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<text id=93TT1860> <title> June 07, 1993: The First Kids with New Genes </title> <history> TIME--The Weekly Newsmagazine--1993 Jun. 07, 1993 The Incredible Shrinking President </history> <article> <source>Time Magazine</source> <hdr> MEDICINE, Page 50 The First Kids with New Genes </hdr> <body> The inside story of two young pioneers whose courage helped launch a medical revolution By LARRY THOMPSON/BETHESDA Larry Thompson is a correspondent for Medical News Network and author of Correcting the Code, a book about gene therapy to be published by Simon & Schuster early next year. Today, Ashanthi DeSilva and Cynthia Cutshall seem like any other cheery schoolkids. Cynthia, 11, a cherubic child from Canton, Ohio, with light brown hair and a golden disposition, loves playing baseball. Ashanthi, 6, a shy, round-faced girl from suburban Cleveland, likes drawing. Their easy smiles and childish energy give no hint of the pain they have suffered--or the prominent place they now occupy in the history of medicine. Ashanthi and Cynthia became medical pioneers because they were afflicted with severe combined immunodeficiency (SCID)--the result of being born with a broken gene that devastated their immune systems and left them vulnerable to every passing germ. From an early age, they came down with one infection after another, from runny noses to life-threatening brushes with pneumonia. Twenty years ago, doctors might have put them in a plastic bubble to keep the germs away. Such a sterile shelter protected David, the famous "boy in the bubble," whose struggle with SCID drew national sympathy in the 1970s and inspired a poignant lyric in a Paul Simon song. Since David's death, the treatments for some forms of SCID have improved. Bone-marrow transplants and new drugs keep kids out of the bubble. But because there was no way to correct the defective gene or cure the disease, Cynthia's and Ashanthi's lives became an endless series of trips to the hospital, accompanied by the fear that their treatments would someday fail. At one point Cynthia asked her mother, "Mommy, am I going to die?" She and Ashanthi might indeed have died if they had not taken part in a remarkable experiment begun in 1990 by Drs. W. French Anderson, Michael Blaese and Kenneth Culver at the National Institutes of Health (NIH). The girls were the first patients ever to receive human-gene therapy, the burgeoning new field that could revolutionize medicine. Using their skill in snipping and splicing DNA, the scientists were able to replace defective genes in the girls' white blood cells with normal genes. Dozens of similar experiments are now in progress, including efforts to treat everything from cancer to AIDS. Earlier this month the public got its first glimpse of gene-therapy patients: two California newborns treated for SCID. But it was Ashanthi and Cynthia who opened the way for this new branch of medicine. When their treatments began, their identities were not made public. Now, more than two years later, their parents and doctors have decided to tell their tale. They will become "research ambassadors" for the March of Dimes, making appearances to tell about their experience and to educate the public on the potential benefits of gene therapy. What follows is their story, based on extensive interviews over the past year with the families and physicians. It is a chronicle of hardship, hope and courage, an inside look at what is likely to go down as one of the most important medical breakthroughs of the 20th century. BORN UNLUCKY Ashanthi's troubles began shortly after she came into the world on Sept. 2, 1986, when the stump from her umbilical cord became infected. Although that was unusual, no one paid much attention; her parents already had their hands full. A few months before, a viral encephalitis had struck the brain of older sister Anoushka, destroying her ability to walk and talk normally. Soon after Ashanthi's arrival, her father Benedict Raj DeSilva moved his family from Sri Lanka to North Olmsted, Ohio, where he worked as a chemical engineer for B.F. Goodrich. Worse times were ahead. "When Ashanthi was less than a year old, the deterioration started," her father recalls. "She would get a cold and have a difficult time throwing it off. Breathing was hard." Her nose ran continuously. It took powerful antibiotics to prevent pneumonia. Finally she began to vomit and started losing weight. Once a happy, quiet infant, Ashanthi cried all the time. The DeSilvas embarked on an odyssey familiar to parents of a sick child with a rare disease. Doctor after doctor failed to find an explanation. Their guesses included asthma, bronchitis and allergies. The DeSilvas scrubbed their house spotless, bought special sheets and pillowcases made from