drugs that offer hope of slowing the disease's progress.
To researchers, such strides offer a multitude of possibilities.
But to patients, the new findings mean something less.
If early test results prove accurate, the drug closest to being approved by federal authorities extends the lives of ALS patients an average of six months. The grim prognosis given decades ago has thus barely changed - death within two to five years.
Research could lead to drugs that are much better, but probably not in time to save people facing paralysis today. This is not lost on patients such as Joseph Schwartz, a Washington lobbyist who began taking an experimental drug soon after he was diagnosed this year.
"There are always times when confronted with something devastating, you just want to throw up your hands and give up," says Mr. Schwartz, who was diagnosed a week after the birth of his second son. "But if I ever feel that way, I look at my wife and kids.
"I think to myself, 'How can I do anything but try the best to stay healthy? To find the best drug I can, even if it doesn't really help me survive.'"
Although excited about recent progress, scientists are bluntly realistic.
nTC "I don't think we have much of the picture," says Dr. Jeffrey Rothstein, a leading ALS researcher at the Johns Hopkins Medical Institutions. "In spite of the fact there are experimental therapies, the fact remains that it is still a progressive disease.
"They're going to die of it. We have to find a way to help them enjoy what they have left."
The disease afflicts about 30,000 Americans, most in their 50s. The early signs can be subtle and easily shrugged off: a weak toe, a drop foot, a twitching muscle, an odd tendency to laugh or cry inappropriately.
There is no precise test for ALS, just symptoms that become unmistakable as weakness and paralysis spread. Buttoning a shirt can become maddeningly difficult, lifting objects or walking close to impossible. Patients need wheelchairs. They lose the ability to speak and swallow. Death comes through suffocation.
Respirators, which mechanically force air in and out of the lungs, can keep patients alive a while longer. But, Dr. Rothstein says, most people decide they'd rather not submit to that level of dependency.
There is no good way to die, but ALS might be one of the worst. It kills the neurons that control voluntary movements - taking a step, waving hello, writing one's name. But it does not kill cells that control thought and sensation. Its victims become knowing witnesses to their own destruction.
Hopkins has about 30 scientists working on ALS - perhaps the nation's largest assemblage of researchers dedicated to the disease.
A gift of $2 million has been promised jointly by Cal Ripken Jr. and Orioles owner Peter Angelos to continue efforts that already have led to major insights.
In the early 1990s, a group headed by Dr. Rothstein discovered that ALS patients have elevated levels of glutamate - one of a class of brain chemicals that relay messages from one cell to the next along the neural pathways of the brain and spinal cord.
Without glutamate, your brain could never tell your pinky to bend or to hang limp. But too much glutamate can be toxic.
In the best of circumstances, a natural protein suctions glutamate off the surface of cells an instant after it has conveyed a message. ALS patients lack this protein. As a result, glutamate lingers too long, and its effect turns from good to bad.
Two years ago, researchers from Massachusetts General Hospital and 12 collaborating institutions found another clue to ALS. Patients who inherit the disease carry a mutated gene. In its healthy form, the gene produces proteins that destroy corrosive molecules known as free radicals.
The logic seemed exquisite: With the mutated gene, and without the proteins, neurons would be vulnerable to destruction. But the theory was far from perfect: Only 5 percent of ALS patients inherit the disorder. The majority of ALS cases occur seemingly out of the blue, without any known genetic cause. Also, no one really knows why the flawed gene causes cells to die.
But some help is coming from mice.
At Hopkins, Dr. Philip Wong and colleagues implanted copies of the defective gene into mice, creating a colony with the paralyzing illness. The mice lose power in their legs and droop onto their stomachs as if anesthetized. They are doomed.
The scientists were surprised to see what happened when they gave the mutated mice normal quantities of the protective protein they lack - enough, it would seem, to protect cells from free-radical destruction. The mice got the disease anyway; it suggests that the mutation produces a new toxin that savages the cell.
Those transgenic animals may later offer more clues to the mysteries of ALS. The mice can be sacrificed, then autopsied at various stages of deterioration.
"You need a videotape of the whole accident, not just when the crowd is gone - before they develop the disease, the first day they develop the disease and through every day of the disease," says Dr. Rothstein.
Though incomplete, theories about ALS' causes have led to development of experimental drugs.
The glutamate theory is responsible for the development of the drug riluzole, which blocks cells from releasing that neurotransmitter.
In June, the Food and Drug Administration allowed the drug's manufacturer, Rhone-Poulenc Rorer, to offer riluzole free of charge to a limited number of patients while the agency decides whether to allow its commercial sale.
Other experimental drugs are based on a separate idea - that natural hormones, called trophic factors, can help injured cells recover before they are lost. One of the drugs, BDNF, is being tested at Hopkins, as was riluzole.
Dr. Rothstein said he doubts that he will live to see the development of a "magic bullet" that will subdue ALS.
He looks to a drug cocktail that would attack the disease in different ways. But he's not counting on a cure.
"I would hope to see a combination of drugs that would really halt the disease," he says.
" 'Halt' may mean that the disease still progresses, but really, really slowly."