Darryl R. J. Macer, Ph.D. Eubios Ethics Institute 1990
Due to recent rapid advances in molecular genetics it is now possible for the initial application of the technique of gene therapy, where the genes that are causing the defect are themselves substituted by correct genes in the patient to cure the disease. There are two levels whereby this can occur, and they differ in the consequences they have for the patient. Also, please note, the expression gene therapy has long been used, but the term genetic therapymay be clearer. The DNA can be repaired by correction of the mutation, which may only require a few base pairs of DNA within a gene to be replaced. Thus our definition for gene therapy does not mean that all the gene must be inserted, only that the repairs are effected upon genes and not proteins or other parts of metabolism.
The genes that are inserted can be put into specific cells of the body where the defect is causing the disease. This is called somatic cell gene therapy. All cells in the body have exactly the same genotype, or DNA, as they were all derived from copies of the same original fertilised egg. What makes them different, as evident in the many different types of tissues in our body performing different functions, is that they use different parts of the total genotype. So the genetic defect is often only noticed in one specific tissue, and the aim of somatic cell therapy is to insert the normal gene in a specific affected tissue. For enzymes with diffusible substrates or products, not all tissues may need to be treated. It is only necessary to treat enough cells to provide adequate amounts of the enzyme in the body, so the affected tissue itself may not even need to be treated, as long as the protein reaches its site of action.
The other class of gene therapy is called germline gene therapy. In this the gene is inserted into the germline (e.g. sperm or eggs), and hence when this individual reproduces their offspring will have this inserted gene also instead of a defective allele. It is also possible to insert a gene into the early embryo so that it will be in the germline of the new individual as well as the somatic cells. Because any gene inserted in the embryo would be heritable by future generations, most governments have limited all gene therapy experiments to only be with somatic cells. This is until the public has had sufficient time to decide if such experiments are desirable at all and on what kinds of disease. This will be considered in chapter 15. Let us first examine the alternative therapies to somatic cell gene therapy.
There are several stages in life in which medical treatment for a genetic disease can occur and these are summarised in Figure 14-1. We have discussed the use of primary prevention in the last chapter. The subject of this chapter is at the next level of the diagram. The advantage of gene therapy is that it will solve the problem. It is like fixing a hole in a bucket, rather than trying to mop up the leaking water. It represents more of an ideal therapy than secondary methods.
Conception
Normal Genotype or Abnormal Genotype
Germline Gene Therapy on Embryo to make Normal
----------- Primary Prevention (e.g. abortion)
Birth
Normal Genotype or Abnormal Genotype
Somatic Cell Gene Therapy to make Normal
------------ Secondary Prevention (e.g. euthanasia)
Health or Disease
Symptomatic Therapy to give health
Protein Replacement
Symptomatic therapy involves using the normal gene product as a substitute for the defective gene product. One of the first diseases to be treated in this way was diabetes mellitus. Diabetes is due to inadequate production of the hormone insulin. The treatment varies from just a diet which is low in carbohydrate, to taking regular amounts of the hormone insulin to ensure a sufficient level in the body for normal function. Insulin is a relatively simple molecule so it has been produced in large amounts for some time. It can be obtained from animal tissue extraction, usually pigs, or the exact human protein can now be produced from specially genetically engineered bacteria. The bacterial production is less cheaper, but more importantly the human protein can be used rather than an animal substitutes. Though in the case of insulin, since the use of the genetically engineered human insulin in 1982, there have been few actual advantages in the use of this protein compared to the porcine insulin, and the market is a mixture.
The production of human growth hormone by genetically engineered bacteria has been more dramatic, as before it was made from bacteria, there was a acute shortage of growth hormone, as it had to be purified from human tissue at a very low yield. The availability of growth hormone has enabled the treatment of dwarf children, so that they can grow to normal height.
Another protein produced by genetically modified bacteria is erythropoietin. This protein can be given to patients suffering from anemia that results from chronic kidney failure (Adamson & Eschbach 1990). It may also be used in increasing blood cell production in patients undergoing surgical operations so that less blood infusion is required. It has recently been used to treat patients suffering from sickle cell anemia, by raising their red blood cell production (Goldberg et al. 1990). There have been numerous other hematopoietic growth factors made (interleukins 1-6) which may be useful in clinical treatment of diseases, including types of cancer (Sieff 1990). A variety of trials are underway, as mentioned in chapters 2 and 7. The protein production using genetic technology is a proven and unrefutable benefit of genetic technology.
A significant advantage is the purity of proteins made in this way. In the case of proteins that have been purified from blood products, such as human blood clotting factors that are abnormal in hemophiliacs, the protein produced from recombinant DNA engineered bacteria is purer than the blood extracted protein. It carries no risk of transmitting viruses such as hepatiti, or the human immunodeficiency virus that causes AIDS. In view of the number of hemophiliacs that have developed AIDS as a result of infected blood transfusions, this type of protein preparation is very desirable.
Dietary Treatment
Substitutional therapy is not successful in every case, as we may not be able to administer the defective gene product or enzyme from outside the body. In phenylketonuria (PKU) the defective enzyme is localised in the liver and a substitute can not be inserted. However, the disease can be successfully treated by a dietary treatment involving a reduction in the intake of phenylalanine. This is possible because the disease only affects people due to the accumulation of an abnormal toxic product derived from a specific substance in the diet, so these people can live otherwise normal lives if they omit this substance from their diet. In many countries it is compulsory to screen newborn infants at birth for such diseases, so that treatment can be employed immediately.
Tissue Transplantation
Many diseases can be treated by blood transfusion, such as thalassemia, hemophilia, congenital emphysema or leukemias. There are increasing concerns over the use of blood transfusion because of the risk of virus transmission. It is also a labourius procedure, requiring continuing visits to a hospital. A better solution is a one off treatment. For some diseases tissue transplants can be used.
Bone marrow and fetal-thymus transplantation have been used in individuals affected by rare genetic immunodeficiency diseases, disorders in which patients have an inability in their immune mechanism. Liver transplants have also become common treatment. Liver transplantation has been used to cure congenital emphysema (Thomas 1986), and kidney transplantation to cure polycystic kidney disease. The problem with tissue transplants is that of tTissue graft rejection, where the patients body sees the newly inserted tissue as foreign and so tries to destroy it. Various immunosuppressive drugs are being used to overcome this problem with growing success, but they have the side effects of making the patients even more susceptible to infectious disease, and also of killing off some cells involved in the immune response with a resultant increase in the chance of developing cancer. Of course in the absence of alternative therapy cancer can be cured whereas the inevitable premature death has been avoided.
In a few countries, such as India or Japan, organ transplantation from dead bodies is not generally practised, and even in those countries which use it is very expensive, and there are shortages of spare organs. Kidney transplants can be performed from living donors, as we have two kidneys. It has recently become possible to transplant a portion of a liver, and for that to regenerate to a functioning liver. This allows one liver to be used for two patients, or for living donors to be used.
