Section 5: Investigation of Subject in Regulating Technology (with Regard to Reproductive Medical Technology)

1. Investigation of Subjects in Regulating

The authors have already stressed in the previous sections that when regulating the freedom of learning & research, it is important to examine the necessity and modality of regulation for individual technologies to be the subject of such regulation. We will investigate modalities which fit to individual technologies in this Section and the necessity of regulation for individual technologies in Section 6. When discussing legal regulation, these two factors, i.e. modality and necessity, are closely interrelated to each other. Accordingly, even when focusing on only one of the factors, the authors will discuss the other factor as appropriate. We consider it natural to first discuss the necessity of regulation and then move onto the issue of modality; however, since the technologies to be regulated are complicated, we instead will first discuss the modality of regulation while giving explanation of these technologies.

This POLICY STUDY Report was intended to investigate regulations on life sciences. From this Section onward, regulations on individual technologies will be discussed, for which it is unavoidable to limit the scope of investigation. As described in the introduction, the authors will thus focus on cloning technology in particular. However, when discussing cloning technology, it is desirable to take a wider look at reproductive medical technology with the aim of positioning cloning technology within the context of the entire reproductive technology field. For this reason, the scope of technology discussed in this Section will be reproduction-related science and technology including that surrounding cloning technology. The authors consider that the way of investigating the scope of this technology in this Section is necessary also for investigating regulations to be imposed more extensively on life sciences in general.

Regarding technology which has already been developed, it is generally reasonable to trace back the chronological cause-and-effect relationships as shown in the example of "chronological evaluation of the development & growth system" in the next section and to impose comprehensive regulations at appropriate stages. The examples based on this idea include the views that experiments regarding manipulation of a fertilized egg should not be allowed past 14 days post-fertilization and that a special position should be granted to an embryo once it is formed since life starts at the time of formation of the embryo. On the other hand, considering the fact that advanced science and technology such as life sciences has made rapid and great progress, it is not always appropriate to examine regulations on life sciences only within the framework of such chronological technology systems. Attention must be paid to the high possibility that among individual chronological acts, those which become serious problems to humankind may exist side by side those which do not cause problems but produce extremely beneficial technology to humankind if such acts are carefully undertaken. It is therefore necessary to carefully classify and examine potentially problematic acts at individual stages of development and growth, on the basis of chronological cause-and-effect relationship (which requires understanding not from a linear view but from an overview). Of course, it is difficult in the present Report to examine the specialized technology necessary for such regulation and therefore, it only presents approximate relation between cloning technology and representative surrounding technologies necessary for discussing legal regulation of application of cloning technology. The authors would like to introduce our evaluation as an example indicating how cloning technology is examined as a subject of regulation on the basis of how extensive life sciences surrounding cloning technology are analyzed.

When introducing our evaluation, the authors will make the following attempts in particular: <1> to separate as distinctly as possible the subjects of regulation (i.e. gametes, embryos, fetuses, etc. at the stage of development and growth which are the subjects of regulation) from the acts to be regulated (e.g. fertilization, nuclear transplantation, and implantation) for the purpose of investigation (since we think that this separation is important when discussing methods of regulation); <2> not to focus only on technology which is directly involved in creation of cloned human babies but to take a wider look at surrounding technologies; and <3> to point out a possibility that evaluation of these surrounding technologies may encounter bioethical problems in addition to legal and ethical problems involved in cloning technology (for example, implantation of a fertilized non-human egg in the woman raises bioethical problems, which is a different issue from examining problems involved in cloning technology itself).

When considering regulations to be imposed on research of life sciences, with special regard to reproduction-related research, and on application of technology, it is necessary to review the types of cells as the subject of regulation, chronological changes of these cells during development, and technology to be regulated, for the purpose of identifying problems in each category. First of all, chronological changes in the process of human development will be shown in the table on the next page.

