Editor's note: As William R. Clark points out in The New Healers, genetic disorders have been as damaging to humans as viral or bacterial diseases - and they have a tragic dimension all their own, in that they are passed on from one generation to the next. With scientific precision enhanced by skillful storytelling, Clark investigates the nature of these devastating diseases, such as cystic fibrosis and severe combined immunodeficiency disease (SCID), and takes us to the latest frontier of medicine - gene therapy - where researchers and physicians seek to repair the tiny defects that have such immense consequences. From Mendel's earliest discoveries, to the mapping and cloning of genes, to the latest clinical trials, to the applications of molecular medicine in treating the modern scourges of AIDS and cancer, Clark gives a full account of this amazing new field, and its profound potential to change and save lives.

Here, a bit of history that has become legend - the story of David, the "boy in the bubble," whose remarkable life continues to prove instructive and inspirational years after its brief span was concluded.

The nation became suddenly aware of SCID through the dramatic and ultimately tragic case of a young boy named David, who was born in Texas in 1971. (David's full name was never made public.) The type of SCID young David suffered from was caused by defects in a single gene that, like the gene in CF, is inherited in standard Mendelian fashion. This particular gene is located on the X chromosome, and so the disease is referred to as X-linked SCID, or simply X-SCID. Human males, being XY, have a single X chromosome. Thus unlike the situation in CF, where a child must inherit a defective gene from each parent, young X-SCID males develop their disease through inheritance of a single defective gene on the X chromosome from their mothers. (Normally only females are carriers of this disease, since males do not usually live long enough to reproduce.) Thus half of the male offspring of a carrier mother will be born with SCID; half the daughters will, like their mothers, be heterozygous carriers. Roughly half of all SCID cases involve X-SCID.

David's parents had lost an infant son to X-SCID less than two years earlier, so the possibility of a second male child with SCID was known well in advance. The first child developed severe infections at five months of age, and died at seven months. Midterm amniocentesis had indicated that David would in fact be male, although at the time it was not possible to determine whether he carried a defective gene. At any rate, the family did not consider abortion to be an option. David was delivered by caesarian section (to prevent contact with the microbes that are a normal part of vaginal birth) and was immediately transferred to a sterile incubator until his immune status could be determined. Within a short time it was learned that he, too, had inherited the defective gene causing SCID.

Since the sterile environment protected him from disease-causing microbes, and since he had not yet picked up his own opportunistic pathogens, young David quickly became the longest living untreated SCID patient. The idea behind this approach to managing a child with SCID was the hope that if he could be kept alive long enough in the absence of disease, his immune system might somehow "kick in" and allow him to defend himself; this was not an unreasonable hope at the time. Over the next several months he was tested for signs of T cell responsiveness, but the cells never became functional. When he began to crawl and eventually to stand, he was moved into a sterile tent that allowed some freedom of movement, consistent with the need to protect him from environmental pathogens. As he continued to grow, the tent eventually became "the Bubble," an ingenious complex of interconnecting plastic tubes that allowed him to move around and explore, in an environment full of variously shaped and colored objects to stimulate his senses of vision and touch. It was constructed in such a way as to allow maximal interactivity with family and playmates on the outside. NASA even built a small space suit for him so he could gain some impression of independent movement in the outside world; he outgrew it within a year. A sterile transporter was developed so that he could be taken home, and learn what it means to be part of a nuclear family. He was given a good education at home in his bubble; his nurses and tutors found him to be a bright, somewhat mischievous youngster, not obviously distinguishable from other boys his age.

But his immune system never developed. As David continued to grow, it became clear that something had to be done. He was healthy and vigorous, and very clever: What if he tried to break out of his bubble? And at twelve years of age he was showing the first signs of normal sexual maturation. No one had thought this far ahead; his medical team found themselves in an enormous and unprecedented ethical dilemma, with no guidelines for how to proceed. How long could someone survive in a sterile bubble? In the beginning doctors were worried that he would not survive long, and now they had to deal with the possibility that he might; there was nothing to suggest that his life would be foreshortened by his disease. What would be the psychological and spiritual state of a person living out an entire life span under these conditions?

Finally, it was decided to give David a bone marrow transplant, with his fifteen-year-old sister Katherine as the donor. David and his sister were not particularly tissue compatible, which is one reason a transplant with her marrow had not been attempted earlier. The chance for success with poorly matched marrow was less than fifty-fifty at the time. In late 1983, when David received his sister's marrow, there were only about two dozen SCID children in the world that had been successfully transplanted, and nearly all of these were with closely matched donor marrow. Never-the-less, it was decided to take the risk. David was taken to a sterile operating room and infused with his sister's bone marrow. He was kept briefly in a sterile postoperative recovery room, and then returned to his bubble.

