REGULATIONS ON LIFE SCIENCES

Chapter 1: Possible Regulations

Part 1: Legal Regulations

Section 1: Present Status and Strategy of Life Sciences

(Authored by Minoru Kuniya and Mami Oyama)

1. Present Status of Life Sciences

The life sciences (note that life science technology is called "life sciences" in the Japanese national government's policies) are intended to unravel the complicated and delicate mechanisms involved in life and reproduction. At the same time, the study results of the life sciences are applied to diverse fields including, among others, medical care, environmental preservation, agriculture/forestry/fisheries, and other industries.

When looking at the recent trends in research and development of the life sciences field, we recognize substantial accumulation of scientific knowledge and we can see the possibility that all life-related phenomena may be uniformly understood according to certain common principles. This is because it has become evident that all life-related phenomenon result from common actions: DNA, proteins and other relevant molecules in the organism undergo interactions in good order over time while receiving stimuli from outside the organism.

These developments in the life sciences were triggered by Watson and Crick (awarded the Nobel Prize for Medicine and Physiology in 1962) who discovered the structural model of DNA in 1953.

DNA is a double-chained molecule, with half of each chain being phosphoric acid and the other being a sugar. The chain consists of combinations of four bases. The subsequent discovery of restriction enzymes, which cut DNA molecules having specific base sequences (combinations), resulted in epoch-making progress in genetic engineering. In 1973, Cohen and Boyer first succeeded in gene recombination, and in 1979, the gene for human insulin was identified. A variety of achievements in diverse areas were attained over an extremely short period of time.

On the basis of findings and knowledge obtained so far, research and development in the life sciences is now progressing in directions aimed at understanding microscopic life-related phenomena on a molecular level in vivo; understanding complicated life-related phenomena such as embryonic development, disease onset, ecological systems and other life phenomena that result from orchestral combinations of these microscopic life-related phenomena; and understanding evolution and diversity in the biosphere.

Regarding future trends, it is anticipated that research and development will intend to understand basic in vivo molecules controlling complicated life-related phenomena, including, among others, DNA, protein, glucose, lipids, through the use of analytical methodology; and to explore the meaning of information, e.g. information of DNA base sequence, information of positioning of genes on chromosomes, and information contained in the three-dimensional structure of proteins. A specific example of the latter R&D objective is to deepen understanding of life-related functions controlled by DNA's specific base sequence. (In fact, research into gene function, and studies at the gene level to analyze the mechanisms involved in the development of the individual are actively performed, and industries utilizing biotechnology, e.g. production of drugs and foods through the use of gene recombination technology, have already made their debut.)

Along with progress in understanding the functions and structures which biological molecules possess, it is also anticipated that regarding life-related phenomena which occur as a result of the complicated correlation among many different factors such as development, disease onset and ecology, research and development will intend to elucidate many different aspects of the individual's life and the status of the ecological system as a group of individuals through the use of a comprehensive methodology involving study methods at the molecular, cellular and organism levels. In addition, on the basis of scientific findings on high-level functions of the individual or of etiologic factors, research and development will aim to control and design such functions, or to prevent and treat diseases. (Cloning technology and other relevant technologies which have attracted substantial attention in recent years are also related to identification of cellular-level phenomena during the developmental process as well as manipulation techniques at this level. This represents remarkable advancement in the life sciences.)

NISTEP conducted the Sixth Technology Forecast Survey (in June 1997) by questionnaire and predicted the time of realization for important topics in the life sciences field on the basis of responses obtained from specialists and other qualified individuals. Regarding hot topics in the life sciences field, the forecasted realization time (expected year) was 2010 for development of drugs to prevent the onset of certain types of carcinomas, 2015 for utilization of information on the individual's gene structure for diagnosis and treatment, 2015 for widespread use of a method to increase stem cell number in a test tube for the purpose of using stem cells in treatment, and 2021 for clinical application of organ regenerating technology utilizing self-cell proliferation.

