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Remembering David

Severe combined immune deficiency (SCID) is a term used to describe several exceedingly rare, but cruel, genetic diseases that mimic AIDS. Affected children are normal at birth, but within months, as the protective antibodies that their mothers provided to them disappear, they are plagued by repeated bouts of unusual infections. They fail to grow well and are often hospitalized for pneumonia. Because of a single small genetic error, their immune systems cannot properly make the T cells and B cells that normally patrol the human perimeter and quickly kill foreign bacteria, fungi, and viruses that are incessantly trying to invade.

Despite its rarity, SCID became a famous disease for a time in the 1970s thanks to a boy named David who lived near Houston, Texas. David was born with an X-linked version of SCID. When it became clear that David was severely affected and would likely die within months or a few years, his parents made the dramatic decision to raise him in a sterile environment. Working with physicians and scientists at Baylor Medical Center, they created a special home for him, a large clear plastic bubble, which was, in effect, an immunological space station. As David grew, the rooms were enlarged, a special van was outfitted to transport him back and forth from his suburban home to the medical center, and a sterile room was set up for him at the hospital. David lived like this for 12 years. After he entered his sterile world, a world almost devoid of microorganisms, a world in which his food was irradiated, David took on a life that no other human had ever experienced. He could see and talk with his family, but he could not sit down to dinner with them. He could be lovingly touched across the flexible plastic walls, but he could never feel the warmth of his mother's kiss. Friends could engage in parallel play with him at the edge of his life-

giving prison, but he could never swing side by side with them at a playground.

In taking David on this extraordinary journey, his parents were fighting to buy time. They were hoping that medical research would come up with a treatment that would free him. Years passed and David became famous. Science journalists loved to report about him, and he became the subject of a made-for-television movie. But there was no major advance in understanding his genetic disorder, and the dream of finding a way to repair his faulty gene remained distant. David's parents knew that the bubble solution could only work for so long. They guessed correctly that as he approached adolescence and realized his situation, David would want to try the only possible cure, bone marrow transplant surgery, even though at the time it carried a substantial risk of death. Since David's disease resulted from defective white cells that are made in the bone marrow, doctors could try, using drugs and radiation, to destroy his marrow entirely, and then reconstitute it with donor cells. If it worked, David could live a normal life. If it failed and David developed a massive postoperative infection that could not be successfully treated, he would die.

When he was 12, David told his parents and his doctors that he wanted to take the risk. Unfortunately, heroic efforts to find a bone marrow donor who would be a perfect immunological match were unsuccessful. There was one other choice. Scientists at the Dana Farber Cancer Institute in Boston had developed a technique to help imperfectly matched bone marrow donations work. David desperately wanted to go forward. In October of 1983, the clinical researchers took bone marrow donated by his sister and prepared it for transplant into David. He was operated on the next day, and quickly put back in a sterile chamber while the doctors waited to see if his body would make a new immune system. At first things seemed to be going well, but in December David developed a bad infection and became very ill. As he got worse and was moved to the hospital, the doctors realized that he was suffering from an incurable infection with Epstein-Barr virus. The virus, to which virtually all of us have been exposed, usually without incident, had apparently been a hidden invader in the donor bone marrow cells. With nothing to stop it, the bug caused a runaway cancer of David's B cells, a kind of lymphoma. His death in January of 1984 was among the most emotionally wrenching losses in medicine, so invested had been the scores of people who had cared for him. Just seven years later, doctors opened the doors to the world of gene therapy by treating a little girl with the same disease.

Gene Therapy: History and Controversy

A few passionately committed individuals, especially Dr. French Anderson, who at the time was directing a laboratory at the National Institutes of Health, started pursuing gene therapy long before there was any reason to hope that it might work. Their collective idea was this: Imagine a serious, untreatable disorder that arises because a defect in a single gene prevents a particular organ or cell type from working (diseases arising in the bone marrow were the first obvious candidates). Perhaps it would be possible to isolate a normal version of the disease gene, amplify it many fold, and attach millions of copies of it to vectors (submicroscopic vehicles such as viruses that would carry it into other cells). One could remove the target cells from the patient, stimulate them to grow in culture, put the vectors carrying the normal version of the gene in the culture, and return them to the individual. If the vectors entered those cells and delivered the normal gene to the nucleus, perhaps some of them would insinuate themselves into the patient's genome and begin making a normal protein. If such cells were then returned to the patient and if the donor genes kept working, maybe the disease in question could be ameliorated or cured. If such an effort worked even once it would usher in a new era of molecular medicine.

