Aspects of Human Gene Therapy

Bradford K. Ramsdale

Copyright 1997


The prospect of human gene therapy was first realized in 1971 when the first recombinant DNA experiments were planned. Gene therapy can be simply viewed as inserting bits of foreign DNA into a patientís tissue in hopes of evoking a biologic response that will effectively eliminate the targeted disease. Major advances in recombinant DNA technology have occurred over the last 20 years so that now gene therapy is becoming a reality. Gene therapeutic techniques have recently been attempted to treat patients with the genetic diseases severe combined immune deficiency (SCID), cystic fibrosis, and Duchenneís muscular dystrophy (Donegan, 1995). The optimist foresees a time when a patient will simply receive a snippet of DNA and go home cured. There are many ethical and scientific hurdles that must first be crossed for such a dream to become reality. The technology has advanced so rapidly that many ethical questions werenít originally addressed and accordingly are now becoming the center of attention regarding human genetic research. Furthermore, scientists must find a way to outwit the bodyís immune system which is primed to fight any foreign material such as inserted genes. There are also difficulties in getting the targeted cells to open up their molecular locks to allow the foreign genes inside. Gene therapy, like other medical advances before it, will have numerous failures before reaching its full potential. It will be important for the public, press, and medical industry to be patient in waiting for the dream of gene therapy to become a reality.

Technological Aspects of Gene Therapy

The underlying principle of gene therapy is the transfer of genetic material to specific cells of a patient in an effort to initiate a biological response to fight or eliminate a disease. There are two possible types of target cells, somatic cells that are non-reproducing, or reproducing germ-line cells. If germ-line cells are permanently altered, all future generations would be effected. Most of the current human genetic research involves somatic cells since the ethical ramifications of germ-line cell modification is still being debated. Some scientists have expressed concerns that even altered somatic cell genes could find their way to reproducing, germ-line cells (Donegan, 1995). Accordingly, regulations are strict in regards to somatic cell gene modification techniques so that this gene migration will not occur.

Transfer of genes to target cells is usually accomplished by some sort of vector such as retroviruses, adenoviruses, or liposomes (Mulligan, 1993; Crystal, 1995). Viral vectors are modified such that the reproductive genes are removed. The therapeutic genetic material is inserted into the genetic makeup of the vector which subsequently attacks the somatic cells. This effectively transfers the therapeutic genetic material into the targeted tissue. The delivery of genetic material can be conducted ex vivo (outside the living body), in vivo (inside the living body), or in situ (in position). In the ex vivo method, the target cells are removed from the body so that the vector can be administered to the cells in the laboratory. After successful gene transfer, the cells are then re-administered to the patient. The in vivo approach involves transferring the vector with the therapeutic genes directly to the target cells inside the patient. A modification of this technique is the in situ method (Donegan, 1995). The vector is inserted directly into the affected tissue rather than the blood so that only the immediate area is treated. The in situ method had been used to treat Duchennesís muscular dystrophy patients.

Retrovirus vectors have been used in many of the first attempts at gene therapy such as the treatment of SCID patients. Retroviruses are best suited for ex vivo gene therapy. One of the most desirable characteristics of retroviruses is that they are able to stably transduce close to 100% of the targeted cells (Mulligan, 1993). Retroviruses also transfer the genetic material to the genome of the target cell so the genotype of that cell is permanently changed. Accordingly, a major risk associated with retroviruses is the potential for chronic over expression or insertional mutagenesis (Crystal, 1995). This could prevent a tumor suppressor gene from being expressed or lead to the expression of an oncogene. One of the reasons why retroviruses are not inserted in vivo is because the target cell must have the appropriate viral receptor in order for the retrovirus to gain entry into the cell. Retroviruses are limited because the target cells must replicate so that proviral DNA can integrate into the cell genome. Since retroviruses are relatively labile, they also suffer from low production problems.

