Between the different pontifical academies which have been created along the centuries in Rome, "in the seat of Peter", following the will of many different Popes, the more recent one is the Pontifical Academy for life, created in 1994 by John Paul II. The various Academies which have been created that way "in the seat of Peter", are a testimony of the interest of the Holy See in science, and, accordingly, of the interest that the Catholic Church has been showing towards scientific research and scientists.
Why is the Church interested in Science, in scientific work and in scientists?
L'abbé Robert Lenoble (1902-1959), a priest who was keenly interested in philosophy, science of nature, and the relationship between religion and science, left us, unfortunately incomplete, a very rich and interesting book entitled "Histoire del'idée de nature". This book, which deals with the way people, along the centuries, have considerated nature, shows how the various conceptions that people have had about nature, in the different periods of history, have inhibited, precluded, or, at the contrary, favored this scientific investigation.
The idea developed by father Lenoble is the following: in his confrontation with the unknown, often threatening or dangerous world of "nature", man has looked for ways of controlling this nature, or at least been protected from the worse. So, he indwelt spirits, deities or gods in all his surroundings, - especially sources, river, trees, rocks or mountains -. That way he felt that he could make "deals" with these unknown powers of nature, from now on given names, through various ways of "exchanges", mainly sacrifices. This gave man the reassuring feeling that he could in some way control nature, or, at least, get some favor, time to times, from these deities, observing the rules of these "deals". In these ways of looking on the material world, "nature" is generally presented as friendly as long as you respect it, or as long as you deal with it through the practice of specific, codified rite-offerings - , but it is felt better not to investigate too much into that nature. This "deification" or "mythicizing" of nature, in animism, paganism, spiritism, magic, or pantheism, does not favor science.
Then came monotheism, and with it the anthropological, and philosophical concept of creation. This brought a revolution in the way man was conceiving nature: monotheism reduces nature to what it is: created matter, with no gods in it. Monotheism, in catching gods and deities out of nature, opened nature to investigation. But true monotheism was rare. Christianity was different. It was truly monotheist. Catching all gods out of the springs, rivers, fountains, trees or animals, cutting sacred trees and deified poles, putting in pieces gods' statues, and pulling down temples, christianity declared that all what surrounds us is created and therefore not sacred. The christian man has no way to make deals with the One God. He has no power on God. He can only listen to the word of God, and speak with this God that he learns to worship and love as Father. In turn, the One God entrust man with the care of the created world, makes him "steward" of this world, with the task to "cultivate" it, to explore it and to make this world a source of good. Demythicizing nature, monotheist christianity opened up widely the door for the exploration of nature, that is for science.
But opening up a door is not enough. You have to invite people to pass through it and enter. Even when and where strict monotheism became a reality - the faith of the hebrew people after the exile, Islam - true science did not come. It was not a granted consequence of monotheism. Something more was needed.
This "something more " came with christianity, starting from the middle ages as soon as the conditions of life became better. Why christianity? This question brings us to the special relationship that exists between the Church and science.
The teaching of Christ invites men to develop the capacities - the talents" - that they receive from God, toward all forms of "wisdom" - and "science" has a large part in wisdom - in order that these talents bring fruit, and that way bear, in man and through man, glory to God from which come all goodness. The Church has a keen interest in the "ratio" of man, his reason, his wisdom, seen as a spark of the divinity inserted in our mortal flesh, our participation in the divinity. And the Church, although it recognizes the legitimate autonomy of science, will always be keenly interested in the development of Sciences by men, as expression of the inner call of man to fulfill his vocation to knowledge and truth on his way toward the Father.
Far from preventing the medieval man to explore his surroundings, christianity gave this man the necessary freedom for inquiring in nature. Contrary to all what is currently said, the long period of the Middle Ages was not a time of "scientific darkness". But everything had to start almost from zero after the fall of the Roman empire and the first centuries od depopulation, anarchy, violence and misery. The support that christianity gave to the onset of scientific inquiry started with the creation of the first universities, staffed by members of the religious orders who had the education and the means to conduct scientific investigation. These universities first taught their students how to use their reason to get to knowledge. They blossomed in the golden age of the XIIIth century. The most famous scholars were also priests, including Nicolaus Copernicus, Robert Grossetete, Roger Bacon, Albertus Magnus. Robert Grossetete (1170-1253) was a theologian who founded the tradition of scientific thought in medieval Oxford. He accurately predicted tides, comets, the light spectrum of rainbows. Roger Bacon (1214-1294) a franciscan friar and a philosopher, who studied under Grossetete, placed considerable emphasis on the study of nature through empirical methods. Father John Peckham (12230-1292) did complex celestial tables and improved the mechanical clock. Nicolaus Copernicus (1473-1543) published his heliocentric theory without encountering other opposition than that of some protestants. In fact Pope Clement VII was so pleased by the explanation of Copernicus system by his secretary that he gave him a valuable present. Galileo (1564-1627), who defended the Copernicus system against the geocentric view of the universe, had trouble with some philosophers and clerics mainly because of his strong and ungrateful character. Copernicus himself had never been attacked for his theory. Denounced to the roman inquisition in 1615, he was cleared of any offence, but heliocentrism was condemned. Tried by the inquisition a second time in 1632 because he had not kept his promise to abandon his support of the heliocentrism, Galileo was forced to recant and spent the rest of his life under house arrest. But Galileo was never imprisoned nor tortured. He spent his brief "incarceration" time either in the residence of the Florentine's ambassador of in the Papal Palace, where he has his own chief and wine tester. Pope Urban VIII (1623-1644), the Pope during Galileo's arrest, honored Galileo in 1624, and Pope Paul V 81605-1621) arranged a special celebration for Galileo in 1610. Benedict XIV (1740-1758) gave finally his imprimatur to all of Galileo's work.
In fact, contrary to what is generally said about the "obscurantism" of the Church at the time of Renaissance, the Popes of this period were very opened to all what the new times were bringing, in term of arts certainly, but also in terms of science. During Galileo's time, the Jesuits had a highly respected group of astronomers and scientists in Rome. In addition, many notable scientists received encouragement and funding from the Church and from individual Church officials. It is precisely at the time of the Galileo's controversy, in August 17 1603, that the Pontifical Academy for Sciences was founded, in Rome, under the patronage of Pope Clement VIII, by the young learned Roman Prince Federico Cesi, who had just reached the age of eighteen. Cesi was a botanist and a naturalist. Three other young men took part in the initiative: Giovanni Heck, a Dutch physician aged twenty-seven, Francesco Stelluti di Fabriano, and Anastasio de Filiis de Terni. The leader of this Academy was none other than Galileo Galilei. Thus it was that the first Academy dedicated to sciences came into being, and it took its place at the side of other academies - of literature, history, philosophy and art - which had arisen in the humanistic climate of the Renaissance. This Academy was given the name of "Linceorum Academia", the "Academy of Lynxes". The example of Cesi was followed some years later in other countries - the Royal Society was created in London in 1662, and the Academie des Sciences was established in France in 1666. This foundation of the first Academy dei Lincei, with the encouragement of the Pope, proved beyond discussion that the Pope of that time were truly "Renaissance men", opened to all intellectual and technical developments of their time and willing to get well informed about all scientific novelties and discoveries.
From the outset, this academy had its up and downs. A few years after its foundation it was strongly obstructed by Cesi's father, the Duke of Acquasparta, who believed that all was not clear in its activities. After the death of Federico's father, the academy knew a new development. Renowned scholars such as Galileo Galilei, Giovani Battista della Porta, Fabio Colonna, and Cassiano del Pozzo joined its ranks, enabling the Academy to progress. The religious character of the Academy cannot be overlooked. It was placed under the protection of St John the Evangelist who was often portrayed in the miniatures with and eagle and a lynx, symbols of sight and reason. Nature was seen non only as a subject of study but also of contemplation. Among the practices of spiritual piety of the members there was the reciting of the liturgical office of the Blessed Virgin Mary and the Davidic Psalter.
After Cesi's death the activities of the Academy diminished to such an extent as to bring about its closure. The first attempt to bring back the "Lincei" into existence took place in 1745 in Rimini, as a result of the efforts of a group of scientists belonging to the circle made up of Giovanni Paolo Simone Bianchi, Stefano Galli and Giuseppe Garampi. But the new academy had a very short life. The attempt at refoundation made by Padre Feliciano Scarpellini (1762-1840) in Rome at the beginning of the nineteenth century met with greater success. Then the authorities of the Papal States took new practical initiatives to refound the Academy during the first half of the nineteenth century in response to the wished of Pope Pius VII (1800-1823) and Leo XII (1823- 1829), with the allocation of the second floor of Palazzo Sanatorio in Campidoglio to the Academy as its headquarters. But it was in 1847 that Pope Pius IX officially renewed the Academy with the name of "Accademia Pontificia dei Nuovi Lincei"(The Pontifical Academy of the New Lynxes). Famous astronomers and priest became members of the academy, such as Francesco de Vico and Angelo Secchi. In 1870, following the fall of the independent Papal States and the unification of the Kingdom of Italy, the Academy divided into two different institutions: the "Reale Accademia dei Lincei", which later became the present Accademia Nazionale dei Lincei, and the "Accademia Pontificia dei Nuovi Lincei" which was transferred to the Casina Pio IV villa in the Vatican Gardens.
Pope Pius XI renewed the institution on October 28 1936 and gave it its present name, with new statutes. These were subsequently updated by Paul VI in 1976 and by John Paul II in 1986. This Academy, along its centuries of life, work and studies, has become a kind of a symbol of the interest of the Church to science and to scientists. Since 1936 the Pontifical Academy of Sciences has been concerned with investigating specific scientific subjects belonging to individual disciplines and with the promotion of interdisciplinary co-operation. It has progressively increased the number of its Academicians and the International Character of its membership.
During its various decades of activity the Pontifical Academy of Sciences has had a number of Nobel Prize winners among its members, many of whom were appointed Academicians before they received this prestigious award. Among these should be listed: Lord Ernest Rutherford (Nobel Prize for Physics, 1908), Guglielmo Marconi (Physics, 1909), Alexis Carrel (Physiology, 1912), Max von Laue (Physics, 1914), Max Planck (Physics, 1918), Niels Bohr (Physics, 1922), Werner Heisenberg (Physics, 1932), Paul Dirac (Physics, 1933), Erwin Shroedinger (Physics, 1933), Sir Alexander Fleming (Physiology, 1945), Chen Ning Yang (Physics, 1957), Rudolf L. Mössbauer (Physics, 1961), Max F. Perutz (Chemistry, 1962), Johyn Eccles (Physiology, 1963), Charles H Townes (Physics, 1964), Manfred Eigen and George Porter (Chemistry 1967), Har Gobind Khorana and Marshall W Nirenberg (Physiology, 1968). Recent Nobel Price Winners who have also been or are presently Academicians may also be listed: Christian de Duve (Physiology, 1974), Werner Aber and George E.Palade (Physiology, 1974), David Baltimore (Physiology, 1975), Aage Bohr (Physics, 1975), Abdus Salam (Physics, 1979), Paul Berg (Chemistry, 1980), Kai Siegbahn (Physics, 1981), Sune Bergström (Physiology, 1986), John C. Plyani (Chemistry, 1986), Jean-Marie Lehn (Chemistry, 1987), Joseph E. Murray (Physiology, 1990), Gary S. Becker (Economics, 1992), Paul J. Crutzen (Chemistry, 1995), Claude Cohen-Tannoudji (Physics, 1997), and Ahmed H.Zewail (Chemistry, 1999).
II - THE PONTIFICAL ACADEMY FOR LIFE
A - HISTORY
Speaking about the prestigious Pontifical Academy for Sciences, we come to our present Pontifical Academy for Life, which is more younger than its older sister, and don't have yet centuries of hard work, studies and competence behind it. But it has certainly something to offer to the Church, and has already some good achievements.
To understand the reasons which brought the foundation of the Academy, we have to go back to the personality of Professeur Jerome Lejeune, the lay founder of the Academy.
Professor Jerome Lejeune, genetician, had been the first to demonstrate a link between a human birth defect with delayed mental development - the Down syndrome - and an anomaly in the karyotype of the babies affected with the syndrome - trisomy 21. This discovery of the trisomy 21 was a gigantic path forward in the field of chromosomic - and, afterward, genetic, diseases. Professor Lejeune became immediately famous and his name internationally know. In 1962 he was named expert in human genetics in WHO. In 1963 he received a prestigious award from President John Fitzgerald Kennedy for his various discoveries. And in 1964 he was nominated director of the french Centre National de la Recherche scientifique, and given the first chair of fundamental genetics at the Faculté de Médecine de l'Université de Paris. Meanwhile Prof. Jérôme Lejeune was very much involved both in genetic research, accumulating discoveries and publications. As a physician and pediatrician, he had the care of trisomic babies and children. Then came the year 1970 with, in France, the adoption by the Parliament of a new law which allowed the voluntary abortion of fetuses found with defects at prenatal diagnosis. Thus Professor Lejeune found with bitterness that this technique of prenatal diagnosis which he had helped to develop, which permitted his main discoveries on chromosomic diseases, and which gave some hope for the possible prenatal treatment of fetuses with defects, had turned out to be used to suppress human life - and, in the first line, the lives of these babies he was caring for, the trisomic babies. That was the starting point of the second part of Professor Lejeune's life, dedicated to the defense of human life. From 1970 onward, while continuing his research on chromosomic diseases, Professor Lejeune intervened in courts, meetings, articles, to defend early human life. This cost him the Nobel prize, and gave him strong enemies all over the world, but Professor Lejeune never gave up this new mission. In 1974 Pope Paul VI named him a member of the Pontifical Academy of sciences, and at the Pontifical Council for health.
Professor Lejeune was very active in the Pontifical Academy of sciences, which pleased him as a place of encounter with famous scientists, member of the academy, who were not catholics, not even christians, but were very competent in their field. But he also found that the Pontifical Academy of Sciences was not very interested with the problems of the beginning of human life, especially because these problems had become sources of political, philosophical and medical conflict. So, in 1992, at the occasion of a private audience he had with Pope John Paul II, Professor Lejeune told the Pope about his idea of the creation of a Papal institute which would be engaged in the defense and promotion of human life. The Holy Father answered him that this was exactly what he wanted to propose to Professor Lejeune. Thus it came that Cardinal F.Angelini, President of the Pontifical Council for Health, in answer to the request of Prof.Lejeune and of Pope John Paul II, proposed the creation of a new Pontifical Academy, which would be dedicated to the defense of human life. On february 11 1994 was published the Motu Proprio "Vitae Mysterium" which instituted the Pontifical Academy for Life. The Motu Proprio gave its mission to the new institution, which was to be dedicated to "study, information and formation on the principal problems of biomedicine and law, relative to the promotion and defense of life, above all in the direct relation that they have with Christian morality and the directives of the Church's Magisterium". Cardinal Angelini brought to Professeur Lejeune, in Paris, the message nominating him President of the new institution. But Professor Lejeune was already gravely ill. He died April 3 1994.
The project of Professor Lejeune, Pope John Paul II and Cardinal Angelini did not end with the death of Professor Lejeune. In fact, it started from then on, and the Pontifical Academy for Life is well and alive 18 years after its creation. The first president of the Academy was a scientist. Juan de Dios Vial Correa. In 2005 Monsignor Elio Sgreccia, bioethician, creator of the bioethics institute at the University of the Sacred Heart in Rome, became its second president. He was succeeded by Monsignor Salvatore Fisichella, who left the presidency to Monsignor Ignacio Carrasco de Paula, upon his nomination as President of the newly created Pontifical Council for the New Evangelization.
B - STATUTES
The Academy is considered as an autonomous entity. It is not part of the Roman Curia, because it is not a congregation nor a Council and has no direct responsibility at the pastoral or magisterial level. However, the Academy is integrated within the official systems of reflection and study of the Holy See: it is linked to the Pontifical Council for Pastoral Assistance to the healthcare workers, and to other dicasteries of the Roman Curia, especially the Congregation for the Doctrine of the Faith, and the Secretary of State. It is responsible for the reflection upon, the development and the promotion of the doctrine of the Church on biomedicine, especially these questions which are relevant to the defense of human life.
The Academy has a President, a Chancellor, an organizational secretary, and a governing council of six members who deliberate two times a year on the general activities of the institution. Its central office, which is the executive body of the Presidency, is divided in two sections, scientific on one part, and technical and administrative on the other part. The Academy has seventy members named by the Pope. These members can be honorary, ordinary or corresponding (these ultimate being named for five years, renewable). There are at the present 46 ordinary members, 19 honorary members, and 74 corresponding members. These members are chosen from the different continents. They are mainly lay people, but some are from the clergy and some are religious. They represent different branches of biomedical sciences, but and are also coming from fields in relation with bioethics and biomedicine, such as pharmacy, law, university teaching, philosophers, religious orders involved in the care of patients. Some are well known authors in bioethics, others are directors of Institutes of bioethics, other are involved in clinical ethics, other are part of governmental departments on health of biomedical research. The main characteristics of all these members are their expertise in their field, their competence, and their diversity. Membership to the catholic Church is not a condition for members' nomination, but they are requested to be in agreement with the teaching of the catholic Church on the defense and promotion of human life. Because all these members are so different in their competencies and in what they are doing, there is not a prevalent socio-professional trend in the academy. What is lacking in the academy is perhaps a stronger representation of emerging countries: there are only four members from subsaharian Africa, 1 from Egypt, 2 from India, 1 from Bangladesh, 1 from Pakistan, one from the Philippines, three from Japan, two from South Korea, 5 from Australia, 15 from the United States, 25 from Latin America, 73 from Europe.
C - ACADEMIC WORKS AND ACHIEVEMENTS
The members of the Academy meet once a year in the "General Assembly". At the occasion of this general assembly, the academy generally holds a Congress, open to public. These Congresses have had a large variety of topics, reflecting the various socio professional condition of the members. During this meeting, various rapporteurs are presenting the different aspects of the chosen theme, and academicians discuss and comments these presentations. They also present their own communications, in relation with the theme chosen for the meeting. The proceedings of these meetings are published afterwards, in a book which can be obtained in libraries. These proceedings constitute a precious source of information and documentation for universities and centers of bioethics. The titles of these books show the great diversity of the themes which have been treated by the assembly: for example: "Identity and statute of Human Embryo"(Febr. 1997), "Human Genome, Human Person and the Sociey of the Future"(febr. 1998), "The dignity of the Dying person"( febr. 1999), "Biotecnologie Animali e Vegetali: Nuove Frontiere e Nuove Responsabilità"(1999), "Evangelium Vitae, Five Years of Confrontation with the Society"(Febr.2000), "The culture of life: Foundations and Dimensions"(March 2001), "The nature and Dignity of the Human Person as the Foundation of the Right to Life. The Challenges of the Contemporary Cultural Context" (febr.2002), "Ethics of Biomedical Research. In a Christian Vision"(febr. 2003). "Sexual Abuse in the Catholic Church. Scientific and Legal Perspectives"(April 2003), "The Dignity of Human Procreation and Reproductive Technologies: Anthropological and Ethical Aspects"(febr.2004), "Quality of Life and Ethics of Health"(febr.2005), "The Human Embryo Before Implantation. Scientific Aspects and Bioethical Considerations"(March 2007), which has been published also as a short synthesis, freely distributed, with the same title, "Christian conscience in Support of the Right to Life"(febr.2007), "Alongside the incurable sick and dying person: ethical and practical aspects"(febr. 2008), "The New Frontiers of Genetics and the Risk of Eugenics"(feb.2009), "Bioetica e legge naturale"(2010).
More recently, the activity of the Pontifical Academy for Life has taken a new direction, with the constitution of groups of study on three topics: umbilical stem cells blood banks, post abortion syndrome, and help to infertility. This why a seminar was organized this year on this later theme to present the ways modern medicine and surgery can help infertile couples to recover a fertility and have children by their own, without going to the substitution act of the in vitro fertilization techniques.
Besides its annual publications of the conferences delivered in congresses, the Academy has also published some short documents, which represent the outcome of studies made by groups of experts, in link with the Congregation for the Doctrine of Faith, and which represent in an official manner the position of the Magisterium on different topics: "Reflections on cloning"(1997), "Declaration on the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells"(2000), "Prospects for Xenotransplantation. Scientific Aspects and Ethical Considerations"(2001), "Il divieto della clonazione nel dibattito internazionale. Aspetti Scientifici, Etici e Giuridici"(2003), "Proposta di impegno etico per i ricercatori in ambiente biomedico"(2003), "Riflessioni sui problemi scientifici ed etici relativi allo stato vegetativo"(2004), "Moral reflections on vaccines prepared from cells derived from aborted human foetuses"(2005).
The staff of the Pontifical Academy for Life, along with some members of the Academy, has also organized various meetings in association with other institutions:
The first of these congresses, which took place in 2004 (17-20 March 2004, Augustinianum) was entitled: "Life-sustaining Treatments and Vegetative State: Scientific Advances and Ethical Dilemmas"(2004), It was realized in association with the FIAMC (World Federation of Catholic Medical Associations)(Pr Gigli) and regarded the care of people in vegetative state.
The second congress was held in 2006 (September 2006, Augustinianum, Rome) and was entitled "Stem cells: What future for therapy? Scientific aspects and bioethical problems". It was organized by the PAV, in association with the Foundation Jérôme Lejeune and the FIAMC (World Federation of Catholic Medical Associations). This was the first of our "international congresses on responsible stem cell research"(RSCR). This congress was honored by the participation of Professor S.Yamanaka, from Japan, the "inventor" of the stem cells named "iPSCs" for "induced pluripotent stem cells", created by reprogramming to the embryonic, pluripotent state, of ordinary, differentiated cells of the skin. This was the first appearance of S.Yamanaka in Europe since his announce of the creation of the iPSCs cells, few months before. K.Yamanaka gave to this meeting an historical talk on "Identification of factors that generate pluripotent stem cells from fibroblast culture".
The third congress was held in 2008 (auditorium della Conciliazione, 2008) and regarded the gift of organs for transplantation and the problem of organ trafficking . It was entitled :"A gift for life. Considerations on organ donation", and was realized in association with The FIAMC e il Centro Nazionale Trapianti.
The fourth congress was the second of the series of the RSCR congresses - international congress on responsible stem cell research. Again realized by the PAV in association with the FIAMC and the Foundation Lejeune, it was held in Monaco (26-28 november 2009, auditorium Rainier III). It was entitled: "Adult somatic stem cells: new perspectives". It focused on clinical uses of somatic ("adult") stem cells. The most interesting progresses in that field reported at the congress regarded the treatment of multiple sclerosis (Prof.Neil Scolding) with bone marrow mesenchymal stem cells, and the cure of epidermolysis bullosa in children with umbilical cord blood stem cells (Prof.John Wagner).