The term "gene therapy" includes two vastly different concepts. The notion of using DNA vectors to treat disease in a human is known as somatic (or body) cell gene therapy. From the start the only major ethical concerns generated by this dream have focused on safety. How could one possibly calculate the risk to the patient of deliberately infecting his cells with a foreign gene that might incorporate anywhere in his genome? Did this create a risk of cancer? Of course, for desperately ill patients for whom all other therapeutic options have been exhausted, the idea of undergoing an experimental therapy and taking novel risks becomes more acceptable, both to them and to society.

The second, far more controversial, idea is germ-line gene therapy, which has never been attempted in humans. This would involve the genetic manipulation of a single egg or sperm cell prior to conception or, more likely, the genetic manipulation of a 4- to 8-cell embryo created in a test tube. A gene or genes added at this early stage of development would become part of the cells that mature to make all of the cell lines that organize during embryogenesis, including the future individual's sperm or eggs. That is, the work of the genetic engineers could be passed on through the patient's descendants, spreading ever so gradually as a tiny ripple in the human gene pool.

Although this is still not technically possible in humans, scientists and bioethicists have been debating the morality of germ-line genetic therapy for 30 years. Some have worried about creating unpredictable biological risks for future generations. Others castigated germ-line engineering as the height of scientific, religious, and ethical hubris. The argument against "playing God" has been a recurrent theme in such discussions. Since we cannot (except in the case of a few mutations known to cause severe, uniformly fatal disease) characterize genes as good or bad, how, some ask, can we possibly decide which ones to replace or alter? The "value" of a gene to an organism changes over time, and it may vary significantly depending on the environment into which the individual who carries it is born.

A classic example of the difficulty in valuing most genetic variation is the gene that makes part of the oxygen-carrying molecule called hemoglobin. A person in whom one copy of the gene for ^-hemoglobin has a single change in the DNA at a particular site (changing the code for the sixth amino acid in the molecule's ^ chain from glutamic acid to valine) and in whom the other copy is normal has a condition called sickle cell trait. This is not an illness, and, depending on the environment, can be a tremendous advantage. Persons with sickle cell trait are highly resistant to developing malaria, still one of the world's great killers, especially of children. On the other hand, persons who inherit two copies of the sickle cell allele (one from each parent) are born with sickle cell disease, a serious blood disorder that is debilitating and with which—until recently—affected persons often died young. In North America in the late 20th century, having a copy of the sickle cell gene is of little value; in equatorial Africa it can be life-saving.

Those who oppose germ-line engineering argue that we should not even contemplate the prospect of taking control of our genetic destiny. They liken those who would undertake this goal to the sorcerer's apprentice in Disney's Fantasia. To do his work, the foolish little apprentice opened a forbidden book and called forth tools he could not manage. In the mid-1970s, more than a dozen major religious groups issued statements condemning germ-line engineering as unethical, unnatural, and against God's will. Reminders of the banishment from Eden resonated through these documents. Most ethicists also viewed such experiments as inherently wrong, largely because they thought them to constitute unethical experiments on human embryos for whom no valid consent could be obtained. This view was incorporated into government policy in the late 1970s when NIH issued regulations that forbade the use of federal funds to conduct fetal research (see Chapter 23).

The most troubling aspect of germ-line genetic engineering is that in addition to the welcome prospect of "treating" embryos to avoid severe disease in them and perhaps their offspring, it raises the much more troubling possibility of "enhancing" the genomes of normal embryos by adding genes that would increase the likelihood that the children would (to mention just a few obvious choices that might intrigue some parents) be more intelligent, have greater athletic prowess, be musically talented, or have greater beauty than if they were conceived naturally. To some this seems like a violation of the ethics of parenting, for it implies that the couple who chose to use germ-line enhancement must have thought that any child they might have conceived naturally was destined to be inadequate in their eyes. Others argue that nothing is more natural than efforts by parents to give their children the best possible genetic advantage in this uncertain and harsh world.