Similarly, in the fields of health, medical care and welfare, the forecasted realization time (expected year) is 2011 for widespread use of biological and immunological therapies which are effective in controlling cancer, 2013 for practical use of effective methods against cancer metastasis, 2014 for widespread use of gene therapies to control malignant tumors; 2007 for development of an HIV vaccine, 2010 for widespread use of methods of eradicating viruses from the blood, 2012 for practical use of gene therapies for the treatment of gene deletion diseases, 2020 for practical use of oral gene treatment; 2013 for development of a completely implantable-type artificial heart, 2018 for practical use of a completely implantable-type artificial kidney, 2016 for development of an artificial liver (with an extracorporeal liver function supporting device) which can be used continuously for extended periods; and 2023 for practical use of artificial cells possessing organ characteristics.

Trends noted in North American and European countries also indicate an acknowledgment of the importance of the life sciences and in particular, it is recognized that life sciences play important roles in creating novel frontier industries which may contribute to strengthening of the economy. Accordingly, international competition is currently very severe, particularly in such fields as originating intellectual property rights.

In Japan, the "Life Science Related Research and Development Basic Plan" (decided by the Prime Minister) in August 1997 selected the following areas that the nation should address with particular interest and effort in the life sciences field: research and development (R&D) of living things as an integrity system, including among others, R&D of the brain, cancer, embryonic development, ecological system and the biosphere; and R&D of fundamental biological molecules including the human genome. In addition, the Plan mentioned the necessity of giving considerations to creation of cloned individuals and other bioethics-related topics.

2. Trends in Life Sciences Strategies in Major Countries with Special Regard to the US

(1) Life Sciences Strategies

Considering the present status of the life sciences, each country tries to address issues in this field in a strategic manner. In this section, we will briefly review life sciences strategies over the world, focusing on the US where there exists overwhelmingly enormous potential for this field.

We cannot discuss world S&T strategies without first mentioning US S&T strategies. Here, we will therefore look back briefly on the history of the US general S&T strategies and in particular, on the history of life sciences related strategies to such an extent as necessary for discussion on what regulations for life sciences should be.

Since World War II, the US has taken the initiative in S&T by promoting major projects (e.g. nuclear power development, space exploration) supported by excellent manpower which fled to the US from Europe and its own huge national power. The fields that were remarkably superior were national defense and basic research. It is acknowledged that the superiority of these fields spun off industries of private origin.

When entering the 1980s, however, the US suffered from both a trade deficit and fiscal deficit, leading to a reduction in its national economic power. This in turn made both national government and non-government parties alike afraid that US industries were relatively less competitive with those of other major industrial countries. In response to the concern, new S&T strategies were formulated one after another during the times of the Reagan and Bush administrations. The "President's Industrial Competitiveness Committee Report" (Young Report) in 1985 presented specific strategies in the initial stage. The "State of the Union Message" by President Reagan in 1987 declared the "competitiveness initiative." For specific research fields, the "superconductivity initiative" was announced in the same year, which aimed at realization of practical use of high-temperature superconductivity, a technology recently discovered at the time (note that in the following year, the superconductivity competitiveness law was established). Subsequently, the US strongly emphasized these attitudes to its own S&T strategies in S&T related conferences and other discussions within the international framework.

These US policies on S&T can be roughly summarized as follows: internally, i.e. inside the nation, promotion of cooperation among public sector, private sector and academic world, acceleration of transfer of national research results to private industries, intensifying protection of intellectual property rights, and strengthening of human resources; and externally, i.e. outside the nation, protection of patents, requirement for symmetrical access, and proposals on international cooperative plans of large-scale projects (e.g. SSC plan, space station plan, international nuclear fusion plan).

What attracted attention under these circumstances was the fact that specific strategies regarding biotechnology were formulated during the Bush Administration. Specifically, the "Report on Biotechnology Polices" (President's Competitiveness Committee, Chaired by Vice President Quayle) was announced in February 1991. The key topics of the Report are stated below, and closely reflect US biotechnology policies at the time.

