KßwthilEl|iGEI[The inside story of twoyoung pioneers whosecourage helped launch amedical revolution

By LARRYTHOMPSON BETIüSDA

ODAY, ASHANTHI DESILVA AND

Cynthia Cutshall seem like anYother cheery schoolkids. CYn-thia, 11, a cherubic child fromCanton, Ohio, with light brown

hair and a golden disposition, loves play-ing baseball. Ashanthi, 6, a shy, round-faced girl from suburban Cleveland,likesdrawing. Their easy smiles and childishenergy give no hint of the pain they havesuffered-or the prominent place they

now occupy in the history of medicine'Ashanthi and Cynthia became medi-

cal pioneers because they were afflictedwith severe combined immunodeficiency(scro)-the result of being born with a

broken gene that devastated their im-

mune systems and left them vulnerable toevery passing germ. From an early age,they came down with one infection afteranother, from runny noses to life-threat-ening brushes with pneumonia. Twentyyears ago, doctors might have put them ina plastic bubble to keep the germs away.

Such a sterile shelter protected Davithe famous

"boy in the bubble," wholstruggle with scto drew sympathy froall over the U.S. in the 1970s and inspirta poignant lyric in a Paul Simon song.

Since David's death, the treatments fi

some forms of sclo have improved. Bonmarrow transplants and new drugs ker

Larrg Thompson is a correspondent for Metcal News Network and author o/Correcting t

Code, a book about gene therapg to be publish

bg Simon & Schtnter early next year-

50 TIME. JUNE 7. 1993

kids out of the bubble. But because therewas no way to correct the defective gene orcure the disease, Cynthia's and Ashanthi'slives became an endless series of trips tothe hospital, accompanied by the fear thattheir treatments would someday fail. Atone point Cynthia asked her mother,"Mommy, am I going to die?"

She and Ashanthi might indeed havedied if they had not taken part in a re-markable experiment begun in 1990 byDrs. W. French Anderson, Michael Blaeseand Kenneth Culver at the U.S. National

NOWTHEYCAN SMILE: Once sick all thetime, Gynthia, left, and Ashanthi got wellthanks to a historic experiment

Institutes of Health (NIu). The girls werethe first patients ever to receive human-gene therapy, the burgeoning rrew fieldthat could revolutionize medicine. Usingtheir skill in snipping and splicing DNA,the scientists were able to replace defec-tive genes in the girls' white blood cellswith normal genes. Dozens of similar ex-periments are now in progress, includingefforts to treat everything from cancer toAIDS.

Earlier this month the American publicgot its first glimpse of gene-therapy pa-tients: two California newborns treated forscID. But it was Ashanthi and Cynthia whoopened the way for this new branch ofmedicine. When their treatments began,their identities were not made public. Now,more than two years later, their parentsand doctors have decided to tell their ta]e.They will become "research ambassadors"for the lVlarch of Dimes hea]th agency, mak-ing appearances to educate the public onthe potential benefits of gene therapy.What follows is their story, based on exten-sive interviews over the past year with thefamilies and physicians.It is a chronicle ofhardship, hope and courage, an inside lookat what is likely to go down as one of themost important medical breakthroughs ofthe 20th century.

BonN UnlucrvT SHANTHI 'S TROUBLES BEGAN

A shortly after she came into the

/ I world on Sept. 2, 1986, when/-l the stump from her umbilical

J- I- cord became infected. Althoughthat was unusual, no one paid much atten-tion; her parents already had their handsfull. A few months before, a viral encepha-litis had struck the brain of older sisterAnoushka, destroying her ability to walkand talk normally. Soon after Ashanthi'sarrival, her father Benedict Raj DeSilvamoved his family from Sri Lanka to NorthOlmsted, Ohio, where he worked as achemical engineer for B.F. Goodrich.

Worse times were ahead. "When

Ashanthi was less than a year old, the de-terioration started," her father recalls."She would get a cold and have a dfficulttime throwingit off. Breathingwas hard."Her nose ran continuously. It took power-ful antibiotics to prevent pneumonia. Fi-nally she began to vomit and started los-ing weight. Once a happy, quiet infant,Ashanthi cried all the time.

The DeSilvas embarked on an odysseyfamiliar to parents of a sick child with arare disease. Doctor after doctor failed tofind an explanation. Their guesses includ-ed asthma, bronchitis and allergies. TheDeSilvas scrubbed their house spotless,bought special sheets and pillowcasesmade from natural fibers, purchased a de-vice to clear Ashanthi's lungs, and kept

her on a steady diet of antibiotics and asth-ma drugs. Nothing helped.

