The Ethics of Gene Therapy

Emilie R. Bergeson

Copyright 1997


Francis Crick was quoted as saying, "We used to think that our fate was in our stars. Now we know that, in large measure, our fate is in our genes." Over 40 years ago, James Watson and Francis Crick discovered the structure of deoxyribonucleic acid (DNA). From this a new technique has evolved called gene therapy. Gene therapy was discovered in the 1980ís a few years after researchers were already able to isolate specific genes from DNA. These techniques matured from the massive surge of ideas generated during the Recombinant DNA (rDNA) era. Gene therapy is basically the repairing of genes to correct for diseases that result from a loss or change in our genetic material. It is hard to comprehend the total effects of gene therapy, because we do not know if it should really be used? Who does it really benefit? And ultimately people can easily contemplate how it affects him or herself and their family. Therefore, to understand gene therapy some technical aspects need to be discussed.

Technical aspects

DNA is present in the nucleus of cells and is the genetic information of all organisms. The information of a human genome could be thought of in terms as an "encyclopedia", the 23 chromosome pairs would be "chapters", each gene a "sentence", three letter words "codons", which are spelled by each letter a "molecular nucleotide"--adenine (A), cytosine (C), guanine (G), and thymine (T) (Elmer-Dewitt, 1994). A gene acts as a blueprint and if these were blueprints for a house and the measurements were off by a foot, it has a huge influence on its total structure. This is the same for our bodies, if a slight alteration in our genetic information occurs like a mutation this could lead to a disease.

Detecting whether an individual has the capacity to develop a specific disease during their life and being able to link the disease to a specific chromosome and ultimately the gene responsible is done by genetic testing. Genetic testing is basically done by cutting a piece of DNA with restriction enzymes and inserting them into a plasmid and finally analyzing the gene. Once a gene is located and defined as the cause of the disease, scientists can then start to develop a plan of action for gene therapy.

There are three sequential steps to gene therapy: first, the partial removal of a patientís cells, second, the introduction of normal, functional copies of the gene via vectors to replace defective cells in the patient, and finally, the reintroduction of the modified cells into the patient once the genes have been fixed in their vectors (Gardner et al. 1991).

According to Mulligan (1993), transfer of appropriate target cells is the first critical step in gene therapy. Many different methods of accomplishing gene delivery are available such as viral methods like retrovirus, adenovirus, adeno-associated virus, herpes virus, vaccinia virus, polio virus, sindbis and other RNA viruses. Nonviral methods like ligand-DNA conjugates, lipofection, direct injection of DNA, or CaOP4 precipitation are also used. For example, retroviral vectors are very promising because of their ability to stably transduce close to 100% of target cells. They have also become a widely used vector because they cannot transfer their own genetic material into their host (only the newly modified genetic material). One of gene therapyís most evasive goals has been the development of safe and effective methods of implanting normal genes into the human cell.

One of several obstacles to human gene transfer has been the reoccurring plague of inconsistent results. For example, two children with an ADA deficiency receiving periodic infusions of T cells modified ex vivo with the normal ADA gene have shown a resulting proportion of normal ADA cells varying from 0.1 to 60%. There have been problems with development of gene transfer in animals and once experimented on humans the predictions have deviated. There have also been significant problems with the production of vectors. The ability to generate replicates and be able to keep them uncontaminated has posed a problem.

The ideal gene delivery vector should be capable of efficiently delivering one or more genes of the size needed for clinical application. The vector should be very specific, unrecognized by the immune system, stable, highly reproducible, and be purified in large quantities at high concentrations. Once the vector is inserted into the patient it should not induce an allergic reaction like inflammation, it should be safe not only for the patient, but also for the environment. This is a huge hurdle for vectors because generally the most effective vectors are the most toxic. They have the ability to get the DNA into the cells, but are very costly to the patient. Finally, a vector should also be able to express the gene for as long as it is required, generally the life of the patient (Crystal 1995).

To deliver vector two techniques have been used: the ex-vivo and the in-vivo. The most common technique has been the ex-vivo method (outside the living body), which uses extracted cells from the patient. First, the normal genes are inserted into vectors like viruses whose disease-causing genes have been removed. Next, the blood cells with defective genes are removed from the patient, the patientís blood is mixed with the engineered viruses, and the genetically engineered blood cells are reinfused in the patient to produce the protein needed to fight the disease.

The in-vivo method (in the living body) does not use cells from the patientís body, thus eliminating expensive, and very time consuming laboratory procedures. Vectors, like viruses are again cut of their disease-causing genes and given the normal genes. The vectors are then injected into the patientís bloodstream to seek out and bind with the targeted cells like ADA diseased cells. The normal gene in the virus is incorporated into the chromosome of the target cell and forces a reaction with the protein needed to reverse the effects of the disease.

