The Ethics of Gene Therapy: Issues and Controversies

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Ethics of Gene Therapy: Issues and Controversies

Gene Treatment can be divided into somatic cell gene therapy, germ cell gene therapy and enhanced cell gene therapy. Somatic cell gene therapy uses somatic cell genetic engineering technology to implant a certain gene into the human body to medically correct the patient's genetic defects. Because many genetic diseases are caused by the lack of a certain gene, gene abnormalities or defects, somatic gene therapy can be used to treat gene deficiencies, abnormalities and defects by implanting that gene into cells. Germ-line gene therapy is to transfer exogenous normal genes into sperm, eggs or fertilized eggs to correct defective genes to 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 such genetic diseases. It is a method to cure genetic diseases. Related to germ cell gene therapy is enhancement 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 a person. Currently, due to technological development and ethical controversies, some somatic cell gene therapies have been used in clinical applications or entered the clinical research stage. Germ cell gene therapy and related enhanced cell gene therapy have not yet been carried out.

1. Ethical controversies of somatic cell gene therapy

Somatic cell gene therapy was first developed in the United States. The initial ethical debate encountered here concerns the legitimacy of this treatment method, which is quite different from ordinary 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 the technology, the potential pros and cons of genetic intervention, the fairness of the participants' opportunities to participate in the study, the authenticity of the informed consent of the study participants, and the privacy and confidentiality of the participants' medical information. wait. Ethicists focus on some basic ethical principles of bioethics: principle of benefit, principle of respect, principle of autonomy, principle of informed consent, principle of confidentiality and principle of justice. But how to apply these principles is a process of practice and controversy. [1]

When somatic gene therapy has been studied in many gene therapy trials in cell culture and animal models, bioethics has emerged as to whether gene therapy can be tried on patients soon. The primary issue discussed by scientists is the expected or potential pros and cons of somatic gene therapy. Critics believe that because there is still a considerable degree of uncertainty about somatic gene therapy, the safety of the modified viral vectors used in the treatment has not yet been determined. The patient's cells may re-integrate viral genes, and the retrovirus cannot accurately reach the target gene in the target cell for replacement. Theoretically, there is also the possibility of retrovirus activating or stimulating oncogenes. [2] However, more scholars believe that this treatment method only affects non-germ cells, and the changed genetic material will not be passed on to future generations. The genetically modified somatic cell products are similar to the drugs taken by the patient. Some of the techniques used in somatic gene therapy are similar to other widely used medical interventions and have the advantage of being less invasive and less rejection-prone. In addition, they also believe that if some diseases can be treated with other methods with less side effects and reasonable cost, then other treatment methods should be selected based on the principle of benefit to the patient. Somatic cell gene therapy is only used for those genetic diseases and cancers. , AIDS and other difficult-to-treat diseases. [3]

As ethical issues continue to arise and debates become fierce, researchers should be more cautious and careful when applying somatic cell gene therapy to clinical applications than when applying technologies such as heart transplantation and in vitro fertilization. . In the early 1980s, when there was a very lack of evidence for clinical gene therapy research, American scientists began to try clinical gene therapy on patients.

The practice was widely condemned because the results were unclear and there was no ethical justification. As a result, somatic cell gene therapy in the United States almost stalled for 10 years. After initial gene therapy experiments in severe combined immunodeficiency disease (SCID) patients yielded some clinically beneficial findings, the first somatic cell gene therapy to receive ethical review was applied to humans, and its initial draft experience It took three years of discussion to get approval. The ethical debate had raged for almost 20 years. [4]

In September 1999, a heartbreaking incident brought new thinking to the bioethics community. Gezingo, an 18-year-old from Philadelphia, USA, suffers from a hereditary disease - benign ornithine base transferase (OTC) deficiency. This disorder of ornithine metabolism could be controlled through nutrition and medication. But he went to the Human Gene Therapy Institute of the University of Pennsylvania to receive a phase I clinical trial of gene therapy. He was also the 18th and last subject of the institute. In the trial, a research team led by James Wilson injected adenoviral vector particles (maximum dose) containing exogenous therapeutic genes into his liver. The next day, Gesingo's condition worsened, his blood ammonia rose sharply, and he became unconscious at night. Four days later, Gesingo's multiple organs failed and he died due to strong immune rejection.

This is the first clinical trial death directly caused by somatic cell gene therapy. At a hearing in January 2000, Gesingo's father said: "This was an avoidable disaster. My son was not informed of any serious dangers (including the death of the experimental monkey). , he was led to mistakenly believe that this human experiment was beneficial to him.” The volunteer subjects were attracted by a patient consultation website. The website calls the gene therapy regimen "very low dose and promising results."