2. Technologies and Acts which can be Problematic, and their Evaluation

The technologies and acts which can become problems in connection with the chronological changes in cells throughout the process of human development will be listed below. In the list, individual subjects of regulation are first classified into categories of cells produced during the process of development and growth. In each of this first-grade category, technologies and acts using these subjects are classified into second-grade categories by reference to the overseas legislation cases. In each of the second-grade category, several examples of specific experiments or studies are shown: in this third-grade category, the expression "(consumed)" indicates "disposed after experiment."

{Note} Definition of symbols in each category are as follows:

* : An event which occurs in the natural reproductive process.

(>): An act of removing from the human body or an artificial manipulation which may produce cells which, after such act or manipulation, will continue to follow the human development process.

(<): An act of returning to the human body.

*: Technologies or acts which lead to the creation of a cloned human baby.

#: Technologies or acts which may entail ethical problems for reasons different from those associated with application of cloning technology, e.g. surrogacy, fertilization between human gametes and animal gametes, transplantation of embryos produced by such fertilization into humans or into animals; transplantation of human embryos into animals, and creation of human chimeras.

Table: Chronological Changes in the Human Development Process

{Notes} For the purpose of facilitating understanding of the above table, the cell types are explained below.

• Reproductive cells: Cells which are formed during gametogony and are of two kinds, i.e. an ovum and a sperm (which are called gametes).
• Primordial germ cells: Reproductive stem cells which are formed in the fetal period.
• Somatic cells: All cells constituting the body with the exception of sperm, ova, and reproductive stem cells producing sperm and ova (and primordial germ cell in the fetal period).
• Stem cells: Cells which exist in animal tissues, possess the ability to undergo cell division, have no limitation on their life, and are able to differentiate into specific types of cells to which the original stem cells belong. (In other words, cells which have limited ability of differentiating into cells within the system where the original cells exist, e.g. in the neurological system, the endocrinological system, the blood system, and the immunological system.) Note that reproductive stem cells and embryonal stem cells (ES cells) have totipotency, i.e. these types of stem cells are able to differentiate into all types of cells.
• Primitive streak: A form which appears during the process of development and differentiation: it appears when the mesoblast and the endoblast start to differentiate after the ectoblast has already differentiated. The ectoblast differentiates into nerve cells, skin, etc. The mesoblast differentiates into blood vessels, muscle, etc. The endoblast differentiates into gastrointestinal tracts, internal organs, etc.

(A) Reproductive Stem Cells, Spermatogonia / Oogonia of Human

<1> Storage

<2> Use Use for the purposes of experiments and research (consumed)
Use for the purposes of tests
Production using animals (e.g. introduction of human spermatogonia into a mouse testicle to allow them to grow) (>) #

<3> Forming gametes *

(B) Gametes

<1> Storage (# for post-death reproduction)

<2> Use Removal of an unfertilized egg from the mother's body
Use for the purpose of artificial reproduction (artificial insemination, in vitro fertilization) (>)
Use for the purpose of experiments and research (consumed)
Artificial change in genetic characteristics (consumed) #
Use for the purpose of tests (e.g. fertilization between a human sperm and a hamster ovum to examine if the fertilized egg is normal)
Fertilization between a human gamete and an animal gamete (>) #
Fertilization of gametes with artificially changed genetic characteristics (>) #
Transplantation of a nucleus of the somatic cell, etc. to an unfertilized egg to create a cloned embryo (>) *

<3> Fertilization *

(C) Fertilized Eggs Prior to Initiation of Cleavage Division

<1> Storage

<2> Use Removal of a fertilized egg from the mother's body
Use for the purpose of artificial reproduction (surrogacy) (>) #
Use for the purpose of experiments and research (consumed)
Use for the purpose of tests (e.g. pre-birth diagnosis)
Artificial change in genetic characteristics (>) #
Removal of a nucleus from a fertilized egg and transplantation of the nucleus to an unfertilized egg (for the purpose of creating a cloned embryo) (>) *