Inserting the gene into specific cells of the body where the defect is causing the disease is called somatic cell gene therapy. Each cell in the body has the exact same DNA as the original fertilized egg. All cells use different parts of their total genotype to develop different tissues that perform different functions. As a result, the genetic defect is often only distinguished in a specific area like tissues. The goal of somatic cell gene therapy is to insert the normal or transformed cell into the specific affected tissue. Not all tissues need to be treated, only enough cells need to be treated to provide the correct amount of enzymes to allow for the protein to develop and reach the site of action in a particular tissue.

The first use of somatic cell gene therapy was for the treatment of adenosine deaminase deficiency (ADA) in children commonly known as "bubble babies." This is a rare immune system disorder that ultimately prohibits the body from defending against invaders like the common cold. Because doctors were able to successful insert healthy, normal cells into the child with the blood from its umbilical cord, their immune defenses were able to fully form. The child did not reject the healthy genes and doctors claim the genes are "expressing" (Gorman 1995).

The other type of gene therapy is germline gene therapy. The altered gene is inserted into the sperm or egg cells (germ cells), and this ultimately leads to a change in not only the individual receiving the treatment, but also future offspring. It is also possible to insert the altered cells into an early stage embryo that would affect both the germline and somatic cells. Yet, most governments have limited all gene therapy experiments to somatic gene therapy because the alteration performed in germ gene therapy would change future generations.

Pro and con arguments

"Medicine has been waiting for this for thousands of years. This is a truly historic moment," said Gerard J. Garrity, chairperson of the Recombinant DNA Advisory Committee (R.A.C.) of the National Institute of Health (N.I.H.). This comment came when the first R.A.C. committee approved two experiments in human gene therapy. The N.I.H. took more than three years to consider and approve these two experiments. The researcher must answer several questions to gain approval of performing gene therapy experiments upon humans. For example, why is the given disease a good candidate for gene therapy, what makes the scientists sure that the new gene will be properly inserted and regulated so as to be expressed usefully in the patient, and what are the technical details of the DNA and vector to be used. The technical aspects involved, risks endeavored by the patient, and the fear of human genetic engineering are some of the major reasons why human gene therapy experiments have long been delayed.

People polled have shown approximately a 50/50 split for and against gene therapy. Dr. Maurice Super, a consultant clinical geneticist at the Royal Manchester Childrenís Hospital in Manchester, England and supporter of genetic engineering capabilities, opened a pavilion type Gene Shop (a motto: "What keeps body and soul together? Your genes") in an airport that aims at educating people about the benefits of new technologies. He has said, "The aim is to decrease the fear of a brave new world and encourage people to be more proactive about their health." Most of the general public remains fearful of the consequences of gene testing, yet more than 7,000 people have visited the Gene Shop

No one denies that gene therapy will yield results that will in some peopleís eyes be a miracle. Yet, even citizens for the advancements of gene therapy are growing increasingly concerned that the initial studies and excitement led to a premature rush of approved gene therapy experiments (Gorman 1995). Researchers are not certain what is the best method of gene transportation. As stated earlier, there are several different types of transport systems such as: viral; retroviral or adenoviral, or non viral; ligand-DNA conjugates or lipofection and deciding the best vector takes time.

Proactive citizens for genetic engineering believe they can use gene therapy to stop a sick child from dying to helping their own children be smarter, jump higher, or even grow bigger. Problems can arise when the parental love will go to the extreme of making their child as superior as possible. These people also believe new developments like the genetically engineered cancer vaccine is an incredible tool that should and could be used by anyone. Proactive supporters often stress that genetic diseases cause suffering to the patient and to their families. They believe in the proactive direction of medicine to try to cure diseases and alleviate suffering. Gene therapy is new and if properly controlled it will help the public from suffering.

Taking bits and pieces of DNA, inserting them, and hope they are expressed is what many people believe our body is ready to ward off against. So how can people against genetic engineering experiments understand the concept of gene therapy? There are some sites on the World Wide Web and journal articles of people who believe that this cannot happen, but these are some people that do not believe in the whole theory of genes and the study of genetics.

These opponents have reservations because gene therapy is so new and unpredictable. The rationalizations of the World War II come flooding back and the believability of Hitlerís dream or eugenics will come true once more. This is a reality and a fear to many people. They often feel that "the advances being made by scientists are running ahead of our ability to deal with the ethical consequences," stated David King, editor of Genethics News. He also went on to say there is nothing holy about a fragment of DNA. Which is contrary to what 58% of the people polled by Time/CNN think, that altering human genes is against the will of God. And that is holy in many peopleís eyes. Of those same people polled, 90% said they thought it should be against the law for insurance companies to use genetic tests to decide who is insured (Elmer-Dewitt 1994).

Other opponents are not so tentative when dealing with advancements in gene therapy. For example eight years ago, Jeremy Rifkin, along with 75 religious leaders, strove unsuccessfully for a permanent ban on gene therapy by submitting a resolution to the U.S. Senate. People honestly believe altering our God given body is very wrong and sinful. It is not right playing around with Mother Nature, she has created something sacred and it should not be changed. Not being a responsible citizen in finding and sorting through the facts has lead to some of the opposition to gene therapy.