This incident not only involves the previously well-known ethical issues of informed consent of subjects, but also involves the conflicts of interest between researchers and subjects and the scientific research responsibilities of researchers that were often ignored in the past. . What is certain is that this incident is not only not a responsible clinical trial study, but also full of misleading and deception. First of all, this test should not be applied to humans, because monkeys had similar reactions and some died during the preliminary study. A previous patient developed liver damage after receiving only a low dose of the virus. The information published on the website not only did not mention the reaction of the animals during the preliminary study, but instead promised that the test could obtain results as soon as possible and that the dose of virus used was very low. The final consent form did not mention relevant facts such as the death of the monkey. Originally, the content included in the informed consent form to participate in gene therapy should have been discussed in detail by an ethics review committee and subject to public scrutiny. However, the researchers deliberately concealed the fact that the viral vector was injected into the subjects' livers from the National Institutes of Health (NIH) Recombinant DNA Advisory Committee.

The ethical issue in this incident is not only what steps should be taken to ensure the true informed and voluntary consent of the subjects, but also the responsibility of the researcher as a scientist and the relationship between the researcher and the subjects. Conflict of Interest. The responsibilities of scientists in research and the conflicts of interest between researchers and subjects have attracted attention and discussion in the bioethics community in recent years. The responsibilities of scientists in research include important issues such as the integrity of scientists, the monitoring of misconduct in science, and the responsibilities of scientists. From the perspective of scientific progress, it is a challenge for scientific researchers to provide important facts to subjects, including the true status of their diseases, treatments, methods used in the research, pros and cons of the research, etc., but from a scientific perspective From the perspective of serving the purpose of humanity, science, and human dignity itself, the integrity and social responsibility of scientists are very important and must not be abandoned.

The person involved in this case, Wilson, owned a company that owned patents on discoveries made in his laboratory. That is to say, he and his colleagues were tempted by the intellectual property rights of this technology and conducted this somatic gene therapy trial in violation of scientific research ethics. At this time, the economic interests of the researchers included in the trial may conflict with the life interests of the subjects.

Instead of avoiding these conflicts of interest, the researchers concealed the truth from the subjects. Conflict of interest is a new bioethical issue caused by economic development. While companies provide huge financial support for experiments, they also inject vitality into scientific research. However, corporate control of the scientific research field can cause some scientists and scientific research institutions to gradually lose their independence, causing the scientific research ethics of some scientific researchers to be eroded and scientific research integrity to be damaged. [5] Conflicts of interest also include conflicts between scientific progress and public interests, corporate interests, etc. Currently, the bioethics community defends the fundamental interests of patients or subjects, and emphasizes the analysis and resolution of various interests in human experimental research. In view of this adverse event in somatic gene therapy research, Wilson's research at the Human Gene Therapy Institute of the University of Pennsylvania has been stopped. However, the incident of somatic cell gene therapy research has been continuously discussed as a typical case. This incident has deepened our understanding of the ethics of gene therapy and promoted the deepening of theoretical research in bioethics.

2. Ethical controversies of germ cell gene therapy

Germ cell gene therapy is under experimental research and has not yet entered the clinical human application stage. But in the United States, relevant ethical discussions began in the 1950s and 1960s. Some people believe that treatment to change genes in human germ cells will be possible by then, while others believe that it will only be possible after the technology is improved and perfected. In September 1992, Dr. Neal submitted a proposal to the NIH review committee on the ethical issues of spontaneous and induced mutations in germ cells, arguing that early discussion of ethical issues can reduce risks and prepare for them. Once technological breakthroughs make germline gene therapy feasible, advance ethical discussions will lay a good foundation for the formulation of reasonable regulatory policies. [6]

Germ cell gene therapy may be applied in these clinical cases: When the wife and husband are both patients with recessive genetic diseases, then their offspring may all suffer from the same genetic disease. When a couple is a carrier of a recessive genetic disease gene, then 25% of their offspring may carry normal genes, 50% may carry the same genetic disease gene as their parents, and 25% may be patients with the genetic disease. Certain genetic diseases can cause severe, irreversible brain damage to a fetus during the first trimester of pregnancy, and there is no known way to genetically repair the fetus in utero. A diagnosed genetic disease affects different cell types in many different parts of the body of the affected parent. While somatic cell gene therapy can only treat a specific cell type, germline gene therapy can be performed at an early stage to affect various types of disease. cells, may be the only feasible way to prevent the disease from being passed on to future generations.

Scientists who favor germ cell gene therapy believe that germ cell gene therapy may be the only way to prevent damage to specific organisms caused by genetic defects. It is even more successful than somatic gene therapy technology because the technological breakthrough it requires is gene replacement or gene repair. Somatic gene therapy technology uses a gene addition method, in which both normal-functioning genes and originally abnormally functioning genes are retained in the target cells. The gene replacement or gene repair method used in germline gene therapy technology avoids this risk, and it can also completely eliminate germline dominant genetic diseases. [7]

Scholars who support germline gene therapy also argue from the perspective of parents: Parents hope that their children and their offspring will be free from genetic diseases at birth and from using somatic cells after birth. Gene therapy. Parents also want to be spared the difficult decisions they face related to genetic diseases that may be passed on to offspring. Any sincere decision parents make for their children's health should be protected by ethics and law. [8]

This argument in favor of germline gene therapy has been met with many refutations. The reason for the refutation is based on technical negative effects, that is, once technical problems occur, such negative effects are serious and uncorrectable. . Because the unpredictable negative effects of technology not only affect the subjects, but also their descendants.

