pp. 8-17 in Human Genome Research and Society
Proceedings of the Second International Bioethics Seminar in Fukui, 20-21 March, 1992.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.

Copyright 1992, Eubios Ethics Institute All commercial rights reserved. The copyrights for the employees of the US Government, are subject to other copyright arrangements. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

p. 8 in Human Genome Research and Society
Proceedings of the Second International Bioethics Seminar in Fukui, 20-21 March, 1992.

Human genome research

George Cohen,
Professor, Institute Pasteur, Paris, FRANCE

It is my pleasure and honour to introduce the lecture of Professor Kenichi Matsubara, Director of the Institute of Molecular and Cellular Biology at Osaka University. In addition to his outstanding research activities, Professor Matsubara is the Vice-President of the Human Genome Organisation and is responsible for the organisation and coordination of Human Genome Research in Japan. It is in this capacity that he will address the meeting today.

We thank you for your presentation. The chairman of this session should have been Prof. Santiago Grisolia from Spain, and unfortunately he is absent. He could not come because of family illness.

pp. 9-10 in Human Genome Research and Society
Proceedings of the Second International Bioethics Seminar in Fukui, 20-21 March, 1992.

Human genome research

Santiago Grisolia,
Director, Instituto de Investigaciones Citologicas, SPAIN
I wish to express my deep gratitude both personally and on behalf of UNESCO to the members of the Organising Committee for the invitation to participate in this Second Bioethics Seminar. I should like, therefore, to address you both as a scientist and as Chairman of the Coordinating Committee for the Human Genome Project of UNESCO. Since the first workshop held in Valencia in 1990 on international cooperation for the project, partially supported by UNESCO, this institution has had a keen and proper interest in this project or "Initiative", as it is commonly referred to, and has organised and supported a number of other meetings and Workshops, as well as the Short Term Fellowships for Scientists in Third World Countries. The UNESCO and the Committee which I preside understand and see clearly the role of UNESCO as one of protecting the interests of the Third World in this the so-called "greatest project of biology".

The reason for this concern is clearly apparent in that the Human Genome is a patrimony of humanity, and thus it comes under the province, mandate and interest of UNESCO. Nevertheless, UNESCO also understands clearly that its role is not that of developing a scientific program, but rather to educate, or help educate, people of the Third World, and to be aware and vigilant for the many, many social issues which, as with other scientific endeavours, will and are arising. Indeed, of great concern to UNESCO and to other organisations such as HUGO and the French National Committee of Ethics, is the recent proposal by investigators of the NIH in the USA and of the MRC in Great Britain to obtain patents for partial cDNA sequences, the so-called expressed sequence tags or EST. We are firmly opposed to such requests because of ethical as well of scientific reasons. Indeed, philosophically speaking, and in addition to the possible negative effect on the exchange of information which is key to scientific development, we should pose the question, "to whom do scientific discoveries belong?" In earlier times when scientists received help and subsidies from private patrons or foundations, their proprietary interest could be defended, but things have changed dramatically in recent times with the massive support which science needs and receives from society. Therefore, specific issues of intellectual property, including representatives of all the relevant disciplines and interest, must be discussed.

The free flow of information derived from the Human Genome Project is crucial and should come into the international public domain by the normal routes of publication and entry into databanks. International organisations can take an active part in stimulating collaboration and cooperation among nations, giving high priority to the bioethical and social issues associated with human genome mapping and its potential applications. Identification and description of all human genes is a worthwhile pursuit, particularly when the findings can be translated into genetic services. Moreover, all countries, even those with less expertise may benefit from molecular genetic techniques by the development of new, simple, rapid and inexpensive tests for identifying pathogenic organisms.

A rapidly expanding consequence, with social and ethical implications, is the completion of genetic registers, both for the benefit of research and of families concerned. Here the question of confidentiality becomes important because diagnostic genetic information must be kept in strict confidence.