Meanwhile, a third daughter, Dilani,was born in November 1987. Before herbirth, doctors detected a chromosome ab-normality, but they assured the DeSilvasthat it would cause no harm. The doctorswere wrong. When she was a few monthsold, Dilani suffered a strange attack that se'verely damaged her brain, leaving her men-tally retarded. The accumulation of trage'dies threatened to overn'helm the family.

Then their luck changed. A pediatricallergist detected that Ashanthi had lowlevels of antibodies, the specialized pro-teins made by white blood cells to helpfight infections. The doctor sent the DeSiI-vas to Rainbow Babies and Children's Hos-pital in Cleveland to see immunology:expert Dr. Ricardo Sorensen. ThoughAshanthi's form of hereditary scID is in-credibly rare-only 30 or so people world-wide now live with it-Sorensen had seensuch patients before. In fact, he was takingcare of onewhen theDeSilvas arrived.

That patient was Cynthia Cutshall. Al-though she seemed healthy at birth, inpreschool she started suffering chronic si-nus infections that often led to pneumo-nia. When she was four, the bacteria froma sinus infection attacked her left hip,threatening to destroy the joint and herabilify to walk. Surgeons worked quicklyto cut away the infected tissue and savethe hip, but she remained bedridden for amonthwhile it healed.

Two weeks after going offintravenousantibiotics, Cynthia came down with an-other sinus infection. Her parents, Susanand William, a respiratory therapist, de-manded that something be done and weresent to Sorensen at Rainbow Babies. Themedical examination showed that Cynthiawas unusual. She lacked tonsils, adenoidsand a thymus gland, a critical part of theimmune system normally located in thecenter ofthe chest. Laboratory tests foundthe problem: Cynthia had inherited a ge-netic mutation that kept her body frommaking an enZyrne called adenosine de-aminase, or ADA. Without ene the whiteblood cells of her immune system diedaborning in the bone marrow, leaving herdefenseless against infection.

Even as Sorensen diagnosed Clnthia, re'searchers at Enzon Inc., a tinybiotech com-pany in NewJersey, were developing a treat-ment. They had found a way to alterchemically the ann from cows so that itcould be used as a drug for humans. DukeUniversity Medical Center doctors had juststarted testing the drug called Adagen. qyn-thia became the fourth child to receive it. Herimmune qystem responded slowly, and in afew months her chronic infections stopped.She even survived chicken pox, apotentiallylethal infection. "We were giving her lessthan one cubic centimeter of this stuffonce aweek, and it changed everything" Sorensensays. "That was really awesome."

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TIME, JUNE 7, 1993 51

A TASTING CURE?

1. with DNA-soticine Itechni.oues, a gene capal

maKrng uynmra s mrssrng Geneenzyme was inserted into avirus.

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So when Ashanthi DeSiIva came toRainbow Babies in September 1988, Sor-ensen already had a pretty good idea ofwhat scID caused by ADA deficiencylooked like. Ashanthi fitthe picture. In No-vember that year she became the ninthchild to receive Adagen.

Although the hightech drug clearlysaved both children, it did not cure them,and there were complications. Ashanthi, "for example, had a bad reaction that tempo-rarily destroyed her blood's ability to clotnormally. Simply pressing on her skincaused bruises; internal bleeding was a se-rious threat. Intensive treatment helpedher recover, but the episode scared herparents. Adagen "is a young drug," saidRaj DeSilva. "There is no history to go by.

THEY HAVE THE POIYER : Culver, Andersonand Blaese were the first to usegenetically altered cells to treat a disease

It works now, but what about the future?"Some children receiving Adagen re-

mained healthy; a few slowly got worse.T\vo died early on, including an extremelysick child who succumbed in the first weekof treatment. The second child, disturbing-ly, developed a condition in which herawakening immune system attacked anddestroyed her own red blood cells. The reac-tion could not be controlled, and she died af-ter a fewmonths. Perhaps the saddest of allwas the September 1992 death of Tara Dew,abright, l5-year-old scmvictim from Belle-vue, Nebraska, who was the second child toreceive Adagen. For four years, the drugboosted her imnunity, but eventually herhealth deteriorated, in part because repeat-ed infections had virtually destroyed herlungs before Adagen treatment began, saysDr. Michael Hershfield, the Duke scientistwho helped develop the drug.

Adagen was, at best, a problematictreatment, not a cure. What was neededwas some way to take on the root cause ofthis particular form of sclo: the defectivegene that causes it.

BmzrNc rHE TRArr'TI HE DREAM OF GENE THERAPY FOR

I I I scto crystallized in 1983 when

I W. FrenchAnderson, avisionary

I at NIH, concluded that ane defi-I ciencv was the best disease for

testing a genetic treatment. His teamworked to take the gene-transfer tech-

52

niques developed bybasic researchers andturn them into a medical therapy. Specifi-cally, Anderson had success in usingviralparticles called retroviruses as carriers tocart genes from one cell to another.

