Should genetic manipulation of human genes that affect future offspring be allowed?
INTRODUCTION
Gene therapy is a novel approach to treating diseases based on modifying the expression of a person’s genes towards a therapeutic goal. Biotechnology has advanced to the point where scientists can alter the DNA; the genetic code that defines us. There are essentially two forms of gene therapy, Somatic Gene Therapy and Germline Therapy. Somatic gene therapy involves the manipulation of gene expression in cells that will affect the patient but will not be inherited.
Germline gene therapy involves the modification of germ cells (gametes) that will pass the change on to the next generation. With germline therapy genes could be corrected in the egg or the sperm that is being used to conceive. The child that results would be spared certain genetic problems that might otherwise have occurred. Because every cell descends from the fertilized egg, every cell in the offspring would possess the transplanted gene. This would be a far more effective way of transferring genes than the ones presently used in somatic cell therapies, where genes into the cells of children or adults usually enter only a small portion of the person’s cells and eventually stop functioning.
Some 2000 to 3000 diseases have been determined to be
genetic or inherited. Up to two percent of newborns in the U.S. have a
genetic disorder. The most common of these, cystic fibrosis affects 30,000
Americans and is found in 1700-2000 newborns each year. Adenosine Deaminase
Deficiency (ADA) is a severe immunodeficiency disorder that affects 40-50
people worldwide.
GENETIC DISEASES CONSIDERED FOR TREATMENT
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Source: Office of Technology Assessment Report – 1982 & 1992
The basic challenge in gene therapy is to develop approaches for delivering genetic material to the appropriate cells of the patient in a way that is specific, efficient and safe. If genes are delivered appropriately they can persist for the life of the cell and potentially lead to cure.
PROCEDURE
The technology of gene therapy is based on the effective delivery of the corrective genes and to do this, scientists have developed gene delivery vehicles called vectors. These vectors encapsulate therapeutic genes for delivery into the target cells. Many of the vectors currently in use are based on attenuated or modified versions of viruses. Plasmids, which are circular pieces of DNA extracted from bacteria, are also used as vectors.
A simplified version of the technique used for transferring genetic material from one cell to another is as follows:
The therapeutic gene to be transferred is extracted from the cell of a healthy individual. The gene is extracted by cutting the DNA using a restriction enzyme (restriction enzymes "digest" DNA at designated nucleotide locations along the DNA chain). There are different types of restriction enzymes, each being specific to the location of the DNA chain that it will cut. The section of cut DNA has to be intact then a technique called electrophoresis is used to separate the selected pieces of DNA and remove the genes that contained the DNA sequence that coded for the polypeptides needed.
Similar restriction enzymes are used to remove a section of enzyme from a plasmid or virus and using ligase (a special enzyme used to "glue" a foreign piece of DNA into a donor cell) the therapeutic DNA sequence is placed in the DNA of the vector. In the case of a virus, instead of causing illness the virus carries the normal genes into the target cells where they begin functioning.
There are methods of inserting genes, such as addition of chemicals to allow the large DNA molecules in solution to pass through the cell membrane. This requires that the cells be removed from the body and treated in a laboratory, making it suitable for treatment of easily transplantable tissues such as blood and bone marrow. This type of gene therapy is referred to as ex vivo, as the cell to be implanted are harvested from the patient, modified and then replaced.
A technique that involves direct insertion of the vector in to the patient is referred to as in vivo gene therapy. There are also other techniques, which include laser micropuncture of the cell membrane, electroporation and biolistics (using high velocity tungsten microprojectiles to insert DNA)
The first somatic cell gene therapy inserted a normal gene into the DNA of cells in order to compensate for the non-functioning of a defective cell. This technique involves obtaining white blood cells from the patient and then introducing the normal genes in the cell. The normal gene is delivered using a domesticated retrovirus that infects the cell and introduces the normal functioning gene. Retroviruses can infect many types of cells so it is important to develop gene transfer techniques that will allow the virus to deliver the genes to the cell and then remain there. It is imperative that the inserted gene gets to the intended gene location because an incorrect destination in the genome of the cell could have disasterous effects.
