Mixed Blessings : The discovery of a gene linked to a disease brings joy to afflicted patients and their families. But soon after comes the letdown: They may not live long enough to see the cure.
Paul Motenko recalls the day last year when researchers announced they had discovered the gene responsible for cystic fibrosis. The father of a 4-year-old daughter with the fatal disease, Motenko was elated to hear that news, but he didn’t expect the event would also leave him feeling empty.
“Believe it or not, it was almost a depressing day for me,” Motenko said. “All of a sudden, after hearing hype, you’re hearing reality. You still really don’t know where you stand. The discovery happens and yet nothing changes. No one has been cured.”
The roller-coaster ride between hope and pessimism is a common experience for families touched by genetic disorders.
The discovery of a gene, while thrilling to researchers, doesn’t mean that a cure or even improved therapy is immediately available to patients.
Patients and their families are heartened to see progress, but the discovery of a gene can set them on a nail-biting race against the clock, hoping that they can outlast the disease until treatment or a cure is found. And, sometimes, the discovery yields information that indicates a cure will be much more complicated to achieve than expected.
“It’s a bittersweet time right now,” says Francis Collins, a University of Michigan researcher who co-discovered the cystic fibrosis gene last year.
“On one hand, we are beginning to get a glimpse of how we might treat (patients). But there are people who don’t have much time left.”
In the past few years, the genes for debilitating, often fatal hereditary disorders such as cystic fibrosis, Duchenne muscular dystrophy and Huntington’s disease have been identified within the body’s complex hereditary code. And, with 3,000 such disorders known, scientists are closing in on many more stunning discoveries.
A flawed gene ultimately gives rise to a disorder or allows it to be passed on to subsequent generations. Identifying the gene is the icebreaker that gives scientists an opportunity to learn what is going wrong in the body and how to fix it.
But the sudden windfall of long-hoped-for gene discoveries has heaped unexpected emotional turmoil on patients and researchers.
For example, the recent cystic fibrosis discovery pinpointed the gene in a key protein that malfunctions in patients with the disease. However, scientists were dismayed to uncover almost 50 mutations within the CF gene. The mutations will make a potential prenatal screening test and treatment much more difficult to construct.
“They were more optimistic before they found the gene than afterward,” Motenko says.
For other hereditary disorders, a potentially lifesaving treatment is only a few more experiments, perhaps one major clinical trial, away. Even the best hope for curing genetic disorders--gene therapy--no longer seems like a fantasy. In September, researchers initiated the first human gene therapy, inserting copies of healthy genes in a boy stricken with adenosine deaminase deficiency, an immune system disorder.
But it will be many months before the success of that treatment is known. And medical experts are still unable to say just how long it will be before patients begin to benefit from gene discoveries and gene therapy.
“That’s the question that is the most frequently asked and is the most difficult to respond to: How long will it be before there is a treatment?,” Collins says. “I try not to list a number of years because I don’t know, nor does anyone without a crystal ball.”
Discovering just where a faulty gene lurks in the body is a major hurdle. Making the leap from the gene discovery to understanding how the gene disrupts or destroys can be just as challenging, says Harvard University pediatrician Louis J. Kunkel. In 1987, Kunkel’s research team discovered the gene that causes Duchenne muscular dystrophy, a disorder that causes muscle weakness and eventually cripples.
“It’s very satisfying to accomplish what was so difficult and long and arduous to do,” Kunkel says. “But there is always a little bit of a letdown after that discovery. You think, ‘Where do you go from here?’ We’ve known about (the cause of) some other genetic diseases for many years, but we still don’t have treatment for them.”
When the Duchenne muscular dystrophy gene was discovered it was “like Christmas” for Albert and Cindy Almada of Pomona and their three children. Four years ago, they learned that their oldest child, Christopher, then 4, had the disease and would probably not live beyond his teen-age years.
The gene discovery gave the family hope that researchers would find a way to help Christopher and others stricken with the disease. But Albert, a dentist, and Cindy, a nurse, knew the discovery didn’t mean that a cure was immediately at hand.
“Being in science, my wife and I know that it takes a while for things to happen,” Albert says. Duchenne muscular dystrophy, which strikes one in 3,500 people, usually males, causes a gradual weakening of the muscles, including those in the heart and lungs.
Last year, Albert heard about animal research in which healthy cells were transferred to an animal with diseased muscle. He learned that doctors in San Francisco would soon test the procedure, called myoblast transfer, in humans. And, after several phone conversations with a researcher there, Albert was invited to enter Christopher, now 8, in the trial.
The therapy will consist of injecting Albert’s healthy cells into Christopher’s muscles in the hope that the healthy cells will fuse with his son’s and cause them to make a protein that is missing in muscular dystrophy patients.
Because the therapy is experimental, father and son have spent the past year making frequent trips to San Francisco so doctors could test the compatibility of their tissues. Researchers also conducted tests to see if Christopher could tolerate the powerful medication needed for treatment.
Albert says Christopher remains a good candidate for the therapy, which they hope will begin in 1991.