From the start, the scientific, bioethics, and religious communities and regulatory bodies drew a sharp line to separate discussions of somatic cell gene therapy from germ-line gene therapy. In June of 1983, Senator Mark O. Hatfield placed in the Congressional Record a resolution signed by 56 religious leaders urging that "efforts to engineer specific genetic traits into the germ line of the human species should not be attempted." Even prior to that statement, the federal Recombinant DNA Advisory Committee had taken the position (from which it has never retreated) that it would not approve any proposals to use federal funds for experiments in germ-line genetic engineering.

Although it is impossible to know how deeply the story affected federal policymakers, religious leaders, or the general public, genetic engineering did begin on a most inauspicious note. In the summer of 1980, a decade before the Human Genome Project was initiated, a time when gene therapy was still only a dream at NIH, word surfaced that Dr. Martin Cline, a prominent hematologist at UCLA, had attempted to treat children suffering from ^-thalassemia (a genetic blood disease) in Israel and Italy with artificial genes. When Donald Frederickson, the Director of the NIH, heard the rumor, he immediately initiated an inquiry, for if the story was true, Dr. Cline had violated federal rules on research involving human subjects, which in addition to being unethical, could provoke a firestorm of criticism in Congress. It was true.

Earlier that year, Cline had submitted a gene therapy proposal to an Institutional Review Board (the name given to the local committees that the federal rules require must review proposals to obtain federal grants to conduct experiments on human subjects) at UCLA, and the IRB had rejected it. Cline had then arranged to conduct his experiment outside the country. In the fall of 1980, investigators concluded that Cline had misled his colleagues in Israel and Italy about key scientific details of his work, and, in treating the children, had violated federal rules. He eventually admitted that he treated human beings with recombinant DNA molecules without first obtaining the required NIH approval but defended his actions on medical grounds, arguing that the course he took might have saved children from a fatal disorder.

Cline was censured; NIH terminated two of his grants and UCLA forced him to resign as chairman of his department. An editorial likened him to Dr. Frankenstein, arguing that his behavior threatened to erode public support of research. Each event was a serious blow; combined they should have been a knockout punch. Cline had the stamina and courage to persist. Despite his self-caused fall from the scientific elite, he has remained highly productive, publishing more than 100 research papers since 1980. With hindsight, it seems that Cline's worst sin was hubris.

A decade passed. Throughout the world in dozens of academic laboratories and a growing number of start-up biotech companies, scientists tried to develop techniques for gene therapy and use them in animal models. At NIH, despite the serious setback caused by the Cline fiasco, Dr. Anderson, then Chief of the Molecular Hematology branch of the National Heart, Lung and Blood Institute, kept the gene therapy dream alive. During the 1980s, Anderson and his colleagues faced huge scientific, ethical, and political obstacles that had to be surmounted before NIH would approve an experiment like the one Cline had conducted improperly. Anderson's tenacity was as impressive as his intellectual prowess. Time and again he went before the Recombinant DNA Advisory Board to propose, explain, and defend his plan to make gene therapy a reality. When his protocol was finally approved by the NIH on September 7,1990, one journalist observed that the process had taken "three years, three months, one week, and one hour," surely a record of some sort.

The First Treatment

On September 13,1990, Anderson's dream became reality. He and his colleagues, a seasoned cancer researcher, Dr. Michael Rosenberg, and a pediatrician, Dr. Kenneth Culver (who went on to direct a gene therapy research center at the University of Iowa), met in a hospital room, and infused genetically engineered bone marrow cells into the vein of a four-year-old girl named Ashanthi. Troubled since infancy by persistent infections, Ashanthi DeSilva had been seen by pediatrician after pediatrician until Dr. Ricardo Sorenson, a physician at Rainbow Babies Hospital in Cleveland finally diagnosed her as having adenosine deaminase (ADA) deficiency, an exceedingly rare form of immune deficiency caused by a defect in a gene on chromosome 20. Fortunately, in 1987 scientists had developed a way to administer the bovine version of this missing enzyme in a way that allowed it to circulate long enough in the body to restore some measure of immune function. It helped, but it was not a cure. Even on the medicine, children with ADA deficiency still get more infections than they should and have to be watched with great care.