Although adenoviruses can be used ex vivo like retroviruses, their greatest potential is for in vivo gene transfer (Mulligan, 1993; Crystal, 1995). This is primarily due to the fact that adenoviruses can transfer genes to both replicating and non-replicating cells and because they can express large amounts of gene product. One factor that distinguishes adenoviruses from retroviruses is that the genetic material is transferred to epichromasomal regions so the cell genotype is not permanently altered effectively eliminating any associated risks. On the other hand, many of the current adenoviruses can lead to inflammation and antivector cellular immunity and consequently limit the duration of gene expression.

In vivo therapeutic gene delivery by the use of plasmid-liposome complexes has received less attention than adenoviruses and retroviruses although there are several distinct advantages to such an approach. These liposome complexes can deliver virtually an unlimited amount of genetic material compared to the limitations of 9 kb for retroviruses and 7.5 kb for adenoviruses (Crystal, 1995). Additionally, there is no danger of the formation of an infection as the result of replication. Since the plasmid-liposome complexes lack proteins, there should be little chance of inflammation or antivector cellular immunity responses. The primary disadvantage is that the complexes are rather inefficient requiring the administration of thousands of plasmids to the target cell to successfully transfer the genetic material.

A relatively new approach of transferring therapeutic genetic material to target cells is by using a bacterial vector (Donegan, 1995). Like the viral vector approach, the reproductive genes are removed from the bacteria in order to prevent a debilitating bacterial level from developing. Scientists believe that bacteria will reliably move to specific areas of the body such as the intestines and bowels. Once the bacteria reach the target cells, it will try to reproduce though unsuccessfully. Consequently, the bacteria will burst open and deliver the therapeutic gene.

Ethical, Legal, and Social Considerations of Gene Therapy

The rapid progression of recombinant DNA technology has stimulated great debate over the numerous ethical, social, legal, and regulatory implications of human genetics research and gene therapy. Questions regarding the need for the strict regulations implemented by the Recombinant DNA Advisory Committee (RAC) and the Food and Drug Adminstration (FDA) have been raised by the biotechnology firms that conduct the genetics research. The decision by the Supreme Court to allow gene patenting is continually being denounced by various religious organizations. Should germ-line gene therapy even be considered is a question that is pondered by not only religious organizations but also the scientific community itself. There are also many questions involving genetic screening such as when and if it should be done as well as whether or not prospective employers and insurance companies should be allowed to require such tests. The fear of a new era of eugenics is also a legitimate concern given past events that illustrate the downside of human nature.

Probably the greatest debate regarding human gene therapy is whether or not germ-line therapy should be pursued. Since germ-line cells are the reproducing cells, each subsequent generation will be effected by such alterations. Proponents of germ-line therapy offer these arguments: 1) there is an obligation to use what ever technology is available to treat genetic diseases; 2) parents should have the opportunity to ensure the health of their children; 3) future generations should benefit from the elimination of genetic disorders (Donegan, 1995). Much of the opposition to germ-line therapy argue that such permanent alterations are too risky since mistakes can not be corrected. Obviously risks should be considered, but morally speaking, do we have the right to determine the fate of our future generations. The alternative to germ-line manipulation, offered by some opponents, is to utilize genetic screening as a tool to identify deadly genetic disorders and selectively eliminate affected embryos or fetuses. This brings up an entirely separate ethical dilemma as to the implications involved in genetic screening.

Dan Brock, a philosopher in the Bioethics Department at Brown University, suggests that women have the moral obligation to have prenatal genetic screening and to abort any affected fetuses thus preventing "wrongful life" (The Gene Letter, August 1997). He described "wrongful life" as one in which the childís existence would be brief and of poor quality as a result of diseases like anencephaly, Trisomy 13, and Tay-Sachs disease. Brock also stated that women have a moral obligation to prevent "wrongful disabilities" by selecting a different mate (or donor sperm or egg). Perhaps the best argument against Brockís "wrongful life" and "wrongful disability" views is where does one draw the line in regards to what is a life not worth living. An alternative view has been adapted by the National Down Syndrome Congress on Prenatal Testing and Eugenics (The Gene Letter, May 1997). Their position is that it is a pregnant womanís exclusive right to decide whether or not to have prenatal testing regardless of age, reproductive history, and disability status. The decision to continue a pregnancy is also solely the right of the woman no matter what the prenatal diagnosis reveals.