The Almadas say they carefully weighed the risks of undertaking an experimental therapy.
“I don’t feel my son is a guinea pig,” Albert says. “We aren’t sitting back. As long as there is no harm to my son, we want to be part of the cure, part of the breakthrough.”
For most genetic disorders, those patients most in need may be the last to benefit, researchers acknowledge. Experts usually predict that before a cure becomes available several other milestones will be reached, such as identification of carriers of the gene, identification of affected fetuses before birth, newborn screening and development of treatment to prolong life.
Cure is a word that is still used with restraint among cystic fibrosis patients, says Dr. Robert J. Beall, executive vice president of medical affairs for the Cystic Fibrosis Foundation.
Since the discovery of the CF gene, for example, researchers have focused on the gene’s normal function and what goes wrong. The hallmark of cystic fibrosis, the leading hereditary cause of death in whites, is excessive buildup of mucus in the respiratory and digestive tracts. Bacteria thrive in the mucus, causing infection while digestive imbalances cause poor nutrition. These problems usually result in the death of patients in their teens or 20s.
“While gene therapy is a very exciting area, we have five to six other (treatments) with CF that will be going to clinical trials within the next year,” he says. “In fact, some are already under way. So we’re not putting all of our eggs in one basket. We have a very large spectrum of options available to (patients). Some will pan out, and we’ll be able to keep these people alive for gene therapy.”
Optimism can vary among the newly diagnosed and those who have lived with a disorder for many years, says Prissi Shapiro, state coordinator for the National Neurofibromatosis Foundation.
Von Recklinghausen neurofibromatosis, which is commonly called by the misnomer Elephant Man’s disease, affects one in every 3,500 people. The disorder causes symptoms ranging from skin discoloration to mental abnormalities to tumor growths around the body. The NF gene was discovered by Utah and Michigan researchers in July.
“For parents, for them to know the gene has been found means that in their child’s lifetime there may be a cure,” Shapiro says.
“For people who have the disease, it’s much harder. It’s what about me? I do get calls from people who say, ‘OK, the gene has been found, what does that mean to me?’ I tell them we’re on the road in the right direction.”
Shapiro says it helps to remind patients and their families how far research has progressed. Just four years ago, she says, few people knew what neurofibromatosis was. Now, because of studies that show the NF gene belongs to a family of genes that suppresses tumor formation--a significant aspect of cancer research--interest among researchers has exploded.
“Here was this disorder that no one had really taken a look at,” Shapiro says. “In 1987, the genetic markers were found and in 1990 the gene was announced. So, for people who never had a hope, all of a sudden there was this excitement.”
Patients and their families do find solace in the rapid pace of research.
Motenko, an accountant who lives in Mission Viejo, says he and his wife, Debbie, still cling to every bit of news from labs worldwide.
When their daughter, Stacy, was born with an intestinal problem related to cystic fibrosis, Motenko checked out a library book on the disorder that turned out to be terribly outdated. The book listed the life expectancy of CF patients at three to five years.
Stacy’s doctor reassured the Motenkos that the outlook had improved, emphasizing that life spans can range into the 20s and that doctors are constantly learning more about reducing infections and improving the quality of life.
“The doctors were very compassionate,” Motenko says. “But no one gave us much hope of a cure in my daughter’s lifetime. That wasn’t even talked about.”
With so much recent progress, and their loved ones demand frequent updates on genetic research.
“I have to know what’s happening in research,” says Motenko, who also has a healthy older daughter, Lisa. “It gives me hope. And how can you keep going along without hope?”
Physicians say it is common for families dealing with genetic illness to be highly knowledgeable about the disorder and the prospects for treatment.
“My sense is they do want to hear about what’s going on,” says Michigan’s Collins, who also helped discover the gene for Von Recklinghausen neurofibromatosis. “I think they do want to hear about something that raises hopes.”
Harvard’s Kunkel says he is sometimes bothered that such discoveries receive intense media coverage. He worries that patients’ hopes will be unrealistically inflated.
“There is so much hype in the media that you think that a treatment is the next thing around the corner,” he says. But he acknowledges that the publicity is good for morale and raising funds.
“It’s a good thing to anticipate a treatment or cure.”
Even though the Almadas are involved in research that could help their son as early as next year, they try not to let their hopes soar too high. They concentrate on daily challenges, such as helping Christopher, who can still move about with the aid of a walker, maintain what little muscle strength he has left. He undergoes frequent checkups at Rancho Los Amigos Medical Center, where many muscular dystrophy patients are treated. The hardest part, they say, is when Christopher asks his parents what the future holds for him.
“I tell him they are working on (treatment) and it’s important that we take each day at a time, and that we have to pray,” Cindy says.
“We try to be honest with him,” Albert says.
Sometimes when they walk down halls at Rancho Los Amigos, Christopher sees children with muscular dystrophy who are in wheelchairs or on respirators. He knows how bad it can become, Albert says.
“He says to me, ‘Dad, I sure hope they find a cure.’ ”
