HUMAN CLONING: PART 3
Pontifical Academy for Life
Viable alternatives to cloning exist today
Cell therapy — the infusion or grafting of cells in a patient's body to replace those that have failed to function or to integrate those that are missing — is neither a new clinical concept nor a recently-introduced practice. Its archetype is the intravenous blood transfusion carried out successfully after 1818, the year in which James Blundel, the English gynecologist, introduced it as a treatment for post-partum hemorrhage. The first treatment to use cells of a staminal type (unspecialized pluripotent cells capable of self-maintenance in culture and of differentiation into the cell lines that make up tissue and organs), was a transplant of bone-marrow, which contains staminal haematopoietic and mesenchymal elements.
Recent remarkable developments in research on the properties, sources and suitability for engineering of various types of stem cells, have led to the prospect of an extension of cell therapy to the treatment of certain metabolic, muscular, cardiovascular, neurological, neo-plastic and other disorders. Although this goal has not yet been attained, its scientific and clinical importance and the great human and Christian value of every effort to alleviate the sufferings of the sick and offer a realistic prospect of recovery to an increasing number of persons has attracted more and more interest to this field of biomedical research; it has also rapidly become the centre of a considerable investment of public and private funds at both national and international levels.
At the start of the new century that has not only seen the beginning of systematic research laying the biological and clinical foundations for therapy using stem cells or cells derived from them, but also the intense confrontation that the moral implications of these investigations have sparked among experts and in society, the Holy Father recognizes this new frontier of transplant surgery as "a great step forward in science's service to man" and "a valid means of attaining the primary goal of all medicine — the service to human life". However, the Pope also stresses that, "as with all human advancement, this particular field of medical science, for all the hope of health and life it offers to many, also presents certain critical issues that need to be examined in the light of a discerning anthropological and ethical reflection" (Address to the 18th International Congress of the Transplantation Society, 29 August 2000; ORE, 30 August 2000,
Among the critical points that are currently the object of public debate as well as of national laws and projects for international legislation, the matter of the origin of the stem cells to be used for therapy arises. This issue does not only provide for the biologically relevant and ethically important distinction between human stem cells of the embryonic and non-embryonic type (from an aborted fetus, perinatal and postnatal), but must also deals with the possibility — contemplated by certain research programmes — that the former type of cell may be taken from embryos of gametic origin (in vitro fertilization), but removed from embryos obtained for this purpose through cloning.
In the address cited above, John Paul II also notes: "Science itself points to other forms of therapeutic intervention which would not involve cloning or the use of embryonic cells, but rather would make use of stem cells taken from adults. This is the direction that research must follow if it wishes to respect the dignity of each and every human being, even at the embryonic stage" (ibid.). The Pope's instruction, fully accessible to reason, is founded on two cornerstones; the first, which is scientific, allows for the status quaestionis of stem cell research, and recognizes the fundamental role that the creativity of the researcher's investigative intelligence plays in conceiving and closely examining various hypotheses for a solution to the problem of cell therapy.
The second, an ethical kind, admits that "once the moral species of an action prohibited by a universal rule is concretely recognized, the only morally good act is that of obeying the moral law and of refraining from the action which it forbids" (Veritatis Splendor, n. 67). The scientific and moral stature of biomedical researchers is built on these two cornerstones: enthusiastic and tenacious openness to reality, which can reveal unexpected and surprising therapeutic opportunities, and an unfailing respect and love for the life and dignity of every human being, which induces researchers firmly to reject every act that intrinsically is contrary to them.
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Many factors interact at the genetic, biochemical, cellular, hystological, physio-pathological and environmental levels in the epigenetic and homeostatic processes that control the development and health of an organism and permit the restitutio ad integrum of its morphofunctional order. Consequently, scientific research and clinical experimentation have a multitude of conceptual and operational processes to choose from in order to achieve a specific objective, in the case of cell therapy as in others.