Donegan, 1995, outlines a hypothetical situation involving Huntingtonís disease which is incurable at this time. The question he offers is when should a genetic screening test be conducted for individuals with a family history of Huntingtonís disease. Should a parent be tested before deciding to have children; should the children be tested after they are born; or should the fetus be screened by amniocentesis. Difficult decisions would then have to made based on the results such as should the fetus be aborted or should the parents seek other alternatives for obtaining a child. Probably the most important aspect of genetic screening is proper counseling so individuals will be well educated as to their options.

Another point of debate is whether gene therapy is being pushed forward too quickly by commercial interests or is the current state of regulation too restrictive. The Biotechnology Industry Organizationís (BIO) view is that the review and approval process conducted by the RAC and FDA is too slow and ultimately restricts major advances from occurring. Congressman Newt Gingrich referred to the process as "the leading job killer in America" (Donegan, 1995). He also pushed to eliminate the FDA from the review process entirely. Instead, he suggested that an organization of "biomedical entrepreneurs" would be best suited for approving new products and research protocols. Supporters of the current review process point to the fact that the RAC reviews are open to the public and press while the FDA sessions are closed. The RAC is a combination of a science and ethics advisory board representing individuals with a diverse background. This representation ensures that ethical issues will be weighed equally against safety issues and potential monetary gains. Recently, there has been a change in the review process such that now the FDA conducts the case-by-case approval while the RAC provides a more holistic regulation and maintains the focus of human gene therapy.

Genetic patenting is an issue which can have an indirect impact on the progress of human gene therapy. In 1980, the Supreme Courtís 5 to 4 decision in Diamond v. Chakrabarty granted the right to patent life forms (Donegan, 1995). Even though this decision was made 17 years ago, it is still a major point being debated today. A coalition of Protestant, Catholic, Jewish, Muslim, Buddhist and Hindu leaders are currently pursuing a joint appeal against the patenting of human and animal life forms. This coalition approves of somatic cell therapy and the patenting of genetically engineered drugs, but disapproves of genetic patenting. Leaders of this movement consider it morally and ethically wrong stating that genetic patenting degrades human life itself. Biotechnology firms argue that patents donít necessarily provide ownership but rather simply provides a means to raise money and protect their investment. Do patents protect investments or rather just limit competition resulting in a monopoly on human gene technology. An interesting argument points to the fact that it took Congress 30 years of debate to allow patenting on plant varieties while the Supreme Courtís decision was made in the infancy of human genetic research (Donegan, 1995).

As scientists continue to reveal the meaning of the human genome, there is an ever increasing fear of using this information for less than noble purposes. If scientists are able to successfully alter human genes for therapeutic purposes, what is preventing them from manipulating other genes that may affect intelligence or physical appearance. A major source of funding for human genetics research is various commercial interests (Gorman, 1995). Biotechnology and medicine is literally a billion dollar industry so, for example, a quick genetic fix for obesity would be quite attractive. Some would argue that the current state of regulation governs against mis-directed genetic research. However, a cloned sheep suddenly appeared from the area of animal husbandry, shocking many medical geneticists who thought cloning could never be accomplished (The Gene Letter, March 1997). The Gene Letter, May 1997, recently reported on a temporary halt imposed by the British Medical Research Council on IQ gene research. Even though this research is being delayed to address ethical issues, it does illustrate that other less noble research projects are being pondered. This brings up an important question. Should research for reasons other than therapeutic advancement be allowed and financially supported?

