June 29, 1999

At Gene Therapy's Frontier, the Amish Build a Clinic

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By DENISE GRADY

STRASBURG, Pa. -- This was not the typical audience for a medical conference, but then again, this was no typical conference. At an inn set in the lush farmland of Lancaster County, doctors attending scientific lectures earlier this month were joined by young Mennonite and Amish couples, the women in bonnets and the men in suspenders, babies fussing in their laps.

	Sal DiMarco Jr. for The New York Times
	Children with Crigler-Najjar syndrome lack a liver enzyme crucial for removing a toxic substance, bilirubin, from the blood. Special lights that break down bilirubin can help. Six-year-old Chris Platt in a $30,000 mirrored bed.

The Amish and Mennonites may travel by horse and buggy and forgo most modern conveniences, but there is one bit of progress that they are eager to embrace: gene therapy.

If all goes as planned, conference participants learned, three children from these communities will become the first human beings to test a new method of gene therapy. If it works, it will spare them the devastating effects of a rare but deadly inherited disease.

In the condition, Crigler-Najjar syndrome, a substance called bilirubin, a waste product from the destruction of worn-out red blood cells, builds up in the body.

Bilirubin is produced constantly in the human body, and normally, it is broken down by an enzyme in the liver and excreted through the intestines.

But in people with the syndrome, the enzyme is either absent or scarce. Bilirubin accumulates, causing jaundice, a yellowing of the skin and the whites of the eyes. More important, bilirubin is toxic to the nervous system, and the children live in constant danger of brain damage.

The only way they can survive is to spend 10 to 12 hours a day under special lights that break down the bilirubin. But as they reach their teens, the light therapy becomes less effective. Unless they can get a liver transplant, they may suffer brain damage or die.

If gene therapy works, the children will have a chance to lead more normal lives. But previous attempts at gene therapy for other diseases have been disappointing. If the new approach, called chimeraplasty, succeeds against Crigler-Najjar syndrome, it would finally open the door to treatment of a host of other, more common genetic disorders, according to Dr. Michael Blaese, a gene therapy expert who left the National Institutes of Health in January to join a Philadelphia company specializing in the new therapy. The other disorders that might be treated include sickle cell anemia, cystic fibrosis and a failure of the immune system known as ADA deficiency.

	Sal DiMarco Jr. for The New York Times
	Amish and Mennonite families, hearing about a new approach to gene therapy that may hope will help children with an inherited liver disorder.

"I left what I thought was the best job in the world to do this because I believe so strongly in it and believe we'll be successful," Dr. Blaese said. "I think it will really fundamentally change the way we practice medicine."

A MISSION
Doctor Draws Others to Help the Children
Dr. Blaese and other researchers, leaders in genetics and disorders involving bilirubin, were drawn to Lancaster County largely through the efforts of Dr. Holmes Morton, a slight, graying man of 49 who still speaks with the twang of his native West Virginia.

A Harvard-trained pediatrician, Dr. Morton first encountered Amish youngsters with genetic diseases while he was working at a Philadelphia hospital in the 1980's. He had trained in biochemical genetics, and he recognized that some of the children had metabolic disorders, not previously diagnosed, that could be managed with specific diets and careful treatment of minor illnesses. But without proper therapy, the diseases could rapidly cause brain damage. Some parents whose children had died or become handicapped sought his help for younger siblings.

"I knew I could take care of them," Dr. Morton said.

In 1988, he began commuting to Lancaster County, driving from one house call to another. A year later, he and his wife, Caroline, and their three children moved to Strasburg. Dr. Morton was 39, and highly regarded by his colleagues, including some who were dismayed to see him put aside a bright future in science and academia to disappear into a small town and treat children with obscure diseases.

But where others saw a backwater, Dr. Morton saw a need and an opportunity to make a difference, to develop treatments for diseases that were taking a cruel toll on children. In 1990, he opened his non-profit clinic. And rather than disappearing from the research world, he brought it to Lancaster County.

"I think of myself as a pediatrician who knows a little more than average about biochemistry and genetics, and can use that in a primary care setting to prevent problems," he said.

His patients think of him in another way: "He is a gift to us," said Miriam Martin, of Mifflinburg, Pa., whose three young children are all under his care for Crigler-Najjar syndrome.

For generations, the Amish and Mennonites, descendants of Swiss and German Anabaptists who settled in Pennsylvania in the 1700's, have suffered from unusually high rates of dozens of genetic disorders. The diseases occur because the communities arose from a small population of founders, and members -- who are forbidden to marry outside their religion -- marry each other. As a result, many people in the groups today are related, increasing the odds that both members of a couple will unknowingly be carriers of a hereditary disease that does not affect them but will show up in their children.

Scientists have eagerly studied the Amish for decades, making discoveries that filled at least one textbook on genetic disorders. But the experts who gathered their data from Lancaster County did not stay to take care of the diseases they identified.

	Sal DiMarco Jr. for The New York Times
	Children like 14-month-old Melanie Bryant spend 10 to 12 hours a day in light therapy.