natural fibers, purchased a device to clear Ashanthi's lungs, and kept her on a steady diet of antibiotics and asthma drugs. Nothing helped. Meanwhile, a third daughter, Dilani, was born in November 1987. Before her birth, doctors detected a chromosome abnormality, but they assured the DeSilvas that it would cause no harm. The doctors were wrong. When she was a few months old, Dilani suffered a strange attack that severely damaged her brain, leaving her mentally retarded. The accumulation of tragedies threatened to overwhelm the family. Then their luck changed. A pediatric allergist detected that Ashanthi had low levels of antibodies, the specialized proteins made by white blood cells to help fight infections. The doctor sent the DeSilvas to Rainbow Babies and Children's Hospital in Cleveland to see immunology expert Dr. Ricardo Sorensen. Though Ashanthi's form of hereditary SCID is incredibly rare--only 30 or so people worldwide now live with it--Sorensen had seen such patients before. In fact, he was taking care of one when the DeSilvas arrived. That patient was Cynthia Cutshall. Although she seemed healthy at birth, in preschool she started suffering chronic sinus infections that often led to pneumonia. When she was four, the bacteria from a sinus infection attacked her left hip, threatening to destroy the joint and her ability to walk. Surgeons worked quickly to cut away the infected tissue and save the hip, but she remained bedridden for a month while it healed. Two weeks after going off intravenous antibiotics, Cynthia came down with another sinus infection. Her parents, Susan and William, a respiratory therapist, demanded that something be done and were sent to Sorensen at Rainbow Babies. The medical examination showed that Cynthia was unusual. She lacked tonsils, adenoids and a thymus gland, a critical part of the immune system normally located in the center of the chest. Laboratory tests found the problem: Cynthia had inherited a genetic mutation that kept her body from making an enzyme called adenosine deaminase, or ADA. Without ADA the white blood cells of her immune system died aborning in the bone marrow, leaving her defenseless against infection. Even as Sorensen diagnosed Cynthia, researchers at Enzon Inc., a tiny biotech company in New Jersey, were developing a treatment. They had found a way to alter chemically the ADA from cows so that it could be used as a drug for humans. Duke University Medical Center doctors had just started testing the drug, called Adagen. Cynthia became the fourth child to receive it. Her immune system responded slowly, and in a few months her chronic infections stopped. She even survived chicken pox, a potentially lethal infection. "We were giving her less than one cubic centimeter of this stuff once a week, and it changed everything," Sorensen says. "That was really awesome." So when Ashanthi DeSilva came to Rainbow Babies in September 1988, Sorensen already had a pretty good idea of what SCID caused by ADA deficiency looked like. Ashanthi fit the picture. In November that year she became the ninth child to receive Adagen. Although the high-tech drug clearly saved both children, it did not cure them, and there were complications. Ashanthi, for example, had a bad reaction that temporarily destroyed her blood's ability to clot normally. Simply pressing on her skin caused bruises; internal bleeding was a serious threat. Intensive treatment helped her recover, but the episode scared her parents. Adagen "is a young drug," said Raj DeSilva. "There is no history to go by. It works now, but what about the future?" Some children receiving Adagen remained healthy; a few slowly got worse. Two died early on, including an extremely sick child who succumbed in the first week of treatment. The second child, disturbingly, developed a condition in which her awakening immune system attacked and destroyed her own red blood cells. The reaction could not be controlled, and she died after a few months. Perhaps the saddest of all was the September 1992 death of Tara Dew, a bright, 15-year-old SCID victim from Bellevue, Nebraska, who was the second child to receive Adagen. For four years, the drug boosted her immunity, but eventually her health deteriorated, in part because repeated infections had virtually destroyed her lungs before Adagen treatment began, says Dr. Michael Hershfield, the Duke scientist who helped develop the drug. Adagen was, at best, a problematic treatment, not a cure. What was needed was some way to take on the root cause of this particular form of SCID: the defective gene that causes it. BLAZING THE TRAIL The dream of gene therapy for SCID crystallized in 1983 when W. French Anderson, a visionary at NIH, concluded that ADA deficiency was the best disease for testing a genetic treatment. His team