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Gene therapy

Some problems faced by babies arise because development goes haywire. Some arise during the birth process. Some problems are hardwired in the baby's genes.

When the problem is genetic, a remote possibility exists for correcting the defect by replacing faulty genes with genes that work properly. Such gene replacement therapy is still a long way off, but researchers are seriously considering it.

How would gene replacement therapy work?

The strategy in gene replacement therapy is to substitute a gene that works right for the gene that is not working. Gene replacement therapy has potential when the disease or condition is caused by a single gene defect. Hundreds of human diseases are caused by defects in single genes. Among these are cystic fibrosis, sickle cell anemia, ADA deficiency, Duchenne muscular dystrophy, and others.

Several criteria must be met for gene replacement therapy to work, and not all diseases or conditions that are caused by single gene defects could be corrected easily.

The defective genes have to be in cells that are accessible, so that a good gene could be put in the cells in place of the defective one.

It is helpful if these cells divide, so that they can repopulate the body with a complete set of working cells; if the cells don't divide, a new gene must be inserted in every single defective cell.

The cells have to function for a long time, so that the therapy would not have to be repeated over and over again.

The defective gene has to be of the type that does not produce a dangerous or destructive product. The best targets for this are the genes that simply don't work; otherwise, not only would a new and good gene have to be inserted but the old defective gene would actually have to be deleted.

Some of the first attempts at gene therapy have been with people who have cystic fibrosis. The gene that is defective in this disease is one that codes for a protein that lies in cell membranes. The protein acts as a channel in the cell membrane through which ions move in and out of the cell. Scientists have attached a normal gene to a virus that transports the good gene into the nuclei of cells. The gene fixes the channel in the membrane such that the ions are correctly transported.

But, the problem cells in cystic fibrosis line the mucus membranes of the respiratory tract and the gastrointestinal tract, and these cells are regularly sloughed off and replaced; they generally live only a few days. Thus, even though it is possible to insert a new gene into the cells and have them produce the product that ensures proper ion flow in the cells, the effect lasts only briefly. As this situation illustrates, gene therapy is not going to be the cure-all for cystic fibrosis, because it is impractical to design an expensive therapy that would have to be repeated every three days throughout a patient's life.

Because so many conditions have to be met for gene therapy to be effective, it is not likely that there will be many diseases for which gene replacement therapy will be suitable. But, for those fitting all the criteria, gene therapy could prove to be a dramatic form of therapy.

An alternative to gene therapy in many situations may involve preimplantation diagnosis. Eggs are fertilized in vitro. Then a single cell is removed from each embryo, and each is tested to see if it lacks the defective gene. Only embryos that lack the defective gene would then be implanted. Preimplantation diagnosis does not ensure a "perfect baby" though, because other genes could be defective. Researchers can only test for those genes that they have a handle on. 

Ethical issues associated with gene therapy

Gene replacement therapy is not just difficult from a mechanical perspective. It also raises some thorny ethical issues.

Scientists have sorted possible types of gene replacements into three categories: gene replacements in somatic cells, gene replacements in germline cells, and gene replacements for the purposes of enhancement. For gene replacement therapies to be effective, the normal genes have to be inserted in all cells (or some high percentage of them) in the person who has the defective genes. The genes have to work in these cells, and their effect must override the effects of the defective genes.

The goal of somatic gene replacement is the substitution of normal genes for defective genes in all relevant cells of a person who has a disease or condition that is caused by a single gene defect. The treatment is geared only to the affected individual, not future generations. Most ethicists see this type of therapy as reasonable. The technical barriers remain enormous.

Germline gene replacements are aimed at fixing genes in the "germ cells"?the sperms and eggs of individuals. Thus, such replacements would affect not just the person with the disease but also future generations. Germline gene replacements have generally been considered unacceptable by most ethicists. Such therapy would violate a key tenet of medical ethics?that patients must give informed consent before they undergo any medical therapy. People who are not yet born cannot give consent. The ethics of germline interventions have been intensely debated, but, in recent years, the absolute prohibition against germline gene therapy seems to have eroded. Some of this has to do with the role of the media and the language used in news reports when steps toward this therapy have been taken: they are reported as deeds accomplished rather than as possibilities to consider. Some of the change comes from what is called "the technological imperative," that because something can be done it will be done.

Enhancement gene therapy falls into a "slippery slope" area. As one ethicist put it, there is no obvious line between negative eugenics that would eliminate deleterious genes and positive eugenics for the purpose of "perfecting" humans. Therapy done to "enhance" characteristics, such as height, is generally considered trivial and not appropriate. Enhancement smacks heavily of eugenics and the effort to improve humans according to some narrow standard (generally enunciated by white male researchers). Enhancement can be ambiguous. For example, suppose scientists discover a gene for shyness. For some people, shyness might just be an inconvenient or embarrassing characteristic. But for others it might be tragic and all-consuming, preventing them from leaving the house, getting a job, functioning socially. Is shyness a trait or a disease? Would the gene for shyness be a suitable target for gene replacement therapy?