Having considered all the aspects of the illness and of the patient that are ascertainable at a given historical moment, the researcher's ingenuity and the clinician's fruitful intuition have always been able to discover different or new possible solutions for previously unsolved or under-treated problems. When faced with a wide range of possible paths for investigation, all of which converge in the same end, the expert and doctor — who are called to choose as the object of their clinical activity and research what is "in conformity with the good of the person with respect for the goods morally relevant for him" (Veritatis Splendor, n. 78) — will have to exclude, in the first place, those paths of investigation that demand morally illicit acts.
Such a decision takes the form of a rational determination of morality in the conduct of researchers and clinicians. "Without recognizing the legitimacy and need for such rational determinations at a practical level, it would be impossible to agree on any legislation for scientific research, worked out in view of its content and binding without exception, and this would be to the detriment of the common good and of respect for the fundamental rights of every human being, starting with the right to life" (J. Vial Correa and E. Sgreccia, Cellule Staminale Autologhe e Trasferimento di Nucleo, in L'Osservatore Romano, 5 January 2001, p. 6).
Yet some authors propose a revision of the ethics of biomedical research, based on a different relationship between the researcher as a person and his actions. They refer to the research scientist's "fundamental freedom" that they believe is more radical than freedom of choice with regard to specific acts; without considering this it would be impossible to comprehend or evaluate the conduct of researchers.
This "basic option" or "radical decision", which is transcendental, would describe the commitment of both researcher and doctor with regard to a good, recognized as "superior", that deserves unconditional dedication and is often identified as a "good of progress" (an increase in scientific knowledge and in its diagnostic, therapeutic and preventative applications). It is also identified as "a good of humanity" (the alleviation of suffering by fighting disease, and the improvement of the expectations and "quality of life"). The specific acts of researchers that derive from this option would be merely temporary attempts to express it. Their immediate object would be a "categorical good", which — because of its partial nature — could not determine the morality of the researcher as a person, even if it were only through the realizing or rejecting of these endeavours or projects that every expert could express his fundamental ethical choice.
Thus, a separation is outlined in certain biomedical circles — and more generally, in certain social sectors that promote and direct these cultural trends — between the two levels of morality: the goodness or malice of the researcher and doctor on the one hand, which would depend on the intention motivating them and on their basic option with regard to the engagement of "a service to science and humanity"; and the rectitude or injustice of individual experimental acts, determined by the calculation of proportionality between the good and evil, "pre-moral" (or "physical"), inherent in or consequent to the actions accomplished.
Given the contingency of the goods connected with a research project or a clinical protocol, it would be impossible to establish absolute moral norms at the categorical level which forbid specific interventions involving, for example, the production, manipulation and suppression of an embryo in vitro.
Such an ethic for research is based on an anthropology conditioned by a spiritualist dualism that considers the person as primarily identified with his
"absolute" freedom which is self-determined or disconnected from any reference to the corporal, historical or social dimension of his practice, whereas human nature is seen as something sub- or pre-personal that does not constitute a normative reference for the procedure. In fact, it is impossible to separate the person from his acts (cf. K. Wojtyla, Persona e Atto, Libreria Editrice Vaticana, 1980, pp. 131-174), nor can a person's morality be disassociated from the quality of his actions: "Idem sunt actus morales et actus humani?" (St Thomas Aquinas, Summa Theologiae, I-II, q. 1, a. 3).
The commitment of biomedical researchers to "the progress of science" that fulfils their professional vocation in the service of "the good of humanity" (or, more specifically, of humanity suffering due to sickness), "to the extent that it is distinct from a generic intention and hence one not yet determined in such a way that freedom is obligated, is always brought into play through conscious and free decisions", and "judgments about [their] morality cannot be made without taking into consideration whether or not the deliberate choice of a specific kind of behaviour is in conformity with the dignity and integral vocation of the human person" (Veritatis Splendor, n. 67).
