Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Director, National Medical Center, JAPAN
These days, results of the study on the changes in DNA isolated from patient's peripheral blood cells or tumour cells have been used for clinical diagnosis in some disorders. At the beginning it was used for the diagnosis of congenital diseases. It was also especially used for fetal diagnosis to find out whether there was any congenital diseases or not. However, even at that stage, there were already many problems arising, as outlined in Dr Yessley's paper. He mentioned that in the USA, there are many cases litigation because of misdiagnosis or even of diagnosis. In Japan, congenital abnormality in a fetus cannot be used in decision making for artificial abortion. This topic has been discussed already intensively, although it is out of my speciality.
DNA diagnosis is useful for finding congential diseases, and as will be mentioned by Dr. Suzumori, it is also used to check for acquired diseases. On cancers, Prof. Nishisho is going to discuss about this. In the previous paper by Prof. Matsuda, uses of DNA anlaysis in immunology were discussed. DNA analysis for clinical diagnosis will be further extended in concommitant with the progress of the human genome project.
DNA diagnosis is very useful in infectious diseases. For example, infection by tuberculosis or malaria can be determined rapidly by this technique. Older methods are slower and difficult. In Japan, DNA analysis is used in central laboratories for the diagnosis of acquired diseases including some cancers and infectious diseases. But in the case of private laboratories, equipment for this method must be prepared. There is also the question of patents on DNA probes. If you have to pay the royalties for the patent on a DNA probe, it is not feasible in terms of economics. The company which is promoting the DNA analysis, can be unsuccessful because of such patent problems. Tuberculosis and malaria are very important in South East Asian and tropical countries. It will become a very important political issue if the most effective DNA diagnostic methods cannot be used because of the patent problems. Solving the patent problems is very important. Such problems can be solved by professional lawyers, but as a strategy of the WHO it cannot be dependent only on lawyers.
Diagnosis can also be used for identification of individuals in criminal cases. As we heard before, adult diseases such as diabetes and hypertension have congenital factors for disease development. Some diabetes patients have an abnormality in the insulin receptor. But in most patients, presence of a DNA mutation making them susceptible to diabetes is suspected. Studies are being rapidly promoted, and in the future, by looking at individual DNA, we may be able to find out whether an individual has a tendency to become diabetic, to develop cancer, or hypertension. Such a day will come very soon. In terms of preventive medicine it is very useful, for example those people who have a tendency to become diabetic should not eat delicious foods. Those people who have a tendency to become hypertensive have to refrain from taking salty foods. A problem is how far we can disclose of personal information. It is a problem of privacy. People who have a tendency to become diabetic or to develop hypertension have a special pattern of DNA and those patterns are the ones that the insurance company wants to know. In most diseases, the degree of severity varies. The individual DNA may be involved with the onset of the diseases, one way or another. This is not a problem of the disease but of the phenotype, and this may be estimated by looking at the DNA. I am not expecting to have such technology soon, but a possible extreme example is that, by looking at one drop of blood you may be able to tell whether a person is capable of entering into a good university or not. If it is so, we don't have to have the entrance examination.
The second application that is very useful, is the use of recombinant DNA technology to produce drugs such as insulin, interferon, and cytokines. Cytokines are products of cells. They can be prepared by biotechnology, and are now applied to clinical medicine. This had never been expected in before. Biotechnology has many advantages in the application of clinical medicine, but in this area as well there is also the problem of patents. This problem is not yet solved fully.
A third application of biotechnology is for patients who have congenital diseases which have no ways of treatment. Is it better for us to let the patients or their families know that he or she has congenital diseases? In order to solve such a problem, gene therapy has started recently for the treatment of certain congenital disorders such as ADA deficency. In the USA there have already been 17 protocols approved by the NIH Recombinat DNA Advisory Committee. In the UK too, the Medical Research Council has provided guidelines for the transfer of human genes. On the overhand, there are no guidelines provided by the Japanese government for human gene therapy. According to the guidelines of the Ministry of Education, genes should not be transferred to people. Therefore, at the moment, genes can not be transfered to human cells in Japan. ADA deficiency afflicted children can achieve very good results from gene therapy, as shown by the NIH trials. The families of children with the same disease in Japan may want to receive gene therapy. How can we cope with them? Gene therapy has already been used for the treatment of cancer in the USA. We do not know whether it is effective or not, but the individuals who have such incurable diseases and their families will want to receive gene therapy in our country too. In the USA and Europe, they will not handle the germ cells, limiting the use of gene therapy only to the somatic cells. But gene therapy only of somatic cells is not sufficient. We may have to go in to the gene therapy of germ cells in order to treat congenital diseases. But we have to discuss seriously whether we go into that stage or not.
Research on gene therapy to treat acquired disorders such as cancer and AIDS will be further promoted by the Human Genome Project. The implications of the progress of the Human Genome Project on clinical medicine must be incredibly great. All researchers in the field of clinical medicine are awaiting the success of this project.
