Ant-OAR - Brugger

Virgin and Child, Enthroned, The Master of Moulins, 1499

A THEOLOGICAL DEBATE on
ANT-OAR as a SOURCE
of PLURIPOTENT STEM CELLS,

ANT-OAR: A MORALLY ACCEPTABLE MEANS
FOR DERIVING PLURIPOTENT STEM CELLS.
A REPLY TO CRITICISMS

“If the cell’s behavior is not commensurate with that of an embryo, the cell is not an embryo.”

In December 2004, Dr. William Hurlbut, physician and professor at Stanford University and a member of the President’s Council on Bioethics, presented a proposal to the Council entitled “Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells.” 1 Hurlbut’s premise stated that, using modern cloning technology, it may be scientifically possible to produce embryonic-like (i.e., pluripotent 2 ) stem cells without ever creating and destroying human embryos. Cloning is accomplished by using somatic cell nuclear transfer (SCNT), in which the nucleus of a somatic (adult body) cell is removed and transferred into an enucleated oocyte (i.e., an egg cell with its nucleus removed). The crucial difference between SCNT for purposes of human cloning and SCNT as proposed by Hurlbut is that in the latter procedure, the genetic material in the somatic cell nucleus is preemptively altered before nuclear transfer in such a way as to create biological conditions incompatible with the coming into existence of embryonic human life, but compatible with the development of pluripotent stem cells. He called his broad conceptual proposal Altered Nuclear Transfer (ANT).

In June 2005, a group of thirty-five scholars (including ethicists, moral theologians, physicians, and scientists), including Dr. Hurlbut, published a joint statement proposing a specific type of ANT called Oocyte Assisted Reprogramming (ANT-OAR). 3 ANT- OAR begins from the assumption that the identity and function of each cell in the human body depends on the precise interrelation, communication, and on-off pre-programming of the approximately thirty thousand genes in the cell’s genome. This condition of cell interaction and expression is called the cell’s “epigenetic state” (or “genetic imprinting”). The epigenetic state of the single-celled human embryo (or zygote) is totipotent, that is, it has the developmental capacity to differentiate in an orderly and coordinated way into all the tissue types necessary for full organismal development, including into the placenta, umbilical cord, and other extraembryonic tissues. From the perspective of epigenetics, we might say that totipotency defines a human zygote. It follows that it is reasonable to conclude that where there is a totipotent human cell, there is a human zygote.

Cloning technology, drawing on this reasoning, has developed a way to “reprogram” the epigenetic state of a cell. Using SCNT, scientists have observed that the cytoplasm of an enucleated oocyte has a remarkable capacity to transform the epigenetic state of a transferred diploid nucleus from its original state to a state of totipotency. The nucleus at the time of transfer has the genetic imprinting of the differentiated cell type from which it was extracted (e.g., cardiac cell, liver cell, skin cell). After nuclear transfer into an enucleated oocyte, the epigenetic state is reprogrammed from its formerly highly specialized state back to a state of totipotency. It goes through a process of epigenetic dedifferentiation. If it reaches its terminus, the reprogrammed cell is a zygote, a one-celled embryo, with the genotype of the donor of the somatic cell. It will develop into an adult who is genetically identical to the somatic cell’s donor. This is how Dolly the sheep was created. 4

Making use of the technique of SCNT, ANT-OAR proposes to utilize the reprogramming capacity of oocyte cytoplasm. But it intends to do so without ever generating human embryos. We know something of the molecular mechanisms underlying pluripotent stem cells, including that several transcription factors are characteristic of the pluripotent state. More than characteristic, certain ones appear to be essential for establishing and maintaining the state of pluripotency. 5 One such transcription factor (and only one of a number, all of which individually or in combination, or combined with other genetic alterations, potentially would be candidates for ANT-OAR) is the homeoprotein Nanog. 6 Its expression characterizes the unique state of pluripotent cells as neither oocytes nor later differentiated cell types. Nanog is found expressed in pluripotent stem cells and not expressed in oocytes or single-celled embryos. When its expression is forced, a cell is not totipotent, but, likewise, cell differentiation is prevented. When its expression is blocked, cells rapidly begin to differentiate. The Joint Statement proposes a procedure that combines the reprogramming of the nuclear genome of a somatic cell with precise genetic alterations forcing the expression of the transcription factor Nanog (or similar factors that are required for the pluripotent state). The alterations in the nuclear genome would be carried out prior to nuclear transfer. When the nucleus is transferred into the enucleated oocyte, we create ab initio a Nanog-expressing cell whose epigenetic character is that of a pluripotent stem cell and incompatible with zygotic existence. The Joint Statement recommends that ANTOAR be explored first through experimentation utilizing nonhuman animal cells.

