Human Gene Therapy

Chris Wharam

Copyright 1999

Ashanthi Desilva is now able to ride her bike in her suburban Cleveland neighborhood. She can play basketball with her friends or go fishing with her family. She is slightly inconvenienced by her weekly shot of the critical immune system enzyme: adenosine deaminase (ADA). Ashanthi was born with a faulty gene that results in the inability for her body to produce ADA, leaving her dangerously susceptible to even the weakest of infections (Brown). In 1990, researchers collected samples of Ashanthi's blood, isolated some of her white blood cells, and incorporated into them a virus engineered to contain a healthy ADA gene. These cells were then injected back into her body. She was the first patient to undergo gene therapy, and without that therapy and the weekly shots of ADA, she would have been destined for a life of isolation.

Human gene therapy is the replacement of an absent or faulty gene with a functioning gene. As a result, the body is able to produce the correct enzyme or protein, thereby eliminating the cause of the disease (Gene_Therapy_Overview). There are essentially two types of gene therapy: somatic cell therapy and germ line therapy. Somatic cell therapy involves treating any cells of the individual, except the gametes, at the cellular level to correct an absent or malfunctioning gene. This can be accomplished in three ways: ex vivo, in situ, or in vivo. Ex vivo involves removing cells from the patient, altering the genetic material, and placing them back into the patient. In situ requires the vector be placed directly into the affected tissues. In vivo gene therapy involves injecting the vector into the bloodstream. The vector then must find the target tissue and deliver the therapeutic genes. Germ line gene therapy treats the gametes or an embryo, which would be used in the case of in vitro fertilization. The difference between somatic and germ line gene therapy may seem to be subtle; however, the alterations obtained through germ line therapy are not only found in that generation, but are passed on to the individuals progeny. That has serious repercussions when it comes to discussing the ethics of using germ line therapy.

Presently, similar techniques are being examined for both somatic and germ line gene therapy, but germ line therapy is more difficult (Coults). This is not to say that somatic cell gene therapy is easily accomplished. One challenge facing researchers is finding a suitable vector that would safely and efficiently deliver the genetic payload into the patients' genome. Retroviruses were recognized early on as a powerful gene-transfer mechanism. They can effectively transfer genes into many cell types and can integrate into the host cells genome, which leads to the potential for long-term expression (Anderson). The retrovirus of choice for clinical protocols has been murine leukemia virus (MuLV). These retrovirus vectors are stripped of all viral genes, which leaves room for up to eight kilobases of DNA (Anderson). Retroviruses as vectors have encountered problems in development. Engineering a retrovirus to efficiently deliver its genetic payload to targeted cells has been challenging. A second problem is that many of the targeted cells are non-dividing, therefore the MuLV will not transduce those cells. Lentiviruses, such as HIV-1, are able to transduce non-dividing cells; however, serious safety concerns are associated with the use of HIV as a vector.

If a retrovirus was developed that was able to effectively deliver its genetic payload to the targeted cells and was capable of transducing the host cells, another problem is encountered. The problem is sustaining an appropriate level of expression on a long-term basis. There are several factors that limit long-term expression. Once in the host genome, the new gene will often be recognized by its viral promoters and will be deactivated. If the new gene is lucky enough to remain active, the immune system quite possibly will recognize the new protein, produced by the new gene, as foreign and will eliminate it. Once long-term expression of a therapeutic gene is developed, the next challenge will be to develop a means of regulating the expression of the therapeutic gene.

Yet another problem associated with the widespread use of retroviruses as vectors is the difficulty in manufacturing mass quantities of the vector. This requires good quality control, which is mandated by the strict guidelines provided by the FDA. As with pharmaceuticals, many years of research and development are involved in the production of a safe, effective product.

Adenoviral vectors are an alternative to retroviruses, and they have some characteristics, which make them suitable vectors. First, they are large so they can carry a large genetic payload. Second, they have the ability to efficiently transduce a wide range of cell types, including non-dividing cells (Anderson). Even with the previously mentioned attributes, adenoviral vectors have some flaws. Similar to retrovirus vectors, an immune response has been observed with the use of adenoviral vectors. This results in the inability for long-term expression.

Other vectors have been studied including, adeno-associated viral vectors and herpes simplex virus vectors. These are both site specific, but will require much more work to be used in a routine manner. Non-viral vectors including liposomes, oil based envelopes packed with therapeutic genes, are being examined (Brown). The advantage of these non-viral vectors is the safety and the ability to produce mass quantities with relative ease.

Vectors will need to be produced for many different situations depending on the particular disease being addressed. Diseases that are already being treated with gene therapy include combined immune deficiency, familial hyperchloresterolemia, cystic fibrosis, and adenosine deaminase deficiency. Many other disorders are potential candidates for gene therapy.

