Ethics of Gene Therapy: Problems and Controversy
Gene therapy can be divided into somatic gene therapy, germ cell gene therapy and enhanced cell gene therapy. Somatic gene therapy is the application of somatic gene engineering technology to implant a gene into human body to correct the genetic defects of patients. Because many genetic diseases are caused by gene deletion, gene abnormality or defect, somatic gene therapy can be used to implant genes into cells to treat gene deletion, abnormality and defect. Germline gene therapy is to transfer foreign normal genes into sperm, eggs or fertilized eggs to correct defective genes and achieve the purpose of treating genetic diseases. Theoretically, germ cell gene therapy can not only treat patients with genetic diseases, but also prevent their offspring from suffering from this genetic disease, which is a method to eradicate genetic diseases. Related to germ cell gene therapy is enhanced gene therapy or enhanced genetic engineering. Enhanced genetic engineering can change the genetic material of somatic cells, as well as the genetic material of eggs, sperm or early embryonic cells, from correcting disease genes to changing normal characteristics of people. At present, due to the development of technology and ethical disputes, some somatic cell gene therapy has been applied to clinic or entered the clinical research stage. Germ cell gene therapy and its related enhanced cell gene therapy have not been carried out.
First, the ethical controversy of somatic gene therapy.
Somatic cell gene therapy was first developed in America. The initial ethical debate encountered here is related to the legality of this treatment, which is very different from the general treatment. Some scientists believe that somatic gene therapy is a natural and logical extension of current disease treatment technology. Bioethicists mainly consider the safety of technology, the potential advantages and disadvantages of gene intervention, the fairness of participants' participation opportunities, the authenticity of informed consent of research participants, the privacy of participants and the confidentiality of medical information. Ethicists pay attention to some basic ethical principles of bioethics: superiority, respect, autonomy, informed consent, confidentiality and justice. However, how to apply these principles is a process of practice and controversy. [ 1]
When somatic gene therapy has been implemented in cell culture and animal models, the primary issue discussed by bioethicists is the expected or potential advantages and disadvantages of somatic gene therapy in terms of whether gene therapy can be tried on patients soon. Critics believe that the safety of modified viral vectors for somatic cell gene therapy has not yet been determined because there is still a considerable degree of uncertainty. The patient's cells may have recombined the virus gene, and the retrovirus cannot accurately reach the target gene in the target cell for replacement. Theoretically, retroviruses may also activate or stimulate oncogenes. [2] However, more scholars believe that this treatment only affects non-reproductive cells, and the altered genetic material will not be passed on to future generations. Transgenic somatic products are similar to drugs taken by patients. Some techniques used in somatic gene therapy are similar to other widely used medical interventions and have the advantages of less invasion and rejection. In addition, they also believe that if some diseases can be treated by other methods with small side effects and reasonable cost, then other treatment methods should be chosen according to the principle of benefiting patients, and somatic gene therapy is only used for those refractory diseases such as genetic diseases, cancer and AIDS. [3]
Due to the constant emergence of ethical issues and heated debates, researchers should be more cautious and careful when applying somatic gene therapy to clinic than when applying heart transplantation and IVF. In the early 1980s, in the absence of evidence of clinical gene therapy, American scientists tried clinical gene therapy on patients. This practice has been widely condemned because the experimental results are not obvious and there is no ethical argument. Therefore, somatic gene therapy in the United States almost stopped 10 years. After the initial gene therapy experiment for patients with severe comprehensive immunodeficiency disease (SCID) obtained some clinical beneficial research results, the first somatic gene therapy subject to ethical review was applied to humans, and its first draft was approved after three years of discussion. Prior to this, the related ethical debate lasted for nearly 20 years. [4]
1September, 999, a sad event brought new thinking to the field of bioethics. Gersingo, 0/8 years old in Philadelphia/Kloc, USA, suffers from a hereditary disease-benign ornithine transferase (OTC) deficiency. This ornithine metabolic disorder can be controlled by nutrition and drugs. However, he went to the Institute of Human Gene Therapy of the University of Pennsylvania to receive the clinical phase I trial of gene therapy, which was also 18 and the last subject of the Institute. In the experiment, the research team led by james wilson injected adenovirus vector particles (maximum dose) containing exogenous therapeutic genes into his liver. The next day, Gersingo's condition worsened, blood ammonia rose sharply, and he began to be unconscious at night. Four days later, due to a strong immune rejection, Gersingo died of multiple organ failure.
