EMBRYO STEM CELLS AND GERMLINE GENE INTERVENTION:
AN ISRAELI PERSPECTIVE
Institute of Science, Rehovot, 7610 Israel.
Chairman, Bioethics Committee, Israel Academy of Sciences and Humanities, Jerusalem, Israel
Part II: Research In Non-Reproductive Cloning
Part III: Genetic Manipulation of Reproductive Cells
The perspectives of applying the cloning technology to human reproduction have generated much controversy. Israel has been one of the first countries to adopt in 1998 a Law that prohibits reproductive cloning. This is a moratorium for 5 years during which neither cloning of an entire human being nor genetic changes affecting human reproductive cells will be allowed. An aim of the Law is to allow the examination of the moral, legal, and social aspects of these technologies and their implications for human dignity. With the intention of not being an obstacle to the advancement of medical genetics, the Law provides for a yearly report to the Israel Health Minister on the state of scientific knowledge in these technologies. This article reflects the 2002-3 report, relating to scientific issues and bioethical opinions in Israel and in the world on human reproductive cloning, embryonic stem cell research and germline gene manipulation. In the Jewish tradition, the primary importance of saving lives and helping suffering patients can take precedence over the fears generated by modern genetic and reproductive research. Provided that new technologies are applied for medical indications and respecting human rights and human dignity, it is legitimate to explore their beneficial potential.
The purpose of the Israel Law “Prohibition of Genetic Intervention (Human Cloning and Genetic Manipulation of Reproductive Cells) 5759-1998, as defined in section 1 of the Law is “to determine a prescribed period of five years during which no kind of genetic intervention shall be performed on human beings in order to examine the moral, legal, social and scientific aspects of such kind of intervention and the implications of such on human dignity.” Section 3 of the Law states: “Throughout the period during which this Law is in force, no person shall perform any act of intervention in the cells of any person with one of the following purposes:
(1) Human cloning [defined in Section 2 as ‘the creation of a complete human being chromosomally and genetically absolutely identical to another person or fetus, living or dead.’]
(2) Causing the creation of a person by use of reproductive cells that have undergone a permanent intentional genetic modification (Germ Line Gene Therapy).”
The Law stipulates that an “advisory committee shall follow up medical, scientific and biotechnological developments in the field of genetic experimentation on human beings, shall report to the Minister [of Health] annually thereon, shall advise the Minister in this respect, and shall make recommendations to the Minister in respect of the force of the prohibitions set out in section 3.” The Law designated a Helsinki Committee appointed under the Public Health (Medical Experiments on Humans) Regulation 5741-1980, as the Advisory Committee.
The present article reflects the report for 2001-2003 on scientific as well as bioethical issues pertinent to the areas covered by the Law. Most of the developments to be reported are related to the issues of human reproductive cloning, and of cloning for the purpose of human embryonic stem (ES) cell research.
Reproductive Medicine has made many striking advances in the past quarter century. Most significant has been the success of in vitro fertilization (IVF) that has allowed millions of infertile couples worldwide to achieve coveted parenthood. These advances have been due essentially to an increasing understanding of the process of oocyte fertilization and the early development of human embryos prior to their implantation in the uterus, which marks the beginning of pregnancy. Clinical IVF and research in the treatment of infertility are very advanced in Israel.
In the line of this research aimed mainly at treating infertility, it has become possible to fertilize oocytes even when the male sperm contains too few spermatozoids for natural fertilization. This was achieved by microinjection of single sperm cells into the oocyte, a technique named ICSI and routinely used today in IVF clinics.
A continuation of this line of medical research would be to succeed in initiating the development of human embryos when no sperm cells at all are available. This could be achieved if any cell of the body could be used to fertilize an oocyte. Sperm cells are haploid gametes (containing 23 chromosomes which complement the 23 chromosomes of the oocyte), whereas other cells of the body (somatic cells) are diploid and contain 46 chromosomes (i.e. the two pairs of 23 chromosomes inherited from father and mother). Research in animals has shown that it is possible to use diploid cells to fertilize eggs and obtain successful pregnancies and birth, provided the oocyte is first enucleated, i.e. the chromosomal DNA of the oocyte is removed and the full set of chromosomes is provided by the somatic cell used for the fertilization. This reproductive method is called fertilization by nuclear transfer. It is also called cloning because the genetic chromosomal make-up of the offspring is the same as that of the donor of the somatic cell used for fertilization, in essence the offspring is genetically a twin of the donor of the cell (the mitochondrial DNA, however, would be different). The same technology could be used when no oocytes can be obtained from the mother, by introducing one of her somatic cell nucleus into the enucleated oocyte of a donor. As in all other forms of human IVF, the resulting blastocysts would be implanted in the uterus to initiate pregnancy in a mother who would eventually give birth to the offspring.
There are a number of potential medical applications of the fertilization by nuclear transfer for reproductive purposes, for example in the treatment of infertility or to prevent the transmission of a severe genetic disease in families of carriers. (Applications which are not for reproduction will be discussed below). However there are overwhelming scientific difficulties and major ethical concerns, which justify the present Law prohibiting human reproductive cloning.
The scientific difficulties have become apparent in the research on animal cloning. The technology of fertilization by nuclear transfer was at first only successful when the donor cell was from another embryo in the very early stage of development, i.e. with pluripotent embryonic stem cells. From 1987 to 1997, a number of successful cloning in cows and sheeps were achieved with such embryonic stem cells. The report on the birth of the sheep Dolly in 1997 was the first success in using a cell derived from an adult tissue. The report indicated that there were 270 unsuccessful attempts and only one birth. Up to this day the efficiency at which life birth can be obtained from attempts of fertilization by nuclear transfer has remained very low, i.e. a few percents. Studies in mice have indicated that certain types of cells, found in the ovary tissue around the oocyte (e.g. cumulus cells), can be used for cloning whereas attempts with other cell types remain unsuccessful. Hence, not any cell from a donor could be used.
A second major difficulty has been that most of the animals born from cloning with adult cells have shown some type of abnormality, the most common being oversize and obesity. Many of the animals have died after birth. There have been also concerns about premature aging in the survivors. This does not detract from the usefulness of cloning for animal genetic engineering, but causes great concern for any medical human use. A recent study from the laboratory of Rudolph Jaenisch entitled “Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei” sheds some light on the fundamental problem in cloning. It shows that the regulated expression of many genes, particularly in the placenta, is disrupted during the development of cloned fetuses.
The scientific explanation of the low efficiency and of the abnormal development of cloned progeny is most probably related to the “reprogramming” process that DNA from an adult cell has to undergo when restarting the early embryonic development. While it is true that any cell in the body contain the same chromosomal DNA as the fertilized egg, there are epigenetic modifications during the differentiation of the cells into the different body tissues, modifications of the DNA itself (e.g. methylation) or of the proteins bound to the DNA. To restart the embryonic development the chromosomal genetic material has to undergo a process of “erasing” or reprogramming, which is taking place under the influence of the cytoplasm of the oocyte. This process is apparently not as efficient on chromosomal DNA from adult differentiated cells, as it is with DNA from gametes i.e. sperm and oocytes. This explains why cloning works much better with embryonic stem cells whose DNA has not been modified by cell differentiation.