So the Pontifical Academy for Life is a well alive organism, with a story still recent, but which has the great advantage over other organisms that it draws its members from a large array of professions and interests, and can be very versatile in the topics that it treats. Given the quality of its members, it should be a place of reflection at a higher level, with a large scope.
III - THE PERSPECTIVE OF THE PONTIFICAL ACADEMY FOR LIFE ON THE FUNDAMENTAL VALUES THAT SHOULD GUIDE CHOICES IN THE FIELD OF BIOETHICS1
For its debate, the guidelines that it could offer, and the judgments that it is called to do, the Pontifical academy for life relies on the principles developed by the Church in her moral theology. Howver, the field of bioethics today is not a peaceful one: various philosophical and anthropological traditions exert their influence on the committees or institutes of bioethics, through the wold, and therefore the academy , and the members of the academy, are frequently opposed arguments and judgements, based on these philosophies or tendencies which contradict the moral doctrine of the Church. We will examine here the moral basis on which the catholic Church - and therefore the Academy - operates, which is the "natural moral law", then the various philosophies or trends which have influence in todays' bioethics and may enter in conflict with the teachings of the Church, and we will come to the personnalist tradition which has given birth to personnalist bioethics, and brings its own riches to natural moral law. One can distinguish three different perspectives in this domain:
- the Christian ethical perspective, based for its principles on the natural moral law;
- the perspective of the philosophical ethics, with its different trends among which the most influential have been and are the eudemonist philosophy, the liberal-radical model, the pragmatist-utilitarian approach, the sociobiologic or evolutionist tgrend, the legal positivism school, and the eugenic movement.
- the perspective of personalism, which will propose for the fullness of its values.There are various lines of thought, often conflicting, at work today in the field of bioethics. It is important in bioethics to be clear about your starting point, that is the highest value that you want to defend and promote throughout your evaluations and your drafting of guiding principles.
A - THE CHRISTIAN ETHICS AND THE NATURAL MORAL LAW
Christianity didn't develop a specific tradition for the elaboration of the ethical judgment at the patient's bedside. It adopted without any difficulty the Hippocratic teaching as it was transmitted in Rome through physicians such as Gallien, that is to say a body of reflections centered on the good of the patient and on the relationship physician-patient, to which the Roman stoicism had introduced solidarity, and compassion towards the patient. The Christ's words enjoining the faithful to visit the sick, identifying hinself to these, as well as the figure of "Christ physician" who came into this world to take care of the sick, found in the Hippocratic tradition a welcoming place.
On the general ethical point of view, on the other hand, Christianity developed a moral theology corresponding to Christ's teaching and at the same time opened to universal values, accessible to all, including to the members of other religions, or of other philosophical traditions. It has been able to secure this balance by basing itself on natural moral law.
What is the "natural "moral law? It is a concept that comes from the Greco-Roman culture, and that has been put back in light by Saint Thomas Aquinas2. It allows the Church to meet with non-believers on this platform of universal values common to humanity.
It has been the subject of a recent study of the International Theological Commission (2009), entitled: "In search of Universal Ethic: A New look at the Natural Law."
1) Definition of the natural moral law
"The natural law, which is inscribed by the Creator on the heart of every person, consists in a participation in the wisdom and the goodness of God. It expresses that original moral sense which enables one to discern by reason the good and the bad. It is universal and inmutable and determines the basis of the duties and fundamental rights of the person, as well as those of the human community and civil law.3
"The natural law, it is what makes that man "is" It is something inescapable, proper to man, whatever is his/her physical, mental condition, his/her/ birth" (R.Tremblay).4 The Pope Benedict XVI defines the natural morals thus as the "ethical message written in the human being" whatever he is.
The "natural moral law "is constituted by the whole of the requirements of moral and legal order that ensues of the structures themselves of human nature, that is of man as an intelligent and free being, endowed with sociability, bound by his most intimate fibers to the universality of humanity. His fundamental norm is none other than this one: man, act in man."5
The natural moral law is the fruit of the ratio naturalis that permits to know God and dictates the most elementary maxims of life, such as the homicide's prohibition and the "don't do to others what you would not like that they did to you"6 (ibid).
- Because human nature is identical to itself through time and space, it has an absolute character. But, because man is a historic, contingent being, it has also a relative character. The natural law is a question of reason. It is not therefore reserved to a standpoint of faith, but can be found by every man, whatever his belief. It is to it that St Paul makes reference in the epistle to the Romans, when it writes:
"When the gentiles, who do not have the law, do by nature what is required by the law, they are a law for themselves, even though they do not have the law.Their conduct shows that what the Law commands is written in their hearts." (Rm 2, 14 -15)
The Decalogue is the oldest formulation of this natural law, made explicit in a certain number of precepts, and assumed in the revealed Law. In the greek times, the Sophocles' Antigone in calls for natural law against the positive law of Creon which forbids the burial of her brother. Closer to us, the Universal Declaration of Human Rights (1948) is a lay version of this natural law, that supposes a "universal human nature." Pope Benedict XVI, in his discourse to the United Nations, April 18, 2008, recalled that the human rights "are based on the natural law inscribed in human hearts and present in different cultures and civilizations." The church can meet with no-believers on this platform of universal values.
2) History of the natural moral law
1) the ancient Greece: Aristotle
The concept of natural moral law makes its beginnings in the ancient Greece, by a contrast between the "physei dikaion" and the "nomo dikaion", (Aristotle)7 between what exists merely "by nature"(phusis) and what exists by "strength of law (nomos)." What exists "by nature" represents the non written law. The term "by nature" was very vague. It meant merely "naturally" "by oneself" It was not a term of philosophy, and this term didn't contain any affirmation on the possibility of an unchangeable general nature in the philosophical sense. What was important was the "nomos", the human law, of human competence.
However the Greek conception of the world had an element that permitted to reduce or to eliminate the contrast between physei and nomo (i): the notion of Kosmos. For the Greek, the world in which he lived was a whole, ordered and harmonious. This implied a "idea" animating this kosmos, an intelligence.
It is the stoical school which developed this theme, saying that one divine Logos impregnates all the universe, and that man participates in this Logos in a special way. Assigning one immanent Logos to "nature" and to man, the stoics suppress the difference between "nature" and "reason." For the stoic thinker, to act according to nature and to act according to reason are related to the same. As the law is the product of the reason, law and nature are united, and this is what allows to speak of "natural law".8 Under this term one can designate two things: the cosmic order of the universe, on one hand, and, of the other, this principle that is in all individual being and through which this being get in harmony with the universe, that is his "nature." Cosmic order and the nature of beings are supposed to be immutables. As such, they express an eternal law. There was however, in this stoic way of thinking, a certain discordance: the first stoical school insisted on nature, the objective element, while the intermediate stoical school rather put the accent on the subjective element, the human reason.
3) Christianity, St. Paul
Christianity is born at the time where the stoical philosophy is flourishing, and bring three elements to this philosophy of the "natural law": the Decalogue, with its universal range; the letter of Saint Paul to the Romans in which Saint Paul, taking for his own use the stoical language, speak of the "law natural" of the pagans, and the Prologue of Saint John. The passage of the epistle to the Romans on "the law that the pagans hold to them same" was determinant for the Christian thought:
"In fact, when the pagans, who don't have the law (mosaic) accomplish the prescriptions of the law naturally (physei), these men, without possessing the law, hold place of law to themselves" (Rom 2, 14 -15).
These are these words that brought the Christian thought to adopt the stoic teaching on the natural law. The Prologue of Saint Jean reflects the concept of the God of the Old Testament, creating the world by his "ruah", by his eternal Word. Saint Augustine joined this concept to the neo-Platonic idea of the eternal law, and also to the concept of the natural law expressed in the Letter to the Romans. In that way the notion was reinforced following which the theological order of nature expresses God's plan and has from a normative value. So the tradition of the first Christians continued the tradition of the stoic philosophers.
3) Natural moral law in St Thomas Aquinas
When in the XIIIth century important efforts were done to organize the theology in view of a wider synthesis, there were four main elements identified with respect to the moral law, and it was necessary to define their reciprocal relations: the "eternal law", the "natural law", the "jus gentium" and the Decalogue. It was the merit of Guillaume of Auxerre to have bound the moral sense present in man with the first principles of the speculative reason9. It is this thesis that underlie the explanation of Saint Thomas on natural law. Saint Thomas has presented the natural moral law in his treaty on the Law (S.Th. I-II, qq.90-108).
The law as a prescription of reason
In this treaty Saint Thomas presents the law in question 90 as "the work of reason", that aims to the common good and is promulgated by the one who has the responsibility of the community.
- The law is an order of reason, a product of reason: it is on this that St. Thomas insists more:
"Under relinquitur quod lex suited aliquid pertinens ad rationem" (I-II, q.90, art.1, repondeo). St. Thomas distinguishes two aspects in the law: the law as measure and the law as rule.
The law is first in the one who puts the rule or establishes the measure, properties proper to reason.
"it is in this case in the reason alone":
"And quia hoc is proprium rationis, ideo per hunc modum lex is in ratione sola" (I-II, q.90, ad primum)
The law is then in all beings who experiment an inclination by the fact of a law, "as a participation"
- The law is ordered to the common good (Q.90, article 2)
- The law is brought to the attention of the concerned persons by the mere fact of its enactment.(I-II q.90, art.4).
From this comes out the following definition of the law by Saint Thomas:
"An order of reason for the common good promulgated by the one who is in charge of the community" (I-II, q.90, article 4)
In the question 91 Saint Thomas dealing with the question of the diversity of the laws develops the notions of eternal Law and natural law. The natural law is defined according to the eternal Law.
The eternal law
- The eternal law: it is God's thought, non subject to the time:
"This is how the eternal thought that constitutes the divine Law has eternal law value, because it is ordered by God to the government of the things that He knows in advance" (I-II, q.90, Ad primum)
The stoics identified the eternal law with the eternal order of the nature of the things: a cosmic value. St. Thomas sees the eternal law as identical to God's being, to His ideas, to His Providence, to His government of the world. The world is governed by God's eternal wisdom. What is in the creation is only a participation in the eternal law.
The natural law: definition
It is this participation in eternal law as creatures that makes that the created beings possess the innate tendencies that push them to the acts that assure their end:
"These beings participate in some way in the eternal Law by the fact that while receiving the impression of this Law in themselves, they possess innate tendencies that push them to the acts and to the ends that are proper to them" (I-II, q.91, art.2, Respondeo)
This participation in the eternal Law expresses itself following two modes:
- the irrational beings participate in the eternal law insofar as they are oriented to their end through their nature. In this case the term of "law", that coincides with their nature, is only used in a metaphorical sense.
- The man, reasonable creature, participates in a more intense way to this eternal Law because he participates in Providence while providing to his own interests. It is what gives him a tendency to act according to the end that corresponds hum. It is this participation in the eternal Law which is the "natural law":
"However, among all these beings, the reasonable creature is submitted to the divine providence in a more excellent manner by the fact that she participates herself in this providence, while providing to her own interests and at the same time to those of the others. In this creature, there is therefore a participation in the eternal Law according to which she possesses a natural tendency to the mode of acting to the end that are in correspondence to him. It is precisely this participation in the eternal Law which, in the reasonable creature, is called the natural Law."(I-II, q.91, art.2, Respondeo):
"Unde patet quod lex naturalis nihil aliud est quam participatio legis aeternae in rationali creatura" (I-II, q.90, art.2, Respondeo).
Man participates in the eternal law by his reason:
"The light of our natural reason, making us discern what is good and what is bad, is none other than a participation in the divine light. It is therefore obvious that the natural law in the reasonable creature" (I-II, q.91, art.2, Respondeo).
While among the animals without reason this participation expresses itself only under the form of the instincts, in man it deserves actually the name of law, because man possesses this participation along an intelligent and rational mode:
"The animals without reason participate themselves, as do the reasonable creature, to the eternal thought, but in their own way. Because the reasonable creature possesses this participation following an intelligent and rational mode, it follows that the participation in the eternal law of the reasonable creature deserves properly the name of law: the law is, indeed, something that pertains to reason" (I-II, q.91, art.2, ad tertium.).
An important point which has to be underlined for a good understanding of the concept of the natural moral law, thus developed by Saint Thomas, is the one of the "innate knowledge", by nature, of man's final goal, which corresponds to his nature: the natural law is what assures in man the primary orientation of his acts toward their end:
"In us, all operation of the reason and of the will is derived (derivatur: it is not a logical operation) of what exists according to nature. Indeed, all reasoning comes out of principles that are known naturally, and all desires which are about what directs toward the end which has to be reached, have their origin in the natural desires to reach this end. It is why the primary orientation of our acts toward their end must be assured by the natural law" (I-II, q.91, ad secundum).
Therefore the natural reason is oriented toward what it knows "by nature." In other words, it is oriented toward what reason cannot ignore without alienating itself. The content of the natural law consists in what man knows by nature.
The different levels of the natural law, of the instincts to the findings of wisdom
But the precepts of the natural law don't limit themselves to this first principle first. In fact they indicate all goods that the reason seizes like such, all those toward that the man feels a "natural slant":
"the human reason seizes as goods, and therefore worthy to be achieved, all things toward which man feels carried naturally; on the other hand it considers as evil to avoid the things opposed to the previous. It is according to the very order of the natural inclinations that the order of the precepts of the natural law is taken" (ST. I-II, q.94, art.2, Respondeo).
This explains that one finds in man "natural instincts", as among the animals, for example toward the union of the sexes, and that one will also find an appeal toward "the good in conformity with his reasonable nature, which is proper to him": from there comes his attraction toward the knowledge of the truth or toward life in society. And finally, at a third level, one will find as belonging to the natural law what is related to these fundamental inclinations: that is to say the research of what contributes to these fundamental goods: to shun ignorance, not to do wrong to one's neighbor. All this makes that the precepts of the natural moral law are in fact "many, while having a "common foundation" (I-II, p.94, art.2, ad secundum).
Making this distinction on the different orders of the precepts contained in the natural moral law, from the instinct of the animals to the precepts of wisdom, while passing through the fundamental principle of the research of the good, St. Thomas clarifies the question: the "natural law" is located at the level of the "first principles" of the practical reason, at its starting point, while the precepts of the Decalogue are already at the level of the conclusions that derive from these principles.
Natural morals and contingent realities
The presentation of the natural law by St. Thomas also offers the advantage of giving us a coherent doctrine of the natural law: the more the field of the natural law widens, the more it becomes difficult to sustain that it is identical for all men, known of all times and in all places, always valid, and that it cannot be erased from the hearts of men. And here stops the analogy with scientific knowledge and speculative reason: while the speculative reason is about what is necessary, and for which there is no alternative, which makes that the truth is found as in particular conclusions as in general principles, the practical reason, itself, treat of contingent realities: the human actions. And therefore, with the practical reason, the more one goes toward the particular, the more one will find exceptions, alternative propositions.:
"The practical reason takes care of contingent realities..it is why, although there is necessity in the universal principles, the more one approaches the particular things, more one meets exceptions" (I-II, q.94, art.4, Respondeo).
This is what explains the diversity in the moral attitudes according to countries, places, times:
"But, in matters of action, truth or practical rectitude is not the same for all when one arrives to the particular conclusions of the practical reason, and even where the same rectitude is found in matters of details, it is not equally known to all" (S.T.I-II, q-94, art,4, Respondeo)
"the greater the number of conditions added, the greater the number of ways in which the principle may fail" (ibid)
"the natural law is the same for all, in its first general principles, both as to rectitude and as to knowledge. But as to certain matters of detail, which are conclusions of these general principles, it is the same for all in the majority of cases, both as to rectitude and as to knowledge, and yet in some few cases it may fail,.. "(S.T. I-II, q.94, art.4, Respondeo)
It is in these exceptions that St. Thomas places the case of the consciences distorted by bad habits:
"it may fail both as to rectitude, by reason of certain obstacles..and as to knowledge, since in some the reason is perverted by passion, or evil habit, or an evil disposition of nature"(S.T.I-II, Q.94, art.4, Respondeo)
St. Thomas mentions, to give an example, the fact that theft, contrary to natural law, was not considered wrong among the germans, as related by Julius Caesar (De Bello Gallico, VI).
4) Content of the natural law
This "natural moral law", "written down in the man's heart", has "as its first and fundamental principle "to do good and to avoid evil."10
"The natural law is written and engraved in the soul of each and every man, because it is human reason ordaining him to do good and forbidding him to sin...But this command of human reason would not have the force of law if it were not the voice and the interpreter of a higher reason to which our spirit and our freedom must ne submitted".11
Based on a certain number of values common to all the humanity, as the justice and the liberty, it has guided, guide and will guide the men, wherever they are, along the centuries.
Among these "laws that the creator wrote down in the man's spiritual and moral nature" one finds the sense of the good, the respect of the human life, the duty to search for the truth, the freedom, justice, solidarity.12 The Magisterium of the Church bases it moral teaching on natural moral law. The Catechism of the Catholic church dedicated a whole page to it. According to the Catechism:
"The natural law expresses the original moral sense which enables man to discern by reason the good and the evil, the truth and the lie."(CCC, nr. 1954)
"The "divine and natural" law (GS 89, nr.1) shows man the way to follow so as to practice the good and attain his end. The natural law states the first and essential precepts which govern the moral life."(CCC, nr. 1955)
5) The natural law in bioethics
The judgments that the Church makes in the field of bioethics are not inspired by some "a priori" insight coming from Scriptures or Tradition, but are based on the natural law, and are therefore accessible to all. It is why the Magisterium of the Catholic Church always recalls the natural law and underlines its importance.
The Holy Father Benedict XVI, addressing lately (February 15 2010) the Pontifical Academy for Life, underlined in the following words the importance of natural law for bioethics:
"Bioethics, like every discipline, needs a reference that can guarantee a consistent reading of ethical issues that inevitably emerge in the face of the disputes that may arise from their interpretation. In this sphere the normative reference to the natural moral law comes into its own."13
With regard to bioethics, the natural moral law underlines the necessity to respect the human life, gift of the Creator, and to respect the human person, in her undissociable totality body-soul, created at the image of God. It underlies that way two essential principles for the bioethics:
- the sacred character of human life, from the beginning of this life at the time of the conception until its natural death.
- the dignity of the human person that orders respect to that person, even though this person seems diminished by a physical or mental handicap, if she is not competent for decision making, or if she is without conscience:
"Bioethical issues often bring to the fore the reference to the dignity of the person. This is a fundamental principle which faith in the Crucified and Risen Jesus Christ has always defended, especially when, in respect to the simplest and most defenseless people, it is disregarded. ...Indeed, the recognition of human dignity as an inalienable right is founded primarily on this law, which is not written by a human hand but is engraved on human hearts by God the Creator. Every juridical order is required to recognize this law as inviolable and every individual is called to respect and promote it (cf.Catechism of the Catholic Church, nn. 1954-1960). Without the founding principle of human dignity the search for a source of the rights of the person would be arduous, and it would be impossible to reach an ethical judgement on the scientific breakthroughs that intervene directly in human life."14
The natural moral law, that the church follows in its ethical approach, permits to avoid the mistakes and the relativistic drifts that of other ethical systems may commit, which have moved away from its truth while choosing as starting point of their reflection some partial or arbitrary goods or in declaring themselves source of ethics. It is especially true when it is about protecting the rights of the weakest against the strongest, of the vulnerable or incompetent person against those who have chosen for disregarding her, using her, or eliminating her.
"In today's context, despite the increasing reference to the rights that guarantee the person's dignity, it is clear that recognition of these rights is not always applied to human life in its natural development or in its weakest stages. A similar contradiction demands that a commitment be assumed in the various social and cultural contexts to see that human life is recognized everywhere as an inalienable subject of law, and never as an object subjected to the arbitrary will of the strongest".15
The natural moral law, because it is universal, permits to avoid the ethical drifts that are ineluctable when an earthly authority - parliament, department of health - "pretends to be the source and the principle of ethics":
"the natural moral law, strong in its universal character, makes it possible to ward off this danger and, above all, offers the legislator a guarantee for the authentic respect of both the person and the entire order of creatures".16
The teaching from natural law, actually accessible to all through reason, has a dimension that goes beyond the "principles of the practical reason" that this law expresses, because it clarifies these principles and give them a wider dimension, that all are not however ready to accept.
4) Today the natural law is often badly interpreted
However, the term of "natural "moral law appears today, to many of our contemporaries, ambiguous or even unacceptable, because the expression makes reference to "nature", a term which is itself greatly contested in the light of what psychology, behavioral sciences and modern anthropology have taught.
As Pope Benedict XVI said to the Congress held in the Lateran in February 2007 on the theme of the Natural Law , the problem is that, for many today, and especially for the scientists who scrutinize nature to find out its rationality, the concept of nature has lost its metaphysical depth to become a simple empirical concept. Keeping only the empiric, material concept of living beings, while eliminating all metaphysical reference to the being in itself, in its ontological reality, our contemporaries have lost the access to the concept of nature, and to the moral message that is bound to it. From that comes that nature, the fact itself of being, are no more transparent for a moral message:
"The method that permit us to know ever more deeply the rational structures of matter makes us ever less capable of perceiving the source of this rationality, creative Reason. The capacity to see the laws of material being makes us incapable of seeing the ethical message contained in being, a message that tradition calls lex naturalis, natural moral law.
This word for many today is almost incomprehensible due to a concept of nature that is non longer metaphysical, but only empirical. The fact that nature, being itself, is no longer a transparent moral message creates a sense of disorientation that renders the choices of daily life precarious and uncertain. Naturally, the disorientation strikes the younger generations in a particular way, who must in this context find the fundamental choices for their life".17
Two types of arguments are presented by contemporary critics against the concept of the natural law18. The first has to do with the idea of nature, the second with the idea of law.