This is the first clinical trial that died directly from somatic cell gene therapy. At a hearing in June 5438 +2000 10, Gesingo's father said, "This is an avoidable disaster. I didn't tell my son in advance that there was any serious danger (including the death of the experimental monkey). He was induced to mistakenly believe that this human experiment is beneficial to him. " Voluntary subjects were attracted by a patient consultation website. The website calls this gene therapy plan "very low dose and gratifying results".
This incident not only involves the ethical issues of informed consent of the subjects, but also involves the conflict of interests between researchers and subjects and the responsibility of researchers in scientific research, which was often ignored in the past. To be sure, this incident is not only not a responsible clinical trial study, but also full of misleading and deception. First of all, this experiment should not be applied to humans, because monkeys had similar reactions in the early research, and some of them were already dead. In the past, a patient who received only a low dose of virus would have liver damage. The information published on the website not only didn't mention the reaction of animals during the preparatory research, but promised that the experiment could get the results as soon as possible, and the dose of virus used was very low. The final consent did not mention the death of the monkey and other related facts. Originally, the contents contained in the informed consent of gene therapy should be discussed in detail by the ethics review Committee and accepted by the public. However, the researchers deliberately concealed the fact that the virus vector was injected into the liver of the subjects from the Recombinant DNA Advisory Committee of the National Institutes of Health (NIH).
The ethical issue of this incident is not only what steps to take to ensure the subjects' true informed and voluntary consent, but also the responsibility of researchers as scientists and the conflict of interests between researchers and subjects. The responsibility of scientists in research and the conflict of interests between researchers and subjects have attracted the attention and discussion of bioethics in recent years. The responsibilities of scientists in research include: the integrity of scientists, the monitoring of scientific misconduct and the responsibilities of scientists. From the perspective of scientific progress, it is a challenge for researchers to provide important facts to subjects, including the real situation of their diseases, treatment methods, methods used in research, advantages and disadvantages of research, etc. However, judging from the purpose of science serving mankind and the dignity of science and mankind itself, the integrity and social responsibility of scientists are very important and must not be abandoned.
Wilson, the party in this case, owns a company, which has the patent right to the discovery of his laboratory. In other words, he and his colleagues, lured by the intellectual property rights of this technology, violated scientific research ethics and conducted this somatic gene therapy experiment. At this time, the researcher's economic interests contained in the experiment may conflict with the life interests of the subjects. Instead of avoiding these conflicts of interest, the researchers hid the truth from the subjects. Conflict of interest is a new bioethical problem brought by economic development. Enterprises have provided great economic support for experiments and injected vitality into scientific research. However, the control of enterprises in the field of scientific research can gradually make some scientists and scientific research institutions lose their independence, leading to the erosion of scientific research ethics of some researchers and the damage of scientific research integrity. [5] Conflicts of interest also include conflicts between scientific progress and public interests and corporate interests. At present, the field of bioethics defends the fundamental interests of patients or subjects, and emphasizes the analysis and solution of various interests in human experimental research. In view of this adverse event in somatic gene therapy research, the Institute of Human Gene Therapy of the University of Pennsylvania has stopped Wilson's research. However, as a typical case, the study of somatic cell gene therapy is constantly being discussed, which deepens our understanding of gene therapy ethics and promotes the theoretical research of bioethics.
Second, the ethical controversy of germ cell gene therapy.
Germ cell gene therapy is in the experimental research stage and has not yet entered the clinical human application stage. But in the United States, related ethical discussions began in the 1950s and 1960s. Some people think that at that time, the treatment of changing the genes of human germ cells can be carried out, while others think that it can only be carried out after the technology is improved and perfected. 1September, 1992, Dr. Neil submitted a proposal on the ethical issues of spontaneous mutation and induced mutation of germ cells to the NIH review Committee, suggesting that discussing ethical issues as soon as possible can reduce risks and make preparations. Once the technology breaks through, gene therapy of germ cells is feasible, and ethical discussion in advance will lay a good foundation for formulating reasonable regulatory policies. [6]
Germ cell gene therapy may be applied to these clinical cases: when the wife and husband are both patients with recessive genetic diseases, their offspring may all suffer from the same genetic diseases. When couples are carriers of recessive genetic diseases, 25% of their offspring may carry normal genes, 50% may carry the same genetic diseases as their parents, and 25% may be patients with this genetic disease. In the first three months of pregnancy, a genetic disease will cause serious irreversible brain damage to the fetus. At present, there is no other known method for gene repair of the fetus in the uterus. A confirmed genetic disease will affect different cell types in many different parts of parents' bodies, while somatic cell gene therapy can only treat specific cell types, while germ cell gene therapy can affect various cells at an early stage, which may be the only feasible method to prevent the disease from being passed on to future generations.