The area of greatest medical promise is in the new approach to treatment of human disease and disorders. Medicine can now begin to be concerned with the defect itself, that is the mutant gene, rather than with the consequences of the defect. Most will agree that genetic treatment of somatic cells is not a cause for particular concern. Few, however, would endorse germ cell modification as appropriate for human beings.

These and other areas of social and ethical interest need to be discussed.

pp. 11-17 in Human Genome Research and Society
Proceedings of the Second International Bioethics Seminar in Fukui, 20-21 March, 1992.

On the analysis of the human genome and the Human Genome Project

Kenichi Matsubara,

Director, Institute for Molecular and Cellular Biology, Osaka University, JAPAN

Distinguished guests, ladies and gentlemen, it is a great honour for me to be able to give a talk at this very important occasion, discussing ethics in conjunction with the rapid progress in human genome research.

At first I want to look at what processes by which the human genome works. Secondly, what do human genes do, thirdly what impact do genes have. To understand these things will be helpful for understanding the rest of my talk. This is my role as a keynote speaker at the beginning of this seminar. The issues relating to bioethics are quite deep and also diversified. Particularly among them genome research is contributing to the identification of relevant issues. Today and tomorrow we are focusing our efforts on the identification of issues that need to be addressed for bioethics. Therefore I would like to provide some background on the Human Genome Project, its scope, function and task.

I will touch on the issue of contact between society and the project. When I finish my talk there will be various informative presentations which will reveal the contact point between bioethics and society. This is an international seminar which is supported by various people's efforts, like Prof. Fujiki and all the parties concerned. We must ask from which issue we should begin our discussion. We should establish this order of importance so that we can proceed with this discussion effectively.

The establishment of the Human Genome Project had some background. When the project was started there were approximately six major scientific discoveries that were related. The first of these were when recombinant DNA technology was started in 1973, which produced an enormous expansion of molecular biology.

What was remarkable about this progress, was that all living creatures on this planet had their basis in DNA. Genetic information was introduced to science, and that genetic information is carried in our body, not only in humans but by minute microorganisms, insects, and plants also. All the creatures on the planet have the same or similar genetic code, therefore living organisms have almost identical genetic structure. About 30-40 million living organisms exist on this planet at this moment, and such an enormous number of organisms derive from the same ancestor. We have the same mechanism for living. Because of that, living organisms carry the same mechanism for life. That mechanism is now being rapidly understood by us. The mechanism helps us a lot to understand the relationship between humans and other living creatures. By introducing that new perspective, we are changing our concept of the position of humans on this planet. We used to think that human was the top and the most sophisticated creature, but because of this new concept we are changing our traditional concept about the relationship between humans and other creatures.

This is having a large impact of industrial activities in society. Recombinant DNA technology is producing vaccines, interferon and other useful pharmaceuticals. That was applied in the pharmaceutical technology from the late 1970's. That was a great advancement of technology and medicine and industry, which is not stopped at all, but is now developing at a rapid pace and is having a large impact on many industries.

For example, something that may not be obvious, is that recombinant DNA technology is prominent in medicine. The pathogenesis at the level of DNA and genes is revealed, which is very remarkable, and that result is utilised for the diagnosis and treatment of diseases. Up to date, about 1000 human genes have been described and coded at the DNA level which are exploited in diagnosis and treatment. This number is rapidly increasing, since more and more people are working to decipher genetic codes, and better technologies are being developed. This pace is exponential.

In total there may be 50,000 -200,000 genes in humans, among which the most significant parts will be completely registered and deciphered. This gene analysis is progressing from single gene analysis to combined gene analysis. The mechanism itself is being revealed at a rapid pace. In our daily life you must be exposed to that news. The rate of increase in the number of analysed human genes is so significant, that in five to ten years more than half of the genes will be deciphered through structural analyses of the genome and through so-called cDNA projects that analyse expressed genes. Understanding large numbers of human genes and their regulation will no doubt open a new era for medical sciences that include diagnosis, developing pharmaceuticals and treatment of diseases. Without doubt, the ideas and technologies developed will be applied for improvement of other useful organisms.