On the side of the idea of "nature", our contemporaries have retained from the existentialist writings which were most appreciated after world war II, that the human being should no more see himself within the static perspective of a "being", but as part of a project. The term of "natural morals" repels thus some because they interpret it as bound to man's psycho-somatic "nature", and therefore reflecting the different cultures and liable of any manipulation. Our contemporaries have the tendency to deny the existence of a human "essence" or "human nature", to keep only the idea of "existences" in the making, signed by contingency and particularity. Any speech pretending to be universal would be for them a manner of camouflage or denial of particular, individual or collective interests. In this perspective, the "natural moral law" doesn't evoke for them other than a resigned submissiveness, all passive, to the physical laws of nature, whereas man rather seeks, understandably, to master and to orient these determinisms for his own good. Others critics consider the natural law as an "objective set of rules" which would impose itself from the outside to the personal conscience, regardless of the work of reason and of the subjectivity of the individual. Natural law is suspected that way to introduce "a kind of heteronomy intolerable to the dignity of the free human person."19
As regards to the "law", the critics of the natural moral law contest the existence of such a "universal morals", taking argument from the wide diversity of the cultures and of the moral attitudes within them, throughout history and from one country to one another. The particular normative systems of each culture, fruits of human creativity, would not have any common measure. The pretension of the moral reason to hold an universal discourse should be denounced in the name of the historicity of the norms written down in the particularism of the cultures and of the human groups. Moreover, they say that this "natural "moral law could not be other than very general, if it had to reveal what is actually in man's heart, beyond what is proper to the different cultures. If it is possible to get an easy agreement on the fact "that one has to look for the good and avoid evil", or on the precept "not to do to the other what one would not like to be done to oneself", the difficulty emerges as soon as one begins to want to define what is this "good" and this "evil", in order to enter in the practical aspects of the moral law. This is why, in a field as concrete that the one of bioethics, the "natural "moral law has to be defined in a way that corresponds to the most general sense of the good of the person, and in a true and comprehensive anthropological perspective. Each one is going to interpret this natural morals, in its aspects more concrete and particular, according to one's point of view, philosophical, anthropological or ideological, and the divergences will reappear. The moral requirement to do the good, henceforth impossible to found universally because not bound to the truth of an "objective" moral order, would not be then other than arbitrary, a mystification, an ideological imposture or a psychological retardation. From there the critics of natural law conclude that it can function only as the affirmation of an ethical dogmatism denying man the right to be creative of norms and values.
The western currents of thought that are utilitarianism and legal positivism have radicalized the critique of natural moral law. The Anglo-Saxon utilitarianism of Bentham, Mill and Smith, with its principle of the search for the highest good for the larger number of people, does not make reference to any natural law which would provide an insight to what could be the greater good.
More than utilitarianism, it is the legal positivism of the XIXth century that came to ruin all possible return to the idea of natural moral law as metaphysical notion. The legal positivism, whose origin goes back to the nominalism of Guillaume of Ockham (1285 -1349), had been relayed by Thomas Hobbes (1588 -1679) (in Hobbes its is up to the Leviathan to defines what is just or unjust, what it is necessary to believe and not to believe) and by his opponent John Locke (the "social contract", the consensus, without reference to any rationality). It opposes the "jus naturalism" that is the idea of a "natural right" coming from a "natural law". According to this current, the right must be described as it is, without reference to any natural right. Only the positive law has legal value, and it is the only norm to respect. Hans Kelsen (1881 -1973) was a major representative of this current. For him, the law is a pure human construction, and must be considered for itself, in its authoritative and normative aspect, out of any reference to ethics, politics or sociology. The rules of the positive law are sufficient in themselves to organize the life of the societies. The just is then what the law prescribes. The law is the product of men, and what men made, men can undo, abrogate, modify it and do it again whenever they want.
B - DIFFERENT PHILOSOPHICAL POINTS OF VIEW ON ETHICS20
The different foundations of the ethical judgment that underlies today the options in the field of bioethics can be brought back to five models, corresponding each to a tradition or to a particular conception of life and of the good of man. Those are the "eudemonist model", the "liberal-radical model", the "pragmatist-utilitarian model", the "sociobiologic" or "naturalistic" model, the positive law trend, and the "personalist model". It is important to have a good understanding of each one of these positions in order to realize how they enter into conflict in today's bioethics.
1) The eudemonism
The oldest way in history of conceiving morals has been to see in human actions the possibility of getting happiness, full well-being and money. Is not that what man is looking for in all his desires and through all his steps? Is not that the "ultimate good" for us? This point of view is that of the eudemonist tradition.
The most usual form of eudemonism is hedonism, very much present in today way of thinking. In this perspective, happiness is sought after through sensible satisfaction - pleasure of the senses . In its more brute form, it is attributed to a disciple of Socrates, Aristippe of Cyrene. This is why the proponents of this philosophy of happiness were called "Cyreniacs". In fact this doctrine was more an ascetic way of living that the dissolute life we think. For the Cyreniacs, happiness is to be found in ordinary life, in the most casual things. The important achievement was to master oneself. A more delicate form of hedonism was found in Epicurus'tradition. For Epicurus, pleasure, the ultimate good, had to be sought in the serenity of the soul, in quietness, a lack of inner turmoil, what was called the "ataraxia".21
In rational eudemonism, the good that is sought is the most complete good, including the good of reason. The best type of rational eudemonism is represented by Aristotelian Ethics. For Aristotle, happiness calls for virtue, that is to say, activity following the rule of reason and an objective equilibrium, the just middleway, whose determination belongs to the wise. Moral virtues are not, however, the chief achievements of all human activities. Intellectual virtues or dianoetic virtues are to be considered higher in the hierarchy of virtues. The highest activity is philosophical contemplation.
The problem with eudemonism is that it contradicts the truth of moral conscience. It is not because it leads to happiness that an action is morally good. The relation to happiness cannot be given as the immediate basis and the norm of moral values. Reason feels that pleasure, taken as the goal and the rule of human action, debases and degrades it. The pleasure-seeker, the man used to avoid everything that would cause him trouble or would require effort from him does not inspire great consideration in us. At the opposite extreme, the man who is able to sacrifice his well-being and even his own life for a just cause deserves our approbation and even our admiration. Moral conscience does not condemn pleasure in itself. It is not rigorist, but it finds in the pleasure-seeker a double disorder: this man takes as an end what is only a secondary consequence, an end that subordinates the universal to the particular. The perspective of eudemonism is always that of a limited, contingent happiness. The perspective of morals is that of a true, full happiness, according to human nature, that is to say according to reason.
2) The liberal-radical model22
In the liberal-radical model the supreme and ultimate point of reference is freedom: what is lawful is what is freely wanted, freely accepted and what does not harm the freedom of others. This is the message that sprang with innovative force from the French Revolution. There is, indeed, in this perspective, a part of the truth. An act accomplished freely is always invested, according to common thought, with some moral quality. Men generally excuse themselves of their evil acts in saying that they were overwhelmed by passions, that they could not resist their impulses. When men do good, they have the conscience to be themselves, to act according to their truer self.
However, this perspective does not provide the full truth about man's actions. The ethic so conceived is necessarily a formal one, more attentive to the external aspect of the action than to its content. In this perspective, what is important is not to be objectively in the truth but to be formally sincere. Authenticity tends to become the unique criterion of morality. Everything is permitted as long as I fully take my responsibilities. This thesis of the existentialist philosophy - that of Jean-Paul Sartre in particular - has made its way in today's culture and permeates the mentality of our fellow men and women. The result of this pure formalism is that existentialist morality cannot be any other than a pure situational ethics, a pure morality of ambiguous situations.
A pure morality of ambiguity: In this there is no good nor evil action in se, and all action is ambiguous in its content. This leads to the famous counsel that we hear in public debates over abortion, euthanasia or homosexuality: "Everybody has to act according to his own conscience!". Everything becomes relative in that way. There is no content.
A pure morality of situation: Morality in this liberal point of view consists in deciding only on the basis of a given situation and never from general norms. Any idea of a possible universal principle is rejected. Everyone has to find out, depending on his particular situation, what is the unique value of his own personal choice. Every attitude, if it is responsible and lucid, is morally good, as long as it is the fruit of an authentic freedom.
In practice, this ethic of freedom and authenticity results in an absolute subjectivism when it comes to values. Everyone is left alone to decide what to do with his or her own freedom.
We all know the results of this proposal: liberalization of abortion ("it is my body"), free choice of the baby to be born (when I want, the way I want), indifference to common good, an individualistic attitude, freedom of the adult to change one's sex, freedom to have access to artificial procreation even for a woman alone, single, divorced or widowed, freedom to engage in homosexual relationships, freedom to indulge in drugs, "soft" as well as "hard", freedom to decide the time of one's own death (living will), suicide as an emphatic expression of freedom, etc... This "liberal" conception of life leads to a total lack of responsibility, which is not without deleterious consequences for all, such as the spread of AIDS, and the absolute refusal of any epidemiological control and any tracing and screening in this contagious, epidemic disease.
This freedom is a reduced freedom: It is freedom for some, for the one who can affirm it and express it. But who is going to defend the freedom of the child condemned to death by his mother? It is a freedom without links, without duties, without commitment, without responsibility. It is not a freedom "for" a project of life or of society, but a freedom "from" all constraints. But there is no human freedom without responsibility; otherwise this is a false freedom, pure selfishness.
We must be very well aware of the real influence of this way of thinking in our society today. It expresses itself in sentences such as "everybody has his own choice", or "for me..."
3) The pragmatic-utilitarian model23
Utilitarianism is an ethical doctrine that prescribes to act (or not to act) in order to maximize the well-being of the sensitive beings. Utilitarianism is therefore a type of consequentialism: it values an action (or a rule) solely according to its consequences, what distinguishes it of the ethical ethics (morals of Kant).
The notion of utility doesn't have among the utilitarians the sense that one assigns to him fluently. What is "useful" designates what contributes to maximize the well-being of a population. It is in this particular sense that one can speak of the calculation of the utility of an act, or that one can compare the utilities of different actions or rules. The thought utilitarian consists therefore in weighing pros and cons of a decision and to compare this last to the advantages and disadvantages of the inverse decision.
One can sum up the heart of the utilitarian doctrine by the sentence: "Always act so that the greatest quantity of happiness" results from it. In this perspective, the good action is the one which tends to promote the greatest happiness for the largest number of persons. Utilitarianism seeks the greater well-being for everybody, with the minimum of suffering, for the largest number of individuals. It is therefore a kind of eudemonist moral with the difference that, contrary to the individualism of some trends in eudemonism, utilitarianism seeks the good for all, and not only for the interested moral agent. There is therefore in the utilitarian perspective a clear interest for common good.
This model comes from a long philosophical tradition, the empirical tradition, of Anglo-Saxon origin. One finds utilitarian trends in Plato (428-347 before JC), Epicure (341-270 before JC), Seneca (4 -65), Hobbes (Leviathan 1651), David Hume (1711 -1776), Claude Adrien Helvetius (1715 -1771). But utilitarianism really started as such only at the end of the XVIIIth century. The main authors who contributed to the birth and development of utilitarianism were Jeremy Benthams (1748 -1832), who fathered it, John Stuart Mill (1806 -1873) and Herbert Spencer (1820 -1903).
1) Jeremy Bentham (1748 -1832)
The father of this philosophy is Jeremy BENTHAM (1748 -1832) who was influenced by the description of the human nature by Hobbes and by Humes of "social utility". It is he who introduced the name of utilitarianism in 1781 and who drew from this principle theoretical and practical implications. Bentham proposed a first type of utilitarianism that was later qualified of "hedonist utilitarianism." His theory was the starting point of the numerous versions of utilitarianism that developed afterward in the XIXth and XXth centuries. The ethical principle from which Bentham judged the individual or public behaviors was the social utility. It was summed up in the formula "the highest happiness for the largest number".
The premise of Bentham'utilitarian theory is that the ethical good constitutes a reality that can be found out and demonstrate. It can be defined from the sole elementary tendencies of human nature: its natural leaning toward the search for happiness, that is a maximum of pleasures and a minimum of sufferings. The principle of his utilitarianism is thus formulated by Bentham:
"The nature has placed mankind under the governance of two sovereign masters, pain and pleasure. It is for them alone to point out what we ought to do, as well as to determine what we shall do. On the one hand the standard of right and wrong, on the other the chain of causes and effects , are fastened to their throne. They govern us in all we do, in all we say, in all we think."24
The hedonism in Bentham presents itself under a form that wants to be scientific. It intends to guide the moral agent toward the largest amount sum of possible pleasures. It is necessary for that to judge correctly the following of our acts, and to make a sort of arithmetic of the pleasures and pains that permits to calculate where is the maximum of the first and the minimum of the second. Through this calculation one can show, for example, the superiority of the temperance over drunkenness. Bentham gives a large room to beneficence, source of the purest pleasures.
For Bentham, the legislator must look for the greater happiness for the largest number. The goal of Bentham is practical: he wants to reform customs, and for that reason he looks for the driving forces which have to be moved in order that men make a choice for what is good.
Bentham affirms that there cannot be a conflict between the individual's interest and the interests of the community, because if one and the other base their action on "the utility", their interests will be identical.
Bentham introduces the animals in this community, as beings able to suffer and therefore participating in the interests of the community. "The question is not: Can they reason? nor: Can they talk? but: Can they suffer?"25
2) John Stuart Mill (1806 -1873)
John Stuart Mill is the immediate successor of Bentham's utilitarianism (utilitarianism, 1863). He followed Bentham, and admired all his life his works, but was not in tune with some of the affirmations of Bentham - in particular on the nature of happiness. Bentham had sustained that there were not any qualitative differences between the pleasures, only a quantitative differences. For Mill on the contrary, there are pleasures that are more adequate than others. The intellectual pleasures are of an order superior to the merely sensual pleasures, that we share with the animals. Where Bentham identified welfare and pleasure, Mill defined the Welfare as happiness. Doing that way, Mill departed from the hedonist utilitarianism and proposed an indirect utilitarianism. In this utilitarianism, the pleasure is no more the end of the morality, but plays an indirect role, insofar as it contributes to the happiness (of the largest number). One also owes to Mill the recognition of the qualitative dimension of the pleasures. Contrary to Bentham that doesn't set up a hierarchy in the pleasures and is only interested in the quantity of these, John Stuart Mill defends a difference of quality between the pleasures. One can thus prefer a smaller quantity of a higher quality pleasure to a larger quantity of a pleasure inferior in quality.
In the perspective of John Stuart Mill, the good action is the one that tends to promote the highest happiness for the larger number. While Bentham sees an increase in pleasure in the partaking of this pleasure with others, Mill says that the morally good man immediately looks for the good of the larger number. Utilitarianism makes its own the golden rule of Jesus of Nazareth: "Therefore all things whatsoever you would that men should do to you, do you even so to them "(Matthew 7,12).
3) The cost/benefit ratio
The basic principle which regulates the evaluation of human acts in the biomedical field from an utilitarian standpoint is the cost/benefits ratio, with the presupposition that there is no criterion of a higher, "metaphysical" order.
If we analyze the most significant point in the Warnock Committee Report, allowing experimentation on the early embryo, prior to 14 days following conception, and justifying the process of artificial procreation (where a certain number of embryos are lost voluntarily, and where a "surplus" of embryos is created) we clearly find a justification principle of the utilitarian type. The same is found when examining the question of prenatal diagnosis, with its link with the selective abortion of the "unfit". Here also, it is accepted as a necessity, for a true, important advantage, to wrong the person of the unborn child.
This estimate of the cost/benefit ratio is indeed valid when it is applied to the same value or the same individual.26 The surgeon is absolutely right when he evaluates the risks and the benefits of a proposed surgical intervention, taking into consideration the health of his patient. Here we have the same person - the patient. In the same way a businessman, before investing money in a project, has to consider what are going to be the risks of the operation, and what are the benefits he expects from it. Here we have the same value, an economic one. But when one places on the tray of risks, in a balance, a human life, and on the tray of benefits, a humane, scientific or economic value, one is no longer applying the cost/benefits principle, but one skids toward ethical utilitarianism of a pragmatical vein.
This approach is always more concerned about the ratio between medical costs and the State economy. One finds that medicine costs a lot, always more, lengthening the time of declared sickness, while the request for health is growing in the population, a state of health which is no longer considered as the end of a particular disease, but as a general state of "well-being". This leads the State to make choices in the field of health care. The public health authority sees itself compelled to decide who is going to be treated and who is not going to be treated, what diseases will be cured at the expense of the State and what diseases will be left at the expanse of the patient. It is clear that the risk here is to make choices in a purely utilitarian perspective, leaving some sick patients without proper treatment, estimated in terms of their possible recovery, or whether they are useless for society. Patients are no longer considered as persons, all to be treated with the same care, but as economic entities.
4) The "quality of Life"
It is this ethical utilitarianism in bioethics which is behind the present theme of the "quality of life". This term comes from the social sciences and corresponds to an analysis Cost/benefit. On one side for example one considers the cost of one proposed treatment for a patient, and on the other side one places the possibility of recuperation, and the quality of life that the patient can hope for. For example one can decide that it is not necessary to feed a newborn child with a congenital malformation, because the future life quality of this child is though to be insufficient. Engelhardt in his book "Foundation of Bioethics" proposes a formula to calculate the duty to intervene medically on a person according to the cost of the treatment, the length of his/her/ hoped for life, and the quality of this life.
D = C x Qdv x Qudv/Oh
D = duty to intervene medically
C = possibility of success
Oh = economic and existential cost
Qdv = Quality of life
Qudv = length of life
Zingherne in Australia values the living beings according to their capacity to feel pain. Seeing that the embryo doesn't have yet this capacity, he classifies the embryo over the salad leaf, but below the animal who suffers. He deduces from this estimate that it is more indicated to experiment on human embryos than on animals.
Contractualism is an orientation of public ethics, analogous in some of its aspects to utilitarianism. Contractualism is based on one criterion: the agreement between the members of the "ethical community", that is to say an agreement between those who have the capacity and the power to decide. H.Tristan Engelhardt ("The Foundations of Bioethics") is the main representative of this line of thought. The contractualist theory, copied from the "contrat social" of J.J.Rousseau, comes from the idea that it is not possible in a pluralistic society to found morality on shared values, because each one has his own values. In order to bring convergence between these various positions, to establish a "public morality", it is necessary to have recourse to the concept of an "ethical contract" in the "ethical community". In this way an ethic of consensus is built up. It is the consensus that determines what is public good. Everyone, in private, has a right to follow his or her own conscience, his or her own religion. Engelhardt distinguishes three types of human beings:
- the persons who are part of the community
- the persons who are not part of the community, but may become part of it, such as fetuses or children. They have no rights. It is the ethical community that agrees to recognize some of their rights (there are no natural rights for Engelhardt). Engelhardt justifies abortion and infanticide in this way.
- the persons who are no longer part of the ethical community, who have lost the capacity to decide (patients in coma, sick persons with no hope of recovery). These cannot be part of the ethical community any more. It is lawful to apply euthanasia to them.
This "social consensus" justifies the undervaluation of those who are not part of the community (embryos, fetuses, babies, children). Their rights depend on adults. They cannot be considered as persons. In this way those who have no social insertion, such as sick persons who cannot communicate or insane persons, are undervalued as "non-persons". The concept of human person is reduced in that way to a sociological concept.
This contractualism is very influential in the United States and threatens to invade European minds.
4) The sociobiological or naturalist model27
This way of thinking finds its roots in different schools: evolutionism on the one hand, with reference to Darwin, sociologism on the other hand, whose chief teacher is Max Weber. One can call these moralities "cosmic" or "biological", because the universe, comprising man, is considered in these schools to be the total reality. The universe contains everything, sustains everything. It is the womb in which all being comes into existence. The universe takes in that way an almost religious character. It becomes object of respect and veneration. For the naturalists, the criterion for good is therefore the conformity of the act with where life is going, the way world is evolving. What facilitates this evolution is good, what impairs it is bad.
For modern naturalistic thinkers, Nature is no longer considered as sacred, but takes the place of God. Nature is asked to give the norm of actions. As evolution has become for our contemporaries the expression and face of nature, morality becomes evolutionist in order to conform to nature.
Naturalist thinkers come to say that, just as the cosmos and the different life forms in the world are subjected to evolution, so in the same way human societies also evolve. Thus, in the course of this biological and sociobiological evolution of human societies, moral values also evolve. The evolutionary force which proceeds from "biological selfishness" or the "instinct of preservation" always generates new forms of adaptation. Law and ethics would be the cultural expressions of this adaptation. Therefore, naturalist philosophers say, when new conditions occur in the evolution process, with a change in the position of man in the cosmos and the biological world, it would be necessary to imagine a new system of values. Indeed, they say, the older system is no longer adapted to the new "ecosystem" which is being set up.
The sociological school of Max Weber, E.Durkheim, L.Levy-Bruhl takes the path of this evolutionism. For these authors, good is not an absolute. It is related to the society which imposes on its members the actions that are useful to its well-being.
To adopt this perspective is to assume beforehand that man is only an "historical moment" in the life of the world, and that all human morality and human values are relative. In practice, this way of thinking expresses itself in these familiar expressions which we find so often on the lips of our contemporaries to justify loose ways of behaving: "One has to keep up with his time""We are in 1997!" or "Why is the Church is so obstinate about abortion. It has become part of our today's culture!"
Concerning this theory, it is necessary to say that, if some cultural elements are indeed subjected to evolution, it is also clear that man in himself does not change, in his absolute difference from all other beings. This constancy of human nature is not only in relation with its biological specificity and especially with its neurological complexity. It is also because good and evil cannot be confused, because the laws of morality cannot be true and wrong at the same time. Death, suffering, thirst for truth, solidarity, freedom are not just cultural elaborations. They are facts and values which accompany man in all his historical situations.
5) The legal positivism and the new rights
The tradition of the legal positivism takes origin from the nominalism of Guillaume of Occam (1285 -1349), for whom man's will changes, depending of his interests and present utilities.
Thomas Hobbes (1588 -1679) applied this nominalism to the law and to the politics. For him, the "state of nature" was that of a perpetual war between the human individuals, each one fighting for his own right to life. In order to put an end to this situation, man resolved to give up their freedom to an omnipotent despot, Leviathan, who decides arbitrarily of what is good and what is unjust, what has to be believed, and what has to be mistrusted. For Hobbes, the law did not come from a "natural order" but from the will of the prince alone. Is right what the prince decides to be right. This opened the way to legal positivism.
John Locke (1632 -1704) opposed the absolutism advocated by Hobbes, and present a "state of nature" in which men not in conflict between themselves but subject to a common law. For Locke, this common law is the result of a "social contract", guaranteeing the right of private property, and of number of other rights, among which the freedom of conscience and the freedom of opinion. But these rights are not based on rationality but on the desires of the group which is able to make them present to the community.
The positivist theory of the right has been elaborated mainly, in our time, by Hans Kelsen (1881 -1973), for whom the law is a pure human construction, and must be considered for itself, in its authoritative and normative ("grundnorm") aspect, out of all reference to ethics, politics or sociology. Under the powerful influence of Kelsen, inventor of the constitutional model of the modern Europe and considered one of the most preeminent jurists of the twentieth century, a new conception of the right, and therefore of the human rights started to propagate in the western world. According to this new conception, the conception that man has inherent rights grounded in his nature of man is rejected. Only subsist the legal norms, these arrangements established in the codes, that can change according to the will or the interests of those who have the power to define them. Everyone can make prevail his/her own conception of the human rights, since any reference to a truth or to human nature do not exist any more in this new conception of rights.