Based on a review of the scientific evidence on animal cloning, the U.S. National Academy of Sciences has issued a Report in January 2002 entitled “Scientific and Medical Aspects of Human Reproductive Cloning"  . A panel chaired by Prof. Irving L. Weissman drafted the report, which concludes:
“Human reproductive cloning should not now be practiced. It is dangerous and likely to fail. The panel therefore unanimously supports the proposal that there should be a legally enforceable ban on the practice of human reproductive cloning. For this purpose, we define human reproductive cloning as the placement in a uterus of a human blastocyst derived by the technique that we call nuclear transplantation. In reaching this conclusion, we considered the relevant scientific and medical issues, including the record from cloning of other species…The scientific and medical considerations related to this ban should be reviewed within 5 years. The ban should be reconsidered only if at least two conditions are met:(1) a new scientific and medical review indicate that the procedures are likely to be safe and effective and (2) a broad national dialogue on the societal, religious, and ethical issues suggests that a reconsideration of the ban is warranted.”
This report by U.S. and UK leading biologists is worth reading in detail. Its considerations are very similar to those that were at the basis of the Law in Israel. Unlike many opponents of cloning (see below section on Ethics), the U.S. Academy of Science document does not condemn the cloning technology a priori on moral grounds or as being against Human Dignity. It advocates a time-limited ban at least until animal research demonstrates safety and efficiency, and until all the societal implications have been well debated.
Whereas quite a large number of animals have been born through the technique of fertilization by nuclear transfer (sheep, bovines, pigs, mice), the first scientifically reported attempt to produce in vitro a human cloned embryo has failed. Typical of the over-publicized atmosphere in which work on cloning is being reported, a press release from the company Advanced Cell Technology (Worcester, Mass, USA) announced in November 2001 the cloning of two human embryos. However, the development of the embryos did not proceed beyond the first few cell divisions, and stopped at 4 and 6 cells (2 and 3 cell divisions, i.e. at about day 2-2.5 of embryo development). The declared aim of this experiment was not reproductive cloning but derivation of cloned human stem cells. However, the development achieved was far less then the blastocyst stage (day 5) at which stem cells could have been extracted. Nevertheless the result was published as “The first human cloned embryo”. This seems to indicate that, as could be anticipated from the difficulty of cloning primates, the present technology of fertilization by transfer of the nucleus of an adult cell is not working in human oocytes.
The above scientific report casts even further doubt on alleged claims that cloned human embryos have been implanted in surrogate mothers and that pregnancies have been initiated. Such claims have been surfacing in the non-scientific press in Italy (Prof. Antinori) and in South Korea (the Raelian religious sect), but have not been substantiated by any evidence. Since none of the physicians involved has presented any scientific data to indicate that their method produces results, where that of Advanced Cell Technology has failed, these claims should not be considered seriously. Nevertheless, these periodical reports in the general press feed the ethical debate on human cloning, a debate that has been going on since 1997 but is now reaching climactic heights.
Ethical DEBATES ON HUMAN Reproductive cloning
One of the aim of the Israel Law “Prohibition of Genetic Intervention (Human Cloning and Genetic Manipulation of Reproductive Cells) 5759-1998, is to examine the moral, legal, and social aspects of such kind of intervention and the implications of such on human dignity. During the past years, a number of discussions, symposia, newspaper articles and radio or TV debates have been devoted to these issues in Israel. In a general sense, it would be fair to state that the attitudes in Israel toward the theoretical prospects of applying cloning technology in Reproductive Medicine are different from those in many countries and international organizations around the world.
Theoretically speaking, if the technique was safe and efficient, it would be possible to obtain the informed consent of a sterile couple to use the cloning technology as part of an IVF treatment. Prospective parents would have the right to make such decision which, unlike germ line gene therapy, does not affect all their generations to come. Considering for example the case of a married infertile couple whose only other alternative is to make use of a sperm or oocyte donation from a third person, there may even be an ethical justification for them to prefer procreation by use of one of their own cell for fertilization by nuclear transfer technology. Jewish religious authorities have expressed grave doubts about the use of anonymous donations of sperm from existing sperm banks, because of the unknown filiation and the possibility that a boy and a girl both born from gametes that originated from the same anonymous donor may eventually commit an incest by marrying. Such Jewish authorities, which do not see in the cloning technology an inherent religious interdiction, would find such procreation less questionable than anonymous gamete donations. The Chief Rabbinate of Israel has not seen an inherent religious interdiction in the cloning technology as form of IVF, but has expressed objections based on the dangers in the technique . Besides the issues of safety and appalling low efficacy (which would require numerous human oocytes), there are also many questions regarding the status of the offspring, who would be a twin brother or sister to the husband or the wife, in term of inheritance or other aspects of religious law. Nevertheless, inasmuch the technology may help a couple fulfill the religious commandment of procreation, it would not be considered immoral from the Jewish religious perspective.
Besides overcoming infertility or preventing transmission of severe genetic diseases in carrier families, other uses of reproductive cloning would be much more objectable. The solution is to draw a line between clear medical therapeutical applications and non-medical uses, such as attempting to “reproduce” a dead person or allowing same-sex couples to have offsprings.
These views are commonly held among Israeli bioethicists and experts in Medical Halacha (for example Prof. Avraham Steinberg and Dr Mordechai Halperin from the Schlessinger Institute of Shaare Tzedek Hospital). The next paragraphs examine how this Israeli consensus position deals with some of the major moral arguments against human cloning, such as found in various international documents.
The issue of excessive Genetic Determination:
There are many who object on moral grounds to reproductive cloning because the child to be born would have the same chromosomal genetic make up as the parent donor of the cell nucleus used in the fertilization by nuclear transfer. On the other hand, genetic twins are born in nature at a frequency of about one in 270 pregnancies. Genetic twins have a stronger identity in their genetic make up than would have a child born by cloning, since the former have also the same mitochondrial DNA. Furthermore, genetic twins in nature are born together, and most often raised together, which even increases their chances to be similar in behavioral characteristics. In contrast, a child born by cloning would differ from his “parental twin” by twenty or more years and never during his development be physically identical. The desire of parents to have children “in their image” is rather common. But some say that in the cloning, one determines too much of the child’s appearance and behavior because one predetermines its genetic make up. This, however, would be true only if one believes in Genetic Determinism, i.e. in the theory that a person is determined by its genetic characteristics. This theory would lead to denying the freedom of choice, and refusing moral and even legal responsibility for one’s actions on the ground that “I was made like that”. Genetic determinism is not a scientific fact: studies on genetic twins that were raised in different environments have shown that the correlation in cognitive and behavioral traits is around fifty percent; this is higher than for other siblings, but shows that there is a large degree of autonomy and that genetic twins are distinct individuals and not copies of each other. This difference should be greater even between parent and “twin” child due to the difference in age and conditions.
The Jewish religion and philosophy emphasizes personal responsibility, as stated in the Mishna of Pirkei Avot  : "Everything is foreseen but freedom is given". Maimonides  comments on this and on the Talmudic saying  "All is in the hands of Heaven except fear of Heaven". Maimonides explains “What is in the hands of Heaven ? Man’s Nature on which he has no choice, being tall or short..but not human moves..these depend on man’s will.”