The negative moral precepts that prohibit semper et pro semper "the direct and voluntary killing of an innocent human being", based upon "that unwritten law which man, in the light of reason, finds in his own heart (cf. Rom 2:14-15)" (John Paul II, Evangelium Vitae, n. 57), do not leave room in any morally acceptable way for the "creativity" of any contrary determination whatsoever (cf. Veritatis Splendor, n. 67).
Instead, they demand a "scientific creativity" that can identify new sources of stem cells — equipped with sufficient potential for reproduction and differentiation, and have the capacity to repair tissue — that will pave the way to cell therapy without recourse to the creation and destruction of human embryos.
Some people's argument, in the attempt to justify the process of human cloning as a way of procuring embryonic stem cells to be cultured, expanded and differentiated in vitro, appeals to three biological applications: immunology, the potential for differentiation and nuclear reprogramming. These fundamental applications are crucial to the success of a therapeutic approach that uses stem cells; but, on close examination, none of them is cogent. Indeed, for each application, a reasonable and realistic alternative to cloning exists whose scientific and clinical value is documented, also and increasingly, by data published in the most recent top-level international literature in this sector.
The immunological application originated in the experience of transplant clinics. Tissue or organ transplantation, when the donor and recipient are not genetically compatible (as in the case of those who are not close blood-relations) generally results in rejection of the graft; immuno-suppressive treatment is required to prevent this. In the case of cell therapy, the immunological barriers "are identical to those of the allografts of tissue from conventional sources" (J.A. Bradley et al., Nature Reviews Immunology 2002, 2: 859-871, p. 861).
The rejection is triggered by the allelomorphic differences between the donor and the recipient in polymorphic loci that give rise to histocompatible antigenes (groups ABO, HLA/MHC and mHC). The hypothesis, prematurely proposed by some, that embryonic stem cells possess an "immunological privilege" that allows them to be tolerated by the recipient, was also doomed to failure because of the discovery that they also express the protein MHC class I (M. Drukker et al., Proceedings of the National Academy of Sciences USA 2002, 99: 9864-9869). The nuclear transfer of a somatic cell from a patient who is a candidate for cell therapy to an oocite whose nucleus has previously been removed (somatic cell nuclear transfer), and the activation of the development process would make it possible to generate a cloned human embryo with a nuclear genome identical to that of the patient whose stem cells, removed at the stage of blastocyst, would be compatible with those of the recipient, with the possible sole exception of the mytochondrial genome.
However, at least in laboratory animals, this heteroplasm does not seem to be an obstacle to the compatibility required by a graft (R.P. Lanza et al., Nature Biotechnology 2002, 20: 689696).
The immunological problem that conditions the success of every possible cell therapy can be addressed by other strategies appearing today on the horizons of stem cell research.
The first is the creation of stem cell "banks" that collect and preserve the donations of a wide range of genetically different subjects, from time to time seeking an immunological match between donor and recipient, as the procedure for organ and tissue transplantation currently requires. Immuno-suppressive interventions would make it possible to overcome the immunological barrier that remains, in this case too, because of an imperfect HLA identity between the graft and the host. The number of immuno-suppressive agents is increasing, and in recent years the survival rate of grafts has increased considerably, although the risks connected with a non-specific depression of the immune response (for example, the onset of opportunist infections) remain.
The genetic engineering of stem cells is a second possible way to get round the immunological obstacle. One possibility is to obtain the cellular phenotype of a "universal donor" by means of the deficiency of expression of the MHC system (class I and class II) by the deletion or modification of the corresponding genes or those that regulate the transcription.
Another approach should also be mentioned: this foresees the onset of tolerance to the graft (the absence of a specific immunological reaction) in the patient awaiting cell therapy, for example, by inducting a mixed haematopoietic chimerism. As well as in rodent models, the latter process has also found a clinical application in kidney transplants (M.T. Millan et al., Transplantation 2002, 73: 1386-1391).