David L. Schindler, dean and professor of theology at the John Paul II Institute for Studies on Marriage and Family in Washington, D.C., has accused the 35 signatories of the ANT-OAR proposal of advancing a “top to bottom” mechanistic account of the origins of human life. 7 His argument goes like this: the signatories argue that the identity of any particular cell depends on its epigenetic state; if this is the case, then by altering the epigenetic state of a cell, we can alter the identity of that cell; it follows that if we make certain precise epigenetic alterations to the genome of a somatic cell nucleus before transferring it into an enucleated oocyte, the entity that we bring into existence will not be a one-celled human being (a zygote), but rather its identity will be that of the type of cell whose epigenetics we have altered it to become, i.e., a pluripotent stem cell. Schindler says this reduces the ontological reality of the entity brought into existence to its raw epigenetic map. But epigenetics, he says, does not determine the identity of a cell, it determines only a cell’s observable features, i.e., its phenotype:

Epigenetics can determine only the phenotypical manifestation of the cell whose identity is at issue, not its (ontological) identity 7 as such. Thus, the mere act of modifying the epigenetic profile of the OAR product cannot be sufficient to prevent that product from being, or having been, an incipient human organism. 8

It follows, he concludes, that ANT-OAR fails in what it sets out to produce since the proposal sets forth a procedure that “is really a means of artificially replicating conception.”

There are two related errors in Schindler’s reasoning. First, he argues that by asserting that the identity of a cell is determined by a cell’s epigenetic state, ANT-OAR reduces ontology to epigenetics, which he calls “a classic mechanistic maneuver:”

For what else can we call the confusion of phenotype (based on epigenetics) with substantial identity upon which the argument for OAR hinges? If, in fact, substantial identity is essentially a matter of epigenetics, then the organismic whole is no more than the sum of its parts, and the absence or presence of an organism is simply a matter of reshuffling the epigenetic pieces. 9

Schindler here badly mischaracterizes ANT-OAR. The joint proposal does not assert, and its signatories would in fact reject, the proposition that “substantial identity is essentially a matter of epigenetics.” The joint proposal states, and Schindler himself quotes it as stating, that “the nature of each cell depends on its epigenetic state.” To say a cell’s identity depends on its epigenetic state is not to say a cell’s “substantial identity” is “no more than” its epigenetic state. Schindler has misinterpreted the joint proposal as putting forward epigenetic disposition as a sufficient condition for the actualization of embryonic life, when in fact its authors intended it only as a necessary condition. They do assert that the identity of a cell depends on the cell’s genetic imprinting, which means that the identity of a one-celled human embryo too depends on its genetic imprinting. To deny this is to deny the biological basis for differentiation among cell types in the human body. 10 If cells are not differentiated by their respective gene expression, what biologically differentiates a skin cell from a liver cell? Not the number of chromosomes, genes, or nucleotides, nor even the DNA sequence, since in cells from the same person, these are identical. Rather, there are epigenetic conditions under which a liver cell is able to be a liver cell, and without which it cannot be a liver cell. Is a liver cell no more than its epigenetic state? No. But to be what it is depends necessarily (among other things) on that state. So too a zygote has precise biological conditions under which it is able to be what it is, and without which it cannot come into existence. Among other things, such conditions include an epigenetic state of totipotency. To assert this is not to assert that it is no more than its epigenetic state. Its genetic imprinting is a necessary condition, but not a sufficient condition for its identity as a human being at the zygotic phase of development.

Schindler’s second and related error is philosophical. In denying that epigenetics is a necessary condition for differentiating a cell’s identity, he implicitly denies that a zygote’s organic bodily material is necessary for its identity as human. Why is this? Because epigenetics and organic identity are integrally connected. The epigenetic state of a cell includes the primordial preprogrammed totality of the activated, inactivated and to be activated and inactivated states of the genes in the cell’s genome. These epigenetic primordia determine the active potentialities of that cell, 11 including in some cases the aptitude to be informed by a non-material human soul. A liver, renal, cardiac, immune, or neural cell, as well as a one-celled human embryo, is what it is, biologically speaking, not because of the presence of some given organic material per se, but precisely because of that organic material’s active potentialities. If a human cell has the requisite set of active potentialities to undergo self-directed, human organismic development, then it is a one-celled embryo. To be sure, an embryo is more than its organic matter and epigenetic primordia; but without them, an entity is not an embryo. If a cell’s active potentiality is to function like a liver cell, then it has the nature of a liver cell. And if ab initio it will only ever do what a liver cell does, then it was ab initio a liver cell. This follows from the 11 principle that the potentialities of a thing determine the possibilities for that thing’s actuations, and hence its identity. This principle was first affirmed by Aristotle in his hylomorphic conception of the relationship between body and soul, a conception Aquinas takes up and develops.