Although exceedingly rare, ADA deficiency was an excellent choice for the first attempt at gene therapy. It is a single gene disorder primarily affecting the function of only one group of cells, those that comprise a crucial wing of the immunological defenses. It was also important that patients who agreed to undergo gene therapy for ADA deficiency would be able to stay on their current medicines. Furthermore, there are objective methods, such as cell counts, assays of the level of immune response, and studies of the frequency of infections, that can be monitored. These measures can be compared to methods used before gene therapy and thus give an indication of whether they are helping.

What French Anderson and his colleagues hoped to do was to turn

Ashanthi into a chimera. In Greek mythology, the chimera is a fire-breathing monster with a lion's head, a goat's body, and a serpent's tail. Bone marrow therapy creates a different kind of chimera. The successfully treated patient goes through life with two versions of a particular cell. Most, of course, derive from the germ cells with which he was conceived, but the engineered blood-forming cells are different. Gene therapy is much more subtle than bone marrow therapy. If it works, the patient is a chimera for only a single gene, in Ashanthi's case the gene that codes for adenosine deaminase.

The experimental therapy was simple. The doctors at NIH removed a large number of white cells from Ashanthi's blood. They then set up cultures to which they added chemicals to spur cell division. To these they added an attenuated virus known to invade white blood cells into which had been inserted a cloned adenosine deaminase (ADA) gene. The hope was that the virus would carry the normal copy of the gene into the white cells and that in some of them the new DNA would be taken into the cellular genome. As such cells grew and divided, they would be replicating the new ADA gene as well as the old. The newly divided cells would be infused through a regular i.v. into a vein in Ashanthi's arm.

There were many uncertainties. Would the cells in culture take up the vector? Would the cells that did, divide normally in culture? Would they continue to divide normally in Ashanthi's body? If they did, would they make enough normal enzyme to restore her immune function? Could the cells with the engineered DNA endanger her? The researchers could only guess.

In 1999, nearly a decade after her gene therapy was initiated, Ashanthi is doing well, and she has been joined by more than a dozen other children with ADA deficiency who have been treated with engineered genes. However, there are still many unanswered questions about the world's first gene therapy experiments. For most of the children, there is good evidence that a sizable fraction of the white cells placed in their bodies that are supposed to make ADA are doing so. But the patients continue to need follow-up treatments, and none of the clinical geneticists is yet confident enough in their work to stop the standard therapy with the bovine enzyme. Nevertheless, there can be no doubt that in treating Ashanthi, French Anderson and his colleagues opened the door to a new era. Since their pioneering work, interest in gene therapy has exploded.

The Commercialization of Gene Therapy

About 1993 the rapidly growing biotech industry began to attract investors who were willing to bet tens of millions of dollars on gene therapy companies. In 1994 and 1995 it may have been fair to claim, as some pundits did, that there were more companies devoted to gene therapy than there were patients who had ever participated in gene therapy protocols, but that is to be expected. The major focus in research had to be on the development of safe and efficacious methods to deliver genes to the cells of patients. This first requires extensive work with animal models; otherwise, the NIH would (appropriately) reject any proposal to offer an experimental somatic cell gene therapy to humans.

During the early 1990s, both efforts to develop delivery systems and early experiments to treat animals that had single gene disorders analogous to those in humans yielded impressive results. Among the most dramatic was work with genetic disorders of cholesterol. The Watanabe rabbit (named for the Japanese scientist who discovered its illness) has too few receptors on its cells to process circulating low-density lipoprotein (LDL), a molecule that transports cholesterol. These animals have a genetic form of heart disease. In December 1991, a team at the University of Michigan led by James Wilson reported that it had ameliorated the disease in these rabbits by a combination of surgery and gene therapy. Wilson and his colleagues removed part of the animals' livers, grew the hepatocytes (liver cells) in culture, treated them with a retrovirus to which had been hooked a normal copy of the LDL-receptor-making gene, and transfused them into the portal circulation (the blood system to the liver). After six weeks, the liver cells in these animals were making about 4% of the normal level of the protein, but even that small amount had cut their serum cholesterol by an impressive 30%. This was not unexpected. In most cases one needs only about 10% of the normal levels of a protein to have adequate bodily function.

