Editors: Michio Okamoto, M.D., Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Professor, Legal Medicine, University of Nagoya School of Medicine
To control medical experiments, ethics committees were set up in all of the 80 medical universities in Japan by 1992. Today, some hospitals not affiliated with universities also have ethics committees. I have been working as a chair on of the Nagoya University School of Medicine Ethics Committee for five years. This committee was founded in 1983, and has reviewed over 100 research projects. Most of them were minor modifications of daily treatments. However, some of them attracted public attention, e.g. organ transplantation from brain dead patients, the treatment of Jehovah Witnesses who refuse blood transfusions, and gene therapy. For the former two, we set guidelines after one or two years of discussion. The gene therapy, submitted three years ago, is still under consideration. Other important projects not yet submitted to our committee include genetic screening programs. Such noteworthy projects always involve value conflicts. Fundamental questions are now being asked as to how the development of life sciences will affect future humankind, and opinion is divided on these issues. Bioethics is a way of resolving conflicts of values, and I believe that this can only be achieved by continuous and open dialogue.
Our committee decided to open our ongoing discussion on brain death to the public in 1991, and since then the discussion of other projects has also been open to the public. However, the authority of our committee is limited to the Nagoya University School of Medicine. Whatever guidelines are determined for a certain medical experiment have very limited application. It goes without saying that the opinion for a certain medical experiment should not be incompatible from one ethics committee to another. In Japan, we do not have any National Ethics Committee, nor a proper system for exchanging opinions among university ethics committees. I am afraid that the present university ethics committee system in Japan will not suffice in order to reach decisions for the nation involving certain conflicts in undertaking various projects. For that purpose, a National Ethics Committee may be necessary.
We now have the presentation of Madame Lenoir, chairperson of the UNESCO International Bioethics Committee. It will be very informative for us to learn a worldwide approach to bioethics. I believe it will be very informative as we go about establishing an appropriate decision-making system for bioethics issues here in Japan.
Yagi: I welcome everyone to Nagoya, and especially Madame Lenoir. I wish to explain a little to you, what others may also not know. In September we held an International Symposium on Human Gene Therapy, that followed up the meeting that produced the Declaration of Inuyama. That earlier meeting was organized by the CIOMS, its 14th Round Table Conference on "Genetics, Ethics and Human Values - Human genome mapping, genetic screening and gene therapy", and was held in Tokyo and Inuyama, 19-23 July, 1990. This meeting invited all the representatives of CIOMS and some ethicists and religious scholars. This meeting was the first of its kind here in Japan, and the conclusion was the Declaration of Inuyama. One of the most important is that it contains internationally accepted guidelines for genetic diagnosis and gene therapy. The Declaration says that gene therapy, if it is performed under strict ethical control, it must be regarded the same as any novel medical therapy. The first Japanese patient to be treated in a clinical trial was five years later. So we wanted to discuss whether the Inuyama Declaration required change, and the conclusion of this meeting was a conference statement expressed at the end of the meeting. We want to send this message to many organizations, including UNESCO, WHO, CIOMS, International Union of Biochemistry, and other Academies.
The message says that that the principles of the ethical guidance contained in the Inuyama Declaration should be retained. This is a very important point. Even though the trials have been conducted the knowledge that we have is incomplete, we need much more complete knowledge by our effort and further basic and fundamental research is needed. The third point is that it is quite natural that gene technology should be promoted for the benefit of human beings but never against human beings. In the USA where the most trials have been done, there is still a message that viral vectors are dangerous. Gene therapy has only just started so we must always consider ethical problems and issues. Gene therapy is only beginning.
Katsumata: Thank you very much Prof. Yagi. Let me also give a welcome address and a few comments. It is with pleasure we invite Madame Lenoir to speak.
Katsumata: Thank you very much for an interesting description. We still have some time, so may we open for questions from the floor.
Yagi: I would like to raise several comments. You stressed the international aspects of this issue. The other is that you mentioned some permanent genetic modification of the genome. You also mentioned the work of the European Commission. In principle, it is better to have international guidelines for gene therapy, and to be open to the public. Some of the people in the USA say that they cannot be open because the research is secret, sometimes in relation to patent issues. Generally to some extent this is much better in Japan, though the early stages in the NIH were also open. We do not know what is happening. Sometimes we do not know what is happening. This is one issue, how to make the research open.
The second question is about gene therapy. There are two possibilities, one is transient expression and the other is permanent expression. In the case of permanent expression there is the possibility to change certain characters such as size, to make a giant animal or virus. But transient expression modifies a gene or plasmid containing a gene so that it disappears within one week of some time. As you know, even if we use an adenovirus, it is still mainly transient expression, it is difficult to transfer into the nucleus. At the time of the Inuyama Declaration we paid a lot of attention to the possibility or danger, of gene technology. Most people were thinking of permanent expression of a gene incorporated into the genome. However, nowadays most people, including myself, are thinking of transient expression, for example using plasmids in cancer therapy, which is only a few days expression. Minigenes can also be used, and some technical advances are not well known. Some type of gene therapy is quite safe. It is difficult to achieve stable expression. Gene therapy is expanding to not only genetic diseases, but cancer and other diseases. Liposomes are less expensive than viruses, gene therapy is very expensive even for the Japanese system. I want to ask how UNESCO is considering all these issues of gene therapy, including use on children. You also mentioned viral vectors, the efficiency of these is not so high. We must be very careful. I am afraid I did not answer all the questions.