One type of transplantation that is not performed widely is pancreatic transplantation. Given the widespread incidence of diabetes, we must ask why this is so. The main reason is that insulin injections are effective therapy, despite the lack of precise metabolic control. The success rate of pancreas transplants is very low, and lifelong immunosuppresion is not a good situation to be in. There is work on the use of Islet cells, the pancreatic cells which produce insulin, however it is likely that the best alternative to insulin treatment will be genetic therapy (Editorial 1990a). The answer to the question is rather simple, the best available medical therapy is used, to balance long life expectancy and quality of life concessions.
Unlike most solid organs, the bone marrow is capable of self-renewal, and some of it may be removed without harm to the donor. Many blood disorders are the result of defective genes in bone marrow cells. The bone marrow is easy to manipulate in vitro and is transferred into a recipient by intravenous infusion. Bone marrow cells all arise from pluripotent stem cells, which are capable of self-renewal and at the same time, of differentiation into various cell lines. There are many factors still to be understood that contribute to cell growth and differentiation. Bone marrow transplantation has an established role in the treatment of some genetic diseases (Parkman 1986). Many patients have now been cured by the transplantation of intact marrow cells who were suffering from beta-thalassemia, ADA deficiency, glucocerebrosidase deficiency (Gaucher's disease) and some other genetic diseases.
The degree of success depends on the status of the disease at the time of transplant, but in all categories there are long-term disease-free survivors (O'Reilly 1983). More than 20,000 bone marrow transplants have now been carried out, though there is still much research needed to determine the major causes of failure (Bortin & Rimm 1986). However, even with good immunosuppressive drugs, there is the problem of tissue or cell rejection, and host-graft disease can lead to the death of 20% of patients within a year (Nichols 1988). When histocompatible donors are available and immunosuppression is used, 90% of the children with beta-thalassemia may be long-term survivors (Lucarelli et al. 1990). Despite the success rate, there are problems in finding histocompatible donors, and many patients cannot be treated (Parkman & Kohn 1990).
Somatic Cell Gene Therapy
The medical idea of gene therapy is to treat genetic disease directly by correcting gene defects in a patients' DNA, rather than the current indirect therapy using drugs or injections and transfusions of the proteins that the defective genes don't make. The strategy involves gene replacement, gene correction, or gene augmentation (Friedmann 1989). Many genetic diseases are not satisfactorily treated by current therapy, and in fact the idea of correcting the disease at the root level, the defective gene, rather than using drugs with various side effects, or transfusions with the risk of transmitting virally-transmitted diseases, is very appealing.
Gene therapy is generally considered to be applicable only for single gene disorders until our genetic knowledge increases. Single gene disorders do have a large impact on human health. They affect more than 1 percent of liveborn infants and account for about 10 percent of admissions to pediatric hospitals (Nichols 1988). The current treatments can only increase lifespan to normal in only about 15 percent of the disorders. It is now considered feasible for diseases in many different tissues, such as the bone marrow, liver, central nervous system, the circulatory system, and for certain types of cancer. Over one hundred human genes that have been shown to be causally related to specific genetic diseases have been already isolated (Davies & Robson 1987), so there is the potential for wide use of the technique once it becomes practically possible. It may replace many of the unsatisfactory treatments.
There was an early unsuccessful experiment in 1980 using human gene therapy, which was halted as it was judged to have been premature and also was unauthorised, by Dr. Martin Cline (Robin et al. 1987). Since then, in each new year the speculation has been that clinical use of gene therapy will begin that year. At last, after much debate and technical delays, the US Government Advisory Board judged a proposal acceptable. This was after various court cases brought by opponents.
First Approved Trial
The first approved human experiments have begun in the USA using the technique of somatic cell gene insertion. It is still very much at the experimental stage but the scientists did have to meet very strict criteria in order to conduct their experiments (Culliton 1989a), and further trials are under regulatory consideration (Gershon 1990a). The first trial did not replace a defective gene, but inserted a marker gene into cells for tracking the cells involved in a cancer therapy.
The therapy involves the use of cells which attack cancer, called tumour-infiltrating lymphocytes (TILs). They are isolated from the patient's own tumour, then grown in large number in vitro. The cells are then given back to the patient, and stimulated by a naturally-occuring hormone, interleukin-2. The procedure is known to help about a half of the patients. In order to discover how this therapy works, the TILs were genetically marked to trace them in the patients. The initial trial involved ten patients, but this number has now been increased following the success of the preliminary group of patients.
The next trial will attempt to insert the gene to express the hormone, interleukin-2, themselves so it is self-sustaining and more targeted as the first trial has been successful (Culliton 1989). A trial involving the insertion of the gene for tumour necrosis factor in TILs which will be conducted in fifty patients with advanced melanoma, passed the final stages of approval in August 1990. The trial will be led by the same researchers, Steven Rosenberg of the National Cancer Institute. It should have been easier to justify ethically because there is some hope of therapeutic value in this trial. Tumour necrosis factor has been shown to shrink tumours in mice, and it is hoped that the TILs will cluster around the tumours, releasing the factor which will kill the tumour, and then the TILs will die so that the production of the tumour necrosis factor is limited to such sites (a high blood level is toxic).
There are another two protocols under review for gene insertion for marking cells in cancer treatments that are being considered in August 1990, from different researchers. These include attempts to determine the mechanism of bone marrow reconstitution following autologous bone marrow transplantation with marked cells (using the same gene marker in TIL cells). More will follow, especially if the results continue to be good. Researchers in other parts of the world will be awaiting the results before pressing ahead with similar trials.
Enzyme Deficiencies
During the 1980's it was thought that the first patients involved in gene therapy trials would be sufferers of several rare enzyme deficiencies, all with fatal symptoms. Because many genetically determined diseases involve the bone marrow, and bone marrow transplantation techniques are effective for curing many diseases, there have been many preliminary animal gene therapy trials aimed at changing the pluripotent hematopoietic stem cells of the bone marrow, the "parental" cells from which all blood cells come (Bernstein et al. 1986, Thomas 1986).
One of these diseases is ADA (adenosine deaminase) deficiency (Caskey 1986). The lack of the enzyme ADA destroys the immune system. There are up to 50 sufferers of ADA born annually in the USA. The cells of the body which make ADA are in the bone marrow. The bone marrow is removed from the patient, and then the cells are infected with a harmless virus which has been made containing the gene for ADA. The gene then becomes part of the recipient bone marrow cells DNA along with the carrier virus. The current efficiency of gene transfer into human hemopoietic stem cells using retroviral vectors varies, up to 25% success has been obtained. However, there are problems with the continued expression of the transferred genes. After genetic modification in the laboratory the cells are placed back in the patient using bone marrow transplantation and the cells need to continue to produce ADA, thus curing the disease and preventing certain infant death.
Up until very recently there was no alternative treatment for sufferers of ADA, a reason why experimental gene therapy methods will be used, since they will die if not treated. Some researchers feel that alternatives will be improved to work more reliably than the gene therapy, but as a longterm cure the gene therapy approach offers much wider scope. The major reason that the trials were postponed was that an alternative treatment was partially successful. In 1987 trials were set to begin, but in December of that year results of another experimental therapy of administering the enzyme, ADA, itself were successful. Using the principal principle of medical ethics, to attempt to benefit the patient using the method with the best chance of success, the trials were postponed by Dr. Anderson, the leader of the group that has been responsible for the approved trial in 1989. While, an earlier trial may have accelerated the progress of gene therapy in general, it may not have been ethical to do so. After there have been some successful gene therapy trials, this disease will be tackled using gene therapy.