The influence of this thought of the positive right, relativizing or even denying the reference of the human rights to an universal right founded on the participation in mankind, succeeded, these last years, to a certain subversion of the notion of "rights", that permitted the vote in the parliaments of legislation made in the name of some "rights" of man, which could prevail over the fundamental human rights to life, freedom of decision, freedom of thought, freedom of expression and religion.
We have seen therefore, these last years, a progressive but very real mutation of the notion of human rights, always moving more away of the model of 1948 based on the universal values inspired by the natural morals, to turn toward a conception more positive of "human rights". These new human rights are the expression of such or such group of pressure which manage to unite around its proposition a parliamentary consensus large enough to make of its proposition a norm, and to impose it to the rest of the country or the interested country group. New "human rights", unknown before, appeared thus in proceedings, in the international or national organizations, rights that often went against the universal rights, causing anger and rejection in the victims of these new rights. These rights concerned the rights of the homosexuals, with the condemnation of the "homophobia", - as example the right of the "gays" to the adoption or to the recourse to the artificial fertilizations and to mothers of substitution - the right given to scientific research to operate without limits, and therefore, for example, to use human embryos as material of laboratory, the right to a child, justifying the artificial procreation and the accumulation of frozen embryos, the right to the genetic or chromosomal normal, flawless child, justifying preimplantation diagnosis and abortion, the right to health, justifying the research on human embryonic stem cells, and the associated destruction of human embryos, the right to some forms of cloning.
These new "rights", that yesterday didn't exist, and which are proclaimed today as evidences, not only don't have an anthropological basis and are not based on any value, but oppose again often to actual, recognized rights proclaimed in the universal Declaration of 1948. This is how one denies to the pharmacists or the gynecologists the right to be able to make objection of conscience to the distribution of the contraceptives, of the pill of the day after, and the abortive pill RU 487. This refusal to take in account the right to conscientious objection is made by governments as an application of the "right to abortion". Abortion is proclaimed like the most fundamental of all rights, a right that would surpass all other rights.
C - PERSONALISM IN BIOETHICS28
The personalist point of view finds its roots in a deep reflection on human nature, human anthropology, on this word of "person", so rich and so complex. Man is a person because he is the only being on earth in which life becomes capable of a "reflection" on itself, of a self-determination. He is the only living being able to welcome and to discover the meaning of the things around him and to give sense to his expressions and to his conscious language.
The ontological distance which distinguished man from animals cannot be compared with what separates plants from reptiles or stones from plants. In each human being, in each human person, it is the whole world which is recapitulated and which takes on meaning. In the meantime, in each human person, the cosmos is surpassed, transcended. In each man one find the whole meaning of the universe, and the whole value of humanity.
1) What is a person?29
The word "person" comes from the latin "Persona" (in Greek prosopon), which means a mask for theater's representations. From this the word came to mean the character played by the actor. Finally the two meanings merged to signify the actor himself, who plays the character. Thus "persona" means both the man himself, with his own character, his own specificity and also his function, his position in the city, what he does, what his social situation and function are. To this notion will be attached the juridical conception of "persona" as:
"a being with rights and duties, specified by the law" (Bossuet). A slave could not be a person (he had no rights, no responsibility). What is more interesting for us is the moral meaning of "person":
"A person is an individual being who possesses the specificities which enable him to participate in the individual and moral society of human spirits: self-consciousness, reason, capacity to distinguish right from wrong, good from evil. Capacity of self-determination for reasons which one can justify in front of other rational beings"
The human person is thus characterized by reason, self-awareness, a capacity to distinguish right from wrong, evil from good, a capacity to determine oneself for reasons which can be justified before other rational beings.
The human person is a being with a body, marked by sexuality. This is a unique, invisible reality, although non perceptible through the senses, because it combines in an indivisible unity: body, soul and spirit.
The human person is free, with a freedom "for", a freedom which entails commitments, responsibilities, to participate in the life of the community.
The human person is unique, non repeatable, in body, psyche, and the personal exercise of freedom.
To understand the main points about human person, one has to refer to the characteristics of a person when adult, in good health, in full possession of his or her intellectual capacities, and able to freely self-determine himself or herself:
a) The person is a being who has a biochemical body belonging to the human species (the fist weeks human embryo cannot be treated as just a mass of immature cells, or as if it were a mouse embryo).
b) The person is marked by a sexuality, at the biological level and at the psychological level (to manipulate someone's sexuality is to manipulate his or her being in one of his or her more profound dimensions).
c) The person is a non visible reality: he or she is an individual. It is possible to take out some part from his or her body, but it is impossible to cut him or her in two parts in order to make two persons out of one. This definition encounters some difficulties when it comes to the genesis of twins, or the possibility of hybridization or cloning from early cells in the embryo's life. Genetics helps in showing that, in twins, by accident, a new program, a new individual comes from of a first program, a first individual. The individuality of each program, of each being cannot be denied.
d) The person is a being who speaks. A dog communicates: a person understands the meaning of a sentence and gives a signification to a speech. Education brings a human being from a state of non-speaking person to a state of a person able to give names to what surrounds her, to give herself a name, to communicate with other persons, to understand the desires of others, to love other persons. From this point of view, it is important to stress that the fruit of conception, zygote then embryo, from the beginning, is taken into the network of human communication. As soon as the mother learns that she is pregnant, communication starts between her and her future child. In his access to the world of culture and language, the human being depends on biology. But biology depends on the quality of the communication between him and other human beings. As a consequence, the more a given behavior separates what is biological from what is cultural in a given person, the more this person is disturbed. For example, artificial insemination with sperm from a donor foreign to the couple (heterologous insemination) separates biological fatherhood from cultural fatherhood, and disturbs the couple.
e) The person is a reflecting consciousness ( a consciousness which reflects on himself or herself, on his or her decisions). He or she is capable to say "I". He or she is conscious of self, of past, present, and anticipated future.
f) The person is free, not with a freedom of autarchy, a "power to do whatever one's wants", but a freedom "for" doing something worthy, a freedom for assuming one's responsibilities as a human being. It is true that this freedom is always conditioned by the body, the psyche, the society. It is from these conditions that freedom is exercised. Man has thus the power to alienate himself, to give up his freedom, to enslave himself (to drugs, pleasures, power, money, possessions, idolatries), and the power to assume his own history and to become more human. It is there that we find the actual heart, the actual core of the person, a heart which does not explain itself, which cannot be demonstrated, but which is revealed through the exigencies and the acts of the human person. True freedom is responsibility. It is responsibility which establishes the dignity of the human person.
g) The person is singular, unique in the world. He or she is singular, unique:
- Because of the body, especially the genetic code and potential, the brain (the specific network of synapsis contacts between her neurons).
- Because of the psyche. The interrelations of one's own desires, tendencies with one's surrounding is never the same from one individual to the other.
- Because of he or she specific way of exercising freedom.
- Because of his or her history.
2) Different kinds of personalism
In teleological personalism, the main concern is with the ends of an action. Without neglecting the intrinsic value of the acts, the objective quality of the acts, the main interest is the realization of the good of the person. As a consequence, the telogical personalist do not recognize to the means, to the intermediary acts, a permanent objective value. They will not therefore recognize the "intrinsece malum", i.e. the evil attached to some specific acts such as contraceptive acts, sterilization, or the destruction of embryos for an in vitro fertilization, considering only the good of the health of the mother or the good of conception.
In the hermeneutical personalism, moral action is valued through an interpretation of the intention presiding to this act. The authors representative of this line of thought say that the only way to judge a human person and its act is an interpretation of his or her intentions - a hermeneutic.30 This results in a subjective interpretation of human acts, which does not respect the fullness of human person - and the objective character of the acts. A person can always claim that she did not wanted to kill somebody, if she did kill this person, even without willing it, she is homicide, and this is grave.
In the relational personalism, the human person receives her definition from his or her capacity to relates to other persons. This point of view has its truth and is rich, but we cannot forget the essential, what is the person in one's self, otologically. If man enters in relation with fellow man, this is because of his nature, of what he is. It is a mistake to oppose relational personalism and ontological personalism.
In the personalism founded on ontology, the human being is first considered from what he is, and not only for what he does. Man is an existential and essential being from the beginning to the end, from conception to natural death. The person is first a spiritualized body, an incarnated spirit, whose value comes from what he or she is. In each one of his or her choices, the person commit what herself, her existence and her essence, her body and her spirit. In each choice, there is not only the exercise of the choice, the possibility of choosing, but also the conditions of this choice.
Because of this "holistic", encompassing vision of what is a person, because the ontological personalism considers the person in her wholeness, in what she is, in her "essere", this personalism proposes to ethics, as prime objective, to realize this "essere", to realize man in man. From the personalist point of view, the first question which one has to ask in front of a proposed human action in the field of bio-medical sciences is:
"does this action contribute to the humanization of human persons?".
3) Personalist bioethics31
From the personalist point of view different principles emerge:
1) The value of the body
The body is not simply an object which can be touched, weighted, which can corrupt. It is also, and before all, a coessential part of the subject, that is to say of the person.
The person, in her body and with her body receives her individuality and her difference. She becomes this particular individual, man or woman. The person, in her body and with her body manifests herself and communicates herself in the society of her fellows persons. She becomes a whole set of "signs" and "languages". In her body the person finds her limits (i.e. physical pain and death). Through the body the spirit becomes flesh and enters into history. It is the body which gives us the time. The moral life is a life inscribed in time.
The body introduces the limits, pain and death, which underline the transcendence of the human being.
The person understood as "I" outpasses the body, is richer than the body, and transcends it. But she lives with the body in a substantial unity.
This conception of the body is important for health education, sexual education.
Everyone of us conceives the body of others through the conception of the body he formed out of experience with his own body. If he has trivialized, undervalued his body, he will also trivialize, undervalue the body of the other persons. If he has treated his body as an instrument, he will treat the body of other persons as an instrument.
Whenever man grows up, rises in humanity, he also promotes in himself the body, in relation with the spirit who dwells in this body.
These reflections on the body have immediate consequences in the field of sexual life, in relation with procreation. The sexual act is not simply a biological act. It is not either the expression of a feeling. It implies the totality of the persons in the unity-complementarity of the sexes. It will have to be considered not only in its intentional dimension and in its realization, but also in the dimension of the unity-totality of bodies and spirits it realizes, that is to say in its procreative dimension. This is important for evaluating the artificial procreation techniques.
The Instruction Donum Vitae32 insists on the importance of the body, as expression of the human person, for any judgment in the field of bioethics. It declares that the moral criteria which have to be applied to clarify the problems encountered in bioethics have to be deducted from a just conception of the nature of the human person:
"Which moral criteria must be applied in order to clarify the problems posed today in the field of biomedicine? The answer to this question presupposes a proper idea of the nature of the human person in his bodily dimension"(Donum Vitae nr 3).
The Instruction explains what is this "proper idea": it means that we have to consider the human person in its unified wholeness.33 The human body is indeed a constitutive part of the human person who reveals herself through it:
"For it is only in keeping with his true nature that the human person can achieve self-realization as a "unified totality" and this nature is at the same time corporal and spiritual. By virtue of its substantial union with a spiritual soul, the human body cannot be considered as a mere complex of tissues, organs and functions, nor can it be evaluated in the same way as the body of animals; rather it is a constitutive part of the person who manifest and expresses himself through it"(Donum Vitae nr 3)
From this, it comes clear that any intervention on the human body has a human signification and brings a human responsibility:
"An intervention on the human body affects not only the tissues, the organs and their functions but also involves the person himself on different levels. It involves, therefore, perhaps in an implicit but nonetheless real way, a moral significance and responsibility"(Donum vitae nr 3)
The Instruction quotes at this point of view Pope John Paul II when he said:
"In the body and through the body, one touches the human person in his concrete reality" (J.P.II, Discourse to those taking part in the 35th General Assembly of the World Medical Association, 29 October 1983)
2) the defense of body life as "fundamental value".
The life of the body is not something out of the considerations of the person. It is the fundamental value for the person. One speaks about "fundamental value" to signify that the life of the body do not resume the whole riches of the person - who is first of all spirit - and this way transcends the body itself and its temporality. But, for the person, the body is essential because he is the incarnation of the "I". It is the unique foundation upon which and through which the person realizes herself and enters time and space. At this point of view personalism, phenomenology, existentialism agree to recognize to the body not only the function of a tool, but also its fundamental importance in the exercise of subjectivity.
Physical life do not resume in itself the value of the human person, but is a fundamental good, open to eternity.
3) The principle of totality or "therapeutic principle"
When the surgeon, in order to save the life of a patient, takes out an organ, he does not violate the principle of the inviolability of human life: in fact this same principle obliges this surgeon to bring an alteration to one part of the body for the sake of the health of the whole body. As this principle is the basis of the licit character of all the medical and surgical therapeutics it is called "therapeutic principle". One can sacrifice a part of the body for the sake of the whole person.34 One can accept the sacrifice of the uterus, the ovaries in case of a cancer for the sake of remaining alive.
However, this principle applies only when it is the whole body which is at stake. It is justified to destroy one part of the body in order to save the life of the whole body. But it is not justified to destroy one part of the body in order to save one another part, or for the benefit of this other part.. For example one cannot "change" his sex (i.e. change some external secondary characters of sexuality) in order to heal troubles of the spirit (transsexualism); in the same way it is not lawful to sterilize a woman for giving her a psychical relief.
4) The principle of freedom and responsibility
Freedom is a fundamental value for personalist ethics. However, for this ethics, the right to defend physical life comes first, before the right to freedom. In other words, freedom must act in a responsible way toward one's own life and the life of others. This affirmation is justified by the fact that, in order to be free, one has first to be alive. Thus life is the primary condition for the exercise of freedom. This priority of the values of human life over those of freedom give a reference point for the medical doctor and for the patient. It sets up for them the privileged object of their responsibility.
5) The principle of sociality
Every particular person has to realize herself participating in the good of fellow men.
In what concerns promoting life and health this implies that every citizen must consider his own life and the life of others as a social good. This obliges the community to promote the life and the health of every citizen.
6) The principle of subsidiarity
This principle of sociality is associated with the principle of subsidiarity. The principle of subsidiarity calls the community to give more help where help is more needed, that is to say to care more for the person who needs more care, to spend more money for the person who is more sick.
III - THE ETHICS OF STEM CELL RESEARCH, RECENT TRENDS
A - DEFINITIONS
Stem cells (SCs) are defined as clonogenic cells capable of both self-renewal and multilineage differentiation .
A ‘stem’ cell has four critical characteristics:
- undifferentiated features (as defined by the lack of differentiation markers),
- self-renewing capacity (the prolonged capacity to multiply without differentiating),
- pluripotentiality (the capacity to create differentiated cells of various kind, progenitors of ‘specialized’ cells (tissue-specific).
- and the ability to regenerate the corresponding tissue or elements of it,
- a fifth characteristic (which has recently been detected at an experimental level) of stem cells is the fact that when transplanted into a damaged tissue these tend to foster the cellular reproduction in this tissue.
The capacity of stem cells to generate more differentiated cells is called ‘potency’. It is said that a stem cell is ‘totipotent’ when it is able to create all the cell types of the human organism, including those of the trophoblast, from which come the embryonic annexes (placenta). The cells that make the early embryo up to the stage of morula (4-5 days after fertilization) are "totipotent".
It is said that a stem cell is ‘pluripotent’ when it has the capacity to give rise to every cell type in the body, but not those of the embryonic annexes. Pluripotent stem cells are derived from germ cells or from cells that can make germ cells, that is the cells of the early embryo. There are three types of mammalian pluripotent stem cells: embryonal carcinoma (EC) cells, (the stem cells of testicular tumors); embryonic stem (ES) cells (derived from pre-implantation embryos); and embryonic germ (EG) cells (derived from primordial germ cells (PGs) of the post-implantation embryo).
Stem cells are said to be "multipotent" when they are able to give rise to different types of differentiated cells, but not to every cell in the body. The so called "adult stem cells" or "somatic" stem cells are multipotent stem cells.
In man, the sources of stem cells that have been identified hitherto are :
- the embryo in the first stages of its development (the internal cell mass of the blastocysts), (“embryonic stem cells”)
- the foetus (in particular the germ cells or EGCs),
- the umbilical cord, the amniotic membrane and the placenta
- and various tissues in adults (bone marrow, muscle, fat, brain, skin, teeth, myocardium, pancreatic tissue, and others).(“somatic stem cells” or “adult stem cells”)
B - HISTORY
The word "stem cell" had been proposed for the first time in 1909 by the russian scientist Alexander Maximov (1874-1928)35 to designate an hypothetic cell, undifferentiated, which he supposed to be at the origin of the different cellular lines participating in the hematopoiesis. But this theory was not accepted because the scientists at that time thought that the cellular differentiation was taking place in the embryo, once and for all, in an irreversible way.
The concept of “ stem cell ” was reintroduced in the years 50 to explain why the graft of bone marrow cells in irradiated animals allowed a total reconstitution of the hematopoiesis, and, from there, of the blood cellular compartment which had been wiped out by the radiations (Lorenze E et al.1951).36
In 1961, Till et McCullough, showed that indeed bone marrow contained such cells able to constitute visible colonies in irradiated animals.37 But it was only in 1962 that the term “ stem cell ” made its apparition in scientific literature to designate multipotent cells (John Goodman et Georges Hogson).38 The discovery of embryonic stem cells came later, and was the fruit of studies in the development of the embryo.
Scientists had realized that there was a restricted period during early mouse development when certain normal cells had a remarkable ability to differentiate into a huge variety of cell types. In particular, the inner cell mass of the mammalian blastocyst was known to contain undifferentiated non-committed cells with the potential to enter a full range of developmental pathways.
Those early embryonic stem cells could be taken from the embryo and grown in the laboratory. They were capable of self-renewal. When placed back in a developing embryo, they contributed to all of the tissues of the mouse - including the germ line (F.A.Brook et al., 1997).39
In 1981 Gail Martin and Martin Evans, independently40, isolated embryonic stem cells from the inner cell masses of mouse blastocysts and have then grown into culture. A true revolution started in the field of stem cells in november199841. In a technological breakthrough that triggered a burst of research and a whirlwind of ethical debate, two teams of researchers, working separately, that of J.A.Thomson42, and that of J.D.Gearhardt (M.J.Schamblott et al., 1998)43 announced simultaneously, that they had managed to isolate and put into culture human embryonic stem cells.
A - RESEARCH ON HUMAN EMBRYONIC STEM CELLS (hES)
1) Interest and limits of hES cells
Human embryonic stem cells (hESCs) offer an unique set of properties, coming from their character of pluripotent stem cells:
- prolonged undifferentiated proliferation in culture, without differentiating, permitting an unlimited self-renewal and therefore a propagation in high numbers in vitro ;
- stable developmental potential to form derivatives from all three embryonic germ layer, even after prolonged culture;
- diploids cells, with no anomalies and with a remarkably stable karyotype;44
- they express high levels of telomerase, and this even after more than 300 population doubling and passage for more than one year in culture;45
- they can give while differentiating all cellular types of the organism, and this is shown when they are injected into a blastocyst.46 ES cell descendants in the resulting chimeric embryo are represented among all cell types, including functional gametes
- When ES cells are aggregated with developmentally compromised tetraploid embryos (ES tetraploid complementation), they can produce all of the cells of the developing fetus, and they support the development of this fetus (A.Nagy et al., 1990)47.
All these properties give to the cells hES a unique capacity to assure the repair of tissues and organs damaged, superior to that of the other types of stem cells.48
Besides, while these hES cells can be extracted in abundance from human embryos, somatic stem cells extracted from tissues or organs of the adult human individuals are rare, of difficult isolation and uncertain culture, and the stem cells from umbilical cord blood are in a limited number by cord unit. For the scientists working in the field of stem cells, the hES cells represent thus the "golden standard" of stem cells, their inescapable point of reference with regard to pluripotence and differentiation.
But these human embryonic stem cells have proved also problematic, since the beginning of this research, and this at a double title, practical and ethical.
From a practical point of view, the hESCs are indeed unusable as they are for a therapeutic purpose, and this for two main reasons:
- The first is that these cells are tumorigenic, growing into teratomas or teratocarcinomas (ESTCs)49 when injected anywhere in the organism of an individual. This property is linked with the pluripotence of these cells. This is why ES cells cannot be used in vivo when they are still in the undifferentiated, pluripotent state. What could be used are cells derived from the hESCs.
- the second reason is the fact that they are rejected by the immune defenses of the organism when administered to an individual. Early work showed that hESCs express very low levels of Major Histocompatibility Complex (MHC) class I molecules, do not express MHC class-II molecules50 and fail to elicit immune responses in immune-competent mice, supporting the hypothesis that these cells have immune-privilege properties. However, some more recent research showed however that some ESCs cells – but not all - are recognized by the immune cells and induce an immunological reaction, although the exact mechanisms of this difference between the ESCs are still not well understood.51
From the ethical point of view, on the other hand, the obstacle is absolute, since it is necessary to destroy human embryos to get hESCs. The only way to get around this obstacle is:
either to ignore it and to carry on research and possible application to patients regardless of ethics, or to look for an alternative way which would allow to get pluripotent stem cells, having the same qualities as the hESCs, but not requiring the destruction of human embryos for obtaining them.
2) Proposals for turning the biological difficulties of hESCs
The application of the regenerative capacities of embryonic stem cells to patients is therefore impeded both by biological obstacles and by the due respect to human embryos.
The first propositions aiming to use in clinic the hESCs tried to get round the immunological obstacle. It was the proposal of “therapeutic cloning”, and, more recently, the proposal of the "cybrides."
a) "therapeutic cloning" for the production of immuno-compatible hES
It is the development of the cloning techniques by transfer of the nucleus of somatic cells in an enucleated ovocyte (Ian Wilmut and K.H.S. Campbell, February 27 1997)52 that provided the researchers working in the domain of embryonic stem cells a way of getting out of the immunological problem of hESCs rejection.
This was called “therapeutic cloning” Now scientists prefer to speak of “research cloning”, or, better, non reproductive “somatic cell nuclear transfer”(SCNT).53 The application of the somatic cell nuclear transfer technique (“cloning”) to the creation of cloned human embryos from which hESCs could be extracted was proposed in 1999 by R.P.Lanza and collaborators54 as a solution to the problem of hESCs histocompatibilty with a prospective recipient (patient). It could give the possibility of obtaining hESCs compatible immunologically with the patient's organism to which they would be destined. The somatic cells used to create the cloned embryos would indeed come from the individual who would be afterward the recipient of the hESCs produced from the cloned embryos.55 However, this proposition of ”therapeutic cloning” immediately came up against serious difficulties, biologic and ethical.