Scientists in favor of germ cell gene therapy believe that germ cell gene therapy may be the only way to prevent gene defects from causing damage to special organisms. It is more successful than somatic gene therapy, because the technological breakthrough it needs is gene replacement or gene repair. Somatic cell gene therapy technology adopts the method of gene addition, which keeps both normal and abnormal genes in the target cell. Gene replacement or gene repair used in gene therapy technology of germ cells avoids this risk, and it can completely eliminate the dominant genetic diseases of germ cells. [7]
Scholars who are in favor of germ cell gene therapy also demonstrate from the perspective of parents that parents want their children and offspring to be born without genetic diseases and somatic cell gene therapy after birth. Parents also want to avoid making all kinds of difficult choices because of genetic diseases that may be passed on to their offspring. Any sincere decision made by parents for the health of their children should be protected by morality and law. [8]
This argument in support of germ cell gene therapy has been refuted by many people. The reason for refutation is based on the negative effect of technology, that is, once there is a technical problem, this negative effect will be serious and irreversible. Because of the unpredictable negative effects brought by technology, it will not only affect the subjects, but also affect their descendants. In view of the ethical defense that parents can make decisions for their offspring's health, opponents refute it from the perspective of future generations' human rights, arguing that future generations have the moral right to inherit their parents' "genetic property" without manual intervention, even if their parents' purpose is to protect future generations from diseases. Everything has a boundary in essence, and no matter how kind it is, it can't go beyond this boundary. [9]
If the gene therapy of germ cells is successful, incurable diseases such as genetic diseases or cancer can be eliminated once and for all. It seems that such a good technology should not be given up. But what we have to consider is what is the negative effect on the technical level, and whether it is unpredictable and uncorrectable. When a technology is not mature enough to be applied to human research or treatment, people should wait for the continued development of its basic research. The function of researchers and health care workers is to freely explore new ways to treat and prevent human diseases. However, only when germ cell gene therapy has the function of preventing genetic defects and treating genetic diseases can it meet the medical purpose and be applied to human clinic. We also hope that ethical discussions will continue and guide the development of technology.
At the end of 2002, the International Bioethics Committee of UNESCO announced the results of technical and ethical argumentation: at the technical level, people can't correct genetic defects, and the research progress in this field is limited. One of the main obstacles is that it is difficult to master gene expression. Any combination of foreign genetic materials may have unimaginable influence on the cell level and damage the growth of embryos, fetuses and children. On the ethical level, the difference between gene therapy for treatment and enhanced genetic engineering for improving normal characteristics is vague. Future knowledge and technology are likely to focus on interfering with "good" and "bad" human characteristics, which will raise some basic moral issues. [10] The Ethics Committee of UNESCO and the ethical guidelines of most countries suggest that embryos with genetic diseases can be diagnosed before implantation and selectively abandoned without genetic modification of germ cells. In other words, not hurting subjects, patients and future generations is the minimum moral bottom line.
Third, strengthen the ethical controversy of cell gene therapy.
Enhanced cell gene therapy is not to correct the disease gene in the true sense, but to change the normal characteristics of people, which is generally called enhanced genetic engineering. Enhanced genetic engineering can be divided into health-related enhancement and non-health-related enhancement. Health-related enhancement: such as enhancing immunity, improving the immune system's resistance function and promoting health. Related ethical issues include: Is genetic enhancement only applicable to adults with informed consent? Can parents accept genetic enhancement morally for the benefit of their children? Should this improvement apply to everyone, or only those who can afford it? Whether the genetic enhancement of germ cells is morally acceptable and so on. For example, in order to make their son grow up to be a tall basketball player, parents can require that the growth hormone gene be implanted into the somatic cells of their normally growing son or their own germ cells. Changing people's skin color, hair color, intelligence, personality and even moral concepts are also the main contents of enhancement unrelated to health. There are more and more ethical disputes about this enhancement.