The more general name for these diseases is severe combined immunodeficiency (SCID). It is extremely rare, affecting about 40 children worldwide each year. About 25 percent of those with SCID suffer from ADA deficiency. ADA degrades certain products that interfere with DNA synthesis, thus killing cells, especially the T-cells of the immune system. The most effective therapy available is complete isolation of the patient so that they are not exposed to infectious agents. Some in the press have called these unfortunate children "bubble" children, because they need to live in a sterile plastic bubble. Bone marrow transplantation can be used if a suitable donor is available. A new conventional therapy was approved in April 1990, is called PEG-ADA, and it combines the protein ADA with another molecule enabling the enzyme to survive intact longer. PEG is a nontoxic polymer. PEG-ADA is not a cure, rather it converts severe combined immunodeficiency to partial combined immunodeficiency. The patients had weekly treatments of PEG-ADA with clinical response to the drug without serious side-effects. Some have been able to go out of isolation and join their families or attend school.
In April 1990, Anderson and Blaese and a group of scientists presented their proposal for gene therapy of ADA deficiency to the Human Gene Therapy subcommittee of the U.S. National Institutes of Health. It had many committees (a total of eight layers of review) to pass through before approval, given in August 1990 for a trial of ten patients. The proposal for gene therapy was measured against this new alternative for treatment, for the interests of the patients in the trial. Even though gene therapy is the better longterm treatment, and it may represent a cure, the procedure must be assessed for the best interests of those children. The test was finally accepted by the final step in the process, the National Institutes of Health (NIH) committee in August 1990. The test entails removing T-lymphocytes from the patient and introducing the ADA gene into them. However, the lymphocytes have a limited life, so the entire procedure will need to be repeated, though they may last twenty years, much more than the current lifetime of these patients. This does represent the beginning of therapeutic somatic cell gene therapy.
ADA deficiency is a useful model for other diseases that affect the lymphoid system. ADA deficiency is heterogeneous, with patients retaining 0.1 to 5% of the normal level of the enzyme, but this level is still too low for normal immune function. A level of 5% normal is adequate, so the expression of the gene does not need to be great (Akhurst 1990). ADA-deficient T lymphocytes have normal ADA levels following retrovirally mediated insertion of the normal ADA gene. There has been very little success in attempts to infect stem cells of the bone marrow, but lymphocytes have very long lives (greater than 20 years) so it is still very useful if they can be treated. By the time twenty years has passed they will be ready for the next round of therapy, which should be improved! The presence of the ADA gene inside cells will probably provide better detoxification than the presence of extracellular PEG-ADA. There is evidence from studies using human cells in SCID-mice that the human lymphocytes are functional (Parkman & Kohn 1990). In the gene therapy trial the patients will not require any chemotherapy.
There are sufferers from other immunodeficiency diseases which could soon be involved in gene therapy experiments (Kantoff et al. 1988). These include Lesch-Nyhan disease (a deficiency in the enzyme HPRT) and PNP deficiency. Effective retroviral vectors carrying the human HRPT and ADA have existed for a few years (Nelson et al. 1986). Lesch-Nyhan syndrome was one of the first models of gene therapy, but it has many limitations. The target organ is the brain, and most neurons are inaccessible to infection by retroviruses. It may be possible to use vectors developed from herpesvirus, which does infect neurons. It may also be possible to graft other cell types, such as genetically modified fibroblasts into the brain to act as the therapy. This type of therapy is also being researched for possible use against Parkinson's disease (Friedmann 1990b). Gene therapy is being considered in several laboratories, particularly in the USA, but there is also research in Japan and Europe.
Thalassemia is a major health problem in many parts of the world. The additional problem in this disease is that the abnormal marrow cells that make the abnormal haemoglobin, must be completely erradicated, unless the genetically corrected cells grow faster, otherwise the abnormal marrow cells will continue to produce the abnormal balance of haemoglobin and there will still be disease problems. There are patients living normally 4-5 years after bone marrow transplantation, so it is possible to treat this disease, but gene therapy is preferable. The major problem is control of the level of gene expression, more important in the production of haemoglobin, than the immunodeficiency diseases. There are many experimental therapies, including drugs which alter the DNA of cells. One drug which has been used medically to alter gene expression is 5-azacytidine (Jones 1985). This was administered to patients with sickle cell anemia and thalassemia in an attempt to correct the haemoglobin expression. In these diseases only the adult haemoglobin is defective, so by switching the expression of haemoglobin genes from adult back to fetal genes, functional haemoglobin was produced (Charache et al. 1983). The mechanism of this switch in gene expression is unknown, but it appears to alter DNA methylation (which alters control of gene expression). The ethical factors involved in using this type of therapy are similar to using somatic cell gene therapy. Because protein expression needs to be more precisely regulated in these diseases, it is further off. Though by the time that gene therapy has been tried, and the techniques tested and improved, the ability to replace genes precisely will be developed. If the possibility of treatment is better than with the alternatives, then it could be ethically tried.
Preliminary tests on the treatment of the disease PKU have begun with the expression of the protein deficient in sufferers with PKU in human and murine liver cells after infection with a recombinant virus containing the gene for correction. This is the first step towards the goal for somatic gene therapy for PKU (Ledley et al. 1986, Woo et al. 1986). One problem is that liver cells, hepatocytes, are normally resting cells, but cell division is required for integration and expression of retroviral sequences. On the positive side, the expression of 1-5% of the normal enzyme level may be sufficient to cure the disorder. Liver transplant, or grafting could be used, as it is increasingly used for surgery but gene therapy may be better as there is a shortage of livers and rejection problems. Another disease of the liver that is a target is familial hypercholestemia.
There are also delivery problems in targetting pharmacological compounds. For many proteins, especially hormones, it is desirable to release the protein continuously at a controlled rate over a period of weeks. Injectable, biodegradable polymers have been developed to give controlled release of proteins (Hutchinson & Furr 1987). For genes expressed in the liver targetting vesicles may be required, which may benefit from this technology. One possible receptor for use in targetting is the liver asialoglycoprotein receptor, which a mutant form of sendai virus uses to infect cells through (Markwell et al. 1985). Possibly altered viruses carrying the chosen genes may be able to enter hepatocytes through this receptor, and so genes could be targeted specifically to hepatocytes if injected into patients.
A more natural type of vesicle is liposomes. They consist of a lipid bilayer enclosing whatever is put inside them, in this case, the genes. The liposomes will fuse with the cell or even nuclear membrane, delivering the gene and disappearing. By putting attractive charges or targetting proteins on the surface of the liposomes they fuse more readily with target cells. This approach has worked in vitro for for some human glioma cell transfections, using an interferon gene (Yagi 1990). It is another approach to gene targetting under development.
Another disease is citrullinemia. Dietary and drug therapy allow for prolonged survival, but a more desirable goal is to cure the disease by the insertion of the gene for argininosuccinate synthetase into the patient. Normally this enzyme is expressed highest in the liver, but in this case, a therapeutic effect could be obtained by expression of the gene transferred successfully into human skin cells which corrects the defect. Skin cells are also possible sites for gene therapy, to cure albinism.