Dr. Morton said it seemed only fair that the Amish, who have contributed so much to the understanding of human genetics, should be given the first chance to benefit from a promising new type of gene therapy.

In 1989, the Mortons were getting ready to build a clinic in Strasburg, when The Wall Street Journal reported on their work there, mentioning that they had to take out a second mortgage on their own home to begin construction. . Within a few months a flood of donations made the loan unnecessary and a year later, in traditional barn-raising style, a team of Amish carpenters raised the Clinic for Special Children. A post-and-beam structure built in Amish style, joined with pegs and no nails, it rests on a fieldstone foundation and is sided with cedar clapboards and roofed with 100-year-old recycled slates. Its cupola looks out on woods and the cornfields of the Amish farmer who donated the land. The parking lot includes space for buggies and railings to tether horses.

The Amish and Mennonites do not accept Medicare or Social Security and do not buy health insurance. They prefer to pay bills themselves and help one another as needed. But although many earn good livings as farmers or carpenters, few can afford what most medical centers would charge to treat the complex diseases that afflict their children.

Caroline Morton, also a Harvard graduate, acts as business manager of the clinic. Patients are charged $25 or $30 for most visits, she said, and lab tests cost a fraction of what most hospitals would charge. The clinic runs on $400,000 a year, she said: from patient's fees, donations and a barbecue and auction held the third Saturday of every September, to sell Amish and Mennonite quilts, furniture, crafts and farm implements.

A DIFFICULT ADDRESS
Frustration for Patients
Dr. Morton first encountered Amish children with Crigler-Najjar syndrome in 1991. But he knew that the disease had first been identified during the 1940's by a professor of his at Harvard Medical School.

Dr. John Crigler had remained a friend since Dr. Morton's medical school days. But 50 years ago he was a young pediatrician at Johns Hopkins Hospital in Baltimore, working with Dr. Victor Najjar. Together, they treated several infants from Amish families, all of whom died from a mysterious illness that caused jaundice and severe damage to the nervous system.

Dr. Crigler and Dr. Najjar knew that some of the babies they examined had siblings who had died of the same condition. Studying family records, they found that the different families were actually related, and that the illness followed the pattern of a hereditary disease caused by a recessive gene, meaning that the parents would be healthy carriers, but that each of their children would have a 1 in 4 chance of inheriting the syndrome.

In a paper published in 1952 they wrote: "The prognosis is extremely poor, the patients generally dying in the first year of life. No therapeutic measures have been found helpful." Eventually, researchers recognized that a milder form of the syndrome also existed, and both forms were discovered to occur all over the world although they are rare, with only about 60 cases known. Many of the families are in touch with one another, and parents and children from New Mexico, Florida, Canada, Kentucky, England and Holland also attended the conference here hoping to hear that a cure might be at hand.

Children began living longer in the 1970's, when doctors realized that phototherapy, treatment with bluish light of a certain wavelength, could break down bilirubin. In milder cases the drug phenobarbital also helps, by stimulating the body to produce more of the needed enzyme. Dr. Morton now has 16 patients with the disease, ranging in age from a few months to 15 years.

But the disease is hard to control. Sleeping under the lamps, known as bilirubin lights, can keep bilirubin in check, but just barely. Families live in fear of routine childhood illnesses -- earaches, sore throats, stomach viruses -- because they can make bilirubin surge out of control. When that happens, brain damage can occur in a matter of hours or days.

	Sal DiMarco Jr. for The New York Times
	Seven-year-old Amy Martin, who has the condition, is monitored as she walks on a treadmill.

In 1994, an 8-year-old boy in Indiana who had the syndrome contracted a strep infection and died two days later from extremely high bilirubin.

"It was a message to the families and to me that we had to think harder about how to take care of these children," Dr. Morton said. He has since written a treatment plan that details ways to take care of acute illnesses and lists drugs that must be avoided because they can raise bilirubin.

Even when the families escape crises, the children still suffer from other problems. They are prone to gallstones, and some must have their gallbladders removed when they are only 3 or 4 years old.

Debilitating fatigue strikes some, especially the older children. It can interfere with schooling and make exercise difficult or impossible. Dr. Morton thinks it occurs because bilirubin poisons the energy processing structures, mitochondria, in both nerve and muscle cells. No matter how carefully they are treated, children with the syndrome often look jaundiced. They are sometimes stared at and teased, families say, and some people assume they have a contagious disease and scold the parents for letting them outdoors.

It is no fun having to sleep without pajamas or a blanket under bright lights every night. Children complain of being too hot from the lights or too cold from the lack of covers, and they find it disgusting that during spring and summer the lights attract bugs. Sleep-overs may be impossible and vacations are hard, too, because the lights are difficult to transport.

Four-year-old Dawn Martin, from Mifflinburg, Pa., complains that she hates her bed because of the lights, and often sneaks out of it, said her mother, Miriam, who must get up several times a night to return Dawn to the lights. Some mornings, Mrs. Martin wakes up to find Dawn sound asleep on the living room couch -- perilously yellow. Dawn's younger brother and sister also have the syndrome, and Mrs. Martin and her husband, eager to learn about research, brought all three children to the conference.