Whether it is health-related enhancement or non-health-related enhancement, as long as it is not aimed at technical abuse, it can be sure that modern people use genetic engineering enhanced by germ cells to carry out ethnic cleansing, create dominant races and create non-human creatures, and impose them on future generations. But as one scholar pointed out; "We make decisions for the future people, entirely for the purpose of kindness, in order to make the future human beings have a valuable quality. But this does not constitute a reason to make decisions for others, but only shows that it is a "good" coercion. This is because it violates the most basic principle of self-determination enjoyed by anyone in ethics. This is a serious violation of human dignity and basic human rights. In the process of gene intervention in germ cells or fertilized eggs, the future human gene configuration is determined by parents, doctors or the state, and individuals are only the result of the former's decision and creation. Secondly, in general, anyone's genetic characteristics are attributed to the contingency of parents' genetic material combination, which is the result of natural random configuration, in other words, it is decided by heaven or God. Now, if we artificially interfere with human genes through genetic technology, it undoubtedly means that doctors or researchers have to play the role of God. [ 1 1]
Many bioethicists question the above view: the birth of many offspring and many aspects of offspring are decided by parents with the help of doctors, and parents have done many good things with the help of doctors and high technology. Doctors or researchers who apply high-tech reproductive technology have played the role of "God" and continue to play the role of God. A scholar also used Confucian philosophy to demonstrate his point of view. He believes that from the Confucian thoughts of "Heaven is benevolent" and "Wisdom helps benevolence", as long as a knowledge or technology is well-intentioned, Confucianism believes that it should be welcomed and supported. [12] Of course, there is a view that what kind of rights people will demand in the future century is unknown. No one knows what people will think of rights in many centuries. It is also possible that they completely reject the claim or do not need the right or are not interested in it. In other words, the values and belief system of the future era will be different from ours, even very different. These views are worth thinking about: to what extent can the benevolence of medical treatment and "benevolent" play the role of "god" What is the ultimate standard of human genetic manipulation?
Some scholars are controversial about how to define valuable quality, and think that it is not easy to produce enhancement effect by enhancing cell genetic engineering, because it is impossible to determine what to enhance and what the criteria are. Some scholars also take aging as a case study: whether the aging process is a disease or a normal state, medical scientists think it is difficult to distinguish. Therefore, it is difficult to determine the significance of prolonging life by genetic means. Even if people will increase their intelligence according to certain values, society will also produce inequality and discrimination caused by these values. [ 13]
In the aspect of enhanced genetic engineering unrelated to health, the views of absolute scientific freedom and individual freedom seem inappropriate. Moreover, from the current technical progress of enhanced genetic engineering, people still can't know the interaction between most behavioral characteristics and genetic and environmental factors. It should be said that many behavioral psychological characteristics of human beings are the result of the interaction between genes and environment, especially human intelligence, sports ability and artistic ability. Therefore, it should be said that it is difficult to achieve this enhancement by changing a gene in germ cells or somatic cells. Even if such enhanced cell engineering is realized to some extent, can we influence the "open future" of future generations by respecting the "privilege" of parents to improve the "quality of life" of future generations? Besides, we are not sure whether this "open future" is good or bad for him, so it is certainly unacceptable in ethics to interfere with his genes and impose risks and consequences on this future person.
refer to
[1] Wang: Research on Contemporary Genetic Ethics in China, beijing institute of technology press, 2003, 1 1, p. 18-28.
[2] Qiu Renzong et al. Introduction to Bioethics, Peking Union Medical College Press, 2003, p. 156.
[3] Sun: Introduction to New Medical Ethics, Harbin Publishing House, 1995, the first 14 1 page.
[4] Zhang Daqing, Ethical Issues in Somatic Cell Gene Therapy, Medicine and Philosophy, No.3, 1996.
[5] Chen Yuanfang et al. Biomedical Research Ethics, Peking Union Medical College Press, September 2003, p. 77.
[6]LeRoy Walters, Julie Gage Palmer, Ethics of Human Gene Therapy, Oxford University Press, 1997, P60.
[7] Hans-Martin Sass, Copernican Challenge of Gene Prediction in Human Medicine, 1988.
[8]LeRoy Walters, Julie Gage Palmer, Ethics of Human Gene Therapy, Oxford University Press, 1997, P70.
[9] Qiu Renzong, Human Genetic Engineering and the Responsibility of the Future Era (I) Medicine and Philosophy, 1996(6), pp. 286-285.
[10] UNESCO International Bioethics Committee, Report on Preimplantation Gene Diagnosis and Germ Cell Intervention, Medicine and Philosophy, 2004 (10), pp.1.
[1 1] Gan, the core issue of genetic engineering ethics. Philosophical trends.2001,(1):33-35 pages.
[12] Zhang Xinqing, "Gene Therapy in China", Proceedings of the Sino-British Bioethics Symposium, August 2004.
[13] Qiu renzong, human genetic engineering and the responsibility of the future era (1) medicine and philosophy, 1996(6), pp. 285-286.
(Input Editor: Mysterious Island)
Institute of Philosophy, Chinese Academy of Social Sciences. All rights reserved. Yiwan China designed and produced. It is recommended to browse with IE5.5 or above.