That humans are not to be considered genetically determined, but as much the product of their education, living conditions and free will, is one of the basic concepts in Bioethics. A very good example is found in the Universal Declaration on the Human Genome and Human Rights , prepared by the Unesco International Bioethics Committee (IBC) and adopted by Unesco in 1997 and later by the United Nations. Article 2 states,
a) Everyone has a right to respect for their dignity and for their rights regardless of their genetic characteristics;
b) That dignity makes it imperative not to reduce individuals to their genetic characteristics and to respect their uniqueness and diversity.
If one should not reduce individuals to their genetic characteristics, why consider a child who would be a genetic twin to one of his parent as too much predetermined?
The issue of violating Human Dignity:
The Universal Declaration quoted above sees Human Dignity in the recognition that human beings are not to be considered as determined by their genetic characteristics. This justifies that the Israeli Law prohibiting reproductive cloning does not base itself on an unavoidable violation of Human Dignity if one day this technology would be used for justified medical applications. In fact the explanatory notes of the law envisage that in case of a justified medical application, the Minister of Health could determine if this application would not be against Human Dignity, as one of the element in deciding whether to make an exception to the law.
Nevertheless, the Unesco Declaration quoted above seems to take another position since Article 11 states: “Practices which are contrary to Human Dignity, such as reproductive cloning of human beings, shall not be permitted…”. Similarly, the Additional Protocol (12-1-1998) of the Member States of the Council of Europe  states: “Considering that the Instrumentalisation of human beings through deliberate creation of genetically identical human beings is contrary to Human Dignity and thus constitutes a misuse of Biology and Medicine..”.
It is difficult to reconcile these different view points, one saying that Human Dignity “makes it imperative not to reduce individuals to their genetic characteristics” and the other that “deliberate creation of genetically identical human beings is contrary to human dignity”. It is, however, important to keep in mind that some of these contradictory statements result from modifications introduced in the Universal Declaration after its redaction was completed by the IBC. Article 11 was added at the request of the delegation of Germany. At the General Conference, at which the Universal Declaration was unanimously adopted, a number of delegations including Canada, Australia, Scandinavian countries and Israel took exception of this Article, because despite the opposition to reproductive cloning it was felt that pinpointing one particular scientific field of research as against Human Dignity was not warranted. Considering that scientific research should be aimed at bringing cure to human diseases and misery, one could not make such a definitive statement that would amount, in a sense, to an a priori demonization of Science and Medicine.
A second comment on the statement that practices are against Human Dignity relates precisely to the aims of these practices. If, as stated by the document adopted by a number of Member States of the European Council, the aim is the “deliberate creation of genetically identical human beings” then most would agree that such an aim is not medically justified. Indeed, there is a dangerous illusion that it is possible through cloning to produce a large group of “clones” that would be copies of each other with “determined” characteristics, an illusion that was first created in the book “Boys from Brazil”  aiming at creating many Hitlers. Another illusion is that one could make a copy of an Einstein or a Marylin Monroe, or of a deceased child or of a rich tycoon who wishes “immortality”.
These are all illusions of genetic identity, based on extreme genetic determinism, and indeed should be a priori condemned and never permitted. First, because it is not true that two individuals with the same genetic make up (twins) would have identical lives and behavior (or even beauty, which is in great part subjective and subject to a desire to be beautiful and to a discipline to achieve this goal, not to speak about intelligence which as shown by the IQ debate is in great part due to environment and education). The human soul cannot be cloned. Second, because these applications would not be justified medical uses whose purpose is to treat a human pathological condition, and hence should not be approved ever by the regulatory bodies that control medical practices, and insure that these are done with respect of Human Dignity and Human Rights.
The Israeli view is clearly to condemn and ban practices that are against Human Dignity, but not to be “an obstacle to the advancement of scientific research, and to developments of the fields of Genetics and Medicine” (as stated in the explanatory notes of the Israeli Law). Medical applications of new technologies in individual cases, provided that they are judged by Health and bioethical authorities to be in line with Human Dignity, should not be banned a priori but only subjected to strict evaluation and control. Such individual applications would also not endanger the diversity of humans as would indeed do mass applications that should never be authorized.
The issue of excessive Instrumentalization:
This argument often used in European texts and also recently by President G.W. Bush (in his White House address on April 9, 2002) is that life should be a creation (procreation) and not a commodity. The control of human reproduction, from the pill to IVF, may indeed be viewed as instrumentalization. This argument was raised twenty years ago when IVF was first authorized: humans should be born by an act of love and not in a test tube. Most countries realize that IVF has only increased the loving desire for a child and allowed countless infertile couples to achieve parenthood. It has not destroyed family values, on the contrary.
The same argument can be made for medical therapeutic applications of Reproductive cloning, if such a method can be proven one day as safe and efficient. If added to the arsenal of IVF techniques, fertilization by nuclear transfer would allow some more couples to achieve pregnancy and give birth to a much desired and loved child.
In summary, one could state the Israeli consensus opinion as follows: human reproductive cloning should be prohibited at the present time because it is dangerous and likely to fail, but not by invoking an unavoidable violation of Human Dignity.
At the other extreme of the ethical debate on human cloning, there has been in the past years a mounting resolution to morally condemn and ban upfront any prospect of using the cloning technology in humans because it is against Human Dignity. This may be motivated in part by the publicity-seeking doctors (Reed, Antinori, Zavos, Ben-Avraham, the Raelian sect) who spread scare by deliberately ignoring the dangers of premature use of an unsafe technology, and ignore the Laws that have been issued to avoid such a use. In January of 2003, the Raelian sect even mounted a false claim that a "cloned" baby girl named Eve had been born, no scientific evidence being ever presented (obviously, since fertilization by nuclear transfer seems to fail in primates). This claim turned out to have been only a mean to gain fame for the Raelian sect by manipulating the press.
However, a large part of the motivation in the UN action is probably rooted in a worldwide trend of suspicion against Science, perceived as “playing God”, and therefore wicked or almost demoniac. This philosophical and religious outlook of “Science playing God” is quite different from the Jewish view of man’s duty to mend the world (Tikun), as an associate with the Creator.
Furthermore, it can also not be ignored that much of the interest in addressing the fears of genetic engineering is fueled by local and national politics. The intrusion of politics to curb the opinions of Bioethic committees has been mentioned above in relation to Unesco’s IBC position on the cloning issue and the forced introduction of a ban on cloning in the Universal Declaration on the Human Genome and Human Rights. The political clout of President Chirac of France has been the moving force behind the European Union resolution condemning cloning 10, 
As a continuation of this line of thought, a French-German initiative has been mounted to pass in the United Nations an International Convention against the Reproductive Cloning of Human Beings. Two sessions of the Sixth Committee of the UN have been devoted in 2002 to prepare this Convention, the last one in September 2002. France and Germany propose a step-by-step approach focusing first of all on a ban on reproductive cloning of human beings, and then at a later stage on measures concerning the regulation of other types of cloning by interested States, including the elaboration of a separate international instrument (i.e. against cloning of embryos for Stem Cell research – see below).
To precise the position that the Israel delegation to the UN would take with respect to the proposed International Convention, the Legal department of the Israel Ministry of Foreign affairs has convened several working sessions with participants from different ministries and bioethics organizations. On this basis the Israeli representative at the UN sixth committee session (Adv. Ady Schonman) drafted a statement  :
“Israel also believes that the primary concern for the preservation of human dignity must clearly be balanced with other important values such as freedom of research, the right to benefit from scientific progress, as well as the autonomy of individuals to make personal decisions about reproduction. Striking the proper balance between these concerns is essential for any future Convention against the Reproductive Cloning of Human Beings.