Secondly, the emphasis of research is shifting from the gene level to gene system level. For example research on 40-50 cancer genes is now being conducted, and now the cancer gene control sequences are being researched now. Without a comprehensive understanding of these mechanisms and systems we cannot analyse how the genes are actually working. By doing that the system of our body is developing very rapidly, and pharmaceutical development has been enormously advanced. Also diagnosis and treatment are enormously developed.

Thirdly, not only the understanding of the human body mechanism can be gained, but through human gene analysis the process of human body construction can be understood. This is another development. We are a multicellular organism, about 700 million years ago that animals, or multicellular organisms started their existence on the earth, and we have become more complicated since then. About 60 trillion cells are existing in our human body, but by what processes have these mechanism been created. This is another target of research. Embryology was the traditional term, but now it is related to medicine. How can a normal functioning body can be maintained? This is another research area, in addition we have research on the neurological system and neurological development. These are basic points of science and technology are revealed. We have enough tools of research to enter that field of technology now.

Fourthly, through DNA research the genetic information is in the genome. The genome and total genetic information system can be fully understood. What we did not expect to find, is now becoming visible. For example, our understanding regarding the genome itself was rather limited, but new research is changing our ideas. For example the human genome is being analysed to some extent. Only a small proportion of our DNA, 5% are functioning, therefore 95% of the DNA in the genome is existing for something else. This is a very surprising discovery. Also, may genes that used to be working in the past do not appear to be working now, very complicated recombination of genes is occurring and mutations, and inserts. It is a very unstable record. The genome is very unstable, there are many things happening on a continuous basis. Therefore, it is still ambiguous, we have come to a point where we can somehow assess that there is a complicated method by which one gene affects another gene. Although it is an unstable record, through generations to some extent those systems are transferred to new generations and some stability is kept. Now we are in a process of discovering this process.

The process of the creation of humans, or of life on this planet, including diversification among different species can be properly read when we look at the genome system. The understanding of the genome will have a large impact on our understanding of life.

Fifthly, there is accumulation of information about information and genetics. There are new movements occuring in society. Information accumulation is rapidly progressing. This information analysis is resulting in the generation of databases. Without using such databases we can never analysis and fully understand life. By improvement of our technology, techniques and tools, there are many influences to society, culture, technology and industry. These processes are all ongoing.

Sixthly, I would like to focus on the continuous progress of science and technology. Some of the recent developments in relevant technologies are summarised in Figure 1. Almost every month a new science and technology is developed which is introduced to aid research activities. Among these I would like to draw your attention to some of the most recent developments, from 1985 to 1988 we have some prominent research technologies. For example in 1985, the technology to isolate individual chromosomes was developed, so that we can extract individual X and Y chromosomes. In 1986, the phenomenon of gene shuffling was observed, that the genome is unstable. Also in 1986 family pedigree analysis was started, based on family pedigree analysis human genome mapping began. Familial pedigree analysis is also a very important tool for the analysis and diagnosis of human genetic diseases. By introducing human genetic mapping techniques, human genes have been identified quite quickly. Also polymorphic markers for human genes have greatly expanded. At this time we entered a new era of human gene and genome analysis. At this time computer graphics was utilised, and software was developed. Also Duchenne and Becker muscular dystrophy genes were identified in 1986, entering a new era of medical treatment and diagnosis. About 400,000 nucleotides or more were identified and established. So by using existing technology we can smoothly conduct this type of work. Also around this time detailed human genetic mapping was started.

In 1987, DNA structure analysis was started using pigments instead of radioisotopes, improving efficiency by ten times. Yeast artificial chromosomes (YACs) were introduced, allowing large fragmentation of genes. The construction of an E. coli clone library was started to analysis the E. coli genome. About 1000/th size of human. The physical sequencing was made possible. In 1988 the DNA polymerase chain reaction (PCR) was introduced.