<3> Formation of an embryo *

(D) Embryos

<1> Storage Storage of a cloned embryo (<) *
Storage of extra embryos

<2> Use {Naturally formed embryos}
Removal of an embryo from the mother's body (>)
Removal of a nucleus from an embryo and transplantation of the nucleus to an unfertilized egg (for the purpose of creating a cloned embryo) (>) *
Artificial division of an embryo in the cleavage division period in order to create a cloned embryo (>) #
Artificial change in genetic characteristics (>) #
Use for the purpose of artificial reproduction (surrogacy) (>) #
Use for the purpose of experiments and research (consumed)
Use for the purpose of tests (e.g. pre-birth diagnosis)
{Artificially created embryos}
Creation of an embryo outside the body through the use of in vitro fertilization
Creation of a cloned embryo by transplanting a nucleus of the somatic cell (derived from born human babies) to an unfertilized egg *
Creation of cloned embryos through the use of nuclear transplantation using nuclei obtained from fertilized eggs, embryos, and fetuses *
Creation of coloned embryos by transplanting a nucleus of the ES cell *
Creation of an embryo by fertilization between a human gamete and an animal gamete #
{Nuclear transplantation}
Transplantation of a normal embryo into the mother's body (<)
Transplantation of a cloned embryo into the mother's body (<) *
Allowing gametes with artificially changed genetic characteristics to unite to form an embryo and transplanting the embryo into the mother's body (<) #
Transplantation of a human embryo into an animal #
Allowing a human gamete and an animal gamete to unite to form an embryo and transplanting the embryo into a human or an animal (<) #

<3> Formation of an individual *

<4> Removal and disposal of embryos (corresponding to artificial abortion)

{Note} In this first-grade category of 'embryos,' embryos existing in the mother's body (i.e. naturally formed embryos), artificially embryos, and transplantation of these embryos to the mother's body are covered. Accordingly, some of the acts listed here may also be listed in the other first-grade categories.

(E) Stem Cells (by Focusing on Special Cells at the Stage of Forming Embryos)

$ Embryonal stem cells (ES cells) [which are produced by culture of the cells in the blastocyst stage after removal of an embryo]

<1> Creation

<2> Storage

<3> Use Use for the purpose of experiments and research (consumed)
Use for the purpose of creation of organs or any other relevant purposes
Removal of a nucleus from the ES cell and transplantation of the nucleus to an unfertilized egg (for the purpose of creating a cloned embryo) (>) *
Creation of a chimera individual (a human chimera, a chimera between a human and an animal) #

$ Stem cells by individual tissue systems (normal stem cells and EG cells)

<1> Storage

<2> Use Removal of stem cells formed in individual tissue systems during the fetal period (>)
Removal of primordial germ cells formed during the fetal period (=Refer to EG cells) (>)
Use for the purpose of experiments and research (consumed)
Use for the purpose of creating of organs and any other relevant purposes
Removal of a nucleus from the EG cell and transplantation of the nucleus to an unfertilized egg (for the purpose of creating a cloned embryo) (>) *

<3> Differentiation and expression as somatic cells *

(F) Individuals (Fetuses)

<1> Use (prohibited and punished as illegal abortion, etc.)

<2> Testing Pre-birth diagnosis

<3> Research Removal of a nucleus from a fetal somatic cell and transplantation of the nucleus to an unfertilized egg (for the purpose of creating a cloned embryo) (>) *
Removal of stem cells of individual tissue systems (>)
Removal of primordial germ cells (>)

<4> Artificial abortion (based on the Mother's Body Protection Act)

<5> Use of artificially aborted fetuses and stillborn babies in research

<6> Natural delivery *

(G) Somatic Cells

<1> Storage

<2> Use Removal of a nucleus from a somatic cell and transplantation of the nucleus to an unfertilized egg (for the purpose of creating a cloned embryo) (>) *

(H) Others

Creation, storage, and use of EG cells as well as transplantation and implantation of EG cells to the mother's body

Transplantation of an animal embryo to a human #

Partial transplantation of human somatic cells to animal embryos #

Manipulation of cells of animal individuals

Products obtained from the above-listed research and technology do not only lead to creation of cloned human babies but may be utilized to achieve the following objectives, including those which have not yet been realized.