From a biological point of view, the technique of the nuclear transfer, even limited to the only production of blastocystes donors of original cells, gave positive and solid results only in some species (mouse, bovine, rabbit). Among the primates, the team of Oregon National Primate Research Center, after years of tentatives with poor results managed to get two lineages of ESCs from 35 blastocysts of macacus rhesus created by SCNT (from a total of 213 created embryos)(J.A.Byrne et al., novembre 2007)56, then, more lately, two other lineages of ESCs from six blastocysts obtained from a total of 71 embryos created by SCNT.57 In man, therapeutic cloning has not given any substantial result. In May 2005, HAS.Murdoch, and Miodrag Stojkovics (United Kingdom)58 had announced the creation of the first cloned human embryo but had not extracted any cell from this embryo. More lately (January 2008), a group of researchers of the Stemagen corporation ( California)(A.J.French, S.H.Wood et al.)59 announced the creation of 14 human embryos by cloning, from 29 ovocytes. Five of these embryos would have been able to develop up to the stage of blastocyst, but these authors didn't try to extract any ES cells from them.Finally, J.Li et al. (Shandong, Chine)(2009)60 made known that they had obtained 5 human blastocysts out of 25 embryos created by SCNT using 135 human ovocytes coming from 12 donors) but there again these researchers didn't try to get hES cells from these blastocysts. The "therapeutic cloning" technique in man remains therefore a very expensive enterprise with poor results, requiring a disproportionate number of human ovocytes to be done.61
On the ethical standpoint, “therapeutic cloning” meets objections even stronger (R.P.Lanza et al (2000)62 than the objections that are raised against the obtention of hESCs from destroyed human embryos. "therapeutic cloning" requires indeed the deliberate creation of an early-stage human embryo, followed by its disaggregation. Even if "therapeutic cloning" were to become more efficient and produce consistent results in the human species, it will always be morally illicit because it makes a deliberate choice against the life of a human being in favor of a possible health benefit to other individuals.
This is a high point in the "commodity making" of human life, for specific interests. Such action would be contrary to the ethical principle expressed by Emanuel Kant, according to which an individual human being should not be thought of solely as a means, but always as an end:
"Acts in such a way that you treat humanity, whether in your own person or in the person of any other, never merely as a means to an end, but always at the same time as an end".63
b) the proposal of the human embryos hybrid cytoplasmic ("cybrids")
Because of the difficulty of “therapeutic cloning” caused by the need for a disproportionate number of human ovocytes, some have proposed to resort to the technique of the interspecies somatic cell nuclear transfer (iSCNT), in which the nucleus of a human somatic cell is transferred in an enucleated non human ovocyte (bovine ovocyte for example).64 The result would be a human embryo "hybrid cytoplasmic", named for this reason "cybrid"65, presenting a human nuclear DNA and a cytoplasm containing an animal mitochondrial DNA. This technique had been proposed to assure the survival of some species in way of extinction, but it had hardly had success, except for the birth of a hybrid gaur/bovine "Noah", who had not survived besides.66
The team of Advanced Cell Technologies (Massachusetts), led by Robert P.Lanza, Jose B.Cibelli and Michael D.West, was the first to study this possibility. In 1999, these authors announced that they have created some embryos by transfer of the nucleus of somatic human cells in the enucleated ovocyte of a cow.67 26% of these embryos (nr 6) would have been able to develop until the stage of 4-16 cells and one among them would have reached the stage of 400 cells. The success of the operation was therefore more that limited. In December 2003, K.H.Chang e collaborators of the Seoul National University (South Korea)68 returned to the creation, by the same technique, of man / cow hybrids embryos, with modest results: out of a total of n 286 embryos thus prepared, only four embryos were able to develop up to the stage of morula or blastocyst, and no hES cells were obtained from these blastocysts. The same authors published in October 2004 a follow-up of this study.69 Out of 194 hybrid man/cow embryos created by SCNT, two embryos only arrived to the stage of blastocyst. Finally, in April 2006, Karl Illmmensee, Panayiotis Zavos and collaborators70 published the creation of 37 man / cow hybrids embryos, of which seven were said to have arrived to the stage of blastocyst. No ES cells were obtained from these blastocysts.
Despite this repeated lack of success, the British HFEA (Human Fertilization and Embryology Authority), declared on 5 September 2007 that it was in favor of the creation of such "cybrids", declaring them “necessary and desirable in both scientific and ethical terms“.71
Pointless and with no future from a biological point of view, the creation of "cybrids" is however a serious matter from an ethical point of view. Even if the individual resulting from this transfer into a bovine oocyte is genetically 99% human, the process itself does not respect the humankind of which the cybrid is a part, as a "member of the human family
3) present proposals
The impossibility to get a success of SCNT in man, including the proposition of the "cybrids", brought the researchers to devise new strategies for bringing the transplanted hESCs.
The most logical means to assure that a patient's organism can accept a transplantation of cells hES during a prolonged period would be to modify the patient's immunological mechanisms, so that his/her organism becomes tolerant toward the antigens of the donor presents on the surface of the transplanted cells. But this requires the persistence of a functional thymus: some studies were made in this sense to restore the thymic function, for example by administration of growth thymic factors.72 But we are there still far from a possible clinical application.
A strategy that could be immediately more accessible would be to cotransplant the hESCs with cells derived from the same hESCs in order to establish chimeras in the bone marrow and the thymus of the recipient that would present the donor's antigens to the T cells in formation, making the recipient tolerant to the cells which will derive from the transplanted hESCs.73
One could also improve the immunological tolerance to these cells by genetic manipulation, thanks to a modification of the expression of the molecules of the major complex major of histocompatibility. There again, such an enterprise appears disproportionate, as long as the advantages provided by the cells hES won't have been demonstrated more clearly.
The more immediate solution appears, at the present time, to find a HLA correspondence between the organism of the donor and a particular line of hESCs. It implies to dispose of numerous hESC lines, and therefore to create actual banks of human embryonic stem cells74, on the model of cord blood stem cells banks.
It has been calculated that a bank of hESCs that would contain about 150 lines of hESCs expressing different combinations of HLA molecules would present enough variations to correspond to the HLA haplotypes of the largest part of the individuals in the population.75 The same type of assessment made for Japan76 showed that, with a bank with hES cell lines derived from 170 embryos selected at random, 80% of the patients could find in such a hESCs bank at least one hESC line with only one lack of match with one of the three HLA loci. But only one difference in the antigens mH (minor histocompatibility antigens) is enough to provoke an acute rejection of the tissues derived from the hESCs.77 In the countries of immigration, where can coexist multiple ethnic groups, the number of hESC lines necessary to cover the major part of population’s needs could be very larger. - 1500 alleles have been identified on 12 HLA loci, and other alleles are discovered.78
Presently, the solution most commonly used to get around the immunological obstacle, is to associate to the graft of the hESCs or their cellular derivatives an administration of immunosuppressive agents , as in a the graft of a solid organ, and to prolong this administration as long as the action of these cells will be necessary for securing the cellular regeneration which is aimed at in the particular treated patient.79 But, even after one prolonged period of immunosuppression, in the long, time, their rejection will be unavoidable, and a new graft of such hES cells will meet an even more vigorous rejection reaction.
5) Clinical trials of hESCs
The clinical trial of phase 1 of the GRNOPC1 cells (hESC-derived oligodendrocyte progenitor cells) by the American company Geron80, authorized in January 2009 by the FDA, suspended in August 2009, and again allowed in July 2010, has interested two patients who had a complete section of the spinal cord. It has been done under the protection of an immunosuppressive treatment81, and therefore don't give an answer to the main questions regarding hESCs transplantation in human - since the doses of injected cells were to limited to have a therapeutic effect, and that the rejection of these cells was avoided by the immunosuppression. This trial has been stopped recently by the company itself. Theoretically for economic reason.
The second clinical trial regarding cells derived from hESCs concerns the retinal pigmentary epithélial cells (RPE)82. It received the approval of the FDA in January 2011. This second test, of I / II phase, conducted by the company Advanced Cell technology, under the direction of Robert Lanza, aims to treat, by administration under the retina of REP, 12 patients suffering of Stargardt disease (childhood macular dystrophy leading to blindness) and 12 patients suffering from dry macular retinal degeneration of the elderly. The clinical trial is based on a thorough preclinical experimentation of the RPE cells in the mouse. The treated animals received an immunosuppressive treatment with cyclosporine83, and it is the same for the treated patients. Two persons have been treated that way up to now, with no side effects and as a result some improvement of their vision.
6) The ethical problem with hESCs remains
Even if the therapeutic cloning were efficient, or if we could dispose of large hESCs banks, or if keeping an immunosuppressive treatment after hESCs transplantation would not raise disproportionate inconvenient for the patients, the present use of hESCs in research, and their possible future use in patients raises serious ethical problems, because hESCs whatever they are, and whatever is the technique used to make them more acceptable to the recipient’s organism’s, are obtained and will be obtained at the price of a voluntary disaggregation of human embryos
Even the scientist who only uses hESC lines bought from a commercial company or obtained from a friendly laboratory , and who do not destroy himself any human embryo cooperates to this illicit destruction, and therefore participates morally to the destruction of human embryos, and even encourages it as a commercial client. Research on pluripotent stem cells, with all its promises in term of possible applications in regenerative medicine stumbles therefore on this inescapable ethical obstacle . The end do not justify the means. You cannot put in the same balance human life on one side, even if its is the lives of human embryos, and a possible, but yet to demonstrate benefit for the health of some patients.
B - ALTERNATIVE PROPOSALS TO GET CELLS hES LIKE WITHOUT HAVING TO DESTROY HUMAN EMBRYOS
The embryonic stem cells, which are the only type of pluripotent stem cells that can be easily obtained from human organic structures, offer an incontestable interest when compared to the well known somatic stem cells, because of their pluripotence that allows them to proliferate abundantly in culture, with a remarkable stability, to differentiate in all cellular types of the organism, and to have proved regenerative capacities, especially in the neural tissues. The scientists working in the field of “adult” stem cells have tried repeatedly to isolate through culture and selection with molecular markers, in the tissues of the human adult organism, a type of cell that would have the same properties of pluripotence that the ESCs, but would not require to be produced through the destruction of a human embryo. Although some lines of pluripotent stem cells have been obtained that way from bone marrow or from umbilical cord blood, this has been very difficult to realize, and more often than not has proved difficult to reproduce.
For that reason, between the research on human embryonic stem cells, and the research on non embryonic, adult stem cells, or stem cells from the umbilical cord, placenta or amnios, a third way of research on stem cells has opened: the research on alternative proposals to embryonic stem cells, with the aim of obtaining pluripotent stem cells with the qualities of the embryonic stem cells, without having to use human embryos for that purpose.
One can distinguish two types of alternative propositions for obtaining hESCs- like, pluripotent stem cells, in an ethical way:
- The alternative proposals based on the use of defective preimplantation human embryos.
- dying embryos rejected by the IVF industry;
- parthenogenetic embryos;
- embryos that are created defective, “altered” .
- The alternative proposals that do not entail the destruction of human embryos, and that are based either on the use of isolated blastomeres or on cellular reprogramming.
1) Alternative proposals to obtain hES-like stem cells from human embryos with no development potential
Four proposals for an ethically acceptable alternative method of obtaining pluripotent, hESC-like stem, without the need to use normal, healthy embryos endowed with the potential of developing into a human fetus have been presented.
They are all based on the use of defective embryos that have lost the potential of developing.
- proposal to use poor-quality embryos rejected by the IVF centres (H.A.Zucker and D.W.Landry).
- proposal to use embryos created by parthenogenesis.
- proposal to use embryos created defective and unable to implant: ANT of W.Hurlbut, OAR of M.Grompe.
a) Utilization of poor quality embryos
The first proposition, that has been presented by D.Landry e Howard Zucker (2004)84 is to use as a source of hESCs these human embryos created in the centers of FIV and that are put aside and eliminated because of their poor development or abnormal morphology. These embryos are unable to implant and have therefore no potential for developing into human fetuses.But they contain still alive cells, which are potential source of hESCs, as shown by J.A.Byrne, J.B.Gurdon and collaborators (2002).85 P.H.Lerou, G.Q.Daley, and collaborators (Harvard Medical School, Boston) (February 2008)86 showed that there was a possibility, but very reduced (0,6%) to derive hESCs from three days poor quality embryos. The efficiency of the derivation of hESCs was clearly better (4,1%) when these embryos of dubious vitality had reached five days of development, and it went to 8.5% when these embryos had become blastocysts.
From the biological point of view, this proposition doesn't bring a true solution to the problem because it requires that the poor quality embryos have reach the blastocyst stage, which is exceptional. Most embryos who stop in their development or present morphological changes don't arrive to this stage of development. It doesn't solve either the problem of the immunological rejection of the hESCs.
From the ethical point of view, the idea of using embryos facing certain death as a source of hES cells might be defended based on the analogy of taking organs from brain-dead patients.
However, to be able to justify taking the inner cell mass of these embryos, there would have to be certainty about their state of "embryonic death". At present there are no reliable, early criteria for declaring an embryo "dead". Exposure to a period of 24h observation in order to establish a diagnosis of embryonic "death" based solely on the absence of division during this period is judged by many to be inadequate.87 In these conditions, the use of apparently viable human embryos for the obtaining of cells hES doesn't appear to be acceptable from an ethical standpoint, since there will be no certainty on their near death.
Parthenogenesis is the process by which a new individual develops from a non-fertilized oocyte. It can be induced in mammals by artificial, chemical or electrical stimulation of an oocyte, which then turns into a zygote, and develops to form an embryo that only has the genetic program of the mother and is called a "parthenote". In primates, embryos created in this way cannot develop correctly and are generally lost before they can implant88 probably due to a lack of expression of the paternal imprinted genes.
J.B.Cibelli et al.(2002)89 have proposed the recourse to parthenogenesis as a way of obtaining immunocompatible hES cells from a female donor. This approach would moreover be ethically acceptable, because it does not lead to destroying normal human embryos. They derived embryonic-like stem cells from four monkey (Macaca fascicularis) embryos at the blastocyst stage, obtained through the development of metaphase II oocytes that were not fertilized but activated by a calcium wave (ionomycin). These ES cells were capable of multiplying in vitro for more than ten months (K.E.Vrana et al., 2003).90 ES cells obtained from "parthenote" embryos have characteristics similar to those of hES cells collected from viable embryos created by fertilization.
With hESCs derived from parthenogenetically created embryos, we would have pluripotent cells of a quality equal to that of ES cells from fertilization-created embryos, histocompatible with the recipient when the parthenogenetically activated oocyte came from that same person, and ethically acceptable, for the supporters of this alternative proposal, because the product of non-fertilized human oocyte activation, i.e. the parthenogenetically created embryo should not be regarded, for them, as a real embryo. This "parthenote", incapable of developing beyond the blastocyst stage, with no future potential, should be considered as potentially dead, an apparent organism breaking down, and treated as such.
This opinion about the ethics of hES cells derivation from parthenogenesis-embryos seems however questionable, because these activated human oocytes behave exactly like normal embryos until their epigenetic imbalance curbs their development and stops them from implanting in utero.91
c) Altered Nuclear transfer: W.Hurlbut
The proposal presented by William Hurlbut (Stanford University, Program in human biology)(2004)92 entitled "Altered Nuclear Transfer "(ANT) aims to create by cloning (SCNT), an "altered" human embryo93, that is to say, incapable of implanting or developing after implantation, which could become a morally licit source of hES cells. This embryo would have been created with a genetic defect preventing it from implanting, but could provide good quality embryonic stem cells. Hurlbut's plan is to create by RNA interference embryos deficient in the cdx2 gene needed for trophoblast individuation.94 cdx2-deficient blastocysts are unable to implant but develop an inner cell mass from which embryonic stem cells can be derived. Once these cells had been obtained, they would have their cdx2 gene re-expressed , turning that way into normal pluripotent hES cells. A.Meissner and R.Jaenisch (2005)95 showed in the mouse that it was effectively possible to neutralize the cdx2 gene in mouse fibroblasts and use these fibroblasts to create through SCNT a cdx2-deficient embryo, unable to implant, but from which it was possible to derive ES cells, to which a normal cdx2 function could be restored afterward by transferring the gene.
According to Hurlbut, the biological result of "altered nuclear transfer" with cdx2 deficiency would not be an embryo, since it would not have the ability to develop, but a "group of cloned cells", comparable to a teratoma, the tumor that forms from embryos arrested in their development, a disorganized mass with no future. W.B.Hurlbut thinks that it would be morally licit to destroy such "altered embryos" in order to collect their inner cell mass (W.B.Hurlbut, 2004).96
However, this idea of W.B.Hurlbut is not without its weak points, scientifically and ethically:97
- From a scientific standpoint, it is not known what might happen to human embryos if they were made cdx2-deficient, given that this gene is a "homeobox" gene, of the "Hox" essential gene family98, which definitely plays a number of important roles in embryo development.
- From an ethical standpoint, the comparison between a defective embryo that does not manage to implant and a teratoma is not correct. The teratoma is a cell formation that has no organization, no internal drive to develop, and is therefore not an "organism" or a biological "individual". The cdx2–deficient embryo behaved like an organism with a development plan, through to the blastocyst stage. The fact that it was unable to implant takes nothing away from its quality as a biological individual.
- The proposal to manipulate the genome of human embryos created by cloning to make them incapable of implantation is perplexing. This would be indeed “intentionally downgrading the moral status of human embryos, in order to render them suitable for research that was otherwise deemed immoral” (L.Turnpenny)99, in other words using immoral means for an end which may be good, a processus unacceptable in ethics.
d) Markus Grompe's Oocyte assisted reprogramming (OAR)
Markus Grompe and Robert George took up William Hurlbut’s idea of ANT and modified it (2005).100 Their idea is to make the nanog gene overexpress, a central requirement for the acquisition of pluripotency by pre-implantation embryo cells.101 M.Grompe thinks that by artificially inducing Nanog to overproduce in the somatic cell nucleus that is to be transferred to an oocyte so as to produce a cloned embryo, the embryo resulting from the transfer would not be a real embryo but a group of pluripotent cells, from which hES cells could be derived without troubling the conscience. M.Grompe's proposal calls up some reservations:
- from a biological standpoint, the scientific basis on which M.Grompe builds his project is very uncertain. Nanog overexpression in the zygote may cause the cells of the embryo in the segmentation phase to become pluripotent too soon, compromising the survival of the embryo, but that has not been proved, especially as Nanog does not act alone and requires the combined expression of at least Oct4, SOX2 and STAT3.102
- from an ethical standpoint, M.Grompe's proposed operation necessarily involves the creation of an embryo by SCNT ; extracting hES, if this is possible, presupposes the prior destruction of the embryo. Here we find the same objections as those directed earlier at W.Hurlbut’s ANT proposal.
e) Summary: the moral status of defective embryos
Hurlbut's ANT project, Grompe's OAR and the proposal to take advantage of the "parthenote" embryos produced by parthenogenesis have in common the idea of creating an abnormal, defective human embryo, unable to implant, which could be considered, as a result, simply as a "biological artefact", whilst still being capable of delivering good-quality pluripotent cells to researchers.
Such an opinion is based on an error of judgement, because at the start the parthenote embryo, the cdx2-deficient embryo or the Nanog overexpressed-embryo still has the principle of unity and of coherent development conferred on it by its genome.
For example, an embryo whose cdx2 gene has been "silenced" by RNA interference, was probably developing well at least up to the 16-32 cell stage, the time when the gene normally begins to be expressed. This embryo would be "normal" at this stage, in the same way as a person is "normal" up to the moment when the genetic defect in his genome makes a Huntington’s disease, for example, appear in his phenotype.103 It does not seems right to take the later expression of cdx2 as a " reference point" in order to work back to a judgement about the embryo and its moral status.104
2) Alternative proposals that do not involve the destruction of human embryos
Other proposals have been made to obtain hES cells without having to destroy human embryos. They are:
- using germ stem cells,
- using blastomeres harvested by embryo biopsy,
- reprogramming somatic cells to embryonic-like cells.
a) Use of embryonic germ cells
Embryonic germ cells, EGCs, are derived from foetal primordial germ cells (M.J.Schamblott et al., 1998).105 They are the functional equivalent of embryonic stem cells, in terms of their capacity for in vitro proliferation and broad cell differentiation. But they are more difficult to harvest and tend to differentiate spontaneously in culture.106
Theoretically, they could be used for regenerative therapy as an equivalent of ES cells, but this but has never been tried.
From an ethical standpoint, it would involve harvesting germ cells from aborted human foetuses (at five-nine weeks after fertilization), which poses problem. This would be acceptable only if there was a proportional therapeutic interest in these cells and if there were no other therapeutic tactic of equal value that could be used to combat the subject’s pathology. Pluripotent somatic stem cells are easier to obtain and probably as efficient.
b) ES cells derived from a single blastomere collected by embryo biopsy
Another proposal is to remove by biopsy one blastomere from an embryo in the segmentation phase. This would be cultured and would multiply to produce hES cells.
Takumi Takeuchi and Ameeta Bahia of the Center for Reproductive Medicine and Infertility (Weill Medical College, Cornell University, New York) reported (June 2005), that they had obtained nine ES cell lines from 46 blastomeres obtained by biopsy from mouse blastocysts.107
- E.S.Sills, G.D.Palermo and colleagues108 (July 2005) have obtained ES cells from mouse blastomeres collected by biopsy from 4-6 cell embryos.
- S.Wakayama et al.109 ( 2007) showed that ES cell lines could be derived from the blastomeres of early-stage mouse embryos, in the very first stages of cleavage, the two-cell embryo blastomeres having the highest success rate: they had established 112 ES cell lines, with a 50-68% success rate for the two-cell embryo blastomeres, 28%-40% for the four-cell embryo blastomeres and 14-16% for the eight-cell embryo blastomeres.
- Robert Lanza, Y.Chung, I.Klimanskaya et al. (Advanced Cell Technology , Worcester, Massachusetts), proposed this method for obtaining hES cells without having to destroy human embryos.
They showed (October 2005)110 that it was possible to obtain hES cell lines from a single blastomere taken from a seven-cell mouse embryo. Then, they reported (August 2006)111, the creation of two hES cell lines from blastomeres obtained by biopsying human embryos (one blastomere per embryo) supplied by an IVF centre, which had not been used and were destined for research The procedure proved however to be very inefficient, since only 2% of the blastomeres collected in this way]. had given rise to an hES cell line. They published (2008) a follow-up to this report, with improved results112, since 29 out of 32 cell aggregates derived from blastomeres collected by biopsy had proliferated and generated hES-like cells in 20% to 40% of cases (groups 1 and 2). In the group in which the blastomeres had been cultivated on a medium with laminin and fibronectin, three blastomeres out of 15 had generated stable hES cell lines. Mieke Geens and coll.(Brussels)113 reported, in 2009, the derivation of two hES cell lines from blastomeres from four 4-cell embryos (success rate: 12.5%). These two lines came from two different embryos.