Germ line therapy which is the focus of this presentation, is technically more difficult and raises many ethical challenges. The two main methods of performing germline therapy would be:
1) To treat a pre-embryo that carries a serious genetic defect before implantation into the mother (this requires the use of in vitro fertilization techniques); or
2) to treat the germ cells (sperm or egg cells) of the afflicted adults so that their genetic defects would not be passed on to their offspring. This approach requires the technical expertise to remove the defective genes and insert a properly functioning replacement.
OBSERVATIONS
Not all genetic diseases can be treated. While there is ongoing research to map the entire human genome (The Human Genome Project). The exact function of each gene is not fully understood. Also genes interact and very little is known about how the change of one gene will affect the functioning of others. Gene therapy is likely to have the greatest success with diseases that are caused by single gene defects. Only genetic diseases caused by errors in a single recessive gene are being considered for treatment, since the insertion of a normal dominant gene should override the effect of the abnormal gene. By the end of 1993 gene therapy (somatic) had been approved for diseases such as severe combined immune deficiency, cystic fibrosis, hypercholesteremia and Gaucher’s disease. Diseases caused by the duplication or extra copies of certain genes cannot yet be treated. Currently the U.S. government prohibits testing and funding of germ-line therapy techniques on humans.
Gene therapy is advancing at a rapid pace, so fast that new technologies are being readied for use without answering concerns about safety. The safety concern of this type of engineering arises because of a lack of knowledge about the human genome. It is quite possible that a valuable gene could be erased. For example, the recessive gene that causes sickle cell anemia might be a good candidate for germ-line therapy, since the defect is caused by a single gene responsible for manufacturing a particular protein chain which is a component of hemoglobin. However, only having one copy of the gene confers added resistance to malaria, making the sickle cell gene beneficial to people living in regions where malaria is prevalent. Since both the function and interaction of many genes are still not fully understood then it would be unwise to remove them permanently as they may prove to be beneficial later.
Experiments using germline gene therapy in animals have been underway for a few years. In the initial demonstration of the use of the technique the human genes for growth hormone along with a regulator were inserted into mice embryos with the resultant expression in the recipient mice being a doubling of their body size. Germline transmission, and expression of inserted genes, has been possible in animals since 1982, however these crude methods involving multiple copies of genes are not applicable to humans. Only targeted gene replacement should be used. Also the technology still has a high failure rate in terms of the large losses of egg cells, and the failure to achieve any expression.
There are major difficulties in the technique if applied to human embryos to avert the expression of a recessive mutant gene, especially in selecting the correct embryo for use. Also the response rate is low for embryos. With the way genetic information is transmitted in humans the genetic disease may not be expressed in the children, as they will only receive one of their pair of genes from the affected parent and would only be a carrier of the disease.
Experiments on other animal models are a prerequisite to experiments on humans. One of the animal systems used for gene therapy was that of Mason et al (1986). Mice that were lacking the gene for the synthesis of gonadotrophic releasing hormone were used in these trials, in which DNA containing the correct gene was injected into fertilized eggs. The successfully treated animals became normal for the synthesis of gonadotropic releasing hormone.
An achievement that
illustrates the use of germ-line therapy to alter psychological abilities.
In September of this year Princeton University researchers announced that
they were able to genetically modify mice to have improved memory and learning.
Neurobiologists found that by adding a single gene to mice significantly
improved their ability to solve maze tasks, learn from objects and sounds
and retain learned information.
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DISCUSSION
Arguments in favor of gene therapy.
The central argument in favor of gene therapy is that it can be used to treat desperately ill patients or to prevent the onset of horrible illnesses. -- In the future germ-line therapy is seen to offer a true cure and not just a symptomatic treatment.
By
preventing the transmission of disease genes, the expense and risk of somatic
cell therapy for successive generations is avoided.
Medicine
should respond to the reproductive health needs of prospective parents
at risk for transmitting serious genetic diseases.
Germ-line
therapy may be the only way of effectively treating certain diseases.
The
scientific community has a right to free enquiry within the bounds of acceptable
human research.
Once
successful techniques are developed the moral dilemma of disposing of "defective"
embryos in the lab could be avoided. It is currently believed that germ-line
therapy is best achieved through in vitro fertilization and treatment
of the embryo in vitro. Unfortunately this may result initially in the
treatment of normal embryos. It also requires that more infants be conceived
by in vitro fertilization.