1) Foster competitiveness and commercialization by new discoveries including new biotechnology

2) Reconsider allocation of the Federal Government's funds to biotechnology researches in the fields of agriculture, clinical medicine, energy, and environmental survey.

3) For the Federal Government's research plans, continue to give priority to basic science, which will receive more support; and more consideration than ever to financially support developments of technologies contributing to realization of practical use and to expansion.

4) Announce principles for management of biotechnology (i.e. planned introduction of organisms possessing modified genetic characteristics into the natural environment).

5) Base regulations on the Four Principles for Regulatory Examination (e.g. a principle of minimizing regulatory burdens) as stated in the Report and protest against any attempt to build a new law system.

6) Protest against programs which will eliminate motives for new drug development.

7) Make every effort to protect manufacturing method patents in the field of biotechnology.

Since the inauguration of President Clinton from the Democratic Party in 1993, the US political priority has shifted to computer network and environmental/disaster prevention technologies. It is considered, however, that there has been no change in the basic positioning of strategies for life sciences technology as advanced S&T: life sciences technology strategies are positioned in relation to general S&T strategies which aim at strengthening US competitiveness.

In addition to the above-described overall strategies, life sciences related large-scale projects have been promoted. Representative of these individual projects is the "Human Genome Analysis Plan" which was started in 1988. This project is promoted by the National Institutes of Health (NIH) and the Department of Energy (DOE), with the objective of sequencing the entire human genome (which sums up a total of 3 billion base pairs) to provide a complete map of human genetic information. It is planned that in 2005, sequencing of the entire human genome will be complete. (In concert with the US policy, several European countries and Japan also are currently promoting human genome analysis projects.)

Review of changes over time in the US Federal Governmental budget for S&T policies by individual objectives reveals the highest increase rate of approximately 30% for health related budget (including the field of life sciences) from $9.226 billion in 1991 to $11.920 billion in 1996. National defense related budget remained large as an absolute value but showed a decrease over the same period of 4%: $39.328 billion to $37.791 billion. The budget for space exploration, which was the lion of the day, recorded an increase over the same period of approximately 20%, from $6.511 billion to $7.871 billion, although in recent years it has shown very little growth. In light of the above-described R&D potential that the US has, and also in comparison to the standards of R&D as compared to Japan, it is recognized that the US has achieved overwhelming supremacy in the field of life sciences (Figure).

European and other countries also actively promote life sciences related R&D activities in parallel with information technology, although the details of activities of these countries will not be discussed here.

Figure: Comparison of S&T standards among Japan, Europe and the US

(1) Comparison between the US and Japan

(2) Comparison between Europe and Japan

Data Source: Report of Survey on Actual Status of Research Activities in Japan in the Year of 1995, Science and Technology Agency

(2) Status of Reproductive Medical Technology

The authors have so far discussed the trends in life sciences as a whole, which covers diverse topics over a wide area. Reproduction supporting S&T, a topic of the life sciences field, differs from the above-described general S&T strategies, however. In Europe, careful discussion about application of reproductive medical technology started in the 1980s and legal regulations were formulated concerning its application starting in the 1990s. These legal regulations will be described later in Section 2. Here, the authors will mention the events in the US since these are unique.

In the US, there already existed serious antagonism regarding artificial abortion, i.e. between pro-choice and pro-life supporters. Although the Supreme Court adjudicated legalization of artificial abortion valid (Roe Judgment in 1973), subsequent Supreme Court judgments permitted some regulations in accordance with individual state laws. To date there are no fixed policies or legal regulations formulated by the nation. On the other hand, the National Research Act was established in 1974, which resulted from discussions about pre-birth examination for genetic diseases and what the limits of studies using human subjects should be. In connection with the Act, it is prescribed that medical institutions have an obligation of establishing guidelines and institutional review boards (IRBs). In this manner, the system to cope with ethical issues in the medical care field has been built up. Research conducted in the US at that time contributed to the establishment of the concept of bioethics.