This success encouraged Wilson to propose, and regulatory watchdogs to approve, an attempt to use somatic cell gene therapy to treat a person with the equivalent human disease. The patient was a 29-year-old Canadian woman who had been born with a severe form of hypercholes-terolemia caused by almost complete dysfunction of her LDL receptors that made her incapable of clearing the "bad" cholesterol from her blood.

At times her serum cholesterol was over 1000. Even with current treatments such as diet, cholesterol-lowering drugs, heart medications for the angina that develops from coronary artery disease, and bypass surgery, such patients usually die of heart failure by early adulthood. In June 1992, surgeons removed 10% of her liver and sent it to the genetics lab. The geneticists then broke the tissue into cell suspensions, treated her cells in essentially the same way that they had the rabbit cells, and in three days returned them to her through a special catheter that delivered them directly to the liver. The results were gratifying. The woman's cholesterol level fell 30% without any use of cholesterol-lowering drugs.

During the mid to late 1990s, research in human somatic cell gene therapy grew steadily. As of June 1999, the Recombinant DNA Advisory Committee, which must review all gene therapy proposals conducted with federal funds (which is essentially all proposals), had approved 313 protocols, of which 40 focused on efforts to treat just 15 single-gene disorders. Many others attempt to treat a variety of cancers, AIDS, and heart disease. However, the large number of trials is not evidence of rapid progress. Indeed, Dr. Harold Varmus, then the Director of the NIH, was openly critical of the field and faulted it for shoddy basic science. Despite the huge research effort, several scientific hurdles have been difficult to clear. For example, it remains difficult to construct a viral vector that will deliver donor DNA into the genomes of enough of the patients' cells to show a positive clinical effect. Even when an effect is seen, it is usually transient, which, given the cost of gene therapy, suggests that the potential treatment would be impractical. Furthermore, the risks of gene therapy remain exceedingly difficult to quantify. As a result, each research trial must begin slowly with a controlled and careful escalation of the dose of viral particles that contain the therapeutic DNA. Those risks took on a new dimension in the fall of 1999 when an 18-year-old man undergoing gene therapy at the University of Pennsylvania died four days after being injected with the engineered virus.

The First Death

Jesse Gelsinger was born with an unusually mild form of a rare and often fatal genetic liver disease called ornithine transcarbamylase (OTC) deficiency, a defect in one of the genes that code for enzymes which partici pate in a biochemical pathway that removes ammonia (a by-product of metabolizing proteins) from the body. His disease was mild for an unusual reason. The causative mutation had arisen after conception and only affected some of his cells. He was in fact a "mosaic," having two different cell lines, one normal and one abnormal. Despite occasional hospitalizations for elevated ammonia levels, Jesse, who lived in Arizona, was doing well, but when his pediatrician informed him about a new research program at the University of Pennsylvania to attempt to treat the disorder by delivering a normal OTC gene (which had been attached to a weakened adenovirus) to the liver, he jumped at the opportunity. He felt a deep sense of commitment to help other children who were much more severely affected with other variants of the same disorder.

Jesse, who was the 17th and last person to be treated under the protocol, underwent his therapy in a radiology suite on September 13. Because the gene vector was intended only to treat liver cells, it was delivered via a special catheter inserted into his groin and threaded through his blood vessels to reach his intrahepatic artery, the major source of blood supply to that organ. Jesse became ill within hours of receiving the maximum dose permitted under the protocol. He spiked a high fever, and over the next 48 hours developed acute, fulminate liver failure followed by adult respiratory distress syndrome. He died on the fourth day.

Of course, the research team immediately reported the death and both the NIH and Penn immediately initiated an investigation of Jesse's treatment as well as those of all the other human subjects who had been treated (no one else had become dangerously ill or died). NIH immediately placed a "clinical hold" on a number of related research trials, including two being conducted by the Schering-Plough pharmaceutical company. The death, the first resulting from gene therapy, received wide attention from the press, sometimes with a sensationalist twist that may help to slow research like this over the next couple of years. For example, the New York Times Magazine ran a major story on November 28 entitled, "The Biotech Death of Jesse Gelsinger," which suggested that the whole field needed to slow down and be subjected to more detailed oversight.