Lastly, the most direct and reliable way to overcome the immunological obstacle to cell therapy is the use of (autologous) stem cells from the same patient, collected in the perinatal (from umbilical cord blood) or postnatal (from somatic tissue) periods, and brought to differentiation or transdifferentiation in vitro or in vivo in a cell line required by the treatment of the pathology afflicting the patient.
One method, that of the autograft, has already been successfully tested in the sectors of blood, bone marrow and skin, but it is neither quick nor easy to achieve as all clinically well-established cell therapy should be. In addition to perfect tolerability, the process would also avoid the possible transmission of infections. This prospect faces the second application proposed by those who champion cloning for cell therapy: the potential for differentiation.
Different lines of stem cells, even if they have a common genetic heritage, possess different potentials for replication (self-renewal and expansion in vitro), epigenesis (differentiation into different cell lines) and regeneration (functional reconstruction invivo of a tissue) (I.L. Weisman, Science 2000, 287: 1442-1446; C.M. Verfaille, Trends in Cell Biology 2002, 12: 502-508). In the human scale of epigenetic potential, the zygote and blastomeres of the embryo in its very earliest phases of segmentation occupy first place; they are the only human cells that can independently lead to an organism complete with all its tissues under specific conditions.
It is possible to isolate from the internal cellular mass of the human embryo at the blastocyst stage certain stem cells with less epigenetic potential (pluripotent), but that can still differentiate to form a mature lineage of cells that belongs to all three germ layers (ectoderm, mesoderm, endoderm).
Embryonic stem cells have also attracted attention because of their high replicative potential (as many as 300-400 continuous cell divisions in culture). Only very recently, however, has it been possible to demonstrate that one type of differentiated cell (dopaminergic neuron) that comes from the culture of rat stem cells has a regenerative potential for Parkinson's Disease in the animal model (J.-H. Kim et al., Nature 2002, 418: 50-56), whereas it has not yet been proven that other specialized cells derived from embryonic stem cells are functionally able to reconstruct a tissue in vivo (N. Lumelsky et al., Science 2001, 292: 1389-1394; M. Kyba et al., Cell 2002, 109: 29-37).
"It is not surprising", observed Stuart H. Orkin and Sean J. Morrison, "that cells generated in vitro are not equivalent to those that are formed in vivo, considering the wide cellular interactions and the 'education' [of cells] that takes place during an organism's development" (Nature 2002, 418: 25-27, p. 25).
Moreover, there is stronger evidence from experimentation on animals that embryonic stem cells, precisely by virtue of their elevated replicative and epigenetic potential, give way after the graft to an uncontrolled neoplasmic proliferation, as has recently been soundly documented in the case of teratomas (S. Wakitani et al., Rheumatology 2003, 42: 162-165). The rigorous exclusion of the presence of residues of non-differentiated cells of an embryonic staminal type in cultures destined for cell therapy, indispensable for the patient's safety, is a matter that cannot be underestimated.
These and other experimental considerations lead one to believe that the choice of cloning as a biotechnological strategy for cell therapy is a therapeutic approach containing serious difficulties and contraindications, albeit, merely biological and clinical. The insistence on this approach seems even more unjustifiable if one considers that the alternative recourse to autologous stem cells of perinatal and postnatal origin, dictated solely by the ethical objections of a consistent number of citizens, is not a choice with any less scientific value or fewer therapeutic prospects; its plausibility and convenience can be found in the attentive and objective consideration of the recent results of research in this sector.
Other than isolating new stem cell lines and lines of progenitor cells from fetal, umbilical cord and adult tissue, their characterization and that of the lines already known testifies to or confirms the remarkable and surprising flexibility of a variety of them (C.M. Verfaille, op. cit.; S.J. Forbes et al., Clinical Science 2002, 103: 355-369; C.V. Joshi and T. Enver, Current Opinion in Cell Biology 2002, 14: 749-755): in addition to the well-known haematopoietic and mesenchymal bone marrow stem cells, whose wide spectrum of differentiation and capacity for regeneration are amply documented (Y. Jlang et al., Nature 2002, 418: 41-49; R. Poulson et al., Journal of Pathology 2002, 197: 441-456; D. Orlic et al., Pediatric Transplantation 2003, 7 [3 Suppl.]: 86-88), those of umbilical cord blood have shown their capacity for differentiation into cells of the neural lineage (J.R. Sanchez-Ramos, Journal of Neuroscience Research 2002, 69: 880-893), of liver cells (S. Kakinuma et al., Stem Cells 2003, 21: 217-227) and osteoblasts (C. Rosada et al., Calcified Tissue International 2003, 72: 135-142).