Aristotle holds that matter and form exist together in an individuating, unified relationship. A thing’s substantial form is what makes the thing the kind of thing it is. It is a thing’s whatness, or essence. 12 Aristotle calls the substantial form in humans the intellectual soul. The human body gets its being as this kind of body—i.e., a human body, from the soul. Another way of saying this is, the soul is the whole body’s actuality. (For the Aristotelian-Thomistic hylomorphic tradition, form equals actuality in a thing.) And so Aristotle writes, “the soul is an actuality of . . . a natural body having life potentially in it.” 13 Saying the same thing, Aquinas writes: “the soul is the primary actuality of a physical body capable of life.” 14 For the human person, this means the intellectual soul is the actuality of a material body capable of being a human body (with the presumption here that only living human bodies are, properly speaking human). 15 What does Aquinas mean when he refers to a body as “capable of life,” and Aristotle when he says, “having life potentially in it”? Something very specific: in the case of a human being, the body must have an active potency to be alive in a specifically human way; the body must already be human in potency: “the actuality of any given thing can only be realized in what is already potentially that thing, in a matter of its own appropriate to it.” 16 (Matter equals potentiality.) The human soul therefore is the actuality of some matter already potentially a human being. Only organic material with an active potential for humanness is informed by an intellectual soul. The constitution of the organic material is a necessary condition for human life’s actualizability; and the presence of the requisite disposition is indicative of its state of being already informed by the specifically human form. 17 This means some organic material precisely because of its active potentialities will be incompatible with the properly human form of an intellectual soul. The organic material of a liver cell, for example, will be incompatible. Why? Not because it does not possess a diploid nucleus with a full human genome, because it does. Rather, because the epigenetic state of that genome excludes the possibility of that cell doing what humans do at that stage of existence, developing as humans develop, and hence (we conclude) excludes the possibility of being human, since, as Aquinas says, agere sequitur esse (action follows being). The organic constitution of a one-celled embryo, on the other hand, is by definition adequate material. Schindler’s argument fails to understand that it is precisely the character of the organic material, which includes inter alia the material’s genetic imprinting, that determines the possibilities for humanness.

Schindler might reply saying he denies nothing of what has just been said about the determining importance of the character of the material. If we grant him this, it becomes clear that his account of what constitutes materia apta for the actualization of humanness is badly flawed. He writes:

OAR presupposes an actual fusion of an oocyte and a somatic cell nucleus, and thus mimics conception. This is true even if the genesis of the new entity and its pluripotent stem-cell-like manifestation occur simultaneously, or with no apparent time interval at all. What OAR proponents call the “epigenetic reprogramming” of the somatic cell nucleus by the oocyte might be more accurately called the pre-planned developmental modification of a human conceptus (brought about by artificial means). 18

The quote illustrates that at the heart of Schindler’s conception of the conditions for the coming to be of human life, is the governing erroneous assumption that the fusion of an oocyte and a somatic cell nucleus, irrespective of the epigenetic character of the so-called “fused” entity, gives rise to a human embryo. There are two problems with this. First, Schindler’s science is flawed. It is not the “fusion” of a somatic cell nucleus and an oocyte. There is no nuclear fusion at all. The entity into which the somatic cell nucleus is transferred, because it has been enucleated, is no longer an oocyte. In fact, it is not even a cell, but rather an ooplast, a bag of cytoplasm. Transferring an altered nucleus into the ooplast does not “mimic” conception, since at conception a sperm penetrates an egg, the nuclei fuse, giving rise to a diploid zygote with a totipotent epigenetic state. Nothing like this is being proposed in ANT-OAR.