In response to the rapid progress of bio-technological research in Israeli institutions, Israel was one of the first countries to adopt legislation imposing a general moratorium on genetic intervention for the purpose of human reproductive cloning. The Israeli law also prohibits germ line gene therapy. This moratorium is in force for an initial period of five years, during which the moral, legal, social and scientific aspects of this issue, and their implications for human dignity, are to be examined by an Advisory Committee specifically established for this purpose. The cautious approach taken by the Israeli Parliament stems from the understanding that science in this field is still in its infancy, and therefore it is only natural that at this stage we have far more questions than answers. Israeli law reflects both an understanding that science should not be demonized in the eyes of the public, yet at the same time the public must be assured that the far-reaching implications of scientific development in genetic engineering, as applied in medicine, are being carefully scrutinized and evaluated for all their multi-faceted repercussions…To some extent, Israeli law on human cloning derives its inspiration from Jewish teachings and philosophy which oppose biological determinism and emphasize both personal responsibility and the imperative to heal and save lives.
[..] We would also like to introduce a few particular concepts to be considered in the framework of a Mandate for a future Convention Against the Reproductive Cloning of Human Beings. First, as the questions raised are universal in scope, national ethics committees and similar advisory bodies can and should play a significant role, not only by drawing the attention of decision-makers to the constantly new questions that arise, but also in triggering the necessary public and democratic debate. My delegation therefore believes that a necessary component in a future international monitoring mechanism should be the establishment of an international cloning commission, whose task would be to follow the progress of scientific and biotechnological developments in the field of genetic and reproductive medicine in national constituencies, in order to provide a comparative updated study of the trends in this field and their implications. [..]And finally, while my delegation supports a legally enforceable ban that criminalizes the reproductive cloning of human beings, we also recognize that there may be those who would try to circumvent this ban and violate it, as with any other criminal activity. In view of the human dignity of the newborn that may be potentially created, irrespective of the unlawful nature of the act which brought him or her into life, my delegation would urge consideration of this unique aspect, so as to reaffirm that any child created by reproductive cloning, irrespective of the unlawfulness of the reproduction techniques which brought them into life, will be accorded the same rights as any other human being, by virtue of the human character they possess, without discrimination. My delegation believes that a clear statement on this matter is required in order to prevent the possible dehumanization of any child.”
At the September 2002 session of the UN sixth committee, many delegations were set to absolutely condemn reproductive cloning of human beings considering it immoral and an attack on Human Dignity. In contrast to the well-balanced statement made by Israel, some delegations take extreme views requesting a total ban on all forms of cloning, even for scientific research. Particularly striking was the draft resolution proposed by the Philippines, Spain and United States of America which in its point 4: " Solemnly declares that, pending the adoption of an international convention against human cloning, States shall not permit any research, experiment, development or application in their territories or areas under their jurisdiction or control, of any technique aimed at human cloning".
This draft resolution, if adopted, would be a definite shift from the original mandate for an International Convention, which was to be against the reproductive cloning of human beings but not on research. This distinction is important to stress: many scientists argue that the fertilization by nuclear transfer (the core technology of cloning) could be very important to understand how DNA is being reprogrammed at the gene level, and explain aberrations of gene expression in cancer for example. This research should not be prohibited. Moreover, the use of cloning for research on embryo Stem Cells (see below) holds many promises for the cure of diseases and should not be included in a ban on Reproductive Cloning. The text prepared for the Israeli delegation to the UN sixth committee made this position very clear: “We believe that a ban on reproductive human cloning should specify that it does not prohibit cloning for Stem Cell therapy”.
Indeed, the opposition of a number of countries to a total ban, including a ban of research on any part of cloning technology, caused the September 2000 meeting of the UN sixth committee to end without any resolution being accepted, and reporting the matter to an unspecified date.
The new U.S. President’s Council on Bioethics : a shift from previous US positions
The shift toward a much more radical condemnation of research on cloning for human (although not animal) uses can be traced to the rise of the new Bush administration. The present US position regarding the UN International Convention is to support “a global and comprehensive ban on human cloning…regardless of the purpose for which the human clone is produced. The United States believes that so-called ‘therapeutic’ or ‘experimental’ cloning, which involves the creation and destruction of human embryos, must be part of this global and comprehensive ban. Thus, the US does not support a ban that is limited to ‘reproductive’ cloning.” This position was announced by President George W. Bush at the White House on April, 9, 2002 based on the grounds that anything beside a total ban would be unethical and not implementable: one would not know who is a clone when embryos are implanted. The position of the US Bush administration is strangely even much more extreme than that of the new President’s Council on Bioethics appointed by President Bush. This Council is composed of 17 members, in majority non-scientists, and is chaired by Leon R. Kass, a Professor on Social Thought affiliated with the University of Chicago. Prof. Kass was on record for his opposition to many aspects of Reproductive Medicine and Genetics, emphasizing social dangers of the type Aldous Huxley had raised in “Brave New World”, dangers that he considers to weigh more than any medical benefit. The Council, however, has not proposed a total ban on all forms of cloning. In its report published in July 2002, two proposals were made because members could not agree on any one proposal. The first proposal backed by ten members is a Ban on Cloning-to-Produce-Children and a moratorium of 4 years on Cloning-for-Biomedical- Research (including in commercial Companies, which until now were under no regulation). The 2nd proposal, backed by 7 members, is a Ban on Cloning-to-Produce-Children, and Regulation of the use of Cloned Embryos for Biomedical Research (which would be authorized immediately). Therefore, none of these two proposals of the official Council on Bioethics supports a total and unlimited ban on all forms of cloning, such as formulated by the Bush Administration.
The present (2002) position of the US government is a definite shift from previously held US positions. The National Bioethics Advisory Committee (NBAC) of the preceding Clinton era had a balanced attitude, considering the risks as wells as pointing out foreseeable medical benefits from the cloning technology, as detailed in its 1997 report on Cloning of human beings. Similarly, the US National Academy of Sciences document on Scientific and Medical aspects of Human Reproductive Cloning quoted above, proposes an interdiction of Reproductive cloning based on the medical dangers and inefficacy of the technology. With respect to other cloning, such as for Stem Cells research, it states unambiguously:
“..the scientific and medical considerations that justify a ban on human reproductive cloning at this time are not applicable to nuclear transplantation to produce stem cells. Because of its considerable potential for developing new medical therapies to treat life-threatening diseases and advancing our fundamental knowledge, the panel supports the conclusion of an earlier National Academies report that recommended that biomedical research using nuclear transplantation to produce stem cells be permitted. A broad national dialogue on the societal, religious, and ethical issues is encouraged on this matter.”
The debate is by far not over in the US, as the Senate is still divided on whether or not to accept the House of Representative endorsement of President Bush total ban on cloning. Even in Germany, at a meeting in May 2003, researchers turned out to be divided over the ethical justification of a ban on cloning . As put by Dan Brock, a bioethicist at the US National Institutes of Health: " It is hard to identify a moral or human right why a healthy cloned child should be different from a healthy normal child ". In conclusion, while human reproductive cloning should never be allowed on any large scale in order to preserve human diversity, the exceptional medical application of this reproductive technology (if ever proven safe and efficient) to overcome infertility or other severe genetic problems should not be banned a priori and for ever. This is in essence the message of the Israel Law 5759-1998.