Other work has confirmed these results, but also shown the inefficiency of the process, because very few human blastomeres, after being removed by biopsy, prove to be capable of multiplication in vitro in order to produce hES. These studies also reported the frequent chromosomal and genetic anomalies affecting the hES cells in these lines (Van de Velde et al. , 2008)114, Anis Feki et coll.,2008)115.
From an ethical standpoint, Robert Lanza, Y.Chung, I.Klimanskaya have stressed the moral aspect of their enterprise. "What we have done, for the first time," said Robert Lanza in 2006 "is to actually create human embryonic stem cells without destroying the embryo itself"116. These statements left the false impression that "embryo biopsy" to obtain a blastomere that is a source of a stem cell line was relatively easy, could be done as part of a preimplantation diagnosis, and would not harm the embryo. The reality is very different: most often the blastomeres taken from the preimplantation embryos do not develop in vitro, and in order to achieve some success, all the blastomeres available in 2 to 4-cell embryos must be taken, which implies in fact the destruction of the embryo. There is therefore no question, at least for the moment, of such a technique being introduced as part of a preimplantation diagnosis for example, where the biopsied embryo could have been allowed to live.
Blastomere biopsy therefore does not solve the ethical problem of hES cell harvesting at all.
c) Somatic cell reprogramming
The third proposal for obtaining embryonic-like stem cells without having to destroy human embryos is "reprogramming", inspired by the results of nuclear transfer cloning.
The epigenetic reprogramming by hybridisation.117
This approach proposes to use the ability of human ES cells to "reprogram" somatic stem cells to pluripotency. This would be done by fusion of a somatic cell and an ES cell (C.A.Cowan, K.Eggan et al., 2005)118. The result of this "reprogramming" would be tetraploid cells with capabilities comparable to those of ES.119 The new stem cell lines obtained in this way would not require the use of embryos or oocytes for their creation.120
However, from an ethical standpoint, this method presupposes the use of an ES cell line, and as a result implies illicit cooperation in the unacceptable act of collecting these ES cells from human embryos. It would also be morally illicit to wish to use the product of this hybridization, i.e. tetraploid cells, on patients, given the uncertainties connected with the presence of such cells in the organism (risk of cancer).
Reprogramming through dedifferentiation
The possibility of "dedifferentiating" the nuclei of the specialized cells to make them go back to an undifferentiated state has been demonstrated for many types of cells.121 This kind of dedifferentiation occurs spontaneously in simple organisms (such as the salamander which can regenerate a limb).122 It has been successfully done on some human somatic cells, such as myotubes (S.J.Odelberg et al.,2000, 2001)123 , myogenic cells (mediated by the purine "reversine")(S.Chen et al.(2004)124, myoblasts (mediated by CNTF, ciliary neurotrophic factor)(X.Chen et al., 2005)125, fibroblasts (mediated by incubation in an extract of T-cell cytoplasm)(A-M.Håkelien et al., 2002)126. From this research it was clear that to obtain the reprogramming of a somatic cell nucleus without involving an enucleated oocyte, the factors in the cytoplasm of ES cells that can convert a differentiated cell to a pluripotent embryonic-like cell thanks to the transient expression of specific genes had to be individuated (S.Eminli et al., 2006)127 (K.Hochedlinger et R.Jaenisch, 2006)128.
Reprogramming through genetic transfer
Shinya Yamanaka et al. (University of Kyoto, Japan) presented in July 2006 at the International Society for Stem Cell Research (ISSCR) in Toronto129 a solution to the problem of reprogramming somatic cells without using nuclear transfer into an enucleated oocyte.130 Using a technique of transferring some of the genes responsible for pluripotency in stem cells (Oct4, Sox2, c-Myc et Klf4)131, S.Yamanaka had been able to change ordinary, "somatic", skin differentiated cells (fibroblasts) in the mouse into undifferentiated "ES-like" cells, called by their creator "induced pluripotent stem cells"(iPS).
K.Takahashi and S.Yamanaka published their results on 25 August 2006, in the journal "Cell"132. A year later, Takahashi, Yamanaka and colleagues published identical cell reprogramming results133, but this time from human fibroblasts.
These results were confirmed by three different teams of researchers, in Japan (K.Okitua et al.)134 and two in the United States (Wernig M. et al., 2007135, N.Maherali et al., 2007136). With the help of cell selection effected by inserting an antibiotic resistance gene into the cells as they were reprogrammed, the authors of these studies were able to isolate a small number of reprogrammed cells and then multiply them electively. At the end of 2007 J.Yu, J.A.Thomson et al. (University of Wisconsin-Madison) published his own cell reprogramming results137, which agreed with those of S.Yamanaka and colleagues. The demonstration by these various authors that somatic cells can be reprogrammed into iPS was greeted as the most important scientific breakthrough of 2008.138
C - THE iPS NEW DEAL
1) hiPSCs have the same properties as hESCs
Human iPS cells (hiPS) as produced by Yamanaka, Takahashi and colleagues, Yu, Thomson and colleagues, Park, Dailey and colleagues139 and Lowry WE and colleagues140 present all the characteristics of embryonic stem cells as regards morphology, self-renewal, and abundant, stable and unlimited in vitro proliferation capability.
- From the genetic point of view, these cells provide the expression of pluripotency related transcription factors, which is the characteristic and specific "hallmark" of ES cells (presence of 27 "specific epigenetic marker" genes of ES cells, and signature of the ES state, especially Nanog, Oct3/4, Sox2, Cripto, and GDF3).
- ES-specific surface antigens are found on the iPS.
By restoring pluripotency in the fibroblasts, the reprogramming resets the biological age of the cell to its starting point, which can be seen in an activation of the telomerase, causing a lengthening of the telomeres.141
- iPS are capable of producing in vitro derived cells representing the three embryonic germ layers, and can subsequently produce all the cell types of the organism, including germ cells (Okita et al., 2007)142.
- Like ES cells, iPS cells form embryoid bodies in vitro and develop into teratomas when they are injected subcutaneously into laboratory mice.
- When iPS cells are introduced into embryos at the blastocyst stage, they take part, as do ES cells, in the development of the three primitive embryonic germ layers, producing a "chimerical" embryo in which the descendants of the injected iPS cells, which originated in these three germ layers, are of all cell types, including gametes.143
- The property of ES cells of being able to generate a whole animal when they are aggregated into tetraploid embryos (embryos incapable of developing by themselves), had been demonstrated for the iPSCs by a Chinese team144 which, through tetraploid complementation, has been able to get a mouse (Xiao Xiao) to develop from iPS cells.
Inefficiency of the reprogramming process
One of the main criticisms of the iPSCs created by S.Yamanaka et al. regards the inefficiency of the reprogramming process leading to iPSCs. Indeed, fewer than 0.1% of the skin fibroblasts that Yamanaka had treated in this way demonstrated effective reprogramming. This obstacle was overcome by Yamanaka, transferring a neomycin-resistant gene into the cells to be reprogrammed, which enabled the effectively reprogrammed cells to be selected and subsequently multiplied in culture. But this procedure could not be used if iPS were to be applied to patients. A.Meissner, R.Jaenisch et al.145, showed that it was not necessary to resort to such a procedure and that it was possible to isolate the iPS based on simple morphological criteria.
Various strategies have since been developed to increase the efficiency of cell reprogramming146, such as the addition of SV40LT and hTERT (Mali et al.2008, Park et al.2008)147, the inhibition of DNA methyltransferase (DNMT)(Mikkelsen et al., 2008)148 or the silencing of p53 and the introduction of UTF1 into the human fibroblasts to be reprogrammed (multiplying one hundred-fold the reprogramming efficiency)(Zhao et al., 2008)149. Another way to improve reprogramming efficiency would be to resort to embryonic stem cell-specific microRNAs. These miRNAs (mir-291, 294, 295) increase reprogramming efficiency by Oct4, Sox2 and Klf4 and can replace c-myc in this reprogramming.150
Use of the c-myc transgene
Another criticism of Yamanaka’s initial work concerned the use of the c-myc transgene for the cell reprogramming, given that this oncogene causes cancers in the host animals, a fact verified by K.Okita et al.151 R.Blelloch et al. (2007)152 showed that it was possible, in the Yamanaka protocol, to substitute the n-myc gene for the c-myc oncogene, without adversely affecting reprogramming efficiency.
James Thomson and co-workers successfully used other reprogramming factors than those chosen by S.Yamanaka and colleagues, especially Nanog and Lin28, without using the c-myc oncogene and the Klf4 gene.153
M.Nakagawa, S.Yamanaka and colleagues published a study in November 2007154 showing that it was possible to reprogram somatic cells according to their own protocol, without resorting to the c-Myc oncogene.
Use of retroviral vectors
A third criticism of the work of Yamanaka and colleagues concerns the use of multiple retroviral vectors - one for every gene transferred - to reprogram skin fibroblasts by pluripotency gene transfer. Indeed, since 1999 and the death of Jesse Gelsinger155, these vectors have had a bad press, and the more recent finding of insertional mutagenesis leukaemias due to the retroviral vectors used in the Necker Hospital (Paris) to treat children suffering from severe immunodeficiency (SCID-X) with gene therapy, did nothing to improve this judgement.156 It was therefore said that Yamanaka’s use of these multiple viral vectors would cause patients receiving iPS to run a disproportionate risk of insertional mutagenesis.
More recent work has shown that this risk can be reduced, and moreover the efficiency of the gene transfer improved at the same time. Efficient reprogramming was obtained for example by using adenoviral vectors157, a single lentiviral, polycistronic vector (carrying four reprogramming genes)158, a non-viral polycistronic vector (plasmid)159, a transposon160, and a vector carrying transgenes that was excised once the reprogramming had been done - transposon161 or non-integrating episomal vector (plasmid whose presence depends on an antibiotic)162. However the efficiency of iPS cell generation when an adenoviral vector or a plasmid is used is very low.
Another way to avoid the viral vector being integrated into the genome with its risk of mutagenesis is to generate iPS by using small molecules that promote or facilitate cell reprogramming. Various groups have already identified such molecules which can replace one or two reprogramming factors during iPS cell generation (Huangfu et al., 2008163; Shi et al., 2008164; Lyssiotis CA et al., 2009165).
A third way, which has already been explored successfully involves resorting not to gene manipulation to achieve cell reprogramming, but to delivering the reprogramming proteins directly to the cells by combining them with peptides (Harvard Stem Cell institute, CD.Kim et al., 2009)166 or with recombinant proteins (team led by Sheng Ding at the Scripps Research Institute, Zhou H.et al., 2009)167.
The most recent approach to get an efficient cellular reprogramming to the stage of pluripotency without having resorts to a transfer of genes consists to call on the specific microARN (miARN) of the embryonic original cells.168 N.Miyoshi et M.Mori (2011)169, while using a combination of miARN (mir-200c, mir-302s and mir -369) showed that it was possible to reprogram to the pluripotency the stromal cells of the adipose tissue, of mouse and human, by direct transfection of microARN doubles sprig mature, without resorting to a transfer of genes.
3) Advantages of iPSCs
Human iPS cells not only present the same characteristics and the same biological and therapeutic potentialities as hES cells, but also offer advantages over the latter in that they are free of any ethical problem and solve some of the biological difficulties that militate against the clinical use of hES.
The cells hiPS offer in particular, in the perspective of a clinical use, the inestimable advantage, respectively to the hESCs, to be derived from cells directly obtained from the patient to treat, and therefore to allow an autologous transplantation of pluripotent stem cells or of their differentiated derivatives, which could not be done with the hES. The cells iPS can be derived from every individual, without restriction, and thus they can be obtained from patients affected by determined pathologies. This gives the opportunity to constitute "cellular models" of pathologies170, very useful for the physiopathologic studies of the human diseases. hiPS enable pathology modelling with much greater technical facility than hES : S.Yamanaka cites the generation of "in vitro" disease models as the first practical future application of this technology171. He recalls the work already done with generations of iPS cells from patients affected by neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson’s disease, spinal muscular atrophy. Given that hiPS can be obtained by simply reprogramming the cells of patients who are carriers of mendelian or complex genetic diseases or suffering of problematic acquired diseases with genetic predisposition, they offer to pharmaceutical research a material of choice for the screening of molecules that could potentially be used therapeutically against these diseases. Moreover they constitute a cell model for the study of the genesis and development of these pathologies. As the iPSCS can differentiate in a large range of cellular types, some of them inaccessible to explorations, they offer a considerable resource to the pharmacological studies aiming at the development of new therapeutic agents. Finally the possibility to have iPSCs developed from a large number of individuals, and offering thus a large range of genetic variations will allow this same pharmacology to develop agents adapted to the specific genetic configuration of the patients.
In the clinical field, the iPSCs have a regenerative potential superior to the regenerative potential of somatic stem cells. They are therefore promising for future regenerative medicine. The pluripotent iPSCs will not be used in patients, because of their tendency to generate teratomas, but their differentiated derivatives should permit the regeneration of tissues and organs, for example the neural cells derived from iPSCs could be valuable for the treatment of the degenerative neural diseases.172
One another aspect of the potential benefits which could come from the iPSCs regarding patient care would be their association to gene therapy for the treatment of numerous pathologies. The cells iPSCs prepared from somatic cells of the interested patient would be genetically modified and then transplanted in the patients as agents of molecular therapy (Hanna J et al., 2007, sickle cell disease173, A.Raya et al., Fanconi anemia, 2009).174
4) Limits of iPSCs
The first, and more obvious, is that the cell reprogramming technique is not very efficient, and results in some heterogeneity in the degree of effective reprogramming reached by the cells that are qualified as iPS, within the batch of reprogrammed somatic cells. Only some of these cells have properties comparable to those of ES, which explains the rather variable results found by different authors in their evaluation of iPS properties.
IPs cells share their second limitation with ES cells: when they are injected as such, without having started a differentiation process, into a subject, they produce tumors at the points at which they were administered into the organism.
iPS also share their third limitation with ES: a great deal of work remains to be done to control their differentiation into different types of cell. But gaining such control is the prerequisite for their clinical application.
The fourth limitation of these iPS cells has only recently been demonstrated. It concerns their efficiency at forming the various cell types by differentiation.175 BY Hu and co-workers (University of Wisconsin)(2010)176 found that the hiPS, whose capacity for differentiation they were studying, used the same transcriptional systems as hES cells to generate neuroepithelia and various types of functional neurones, and took the same time to do so, but did it with less efficiency and greater variability. Q.Feng and R.Lanza of Stem Cell and Regenerative Medicine International (Worcester, MA) (2010)177, also found a relative lack of iPS efficiency in their differentiation into hemangioblasts, endothelial cells and hematopoietic cells. Comparing the capacity of eight hiPS cell lines and 25 hES cell lines to differentiate into these various types of cells, they found, in a test, that the hES cells generated a thousand times more of the desired cells than the iPS. They also found that various types of cell produced by the iPS were beginning to show signs of cellular ageing leading to death after only a short time in culture.
These results must, of course, be interpreted in the light of more specific studies, as G.Daley suggests178, because they may simply be the result of an incomplete reprogramming of cells regarded as being iPS. Considering the results of other iPS studies, we may indeed imagine that when iPS are completely and homogeneously reprogrammed, they are practically identical to ES. In any case, we must be prudent in estimating iPS performance, and wait for a full exploration of all their possibilities to shed light on these issues.
The most important question concerns the risk associated with iPS of causing cancer in the host, either because of the inclusion of oncogenic transgenes, or because of the persistence of undifferentiated cells in the differentiated batch that will be administered to the patient, or because of still unknown factors connected with the reprogramming. Detailed animal experimental studies will therefore be required to verify the harmlessness of hiPS, before going on to a clinical application.
5) Ethical perspectives on iPSCs
From the ethical standpoint, the development of iPS offers a valuable alternative method to the collection of hES through the harvest of the inner cell mass of human blastocysts.
In effect, it enables stem cells to be obtained that are of comparable quality to hES in terms of stability, in vitro proliferation in the undifferentiated condition, differentiation into all types of tissue, without the ethical barrier of embryonic destruction that paralyses research on ES cells and their clinical use.
iPS cells thus solve the ethical dilemma that began in 1998 with the demonstration by James Thomson that it was possible to culture hES cells. The way they are obtained does not pose any ethical problem, they do not involve the destruction of any embryo, and their production fully respects the dignity of the person who supplied the initial somatic cells.
Although the iPS technology eliminates certain ethical questions proper to hES cell research, it raises new questions, and possibly new challenges, (Timothy Caulfield, Alberta Health Law Institute).179
A first issue must be mentioned, which came in S.Yamanaka’s mind180 when the media began to make the existence of iPS known to the public. This concerns the possible generation of germ cells from iPS. As soon as the possibility of deriving hES cell lines from human blastocysts was demonstrated by J.A.Thomson in 1998, researchers began to want to differentiate hES cells into gametes. Thus in 2003, Hans R.Schöler et al.181 (University of Pennsylvania) observed the formation of oocyte-like cells from cultured murine ES cells. Again in 2003, Toshiaki Noce et al.(Tokyo, Japan)182, using BMP4 (bone morphogenetic protein-4) to stimulate the differentiation of murine ES cells into primordial germ cells (PGS) observed that these cells could play a part in spermatogenesis when they were transplanted into seminiferous tubules. In 2006, Karim Nayernia (Göttingen) caused a wave of interest in the question of the transformation of hES cells into gametes by showing that it was possible to obtain functional haploid male gametes from spermatogonial cells derived from ES cells.183 In 2009, K.Kee, R.A.Reijo Pera etal.(Stanford University) identified the role of the DAZL, DAZ and BOULE genes in the successful differentiation of hES cells into primordial germ cells and haploid gametes.184 Although this work is still preliminary, it certainly opens the door to the possibility of obtaining gametes by the managed differentiation of pluripotent cells, with all the consequences that may have for procreation.185
The arrival of iPS drastically changes the normative and ethical perspective on stem cells (I.Hyun, 2010)186: dominated until recently by the question of whether or not preimplantation embryos are respected, stem cells ethics must now confront an increasingly active field of research, at a time of great interest in perfecting iPS technology in order to produce cell disease models, but also at a time of renewed interest in hES cell research, to the extent that these cells serve as a sort of benchmark, mirror, and counterpart to iPS cells. Over and above the current buzz of excitement that for the moment only affects the research laboratories and centers, possibilities are opening up for the translation of this research into clinical applications on patients. The pressure exerted today by private clinics, operating in an uncontrolled manner, in favor of the immediate and indiscriminate clinical application of stem cells will make it tempting to apply the iPS technology to patients, especially in terms of regenerative medicine, even though this technology is still in its infancy. iPS are certainly rightly regarded today as prime candidates for a major role in regenerative medicine. But the time has not yet come for them to be employed in the clinic. Too many obstacles remain to be overcome or clarified for it to be possible to envisage such an application to patients at present.187
The development of induced pluripotent cells, or iPS, obtained by somatic cell dedifferentiation, constitutes considerable progress, not only in stem cell studies, but for cell biology in general. It shows in effect that it is possible to "reprogram" differentiated cells epigenetically, making these cells go back to their developmental starting point by erasing their epigenetic adult cell "memory" and re-activating the expression of pluripotency genes in their genome. iPS cells offer a clear, simple and effective alternative solution to embryonic stem cells. Today they are as promising as embryonic stem cells in terms of in vitro self-reproduction-expansion capability and their clinical and ethical advantages cannot be ignored. But these cells are not yet applicable in the clinical field, in the present state of knowledge.
The technical, biological and ethical progress represented by the development of the cell reprogramming method does not eliminate, far from it, the use of somatic (adult) stem cells and umbilical cord blood cells. The individuation of stem cells capable of prolonged self-renewal and pluripotency that are derived from already individuated stem cells in umbilical cord blood and in various tissues of the adult organism is now well established, and has produced positive results in the clinical field. This does not require any embryonic destruction, any oocyte, and does not present an ethical problem. And it is safer and more reliable than reprogramming, which involves gene manipulation. It is to be hoped that in the future the scientists working in the adult stem cell field will succeed in developing stable lines of these pluripotent "somatic" stem cells, that will take their place alongside iPS for the regenerative medicine of the future.
Certain "clinics", taking advantage of local conditions, and banking on the distress of patients and on their hopes, use adult stem cells in an ill-considered way for purely commercial reasons.188 They risk damaging stem cell research in public opinion, either because of negative effects of the "treatments", or when the falseness of their promises has become obvious. For that reason, the establishing of national and international regulations codifying the use of stem cells is becoming a necessity.189
To succeed in developing iPS, the other avenues discussed here had first to be explored. And iPS themselves are probably only a new "frontier" to be crossed. Stem cell research has already contributed greatly to science. It to be hoped that tomorrow it will also do a great deal for patients.
1See: L.Palazzani, Bioetica dei principi e bioetica delle virtù: il dibattito attuale negli Stati Uniti, Medicina e Morale, 1992, N.1, gennaio-febbraio, pp.59-65.
2Summa Theologiae, I-II, Question 94, De legi naturale.
3Compendium of the Catechism of the Catholic Church, n.416.
4R.Tremblay, Vous, lumière du monde, Montreal, Editions Fides, 2003, cité par I.de Gaulmyn dans "La loi naturelle, fondement de la morale chrétienne", La Croix, 10 Mars 2009, p.24.
5R.Coste, Loi naturelle et Loi évangélique, Nouvelle Revue Théologique, janvier 1970, vol.92, pp.76-89.
6O.Lottin, La loi naturelle depuis le début du XII siècle jusqu'à Saint Thomas d'Aquin, dans Psychologie et morale aux XII et XIII siècles, vol.II, I partie, p.71.
7 Aristote, Ethique à Nicomaque, Livre 5, c.10, 1134b, 18-21.
8J.Arntz, La legge naturale e la sua storia, in Dibattito sul Diritto naturale, Queriniana, Brescia, 1970, pp.89-113.
9O.Lottin, Psychologie et Morale aux XII et XIII siècles, Louvain, 1948, vol.II, I, 75 et 87, cf. p.114.
10Benedict XVI to the participants in the international congress on natural moral law, 12 february 2007.
11Leo XIII, Libertas praestantissiumum, 597.
12Benedict XVI to the participants in the international congress on natural moral law, 12 february 2007.
13Address of His Holiness Benedict XVI to members of the Pontifical Academy for Life, 13 february 2010.
14Address of His Holiness Benedict XVI to members of the Pontifical Academy for Life, 13 february 2010.
15Address of His Holiness Benedict XVI to members of the Pontifical Academy for Life, 13 february 2010.