Tachibana: Yes, various diseases and genes are now being identified. There is accumulation of knowledge. The more I listen to the presentations the more questions come into my mind. How can we treat and cure these genetic diseases, this is a very big question relating to these issues isn't it. Is there any information available on this. What is the current state of curing genetic diseases? What is possible and what are the limits of treatment in reality? When treating and curing patients of a deadly disease, what sort of risks are involved? Can you briefly discuss those points?
Takaku: So as part of the moderator's task, I will answer this question as far as I can, and if there is a missing link others please give some additional comments. The original idea of curing and treating genetic disease is based on removal of the causative DNA, replacement of abnormal DNA with normal DNA. On this particular point, as far as we have come, the precise and correct extraction of abnormal genes and replacement with normal genes is still impossible. We do not yet have enough resources or scientific technology available to do this. Therefore the treatment of genetic diseases must still use indirect methods. For example, in the case of ADA deficiency, the missing enzyme, ADA, can be replaced to treat the disease. With gene therapy, the ADA gene can be inserted into the lymphocyte, and the modified lymphocyte can be returned to the patient's body. Is the future blood stem cells will be used instead of lymphocytes. This is recently developed. Another area is related to cancer patients. The carcinoma tissue or blood is used to obtain lymphocytes, these lymphocytes are then used for gene transfer in vitro. After multiplication of the modified cells in vitro, the cells are put back into the body of the patients. Genes such as those for cytokines like IL-2 or GM-CSF are put into the cells, then the modified cells are injected into the body, where they aid the disappearance of the cancer due to enhanced immunological recognition of the tumours. This may be an effective treatment method. If one point mutation is identified, as discussed today, then replacement is the ideal, but current technology cannot do this. There are many ethical questions to be addressed in the replacement of abnormal genes with normal genes, before we implement such a method of replacement. In currently available techniques, retroviruses are used for gene transfer. The genes are inserted into the RNA viruses, so that when the viruses are used to infect the body cells, the genes are put into the DNA of those cells. Such RNA viruses must not be carcinogenic, this is another point. In patients with cancer, there might be some effect, because if you don't do anything such patients will die. It is inevitable in fact that some effect will occur, but we need to attempt to use these new techniques. There is therefore no perfect treatment method developed yet. There are many issues to be addressed from now on. But, in the future I am quite optimistic and positive about these techniques, and that these problems will be solved, though we don't know how long it will take. Judging from the advancement of technology the replacement of abnormal genes with normal genes can be successfully performed.
Watanabe: In actuality, what is understood in the brain is the definition of normality. Reproductive cells can be changed and can be made normal. That is one target that is shared by many researchers in their minds. However, there are more urgent factors facing us. In DNA there are factors which cause diseases. If patients have diseases, there are factors causing them. We have to cure those diseases, not just by DNA. Genetic diagnosis is made possible, and maybe the development of genetics will allow the causes of diseases to be found. The research for curing the diseases should be concomittantly done. However, at the moment there is no parallel movement. Actually, the methods for the analysis of DNA and genes are getting very advanced. Perhaps the way that we identify the relationship between DNA and diseases, may mean that we do not need to bother about DNA modification, but we should look at curing the diseases and the mechanism of diseases. In order to do this the government should take the initiate in prediction of the future developments, and the funding should be provided by the central government to allow this, for the ultimate goal of adequately treating patients. Therefore in that case it is related to medicine, the treatment and curing of genetic diseases is the ultimate goal. We must all make a concerted effort. Therefore the genetic medicine issue is one thing. However, at the moment we may not be greatly involved in the genetic medicine issues which are facing us. What is pointed out today is not bioethics but also the formulation of a new concept for the formation of new medicine. And in that sense ethics is related, of course. Dr Aoki and Dr Yosida presented us with rather abstract issues. DNA research has given us the advent of new medical issues, the ultimate goal is how to eliminate all diseases. DNA treatment is one issue, as part of the problems, but how to do that is of course important.
Takaku: Excuse me the time is limited, so could you please conclude your remark briefly. DNA treatment is a very important issue. I don't think it is limited to Universities, and there is no guidelines published yet. But it is a big problem in medicine, therefore we have to make clear who should be assuming responsibility. Should the Ministry of Health and Welfare, said it is an issue for Universities. But if they take such a stance, things are not solved. We have to discuss towards what goal are these things directed in order to make progress. My idea is that we don't bother too much about medicine itself. I would like to invite more comments from the floor.
Nishisho: My speciality is surgery, and in clinical study I am observing patients. As mentioned by Mr. Tachibana genetic treatment is of course important, however, what we are concerned about is how we can utilise that technology in the diagnosis of diseases. In the case of cancer, not everything can be diagnosed 100% clearly, there are some borderline areas. So an important issue for us is how to reach an objective diagnosis. DNA is a tool through which 100% diagnosis can be reached. The first point we would like to reach is diagnosis. One diagnosis is made, and the pathogenic genes are identified at the DNA level, we can proceed with decisions on what the proper action to be taken is. So idenficiation of pathogenic genes is the first goal to be reached.
Takaku: Time is getting on, so although we wanted to expand this issue further, we have to close this session. In the reception we can have informal discussion. I want to thank all the presenters.