Under these circumstances, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research was organized in 1981 through to 1983 and undertook diverse discussions and investigations regarding "health care" and "research." However, the Biomedical Ethics Advisory Committee (BEAC), which was established in Congress following the President's Commission, was disorganized and did not issue any report. Since then, in the US no opinion regarding reproductive medical technology has been submitted. Under these circumstances, the US Government did not announce any national policy and it discontinued national research funding in the field of reproductive medical technology, studies of which therefore have been promoted by private funding. At present, application of reproductive medical technology is very active in the form of venture business. For example, DNA fingerprinting is a reproductive medical technology business born in the US and is commercially utilized in Japan also. In the future, life sciences related business is likely to be undertaken in diverse regions irrespective of country borders.

The birth of a cloned sheep in 1996 triggered arguments for and against human cloning. In the US, President Clinton immediately made a proposal to ban cloning related studies. However, a bill of legislation to outlaw cloning was rejected due to differences in opinions between the Democratic and the Republican Parties. Possible future legalization in the US is thus not clear. It has already been reported by the mass media that some private companies are attempting to undertake business based on the application of cloning technology (refer to an article of the Mainichi Shinbun: "Attempt to clone a man in Japan" dated December 2, 1998).

These circumstances are not conducive to the nation's strategies for life sciences. We have to take into account these issues, however, when we investigate legal regulations on application of life sciences in Japan. As the Warnock Report in the UK points out, which the authors will discuss later, it is highly likely that the needs for reproductive medical technology (which is expressed as "surrogacy" in the Warnock Report) will remain in changing forms, despite what ideas a nation has. Even if there are regulations placed on medical care or there are actual limitations to surrogate mothering therapies, people may go to foreign countries where such therapies are easily available. We have to therefore consider the possibility that regulations in only one country may not resolve problems. (According to the book "Laws on Artificial Reproduction" by Michiko Ishii, at a center offering surrogate mother services, located in the suburbs of Los Angeles in the US, 4 Japanese couples had 4 babies by 1990 and an additional 9 Japanese couples had attempted to do so; while at a hospital located in Seoul in the Republic of Korea, a total of 4 Japanese couples received or requested surrogate mothering therapies.)

3. Relation between Life Sciences and People & Society (With Special Regard to Government Related Activities)

(1) When investigating life sciences and legal regulations, those concerning reproductive medical technology are significant in particular, from the viewpoint of the above-described global S&T strategies. In Section 2, the authors will therefore review what types of investigations have been conducted to address issues of reproductive S&T in industrialized countries. In Section 3, the authors will discuss viewpoints on which to base investigations of legal regulations in the field of reproductive S&T in Japan, in light of the fact that to date no legal regulations have been formulated. Prior to the review and the discussion, the authors consider it useful to review retrospectively Japanese regulations on reproductive medical technology and even more widely, what investigations were conducted in Japan with regard to the relation between life sciences and people & society.

The relation between life sciences and people & society is not an entirely new issue to Japan. Researcher, private companies and governmental agencies have already been engaged in relevant investigations which were ahead of their time. In this section, the authors will mainly review the governmental actions involved in the "relation between life sciences and people & society." The Table in the next page chronologically lists governmental recommendations, reports, councils, and the establishment of laws and ordinances, together with some overseas movements. As the Table shows, some issues were already submitted for examination, and partial discussion has already started. The authors would like to take these issues as reference when discussing the main topic. (Events in the square parentheses occurred overseas.)

Table: Chronological Table on Relation between Life Sciences and People & Society

(2) As clearly indicated by the chronologic table, investigation of the relation between life sciences and human society can be traced back to Recommendation No. 6 of the Council for Science and Technology (note that the authors omitted prior investigations to this recommendation, which focused on medical ethics.) This Recommendation proposed promotion of life sciences, which initiated specific actions that prompted various individuals in different segments of society to consider the influence of life sciences on people and society. An early example of these reactions was that from 1971 to 1973, when the All Nippon Buddhist Association annually held a symposium on life sciences and Buddhism.