16Address of His Holiness Benedict XVI to members of the Pontifical Academy for Life, 13 february 2010.
17Benedict XVI to the participants in the international Congress on natural moral law, 12 february 2007.
18G.Médevielle, La loi naturelle selon Benoît XVI, Études, Mars 2009, nr 4103, pp.353-364.
19Commission Théologique Internationale (2009), intitulée: "A la recherche d'une éthique universelle: nouveau regard sur la loi naturelle", 2009, nr 10.
20J.de Finance S.J., «Ethique Générale», Presses de l'Université Grégorienne, 1967, pp.103-119. F.Duchesneau, La philosophie anglo-saxonne de Bentham a William James, dans «La Philosophie», vol.III, Le Marabout, Hachette, Paris, 1973, pp.196-200. E.Bréhier, «Histoire de la philosophie», vol.III, seconde ed., PUF, Paris, 1983, pp.593-595.
21P.Gassendi, Syntagmata philosophiae Epicurii, III, XXI.
Y.Grisé, "l'épicurisme" dans Le suicide dans la Rome antique, Monréal-Paris, Bellarmin-Les Belles Lettres, "Noesis", 1982, p.177.
22J.de Finance, «Ethique Générale», op.cit., pp.145-155.
23T.L.Beauchamp & LeRoy Walters, Ethical Theory and Bioethics, in Contemporary issues in Bioethics, pp.12-19. J.de Finance, «Ethique Générale», Presses de l'Université Grégorienne, Roma, 1967, pp.121-122, 127-133. F.Duchesneau, La philosophie anglo-saxonne de Bentham à William James, dans «La Philosophie», vol.III, Le Marabout, Hachette, Paris, 1973, pp.200-206.
24J.Bentham, An introduction to The principles of Morals and Legislation, 1789, chap.I, p.1.
25Introduction to the Principles of Moral and Legislation, 1789, chapter 17, note 122.
26The anglo-saxon point of view on moral judgment and decision-making is largely inspired of the utilitarian point of view of cost/benefits, with a priority given to justice. The principles of anglo-saxon judgement in the field of medical ethics are: non-maleficence, autonomy, confidentiality, beneficence, justice, and good quality of medical care. They can also be summed up in the formula: just cause, legitimate authority, probability for success, just intention, due proportion, just means, declaration, last resort.
Ms A.B.Baker, The application of the criteria of the Just War Theories in the Resolution of Medical-Ethical Dilemmas at the Bedside., Linacre Quaterly, Nov.1995, pp.3-19.
27J.de Finance, «Ethique Générale», op.cit., pp.122-124.
28See the discussion between Childress's bioethics principles (typical of north-american bioethics) and a christian point of view from the concept of the human person in:
F.Gomez, Relevant Principles in Bioethics, Unitas, vol.68, nr 2, june 1995, pp.7-25.
29X.Thévenot, "La Bioéthique", Le Centurion, Paris, 1989, pp.53-63.
J.P.Durand, Retour au concept de personne. Pour une métaphysique de la personne. Qu'est-ce que la personne humaine?, Le Supplément, Dec.1995, nr 195, pp.13-27.
S.Plourde, Incontournable en éthique biomédicale: le concept de personne, Le supplément., dec.1995, Nº195, pp.29-58.
30A.Pessina, L'ermeneutica filosofica come sfondo teorico della bioetica. Elementi per una valutazione critica, Medicina e Morale, 1996,1, pp.43-70.
31J-F.Malherbe, Médecine, Anthropologie et Ethique, Médecine de l'homme, Mars-Juin 1985, Nr 156-157, pp.5-12.
32Congregation for the Doctrine of Faith, Instruction on respect for human life in its origin and on the dignity of procreation. Replies to certain questions of the day, February 22 1987.
33"As an incarnate spirit, that is a soul which expresses itself in a body, and a body informed by an immortal spirit, man is called to love in his unified totality", Apostolic Exhortation Familiaris Consortio, November 22, 1981, nr 11.
34The principle of Totality is not a creation of personalist tradition. It belongs to classic moral christian theology. See: M.Nolan, The Positive Doctrine of Pope Pius XII on the Principle of Totality, Augustinianum, 3, 1963, pp. 28-44; 290-324; 4, 1964, pp.537-559. J.Gaffney, The over-extended Principle of Totality and some Underlying Issues, The Journal of Religious Ethics, vol.IV, 1976, pp.259-267.
35Maximow AA, The lymphocyte as a stem cell, common to different blood elements in embryonic development and during the post-fetal life of mammals, Lecture with a demonstration, held at a special meeting of the Berlin Hematological Society on 1 June 1909, Cellular Therapy and Transplantation, vol.1, nr 3, pp.14-24. Konstantinov IE, In search of Alexander A.Maximov: The Man Behind the Unitarian Theory of Hematopoiesis, Perspectives in Biology and Medicine, winter 2000, vol.43, nr 2, pp.269-276.
36Lorenze E, Uphoff D, Reid TR, Shelton E, Modification of irradiation injury in mice and guinea pigs by bone marrow injections, Journal of the National Cancer Institute, August 1951, vol.12, nr 1, pp.197-201. Congdon CC, Uphoff D, Lorenz E, Modification of acute irradiation injury in mice and guinea pigs by injection of bone marrow; a histopathological study, Journal of the National Cancer Institute, August 1952, vol.13, nr 1, pp.73-107. Ford CE, Hamerton JL, Barnes DW, Loutif JF, Cytological identification of radiation-chimaeras, Nature, 10 March 1956, vol.177, nr 4506, pp.452-454.
37Till JE, McCulloch EA, A direct measurement of the radiation sensitivity of normal mouse bone marrow cells, Radiation Research, february 1961, vol.14, pp.213-222. Till JE, McCullough EA, Early repair processes in marrow cells irradiated and proliferating in vivo, Radiation Research, January 1963, vol.18, nr 1, pp.96-105.
38Goodman JW, Hodgson GS, Evidence for stem cells in the peripheral blood of mice, Blood, June 1962, col.19, pp.702-714.
39F.A.Brook, R.L.Gardner, The origin and efficient derivation of embryonic stem cells in the mouse, Proceedings of the National Academy of Sciences, USA, May 1997, vol.94, nr 11, pp.5709-5712.
40M.J.Evans, M.H.Kaufman, Establishment in culture of pluripotential cells from mouse embryos, Nature, 9 July 1981, vol.292, nr 5819, pp.154-156. G.R.Martin, Isolation of a pluripotential line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells, Proceedings of the National Academy of Sciences, USA, 1981, vol.78, pp.7634-7638.
41G.Keller, H.R.Snodgrass, Human embryonic stem cells: The future is now, News and Views, Nature Medicine, February 1999, vol.5, nr 2, pp.151-152.
42J.A.Thomson, J.Itskovitz-Eldor, S.S.Shapiro, M.A.Waknitz, J.J.Swiergiel, V.S.Marshall, J.M.Jones, Embryonic Stem Cell Lines Derived from Human Blastocytes, Science, 6 november 1998, vol.282, nr 5391, pp.1145-1147.
43M.J.Schamblott, J.Axelman, S.Wang, E.M.Bugg, J.W.Littlefield, P.J.Donovan, P.D.Blumenthal, G.R.Huggins, J.D.Gearhardt, Derivation of pluripotent stem cells from cultured human primordial germ cells, Proceedings of the National Academy of Sciences, USA, 10 November 1998, vol.95, nr 23, pp.13726-13731.
44J.S.Odorico, D.S.Kaufman, J.A.Thomson, Multilineage Differentiation from Human Embryonic Stem Cell Lines, Stem Cells, 2001, vol.19, nr 3, pp.193-204. See p.195.
45M.Amit, M.K.Carpenter, M.S.Inokuma, C.P.Chiu, C.P.Harris, M.A.Waknis, J.Itskovitz-Eldor, J.A.Thomson, Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture, Developmental Biology, 15 November 2000, vol.227, nr 2, pp.271-278.
46K.Prelle, N.Zink, E.Wolf, Pluripotemt stem cells - model of embryonic development, tool for gene targeting and basis of cell therapy, Anatomia Histologia Embriologia, June 2002, vol.31, nr 3, pp.169-186.
47Nagy A, Gozca E, Diaz E.M, Prideaux VR, Ivanyi E, Merkkula M, Rossant J, Embryonic stem cells alone are able to support fetal development in the mouse, Development, November 1990, vol.110, nr 3, pp.815-821.
48The current advantages and limitations of human embryonic stem cells and human somatic stem cells, in Commission of the European Communities, Commission staff working paper, Report on human embryonic stem cell research, nr 2.4, Brussells, 3.4.2003.
49B.E.Reubinoff, M.F.Pera, C-Y.Fong, A.Trounson, A.Bongso, Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro, Nature Biotechnology, April 2000, vol.18, nr 4, pp.399-404.
50Byrne JA, Pedersen DA, Clepper LL, Nelson M, Sanger WG, Gokhale S, Wolf DP, Mitalipov SM, Producing primate embryonic stem cells by somatic nuclear transfer, Nature, 22 november 2007, vol.450, nr 7169, pp.497-502.
51Kadereit S, Trounson A, In vitro immunogenicity of undifferentiated pluripotent stem cells (PSC) and derived lineages, Seminars in Immunopathology, 5 april 2011, (epub ahead of print).
52I.Wilmut, A.E.Schnieke, J.McWhir, A.J.Kind, & K.H.S,.Campbell, Viable offspring derived from fetal and adult mammalian cells, Nature, vol.385, Nº6619, 27 February 1997, pp. 810-813.
53Grieshammer U, Shepard KA, Nigh EA, Trounson A, Finding the niche for human somatic cell nuclear transfer, Nature Biotechnology, 5 August 2011, vol.29, nr 8, pp.701-705.
54R.P.Lanza, J.B.Cibelli, M.D.West, Human therapeutic cloning, Nature Medicine, September 1999, vol.5, nr 9, pp.975-977. R.P.Lanza, J.B.Cibelli, M.D.West, Prospect for the use of nuclear transfer in human transplantation, Nature Biotechnology, December 1999, vol.17, nr 12, pp.1171-1174.
55P.Aldhous, Can they rebuild us?, Nature, 5 April 2001, vol.410, nr 6829, pp.622-625.
56J.A.Byrne, D.A.Pedersen, L.L.Clepper, M.Nelson, W.G.Sanger, S.Gokhale, D.P.Wolf, S.M.Mitalipov, Producing primate embryonic stem cells by somatic nuclear transfer, Nature, 22 November 2007, vol.450, nr 7169, pp.497-502.
57Sparman M, Dighe V, Sritanaudomchai H, Ma H, Ramsey C, Pedersen D, Clepper L, Nighot P, Wold D, Hennebold J, Mitalipov S, Epigenetic reprogramming by somatic cell nuclear transfer in primates, Stem Cells, June 2009, vol.27, n6, pp.1255-1264.
58M.Stojkovic, P.Stojkovic, C.Leary, V.J.Hall, L.Armstrong, M.Herbert, M.Nesbitt, M.Lako, A.Murdoch, Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes, RBMOnline, August 2005, vol.11, nr 2, p.226-231.
59A.J.French, C.A.Adams, L.S.Anderson, J.R.Kirchen, M.R.Hughes, S.H.Wood, Development of Human cloned Blastocysts Following Somatic Cell Nuclear Transfer (SCNT) with Adult Fibroblasts, Stem Cells, February 2008, vol.26, nr 2, pp.485-493,
60Li J, Liu X, Wang H, Zhang S, Liu F, Wang X, Wang Y, Human embryos derived by somatic cell nuclear trasnfer using an alternative enucleation approach, Cloning Stem Cells, March 2009, vol.11, nr 1, pp.39-50.
61D.Beeson, Egg harvesting for stem cell research: medical risks and ethical problems, RBMonline, October 2006, vol.13, nr 4, pp.573-579. E.Singer, Lack of human eggs could hamper US cloning efforts. Researchers want to make patient-matched cells, but success could depend on gaining a reliable source of human eggs, Technology Review , Thursday, June 15 2006. E.Singer, Human Therapeutic Cloning at a Standstill. A lack of human eggs has Created a Major roadblock in one of the most promising areas of stem-cell research, Technology Review (MIT), Tuesday, October 9 2007.
62Lanza RP, Caplan, Silver LM, Cibelli JB, West MD, Green RM, The Ethical Validity of Using Nuclear Transfer in Human Transplantation, JAMA, 27 December 2000, vol.284, nr 24, pp.3175-3179.
63E.Kant, Grounding for the Metaphysics of Morals, Métaphysique des moeurs, deuxième section, 3.
64R.T.Tecirlioglu, J.Guo, A.O.Trounson, Interspecies somatic cell nuclear transfer and preliminary data for horse-cow/mouse iSCNT, Stem Cell Reviews, 2006, vol.2, n4, pp.277-287.
65J.St John, R.Lovell-Badge, Human-animal cytoplasmic hybrid embryos, mitochondria, and an energetic debate, Nature Cell Biology, September 2007, vol.9, n9, pp.988-992.
66R.Lanza, B.Dresser, P.Damiani, Le clonage de l'arche de Noé, Pour la Science, Janvier 2001, nr 279, pp.46-49.
67R.P.Lanza, J.B.Cibelli, M.D.West, Human therapeutic cloning, Nature Medicine, September 1999, vol.5, nr 9, pp.975-977.
68K.H.Chang, J.M.Lim, S.K.Kang et al., Blastocyst formation, karyotype, and mitochondrial DNA of interspecies embryos derived from nuclear transfer of human cord fibroblasts into enucleated bovine embryos, Fertility and Sterility, December 2003, vol.80, nr 6, pp.1380-1387.
69K.H.Chang, J.M.Lim, S.K.Kang, B.C.Lee, S.Y.Moon, W.S.Hwang, An optimized protocol of a human-to-cattle interspecies somatic cell nuclear transfer, Fertility end Sterility, October 2004, vol.82, nr 4, pp.960-962.
70K.Illmensee, M.Levanduski, P.M.Zavos, Evaluation of the embryonic preimplantation potential of human adult somatic cells via an embryo interspecies bioassay using bovine oocytes, Fertility and Sterility, April 2006, vol.85, suppl.1, pp.1248-1261.
71Michael Hopkin, Britain gets hybrid embryo go-ahead. Human-animnal embryos given green light after public backing, Nature News, 5 September 2007. HFEA statement on its decision regarding hybrid embryos, 5 september 2007. http://www.hfea.gov.uk/en/1581.html
72Min D, Panoskaltsis-Mortari A, Kuro-O M. Holländer GA, Blazar BR, Weinberg KL, Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging, Blood, 15 March 2007, vol.109, nr 6, pp.2529-2537.
73Chidgey AP, Layton D, Trounson A, Boyd RL, Tolerance strategies for stem-cell-based therapies, Nature, 15 may 2008, vol.453,nr 7193, pp.330-337.
74Kahn A, Cellules souches et médecine régénératrice, Médecine Sciences, Avril 2002, vol.18, nr 4, pp.503-509.
75Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA, Banking on human embryonic stem cells: estinmating the number fo donor cell lines needed for HLA matching, The Lancet, 10 December 2005, vol.366, nr 9502, pp.2019-2025.
76Nakajima F, Tokunaga K, Nakatsuji N, Human leucocyte antigene matching estimations in an hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy, Stem Cells, April 2007, vol.25, nr 4, pp.983-985.
77Robertson NJ, Brook FA, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ, Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance, PNAS, 26 Dec 2007.
78Rao MSA, Auerbach JM, Estimating human embryonic stem-cell numbers, The Lancet, 25 february 2006, vol.367, nr 9511, p.650.
79J.A.Byrne, D.A.Pedersen, L.L.Clepper, M.Nelson, W.G.Sanger, S.Gokhale, D.P.Wolf, S.M.Mitalipov, Producing primate embryonic stem cells by somatic nuclear transfer, Nature, 22 November 2007, vol.450, nr 7169, pp.497-502.
80Clinical Trials.gov, Safety Study of GRNOPC1 in Spinal Cord Injury, http://clincaltrials.gov/ct2/show/NCT01217008.
81Bretzner F, Gilberet F, Baylis F, Brownstone RM, Target Populations for First-In-Human Embryonic Stem Cell Research in Spinal Cord Injury, Cell Stem Cell, 6 May 2011, vol.8, nr 5, pp.476-478.
82Clinical Trials.gov, Sub-retinal Transplantation of hESC Derived RPE (MA09-hRPR) Cells in Patients With Stargardt's Macular Dystrophy, http://clinicaltrials.gov/ct2/show/NCT01345006.
83Lu B, Malcuit C, Wang S, Girman S, Francis P, Lemieux L, Lanza R, Lund R, Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration, Stem Cells, September 2009, vol.27, nr 9, pp.2126-2135.
84D.W.Landry, H.A.Zucker, Embryonic death and the creation of human embryonic stem cells, The Journal of Clinical Investigation, November 2004, vol.114, nr 9, pp.1184-1186
85J.A.Byrne, S.simonsson, J.B.Gurdon, From intestine to muscle: Nuclear reprogramming through defective cloned embryos, Proceedings of the National Academy of Sciences, USa, 30 April 2002, vol.99, nr 9, pp.6059-6063.
86P.H.Lerou, A.Yabuuchi, H.Huo, A.Takeuchi, J.Shea, T.Cimini, T.A.Ince, E.Ginsburg, C.Racowsky, G.Q.Daley, Human embryonic stem cell derivation from poor-quality embryos, Nature Biotechnology, February 2008, vol.26, nr 2, pp.212-214.
87C.Holden, Scientists Create Human Stem Cell Line form "Dead" Embryos, Science, 29 september 2006, vol.313, nr 5795, p.1869.
88M.A.H.Surani, S.C.Barton, Development of Gynogenetic Eggs in the Mouse: Implications for Parthenogenetic Embryos, Science, 2 December 1983, vol.222, n?4627, pp.1034-1036. D.A.F.Loebel, P.P.L.Tam, Mice without a father, Nature, 22 April 2004, vol.428, n?6985, pp.809-811.
89J.B.Cibelli, K.A.Grant, K.B.Chapman, K.Cunniff, T.Worst, H.L.Green, S.J.Walker, P.H.Gutin, L.Vilner, V.Tabar, T.Dominko, J.Kane, P.J.Wettstein, R.P.Lanza, L.Studer, K.E.Vrana, M.D.West, Parthenogenetic stem cells in nonhuman primates, Science, 1 February 2002, vol.295, nr 5556, p.819. Trounson A, The genesis of embryonic stem cells. Does parthenogenesis offer a more promising means of developing immune-matched ES cells?, Nature Biotechnology, March 2002, vol.20, nr 3, pp.237-238.
90Vrana KE, Hipp JD, Goss AM, McCool BA, Riddle DR, Walker SJ, et al. (2003.) Nonhuman primate parthenogenetic stem cells. Proc Natl Acad Sci USA. 100, Suppl 1, 11911-11916.
91M.S.Latkovic, The Science and Ethics of Parthenogenesis, The National Catholic Bioethics Quarterly, Summer 2002, vol.2, nr 2, pp.245-255.
92W.B.Hurlbut, Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic stem cells, commissioned working paper discussed at the Council's December 2004 meeting, The President's Council on Bioethics, http://www.bioethics.gov/background/hurlbut.html. W.B.Hurlbut, Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic stem cell , The National Catholic Bioethics Quarterly, Spring 2005, vol.5, nr1, pp.145-151..W.B.Hurlbut, Altered nuclear transfer as a morally acceptable means for the procurement of human embryonic stem cells, Perspectives in Biology and Medicine, Spring 2005, vol.48, n?2, pp.211-228
93E.Check, Altered embryos offered as solution to stem-cell rift, Nature, 21 July 2005, vol.436, n?7049, p.308
94K.Deb, M.Sivaguru, H.Y.Yong, R.M.Roberts, Cdx2 Gene Expression and Trophectoderm Lineage Specification in Mouse Embryos, Science, 17 February 2006, vol.311, nr 5763, pp.992-996. Sritanaudomchal H, Sparman M, Tachibana M, Clepper L, Woodward J, Gokhale S, Wolf D, Hennebold J, Hurlbut W, Grompe M, Mitalipov S, CDX2 in the formation of the trophectoderm lineage in primate embryos, Developmental Biology, 1 November 2009, vol.335, nr 1, pp.179-187.
95A.Meissner, R.Jaenisch, Generation of nuclear transfer-derived pluripotent ES cells from cloned cdx2-deficient blastocysts, Nature, online advanced publication, doi:10.1038/nature04257, 17 October 2005.
96W.B.Hurlbut, Altered Nuclear Transfer, The New England Journal of Medicine, 17 March 2005, vol.352, nr 11, pp.1153-1154
97D.A.Melton, G.Q.Daley, C.G.Jennings, Altered Nuclear Transfer in Stem-Cell Research - a flawed Proposal, The New England Journal of Medicine, 30 December 2004, vol.351, nr 27, p.2791.
98F.Beck, Homeobox genes in gut development, Gut, September 2002, vol.51, nr 3, pp.450-545.
99L.Turnpenny, Embryo's moral status is unaffected by alteration, Nature, 1 September 2005, vol.437, nr 7055, p.26.
100G.Vogel, Embryo-Free Techniques Gain Momentum, Science, 8 July 2005, vol.309, nr 5732, pp.240-241.
101G.Pan, D.Pei, The stem cell pluripotency factor NANOG activates transcription with two unusual point subdomains at its C terminus, The Journal of Biological Chemistry, 14 January 2005, vol.280, n?2, pp.1401-1407.
102L.A.Boyer, T.I.Lee, M.F.Cole, S.E.Johnstone, S.S.Levine, J-P-Zucker, M.G.Guenther, R.M.Kumar, H.l.Murray, R.G.Jenner, D.K.Gifford. D.A.Melton, R.Jaenisch, R.A.Young, Core Transcriptional Regulatory Circuitry in human embryonic stem cells, Cell, 23 September 2005, vol.122, n?6, pp.1-10.
103W.M.Byrnes, Why Human "Altered Nuclear Transfer" Is Unethical. A Holistic Systems View, The National Catholic Bioethics Quarterly, Summer 2005, pp.271-279[
104D.A.Melton, G.Q.Daley, C.G.Jennings, Altered Nuclear Transfer in Stem-Cell Research - a flawed Proposal, The New England Journal of Medicine, 30 December 2004, vol.351, nr 27, p.2791.
105M.J.Schamblott, J.Axelman, S.Wang, E.M.Bugg, J.W.Littlefield, P.J.Donovan, P.D.Blumenthal, G.R.Huggins, J.D.Gearhardt, Derivation of pluripotent stem cells from cultured human primordial germ cells, Proceedings of the National Academy of Science, USA, 10 November 1998, vol.95, n?23, pp.13726-3731.