Multiple Gene Disorders
These diseases have a known gene cause, but are only a small proportion of the total. Current research is concentrated on single gene defects. However, most common diseases, such as cancer, are caused by multigene events (Marx 1989b), so by the time that the initial trials of gene therapy have been judged safe, our knowledge will have developed to the stage of tackling a broader spectrum of diseases. By the time the technology of gene therapy has been used and improved many more genes will be known and thus diseases treatable. Within the next two or three decades the entire human genome will be sequenced, and potentially all will be treatable. The ethical question will have moved from safety to the desirability of treating all genes. Many genetic diseases are caused by complex traits, multiple genes, and it is not thought that these would be able to be treated by insertion of single genes. Though in some cases insertion, or replacement of single genes will have some worthwhile affect, but currently the affects are unknown. Some single gene disorders are caused by dominant traits, these may be treatable if the damaging gene can be deleted and possibly replaced by the normal allele.
The progress in gene targetting in the last five years has increased the possibility for precise gene repair, and by the time that these diseases are understood, such repair should be possible. Gene therapy is now considered feasible for diseases in many different tissues, such as bone marrow, liver, central nervous system, the circulatory system, and for certain types of cancer (Friedmann 1989).
In August 1990 a gene therapy trial was approved to treat a type of cancer. The gene for tumour necrosis factor, a protein that kills cancerous cells, will be inserted into TILs, as described above. This is indirect therapy. It will be possible to use directed genetic screening and therapy to detect and prevent some cancers. Cancer is a very broad term for many diseases. About 2% are directly inherited disorders, such as familial polyposis. This type of disease suggests a single dominant mutation is responsible (Ponder 1990). There are also many cancers which appear in familial clusters, such as breast and ovarian cancer. The degree of risk in the family may be 2-3 times higher than the general population. Genetic diagnosis is feasible, so that regular screening for cancer can be given to those at high risk. With the development of gene therapy, the risk groups may be treated so that they are no longer at high risk for these conditions.
In the future it may be possible to insert genes from harmful viruses into our cells for immunization. The products of such genes would not be harmful, but would prevent the effects of harmful viruses in a type of intracellular immunization (Baltimore 1988). It is suggested that it may work with AIDS virus, but it is more speculative than the other uses of gene therapy discussed. It would only be used with infected patients, time will tell if it can work.
Fetal Gene Therapy
Another major purpose of somatic cell gene therapy will be during fetal life, as many diseases require treatment to begin during fetal life (Robertson 1985). The alternative is selective abortion, at an early stage. The future situation, as we considered last chapter, may make early fetal screening routine, by chorionic villi sampling at 6-8 weeks, allowing the screening of any genetic disease. If a disease is detected then the decision will be whether to to have a selective abortion, and have another fetus, or try to treat the disease. As the number of gene probes increases it is possible that all the embryos will be shown to carry the 5-10 harmful recessive alleles that they contain, and one could imagine the situation where it is very hard to find a fetus free of a potentially harmful allele, or that will not have a risky allele and the tendency for some disease, so therapy will eventually dominate.
Fetal surgery or therapy or dietary supplements have been used for many diseases already, and the increasing use of conventional therapy will be supplemented by gene therapy. If there is a risk of harm to the fetus then it may be more ethical to use selective abortion at that early stage. It is seen by many that it is more ethical to end the life of a presentient human embryo than to let the embryo grow to become a person, or to try experimental therapy on the embryo and risk the damage to the child. The question of selective abortion comes down to the status of the human embryo, and the possibilities of earlier screening. The technology is here, and already some parents have had to make these type of decisions, we all need to examine our response. The choice will depend on the type of disease.
The situation will be reached where if a disease is diagnosed that requires treatment, it will either be abortion or therapy, it will be unethical for parents to knowingly fail to treat their fetus or children that are sick. There will be major ramifications of the new technology, and it will change the way that we reproduce. There will be some objections from people who do not want this treatment imposed on what they see as their property. We need to be responsible for our children, and that includes the time that they are still in the womb. Does this mean that we should not overdrink or smoke or take harmful drugs during pregnancy? In my opinion, yes, we do not have the right to do whatever you like, but rather that we should be responsible to the poor, the sick, and weak, and heal them. Almost all parents want the best for their children, and should seek medical help. Rather than being full of fear, we should welcome the ability to treat more of the diseases, and alleviate more of the suffering that they cause.
There have been experiments on animal models as a prerequisite to experiments on humans. There have been several animal systems for testing human gene therapy made. Retroviruses have been successfully used to target genes into animal cells for several years (Thomas 1986) and foreign genes have been expressed in mice, using treated cells (Bernstein et al 1986, Keller & Wagner 1986). Larger animal models are under study to determine the persistence of infected bone marrow cells in transplanted animals (Anderson et al. 1986, Kwok et al. 1986). Various types of retrovirus vectors have been developed. Human bone marrow cells have been infected and expressed inserted drug-resistance genes (Miller et al. 1986). There was expression of the human ADA gene in murine cells in vivo (Williams et al. 1986). One group of scientists placed the human gene for the production of ADA into the bone marrow of Rhesus and Macaque monkeys and fetal sheep in preliminary experiments (Anderson et al. 1986). Several experiments using SCID-mice and human ADA-deficient lymphocytes expressing an inserted ADA gene have been successful, as described. Other groups continue to work on procedures to infect hematopoietic stem cells, for diseases such as ADA deficiency (Cournoyer et al. 1990). These are the reason for optimism with the approved gene therapy trial, it is based on years of preliminary work by many groups. The human globin gene has been expressed in mice that were treated with retrovirus infected stem cells, so the expression problem in stem cells may be soon overcome (Dzierzak et al. 1988).
Another experiment performed in mice was to test a model for treating retinoblastoma In tumour development both positive acting oncogenes needed to be switched on, and negative acting tumour suppressor genes need to be mutated. Both alleles of the suppressor gene need to be turned off before cancer can proceed. In gene transfer studies the suppressor gene function for retinoblastoma could be reinserted and tumour cell formation repressed preventing the tumour formation (Freidmann 1990b). This work may be extended to humans.
There is a contrast between diseases that affect the lymphoid cells and diseases that affect the hematopoietic system. The hematopoietic cells have a short life so they cannot be useful targets of gene therapy. One of these diseases is Gaucher's disease. Human cells have expressed the gene for glucocerebrosidases needed for correction of Gaucher's disease (Choudary et al. 1986, Sorge et al. 1986). It is another disease with no known cure, which affects 0.2% of people born (2% of Jewish population). The absence of glucocerebrosidase results in the accumulation of non-degraded membrane lipoproteins within the reticuloendothelial cells. An appropriate in vivo model for the detection and measurement of pluripotent hematopoietic stem cells does not yet exist. Further experiments are needed, but there is some progress (Parkman & Kohn 1990).
The virus must not only be efficient for transferring and expressing the transduced gene, but it must also be safe. It is possible that the retroviral vectors might activate endogenous retroviral genomes in target cells by recombining with them and expression of the genes inserted has proved difficult. The use of disabled viruses is probably essential to "ensure" safety. The study of gene expression is also essential, it has been found the retroviral vector used to transfer genes into cells does alter the expression of the inserted gene. The chromosomal sites which retroviruses integrate may be fundamentally different from sites into which DNA segments integrate using DNA transfection without a viral vector.