Everything seemed to go well at first. But a few weeks later he developed symptoms that seemed possibly related to one of the principal dangers of bone marrow transplantation: GVH ( "graft-vs.-host") disease. GVH disease arises when mature T cells in the donor bone marrow settle into the recipient's body and begin to regard it as a huge organ transplant. The graft in this case begins to reject the host. Appropriate steps were taken immediately to control GVH, but to no avail. There were also puzzling signs of a viral infection. David's condition grew rapidly worse; he finally died on the one hundred and twenty-fourth day post-transplant. He was twelve years old.

It turned out that David did not die from complications of GVH disease; in fact hematopoietic stem cells from his sister's bone marrow had failed completely to implant and function in his body. He died of congestive heart failure secondary to a B cell lymphoma. His sister, like much of the population, carried an opportunistic pathogen called the Epstein-Barr virus (EBV) in her blood cells. EBV is normally kept under control by the body's immune system; when it occasionally breaks out, it may cause a flu-like state known as mononucleosis. In patients with a compromised immune system, however, it can progress into a deadly form of cancer, called B cell lymphorna. Bone marrow is always contaminated with blood that seeps in during its removal from bone cavities. Once inside David's own system, EBV apparently escaped from his sister's blood cells and infected his own B cells, some of which eventually became cancerous.

Just before David died, some of his T cells were harvested and frozen away for future study. In 1993, scientists working with DNA isolated from his cells, among others, were able to pinpoint the defective gene that caused his form of SCID. The gene encodes a protein found on the surface of T cells that allows them to receive a crucial chemical growth signal from the environment. This growth factor receptor is absolutely crucial to the normal development of T cells in the body; without it their growth is halted at a very early stage, and they die. Because of the key role played by T cells in immune responsiveness, the patient is left with only the most rudimentary immune defenses. The IL-2 receptor gene has now been isolated and "cloned", and should be ready for gene therapy trials in the very near future.

The MRC Clinical Sciences Centre - An HMS Beagle Profile. Research focuses on molecular genetics and noninvasive imaging. Collaborative efforts are leading to new modes of gene therapy for cystic fibrosis, insights into transplant rejection, and novel diagnostics for fetal brain damage.

Early Repair Job - an HMS Beagle Meeting Brief on the Second International Meeting on In Utero Stem Cell Transplantation and Gene Therapy (Nottingham, United Kingdom, September 1-2, 1997); discussions included an overview of the current state of the field; new techniques; and major challenges involved in such procedures.

The Immune Deficiency Foundation - foundation promotes research and training in primary immune deficiency diseases, and disseminates information. Related links list research organizations, societies, and support resources, including the IDF Patient Family Handbook; Our Immune System (for children); Clinical Updates; the Clinical Presentation of the Primary Immunodeficiency Diseases: a Primer for Physicians; and the IDF newsletter.

The SCID Homepage - developed by the parent of a child with SCID, this page offers numerous links to research, professional, support, and informational resources, under headings such as Foundations; Professional; Duke (University); NIH/NHGRI (National Human Genome Research Institute); St. Jude (Hospital); Genetics; SCID; Journals; Research; Government; and IVIG (intravenous immune globulin).

Starbright Foundation - develops network systems so children in medical intensive-care and isolation environments can play online with similarly hospitalized children across the world. An alternative approach called Billow similarly proposed alleviating such children's loneliness, but by allowing child interaction within a local pediatric ward.

The American Association of Immunologists - information on training and job opportunitites; events; educating the public; related links; and more. Access to the full text of the Journal of Immunology for AAI members.

Bone Marrow Transplant to a Fetus to Treat SCID - Brief article on the transplanting of bone marrow cells from a father to a 4-month-old fetus with SCID - as a result, the baby's immune system developed normally.

Gene Therapy - some common examples of genetically transmitted diseases, and a case study of SCID, including a brief description; treatment options; requirements for gene therapy; and a discussion of cells used as target cells.

The American Institute of Immunology - well-organized site providing in-depth, although not particularly technical, information. This site is searchable and offers a list of cross-referenced definitions.

Immunology Link - includes worldwide associations, journals, job opportunities, and technical information for immunologists.

Immunology Databases

International Immunogenetics Database - contains sequences belonging to the immunoglobulin superfamily that are involved in immune recognition.

KabatMan Database - provides information on antibody structure and sequence.

V Base - database of human germ-line variable region sequences.

MHCPEP - contains sequences of MHC-binding peptides.