"You have all these dreams of having a healthy child," Mrs. Martin said. Now, she dreams of a cure.

NEW HOPE
More Sophisticated Genetic Procedure
As children approach puberty, phototherapy becomes less effective and bilirubin starts rising to dangerous levels. Doctors are not sure why. At that point, liver transplant is considered.

But Dr. Morton tries to keep children well enough to put off transplants for as long as possible. "These are beautiful, healthy, active children," he said. "They're a little bit yellow. You hate to put them through a transplant."

Doctors have tried transplanting partial livers or liver cells into children with the syndrome, to avoid removing their own livers, which are normal except for the missing enzyme. But those procedures have not worked well.

Dr. Morton is hoping that gene therapy works, and is trying to buy time for his patients until it becomes available.

Earlier attempts at gene therapy for other diseases tried to compensate for defective genes by giving patients normal versions of those genes. Scientists would attach the replacement genes to viruses and deliver the viruses to the body intravenously or by a nasal spray , hoping the viruses would invade cells and the genes would insert themselves into their DNA and begin working, causing the cells to function normally.

But the viral approach has not worked well. Dr. Morton called it "messy" and "biologically naïve." There was no way to control where the virus would add the new genes, and no way to make sure that the new genes would work.

He and other researchers see far more promise in the new approach, chimeraplasty. It does not use viruses, and it does not attempt to replace an entire gene. Instead, it is intended to stimulate the patient's own cells to repair just the defect in the gene, using a molecule called a chimeraplast, a manufactured blend of DNA and the related molecule RNA.

Chimeraplasts will be made to match the sequence of base pairs -- the molecular building blocks of DNA -- in part of the gene that directs the body to make the enzyme that normally breaks down hemoglobin. People with Crigler-Najjar syndrome often have a genetic defect known as a point mutation: one base pair that is either incorrect or missing. Different point mutations can cause the disease, but the Amish and Mennonites all have the same mutation, and the first chimeraplasts will be tailored to it. The chimeraplasts will be identical to the patient's own DNA except for the point mutation: instead of the defect, they will have the correct base pair.

The chimeraplasts are expected to attach to the patient's DNA, and activate a system that cells normally use to correct their mistakes in replicating DNA. But in this case the repair system will be tricked into treating the chimeraplast as the correct version of the DNA, and changing the patient's gene to match the chimeraplast -- undoing the mutation.

Even the scientists are not sure precisely how the chimeraplasts bring about genetic changes.

"We know it works," said Dr. Clifford Steer, a researcher at the University of Minnesota who has been studying the technique. "We can spend the rest of our lives trying to figure out how."

Successful experiments in dogs and rats have convinced researchers that it is time to try the technique in people. Dr. Blaese said he and colleagues at Kimeragen, the company that has developed the technology, will ask the Food and Drug Administration for permission to proceed sometime this fall.

They expect to test the therapy in three children, who will be treated at Lancaster General Hospital under Dr. Morton's supervision. A total of more than a trillion chimeraplasts -- enough to outnumber cells in the liver -- will be dripped in as an intravenous solution, on six separate days over the course of a month. With each treatment, the dose will be increased. The chimeraplasts will be encased in microscopic envelopes called liposomes, which will be studded with molecules that will make them attach to liver cells, where the missing enzyme should be produced.

One reason the researchers chose Crigler-Najjar syndrome as a test case for the treatment is that if it works, the results will be easy to detect: the children should become less jaundiced, and their bilirubin levels, measured by a simple blood test, should fall.

Scientists do not expect bilirubin to drop to normal, which would be zero. But they hope it will drop enough to let the children live without lights or at least with less time under the lights, and enough to free them and their parents from the constant worry about brain damage and death.

Parents who listened to scientists' descriptions of the technology said that even a partial success would be worthwhile, and they were eager to see the research go ahead. They even burst into applause during an especially enthusiastic lecture by Dr. Steer, who said he hoped to "ultimately make this community famous."

Dr. Crigler said he hoped he would see the syndrome he identified come full circle in his lifetime. It has already gone from uniformly fatal to treatable, and Dr. Crigler said he thought chimeraplasty might cure it.

"This is the first time I've had a lot of enthusiasm about any form of gene manipulation," he said.

Dr. Morton invites families to conferences to inform them about advances that may help their children. But he also invites them to remind scientists, including some who have never met a patient with the disease, that time is short and these children's hopes lie with their research.

"The families and children are here to remind us of what this is all about," Dr. Morton said. "I think people will step a little faster to get things done, having been at a meeting like this."

For Dr. Blaese, the families' daily struggle became vivid one evening at the confernce, when he strolled outside the inn. A purplish-blue light in a window caught his eye. And then another. And another and another and another. They were bilirubin lights, he realized, and a sick child was sleeping under each of them. Suddenly he knew how important his work was to those families.

"I saw five rooms with that eerie blue glow, and it really hit me," he said. "I'll never forget it."