In the background of human genome analysis there are many new technologies. We are still developing new technologies such as robotics. The basic image of the structure of human is made clearer. Through this comprehensive analysis and research we are attempting to understand all the genes and the whole genome. Medical science was the forerunner of these aspirations. We can understand why medical science was the forerunner for such development. Humans are the target of medicine. Genes were analysed at first, then gene systems. Every year more than 100 pathogenic human genes are identified and analysed. Together with this advancement more and more diseases are identified as a result of multiple gene action. If this was so, it was asked why don't we attempt to decode all the human genes in the genome. This was the underlying aspiration behind such an effort. So we should start with what is available with currently available technology and it should be carried out as an international project. The concept was started around 1987 or 1988, forming an international collaboration.

Figure 1: Some recent progress in relevant technologies
Determining genetic structure can be rather complicated. One example is cystic fibrosis. To identify this one gene it took four years. A clone of 500 kb size was isolated. It was analysed at 25 kb per year, each nucleotide position that was determined cost about US$4, which means that it is more effective to analyse genes as a total unit rather than one by one, under international collaboration.

How can we proceed in this project. Human genome analysis covers these five areas:
1. Genome structural analysis. e.g. cystic fibrosis was most sophisticated.
2. Genome functional analysis. Which genes are functioning in different organs and what is their relationship to the function of the body?
3. Relationship between human genome analysis and genome analysis of other organisms. By analysing different genomes we can expand the information.
4. Information processing knowledge
5. Sophistication of technology

The human genome consists of about 3 billion nucleotides, and some people criticise that it is wasteful of resources and time to sequence it all. But it is not wasteful, we are trying to accumulate a massive accumulation of knowledge in a comprehensive manner. In the Human Genome Project, we are bound to construct a large database that requires intensive international collaboration. In the project, a global approach is being taken towards understanding the blueprint that underlies and controls biological phenomena. This style of work has not hitherto been attempted in existing biology, such as embryology, immunology, or brain science which focuses on studies with mechanisms acting in individual biological phenomenon. Genome projects with the unique style of work are being organised with many other organisms, including mouse, flies, nematodes, rice, Arabidopsis, yeasts and bacteria. The concerted efforts for understanding genomes of many organisms will no doubt change the future of biology, and will effect our understanding of the human species.

Dr. Ishihama at the National Institute of Genetics at Mishima gathered all the information on the E. coli genome. He classified the genes into four categories: genes for energy production (about 70% of the total genes), genes for substrate production (about 27%), genes for cell envelope (about 26%), and genes for core machineries which involve protein synthesis, DNA synthesis and RNA synthesis. Among all of the genes so far studies, about half of them are acting in regulation of other genes.

It is highly likely that most of the genes found in E. coli will find counterparts in higher eukaryotes such as humans, mice, rice and insects. Thus, the E. coli genome project can have an important influence on other genome studies. It is being conducted in Japan as well as in Europe and the USA. Although the human genome is almost 1,000 times more complex than the E. coli genome, we will soon be able to discuss its genetic constitution at a similar level to that of E. coli, as analyses of the linear structure of the human genome (the so-called mapping efforts) and the studies with phenotypic expression of human genes in tissues (the so-called cDNA project) progress.

What benefits can we enjoy? Sophistication of life science, and a pool of knowledge available for biotechnology. Being supported by these factors, life science research will surely change. This will be applied to medicine, pharmaceuticals, agriculture and engineering. These areas will be fully influenced by biotechnology. In line with the development of biotechnology the environment might be affected.