Arguments for and against gene therapy

The strongest argument for gene therapy is that it may be the only method to treat the gravely ill or prevent the onset of otherwise unavoidable illness. Those individuals with a family history of a genetic disease could be screened to determine if they have the potential for developing the disease. If the individual had the potential for disease, somatic gene therapy may be used to correct the disease causing genetic sequence. For some, gene therapy may be the only hope. It is reasoned by those in favor that gene therapy, particularly somatic cell gene therapy, can be at least as safe and more effective that current medical procedures, and should simply be viewed as one of the very powerful tools in the medical toolbox. Those involved in medicine are bound by oath to treat patients to the best of their ability, thereby, withholding gene therapy would be to withhold a dramatic way to treat patients.

A second strong argument for the use of gene therapy is that unlike many conventional medical practices, gene therapy addresses the cause of the disorder rather than the symptoms. Gene therapy can provide a lifetime unencumbered by chemotherapy, radiation, or other conventional medical solutions.

As mentioned previously, the main difference between somatic cell and germ line gene therapy is that the results of germ line therapy is persistent through subsequent generations. Those in favor of germ line gene therapy argue that it is the only way to prevent the transmission of genetic disease, thereby, avoiding the cost and risk involved in other treatments including somatic cell therapy for generations to come. Supporters of germ line therapy also suggest some genetic diseases can only be addressed via germ line therapy. This is the case with very severe genetic disorders that do not allow the embryo to develop to the point that other medical procedures can treat the problem.

There are two recurring phrases use by those against gene therapy: "slippery slope" and "playing God". The "slippery slope" is referring to the development of gene therapy for a valid medical reason, but used for purposes not initially intended. At the first Gene Therapy Policy Conference sponsored by the Recombinant DNA Advisory committee (RAC) of the National Institutes of Health ( NIH), scientists predicted that within 2 years, a researcher will propose a gene-therapy experiment that, although initially aimed at curing disease, could eventually be used to enhance a trait in healthy people (Vogel). One such example has to do with hair loss as a result of chemotherapy. A biotechnology company has developed a means of transferring genes into hair follicles, and is looking for the genes that promote hair growth. The objective is to reverse hair loss due to chemotherapy, which seems to be a worthy cause. If the company is successful and develops a protocol to stop hair loss, cancer patients would no longer have to be bald. However, those opposed to gene therapy worry that many naturally balding people will be receiving gene therapy to treat their hair loss (Anderson). This example is quite petty, but those against gene therapy cite it as just the beginning in a "slippery slope" towards the development of a superior human. The creation of a super human is also the fear motivating those who believe science is "playing God". The reasoning behind this belief is that we are to play the hand we are dealt, and science is trying to alter the hand. Those opposed to germ line therapy fear it involves too much uncertainty, risk, and the long-term effects are unknown (Anderson). The ability of alterations made through germ line therapy to persist in the population is a grave concern held by those opposed to this type of therapy. The creation of unconsenting research subjects due to the persistence of germ line therapy is another concern of those opposed.

My perspective

I am split in my opinion on gene therapy. If it is strictly monitored and regulated, I believe that somatic cell gene therapy as a treatment for terminal disorders would be a very valuable option. I feel that once the techniques involved in somatic cell therapy are refined to the point that the benefits outweigh the potential problems, there is no reason to treat this procedure any differently than other medical procedures. I would even support more widespread use of somatic cell gene therapy after the techniques had been perfected in more serious disorders. If I had a child diagnosed with ADA deficiency like the young girl, Ashanthi DeSilva, mentioned previously, I would like to have gene therapy as a option in treating the condition.

On the other hand, I am not comfortable with the use of germ line gene therapy for a couple of reasons. The persistent nature of germ line therapy could be devastating if abused. It seems like science fiction, but if used carelessly a super human could be produced. This technique has the potential to allow disorders to be eliminated, but it also could allow for choice rather than chance in other traits. A second concern is that by removing deleterious genes potential problems may arise. In some cases, it is difficult to distinguish deleterious from normal or healthy genes. A classic example is the relationship between sickle-cell anemia and malaria. Only individuals having two copies of the sickle-cell gene suffer from the disease. Those with one sickle-cell gene and one normal gene are unaffected, and are able to resist malaria (Altered Genes). If this relationship exists, I would speculate others remain unknown. There is a chance that by replacing deleterious genes with normal genes the population could be left unable to fend off other problems.

As a whole, gene therapy appears to be very promising; however, there are many challenges still facing this fledgling technology. I feel one of the largest challenges will be the public debate surrounding the use of genetically engineered material in human subjects. The debate encompasses such fields as biology, government, law, medicine, philosophy, politics, and religion. Each of these groups brings a different view. I feel these groups will have a difficult time coming to an agreement on the use of gene therapy, but those in support have the successful story of the first gene therapy patient, Ashanthi DeSilva, to use as a trump card.


Brown, Kathryn S. "Mending Broken Genes." Obtained from the WWW. 10/13/99:
Coutts, Mary Carrington. "Human Gene Therapy." Obtained from the WWW. 10/13/99: 1998:
French Anderson, W. "Human Gene Therapy." Nature. 30 April 1998; v392, pg. S25-S31.
Vogel, Gretchen. "From Science Fiction to Ethics Quandry." Science. Sept. 19 1997; v277, pg. 1753-1755.
"Gene Therapy- An Overview." Obtained from the WWW. Access Excellence@ the National Health Museum. 10/13/99: 1990:

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