No topic in genetics has provoked as much controversy as patent rights to human life forms. The Supreme Courtís 5-4 decision in Diamond v. Chakrabarty in 1980 permitted the right to patent life forms. Many opponents said the courtís decision permits ownership of things that cannot, morally or ethically, be owned. Other objectors also say "it debases life itself" by commercializing human and animal life forms, and again fuel supporters of eugenics. Jeremy Rifkin, president of the Foundation on Economic Trends, said, "It took Congress 30 years of debate before allowing patents for some varieties of plants. The Supreme Courtís decision was a construction created out of sand that has no foundation."

Chief Justice Warren E. Burger, writer for the majority of the Supreme Courtís decision, argued that the decision for patents was justified. Their example was the case of genetically engineered bacteria that was designed to degrade petroleum and help clean up oil spills. He said the bacteria were different than any found in nature and could not be considered Godís handiwork, but the result of human ingenuity. Patent supporters do not confer ownership or try to make gods of human beings, but enable researchers to raise money. Investors could not support expensive and uncertain biotechnological endeavors without the guarantee of a patent (Donegan 1995).

Personal opinion

People dream of a life without disease and sickness. I know I do. Being able to have a healthy, normal child and die from plain old age, is something I believe everyone has thought about or even prayed for. I believe that gene therapy is a necessity. But I must be specific in saying that I believe somatic gene therapy is essential to the development of making a sick child healthy. I do not believe in "playing God" and therefore think that germ line gene therapy is off limits, more so not even comprehensible.

What makes a disease suitable for gene therapy? Darryl Macer, Ph.D. (1990) stated that gene therapy is generally considered for single gene disorders until researchers understand more. I think diseases that are easily understood medically and genetically and have no other recourse for treatment (a last resort) are suitable diseases. This can cover a broad base of diseases from enzyme deficiencies to AIDS or cancer. I do not like to see people suffering, especially when it is someone very close to me. If a somatic cell gene therapy were medically available, I know I would use it to help them. But who is really suffering? A child that canít shoot the ball as well as a professional athlete? No, none of these children are physically suffering from a genetic disease it has no control over, but suffering from a society that places a lot of pressure on kids to be an all American.

I think we will talk about gene therapy for years to come. But I strongly believe that my views will help shape the 21st century. As a responsible citizen, I need to listen, think, and be involved with the decision-making processes or gene therapy could lead to a dark side. Recombinant DNA techniques need to be regulated and I believe our government has done the right thing ever since the Asilomar conference by forming the Recombinant DNA Advisory Committee (R.A.C.) of the National Institute of Health (N.I.H.). We are not changing the car to be more aerodynamic or one that can travel by air, as many people believe the 21st century will bring, but we are changing people. I know I would always try to make my opinion be heard and incorporate them into the huge pool of philosophies. I do not want the practice of medicine or the human race to be heading down a very dark tunnel.

The "blueprint is written not in the helix, however, but rather in our wills" (Keenan 1990). I also believe that whatever moral trespassing we entrust is not caused by the things that we discover, but what we decide as a responsible citizen. Researchers have promised a life free of diseases like cystic fibrosis, cancer, and AIDS. But crossing the line to diseases that are germ line have not been considered, nor do I believe they ever should be. God has been the one to create us and determine our purpose on earth. He is the one who was holy and wise when he designed us, lets not change that too.

Literature Cited

Becker, A. and E. Soderberg. Gene therapy: the future of medicine. Obtained from the WWW:

Crystal, R.G. 20 Oct 1996. Transfer of genes to humans: early lessons and obstacles to success. Science p. 404-410.

Donegan, G. 8 Dec 1995. Gene therapyís future. CQ Researcher p. 1091-1107.

Elmer-Dewitt, P. 17 Jan 1994. The genetic revolution. Time p. 46-52.

The Guardian Scripps Howard News Service. Mining the gold in DNA. Obtained from the WWW:

Gardner, E.J, M.J. Simmon, and D.P. Snustad. 1991. Principles of genetics. 8th ed. New York, NY: John Wiley & Sons, Inc.

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

Henderson, C.W. 5 May 1997. Researchers use gene therapy to protect human cell from HIV. AIDS Weekly Plus p. 16-17.

Henderson, C.W. 5 May 1997. Hopkins researchers complete human gene therapy trial of kidney cancer vaccine. Cancer Weekly p. 29-30.

Keenan, J.F. 20 Oct 1990. Human gene therapy: and ethical advance? America p. 262-263.

Macer, D.R.J. Shaping genes: ethics, law and science of using new genetic technology in medicine and agriculture. Obtained from the WWW:

Meiser, C. Medical ethics symposium on gene therapy. Obtained from the WWW:

Mulligan, R.C. 1993. The basic science of gene therapy. Science 260:926-932.

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