106L.Turnpenny, S.Brickwood, C.M.Spalluto, K.Piper, I.T.Cameron, D.I.Wilson, N.A.Hanley, Derivation of Human Embryonic Germ Cells: An Alternative Source of Pluripotent Cells, Stem Cells, 2003, vol.21, n?5, pp.598-609, See p.607.
107New method of obtaining embryonic stem cells could reduce embryo wastage, European Society for Human Reproduction and Embryology, released 20 June 2005. Baha A, Takeuchi T, Tanaka N, Neri QV, Rosenwaks Z, Palermo GD, Examination of individual blastomeres as a source of stem cells, Session 04, Stem Cells, Abstract O-018, p.i7, Abstracts of the 21st Annual Meeting of the European Society of Human Reproduction and Embryology, Copenhagen, Denmark, 19-22 June 2005, Human Reproduction, June 2005, vol.20, suppl.1, p.i7.
108E.S.Sills, T.Takeuchi, N.Tanaka, Q.V.Neri, G.D.Palermo, Identification and isolation of embryonic stem cells in reproductive endocrinology: theoretical protocols for conservation of human embryos derived from in vitro fertilization, Theoretical Biology and Medical Modelling, 18 July 2005, vol.2, pp.1-8.
109Wayayama S, Hikichi T, Suetsugu R, Sakaide Y, Bul HT, Mizutani E, Wakayama T, Efficient establishment of mouse embryonic stem cell lines from single blastomeres and polar bodies, Stem Cells, April 2007, vol.25, nr 4, pp.986-993.
110Y.Chung, I.Klimanskaya, S.Becker, J.Marh, S-J.Lu, J.Johnson, L.Meisner, R.Lanza, Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres, Nature, 12 january 2006, pp.216-219.
111I.Klimanskaya, Y.Chung, S.Becker, S-J.Lu, R.Lanza, Human embryonic stem cell lines derived from single blastomeres, Nature, 23 November 2006, vol.444, n?7118, pp.481-485.
112Y.Chung, I.Klimanskaya, S.Becker, T.Li, M.Maserati, S-J. Lu, T.Zdravkovic, D.Ilic, O.Genbacev, S.Fisher, A,Krtolica, R.Lanza, Human Embryonic Stem Cell Lines Generated without Embryo Destruction, Cell Stem Cell, February 2008, vol.2, pp.1-5.
113Geens M, Mateizel I, Sermon K, de Rycke M, Spits C, Cauffman G, Devroey P, Tournaye H, Liebaers I, Ban de Velde H, Human embryonic stem cell lines derived from single blastomeres of two 4-cell stage embryos, Human Reproduction, November 2009, vol.24, nr 11, pp.2709-2717.
114Van de Velde H, Geens M, Mateizei I, Spits C, Sermon K, De Rycke M, Van der Elst J, Devroey P, Tournaye H, Liebaers I, A human embryonic stem cell line derived from a single blastomere of a 4-cell stage embryo, Abstract of the 24th Meeting of the ESHRE, Barcelona, Spain, 7-9 july 2008, Human reproduction, July 2008, vol.23, suppl.1, p.i110, Abstract 0/274.
115Feki A, Bosman A, Dubuisson JB, Irion O, Dahoun S, Pelte MF, Hovatta O, Jaconi ME, Derivation of the first Swiss human embryonic stem cell line from a single blastomere of an arrested four-cell stage embryo, Swiss Medical Weekly, 20 September 2008, vol.138, nr 37-38, pp.540-550.
116Abbott A, "Ethical" stem-cell paper under attack, Nature, 7 September 2006, vol.443, nr 7107, p.12.
117M.A.Surani, Reprogramming of genome function through epigenetic inheritance, Nature, 1 November 2001, vol.414, nr 6859, pp.122-128.
118C.A.Cowan, J.Atienza, SD.A.Melton, K.Eggan, Nuclear Reprogramming of Somatic Cells After Fusion with Human Embryonic Stem Cells, Science, 26 August 2005, vol.309, nr 5739, pp.1369-1373.
119N.Strelchenko, V.Kukharenko, A.Shkumatov, O.Verlinsky, A.Kuliev, Y.Verlinsky, Reprogramming of human somatic cells by embryonic stem cell cytoplast, Reproductive BioMedicine Online, January 2006, vol.12, nr 1, pp.107-111.
120E.Check, Rebooted cells tackle ethical concerns. fusion technique resets adult skin to embryonic state, Nature News, published online 27 june 2005; doi: 10.1038/news050627-1.
121I.S.Abuljadayel, Induction of stem cell-like plasticity in mononuclear cells derived from immobilized adult human peripheral blood, Current Medical Research and Opinions, 2003, vol.19, nr 5, pp.355-375.
122S.J.Odelberg, Unraveling the molecular basis for regenerative cellular plasticity, PLOS Biology, August 2004, vol.2, n8, p.E 232.
123S.J.Odelberg, A.Kollhoff, M.T.Keating, Dedifferentiation of mammalian myotubes induced by msx1, Cell, 22 December 2000, vol.103, n?7, pp.1099-1109. C.J.McGann, S.J.Odelberg, M.T.Keating, Mammalian myotube dedifferentiation by newt regeneration extract, Proceedings of the National Academy of Science, USA, 20 November 2001, vol.98, n?24, pp.13699-13704.
124X.Wu, S.Ding, Q.Ding, N.S.Gray, P.G.Schultz, A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells, Journal of the American Chemical Society, 11 December 2002, vol.124, nr 49, pp.14520-14521. S.Chen, Q.Zhang, X.Wu, P.G.Schultz, S.Ding, Dedifferentiation of lineage-committed cells by a small molecule, Journal of the American Chemical Society, 21 January 2004, vol.126, nr 2, pp.410-411. S.Kim, G.R.Rosania, Y-T.Chang, Dedifferentiation? What's next?, Molecular Interventions, April 2004, vol.4, nr 2, pp.83-85
125X.Chen, Z.Mao, S.Liu, H.Liu, X.Wang, H.Wu, Y.Wu, T.Zhao, W.Fan, Y.Li, D.T.Yew, P.M.Kindler, L.Li, Q.He, L.Qian, X.Wang, M.Fan, Dedifferentiation of adult human myoblasts induced by ciliary neurotrophic factor in vitro, Molecular Biology of the Cell, July 2005, vol.16, nr 7, pp.3140-3151.
126A-M. Håkelien, H.B.Landsverk, J.M.Robl, B.S.Skålhegg, P.Collas, Reprogramming fibroblasts to express T-cell functions using cell extracts, Nature Biotechnology, May 2002, vol.20, nr 5, pp.460-466.
127S.Eminli, R.Jaenisch, K.Hochedlinger, Strategies to induce nuclear reprogramming, Ersnt Schering Foundation Symposium Proceedings, 2006, vol.5, pp.83-98.
128K.Hochedlinger, R.Jaenisch, Nuclear reprogramming and pluripotency, Nature, 29 june 2006, vol.441, nr 7097, pp.1061-1067.
129International Society for Stem Cell Research, 4th Annual Meeting, 29 June-1 July, Toronto, Canada.
130G.Vogel, Four Genes confer Embryonic Potential, Science, 7 July 2006, vol.313, nr 5783, p.27.
131G.Vogel, Four Genes confer Embryonic Potential, Science, 7 July 2006, vol.313, nr 5783, p.27.
132K.Takahashi, S.Yamanak, Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblasts Cultures by Defined Factors, Cell, 25 August 2006, vol.126, nr 4, pp.663-676.
133K.Takahashi, K.Tanabe, M.Ohnuki, M.Narita, T.Ichisaka, K.Tomoda, S.Yamanaka, Induction of Pluripotent Stem Cells from Adult Human fibroblasts by Defined Factors, Cell, 30 November 2007, vol.131, nr 5, pp.861-872.
134Okita K., Ichisaka T., Yamanaka S., Generation of germline-competent induced pluripotent stem cells, Nature, 19 July 2007, vol.448, nr 7151, pp.313-317.
135Wernig M., Meissner A., Foreman R., Brambrink T., Ku M., Hochedlinger K., Bernstein B.E., Jaenisch R., In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state, Nature, 19 July 2007, vol.448, nr 7151, pp.318-324.
136N.Maherali, R.Sridharan, W.Xie, J.Utikal, S.Eminli, K.Arnold, M.Stadtfelt, R.Yachechko, J.Tchieu, R.Jaenisch, K.Plath, K.Hochedlinger, Directly reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution, Cell Stem Cell, June 2007, vol.1, nr 1, pp.55-70.
137J.Yu, M.A.Vodyanik, K.Smuga-Otto, J.Antosiewicz-Bourget, J.L.Frane, S.Tian, J.Nie, G.A.Jonsdittir, V.Ruotti, R.Stewart, I.I.Slukvin, J.A.Thomson, Induced pluripotent Stem cell Lines Derived from Human Somatic Cells, Scienceexpress, 20 November 2007.
138Breakthrough of the Year, Reprogramming Cells, Science, 19 December 2008,vol.322, nr 5909. pp.1766-1773.
139Park L.H., Zhao R., West J.A., Yabuuchi A., Huo H., Ince T.A., Lerou P.H., Lensch M.W., Daley G.Q., Reprogramming of human somatic cells to pluripotency with defined factors, Nature, 10 January 2008, vol.451, nr 7175, pp.141-146.
140Lowry W.E., Richter L., Yachechko R. et al., Generation of human induced pluripotemt stem cells from dermal fibroblasts, Proceedings of the National Academy of Sciences, USA, 2008, vol.105, pp.2883-2888.
141Marion RM, Strati K., Li H., Tejera A., Schoeftner S., Ortega S., Serrano M., Blasco MA, Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells, Cell Stem Cell, 2009, vol.4, pp.141-154.
142Okita K., Ichisaka T., Yamanaka S., Generation of germline-competent induced pluripotent stem cells, Nature, 19 July 2007, vol.448, nr 7151, pp.313-317.
143K.Prelle, N.Zink, E.Wolf, Pluripotemt stem cells - model of embryonic development, tool for gene targeting and basis of cell therapy, Anatomia Histologia Embriologia, June 2002, vol.31, nr 3, pp.169-186.
144Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo C-I., Ma Q-W, Wang L, Zeng F, Zhou q, iPS cells produce viable mice through tetraploid complementation, Nature, advanced online publication, 23 july 2009, doi:10-1038/nature8267(2009)
145A.Meissner, M.Wernig, R.Jaenisch, Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells, Nature Biotechnology., October 2007, vol.25, nr 10, pp.1177-1181.
146Feng B, Ng J-C., Heng J.C., Ng H-H, Molecules that Promote or Enhance Reprogramming of Somatic Cells to Induced Pluripotent Stem Cells, Cell Stem Cell, 3 April 2009, vol.4, nr 4, pp.301-312.
147Mali P., Ye Z., Hommond H.H-, Yu X., Lin J., Chen G., Zou J., Cheng L., Improved efficacy and pace of generating induced pluripotent cells from human and fetal fibroblasts, Stem Cells, 2008, vol.26, pp.1998-2005
148Mikkelsen T.S., Hanna J., Zhang K., Ku M., Wernig M., Schorderet P., Bernstein B.E., Jaenisch R., Lander E.S., Meissner A., Dissecting direct reprogramming through integrative genome analysis, Nature, 2008, vol.454, pp.49-55.
149Zhao Y., Yin X, Qin H., Zhu F., Liu H., Ysang W., Xiang C., Hou P., Song Z., et al., Two supporting factors greatly improve the efficiency of human iPSC generation, Cell Stem Cells, 2008, vol.3, pp.475-479.
150Judson R.L., Babiarz J.E., Venere M., Blelloch R., Embryonic stem-cell-specific microRNAs promote induced pluripotency, Nature Biotechnology, 12 april 2009, doi: 10.1038/nbt.1535.
151Okita K., Ichisaka T., Yamanaka S., Generation of germline-competent induced pluripotent stem cells, Nature, 19 July 2007, vol.448, nr 7151, pp.313-317.
152R.Blelloch, M.Venere, J.Yen, M.Ramalho-Santos, Generation of Induced Pluripotent Stem Cells in the Absence of Drug Selection, Cell Stem Cell, 13 September 2007, vol.1, nr 3, pp.245-247.
153J.Yu, M.A.Vodyanik, K.Smuga-Otto, J.Antosiewicz-Bourget, J.L.Frane, S.Tian, J.Nie, G.A.Jonsdittir, V.Ruotti, R.Stewart, I.I.Slukvin, J.A.Thomson, Induced pluripotent Stem cell Lines Derived from Human Somatic Cells, Scienceexpress, 20 November 2007.
154M.Nakagawa, M.Koyanagi, K.Tanabe, K.Takahashi, T.Ichisaka, T.Aoi, K.Okita, Y.Mochiduki, N.Takizawa, S.Yamanaka, Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts, Nature Biotechnology, January 2008, vol.26, nr 1, pp.101-106.
155S.Lehrman, Virus treatment questioned after gene therapy death, Nature, 7 october 1999, vol.401, nr , pp.517-518.
156S.Hacein-Bey-Abina, C.von Kalle, M.Schmidt, F.Le Deist, A Serious Adverse Event after Successful Gene Therapy for X-linked Severe Combined Immunodeficiency, The New England Journal of Medicine, 16 january 2003, vol.348, nr 3, p.255.
157Stadtfeld M., Nagaya M., Utikal J., Weir G., Hochedlinger K., Induced pluripotent stem cells generated without viral integration, Science, 2008, vol.322, pp.945-949.
158Carey B.W., Markoulaki S., Hanna J., Saha K., Gao Q., Mitalipova M., Jaenisch R., Reprogramming of murine and human somatic cells using a single polycistronic vector, Proceedings of the National Academy of Sciences, USA, 6 january 2009, vol.106, nr 1, pp.157-162. Sommer CA, Stadtfeld M., Murphy G.J., Hochedlinger K., Kotton D.N., Mostoslavsky G., Induced Pluripotent Stem Cell Generation Using a Single Lentiviral Stem Cell Cassette, Stem Cells, 2009, vol.27, pp.543-549.
159Okita K., Nakagawa M., Hyenjong H., Ichisaka T., Yamanaka S., Generation of mouse induced pluripotent stem cells without viral vectors, Science, 2008, vol.322, pp.949-953. Gonzalez F., Barragan Monasterio M., Tiscornia G., Pulido N.M., Vassena R., Morera L.B., Piza I.R., Izpisua Belmonte J.C., Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector, Proceedings of the National Academy of Sciences, USA, 2 June 2009, vol.106, n22, pp.8918-8922.
160Woltjen K., Michael I.P., Mohseni P., Desai R., Mileikovsky M., Hämäläinen R., Cowling R., Wang W., Liu P., Gertsenstein M., Kaji K., Sung H-K., Nagy A., piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells, Nature, 1 March 2009, doi:10.1038/nature07863.
161Kaji K., Norrby K., Paca A., Mileikovsky, Mohseni P., Woltjen K., Virus-free induction of pluripotency and subsequent excision of reprogramming factors, Nature, 1 March 2009, doi:10.1038/nature07864.
162Yu J., Hu K., Smuga-Otto K., Tian S., Stewart R., Slukvin I.I., Thomson J.A., Human Induced Pluripotent Stem Cells Free of Vector and Transgene Sequences, Science, 8 May 2009, vol.324, pp.797--801.
163Huangfu D., Osafune K, Maehr R., Guo W., Eijkelenboom A., Chen S., Muhlestein W., Melton D.A., Induction of pluripotent stem cells by defined factors is greatly improved by small-molecules compounds, Nature Biotechnology, 2008, vol.26, pp.795-797. Shi Y., J.T.Do, Desponts C., Hahm H.S., Scholer H.R., Ding S., A combined chemical and genetic approach for the generation of induced pluripotent stem cells, Cell Stem Cell, 5 june 2008, vol.2, pp.525-528.
164Shi Y., Do J.T., Desponts C., Hahm H.S., Scholer H.R., Ding S., Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors, Cell Stem Cell, 17 december 2008, vol.2, pp.525-528.
165Lyssiotis C.A., Foreman R.K., Staerk J., Garcia M., Mathur D., Markoulaki S., Hanna J., Lairson L.L., Charette B.D., Bouchez L.C., Bollong M., Kunick C., Brinker A., Cho C.Y., Schultz P.G., Jaenisch R., Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of KLf4, Proceedings of the National Academy of Sciences, USA, 9 April 2009, PNAS.0rg/doi/10.1073/pnas0903860106.
166Kim D., Kim C-H., Moon J-I, Chung Y-G., Chang M-Y., Han B-S., Ko S., Yang E., Cha K.Y., Lanza R., Kim K-S., Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins, Cell Stem Cell, 5 June 2009, vol.4, nr 6, pp.472-476.
167Zhou H, Wu S., Joo J.Y., Zhu S., Han D.W., Lin T., Trauger S., Bien G., Yao S., Zhu Y., Siuzdak G., Schöler H.R., Duan L., Ding S., Generation of Induced Pluripotent Stem Cells Using Recombinant Proteins, Cell Stem Cell, 8 May 2009, vol.4, nr 5, pp.381-384.
168Chang HM, Gregory RI, MicroRNAs and reprogramming, Nature Biotechnology, June 2011, vol.29, nr 6, pp.499-500.
169Miyoshi N, Ishii H, Nagano H, Haraguchi N, Dewi DL, Kano Y, Nishikawa S, Tanemura M, Mimori K, Tanaka F, Saito T, Nishimura J, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Doky Y, Mori M, Reprogramming of Mouse and Human Cells to Pluripotency Using Mature MicroRNAs, Cell Stem Cell, 3 june 2011, vol.8, nr 6, pp.633-638.
170Untermaehrer JJ, Daley GQ, Induced pluripotent stem cells for modelling human diseases, Philosophical Transactions of the Royal Sociey of London, Series B, Biological Sciences, 12 August 2011, vol.366, nr 1575, pp.2274-2285.
171S.Yamanaka, A fresh Look at iPS Cells, Cell, 3 April 2009, vol.137, nr 1, pp.13-17.
172Rhee YH, Ko JY, Chang MY, Yi SH, Kim D, Kim CH, Shim JW, Jo AY, Kim BW, Lee H, Suh W, Park CH, Koh HC, Lee YS, Lanza R, Kim KS, Lee SH, Protein-nased human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease, The Journal of Clinical Investigation, 1 june 2011, vol.121, nr 6, pp.2326-2335.
173Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R, Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin, Science, 21 December 2007, vol.318, n5858, pp.1920-1923.
174Raya I, Rodriguez-Piza I., Guenechea G., Vassena R., Navarro S., Barrero M.J., Consiglio A., Castella M., Rio P., Sleep E., Gonzalez F., Tiscornia G., Gerreta E., Aasen T., Veiga A., Verma I.M., Surrallés J., Bueren J., Izpisua Belmonte J.C., Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells, Nature, 2 July 2009, vol.460, nr 7251, pp.53-59.
175Vogel G, Reprogrammed Cells Come Up Short, for Now, Science, 5 March 2010, vol.327, nr 5970, p.1191.
176Hu BY, Weick JP, Yu J, Ma LXC, Zhang XQ, Thomson JA, Zhang SC, Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency, Proceedings of the New York Academy of Science, USA, 2 March 2010, vol.107, nr 9, pp.4335-4340.
177Feng Q, Lu SJ, Klimanskaya i, Gomes I, Kim D, Chung Y, Honig Gr, Kim KS, Lanza R, Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence, Stem Cells, April 2010, vol.28, nr 4, pp.704-712.
178Straight talk with George Daley, Nature Medicine, June 2010, vol.16, nr 6, p.624.
179Leibel C, New ethical Questions Are Being Raised in Stem Cell Research, Medical News Today, 12 December 2009. http://www.medicalnewstoday.com/article/173785.php
180Geddes L, No embryos were harmed..., New Scientist, 15 December 2007, pp.44-45.
181K.Hübner, G.Fuhrmann, L.K.Christenson, J.Kehler, R.Reinbold, R.De la Fuente, J.Wood, J.F.Strauss Ill, M.Boiani, H.R.Schöler, Derivation of Oocytes from Mouse Embryonic stem cells , Science, 23 May 2003, vol.300, nr 5623, pp.1251-1256.
182Y.Toyooka, N.Tsunekawa, R.Akasu, T.Noce, Embryonic stem cells can form germ cells in vitro, Proceedings of the National Academy of Science, USA, September 30 2003, vol.100, nr 20, pp.11457-11462.
183K.Nayernia, J.Nolte, H.W.Michelmann, J.H.Lee, K.Rathsack, N.Drusenheimer, A.Dev, G.Wulf, I.E.Ehrmann, D.J.Elliott, V.Okpanyi, U.Zechner, T.Haaf, A.Meinhardt, W.Engel, In Vitro-Differentiated Embryonic stem cells Give Rise to Male Gametes that Can Generate Offspring Mice, Developmental Cell, July 2006, vol.11, nr 1, pp.125-132.
184Kee K, Angeles VT, Flores M, Nguyen HN, Reijo Pera RA, Human DAZL DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation, Nature 12 November 2009, vol.462, nr 7270, pp.222-225.
185Mathews DJ, Donovan PJ, Harris J, Lovell-Badge R, Savulescu J, Faden R, Pluripotential Stem Cell-Derived Gametes: Truth and (Potential) Consequences, Cell Stem Cell, 2 July 2009, vol.5, nr 1, pp.11-14.
186Hyun I, The bioethics of stem cell research and therapy, The Journal of Clinical Investigation, January 2010, vol.120, nr 1, pp.71-75.
187Sun N, Longaker MT, Wu JC, Human iPS cell-based therapy: considerations before clinical applications, Cell Cycle, March 2010, vol.9, nr 5, epub 2 March 2010.
188Murdoch CE, Scott CT, Stem Cell Tourism and the Power of Hope, The American Journal of Bioethics, May 2010, vol.10, nr 5, pp.16-23.
189Regulators must step up stem cell oversight, Nature Medicine, May 2010, vol.16, nr 5, p.492. Caulfield T, Scott C, Hyun I, Lovell-Badge R, Kato K, Zarzeczny, Stem cell research policy and iPS cells, Nature Methods, January 2010, vol.7, nr 1, pp.26-33. Zarzeczny A, Scott C, Hyun I, Bennett J, Chandler J, Chgarge S, Heine H, Isasi R, Kato K, Lovell-Badge R, McNagny K, Pei D, Rossant J, Surani A, Taylor PL, Ogbogu U, Caulfield T, iPS Cells: mapping the policy issues, Cell, 11 December 2009, vol.139, nr 6, pp.1032-1037.