Immediately after that, the Ashiroma Conference was held in the US to discuss what regulations should be imposed on gene recombination experiments from the viewpoint of researchers. On the basis of the discussion of this Conference, NIH first issued guidelines for experiments on gene recombination. Subsequently, this movement spread over to many other countries. In Japan also, the Ministry of Education and the Council for Science and Technology initiated investigations for setting guidelines.

In addition to these safety related investigations, Japanese Prime Minister Nakasone proposed organization of the "Life Sciences and People Conference" at the Williamsburg Summit in the US, in April 1983. On the basis of this proposal, "the First Assembly of the Life Sciences and People Conference" was held at Hakone in Japan in May 1984, and consisted of 4 sessions: (1) present status and future of life sciences, (2) significance of life sciences to society, (3) significance of life sciences to the individual, and (4) international cooperation on life sciences. This was important since these discussions were driven by top-leaders. The discussion results of this 1^st Assembly was reported to the following London Summit. Subsequently, a total of 6 assemblies of the "Life Sciences and People Conference" were held in different countries (2^nd: Bioethics (in France), 3^rd: Neuroscience and ethics (in West Germany), 4^th: Towards international ethics for the sake of studies concerning humans (in Canada), 5^th: Human gene DNA sequence-various ethical issues, and 6^th: Earth environment and bioethics (in Brussels, Belgium)).

For conferences at the level of specialists in Japan, a "Round-Table Conference on Life and Ethics" was organized by the Ministry of Health and Welfare (MHW). This Conference held 18 meetings for discussion and issued a report in September 1985. The report consisted of (1) various issues concerning organ transplantation, (2) medical care when approaching death, (3) problems related to brain death, (4) development of reproductive medicine, (5) treatment of genetic diseases, (6) relation between medical doctors and patients, (7) harmonization of medical progress and ethics, and (in a separate chapter) various viewpoints on life. As indicated by the report, the conference covered diverse topics.

Subsequently, in the Council for Science and Technology also, a "Round-Table Conference on Life Sciences and People" (Chairpersons: Michio Okamoto, followed by Wataru Mori, both of whom were members of the Council for Science and Technology at the time) was organized. The Conference held a total 19 meetings. This Conference was not intended to draw conclusions, but to report the progress of their discussion to the Council for Science and Technology, the chairperson of which is the Prime Minister.

Subsequently, investigations on the relation between life sciences and people & society was transiently suspended for a while. This was because during this time attention focused on new topics such as environment related issues and problems surrounding brain death, or on individual topics. (The present chronological table does not include events related to the environment or brain death.)

The next peak of discussion occurred after the birth of the first cloned sheep, which took place in the UK and received considerable media attention. This development in research created a number of debates that remain unresolved. Furthermore, the birth of the sheep is considered an epoch-making event since it resulted in initiation of experiments using human ES cells and thus, raises issues not only related to cloning but also to that involving human reproduction. The authors will introduce the status of investigations that resulted from this event later in this Policy Study Report, as appropriate.

The overall picture indicates that Japan is not always behind the US and European countries in life sciences related investigation, and in some areas, Japanese activities may be positioned at the forefront of the discussion on life sciences and society. Although Japan has often overcome considerable challenges, it has not always been able to respond successfully to difficult problems, which may at the time seem unavoidable. Accordingly, when we consider the past experiences that Japan has had and what Japan hopes to define itself as in the future, we expect as a country to take self-directed actions at an appropriate time. For the moment, we have to pay special attention to the fact that Europe considers the relation between life sciences and society in the framework of reproductive medical technology, and have drawn some conclusions such as establishment of laws and legal regulations, whereas Japan does not take any such actions. We therefore have to return to the starting point to assess whether issues of cloning technology fall under those of reproductive medicine or those of life sciences. In this Policy Study Report, detailed discussion of individual technologies will only be made for cloning technology. Comprehensive discussion will be further required, however, regarding what the relation should be between investigation of reproductive medical technology and investigation of life sciences.

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