Kameyama: What did you mean by a moratorium?
Yagi: During the International Symposium on Gene Therapy in September, some American scientist suggested we wait a few years. We should not repeat all the experiments until sufficient evidence that the trials will work is made.
Lenoir: Have you got legislation in Japan about genetically modified organisms, and bacteria and viruses?
Katsumata: We have a committee in each university to examine proposals for experiments using genetic engineering. This committee reviews and discusses, and if it is safe, we proceed.
Lenoir: Is there any problem in the public opinion?
Lenoir: A happy country. As you may know, in Europe it is a great issue.
Yagi: I had some experience when I represented Japan at a CIOMS meeting in Europe. The Europeans were very seriously discussing the issue, and I was almost attacked because I was doing animal experiments. I remember that a lady from the English organization, Animal Care, attacked my opinion very much. Do you have the same issue in France?
Lenoir: In Europe you have two countries where public opinion is very much opposed to animal experiments, Germany and England. The Association for Protection of Animal Welfare is very rich and strong, and most of the laboratories in those two countries cannot use transgenic animals as models for cancer, for example. I wanted to know whether there is a social debate here, and how do you use those animals. Do you use for medical experimentation, or do you use them to test drugs or growth factors, or xenografts.
Suzumori: I think there is a big difference between Europe and Japan, in the use of gene therapy and genetic engineering. I think it is the same as organ transplantation. In Japan organ transplantation it is very difficult but not in Europe. So I have a question about the activity of bioethics. If there is a very big difference between countries, depending on culture, history and religion, you must make principles or standards for these difficult issues. How can you do this? What is the standard. For example, in Europe, Greenpeace or Animal Welfare groups are very active, but not in Japan, so how can you make standards which is acceptable for all people?
Lenoir: You are right, it is a problem for each international body. For example, when you discuss the issue of the right to education, you have countries where they are poor, there are countries where there are social barriers. Each national government must then ratify international conventions of the United Nations. It is difficult to answer, but each nation has some problems, because of different levels of development. Secondly, I note that in spite of strong differentiation in cultures every culture wants to benefit for scientific progress, sooner or later. For example in Islam it is prohibited to touch the dead body, in Tunisia there has been modernization and legislation in 1991 allowing organ transplantation was passed, despite its conflict with some religious texts. In France scientific reasons have also put aside religious barriers to allow organ transplants. Each country must decide how to benefit from scientific progress, and to balance the cultural traditions. In Europe there are large differences seen in animal concerns, In France it is traditionally a rural country, and each French person has some ancestor who is a farmer. Each person is used to living with them, they like them, kill them, and eat them. It is a natural behaviour to raise animals to eat. The animal welfare movement doesn't exist in France, whereas in Germany which has a traditional philosophy of nature, that nature has the same value as humans. Therefore the philosophy that you should not create unnatural animals is much stronger. Therefore even in Europe we have great contrasts, each country must find a solution between tradition and reality. The Declaration on the Human Genome, has arisen in a consensus atmosphere, not to deal with practices, but we consider the views of scientists working with practical issues, but we do not make recommendations of practice because there are too many differences between contemporary countries and the others. But we try to say risk assessment is an important idea, or that human experiments have to respect the dignity of human beings. There have been abuses in the developed and developing countries. The second principle is the concern that a new experiment is risky, not every consequence can be predicted. Another issue is who makes the decisions, individuals or families. There is also the issue of discrimination, for example in China or India where girls are not wanted by some. I think that we can reach a consensus, and pacify a subject.
Fujiki: Let me answer your questions about the regulation of GMOs. When a researcher makes a GMO, they must ask permission from several ethics committees for field releases. There could be a problem about public acceptance, because there is misunderstanding and prejudice about genetics seen in public opinion surveys. This means education is a very important issue. We have had several meetings during the visit of Madame Lenoir to inform people about the UNESCO IBC. We also have some meetings with the general public. Although we have ethics committees to review proposals, we have no national ethics committee, as Prof. Katsumata also pointed out. The opinion can vary between places, also you mentioned there are differences in opinion between countries in Europe. This means education is even more important, as former director of HUGO Prof. McKusick said, "Education, education, and education". That is our duty. We need to pay much more attention to the general public. There has been some misunderstanding about the role of UNESCO IBC, which has no power to establish an international instrument, just asking our members to seek the opinion and debate the issues in each country.