PART II: RESEARCH IN NON-REPRODUCTIVE CLONING
The non-reproductive cloning is defined as the fertilization of an oocyte by the nuclear transfer technology and in vitro culture to the blastocyst stage without implantation in a uterus. This area of research is aimed at allowing major therapeutic advances that may save the lives and alleviate the suffering of patients with severe diseases, hence its usual denomination as “Therapeutic cloning”. Blastocysts contain a mass of pluripotent Embryo Stem cells (ES cells), which are cells that can be cultured and made to develop into specialized tissues such as insulin-producing pancreatic islet cells, heart muscle cells, various types of nerve cells or of glial cells producing the myelin cover of nerves. Transplantation of these laboratory-produced tissues may replace the damaged tissues or organs respectively in diabetic patients, in victims of heart infarctions, or in sufferers of neurological diseases such as Parkinson, Alzheimer’s or Multiple Sclerosis. A major problem in organ and tissue transplantation is the immunological barrier, which can cause rejections of the graft or graft-versus-host disease, unless the tissues are matched to the donor. The hope to be able to derive the ES cells from blastocysts that have been obtained through oocyte fertilization by the transfer of a nucleus from a patient in need of a transplant (“cloned” blastocysts) would allow producing tissues that are fully compatible (autologous or “self”) to this patient. ES cells had been studied in mouse for and their transplantation has been tested in several animal models of diseases, and shown to have the potential to cure diseases.
Research on the development of human ES cell lines in the U.S.A., Sweden, Australia and Israel has indicated that there is an enormous potential for Medicine. The research on ES cells in Israel is particularly strong and has been highlighted by the journal Science in its 8 March 2002 issue, under the title “In the Mideast, Pushing back the Stem Cell Frontier”. The Rambam Hospital and Technion Rappaport Institute groups of Prof. Joseph Itskovitz-Eldor, Karl Skorecki, Lior Gepstein have obtained differentiation of human ES cells into insulin-producing cells and cardiomyocytes that in the future could be used for diabetes and myocardial repair. The groups of Dr Benjamin Reubinoff and Tamir Ben-Hur at the Hadassa Medical Center have obtained differentiation of human ES cells into neuronal progenitors, aiming at transplantation for neurological diseases. At the Hebrew University, the laboratory of Dr Nissim Benvenisty have transfected human ES cells with gene constructs that can increase their safety and therapy potential.
It is clear that some of these Israeli scientists will want to isolate more human ES cells and also attempt to produce ES cells from "cloned" blastocysts. There will be many problems to achieve this latter goal, because one can expect that numerous oocytes will be needed in the attempts to obtain cloned blastocysts. This has up to this day not been been successfully achieved. As indicated already, the group of Michael West working in the U.S. Company Advanced Cell Technology, reported 4 that the development of oocytes fertilized by nuclear transfer stopped after two days and did not reach the 5-day blastocyst stage when ES cells can be prepared from the inner cell mass.
One should also keep in mind that research on fertilization of oocytes by nuclear transfer has a number of important medical applications and not only for the production of autologous transplantable tissues. Elucidating the reprogramming of the chromosomal DNA, which is needed to allow it to initiate the early embryo development, has importance for research on aging, on cancer and on cell differentiation.
Ethical debates on Human Embryo Stem Cells and Therapeutic cloning
The debates on these two issues, although distinct, are nevertheless related.
Opinions on Human ES cell research in various countries:
Ethical debates have surrounded the development of human ES cell research. The first publication in 1998 by the group of J.A. Thomson from Madison University in collaboration with J. Itskovitz-Eldor from the Technion’s Rambam Hospital described the derivation of ES cells from supernumerary IVF human embryos, i.e. that remained after a successful treatment for infertility and could not be used anymore and for which the only alternative was frozen storage or destruction. Such supernumerary IVF embryos, donated with informed consent of the parents, have been the source of the about 70 lines of human ES cells that are part of the world Registry compiled in 2001 by the U.S. National Institutes of Health (NIH). The present status in the U.S.A., is that scientists working with federal funding (in the U.S.A. or abroad) can use the human ES cell lines from the Registry but cannot produce new such cell lines. This restriction may not apply to private companies.
The International Bioethics Committee (IBC) of Unesco issued in 2001, a report on the Use of Embryonic Stem cells in Therapeutic research (A. McCall-Smith and M. Revel, rapporteurs) which was adopted by the Intergovernmental Committee (IGC) and by the General Conference of the 170 member States of Unesco. The report establishes that a pluralism of opinions exists, including the opinion to allow donation of supernumerary embryos.
“Every Society has the right and the duty to debate and decide upon ethical issues with which it is confronted…The IBC recognizes that human embryonic stem cell research is a subject on which it is desirable for a debate to occur at national level to identify which position on this issue is to be adopted, including abstaining from this research…Whatever form of research involving embryos is allowed, steps should be taken to ensure that such research be carried out within the framework of a State-sponsored regulatory system that would give due weight to ethical considerations and set up appropriate guidelines. When authorization of donations of supernumerary pre-implantation embryos from IVF treatments for therapeutic embryonic stem cell research is under consideration, particular attention should be given to the dignity and rights of both parental donors of embryos.”
A similar pluralistic position was expressed by the European Group on Ethics in Science and New Technologies (EGE) in November 2000: “The derivation of stem cells from embryonic blastocysts raises the issue of the moral status of the human embryo. In the context of European pluralism, it is up to each Member State to forbid or authorize embryo research. In the latter case, respect for human dignity requires regulation of embryo research and the provision of guarantees against risks of arbitrary experimentation and instrumentalisation of human embryos.” Many European countries have made such bioethical provisions and authorized the use of supernumerary embryos. The ethical evaluation has been particularly intense in the U.K. culminating in approval by the House of Lords. The Commission of the European Communities has extensively reviewed the ethical and legal positions of different countries on the issue of human Embryonic Stem cell research .
The ethical position of individual societies and countries on deriving Stem cells from supernumerary embryos, which puts an end to their capacity to develop, derives from considerations on the moral status of pre-implantation embryos, which is contingent to religious, cultural, philosophical and sometimes constitutional considerations in diverse societies. The magister of the Catholic Church is that the personal status of a human being is acquired at the moment of fertilization of the oocyte; the Holy See does not authorize IVF, among other because it would necessarily create embryos that could not fulfill their potential to become human beings. A fortiori, it condemns ES cell production from blastocysts, or research on such cells derived by third parties, and of course cloning for ES cell research. That a pluralism of opinions exists on the moral status of the embryo is shown by the facts that many countries in the Christian sphere of influence authorize IVF because of its therapeutic value in treatment of infertility. It must be realized that accepting IVF has implied accepting research for improving the IVF reproductive technique, for example the in vitro culture of embryos for about a week in order to select the embryos with the highest chances for implantation, discarding some that are unsuitable. Other research on pre-implantation embryos led to new medical procedures, such as ICSI (sperm injection into oocytes to treat male infertility) or PGD (preimplantation diagnostic to help carriers of severe genetic diseases select embryos not affected by the disease and discard the affected ones). The moral questions on the status of the pre-implantation embryo posed by these IVF procedures are not different from those on ES cell derivation from embryos created for IVF but that are no more destined to implantation, and can be used for medical therapeutic aims aimed at developing methods to save lives of others. In various countries there is nevertheless a pluralism of opinions on whether or not to authorize these individual procedures or research, leading to situations which are not always morally consistent. In France, IVF for procreation is permitted but the derivation of human ES cells is forbidden. The use of human ES cells derived in other countries (e.g. NIH registry) is not permitted but a law is being examined in the fall of 2003 that may approve exceptional use of such human ES cells for live-saving research based on a case-by-case review by a special committee.
