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The Made-to-Order Savior

By LISA BELKIN
Published: July 1, 2001

Henry Strongin Goldberg was the first to arrive in Minneapolis. His parents decorated his room on the fourth floor of the Fairview-University Medical Center with his inflatable Batman chair, two Michael Jordan posters, a Fisher-Price basketball hoop and a punching bag hanging from the curtain rod over the bed. They took turns sleeping (or not) in his room for more than a month. It was too risky for his little brother to visit, but there was a playground across the courtyard, and if Henry, who was 4, stood at the window and Jack, who was 3, climbed to the top of the slide, the boys could wave to each other.

Henry had lost his hair by the time 6-year-old Molly Nash moved in down the hall on the bone-marrow transplant unit. Soon she, too, was bald. The two children had always looked alike, just as all children with this type of Fanconi anemia look alike, with their small faces and small eyes and bodies that are tiny for their age. The "Fanconi face" is one more reminder of the claim of the disease. Over time, Fanconi children also come to sound alike, with a deep, mechanical note in their voices, the result of the androgens they take to keep the illness at bay. Once their scalps were bare, Henry and Molly looked nearly identical. But there was one invisible difference between them -- a difference that could mean everything.

These two families, the Strongin-Goldbergs and the Nashes, had raced time, death, threats of government intervention and (although they cringe to admit it) each other, to make medical history. The best chance to save a Fanconi child is a bone-marrow transplant from a perfectly matched sibling donor. Many Fanconi parents have conceived second children to save their first, hoping that luck would bring them a match. These two couples became the first in the world not to count on luck. Using in-vitro fertilization, then using even newer technology to pick and choose from the resulting embryos, they each spent years trying to have a baby whose marrow was guaranteed to be an ideal genetic fit.

One family would succeed and one would fail. One child would receive a transplant from a perfectly matched newborn brother and the other from a less well-matched stranger. One would have an excellent chance of survival; the fate of the other was not as clear. Their parents, now friends, would find themselves together in the tiny lounge at the end of the transplant hall, waiting for the new cells to take root, sharing pizza and a pain that only they could understand.

When the rest of the world learned about the baby born to be a donor, there were questions. Is it wrong to breed a child for "spare parts"? ethicists asked. If we can screen an embryo for tissue type, won't we one day screen for eye color or intelligence? There was talk in the news media of "Frankenstein medicine" and threats by Congress to ban embryo research, which had made this technique possible.

It is the kind of talk heard with every scientific breakthrough, from the first heart transplant to the first cloned sheep. We talk like this because we are both exhilarated and terrified by what we can do, and we wonder, with each step, whether we have gone too far. But though society may ask, "How could you?" the only question patients and families ask is, "How could we not?"

Which is why there is virtually no medical technology yet invented that has not been used. It is human nature to do everything to save a life and just as human to agonize over everything we do. The story of Molly and Henry is the story of groundbreaking science. It is also the story of last-ditch gambles on unproven theories, of laboratory technique cobbled from instinct and desperation, of a determined researcher who sacrificed his job and more trying to help and of a frantic drive through a hurricane to deliver cells on time. In other words, it is simply the story of what it now takes, in the 21st century, to save one child.

Back at the beginning, it was Molly who arrived first. She was born on July 4, 1994, at Rose Medical Center in Denver, and from the start it was clear that something was terribly wrong. She was missing both thumbs, and her right arm was 30 percent shorter than her left. Her parents, Lisa and Jack, saw her, but could not hold her, before she was whisked off to the I.C.U., where doctors would eventually find two separate malformations of her heart. (She was also deaf in one ear, but that would not be known until later.) Lisa, wide awake and distraught at 4 a.m. in the maternity ward, made a phone call to the nearby university hospital where she worked as a neonatal I.C.U. nurse caring for babies just like this one, and asked a friend to bring her the book of malformations. Flipping from page to page, she landed on a photo of a Fanconi face and saw in it the face of her newborn daughter.