Yagi: You raised the issue about genetic engineering. In the Ministry of Education, Science and Culture guidelines about GMOs in Japan, every experiment must be approved.
Lenoir: Not just a general laboratory permission?
Yagi: No each experiment, each idea, must be passed by a committee. There are four grades of containment, the international standards, P1...P4. There are restrictions on transgenic animals. It raises the question, what if we produce very interesting animals? What is the control? How can we treat these animals? If we produce dangerous bacteria there are clear restrictions, but I do not know what the clear role of the law is, I would like to ask all those here?
Aussarge: I would like to know the guidelines about the use of transgenic animals for carcinogenesis studies and risk reduction. Are there university guidelines?
Yagi: There are Japanese guidelines which we can follow. If an unexpected animal or dangerous organism is made it is clear what we should do, but what I wondered what if it is interesting for research, and the law in France or Germany? For example if I make an enzyme-deficient animal, and we make a cure it is no problem?
Lenoir: In France there is a regulatory organization and we have the P1, P2, etc. standards. There is also European legislation which has to be introduced in each country as national law, which we have had since 1992. The problem of unexpected results is not anticipated, it is only concerned with safety and risk assessment. They are independent from the use. There are two guidelines, one for contained use and the other for deliberate release of GMOs, such as wheat. We also have products made from GMOs.
Yagi: My point is simple, there are guidelines to protect against dangerous animals, plants and microorganisms, but these did not recognize the utility of DNA techniques to produce improved vegetables for example. We should judge the suitability by the usefulness and safety. There seems to be no coordination.
Lenoir: In Europe there is a movement against making foods from GMOs. There is great discussion in Europe, beyond national committees. There is great discussion of labeling of products, and commercialization of the Calgene tomato. It has begun to be commercialized in the UK and in Switzerland and in some other countries. There is great opposition of the public in Northern Europe. There is division over biotechnology between the South and North of Europe. The North includes Germany, and Scandinavia, and the South includes France, where people are more in favour of genetic engineering. Most of the public in Germany, UK, Denmark and Sweden, wanted labels to mention all the details of the genetic engineering products.
Katsumata: These are very important issues. I wonder if any other participants also want to ask a question?
Nudeshima: You mentioned the issue of patentability several times. This is a very important issue for industry as well as for researchers. Many of the scientists at my institute, the Mitsubishi Kasei Institute for Life Sciences, are interested in this because it does affect them. In the third draft of the Declaration there is no article about patentability, but you have suggested in Tokyo that the fourth session of the UNESCO IBC may consider access to genetic information, including the issue of economic exploitation. Will there be any article about this issue in the Declaration?
Lenoir: No. As you have seen in the draft Declaration which is just a document on the international problems of bioethics, which is different from the international instrument as perhaps the states will sign, in 1997. In this instrument we just mention the international conventions regarding patents, as the basis of our thinking. First of all we do not think it is appropriate to discuss those conventions, they are applicable, and it is not our role to cover that. Furthermore, as we say UNESCO has no competence in patents, UNESCO has a specific competence in copyright property. There is a 1950 international convention, which must be considered, even if it is changed it is not our role. It would be a completely new topic to say there should be no more patents under this convention. That is the point. As Prof. Fujiki perfectly knows, one of the main causes of misunderstandings, and in each session people say, it is horrible to patent nature or play God, etc., we think that according to the interests of industry, technology and science. One of the main problems is misunderstanding, and we are going to think of this in a very simple way, but each time we deal with a specific problem, for example gene therapy in 1994, it is just discussion. We refuse to make any advice or recommendation, at that time, and that is how we maintain a consensual atmosphere. I am personally happy to see people, like myself a few years ago, or those who are famous writers, or presidents of supreme courts, or ambassadors, who did not know anything about science or bioethics, as they began to understand what is going on they began to be much less in favour of the developments of science.
Yagi: Maybe this is the almost the last comment, since time will soon be over. So far as I know in Japan, the so-called new biotechnology using recombinant DNA is unfortunately it is only a strong beginning, unlike France. As far as improvement of vegetables it is highly advanced in Japan, we can make pomato, a mixture a tomato or potato. We have many good vegetables in Japan. It is however not due to the new genetic engineering. Sometimes journalists use the words old-bio, and new-bio. The other issue about patents, in my personal opinion, there is no strong organization to control patenting in the world, even UNESCO cannot do that. I am a vice-president of a biotechnology company, and in my opinion the United States patent position is not good. Japanese patent finally belongs to the person as individuals, I think the same as the UK and France. Prof. Dausset and Prof. Fujiki, in MURS pay a lot of attention to the responsibility of scientists, that if you think of this kind of issue you need to pay special attention to patents. In patent law, there is an exception if it is used against human beings, and if people say no. However in the United States, even if people say no it is still approved. That is a very important difference.
Katsumata: I am sorry but our time is up so we must cut off the discussion now.