My View

Several moral, ethical, social, and legal issues regarding human gene therapy have been discussed in the preceding paragraphs. I would like to take this opportunity to express my opinions on the many questions that the reality of gene therapy creates, most of which I didnít know even existed a short time ago. The following can be considered as Ramsdaleís rules of human gene therapy and related issues:

  1. I approve of somatic cell therapy techniques as this should be the area where the research dollars are concentrated.

  2. At this time I feel that germ-line therapy should not be pursued not only because of the potential risks but also because I feel we donít have the right to determine our future generationís fate.

  3. I feel it is important to keep the current regulatory agencies in place (i.e. the RAC and FDA). Policies should not be dictated by the commercial interests even though they are a major source of funding. There is a unique opportunity for gene therapy to give equal consideration to ethical issues. This wasnít always the case with past technological advancements. These agencies will hopefully keep the focus of all research projects on developing gene therapy techniques.

  4. As I understand it, there has been legislation implemented which prevents insurance companies and potential employers from discriminating based on genetic screening tests. I completely agree with this policy.

  5. Genetic manipulation should only be used to treat diseased genes. At no time should this technology be used for other means such as physical appearance or mental capability. A eugenics movement should definitely be guarded against.

  6. Genetic patenting is an issue than I am not completely sure about. I do not view genetic patents as signifying ownership of human life forms but rather as the right to the technology of working with that life form. The question I have is what is most beneficial to the overall advancement of gene therapy. Is it exclusive rights to protect investments or would it be more beneficial to allow competition by sharing this information?

  7. I donít think anyone has the right or obligation to abort a fetus which has been diagnosed as having a genetic disorder or disability. It should be an individuals choice as to whether or not to be genetically screened before deciding to conceive a child. If it is determined that there is a possibility of a diseased child, then the couple could seek other alternatives such as adoption. However, if a couple decides to have a child realizing the potential risks, it should be followed through to the end.

  8. Gene therapy should proceed with cautious optimism and shouldnít be considered as the only alternative. Additionally, genes should not be viewed as the sole source of diseases such as cancer in which the environment may also contribute to disease development.

At this time I would question any gene therapy that would affect an individual before that individual has a chance to take its first breath. This of course would include germ-line therapy and any fetal gene therapy. The question I would raise is can we truly decipher what a person has to offer by his or her existence here on earth. I feel that each individual has some unique quality to contribute to those who come to know them, whether that individual is disabled or even if their time is limited. Philip Elmer-Dewitt (1994) concludes his article on "The Genetic Revolution" by stating ", even after the genetic revolution, is still a poker game. Our genes are simply the cards we are dealt. What matters most is how we play the hand." God has graced each and every one of us with numerous gifts, some of which we havenít even realized yet. We should ultimately concentrate on living life as he would want us to.


Crystal, R. G. 20 October 1995. Transfer of genes to humans: Early lessons and obstacles to succuss. Science 270:404-409.

Donegan, C. 8 December 1995. Gene therapyís future. CQ Researcher, p. 1091-1107.

Elmer-Dewitt, P. 17 January 1994. The genetic revolution. Time, p. 46-53.

Gene Letter, The. Volume 1, Issue 5, March 1997. Germ-line gene therapy: Is it almost here? World Wide Web at

Gene Letter, The. Volume 1, Issue 6, May 1997. British Medical Research Council (MRC) delays proposal in IQ genes. World Wide Web at

Gene Letter, The. Volume 1, Issue 6, May 1997. Position statement of the National Down Syndrome Congress on Prenatal Testing and Eugenics: Families' rights and needs. World Wide Web at

Gene Letter, The. Volume 2, Issue 1, August 1997. Is there ever a moral duty to use prenatal diagnosis and selective abortion? World Wide Web at

Gorman, C. 9 October 1995. Has gene therapy stalled. Time, p. 62-63.

Mulligan, R. C. 14 May 1993. The basic science of gene therapy. Science 260:926-931.

Student Essay List

Course Homepage