In 19BB and 1989, Cleveland doctorssent blood samples from Ashanthi andCynthia to Anderson's collaborators at NIH,Michael Blaese and Kenneth Culver. WithAnderson's gene-transfer method, Culvershowed that the normal ADA gene couldbe inserted into the girls' defective bloodcells. Once in place, the new gene pro-duced the missing ADA, making the cellsnormal. It worked in the lab: the mu sci-

The rnew procedure rper,formed,onG)rrthia Gutshall May 4-15

gadfly.In Rifkin's view, scientists were get-ting into the business of playing God, andany tampering with genes, no matter howwell intentioned, set a dangerous precedent.

While the experts argued, the familiesagonized. "I was hoping and praymgAshanthiwould get the gene treatment," re-calls her mother Emma Van Cuylenberg De'Silva. "I knew that it would cure her, that itwould be better than the Adagen. That itwould be a permanent cure. That is what Ithought. It is a cure for myAshanthi."

Susan Cutshall remembers her feel-ings more succinctly: "Hurryup!"

The technical and political arguments

4. The altered stem cells were ' l

inibctgd into Oynthia with the hope'that they would permanently bolsterher immune system.

IIME Graphic by.loe Lertola

entists hoped it would work in children.In early 1990 the doctors began the ar-

duous process of winning permission totry gene therapy in humans. They pro-posed removing only white blood cellsfrom the children's bodies and insertingthe normal gene into them. Next the cellswould be grown in the laboratory untilthey numbered in the billions. Finally thedoctors would put the cured cells back inthe children. Theoretically, the repairedcells would function normally.

The proposal proved controversial.Some scientists correctly pointed out thatthe treatment would not cure the children.The white blood cells live only a fewmonths, and so the patients would have tocome back for repeated treatments. Itwould be better to wait, opponents said,until scientists could identify stem cells,the long-lived mother cells of the bonemarrow that give birth to all other bloodcells. Genetically curing stem cells wouldforever cure a]l blood cells in the children.

In the background were the complaintsof genetic-en$neering critics, led by lawyerJeremy Rifkin, the well-knolvn scientific

raged through the spring and summer of1990. Finally the Nrn doctors prevailed,convincing various review boards that theexperiment was reasonable and that thetime to start had arrived.

Hrsronv rN THE MaxrucN SEPT. 14, ].990, CULVER AR-rived at Ashanthi's bedside inthe intensive-care unit of the tvluhospital in Bethesda, Maryland.He was carrying a small plastic

bag containing the first genetically engr-neered cells intended to treat a humandisease. As Ashanthi watched tearlessly,Culver connected the bag to the intra-venous tubing snaking up from the needlein her left hand. In a moment he wouldinfuse the cells into Ashanthi's body.Human-gene therapy, a much ballyhooedbut often delayed technology, was about tobecome a reality. A simple procedure, amere injection really, would symbolicallyalter forever the way doctors lookedat patients, their diseases and humangenes. Behind that shot lay a Z0-yearquest to turn the genetic-engineering tri-

TIME, JUNE 7, 1993

umphs of the early 1970s into a treatmentthat cures patients from the inside out.

Culver plunged a syringe into the tVtubing's plug. The Nrn teamitarted with atest dose, 50 million of the girl's own cellsnow engineered to carry the substitutegene.Jn an eye blink, the syringe emptied,and the room tensed. .',Geez, [e aiA tnatfast," thought Blaese, a pediatric immu_nologist and Culver's bosi. Blaese alwavspreferred a measured pace.

Doctors, nurses and parents al lwatched for a reaction. Ashanthi sat se_.glgly on the government-white sheet,shifting her absent stare between theroomful of people and SesameStreet on the tiny TV aboveher bed. To her this was notmedical history but just an-other of the ceaseless clinicalprocedures that f i l led heryounglife.

The rest ofher engineeredcells, a billion in all, wereready to follow. Culvero_pened the stopcock, allowingthe cells to pour headlong to--ward Ashanthi's body. Ander-son, a longtime and often con-troversial proponent of genetherapy, intervened, orderingthe Icu nurse to slow the cells.Culver looked up, protestwritten on his face. Let,s geton with it, the younger manurged. But Anderson arguedcaution. The sudden flood ofgene-altered cells mightcause some unexpected reac_tion. He didn't want this firstpatient to die.

As the history books willrecord, Ashanthi DeSilvadidn't die. In fact, she thrived. Soon theNIH group was ready to give the sametllatment to Cynthia, then g. On Jan. 80,1991, she became the second person everto receive human-gene therapy.

