"I think we may have found the gene for Duchenne muscular dystrophy." Those words came in a call to my office at the Muscular Dystrophy Association in the spring of 1986 from MDA grantee Louis M. Kunkel. Over the next few months, intense research went on to confirm the finding, which ranks as one of the most significant events in genetic research history.

That call was perhaps the most exciting moment in my 25 years of involvement with MDA's research effort. The horizon we could see then -- using gene therapy techniques to stop the destructive progress of Duchenne (DMD) -- now looms much closer, as we rapidly approach the possibility of beginning preliminary human trials of gene therapy in various forms of muscular dystrophy.

STEP BY STEP TO A DREAM

In October 1986, the location of the gene underlying DMD was reported in the scientific press, and Jerry Lewis went "live" via satellite to announce to the American public that one-half of the Association's great dream had come true: An MDA-supported research team had discovered the cause of the most common and deadly childhood form of muscular dystrophy.

From that moment to this, MDA-supported investigators have worked continuously to realize the other half of the Association's dream: a cure for DMD. A cure will involve slowing and eventually stopping the progressive muscle wasting that leads to life-threatening weakness, and then re-establishing muscle strength.

Early this summer I was asked by a television reporter what I thought about the possibility of curing DMD. Before answering I thought back to 1986 when I got the call from Kunkel.

The DMD gene was the first one underlying a human disease that had ever been discovered without knowledge of the gene's normal function. MDA-supported scientists made medical history that day. Less than a year later they crossed another "impossible" barrier by discovering the protein the gene made and naming it dystrophin. DMD occurs when the gene fails to make dystrophin; Becker MD results when it makes some but not enough.

Nobody had ever seen such a protein. Nobody knew the human body was capable of making such a protein. It remains today the largest known protein made by a single human gene.

I looked at the reporter with thoughts of past progress, past discoveries and past triumphs in my mind. With confidence I replied, "I am more optimistic today than I have ever been that we will find a cure for this disease."

A FOUNDATION IS BUILT

I've been involved with MDA's research effort for about 25 years, starting as a young postdoctoral student at Columbia Presbyterian Medical Center in New York City. One memorable day there, a tall, imposing-looking man came striding through the laboratory. He asked each of the postdocs what research we were doing and why.

When it came my turn I explained that I was studying how muscle cells regulated calcium, a critical element in muscle's ability to contract. The man listened for a while, then stopped me and said: "Why don't you do something useful with this research and study muscle disease?"

The man was Lewis P. Rowland, chairman of the Department of Neurology at Columbia Presbyterian, a physician-scientist of international stature and a member of MDA's prestigious medical and scientific advisory boards, as well as an MDA vice president. I started my study of muscular dystrophy the very next day.

Today, MDA's textbook of muscle knowledge has grown to prodigious proportions, and the search for a treatment for DMD has increasingly focused on the early events in young muscles that lack dystrophin. Our understanding of these early events -- how they lead to muscle weakness and how they might be treated effectively -- has been greatly aided by the study of animals that also lack dystrophin.

In an extraordinary series of non-stop studies stretching over the better part of three years and involving the most advanced genetic technology available, MDA investigators have shown conclusively that when dystrophin is made available to dystrophic muscle, the muscle can get stronger. Recently, with MDA's support, Kay E. Davies showed that another protein, utrophin, can substitute for dystrophin in dystrophic animals (see related article).

These animal studies are setting the stage for human trials. Because of them, scientists know the direction their research must take: Find a way to get dystrophin or, possibly, utrophin into the muscle cells of patients.

A MEETING OF MINDS

This May I co-chaired the annual MDA/AFM Duchenne muscular dystrophy gene therapy workshop in Tucson, Ariz. (see related article) Three years ago I suggested MDA hold such regular meetings with our French counterpart for the purpose of accelerating research progress. They are spirited meetings with an open debate atmosphere and a roll-up-your-sleeves workshop approach. The workshops are intended to sharpen ideas, to refine research directions and, most of all, to develop among scientists agreements about what is working and what is not.

I watched and listened at this year's meeting as the data from research laboratories around the world were put on the table. Over the course of two days the investigators shared their laboratory secrets, the unpublished data that haven't yet been publicly released.

They shared their hypotheses, the intellectual currency of the scientific marketplace. An hypothesis is frequently an idea expressed in the form of a yes or no question from which, ideally, scientists can, under tightly controlled laboratory conditions, obtain an answer. For example: Can increased amounts of utrophin make up for a lack of dystrophin? Can a synthetic dystrophin gene produce the missing protein when inserted into muscle tissue?

Determining whether such an hypothesis is answerable or not is the stuff of research. In 25 years, I've heard thousands of hypotheses proposed and have participated in testing hundreds of them.

Listening to scientists at this year's gene therapy workshop reminded me of another memorable MDA workshop. In 1983, MDA brought together a group of neuromuscular disease experts to create a road map for finding the DMD gene. One by one, the experts put forward hypotheses they thought could be tested. And one by one, the most rigorous scientific minds in the world found the logical flaws that made it impossible to test the hypotheses.

Around midnight it became apparent that no one was going to offer a testable hypothesis that would lead to the gene. About then a young investigator whose picture just a few weeks earlier had appeared in Time magazine as one of the country's 25 brightest "new" scientists spoke up. "Has anyone ever done what we are trying to do?" he asked. It was a rhetorical question because, of course, everyone there knew the answer was no.

Then came the most important insight of all: No one had ever seen a gene that caused muscular dystrophy, so how, exactly, would we know it even if we saw it?

And that broke the ice. Teams of investigators left that meeting no longer looking for the "perfect hypothesis." Instead, they decided to do a lot of what is known as "high risk - high payoff" research. In applying this approach to gene finding, you use the best methods you can find and search for something that looks like a gene and, if you find it, you can figure out later what it does. And that's pretty much how the gene for Duchenne and Becker muscular dystrophies was discovered before what it does (make the protein dystrophin) was understood.

The DMD gene was located through the scientific equivalent of daring and courage. For a period of time, only MDA had the courage to fund this daring research because traditional government funding avenues often require researchers to investigate only relatively low-risk, testable hypotheses.

A NEW PERSPECTIVE

The perspective I've had since MDA's 1997 gene therapy workshop is different from my perspective following the 1983 gene discovery workshop. For one thing, animal models have shown us that gene therapy for muscular dystrophy can work. For another, detailed road maps of how such therapy might be accomplished in humans are being developed. For still another, testable hypotheses are everywhere.

That same television interviewer I referred to earlier also asked me how long it would take to find a cure for DMD. I'm asked that question a lot. Not just by reporters, but also by the people for whom the answer truly matters: those with the disease and their families.

My answer to the question "when?" is simple. Based on my involvement with virtually every significant breakthrough in this disease for the past 25 years, I can say in 1997 that I have more hope that a treatment for DMD will be found than I had in 1983 that the gene for the disease would be discovered.

In 1983, we weren't sure we could recognize the gene if it walked up and said hello. In 1997, it's a safe bet we'll recognize the cure -- when a child with Duchenne muscular dystrophy walks up and says "Thanks."