As I said at the beginning, the genome structure and analysis will give us many insights, and some of these are summarised in Figure 2. We can deepen our understanding of many issues. This will surely influence society. Animals, plants, microorganisms, and all living organisms on the earth use essentially the same genetic code. This finding strongly suggests that they are derived from one and the same ancestor, however they look different. The genome studies will unravel unique features of DNA that underlie this paradoxical situation, viz. uniformity and diversity of genetic systems, and will lead us to understand two important aspects of humans. Firstly, it will provide us with better understanding on the relationship between humans and other organisms. Secondly, it will unravel the course of our evolution, since the histories are recorded in the genomic DNA. Our culture, based upon understanding humans, can not escape from the impact brought forward by unravelling these problems. There may be another "revolution in understanding humans", for the second time since Darwin proposed the theory of evolution.

Figure 2: Affects of Human Genome Research
Development of life science research technology

Development of information processing in life sciences

Life science research will change:

Medicine; Research such as that on Ideas;

Pharmaceuticals; environmental problems; Thinking


Industry, Society, etc.

The Human Genome Project can also cast light on our biological history, because DNA in the genome carries all records of evolution. Through analyses of the global distribution of polymorphic markers among races and tribes, much will be learned about their migration, and massive changes in their populations. In addition to these short term historical records since humans appeared on the earth, we will learn much about our longer course of evolution. Genes in prokaryotes, such as E. coli and B. subtilis, are densely located along the genome, and possibly about 70% of the genomic DNA is occupied by open reading frames. In contrast, only about 5% of the human genomic DNA is assigned to open reading frames, leaving the function of the rest mostly unknown. It looks as though prokaryotes have come towards minimizing their genomes, and that eukaryotes, such as humans, have come towards expanding genomes. many intriguing questions can be asked to connect such huge differences: How aerobic cells emerged from anaerobic cells? How they became eukaryotes, viz. cells carrying nuclei? How multiple cellular systems evolved? How such complex animals as vertebrates emerged, and how mammals have replaced dinosaurs in the past...? As an optimist, I believe that some of these questions may be answered through genome studies. Learning about our relationship to other organisms will give us a clue to think how we, the living creatures on the earth, should interact with one another.

Searching for records of events that have happened relatively recently in our genomes can provide us with interesting and rewarding findings. The human genome carries thousands of retroviral genome copies, some of which have been converted into control elements for human amylase gene expression. Similar cases will be discovered in other genes.

Let me come back again to the realistic part of the Human Genome Project. The project, of necessity, promotes development of very efficient and high speed DNA technologies. In addition, there will be a flood of genetic information, that will lead to the fusion of biological and information sciences. For this reason and for the expected revolution in biology, biotechnology, and medicine, many developed countries are participating in the genome project. However, this project is influenced by science policy makers who are mostly interested in technology developments and its applications. In contemporary society where developments in basic and applied science go almost simultaneously, I think that the Human Genome Project is also providing an interesting social experiment for considering the relationship between biology and its application.

In many countries in the world this research is being developed. Some countries are taking part in international collaboration. Countries have to establish particular policies and approaches, and some countries have established domestic Human Genome Projects. The Human Genome Projects run by different countries are different, as each project is strongly influenced by grantors under influence of national interests, and by the personality of the scientific and political leaders. In some countries, leaders have put strong emphasis on the usefulness of the expected outcome from the project. As to the usefulness, some of the prominent proponents in the human genome project have gone so far as to declare that talents in mathematics or music, for example, could be predicted in individuals, through developing the project. I do not, however, like to see such oversellings: It should be made clear that the Human Genome Project at this stage is not to understand individual human genomes for useful information. It should be clearly declared that the current project is for understanding the human species.

When this genome research has been performed we can ask what problems and issues will arise in society. These should be discussed ethically, economically and legally. We need to consider the impact of such research work. Needless to say, just as in other advanced nations, in Japan the contact point between life science and society is being considered. More and more people are paying attention to the importance of this contact point. Therefore in this sense, this symposium is organised at the most timely occasion, and we hope that many issues can be identified and addressed, and that we can discuss and exchange ideas as to what extent this resolution has been started. On the part of the people involved in this research doing the activities from scientific and technological view, I will be very interested in the discussion that develops from this seminar.

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