Some problems have been eliminated, and others will be as further trials are undertaken. One of the positive outcomes of extensive animal trials has been the development of effective and stable retroviral vectors for gene transfer. There are alternatives to retroviral vectors being developed, such as methods of targetted modification of human genes (Gregg & Smithies 1986, Thomas & Capecchi 1986, Capecchi 1989), and these will soon be possible. Promising alternatives to retroviral vectors are being developed, such as the use of laser micropuncture of the cell membrane to facilitate direct gene transfer. This technique has been used on cultured human cells with an efficiency 100-fold more than the standard calcium phosphate mediated method of DNA transfer in which cells are passively incubated in the DNA solution (Tao et al. 1987). There are also new techniques for electroporation, and microinjection, and even high velocity tungsten microprojectiles containing DNA. The efficiency of the physical methods is about 1% of the target cells incorporate the genes (Friedmann 1989).
If there are no naturally occuring animal models for some human genetic diseases, targeted gene mutagenesis can be use to create diseased animals. Mice have been genetically engineered using embryonic stem cells to be HPRT-deficient mice. These were hoped to provide mouse equivalents of Lesch-Nyhan disease suffering humans. Genetic therapy has been tried on them, as preliminary experiments for human gene therapy (Friedmann 1987), correcting the gene deficiency. However, in this case the HPRT-deficiency in mice has been found not to result in a disease such as human Lesch-Nyhan syndrome, so it is not a full model at the animal level, only at a level of restoring gene function. It is still useful for studying gene function, though some people disagree with the creation of diseased strains of animals (Macer 1989).
There have been a variety of trials in animals. There is some progress on gene transfer methods. Lipoprotein vesicles using the substance lipofectin have been used to insert genes into the neuroepithelium of frog embryos, as well as into skeletal muscle cells of young mice. The biolistics approach used in plants for gene transfer is being applied to animals, and will also be used in the gene therapy trial on ADA gene insertions in humans that has been approved. The gun shoots DNA-coated gold microprojectiles, using high pressure gas, instead of the gunpowder used in plants. It has been used for different animal tissues with some success, and will be useful.
In a recent report, work on heart disease was reported. Heart disease afflicts millions of people, so is much more numerically significant than ADA deficiency. Rabbits of a strain called Watanabe lack the receptors for low-density lipoprotein (LDL), cholesterol. This means that they cannot remove the bad type of cholesterol from their blood, so they develop atherosclerosis. A team of researchers led by Wilson and Mulligan, took the rabbits liver cells out, and inserted the gene for this receptor, and implanted into the rabbits. For two weeks the genes worked, although they only expressed about 4% of the normal activity of LDL receptors, the blood level of LDLs dropped 35% (Marx 1990). However, for some reason, yet unknown, the genes did not work for longterm. This type of gene transfer experiment is becoming very common, and within this decade we can expect more therapeutic use of somatic cell gene transfer.
Inserting Organoids
There are important limitations on the use of specific tissues, such as bone marrow cells. An alternative approach to removing, altering and replacing bone marrow (or most other specific tissue cells) is to remove and transfect cells from a chosen source in the affected individual. This involves isolating a suitable cell from the patient (to avoid immune rejection upon subsequent insertion). After genetic manipulation in vitro, chosen cells are cloned (grown to increase the number of identical cells), than tested to check if there is proper regulation of the transfected gene, and then these cells are reintroduced. Of course many tissues are impossible to replace.
In a preliminary test, a gene was transferred into cultured mouse fibroblasts and subsequently these cells were implanted into various locations in mice (Selden et al. 1987). It was found the function of implanted cells depended on the location and size of implant. The technique is called tTranskaryotic implantation, and it is a promising extension to the range of possible gene therapy techniques. The efficiency of gene transfer into different cells varies, and it is highly efficient into human fibroblasts, 87% efficiency is already obtained (Miller et al. 1986).
Hemophilia B is a disease caused by a lack of blood clotting factor IX, affecting 1 in 30,000 males. Current therapy involves injection of the protein. The protein is normally made in liver hepatocytes, but recently the gene has been transferred by retrovirus, and expressed in a fully active form in human skin fibroblasts. This may allow the use of skin grafts for gene therapy of hemophilia B (Anson et al. 1987). Human skin cells from patients with ADA deficiency have been infected with the ADA gene in a retrovirus and have expressed the gene, making the enzyme ADA (Palmer et al. 1987). The next step is grafting the treated skin cells back into the donor to see if the level of expression of ADA is sufficient to cure the disease.
Many disease treatments do not require the production of the corrective protein at a specific site. For blood protein disorders it would be possible to insert a cluster of cells making the required protein at any site where blood vessels could deliver the protein to the rest of the body. Because skin cells are easier to graft, they may be used, or fibroblasts could be inserted into other solid tissues. Because bone marrow stem cells are more difficult to correct, this alternative delivery system may be chosen.
Researchers have recently created an artificial organ, or organoid. The first such organoid was an artificial liver which was implanted into the peritoneal cavity of a rat. It was made using an artificial fibre, "Gore-Tex", and cells. The trial involved using cells that produce Heparin-binding growth factor 1, a factor that induces the development of blood vessels (Thompson et al. 1989b). There needs to be cells to generate blood vessels to flow through the organoid, and cells to produce the protein, or other product. The first use may be to produce a protein, CD4, which helps slow down the development of AIDS (Culliton 1989b). There are many potential uses for this approach in medicine, and it should result in rapid progress.
There are certain organs which may be very difficult to use somatic cell therapy on. If the gene is required intracellularly, and inside a particular organ, germline gene therapy may be the only way. However, tissues such as muscle and the brain, which are nondividing cells and were thought to be very difficult for somatic cell therapy, are now being investigated as serious research. Once tissue targetting vectors have been developed, then they should be possible. One approach is to use other cells to associate with these organs and transmit diffusable gene products to the cells that need it.
Those people who support the use of gene therapy stress the teological principles that genetic disease causes suffering, both pain to the individuals suffering and their being a burden on others. Medicine is right to try to cure disease and alleviate suffering. Gene therapy is a new form of medicine and if properly controlled it will lead to the sufferers' being able to live healthier and fuller human lives, which can lead to a higher quality of life. Biologists may feel that the very nature of DNA and ease of manipulation to cure disease makes it an obligation of stewardship, not just of greater good. The opponents have reservations as they feel that gene therapy is unusual and untried, and wonder if there has been enough experimentation to warrant use of such techniques on humans (Friedmann 1983, Anderson 1984, Culliton 1985, Robertson 1986, Walters 1986, Nichols 1988). It may lead to the abuse of genetic control and to decreasing human value. And the legalists ask who has responsibility for unforseen problems.
The deontological argument applies to the patients, and to whether their rights are being removed and whether man should be altered genetically. God is concerned with every individual human in creation, but while we are all given a unique genotype, the defects caused by mutations are treated in medicine and there is nothing inherently evil in altering the genotype to cure disease. First we will examine the government guidelines that apply to gene therapy, and the factors that they concentrate on.