Anderson felt an enormous sense of ac_complishment. "More than anything else,the first treatment was a social and a cul_tural victory," he recalls. ..It launched thefield of human-gene therapy.,,

Although the children continued to re_ceive Adagen injections, laboratory testsshowed convincingly that the chiidren'simmune systems improved because of thegene treatments. The uur doctors will notdiqcuss specific lab findings until they canpublish a scientific paper, but at variouspublic meetings they have described thechildren's progress. For example, theirstrengthened immune reactioni enabledthem to be vaccinated against commonchildhood diseases such as whooping9ough. In addition, both children grewhealthy tonsils.

The DeSilvas used to confine Ashanthito home, never taking her out in public,even to the mall. After beginning the ,qoa

treatments, she was able to go to publicschool and swim with the othär chiidren.For Cynthia, the painful sinus infectionsshe once suffered disappeared.

Still, both families wanted more. Thevwanted an end to the uncertaintyand to thäfrequent, lifedisrupting trips tä Bethesdafor repeated gene treatmenti. Theywanteda cure. "You feel like you are on ä -"rrv-go-round," said Susan Cutshall. The treai_ments meant many days away from workand school for parent and ctrla. Cynthia.nowin sixth grade, would refuse to iell herschool chums where she was going fearingthey would tease her as abnormal. She of_

ten cried inconsolably at the hospital, espe.cially duling portions of a three-hour pro_cess in which a device sucked out her whiteblood cells. Putting the generorrected cellsinto her body sometimös caused fever andnausea two weeks later.

Although Ashanthi did not sufferthese side effects, the normally stoic childwould squirm with displeasure on thewhite_hospital-bed sheets during thehours{ong procedure. Ashanthi was tooyoung and shy to talk about the radicaltreatment she received. Even the olderCynthia had little to say: ,,I don't like totalk about it. It is too weird.', When shewalked through the doors of r.rrH's 500_bed hospital qrnthia often said, .,I hatethis place, Mommy."

THn Qunsr FoR a PnnuaNENT CuRE

both blood experts. Using a newly devel_oped technology, Nienhuis and

-Dunbar

found a way of isolating the bone mar-row's stem cells. If the xrH doctors couldgather and genetically correct enoughstem cells, these could continuouslv pro_duce enough new white blood ceiti tocure the girls permanenily.

Thll spring the scientists were readyto try the procedure.

Thus it was that Cynthia went to mHin early May to become one of the firsth"T?T beings whose genetic makeupcould be permanently altered by humanhand. (A similar experiment had been

, tried a few weeks earlier on! an anonymous child in Italy,

and it would also be used aweek or so later on the twobabies in California.) For thefirst five days, Cynthia wasgiven a drug that flushed theall-important stem cells outof her bone marrow and intoher b loods t ream. Then aplastic tube rü/as insertedinto a large vein in her chest.The doctors drew out blood,isolated the stem cells andexposed them to retrovir-uses containing the normalADAgene.

The doctors could not tellhow many stem cells took upthe new gene, and they wilhave to wait and see if thecells migrate back to thebone marrow as they aresupposed to. Without know-ing what the results willbe, the researchers werepleased that Cynthia camethrough the procedure with

joined forces with another rqrs group ledby Arthur Nienhuis and CynthiiDunbar,

LL THE WHILE, THE GIRLS'doctors were searching for away to set them free from thehospital and the treatments.Anderson, Blaese and Culver

no unexpected side effects. ,.She wasfine," said Blaese. "She tolerated it rath_er well." For her part, Cynthia was justrelieved that the operation was ovei. Ifthe experiment continues to go well withCynthia, Ashanthi will receive the treat_ment sometime this summer.

And if it works? Then the chitdren willbe completely normal for the first time intheir brief lives. It will mean no more tripsto Nru; this therapy will become a one_time treatment, a genetic cure. It willmean the kinds of diseases that locked Da_vid inside his bubble can be banished.Ev_entually, thousands of people sufferingother strange and exotic dlsoiders causedby minute genetic mutations-such ascongenital diabetes, cystic fibrosis, Du_chenne muscular dystrophy and hemo_philia-will have a chance af normal lives.Ultimately, more common ills that arepa{ly hereditary-including heart diseaseand cancer-will come undlr genetic at_tack. All because some scientists dreamedof genetic cures, and soine gutsy familiesfrom Ohio-with two couiageäos htilegirls-dared to believe in those dreams. I

BACK To KtD sruFF: The girrs used to be homebound, but now theycan go to school, take a swim or swing a bat

TIME, JUNE 7. 1993 53