Also, the stem cells of the skeletal muscle (H. Geiger et al., Blood 2002, 100: 721-723; A. Asakura, Trends in Cardiovascular Medicine 2003, 13: 123-128), of the nervous system (A. Vescovi et al., Cells Tissues Organs 2002, 171: 64-76; R. Galli et al., Circulation Research 2003, 92: 598-608) and of the skin (J.G. Toma, Nature Cell Biology 2001, 3: 778784) display a multi-differentiational capacity whose potential for tissue repair is waiting to be investigated.
Recently, S. Pluchino and his associates (Nature 2003, 422: 688-694) have elegantly demonstrated the therapeutic capacity of cultures of neural stem cells taken from adult animals, by means of intrathecal or intravenous injection, in a rat model chronically affected with multiple sclerosis.
Lastly, certain specialists, while rejecting the hypothesis of a cell therapy based on the so-called "therapeutic" cloning, claim that a temporary phase of experimentation with somatic cell nuclear transfer on human beings is justified by the need to acquire information on cytological factors that permit nuclear reprogramming, knowledge of which, they say, is crucial for the effective differentiation, dedifferentiation or transdifferentiation in vitro of stem cells from adult tissue.
The application of nuclear reprogramming is motivated by the attempt in principle, biologically plausible and ethically acceptable, to obtain multipotent or pluripotent non-embryonic stem cells, starting with stem cells or pre-differentiated cells from adult tissue, through their culture in cytoplasmatic conditions which have been made to resemble in certain aspects the ooplasmic environment. This experimental project is not the same as the reprogramming of the nucleus in an oocite (W. Shi et al., Differentiation 2003, 71: 91-113), nor the fusion of a somatic stem cell with an embryonic stem cell (M. Tada et al., Current Biology 2001, 11: 1553-1558; Q. L. Ying et al., Nature 2002, 416: 545-548), both of which raise serious issues of grave moral importance: the first, because of the development of a precocious embryonic type (segmentation, compaction, cavitation), which the oocite containing the nucleus would encounter; the second, in virtue of the use of stem cells illegally obtained through the destruction of a human embryo.
Nevertheless, the identification of the ooplasmatic factors that facilitate nuclear reprogramming can also occur experimentally in an animal model for somatic cell nuclear transfer, and can be reapplied indirectly (through the analysis of structural homology) to the human being.
Furthermore, a certain initial success has been achieved in the attempt to induce nuclear reprogramming that produces a cellular phenotype by fusion with a differentiated cell (A. Medvinsky and A. Smith, Nature 2003, 422: 823-825) or with extracts from a cell also already differentiated (A.M. Håkelien et al., Nature Biotechnology 2002, 20: 460-466).
It would therefore seem that recourse to human cloning in order to learn how to reprogramme the nuclei of cells destined for therapy is not indispensable.
In the light of these considerations, the exclusion of human cloning from research in cell therapy is a morally reasonable, scientifically acceptable and socially responsible decision.
"In presenting the moral orientations dictated by natural reason, the Church is convinced that she offers a precious service to scientific research, doing her utmost for the true good of the human person. In this perspective, she recalls that, not only the aims, but also the methods and means of research must always respect the dignity of every human being, at every stage of his development and in every phase of experimentation" (John Paul II, Address to Members of the Pontifical Academy for Life, 24 February 2003, n. 4; ORE, 5 March 2003, p. 4).
Weekly Edition in English
24 September 2003, page 9
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