Particularly interesting is the situation in Germany, where derivation of human ES cells is not permitted. Germany has an Embryo protection Law (1992) that aims to protect human life from the early embryo stage. Before April 2002, it would have been legally possible to import ES cells, taking advantage of the NIH Registry of 2001. However, it was considered that allowing import might incite other persons working abroad to produce ES cells and thereby destroy embryos, and that this was a criminal act under the German Law. Following intense debates, a Stem Cell Import law was passed in the Bundestag that prohibit the import and use of human Stem Cells, but allows some exceptions if the ES cells were derived under strict bioethical control from spare (supernumerary) embryos and if the ES cell lines were made before 1/1/2002. During the past year, there has been intense interest from the German Science Ministry in the bioethical regulations for ES cell research in Israel, and the possibility to import ES cells from Israeli laboratories, principally that from the Rambam Hospital. A German-Israel symposium organized by GIF, July 8-10, 2002 in Heidelberg was dedicated to an in-depth examination of the ethical and legal positions in Germany and in Israel on ES cell research. This symposium examined the achievements of scientists in the two countries and the possibilities of collaborations in the field of ES cells therapeutic applications. Such international meetings are of utmost importance for a true understanding of the ethical and legal positions taken by different countries on the issue of human ES cell research.
Ethical Opinions on Human ES cell research in Israel:
The Bioethics Committee of the Israel National Academy of Sciences and Humanities has issued in August 2001 a report on The Use of Embryonic Stem cells for Therapeutic Research , circumscribing the ethical questions in the context of Jewish law, as compared to Christian and Moslem religious views.
Judaism places a high value on the religious obligation of treating serious illness even if it requires transgression of religious commands such as the sanctity of Sabbath. This stems from a deep respect of human life and of the human person, as has been restated by many modern Rabbinic decisors (Posekim), starting with Rabbi Moshe Feinstein and Israel Chief Rabbi Goren. The obligation of saving life cannot obviously be done at the expense of another life. However, in Judaism, the obligation of saving the life of a pregnant mother, or preventing grave damage to her health, is viewed as taking precedence over any moral status of the embryo, up to the moment of birth. With respect to the embryo prior to implantation, it is further viewed that there is no potential of the fertilized egg or the blastocyst to initiate pregnancy and develop to birth unless there is a parental decision to do so. These moral stances have been the basis for authorizing IVF and related medical procedures (ICSI, PGD), often with religious consent and with moral consistency. These views on respect of human life and dignity were taken into consideration in the report.
In the report, the specific recommendations on human ES cell research stemming from these moral considerations are in brief that “within the framework of IVF treatments, it will be permissible to donate supernumerary embryos that are no more destined to implantation, and this specifically for the purpose of therapeutic research”. There must be regulations to insure free and informed consent for the donation, respect of human dignity, autonomy and liberty of the donors. The regulations should protect the rights of parents who find embryo research unacceptable. There should be a separation between the medical team responsible for the IVF treatment and the medical and scientific teams involved in ES cell research who receive the donation. Pre-implantation embryos should not be sold or bought; imperatives of justice and equality in the access to the modern medical technologies such as ES cell research must be upheld. Research involving the derivation of stem cells from human embryos should be scrutinized meticulously in order to avoid unethical aims, and the medical applications of human ES cell research must be restricted to well-identified therapeutic aims.
The report supports also the continuation of research into other sources of human stem cells, including so-called adult stem cells, which are often proposed as alternatives to those derived from supernumerary embryos.
Ethical views on cloning to obtain autologous Embryo Stem cells:
As indicated above in the Scientific Medical aspects of ES cell research, the subject of the so-called therapeutical cloning can only be understood as part of the research aimed at producing transplantable tissues which would be compatible (autologous) to the patient in need of the transplant. This procedure is restricted to the use of fertilization by nuclear transfer to obtain blastocysts from which ES cells can be derived (in vitro and without implantation). This is why it is important to replace it in the framework of human ES cell research, in order to avoid confusion in the use of the term “human cloning”. Once the moral principles on which derivation of human ES cell are accepted, there is only the need to consider the particular ethical issues in ES cells from cloning technologies.
In one sense the ethical issues may be considered less severe than with IVF supernumerary embryos. The “cloned” blastocysts that would be used are a priori not destined to implantation, since this is prohibited by the Israel Law “Prohibition of Genetic Intervention 5759-1998 ". There would be no question of ending a potential to life, since this potential would not exist.
Why can it be ethically acceptable to a priori "create" blastocysts by nuclear transfer in order to derive ES cells for therapeutic purposes ?. This is because sperm and intact ova are not used and the process differs from IVF. In IVF, the purpose is procreation justifying the use of sperm which the Jewish law forbids to waste in vain. IVF embryos should not be created a priori for another end than reproduction, other wise the embryo becomes a mean and not an end in itself. Only when some of these embryos cannot be used for initiating a pregnancy, they become supernumerary and such blastocysts may then be donated for therapeutic research. In the case of blastocysts made by nuclear transfer, the reproductive end is not a priori a possibility and using them for ES cell derivation does not imply altering the end for which they are produced.
In the world, one of the major objection that has been raised against “therapeutic cloning” is that if research on producing human blastocysts by nuclear transfer would be authorized, it would not be possible to control whether this research would not be a first step toward reproductive cloning. This is the major objection raised by President G.W. Bush in his February 9, 2002, address asking for a ban an all forms of cloning research. He stated: “Anything beside a total ban on human cloning would be unethical, it would not be implementable, one would not know which embryos is a clone or when such embryos are implanted.”
However, from the ethical point of view, the same objections may be raised against IVF or any medical practice. Medical ethics have allowed to set up strict regulations which ensure control over which sperm is used to fertilize which oocyte, ensure that the embryos produced in vitro are implanted in the mother to whom they belong and in a precisely determined number. This strict control over the medical practice of IVF has shown that it is possible to entrust physicians to act responsibly, (a recent case in the UK where an embryo from another couple was mistakenly born from the wrong mother, has not led to banning IVF). In Israel, utmost care is made; each IVF process is witnessed often with the help of the religious Puah organization. Strict implementation of a ban that would not permit reproductive cloning should be possible while allowing the beneficial research on “therapeutic” cloning to proceed.
The Unesco IBC report on Human ES cells 25 concludes that “nuclear transfer should be used only for therapeutic research”. It, therefore, considers that such research is not in contradiction with the Universal Declaration on the Human Genome and Human Rights and the close against reproductive cloning therein. The IBC reports puts forward the argument that the benefits of the procedure [of nuclear transfer to produce embryonic stem cells] can take precedence over the fears deriving from this “slippery slope” argument [i.e. that one type of scientific activity should be banned because it is close to another not authorized practice]. The role of Bioethics is to define the limits of the permissible and not to ban upfront and completely medical advances that may save lives and alleviate suffering.