Government Guidelines
The situation regarding the major ethical debate over gene therapy before its use, is in major contrast to the situations with the use of other new reproductive and genetic techniques, such as genetic screening, selective abortion, embryo experimentation and IVF. With a few exceptions, these other techniques were discussed in greater depth after they were technically possible, and while they were being clinically used. However, there have been ethical guidelines preventing human gene therapy for the last decade in the United States, since the first use of gene therapy in 1980. The European Medical Council (1988) has also recently made a statement on gene therapy. There have been statements from other countries, such as Australia, and there is currently a committee examining guidelines appropriate for Britain.
The procedures that have been decided upon in the USA for researchers to obtain US government approval for gene therapy experiments upon humans are quite elaborate (RAC 1986). The researcher must answer the following questions.
Why is the given disease a good candidate for gene therapy?
Will the therapy cure the disease or merely halt its progress?
What alternative therapies exist, and how effective are they?
Technical details of the DNA and vector to be used.
What makes the scientists sure that the new gene will be properly inserted and
regulated so as to be expressed usefully in the patient?
Has a similar experiment been conducted on nonhuman primates?
The major reasons that human gene therapy has been long delayed are technical delays, the risks to the patients of experimental therapy, and the fear of human genetic engineering. The government guidelines consider all of these factors. Of most importance is the regulations are the technical factors, and protecting the patients from unethical experimentation. There have been problems with the development of techniques that has delayed the date of the clinical experimental use, but overall the progress has been rapid since the first experiments with genetic manipulation of bacteria in 1974. The major technical problems can be divided into three areas (Anderson & Fletcher 1980, Culliton 1985, Walters 1986) the delivery system, the gene expression, and safety. These are important for ethical consideration of the techniques as they apply to individual patients.
The assessment process begins with an evaluation of the genetic disease to be treated. The diseases that will be the target of the first human trials are considered so devastating that experimentation in patients may be justified ethically as long as some animal data are in hand. In the case of terminal cancer patients, there is also the argument that patients should be able to consent to experimental therapy, so that they feel useful, even if the chances are very low. However, in order to protect patients from possible abuse, this is not usually sufficient justification for experimental therapy. Gene therapy has not been tested so will often be the last resort, after all other alternatives have been considered, and if the transition from animal to human studies is considered appropriate. The trial must be of potential benefit to the patient, and should be designed so that useful information will also be obtained to aid in the design of future trials.
The first approved clinical trial for human gene insertion was approved only after being reviewed fifteen times by eight different committees (Anderson 1990). This is more than any other clinical treatment. One must say that this is a case of extreme regulation, why so many different ethical committees. We can hope that the regulators will change the procedure, as after we examine the ethical issues we will see that there is little to distinguish this treatment from other types of experimental therapy.
At the end of 1989 there was a committee established in the U.K. to look at the issues of gene therapy. It is chaired by Sir Cecil Clothier and its purpose is "to examine the implications of the prospect of treating certain conditions by gene therapy". They are to draw up ethical guidance for doctors who wish to use these techniques, and give guidance to any who want to perform such therapy (IME 1990).
Efficacy of Treatment
The new gene must be correctly put into the target cells, and remain there long enough to be effective. It would be an advantage if the cells to be directly exposed to the virus were outside the body in case something unforeseen did occur. The major problem of the viruses being used is that they can rearrange their structures once incorporated into the patient's DNA, and they may then form new viruses. But the latest designed viruses seem to be stable enough for use without likelihood of this occuring. Still studies in human bone marrow tissue cultures and studies on the incorporation of genes into mice and primates are needed, to see if infectious viruses or malignant cells can be detected, before patient trials begin. There are also alternative delivery systems that need testing.
The new gene must be expressed in the cell at the appropriate level, and only in that tissue. With ADA deficiency the proper control of gene expression is not critical because the production of any of the enzyme would be beneficial. But with diseases where many genes are defective and the products of the genes circulating in the blood stream have to be at a fixed critical concentration, simply inserting the gene is not enough as the control mechanisms may not work normally. It is safer and easier to treat these diseases by injecting precise amounts of the hormone or enzyme into the patient.
Safety of Transferred Genes
The new gene must not harm the cell or the patient as a whole. However, unlike most other medical treatments, the introduction of a virus could possibly threaten other people. The risks to the patient themselves are no higher than many other experimental therapies. This is a contentious issue because the stability of the genetic arrangement is difficult to predict. Possibly many years after treatment some environmental could trigger an unforseen event. It is however unlikely that an infectious mutant virus would be formed if the delivery system was sufficiently stable. It has recently been observed that some retrovirus vectors recombine inside the cells at frequencies of 1 in 10,000, producing wild type infectious viruses. These virus particles probably stay within the individual so are not an outside threat, but they are a potential safety concern. The fear of a contagious virus, which even in its' worst scenario might be spread like HIV, that is by serum contract only. On the basis of the limited animal experiments done, this does not appear to be a risk.
However, gene therapy is only a new technique for the treatment of disease so it should be considered in the same light as other treatments. It strikes a deeper response because it involves changing our biological foundation which has only been altered in the past by drugs. It actually seems a better and potentially safer treatment for individual patients, since it would avoid the many side effects caused by dangerous drugs. We will also avoid problems to the patient, such as negative side effects, of conventional treatments. Potentially, gene therapy may lead to greater unforseen problems than alternative treatments because it is directly altering DNA, but in the long term it should be much safer.
For the gene therapy to remain in the class of 'somatic' therapy, affecting only the patients body cells, the gene should not be incorporated into the germline cells. The gene or viral vector should stay in the initial target tissue, if it may harm the patient being elsewhere. The risk of genetically altering the germline is not unique to gene therapy, as several other medical practices, such as vaccination, cancer chemotherapy and radiation therapy also carry this risk. The idea of germline gene therapy is more objected to, as it would after future generations. However, to most patients with the likelihood of being treated soon by such a therapy, their life expectancy being under 25 years, and who may only expect to have less than a year to live, the thought of this being a barrier to a possible treatment is far from their mind.
Some feel that genetic manipulation differs in principle from other therapeutic techniques. However, it should be judged in a similar way to any other technique. Altering the expression of genes by drugs so that some of these drugs may cause secondary changes in the genes themselves, is effectively the same as altering the patient's genotype by inserting new genes directly.
Human experimentation
Experimentation and Protecting Human Life
The major safety concern seems to be the same as with other treatments, despite the fears of a potential viral epidemic, the safety to the patient, that is do no harm. As clinical experience is gathered it may be justified to use somatic cell gene therapy as a prefered treatment in many disorders that may have alternatives. The sole determinant on choice of treatment should be what is in the best interests of the individual patient, assuming no one else is at risk. The safety argument would be the major reason not to try germline gene therapy at present, as we do not know enough about the possible side-effects on the individual patient's or the long term risks of some sort of viral epidemic. We need to know much more about gene regulation and developmental changes before it would be ethical to try this.