Secondly, under normal circumstances, any person's genetic characteristics are attributed to the chance of the combination of his or her parents' genetic material and are the result of natural random configurations, in other words, determined by heaven or God. Now, if we use genetic technology to artificially intervene in human genes, this undoubtedly means that doctors or researchers have to play the role of God. [11]

Many bioethics scholars have questioned the above point of view: Many aspects of the birth of future generations and the future generations are determined by parents with the help of doctors. Parents are influenced by doctors and high technology. Many good deeds have been done with the help of. Doctors or researchers who apply high-tech reproductive technologies have played the role of "God" and continue to play the role of God. One scholar also used Confucian philosophy to demonstrate his point of view. He believes that from the Confucian ideas of "the way of heaven is the way of benevolence" and "wisdom assists benevolence", as long as a piece of knowledge or technology is motivated by good intentions, Confucians believe that it should be welcomed and supported. [12] Of course, there is a view that it is unknown what rights people in the next century will demand. No one knows what people's views on rights will be many centuries later. Or they may reject the claim of rights altogether or have no need for or interest in rights. In other words, the value and belief systems of the future era will be different from, or even completely different from, ours. Regarding these views, it is worth thinking about: To what extent can the benevolence of medical care and the "benevolent person" play "God"? What is the ultimate standard for human genetic manipulation?

Some scholars have disputed how to define valuable qualities, arguing that it is difficult to use enhanced cell genetic engineering to produce enhancement effects because it is impossible to determine what is enhanced and what is the standard for enhancement. Some scholars also use aging as a case to illustrate: Medical scientists believe that it is difficult to distinguish whether the aging process is a disease or a normal condition. Therefore, the significance of using genetic methods to extend life is difficult to determine. Even if people follow certain values ??to become taller and smarter, society will still produce inequality and discrimination caused by these values. [13]

It seems that the views of absolute scientific freedom and personal freedom are inappropriate when it comes to enhanced genetic engineering that has nothing to do with health. Moreover, current technological advances in enhanced genetic engineering mean that the interactions between most behavioral traits and genetic and environmental factors are not yet known with certainty. It should be said that many behavioral and psychological characteristics of human beings are the result of the synergistic effect of genes and environment, especially human intelligence, athletic ability, and artistic ability. Therefore, it should be said that it is difficult to achieve this kind of 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 because we respect the "privilege" of parents to improve the "quality of life" of their offspring in reproduction? Moreover, we cannot even determine whether this "open future" is beneficial to him or not, so it is of course ethically unacceptable to intervene in his genetic genes and impose risks and consequences on this future person. Unacceptable.

References

[1] Wang Yanguang: "Research on Contemporary Genetic Ethics in China", Beijing Institute of Technology Press, November 2003, pp. 18-28.

[2] Qiu Renzong et al.: "Introduction to Bioethics", China Union Medical University Press, 2003, page 156.

[3] Sun Muyi: "Introduction to New Medical Ethics" Harbin Publishing House, 1995, page 141.

[4] Zhang Daqing, Ethical Issues in Somatic Cell Gene Therapy, "Medicine and Philosophy" 1996, Issue 3.

[5] Chen Yuanfang et al. "Biomedical Research Ethics", China Union Medical University Press, September 2003, page 77.

[6]LeRoy Walters, Julie Gage Palmer, The Ethics of Human Gene Therapy, Oxford University Press, 1997, P60.

[7]Hans-Martin Sass, Copernican Challenge of Genetic Prediction in Human Medicine, 1988.

[8] LeRoy Walters, Julie Gage Palmer, The Ethics of Human Gene Therapy, Oxford University Press, 1997, P70.

[9] Qiu Renzong, Human Genetic Engineering and the Future The Responsibility of the Times (Part 1) "Medicine and Philosophy", 1996 (6), pp. 285-286.

[10] UNESCO International Bioethics Committee, "Report on Preimplantation Genetic Diagnosis and Germ Cell Intervention" "Medicine and Philosophy", 2004 (10), page 11.

[11] Gan Shaoping, Core Issues in the Ethics of Genetic Engineering. Philosophical Trends. 2001, (1): pp. 33-35.

[12] Zhang Xinqing, "Gene Therapy in China", "Proceedings of the Sino-British Bioethics Symposium", August 2004.

[13] Qiu Renzong, Human Genetic Engineering and Responsibility in the Future Era (Part 1) "Medicine and Philosophy", 1996 (6), pp. 285-286.

(Input editor: Mysterious Island)