Second, if ANT-OAR produced a human embryo, then the entity created would have, or pass through, a totipotent epigenetic state. But the product of ANT-OAR never is totipotent nor passes through such a state. This is where Schindler’s governing erroneous assumption imposes itself with particular force: “ANT-OAR . . . mimics conception . . . even if the genesis of the new entity and its pluripotent stem-cell-like manifestation occur simultaneously, or with no apparent time interval at all.” 19 In other words, it does not matter if the entity created is pluripotent, it is still an embryo. This belies scientific fact. A one-celled embryo is by definition totipotent. The entity created by ANT-OAR is ab initio pluripotent. It therefore cannot be an embryo. But might not it pass, ever so instantaneously, through a state of totipotency during reprogramming? In principle, no. If Nanog expression (or expression of some other transcription factor, or combination of transcription factors, or combination of transcription factors and precise gene modifications, etc.) is definitional of the state of pluripotency; and forced Nanog expression (or forced expression of . . . ) characterizes ab initio the biological “artifact” 20 that ANT-OAR brings into existence, being intentionally made to do so before nuclear transfer, then the entity never was totipotent. Further, the reprogramming to a state of pluripotency is not a process of developmental differentiation beginning with totipotency and moving to pluripotency, as with embryonic development. It is a process of dedifferentiation moving from the highly specified epigenetic state of the adult nuclear genome “backwards” (we might say, albeit not without some imprecision) to a state of pluripotency. It never reaches a state of totipotency, because it is intentionally prevented from doing so. 21

Schindler may reply: your thesis may work in principle, but how can you ever verify empirically that the kind of cell ANTOAR produces is not a human embryo? Our answer: the same way we come to know what any cell type is and is not. We perform a material analysis. We screen and see what genes the cell expresses. If the genes expressed are characteristic of embryo genes, then we conclude it is a zygote. If they are not, say they are identical to those expressed in liver cells, then we conclude it is not an embryo but a liver cell. We also perform a temporal analysis. We observe the cell’s behavior over time. We see how it acts. If it acts like an embryo we conclude it is an embryo. 22 If it acts like a liver cell, we conclude it is a liver cell. Schindler writes:

Determination of the presence of life in its most subtle beginnings is precisely not obvious in the manner of a positivistic fact, but always involves philosophical mediation (even if only unconsciously). Apprehending life in its most subtle beginnings involves a cognitional act that is not only empirical but also (at least implicitly) metaphysical in nature, an act which, rightly exercised, recognizes the mystery characteristic of the organism in its very givenness. . . . God gives the organism to itself and so creates an originality that by definition we cannot know or control exhaustively, an originality that we therefore should not attempt or claim to know or control exhaustively. 23

I see no problem affirming—if I understand Schindler—that we cannot “exhaustively” know and control the “originality” of life, if by originality he means having its unique, irrepeatable origin ultimately in God. And certainly we should not attempt to “exhaustively” control human life’s origin. But according to Schindler’s logic, we can never know through empirical observa-tion—which I take him to mean by the term “positivistic fact”—that a human cell is or is not a human embryo. This is absurd. We can know the difference between a one-celled embryo and a liver cell because the cells express different genes and act differently: agere sequitur esse. If we transplant a liver cell into a female uterus, it does not do what a human embryo does when transplanted in a female uterus. If the cell’s behavior is not commensurate with that of an embryo, the cell is not an embryo. To deny that science is able to apprehend such fundamental biochemical and behavioral cell distinctions, and to apprehend them with certitude, is to operate from a doubt that can only be termed irrational. Schindler has severed the link between what something is and our ability to know what it is. This implies an erroneous epistemology, one which denies that human intelligence, even weakened by sin, can attain to a certain knowledge of reality. 24 Further, if the embryo cannot manifest itself bodily in any observable way, then this implies the embryo is something other than its body, i.e., that a human being can be present without bodily manifestation. This is dualism and is inconsistent with sound reasoning and Catholic moral teaching: “it [dualism] contradicts the Church’s teachings on the unity of the human person, whose rational soul is per se et essentialiter the form of his body.” 25 John Paul II affirms that the “spiritual and immortal soul is the principle of unity of the human being, whereby it exists as a whole—corpore et anima unus—as a person.” 26 If the human person subsists in a body-soul unity, then human activity, including zygotic activity, will always also be bodily activity. As bodily activity it will be observable and knowable. By what criteria does Schindler assess the ontological identity of an entity of human origin? What tells him the ontological identity if not the physical characteristics?