(a) To obtain fundamental knowledge and findings in biology, embryology, cytology, gene engineering, embryological engineering, etc.
{This is related to all of the above-listed technologies.}

(b) To promote advancement in regenerating medicine such as production of organs and tissues for transplantation which will not cause immunological rejection

(e.g. Production of organs for transplantation through the use of culture of stem cells in individual organs: using a technology of transplanting a nucleus derived from a somatic cell to an enucleated ovum and manipulating genes of a nucleus to be created by the technology with the aim at producing not an individual but a specific tissue only such as an organ)

{This is related to technologies involving "(E) Stem cells" in particular among the above-listed technologies, and also related to technology of nuclear transplantation and artificial change of the genetic characteristics of an embryo.}

(c) To accelerate progress in reproductive medicine

(c)-1. Diagnosis and complementation for malfunction of spermatogonia, sperm, etc.

(e.g. Introduce a human spermatogonia into a mouse testicle to allow them to grow sperm. Allow the sperm and an egg from a hamster or other animal to unite for the purpose of examining fertilization rates and if the sperm is normal. Destroy the formed embryos before they reach the two-celled state.)

{This is related to technologies involving "(A) Reproductive stem cells and spermatogonia" in particular among the above-listed technologies.}

(c)-2. Treatment of mitochondrial abnormality (When the mother suffers from mitochondrial abnormality, use technology of transplanting a nucleus derived from the fertilized egg to the other enucleated ovum to prevent the child from inheriting the abnormality from the mother.)
{This is related to technology of nuclear transplantation in particular among the above-listed technologies.}

(c)-3. Diagnosis and treatment of other hereditary diseases
{This is related to technology of nuclear transplantation and artificial change in genetic characteristics in particular among the above-listed technologies.}

(c)-4. Diagnosis and treatment of infertility

(e.g. Use technology of dividing an embryo to produce several embryos from a single embryo, and transplant these embryos with the aim at compensating for low success rates of pregnancy.)

From the viewpoint that it is necessary to impose restrictions on implementation of the above-listed technologies, safety-related and several other types of problems may occur when implementation of a technology is associated with production of an individual, and brings about the creation of a cloned human baby in particular. The justification for regulation will be described in detail in Section 6.

In addition, surrogacy, fertilization between human gametes and animal gametes, transplantation of embryos produced by such fertilization into humans or animals, transplantation of human embryos into animals, and creation of human chimeras (i.e. acts and technologies marked with #) may raise ethical problems, which is a different issue from examining problems involved in application of cloning technology (note that artificial insemination, in vitro fertilization, examination of reproductive cells and other relevant technologies which have already been put into practice in Japan are excluded.)

Regarding handling of these technologies, the subject of regulation will be decided after comparing advantages and drawbacks of accepting research and technology application on the basis of the currently available scientific knowledge and current status of technology as well as the sense of values that the society has, and such decision will be made on the basis of political and ethical judgment. Such decision-making will require exact identification of subjects and acts.

For the purpose of preventing creation of cloned human babies (as described at the beginning of this section, the conclusions to be stated in Section 6 are described here in advance), we have to look at several acts involving several subjects at the development and growth stage such as gametes, fertilized eggs, and embryos as shown in the figure (note that these acts are indicated by the mark * in the above list). Assuming that all of these acts be individually regulated, such regulation can be complicated and impractical. On the other hand, an attempt to regulate the acts of transplanting of embryos to the mother's body for the purpose of implantation may be relatively clear and surely effective in prohibiting creation of cloned human babies (refer to the table on the next page).

(If acts intended to create individuals are only regulated, how to handle experiments and research not intended to create individuals can be problematic. Even in the latter type of experiment and research, an individual may either willfully or negligently be created from embryos for research since the research itself directly connects to the process of producing an individual. It is therefore considered that also regulating activities not intended to create individuals is reasonable.

Furthermore, due to the remarkable pace of achievement in the life sciences, it is likely that new technologies not included in the above list may be put into practice in the near future. The social order and sense of values will change. Reexamination after a certain period will be required.)

Table : Manipulations, etc. involved in creation of cloned human babies

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