Students may find it interesting to discuss which traits they would consider would be worth correcting if they are caused by single genes and are amenable to fixing.

Other issues in gene therapy

Not long ago, gene therapy seemed to be only on the distant horizon. In an editorial in 1993, the geneticist J.V. Neel, who was asked to discuss the prospect with the Recombinant DNA Advisory Committee, wrote that he "could not imagine serious organized discussions of this subject by such a group within the next 20 to 30 years (1)." He pointed out that the DNA of the human species has been evolving for 4 billion years and that it is simply "intellectual arrogance" to expect to know enough about the complexities of DNA?which has only been under study for 40 years?to make appropriate changes in its structure that would not backfire. Now gene therapy seems to be just around the corner.

Neel recalled that the eugenics records at the Cold Spring Harbor Laboratory in the 1920s and 1930s proved to be incredibly naïve. He wrote that the lessons from somatic cell gene therapy are "barely divulged," and their nuances are not yet known. "To me, as a population geneticist, germline gene therapy represents the ultimate in the manipulation of the biological order. Let's for once take our time," he concluded. In addition, he noted that somatic gene replacements are likely to result in at least some inadvertent germline gene transfers that will affect future generations.

If somatic gene therapy actually works, some people who would not have reached maturity otherwise will be able to have children. One concern is that this could create more problems than it fixes, because the babies born to these individuals will have the same genetic problems that their parents have.

Another concern about gene therapy that its opponents have raised is that genes might be eliminated from the population that could be needed for survival in the future. This argument is a bit off the mark, because eliminating a gene in a few individuals is not going to eliminate it in a population. For the disease Tay Sachs, for example, even if the gene is replaced in all affected embryos (to have the disease, an individual must receive a copy of the defective gene from each parent), the frequency of carriers in the overall population will only change from .01000 to .009000 in one generation.

The current technology for replacing genes involves putting new genes into chromosomes, but the genes do not go into the "slot" where the defective gene is. It is possible that the new gene could end up in the middle of another gene and cause more problems than it solves. At the moment, gene therapy is not all that safe.

Things to think about

In 1967, Marshall Nirenberg said humans will be able to program their own cells in 25 years, but they won't know how to address the long-term consequences of the program (3). How accurate was he?

Jeremy Rifkin has had a strong influence on public opinion. He has drawn attention to recombinant DNA research and human gene therapy. Students may find it interesting to learn about his positions and arguments and how they have influenced public opinion about genetic research.

Students may be interested in the "technological imperative"?the concept that there is no distance between possession of a new capability and its actual use?and how this fits in with acceptance of gene therapy.

  1. JV Neel, Human Gene therapy 1993 4(2): 127-128. Germ-line gene therapy: another view.
  2. Ethics of Gene Therapy, Chapter 10, Morality and the New Genetics, B. Gert et al., Jones and Bartlett Pub. MA 1996.
  3. Latchman, DS, Gene Therapy 1994, 1(5): 277-279. Germline Gene Therapy?


The supporters of the eugenics movement sought to permanently improve the human race. And, what constituted an improvement? They generally used themselves as the models for the types of humans that they considered worth salvaging and breeding.

Sir Francis Galton came up with the word "eugenics" in 1883. It meant good heredity. The eugenics movement had two broad branches: positive eugenics, through which certain matings were promoted in order to increase the prevalence in the population of individuals with desired genes, and negative eugenics, which involved getting rid of people with undesirable genes or at least preventing them from reproducing. The eugenicists' approaches to creating "superior" humans included "better baby contests," which were like the cattle shows at county fairs, restriction of immigration of certain groups of individuals (from Asia and eastern Europe, mainly), strong support for killing people considered defective, selective breeding, and sterilization of criminals, institutionalized individuals, epileptics, prostitutes, the poor, alcoholics, orphans, and others considered to be leading "lives not worth living."

