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GENE THERAPY

By Reas Kondraschow
  

Gene therapy was discovered in the 1980's 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. Over 40 years ago, James Watson and Francis Crick discovered the structure of deoxyribonucleic acid (DNA). 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 a process that results in the correction of a genetic disorder by the addition of a piece or fragment of DNA into the genetic material of a living, functioning cell. It is hard to comprehend the total effects of gene therapy, because we do not know if it should really be used? It's hard to try to comprehend the extent of gene therapy. Should research continue? Who will benefit from its use? Should it be used at all? How is it affecting society? How do we answer all of these questions? Can we answer all these questions? There are answers to these questions but which is the best? Is it even ethical to answer these questions? To even begin answering the ethics behind gene therapy we need to know what it is.

The goal of gene therapy is to correct mistakes that have occurred within the genetic material, or DNA, of the living cell. In very simple terms, DNA is often thought of as the "language" of the biological functioning of organisms. This language is organized by letters (nucleotide pairs), words (codons), sentences (genes), and books (genomes). Before being able to repair the damaged or defective genetic material, the location of the gene or genes causing the dysfunction in the individual must be determined. 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. Over the last forty years or so, scientists have made a great amount of progress in this area, including the development of techniques that allow for the controlled manipulation and replication of specific segments of the human genome. These types of techniques have come to be known as recombinant DNA (rDNA) technology and have allowed scientists to analyze functions of genes that are not necessarily directly expressed at the phenotypic level. This is done by excising a particular segment of DNA of interest from the genetic material of an individual and inserting it into a bacterial plasmid (a tiny ring of DNA in addition to the normal chromosomal material found within the cells of bacteria). The excising is done with the use of restriction enzymes, which are a group of molecules capable of "cutting" the DNA at specific points along its sequence of nucleotide pairs. By observing the end products of these gene inserts, scientists are able to determine the functions of the genes themselves and are therefore better able to analyze and understand the dysfunction of certain genes at the molecular level. 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. They now begin to read our blue prints and fix the areas that are wrong.

There are three sequential steps to gene therapy: first, the partial removal of a patient's 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). The blue print has been read and the design fixed.

According to Mulligan (1993), transfer of appropriate target cells is the first critical step in gene therapy. There are many different methods of accomplishing gene delivery and these viral methods are 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. So far retroviral vectors seem to work the best because they do not transfer their own genetic material into their host only the new genetic material is passed. One of gene therapy's most evasive goals has been the development of safe and effective methods of implanting normal genes into the human cell.

One of the biggest problems in gene therapy is the reoccurring plague of inconsistent results. An example is 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 outcomes varied. 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. Then once the vector is inserted into the patient it should not create an allergic reaction like vomiting or nausea. 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.

To execute the repairing of our blue prints there are two techniques used to deliver these vectors and they are the ex-vivo and the in-vivo. The most common technique of delivery 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 patient's blood is then 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 patient's body. Vectors, like viruses are again cut of their disease-causing genes and given the normal genes. The vectors are then injected into the patient's 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. Since the cells are not taken from the patients own cells the time and money spent on the procedure are much less.

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 second type of gene therapy is germinal gene therapy. Germinal gene therapy consists of introducing new genetic material into the germ line cells (those cells from which the gametes are derived). 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. Germinal gene therapy has yet to be tried on humans. It is also possible to insert the altered cells into an early stage embryo that would affect both the germ line 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.

Until the development of this technology, people have had to deal with genetic inequality as a fact of life. With the advent of gene therapy, this may no longer be the case for some people. Most people feel that it is okay to use gene therapy to treat human genetic diseases. Surprisingly, even the Catholic Church has taken a stand for the use of gene therapy. Reverend Russell E. Smith, president of the Pope John XXIII Medical-Moral Research and Education Center, stated that gene therapy is "a very noble enterprise, because it is aimed at the actual cure of actual diseases." Some individuals, however, are concerned that the technique may be used for "treatment" of genetic "disorders" other than diseases. For example, in January of 1993, it was reported in USA Today that an 11-year-old boy was receiving gene therapy treatments at a cost of $150,000 per year to increase his height. At 4' 11", four inches below average height, he was tired of being picked on at school for being short. His father was quoted in the article as saying, "You want to give your child that edge no matter what. I think you'd do just about anything." Is this ethical? What makes this child a good candidate for gene therapy? Should we be able to give ourselves gene therapy to change who or what we are? Isn't it vital to our development that we learn through socialization? Won't we be changing the way we were meant to be and if so won't this have repercussions later in life?