Named for the Swiss physician who first identified it in 1927, Fanconi anemia causes bone marrow failure, eventually resulting in leukemia and other forms of cancer. Until very recently, children with Molly's form of F.A. rarely lived past the age of 6, the age Molly is right now. Fanconi is a recessive disorder, which means both parents must pass along one copy of the mutated gene in order for a child to develop the disease. Among the general population, one of every 200 people has a Fanconi mutation. Every ethnic group carries its own genetic baggage, however, and among Ashkenazi Jews like the Nashes and Strongin-Goldbergs, the incidence is 1 in 89, meaning that if both parents are Ashkenazi Jews the chance of having an affected baby is 1 in 32,000. But Lisa, with all her medical training, had never heard of the disease, and Jack, a Denver hotel manager, certainly had not, either.

The holes in Molly's heart closed by themselves, but her other problems remained. She failed to eat, she failed to grow and she was always sick. She had already been through three major surgeries by Oct. 25, 1995, when Henry Strongin Goldberg entered the world at the George Washington University Hospital in Washington. Doctors had warned his parents that he would be quite small, but Laurie Strongin and Allen Goldberg were not worriers, because life had never given them anything to worry about. "Our family history," Laurie says wistfully, "was blue, sunny skies."

Henry was born with an extra thumb on his right hand and a serious heart defect that would require surgery to fix. His parents were devastated, but within days the prognosis worsened. "Fanconi anemia," Laurie wrote in her journal. "If only it was just the heart and thumb. Please take me back a minute ago and make me feel lucky that is it only the heart and the thumb. Fanconi anemia. Rare. Fatal. Henry."
Laurie had spent her career working for nonprofit organizations; Allen had spent his in the computer industry. Both in their early 30's, they were new to parenting and to Fanconi anemia, but they both knew how to navigate a medical database, and within days they found Arleen Auerbach, a researcher at Rockefeller University in New York and the keeper of the Fanconi patient registry in the United States and Canada, a list that contains about 800 names. Although Molly's parents and Henry's parents still knew nothing of each other, the Nashes had found Auerbach, too, because all Fanconi children eventually find their way to her cluttered Manhattan office.

The rarer the disease, the more it needs a single champion, someone to keep the lists, track the trends, follow the research of others while relentlessly pursuing his or her own. Arleen Auerbach is that person for Fanconi anemia -- a sweet, grandmotherly type at the core but with sharp outer edges, armor born of years spent delivering bad news.

She had little but bad news for the Nashes and the Strongin-Goldbergs when they first called. Of the eight separate genes that can mutate and cause Fanconi anemia, Molly and Henry both had Type C, which bares its teeth early and kills often. Had these children been born as recently as 1982, Auerbach explained, there would have been no possible treatment. Bone-marrow transplants -- obliterating the faulty immune system and then replacing it with a donated one -- used to be fatal for Fanconi patients, because their cells were fragile and crumbled during the chemotherapy and radiation that cleared the way for the actual transplant.

Then, in 1982, doctors in France found that if Fanconi patients were given a significantly lower dose of the chemotherapy drug Cytoxan they could survive. The chances of their survival were increased even further if the donor was a sibling who was a perfect match. The reason for this is found in a web of six proteins that together are known as human leukocyte antigen, or H.L.A., which is the radar by which bodies recognize what is "self" and what is "intruder." H.L.A. is key to the immune system, and since a bone-marrow transplant is a replacement of the immune system, the H.L.A. of the donor must be as close as possible to that of the recipient, or the new immune system can reject its new container, a life-threatening condition known as graft-versus-host disease.

Over the years it was discovered that the rate of success for sibling transplants was even higher if the sibling was a newborn, because then the transplanted cells could come from "cord blood" taken from the umbilical cord and placenta at birth. These are purer, concentrated, undifferentiated cells, meaning that they are less likely to reject their new body. Back in 1995, when Auerbach first spoke to the Nashes and the Strongin-Goldbergs, the survival odds of a sibling cord-blood transplant were 85 percent, while the odds of a nonrelated bone-marrow transplant were 30 percent and the odds of a nonrelated transplant for patients with Henry and Molly's particular mutation were close to zero.