Early in this century, the eugenicists translated Mendel's discoveries with peas?that size, number of peas, and other traits were inherited?to mean that all traits of humans, including social ills, were genetic. Thus, they believed that everything is hardwired into a person's genes. Various economic and social factors caused them to worry that the natural process for weeding out the weak?survival of the fittest?would be subverted by new public health measures. They feared that the sickly would not die out but would live to breed and even reproduce faster than the strong, superior individuals. They energetically opposed certain public health measures. Said one, "The growth of sanitation, hygiene, and State medicine . . . attempts to secure an ever-increasing survival rate for the least competent types . . . This interference with Natural Selection (is) disastrous. " (See 1)

The leading eugenicist in the United States was Charles Davenport, who ran the Eugenic Records Office at the Cold Spring Harbor Laboratory (2). He commented that "the artificial preservation of those whom the operation of natural agencies tends to eliminate . . . may conceivably destroy the race." He said it was antisocial to "unduly restrict the operation of what is one of Nature's greatest racial blessings?death." (See 1) 

The first law permitting sterilization in the United States was enacted in Indiana in 1907, and 31 other states passed similar laws by 1937. Somewhere between 60,000 and 100,000 people were involuntarily sterilized in the United States. Their "defects" included epilepsy, poverty, mental retardation, insanity, prostitution, and being orphans (3). Often people did not know that they had been sterilized; sometimes, the procedure became a precondition for letting the person out of an institution.

It seems surprising today that the Nazis credit the eugenics movement in the United States for giving them some ideas, programs, and models for some of their crimes against humanity. The Germans began their sterilization program in 1937, sterilizing all the children who were born of white German mothers and African troops in the French Foreign Legion (3). Soon, the Germans were sterilizing Jews, Gypsies, people who did not go along with government policies, and others.

As a result of the Holocaust, the term "eugenics" no longer has any positive connotation, and today it is considered a dangerous movement.

Thus, people today are wary of the Human Genome Project and legislation that might allow for physician assisted suicide. Both of these have the potential to bring back the old slippery slope problems of eugenics. Both could degenerate into arguments about a hierarchy of human worth (2).

Things to think about

A half century after the end of the Holocaust, people are still unsure how to explain the complicitous role of German doctors in the Nazi war crimes?sterilization, euthanasia, and cruel experiments on humans. In Germany, by 1942, about half of the physicians in the country had joined the Nazi party and were willingly going along with the government's race hygiene policies. How is it that physicians, who swear the oath of Hippocrates to protect patients and do no harm to them, could so readily buy into the party's racist policies? Few of the Nazi doctors were ever held accountable for what they did. What actions and policies would help to ensure that similar injustices do not happen again?

  1. American Journal of Public Health 1997, 87(11): 1767-1772.
  2. JAMA 1996, 276(20): 1657-1661.
  3. Am. J. Hum. Genet. 2994, 54:148-158.

Steroid Therapy for Premature Infants

The nine months that a fetus spends inside its mother are crucial for complete maturation of its organs. But some babies start making their way into the world before they are fully developed. Babies born early are called "preemies," because they start their lives prematurely.

The hearts, lungs, nervous systems, and gastrointestinal tracts of normal healthy babies get a jumpstart at birth from hormones that are released by the adrenal glands. For a preemie, these hormones are not released, because the adrenal glands are immature and not ready for the release. The other organs and systems remain dormant, and the preemie requires artificial help in order to breathe and eat.

The most common and costly medical problem associated with preemies is respiratory distress syndrome, and it is a complication that begins when the newborn preemie attempts to take its first breath. The average hospital stay for a baby with respiratory distress syndrome is 50 days and the average bill for such a baby's hospitalization is $49,000 (Washington Post Health, 1998, April 21, 7).

Thus, today an effective therapy for many preemies is injection of the missing hormones. This promotes the maturation of the lungs, the gastrointestinal tract, and other organs and tissues.

The hormones stimulate the synthesis of a variety of proteins and peptides that are crucial for infant development. In the lungs, for example, the hormones induce several changes that increase lung capacity and decrease the likelihood that the baby will experience respiratory distress. They also induce surfactant, which coats lung tissue and prevents the lungs from collapsing.

When it is apparent that a fetus could be born prematurely, the hormones will be given to the pregnant woman. Hormones also are helpful after birth for weaning the infant from the ventilator that is helping it to breathe. All babies?female and male, black and nonblack, babies born at different gestational ages?seem to benefit from the hormone treatments.

But not everything is rosy about hormone treatments. A recent report indicated that there may be a period right after birth?during the infant's first couple of weeks of life?when the hormones cause more trouble than they prevent. During that period, they may temporarily suppress the immune system, making the infant vulnerable to infections. They may also increase blood pressure and slow weight gain for a time.

Overall, though, hormone treatment for fetal organ maturity seems to clearly save lives. Yet only 15% of premature infants in the United States receive hormone treatments. A day in the neonatal intensive care unit costs about $1000; the hormones cost less than $20 a day. Some of the women who are at risk for delivering a preemie lack adequate prenatal care, have no insurance, or simply don't recognize that their pregnancy and fetus are in trouble.


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