worked to take the gene-transfer techniques developed by basic researchers and turn them into a medical therapy. Specifically, Anderson had success in using viral particles called retroviruses as carriers to cart genes from one cell to another. In 1988 and 1989, Cleveland doctors sent blood samples from Ashanthi and Cynthia to Anderson's collaborators at NIH, Michael Blaese and Kenneth Culver. With Anderson's gene-transfer method, Culver showed that the normal ADA gene could be inserted into the girls' defective blood cells. Once in place, the new gene produced the missing ADA, making the cells normal. It worked in the lab; the NIH scientists hoped it would work in children. In early 1990 the doctors began the arduous process of winning permission to try gene therapy in humans. They proposed removing only white blood cells from the children's bodies and inserting the normal gene into them. Next the cells would be grown in the laboratory until they numbered in the billions. Finally the doctors would put the cured cells back in the children. Theoretically, the repaired cells would function normally. The proposal proved controversial. Some scientists correctly pointed out that the treatment would not cure the children. The white blood cells live only a few months, and so the patients would have to come back for repeated treatments. It would be better to wait, opponents said, until scientists could identify stem cells, the long-lived mother cells of the bone marrow that give birth to all other blood cells. Genetically curing stem cells would forever cure all blood cells in the children. In the background were the complaints of genetic-engineering critics, led by lawyer Jeremy Rifkin, the well-known scientific gadfly. In Rifkin's view, scientists were getting into the business of playing God, and any tampering with genes, no matter how well intentioned, set a dangerous precedent. While the experts argued, the families agonized. "I was hoping and praying Ashanthi would get the gene treatment," recalls her mother Emma Van Cuylenberg DeSilva. "I knew that it would cure her, that it would be better than the Adagen. That it would be a permanent cure. That is what I thought. It is a cure for my Ashanthi." Susan Cutshall remembers her feelings more succinctly: "Hurry up!" The technical and political arguments raged through the spring and summer of 1990. Finally the NIH doctors prevailed, convincing various review boards that the experiment was reasonable and that the time to start had arrived. HISTORY IN THE MAKING On Sept. 14, 1990, Culver arrived at Ashanthi's bedside in the intensive-care unit of the NIH hospital in Bethesda, Maryland. He was carrying a small plastic bag containing the first genetically engineered cells intended to treat a human disease. As Ashanthi watched tearlessly, Culver connected the bag to the intra venous tubing snaking up from the needle in her left hand. In a moment he would infuse the cells into Ashanthi's body. Human-gene therapy, a much ballyhooed but often delayed technology, was about to become a reality. A simple procedure, a mere injection really, would symbolically alter forever the way doctors looked at patients, their diseases and human genes. Behind that shot lay a 20-year quest to turn the genetic-engineering triumphs of the early 1970s into a treatment that cures patients from the inside out. Culver plunged a syringe into the IV tubing's plug. The NIH team started with a test dose, 50 million of the girl's own cells now engineered to carry the substitute gene. In an eye blink, the syringe emptied, and the room tensed. "Geez, he did that fast," thought Blaese, a pediatric immunologist and Culver's boss. Blaese always preferred a measured pace. Doctors, nurses and parents all watched for a reaction. Ashanthi sat serenely on the government-white sheet, shifting her absent stare between the roomful of people and Sesame Street on the tiny TV above her bed. To her this was not medical history but just another of the ceaseless clinical procedures that filled her young life. The rest of her engineered cells, a billion in all, were ready to follow. Culver opened the stopcock, allowing the cells to pour headlong toward Ashanthi's body. Anderson, a longtime and often controversial proponent of gene therapy, intervened, ordering the ICU nurse to slow the cells. Culver looked up, protest written on his face. Let's get on with it, the younger man urged. But Anderson argued caution. The sudden flood of gene-altered cells might cause some unexpected reaction. He didn't want this first patient to die. As the history books will record, Ashanthi DeSilva didn't die. In fact, she thrived. Soon the NIH group was ready to give the same treatment to Cynthia, then 9. On Jan. 30, 1991, she became the second person ever to receive