Almost every action taken by the doctor in the process of relief of suffering is experimentation, as people vary in their response. No one type of diagnostic procedure or treatment may have been proved to be superior to all others in the management of a particular disease. When the patient stands to gain from investigations performed some risks are acceptable when weighed against the likely rewards. The difficulties arising from the use of technological advances are often temporary ones resulting from a lack of expertise. Common sense is required in the decision when to use these techniques. But if the patient will receive no personal advantage and is merely contributing to the welfare of future patients, any significant risk is only permissible provided the subject can appreciate the hazards and give his consent without coercion. There are obvious moral considerations involved in the choosing of a particular procedure on behalf of an individual who may be too young or mentally incapable of making a decision. Any experimentation should be in the best interests of the patient, and a basic rule is to "do no harm". From the principle of double effect the genetic manipulation to treat disease is morally justified.
The Recombinant Advisory Board (RAC) in the USA has been asked by the Boston-based "Committee for Responsible Genetics", to ban for the indefinite future any tests of gene therapy not aimed solely at the relief of a life-threatening or severely disabling conditions. The measure of risks to be accepted in proceeding with genetic treatment is the balance of the seriousness of the illness to be relieved against the possible dehabilitating outcomes of the treatment itself. To proceed against Tay-Sach's Disease or ADA deficiency, for which there is no known cure, yes but against cystic fibrosis, for which there is some relief, there is less certainty. To proceed to gene therapy in the case of diabetes would be an immoral trial until the technology is proven. The aim of medicine is to make a patient well or at least less ill than before.
Where there is an established treatment to cure the disease that treatment should be used. If however, compared to another technique it is more likely to be a successful therapy for that individual, the one best suited should be used. Some predict bone marrow transplantation will be used more than gene therapy, at least in this next decade, as the immunosuppressive drugs being used are good. Gene therapy may be used only when it is judged by the physicians to be in the best interests of each patient.
The patients that are current candidates for gene therapy are all suffering from a fatal disease, normally a genetic disease, but in the case of the most recently suggested trials suffering from major cancer. The first test will not require the expression of the gene, but merely the insertion of it as a marker for immune cells that attack tumours. The cells will be treated with a natural substance, interleukin-2, which aids the cells attack on the tumour. It has not been possible to trace these cells to see how they attack the disease, so a marker gene may be useful. If this works, they may insert the active gene for interleukin-2 into these cells, which my aid their activity. This possible second trial might be easier to judge ethical, as it will include the possibility of benefit to the patients. One of the genetic diseases, ADA deficiency, previously thought to be a good candidate for gene therapy trials (Kantoff et al. 1988), now has an alternative treatment which is currently being tried which has lessened the current case for using gene therapy.
One of the researchers behind these cancer patient trials, W. French Anderson, of the National Institute of Health, U.S.A., has written extensively on the ethics of gene therapy, which one could say has been a good example of a scientist thinking of the ethics of using techniques they are trying to develop, and raising these issues for public discussion. Much of the responsibility (and thus accountibility) for the use of gene therapy lies with those involved in medical practise and research. The possible side effects may not be imagined by the medical practitioners, so more responsibility rests with the researchers. Our knowledge should be used creatively, but it must at all times be used responsibly, too.
The ethics of using a experimental medical technique are well discussed, and the use of gene therapy should come under the same examination, such as the guide lines of experimental medicine on human subjects. We should not do harm, but we may undertake an "experiment" on a patient if there is a reasonable chance of therapy, and informed consent, and taking into account the life expectancy and quality of life, without this therapy. As an exercise, can you think of what percentage of success of recovery you would consent to as worth the risk if you had three months life expectancy at the age of 20 years having spent most of your life in hospital. This is using the old maxim, would you use it on yourself?
The delays in the introduction of trials using gene therapy have partly been due to a consideration of patient rights. There has been some caution, correctly, used to protect patients from merely being "guinea pigs" when the therapy has not been previously shown to work in animals. It is not possible to regulate the use of genetic engineering by consent alone, as inadequate knowledge may be available. Parental proxy is often necessary. Poverty may lead patients to research hospitals, rather than to hospitals which use expensive alternative therapies. We must be careful in the use of new technology. However, many patients, or their families, have been frustrated by the delays over what they see as their only hope. Sometimes the media has falsely raised the hopes of the public, so that their optimism is not based on fact, but there still could be a case that the regulatory bodies have been over cautious.
Many of the diseases that gene therapy will be used on afflict children. There are special problems associated with medical experimentation on children, in the way consent is gathered. There are existing medical agreements to cover this, such as the Helsinki declaration. These allow for experimentation when it is in the best interests of the child, in light of alternatives. The research will involve children if it is their only hope. This will provide further challenges to the decision making of medical ethics.
Alleviation of Suffering
When we see suffering, or feel it, it is the more immediate solutions which are more important than the future sometimes seemingly fantastical conjectures about its longterm misuse. This is a fundamental principle of bioethics, and is called beneficience. It is important to realise that it is unethical to misuse it, but equally unethical to delay the use of techniques which are medically safe. There will be an urgent desire to treat patients that are close to death with promising but untested experiments. In many respects the use of somatic cell gene therapy may give rise to no new ethical problems compared to other treatments, but we will need to have a healthy respect for the degree of ignorance of the possible side effects of the techniques.
Already we have existing medical values to decide who is responsible when deciding treatment. There is always a danger in the unknown, the realisation of which is a good thing, but we must decide if we are objecting to something because it is wrong or because it is not "normal". In some ways all medical treatments are unnatural, but they are beneficial in that they aid the natural course of human life. The development of these technologies will involve experimentation upon future children. While we shall not kill, the primary motive in any treatment is compassion, and there is certainly no murderous intent. We will expose children to additional risks they would not otherwise be exposed to, but we will also be offering them possible life they would not possibly have. To delay beyond the point of reasonable prudence means that an undetermined number of patients will die, not only those individuals who would directly benefit, but also those in the future that could be saved if the techniques had been developed earlier.
Affect on Family Life
We may ask whether somatic cell gene therapy techniques will affect the nature of our family life. It will only affect a few people, and one would generally imagine that healthier people will be at least as good and usually better than sick. The ability to cure disease will not necessarily lead to the situation where parents will only accept a healthy child, though with the advances in medical care during this century generally people now expect to be cured. Gene therapy will certainly not erradicate genetic disease. Children may have psychological problems in knowing they are "corrected", but already therapy is performed on many. A serious concern are any physical safety problems during the development of the techniques. However, without treatment they would be dead, so this is no real problem! One future risk some see is that some parents may decide to chose their children's characteristics by genetic manipulation, which may have the affect of encouraging the replacement of personal and permanent relationships characteristic of a family with instrumental and impermanent relationships, but this should not be confused with somatic cell gene therapy in the case of diseases. Once an individual exists, human relationships are critical. Human concerns are more important than abstract speculations.
Economic Factors
The economic factors are important to consider as we use our limited medical budgets. Some ask whether we should spend our health resources in this way rather than on other areas of medicine. It may cost US$ 100,000 dollars for one year costs for cardiac transplantation (Walters 1986), so medical costs currently accepted as justified for medical treatments in developed countries are already very high. Some would say too high. With the high cost of lifetime treatment of sufferers of genetic disease (which is not possible in some countries), once a therapy is developed it would be cheaper to treat the patients only once so that then they could be working individuals in society and would not depend on hospitalisation. The argument could be extended to using germline gene therapy since it would be cheaper than somatic cell therapy, though other factors may be considered more overriding. Once a person exists, that individual is to be treated as of utmost importance, regardless of any deleterious genes they carry, or of the cost to society.