The research on human ES cells from blastocysts produced by nuclear transfer holds the highest promises for obtaining transplantable tissues that would not be rejected by the patients. This has led the U.S. National Academy of Sciences in its January 2002 document on Cloning 3 to recommend that: “research on approaches that prevent immune rejection of stem cells and stem cell-derived tissues should be actively pursued. These scientific efforts include the use a number of techniques to manipulate the genetic makeup of stem cells, including somatic cell nuclear transfer.”
Ethical debates are still ongoing in many countries that have authorized human ES cell research. In Europe, most of these countries have or tend to prohibit cloning for ES cells. The European Commission, the Group on Ethics of Science 26 “considers that, at present, the creation of embryos by somatic cell nuclear transfer for research on stem cell therapy would be premature, since there is a wide field of research to be carried out with alternative sources of human stem cells (from spare embryos, foetal tissues and adult stem cells)”. Most of this does not really answer the quest for autologous ES cells. The U.K. is for the moment the only European Member State with a specific law that permits the creation of human embryos by fertilization or by somatic cell nuclear transfer 28. The UK authorized this research in an extension of its Embryology Act that has been approved by the House of Lords. The UK position will be reexamined in a couple of years. In the U.S.A. (see above) the Senate is still considering whether the ban on cloning should include cloning to produce stem cells. In Australia, a recent decision was to support a ban on Reproductive Cloning but not to include Non-reproductive cloning research. As already indicated above, there are pressures to extend the proposed UN International Convention against Reproductive cloning to any research on cloning, even for therapeutical ends, such as ES cells.
Situation of cloning to produce stem cells in Israel
From the legal point of view: the Israel Law “Prohibition of Genetic Intervention 5759-1998 ", while prohibiting the creation of a ‘complete human being’ by reproductive cloning, does not rule out producing cloned embryos that will not be implanted.” This was confirmed by an opinion from the Attorney General Office of the Israel Government, based on the definition of cloning in the text of the law, which specifies that it is “creation of a complete human being”.
The Bioethics Committee of the Israel Academy of Sciences and Humanities in the Recommendations of its August 2001 report 31 “considers it ethically permissible to experiment with new in vitro technologies to produce ES cells, such as reprogramming somatic cell nuclei by transfer into enucleated oocytes (so-called therapeutic cloning without reproductive purposes).” The Committee bases its recommendation on ethical grounds many of which were exposed above, including those related to ES cells from supernumerary IVF embryos. However, the production of cloned blastocysts for ES cell research must be viewed as experimental and be strictly supervised and regulated.
The position of the Bioethics Committee is also based on Jewish Law, as stated in its above quoted report under Halachic Conclusions (p.12, paragraph 4): “The creation of any embryo for such research purposes is prohibited. Nevertheless, the creation of in vitro pre-implantation embryos for research should be allowed if it is probable that this research will help save human life. This includes creating embryos by the cloning technology.” As in the U.K., the opinion in Israel is that the respect for human life and human dignity is not violated by authorizing research that has the potential to alleviate suffering of patients, provided it is carried out under strict bioethical regulations.
The Bioethics Committee of the Israel Academy defines in its report 31 a number of guidelines for the strict monitoring of this research The research and therapeutic applications of nuclear transplantation to produce stem cells can and must be and can be done with complete respect of Human Dignity. The ethical rules for organ transplants are in this sense a model: these are donations and not commodities.
In addition, strict regulations should ensure that the numerous human oocytes needed for cloning research are obtained with respect of the bioethical regulations set up for IVF. A new Israeli Law is being prepared on oocytes donation for reproductive purposes  . This Law does not address the question of oocytes donations for research, or the use of supernumerary and oocytes unfit for IVF in research such as cloning for ES cells. This question should be addressed sometime. In the future, there may also be other methods to obtain cytoplasts (enucleated cells) suitable for research on cloning for ES cell research, such as cytoplasts from existing ES cell lines. Human oocytes could also be produced by maturating in vitro cells from ovary biopsies or producing oocytes from ES cell cultures.
Methods to obtain ES cells that would be more efficient than nuclear transfer could be eventually developed reducing the number of human oocytes needed. Parthenogenesis, for example, is presently under study 
The guidelines on ES cell research proposed by the Israel Academy Bioethics committee 31 are in the process of implementation. The Health Ministry's National Helsinki Committee for Genetic Research in Humans has in January 2003 proceeded along these guidelines in dealing with specific research applications on new ES cell production and on cloning for ES cells.
Impact of the possible International Convention against human cloning on the situation in Israel
The final form of the International Convention, which is now being discussed at the UN, will probably not be known for several years. Several scenarios must be taken into account. If the UN convention is limited to Reproductive Cloning, it will be most likely a ban without time limit. The question will, therefore, arise of whether Israel should change the present legal situation. Based on the ethical and philosophical principles that led to opt for a time-limited moratorium on any medical application of Reproductive Cloning, it would appear justified to continue to have a time limited prohibition. The Israel Law having a built-in periodical review process of the scientific, medical and ethical situation, allows to renew the moratorium as many times as needed. This position can be defended on moral grounds, since practically the effect of the ban is the same whether it is time-limited or not. The difference is that there is no condemnation of an area of Scientific inquiry. If, in a distant future, some important medical applications of the technology will become apparent as a result of animal experimentation, which will also be proven safe and efficient, it is likely that the Internal Convention may also be reexamined.
Another scenario is if the International Convention stipulates a total ban, including cloning for Stem Cells or for other research purposes. In this case, Israel will not be the only country confronted with the dilemma of whether or not to allow the continuation of Non-reproductive cloning research. There will probably be a concerted review of the situation in all countries, such as the UK, where cloning for Stem Cell research is permitted. Much will depend on whether or not the medical promises of cloned Stem Cells will be such that banning the research will appear less ethical than allowing it to proceed. On the diplomatic front, Israel should side with those nations who do not want a total ban on all forms of cloning.
PART III: GENETIC MANIPULATION OF REPRODUCTIVE CELLS
In contrast to the cloning technology, which is practically not possible today for any medical application due to its dangers and likelihood to fail, the genetic manipulation of reproductive cells or germline gene modification appears much more feasible from the practical point of view. The technology has been developed to a point where it is efficient in animals, as shown by the numerous studies on producing “transgenic” animals. Almost every major research center in the world has laboratories where intentional genetic and heritable changes can be made in mice, either addition of a gene or production of a targeted gene deficiency (knock-out). Early on the modifying gene was injected in the pronucleus of a fertilized egg. The main technology used today is to make the genetic change in cultures of ES cells, which are then reintroduced into in vitro fertilized embryos. In animals, it is then possible to screen the mosaic offsprings, for those males and females that transmit the genetic change. Alternatively, it is possible to transfer the nucleus of a genetically modified cell into an enucleated oocyte, thereby obtaining an organism where all cells, including the reproductive gametes, contain the gene alteration. This would be like cloning, but use of embryonic or ES cell nuclei for cloning is more efficient and less problematic than use of an adult somatic cell nucleus. The application of these germline gene modification techniques to humans is feasible but not simple, since screening of mosaic offspring is not possible in humans.