human-gene therapy. Anderson felt an enormous sense of accomplishment. "More than anything else, the first treatment was a social and a cultural victory," he recalls. "It launched the field of human-gene therapy." Although the children continued to receive Adagen injections, laboratory tests showed convincingly that the children's immune systems improved because of the gene treatments. The NIH doctors will not discuss specific lab findings until they can publish a scientific paper, but at various public meetings they have described the children's progress. For example, their strengthened immune reactions enabled them to be vaccinated against common childhood diseases such as whooping cough. In addition, both children grew healthy tonsils. The DeSilvas used to confine Ashanthi to home, never taking her out in public, even to the mall. After beginning the ADA treatments, she was able to go to public school and swim with the other children. For Cynthia, the painful sinus infections she once suffered disappeared. Still, both families wanted more. They wanted an end to the uncertainty and to the frequent, life-disrupting trips to Bethesda for repeated gene treatments. They wanted a cure. "You feel like you are on a merry-go-round," said Susan Cutshall. The treatments meant many days away from work and school for parent and child. Cynthia, now in sixth grade, would refuse to tell her school chums where she was going, fearing they would tease her as abnormal. She often cried inconsolably at the hospital, especially during portions of a three-hour process in which a device sucked out her white blood cells. Putting the gene-corrected cells into her body sometimes caused fever and nausea two weeks later. Although Ashanthi did not suffer these side effects, the normally stoic child would squirm with displeasure on the white hospital-bed sheets during the hours-long procedure. Ashanthi was too young and shy to talk about the radical treatment she received. Even the older Cynthia had little to say: "I don't like to talk about it. It is too weird." When she walked through the doors of NIH's 500-bed hospital, Cynthia often said, "I hate this place, Mommy." THE QUEST FOR A PERMANENT CURE All the while, the girls' doctors were searching for a way to set them free from the hospital and the treatments. Anderson, Blaese and Culver joined forces with another NIH group led by Arthur Nienhuis and Cynthia Dunbar, both blood experts. Using a newly developed technology, Nienhuis and Dunbar found a way of isolating the bone marrow's stem cells. If the NIH doctors could gather and genetically correct enough stem cells, these could continuously produce enough new white blood cells to cure the girls permanently. This spring the scientists were ready to try the procedure. Thus it was that Cynthia went to NIH in early May to become one of the first human beings whose genetic makeup could be permanently altered by human hand. (A similar experiment had been tried a few weeks earlier on an anonymous child in Italy, and it would also be used a week or so later on the two babies in California.) For the first five days, Cynthia was given a drug that flushed the all-important stem cells out of her bone marrow and into her bloodstream. Then a plastic tube was inserted into a large vein in her chest. The doctors drew out blood, isolated the stem cells and exposed them to retroviruses containing the normal ADA gene. The doctors could not tell how many stem cells took up the new gene, and they will have to wait and see if the cells migrate back to the bone marrow as they are supposed to. Without knowing what the results will be, the researchers were pleased that Cynthia came through the procedure with no unexpected side effects. "She was fine," said Blaese. "She tolerated it rather well." For her part, Cynthia was just relieved that the operation was over. If the experiment continues to go well with Cynthia, Ashanthi will receive the treatment sometime this summer. And if it works? Then the children will be completely normal for the first time in their brief lives. It will mean no more trips to NIH; this therapy will become a one-time treatment, a genetic cure. It will mean the kinds of diseases that locked David inside his bubble can be banished. Eventually, thousands of people suffering other strange and exotic disorders caused by minute genetic mutations--such as congenital diabetes, cystic fibrosis, Duchenne muscular dystrophy and hemophilia--will have a chance at normal lives. Ultimately, more common ills that are partly hereditary--including heart disease and cancer--will come under genetic attack. All because some scientists dreamed of genetic cures, and some gutsy families from Ohio--with two courageous little girls--dared to believe in those dreams. </body> </article> </text>