If there was one thing working in their favor, Auerbach told them, it was that their children's disease was diagnosed so early in life. Fanconi anemia is rare, and few doctors have ever seen a case, which means the condition is often missed or mistaken for something else. Auerbach has seen too many children with this same Fanconi mutation whose blood fails, with little prior warning, at age 5. Those parents don't have time to do the only thing there is to do, the one thing the Nashes and Strongin-Goldbergs could do -- have a baby.

Ten weeks into a pregnancy, Auerbach explained, a chorionic villus sampling test can determine whether the fetus is healthy and if it is a compatible donor. Couples regularly abort when they learn that the unborn child has Fanconi, Auerbach says; having seen the devastation wrought by the disease on one of their children, they refuse to allow it to claim another. Few couples abort, however, when they learn that the baby is healthy but not a donor. "Only three that I know of terminated for that reason," she says. "They were getting older, their child was getting sicker and they were running out of time." Far more common, she says, is for couples to keep having children, as many as time will allow, praying that one will be a match.

Timing a child's transplant means playing a stomach-churning game of chicken with leukemia. The younger a patient is when undergoing a transplant, the better the outcome, because the body is stronger and has suffered fewer infections. On the other hand, the longer the transplant can be delayed, the greater the odds of conceiving a sibling donor, and the better the chance that transplant technology will have improved. The risk of waiting is that every Fanconi patient will develop leukemia, and once that happens a transplant is all but impossible. "You want to wait as long as you can," Auerbach says, "but not so long that it's too late."

Good doctors learn from their patients, and so it was when Dr. John Wagner answered his telephone one afternoon seven years ago. A lanky, easygoing man, Wagner is scientific director of clinical research in the Marrow Transplant Program at the University of Minnesota, and he says he believes he has performed more bone-marrow transplants on Fanconi children than any other doctor in the country. The caller who set him thinking, however, was not the parent of a Fanconi patient, but rather the father of a toddler with thalassemia, another rare blood disease. The man was calling to inquire about a sibling cord-blood transplant. "You have another child who is a match?" Wagner asked. "No," came the reply. "But we will."

The father went on to explain that he and his wife were using a relatively new technique known as pre-implantation genetic diagnosis, or P.G.D., to guarantee that their next child would be free of thalassemia. P.G.D. is an outgrowth of in-vitro fertilization; sperm and egg are united in a petri dish, and when the blastocyst (it is still technically too small to be called an embryo) reaches the eight-cell stage, it is biopsied (meaning one of those cells is removed and screened). Only blastocysts found to be healthy are returned to the womb. Then the waiting game begins -- more than two months until it is possible to know if the fetus is a transplant match, then an agonizing choice if it is not. Why, the caller wondered, can't the donor-compatibility tests be done before the embryos are implanted?

Wagner was intrigued by the possibility. Why use P.G.D. just as prevention, he wondered, when it could be used as treatment? Why not, in effect, write a prescription that says "one healthy baby who is going to be a perfect donor"?

Wagner called Mark Hughes, who pioneered the technique and who was working with this family. Hughes is known as a brilliant researcher, simultaneously passionate and wary, a scientist and physician who chose the field of genetics because it combined the intellectual rigor of the lab with the emotional connection to flesh-and-blood patients. In 1994, at about the time he first spoke to Wagner, Hughes was recruited to work at the National Institutes of Health and also as director of Georgetown University's Institute for Molecular and Human Genetics, where his salary was paid in part by the N.I.H. In other words, much of his research was supported by the government. At that time he was also a member of a federal advisory committee that developed guidelines for the type of single-cell embryo analysis that was central to P.G.D. But no sooner had those guidelines been developed than Congress banned all federal financing of embryo research, and Hughes was forced to continue his research with private funds only.

Under the current Bush administration there is talk of banning all embryo research, even work supported by private funds. For that reason -- and for reasons that will become clearer as this tale unfolds -- Hughes has developed a healthy distrust of the limelight and refused to be interviewed for this story. As Wagner and Auerbach tell it, Hughes had certainly thought of the possibility of using P.G.D. to determine H.L.A. type long before Wagner called, but he had several concerns.