A study showed that approximately a 50/50 split for and against gene therapy. Dr. Maurice Super, a consultant clinical geneticist at the Royal Manchester Children's 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 Because many people are concerned about the safety of gene therapy a special committee called the National Academy of Science was created to look into the consequences of releasing rDNA engineered organisms into the environment. The committee concluded that "there is no evidence that unique hazards exist either in the use of rDNA technique or in the transfer of genes between unrelated organisms," and that, "the risks associated with the introduction of rDNA engineered organisms are the same kind as those associated with the introduction of unmodified organisms." However, John Fagan, a professor of molecular biology at Maharishi International University in Fairfield, Iowa, is highly concerned about the fact that very little is known about the long-term effects of the existence of genetically engineered organisms in the environment. To make known his concern, he returned about $614,000 in grant money to the National Institutes of Health. His underlying concern is that an engineering mishap with devastating effects does not occur as a result of carelessness and or lack of precaution.

No one denies that gene therapy will yield results that will in some people's 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.

Important issues concerning decision-making and regulation of research were addressed at the now famous Asilomar Conference held in 1975. This conference, which involved mostly molecular biologists, the press, and some government officials, set the tone for dealing with rDNA public policy issues. The major concern at the time was the possible health risks to researchers and the public at large. Many people were also concerned about the possible environmental affects. These concerns are normal and even expected with the advent of new technology; however, there existed then and to a certain extent still exists today a concern unique to the study of rDNA and its related fields. The concern is for the possible development, by some engineering mistake, of a kind of Frankenstein running rampant throughout the environment. This concern has been considered very carefully and has had a large impact on the development of public policy concerning rDNA technology.

More so than gene therapy to grow taller and change your hair color patenting rights to human clones is even more unethical in the eyes of many. The Supreme Court's 5-4 decision in Diamond v. Chakrabarty in 1980 permitted the right to patent life forms. Many opponents said the court's 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 Court's decision was a construction created out of sand that has no foundation." Chief Justice Warren E. Burger, writer for the majority of the Supreme Court's 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 God's 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).

Some arguments against gene therapy stem from World War II. At that time Hitler was experimenting with eugenics and creating his own master race. 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 people's 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). Did God intend for us to change ourselves as we saw fit? Are these changes not to occur naturally? What will happen to the evolution of our species?

So how should the development and use of gene therapy be regulated, and who should be doing the regulating? I would imagine that there are as many answers to these questions as there are people on the planet. So how do we come to any decisions about anything, how do changes come about, and how do we incorporate these changes into our individual lives? I believe these things come about as a result of natural processes. For example, it is very natural for people to be interested in what controls our physical, mental, emotional and social development. It is as equally natural for people to be interested in finding cures for diseases and ailments that afflict humankind. Once these interests are carried over into research, and answers to some of these questions about our development are found, it is quite natural for people to want to regulate how these findings should be used. 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 believe in continued careful and regulated research of gene therapy techniques for the benefit of individuals suffering from genetic diseases. I, like most people, do not like to see human suffering, most especially that of individuals close to me. If the technology is available to provide relief, I most definitely believe that it should be used. However, this seemingly black and white issue becomes very gray when one tries to define human pain and suffering. It is obvious to most that Parkinson's disease fit this definition, but what about the eleven year old boy who is tired of being picked on at school for being short? Should being below average height be considered a source of pain and suffering? A point must be made that practically everyone gets 'picked on' at some point in his or her life because of a particular physical trait. Perspective is needed here. Having to deal with being below average height simply cannot be compared to having to deal with Parkinson's disease. I do believe that it will be necessary to develop new laws and regulations to prevent industries and individuals from taking advantage of human gene therapy techniques. I understand that forming such regulations would be a very difficult and complex task, but I personally believe it to be very necessary. . 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.).

Sources Cited:

999 American Society of Gene Therapy Presidential Address www.med.upenn.edu.
"Ethical Issues in Genetics in the Next 100 Years www.upen.edu
"How Far Should We Go, Time Magazine, www.time.com
"The Limits Which Society May Place On Genetic Technology www.srtp.org



1 WCED Report. Our Common Future. 43.

2 UN Agenda 21. Preamble. Chapter 1.1.

3 UN Sustainable Development and CSD webpage: www.un.org/esa/sustdev/csd.htm

4 ibid.

5 NCSD homepage, Frequently Asked Questions: www.ncsdnetwork.org

6 ibid.

7 NCSD Sustainable Development Report: www.ncsdnetwork.org/global/reports/ncsd1999.htm

8 Citizens Network for Sustainable Development homepage: www.citnet.org

The Earth Council homepage: www.ecouncil.ac.cr/

9 UN Agenda 21. Introduction. Chapter 2.3.

10 UN Agenda 21. Integrating Environment and Development in Decision-Making. Chapter 8.3

11 Andre de Moor. Perverse Incentives: Subsidies and Sustainable Development.???

?? www.ecouncil.ac.cr/rio/focus/report/english/subsidies.htm

12 ibid. Summary, p.2.

13 ibid. Chapter 7.4

14 John T. Preston. Technological Innovation and Environmental Progress. In Chertow M.R. 1997. p.136.

15 ibid. p. 140-145.

 


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