There is a more fundamental question of what proportion of health funding should be spent on research versus clinical practise. If we converted the results of research into clinically useful results there would be more shortterm advances, but longterm progress would slow. There is much research in gene therapy techniques in the USA, and in 1990 several trials have been approved. At last it may get to the clinical stage. The longterm projection means that this therapy is economically feasible. Given that the developed countries maintain that they are entitled to using high cost medicine while people in the developing countries can not afford basic costs such as vaccination programs, gene therapy is justified. It may be more justified than many other expensive therapies because of the longterm effect of reducing costs. It will be many years before people in the developing countries can use such a technique, and it is therefore not a priority of WHO nor should it be. However, in developed countries it is economically justified. Not only will the economic costs be reduced but the cost in reducing suffering will also be on the positive side, something that not all new medicine can claim.
Public Attitudes and Fears of Genetic Engineering
The name "gene" therapy is a suitable one from the point of view of the technique, but it has raised many unnecessary fears in many peoples minds. The picture conjured up, thanks in part to some creative writers and confusion with germline gene therapy, is that gene therapy will mean gGenetic engineering of the human race. However, this is not what somatic cell gene therapy will do, as it only concerns individuals who are to be treated, as they have been for milleniums by medicine. The effects of some modern drugs leave more to be worried about. Some cause major damage to the patients DNA have been used (Charache et al. 1983), and many prescribed drugs alter patients behaviour markedly which may give more cause for fear or more potential for misuse. The techniques for selective abortion have greater affect on the population gene pool than any other medical treatment.
In an apt term, Gaylin has described the fear of genetic technology by the term "Frankenstein Factor" (Gaylin 1990). Part of this is common to all high technology research that may be unknown to the public. The fear of the unknown, is a factor in people's fear of genetic engineering. This can be diminished by good public education, which should be a lesson applied in many areas of science. The second part is that we are changing the very nature of ourselves, or at least that is how it may be perceived. While we do this by our diet, environment and other forms of medicine, for some reason the genes seem more fundamental. The ironic thing is that our culture and social system change our very personalities, what is the distinctive part of a human being or person, in greater ways than altering a few genes. This attitude may take more than education to change, but at least education of the place of genetic therapy among the many other aspects of changing our life, would help. Some caution is of course useful also.
What may occur in the future is a shift in public opinion towards a pressure upon all parents to undergo such a type of treatment once it has become routine. However, if it is beneficial, than few parents would object to it. We can see the differences between what technological societies and third world countries regard as a need today, public standards do change. It will be necessary to widely educate people about the new techniques as misinformation, old wives' tales and general ignorance have already led to some popular misconceptions. While some feel that the idea of genetic therapy is unnatural there will be a shift in opinion when it becomes routine, and it is understood for what it is, not fears of beyond that could be associated with excesses of most human endeavours. Nevertheless some people may still view it as unethical, and while they do so there may be doubts as to whether it should become enforced routine treatment. Perhaps once it has reached a certain stage of reliability it may be seen by most as a necessary part of health care. This may only be a few years away, though is a problem currently faced with some medical techniques by those people who feel the body should not be treated by transplants - maybe since it would be their own body tissue being treated it would be less of a disruption of their moral values. The judgement of use of the treatment will fall on the physicians, as with other medical techniques, but this should only be used when medically necessary, as are current therapies.
The slippery slope arguments that because we do some act, we will do another, are not always logical. If we do gene therapy to treat disease it does not mean that we will use gene manipulation to alter behaviour, morality, or appearances. They are two very separate questions, and there is a moral gulf between them. Every technology has a slippery slope, along which we decide to stop. Growth hormone replacement therapy for dwarfs allows them to become normal height, but it is objected to if suggested to make normal people very tall for certain sports. Another more difficult problem will be the use of memory-improving drugs, which while being developed to help below average intelligence children learn normally, could also be applied to normal children to help them.
Man will have the power to shape his own biological destiny. Such power can be used wisely or unwisely, for the betterment or the detriment of man. There are many issues raised by the possibility of shaping the genetic constitution of the human race, but perhaps if we are concerned about the maximal fulfilment of the potential of our fellow human beings than this could be of more benefit than potential harm. While humans do have a limited rationality, we may not always be able to discern which qualities are desirable though we can often see ones which are not, such as disease.
When We Should Use Gene Therapy?
The goal of biomedical research has always been to alleviate human suffering, and as we have seen gene therapy is a proper part of that. The techniques are necessary and they provide new approaches. What remains undecided is whether they are ethically and socially acceptable. Just because a new technology becomes available it is not necessarily the most rational course to use it. Even if human society all agreed on a rational action, we are still sinful and so incapable of always making perfect decisions. Gene therapy has been described as a preventative therapy, preventing disease at the fundamental level. We should not forget that there are other causes of disease, and poor health, such as good diet, and health education, which are also root causes to be focused on.
Because of the doubts about success, the immediate prospect of gene therapy is limited to life-threatening diseases that do not have any other cure, and are due to a single gene defect whose effects can be corrected by the insertion of the normal gene into the bone marrow without the need for precise regulation of gene expression. Diseases of the gut and skin are similar in that like bone marrow these tissues have dividing stem cells in adults, so they may also be treatable. Since there may be no alternative treatment these new methods are necessary if we wish to treat these conditions, and they promise new approaches to disease treatment. The major disadvantage of gene therapy is the technical difficulty of expression and appropriate regulation of new genes in somatic cells. The main advantage is the compatibility of the reintroduced cells with the patient and the avoidance of immune rejection. Many patients with genetic disease do not have suitable donors for transplantation.
Gene therapy also offers the possibility of introducing novel genetic elements that, for example, may confer drug resistance to normal bone marrow cells to allow their survival during chemotherapeutic treatment for cancer. Gene therapy is another medical tool to help individuals overcome an illness, and somatic cell therapy has basically no new ethical problems from existing treatments.
What is essential is full public review of the results, which will have to be debated much before the techniques become of wider use. While this is not required for most medical treatments, there has been so much publicity associated with gene therapy, that the results and comparisons to alternatives, should be made available to allay public anxiety. The patients, or their guardians must be educated so as to be able to decide if they will submit to the experiments, which will have to include longterm followup studies of patient progress.
The point at which we stop using gene therapy is discussed in the next chapter. It is when it no longer is a treatment for a disease, but becomes enhancement. This problem is not only when we use genetic therapy, but is also found in common practise, such as cosmetic surgery, or in the more serious case, on deciding the limits of growth hormone replacement therapy. When therapy no longer adds to human dignity we should stop using it, the same as other applications.
We must be clear that a pursuit for our lives to be free of physical suffering is not going to make the ideal world. Genetic defects have a smaller effect on people than the moral, spiritual defects and lack of love. The goal of healing is to benefit the patient - the actual patients are the "ends" rather than the "means". In this case individuals are more important than hypothetical individuals (ones as of yet unconceived), or the human species in general. Using gene therapy to improve the health for our children is not really going to trade away a part of our humanity that is worth preserving. Love can be shown in many other ways than through sympathy to people suffering from genetic disease, and may be shown more by the cured patients.
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