The ones that weighed heaviest were ethical. It could be argued that using P.G.D. to eliminate embryos with disease helps the patient -- in this case, the embryo, the biopsied organism -- by insuring that it is not born into a life of thalassemia or cystic fibrosis or Duchenne muscular dystrophy or any of the other agonizing illnesses for which Hughes was screening. Using the same technique to select for a compatible donor, however, does not help the "patient" whose cells are being tested. "It helps the family," says Arleen Auerbach, "and it helps the sibling with Fanconi, but it does not help the embryo."

What Wagner proposed, therefore, would be stepping into new territory. If society gives its blessing to the use of one child to save another, then what would prevent couples from someday going through with the process but aborting when the pregnancy was far enough along that the cord blood could be retrieved? Or what would prevent couples whose child needed a new kidney from waiting until the fetal kidney was large enough, then terminating the pregnancy and salvaging the organs? What would stop those same couples from waiting until the child was born and subjecting it to surgery to remove one kidney? Once the technology exists, who decides how to use it?

Ethicists think in terms of a slippery slope. But is the potential for abuse in some circumstances reason not to pursue research that can be lifesaving under the right circumstances? Unlike donating a kidney, or even donating bone marrow, donating cord blood involves negligible harm to the newborn donor. The stem cells are collected at birth, directly from the placenta, not from the baby. That is one reason why Wagner argued that H.L.A. testing is ethically defensible. A second reason, he said, was that it is indefensible not to try.

"I'm here as the patient's advocate," he says, meaning Molly and Henry and all the other children in need of transplants. "It's my obligation to push the envelope because I see how bad the other side can be. I see the results of a sibling transplant; they're the easiest transplant to do. And then I walk into the room of the patient who had an unrelated donor, I see that their skin is sloughing off, the mucous membranes are peeling off and they have blood pouring out of their mouths. You cannot imagine anything so horrible in your entire life, and you're thinking, I did this -- because there was nothing else available for me to do."

That was apparently what Hughes's gut told him, too, and he agreed to try to develop a lab procedure to screen H.L.A. at the single-cell level. His participation came with certain conditions. First, that the mother must be younger than 35, because younger women produce more eggs, increasing the odds of a healthy match. Second, that he would work only with families who carried a specific subset of the Type C mutation, known as IVS4, because it is the most common. And, last of all, the child being created must be wanted. Only families who had expressed a wish for more children would be approached for this procedure. Hughes did not want to create a baby who was nothing but a donor.

Arleen Auerbach immediately thought of two couples who were the right age, fit the specific genetic profile and who had always planned to have a houseful of children. Her first phone call was to Lisa and Jack Nash in Denver. Without a moment's hesitation, they said yes. Her second call was to Laurie Strongin and Allen Goldberg in Washington.

"If I told you that you could potentially go into a pregnancy knowing that your baby was healthy and a genetic match for Henry, would you be interested?" she asked.

Two hours earlier, Laurie had taken a home pregnancy test. It was positive. If early test results were negative for Fanconi she would carry to term, she answered, even if the baby were not the right H.L.A. type to save Henry's life.

Henry was only 5 months old. His heart surgery had gone smoothly, he was happy and looked deceptively healthy. Fate seemed to be on his side. "If this baby's not a match, we'll try it your way in nine months," Laurie remembers telling Auerbach. "We still thought," she says, "that we had a lot of time."

Henry became a big brother in December 1995. Jack Strongin Goldberg was free of Fanconi and was not even a carrier of the disease, so there was no chance that he might pass it on to his own children. His H.L.A., however, was as unlike Henry's as a biological brother's could possibly be. Laurie and Allen admit that they were briefly disappointed when they heard this last piece of news, three months into the pregnancy. Then they brushed off their psyches and called Mark Hughes, telling him they would be ready to try P.G.D. at the start of the following year.

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