Any avoidable death is a tragedy. Surely, those committed to advancing gene therapy and those who must review and approve or reject new protocols will long remember Jesse Gelsinger's death. But the prospects are much too promising to stop. In the summer of 1999, an American com pany called Vical announced that it had used gene therapy to treat prostate cancer and had seen dramatic reduction in tumor size in all 12 men who were treated. In October, Dr. Victor Dzau, chief of medicine at the Brigham and Women's Hospital in Boston, reported that he had successfully used gene therapy to treat clogged leg vessels. His aim is to do the same for heart vessels.

Given that in September 2000 somatic cell gene therapy will celebrate its tenth birthday, it is fair to say that progress has been slow. By the close of 2000, scientists will probably have attempted gene therapy in fewer than 1500 people, and they will not be able to claim an absolute cure for any of them. However, this limited progress must be put in perspective. Once scientists develop highly effective ways to deliver corrective DNA to target cells, an area where there has been steady progress, the use of this therapy will greatly increase.

I expect that between 2005 and 2010, somatic cell gene therapy will emerge as routine treatment for a variety of single-gene disorders, especially all those currently treated with donated bone marrow cells (there are more than a score ranging from the relatively common thalassemias to the rare Wiskott-Aldrich syndrome, a disease of premature aging). One of the great advantages of using gene therapy is that the work is done on the patient's cells so there are no immunological problems such as those that plague persons needing organ transplants.

What is the likely future of germ-line genetic engineering? As we become more therapeutically proficient, there will be instances where it will make sense to go forward in the clinic. For example, consider a couple facing a 1 in 4 risk of having a child with Tay-Sachs disease (a uniformly fatal brain disease of early childhood) who are unalterably opposed to abortion. The couple might opt to conceive by in vitro fertilization, undergo a test called preimplantation diagnosis, and, if the embryo is destined to have the disease, have gene therapy to correct the defect before the future child is transferred into the mother's womb. Such a therapy alters in a minuscule way the future of the human gene pool. It permits a child who might have died in childhood to grow to adulthood and have children of his own, passing on, as all parents do, reshuffled combinations of his genes. Of them, one will be an artificial, but functional, version of the gene for hexosaminidase A, the enzyme which when dysfunctional causes Tay-Sachs disease. It poses no threat to future generations.

Before 2020, germ-line engineering to cure severe genetic disease in human embryos will be an established therapeutic option. It will, however, be used infrequently. Many couples who know they have a 1 in 4 risk of bearing a child with a severe genetic disorder will continue to use prenatal diagnosis and selective abortion (the course followed today by the vast majority of couples who know they are at risk for having a child with Tay-Sachs disease) or preimplantation diagnosis. Preimplantation diagnosis combines the techniques of in vitro fertilization with highly sophisticated DNA-based testing. Technicians tease a single cell away from an 8-cell embryo and test it for the disease. If the embryo is not burdened with the disorder, it is implanted in the woman.

Perhaps even more exciting is the prospect for treating many fetuses known to have genetic disorders in utero. Although this has not yet been attempted in humans, it is attractive because (1) it could avert the signs and symptoms of disease, (2) fetal cells are likely to be more efficient at taking up and incorporating gene vectors, and (3) immunosuppression will not likely be needed. During the last decade, there have been impressive strides in performing surgery in utero to treat major birth defects. As gene therapy requires merely delivering cells to a fetus, the necessary surgery will be comparatively simple.

The great scientific, ethical, and political debate that looms ahead is not over the use of germ-line gene therapy to treat persons suffering from disease, which is as inevitable as it is welcome. The controversy will surround efforts to "improve" prospects for success in life by making humans smarter, more beautiful, more athletic, or more outgoing, or by improving some other potential in their lives. As the technology to accomplish this will eventually be indistinguishable from that used to treat serious disease, this will happen. However, we know so little of the genetic contribution to such qualities, one can confidently predict it is still many decades from realization. It is still anybody's guess, but it is possible that by 2050 germ-line enhancement therapy might be as common as and no more controversial than cosmetic surgery.

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