It is clear
that gene therapy is the economically favorable alternative, assuming that
a single treatment has a permanent effect. For example, cystic fibrosis
could cost a patient up to an average of $46,500 per year and $146, 500
over a lifetime. Clearly, a single treatment is preferable to continuous,
expensive medical care.
Many people use the "slippery slope" argument against gene therapy. Asking whether it is possible to distinguish between good and bad uses of gene modification techniques. There are also issues of resource allocation, many believe that the health car system is strained as it is and we cannot afford such expensive therapy. And if it only made available to those who can afford it, the distribution of desirable biological traits among different socioeconomic groups and ethnic groups could be badly skewed.
Arguments specifically against germ-line therapy include:
Germ-line
therapy involves too much scientific uncertainty and risk.
As germ-line
therapy involves research on early embryos, such research essentially creates
generations of unconsenting research subjects.
Germ-line therapy
would violate the rights of subsequent generations to inherit a genetic
endowment
that has not been intentionally modified.
Such gene therapy would open the door to attempts at altering human traits that are not associated with any disease (which could exacerbate problems of social discrimination). Gene therapy would allow people to choose how they or their children look.
People may seek genetic treatments that would make them look younger, have more hair or lose weight. If researchers figure out how genes control for behavior, people may try to alter their children’s genes to make them more intelligent or have more athletic ability. The Princeton research on mice shows that genetic improvement of intelligence and memory is now feasible, thus offering a striking example of how genetic technology may affect mankind and society in the next century.
This kind of therapy would be the equivalent of genetic plastic surgery. People today spend thousands of dollars to achieve perfection, imagine if they could not only change their physical appearance; what if they could alter their genes so that not only are they themselves perfect but they ensure that they children would be perfect too. So there is little doubt as to the potential misuse of this technology in this area.
The word used to describe the use of genetic knowledge to improve the human race is "Eugenic" coming from the Greek meaning "wellborn". Many societies through history as well as today have tried to create eugenic populations. This is what happened in Nazi Germany, hundreds of thousands of people were sterilized and millions killed to purify the German race. Many U.S. states in the early 1900’s adopted laws that prevented the "overbreeding " of people from poor stock and the Immigration Act of 1924 was adopted to restrict the number of supposedly unfit people from Southern and Eastern Europe. Eugenic ideas are even popular today. China has a law forbids mentally retarded people from marrying unless they are sterilized. Singapore offers cash incentives to well-educated women who have babies. The ethnic cleansing of Albanians in Serbia is a most recent and profound example.
CONCLUSION
Although germ-line therapy is not yet safe enough to use on humans, we must consider technology before it is ready to be used especially when such high stakes are involved. Germ line therapy will likely become available for human applications in the next 10 to 20 years according to scientists though it will likely appear under less threatening names. So the question is really not if this technology will be used but when and in what ways.
Gene therapy is new technology being developed by scientists in the forefront of their fields. The final form that this technology will take depends on new advances and political influences by decision-makers. Concerns about gene therapy include safety, effectiveness, impact on the genome, funding of research, the future applications and direction of research. Problems will inevitably arise if the technology is not carefully monitored and scrutinized with drastic consequences. The decisions should be made by skilled committees with knowledge of the technology. Citizens also need to remain informed about the scientific advances being made in genetic therapy as well as its pros and cons and should actively participate in their community to make sure their opinions are heard.
The total elimination of all disease-causing alleles is an unrealistic goal, and is unobtainable. It is not possible to eradicate genetic disease completely as many people are carriers for genetic disease and are not aware of it, and many occur spontaneously as quickly as we would be able to get rid of them new mutations would occur. I believe germ-line therapy hold great potential for the treatment of many devastating genetic disorders but the technology is like a "Pandora’s Box" once you breech the gates and enter the realm of genetic therapy you have to accept the good with the bad. We may have to live with the disadvantages to benefit from the techniques. But a danger exists if we do not use germline gene therapy alongside somatic cell therapy. Somatic cell gene therapy could not prevent perpetuation of the disease, so the future generation would need to be treated as their parents needed.
Given the inherent hazard it poses, germ-line therapy
is a technology best postponed until adequate knowledge of the human genome
is available, and implications of this process for the future of the human
race. Then and only then can mankind safely decide whether germ-line engineering
is the true answer to our genetic problems. We need to ensure future generations
retain the same power over their destiny as we do, while benefiting from
the culture and technology we have.
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