Resnik and Langer  review the different options. The prefered technology would be an ex vivo modification of a cell followed by nuclear fertilization of an enucleated oocyte. In a couple where both male and female are homozygous for a recessive genetic defect, or where one of the two is homozygous for a dominant defect, an IVF embryo could be produced who would necessarily carry the defect. From such embryos, ES cells or other embryonic cells could be derived in vitro, genetically modified to repair the defect or introduce a non-defective gene, and then selected by in vitro culture to ascertain that the defect has been corrected. The nucleus of the cell would be used to fertilize an enucleated oocyte. However, it remains to be demonstrated that such an embryo would develop normally, remembering that until now fertilization by nuclear transfer has not given normal blastocysts that could be implanted. The authors do not favor direct gene injection into the fertilized egg, although the gene insertion could be monitored by taking cells from the 8-16 cell stage for a type of PGD (preimplantation genetic diagnostic). The authors also do not favor the genetic modification of gametes that could be done as a sort of “somatic” gene therapy of gonadal progenitors cells with viral vectors. In brief, germline gene therapy does not appear to be a procedure likely to be applicable soon in human Medicine.
One form of genetic manipulation of reproductive cells has been carried out with some success to overcome infertility due to aging oocytes or to repair a defect in mitochondrial DNA. This technique is named ooplasmic transfer, i.e. injecting in the fertilized egg some cytoplasm from donated young oocytes (containing also mitochondrial DNA which is always maternal) . The oocyte of the infertile mother is indeed modified by the mitochondrial DNA, as the developing embryos and subsequently born children have mitochondrial DNA from the donor of the ooplasm . Nevertheless, since genes of the mitochondrial DNA are similar in all humans, the change has not been considered as germline gene therapy as would a change in chromosomal genes.
Bioethical aspects of germline gene interventions:
As argued by Resnick and Langer 35, germline gene therapy could repair a defective gene causing a grave familial genetic disease, for example Tay-Sachs. Since even in the case of a genetic disease that becomes clinically manifest in the embryo or in the newborn, the genetic manipulation would be done before the disease appears, one should consider this as Preventive medicine and not as therapy. In their view, a preventive medical intervention would be justified even for less life- threatening conditions, including for postponing aging. The limit between preventing a well-recognized pathological condition on the one hand, and using the technique for “enhancement” of some traits that are in the normal range of human variations, becomes then very thin. For some this is the main ethical problem: “Human germline enhancement is very difficult to justify because it raises issues of eugenics, playing ‘God’, perfectionism – i.e. the ideal baby -, social justice, etc.” However, such objections are not specific to germline genetic manipulations, but have been raised against prenatal genetic testing and PGD. The public should be educated to understand that there is no ideal genome, but that the variations in the genome are essential for what makes each individual. The individual decision of parents, after genetic counseling, to give birth or not to give birth to a child with a genetic disease or malformation is not eugenics. Society should never impose genetic selection, which would revive the terrible dangers of eugenics. Enhancing human capabilities should be first and foremost through education and improvement of living conditions. Man is not “playing God”, but a partner in the bettering of the world by Science.
The main ethical issue which distinguishes somatic cell and germline gene therapy is that it is possible to obtain informed consent of a patient for gene therapy on his own body, but it is not possible to obtain this consent from yet unborn generations that would receive the modified gene in case of germ line gene therapy. While prospective parents may have the right to authorize the procedure to cure a genetic disease in an embryo obtained in an IVF treatment, they cannot have the right to decide for all their generations to come. In fact, heritable genetic changes which seem beneficial now might turn out to be detrimental in future generations and under different environmental conditions. This is the major motive to be extremely careful with germline gene therapy, which could lead to “eradicate” what we consider today as disease-causing genes but may protect from other diseases, like the sickle-cell anemia in the heterozygous state protects from paludism.
Gene therapy in non-reproductive cells, i.e. in somatic cells such as blood cells, is still in its infancy in Medicine. It still faces major problems, one revealed in October 2002 being a leukemia caused in a child by the insertion near an oncogene of the retroviral vector used to repair his X-linked immunodeficiency . Would this occur in germline gene therapy, the leukemic condition would become an inheritable disease. There is certainly not sufficient evidence concerning short-term and long-term safety and efficacy of germline gene therapy.
The time-limited moratorium on genetic manipulation of reproductive cells, or germline gene therapy, in the Israel Law 5759-1998 is fully justified and should be maintained. The purpose is not to ban research in this area, which with the progress of Science may become an important tool in Preventive medicine. The purpose of the Law prohibiting genetic manipulations of reproductive cells is to insure that scientists will not rush into using this technology before having a complete understanding of the human genome and of what is at stake when intentionally modifying it.
This review of the scientific state-of-the-art indicates that any potential benefits that cloning technologies may bring to human reproductive medicine, are at the moment overshadowed by the dangers and inefficacy of the method. Nevertheless, it is important to proceed with an in-depth analysis of the bioethical opinions on the perspectives of medical applications of cloning, and to set the limits of what may be permissible in case the scientific obstacles can be overcome. There is a rather large degree of consensus among Israeli bioethicists (philosophers, rabbis and lawyers) on the moral and societal issues raised by reproductive cloning, and these views should be of interest for the world-wide debate, that is unfortunately often one-sided. Similarly, on the questions raised by human embryonic stem cell research, Israeli ethicists have a distinct outlook reflecting the age-old judaic teachings. The primary importance of saving lives and releaving suffering of patients in the jewish tradition, takes precedence over many fears generated by modern genetic and reproductive research. Provided that new technologies are applied for medical indications and in full respect of human rights and human dignity, it is legitimate to explore their beneficial potential. Israel has adopted a balanced Law that on the one hand ensures that no physician or researcher will unduly hasten into premature experiments on reproductive cloning and germline gene manipulations, but on the other hand sends to the public a message that eventual benefits from the advancement of Science in these fields will not be a priori rejected. The Law was for five years (1998-2003) and will most probably be prolonged for another five years, on the basis of the considerations detailed in this report.
 For review: Revel, M. (2000) Ongoing research on mammalian cloning and embryo stem cell technologies: Bioethics of their potential medical applications. Israel Medical Association Journal (IMAJ) 2, July supplement, pp 8-14.
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Participants included from the Foreign Ministry: Mr Alan Baker, head of the Legal Department, Adv. Ady Schonman (who was the Israel delegate to the September 2002 session), Amb. Shabtai Rosenne. From the Health Ministry: Adv. Mira Huebner, Dr Mordechai Halperin. From the Science Ministry: Prof. Hagit Messer-Yaron, Dr Yair Degani. From the Justice Ministry: Adv. Gali Ben-Or. From the Bioethics Committee of the Israel Academy of Sciences and Humanities: Prof. Michel Revel. From the Gertner Institute: Dr Carmel Shalev.
 The text was published at http://www.israel-un.org/committees/sixth/shonman.htm
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 Pontificia Academia Pro Vita: Declaration on the production and the scientific use of human Embryonic Stem cells. 2000.
 The Bioethics Committee is pluridisciplinary and includes ethics philosophers (Prof. Asa Kasher and David Heyd), a Rabbi and physician ( Dr Mordechai Halperin,), jurists (Judge Shoshana Berman and Prof. Amos Shapira), geneticists/bioethicists (Prof. Hermona Soreq, Dr Efrat Levi-Lahad, Prof. Michel Revel, chair) and Academy officers (Prof. Alex Keynan and Dr Yossi Segal).
 see http://www.health.gov.il/units/egg_cont/law.htm
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