Schindler is worried because the technique used in ANTOAR (namely, SCNT) is the same technique that is used in human cloning. And in human cloning a one-celled embryo is created. But why do we, or Schindler, or anyone know that using SCNT for purposes of cloning human embryos does or can create a human embryo? Because when it is done, we sometimes get an entity that behaves like an embryo. We know the entity from what it does, and we draw our conclusions accordingly. We will know ANT-OAR does not create an embryo and therefore does not “mimic conception,” because we do not get an entity that expresses itself and acts like an embryo. Scientists did not conclude a priori that SCNT

24 25 26 creates embryos; they concluded that it creates embryos because when it was carried out with that intention, it sometimes worked. If it did not work, nuclear transfer for the purpose of creating pluripotent stem cells would be, I presume, non-controversial. It seems that Schindler has stigmatized all forms of nuclear transfer with a sort of mysterious embryo-creating power simply because SCNT for purposes of cloning human embryos sometimes works. The fact that in ANT-OAR a diploid nucleus is transferred into an enucleated oocyte is not sufficient ground for concluding the entity that arises possesses the active potentiality to undergo organized, self-directed development in a way characteristic of a human being. Parthenotes, teratomas, 27 and certain kinds of hydatidiform moles 28 begin as oocytes with diploid nuclei. We can even make a hydatidiform mole: enucleate an oocyte and transfer into it the nuclei of two sperm cells. We get an oocyte with a diploid nucleus. Have we made a zygote? Nor can Schindler fall back on the ambiguous term “fusing of oocyte and somatic cell nucleus.” We can “fuse” an enucleated oocyte and a somatic cell nucleus in a high speed blender. Do we get an embryo? The constituents after all are very much “fused.” We can “fuse” sperm and eggs in a blender. Have we mimicked conception? No. How do we know? Because we do not get an entity that expresses itself in any recognizable way like an embryo. But if the “fusion” of sperm and egg in a blender resulted in entities that behaved like human embryos, if they went on to divide, differentiate, express the biochemical patterns of human embryos, then we would conclude that such a procedure gives rise to human embryos. It is absurd to claim that an entity is a human organism when it expresses itself neither materially nor temporally in ways characteristic of human organisms. As I said, this is dualist; it denies discernibly human material characteristics to something human; the entity looks, expresses itself, and behaves like a pluripotent stem cell; it does not express itself in a way characteristic of a human organism, nor does it have any peculiarly human organismic behavioral characteristics; but it just might be informed by a human soul. This is like claiming that a human soul might be trapped inside a stone. If we can distinguish between any cell and a zygote, we should be able to distinguish between an ANT-OAR cell and a zygote. 29

Critical questions regarding ANT-OAR’s fitness for producing pluripotent stem cells in a morally legitimate way need to be answered through initial research using nonhuman animal cells before the technique is ever tried with human cells. The signatories state: “if, but only if, such research establishes beyond a reasonable doubt that oocyte-assisted reprogramming can reliably be used to produce pluripotent stem cells without creating embryos, would we support research on human cells.” 30 The presence of Nanog and similarly acting transcription factors in oocytes and zygotes will need to be ruled out. The incompatibility of their expression with embryonic existence will need to be conclusively established. Present evidence demonstrates that such factors maintain the pluripotency of a stem cell by preventing cell differentiation; are we sure their forced expression will also prevent cell dedifferentiation? Another question is, if oocyte cytoplasm is potent enough to reprogram a genome back to a state of totipotency, is it possible that it will also reprogram the altered gene for Nanog expression? This problem may be obviated by employing techniques for forcing gene expression that circumvent the “reprogramming” mechanisms used by oocytes (e.g., forcing RNA expression—the oocyte does not “reprogram” RNA).

One criticism maintains that the reliability of the method used for detecting Nanog is not sufficient to establish moral certitude that the entity created through ANT-OAR is not an embryo: “the lack of detection of Nanog in the zygote does not mean that it is not present. Thus the biological underpinning of the OAR hypothesis, namely that the zygote differs from the morula or ICM cells of the blastocyst because it lacks Nanog, cannot be proven with moral certainty.” 31 This criticism raises a general question worth asking. Can any scientific protocol be developed that delivers results precise and consistent enough to establish beyond a reasonable doubt that the entity created through ANT-OAR is or is not a human embryo? This question brings us back to the fundamental doubt as to whether science is capable of apprehending the difference between different types of cells. I called the doubt “irrational” since its affirmation implies a denial that science, and by implication the reasoning that derives from sensible observation, can know things with certitude. Although the methodological exactitude of any proof will be limited by the inherent epistemological constraints imposed by the subject matter, and in the case of the scientific method we operate in the domain, not of doubtless certitude as in the domain of divine Revelation, but of statistical certitude in which doubt is never ruled out; nevertheless, it is possible to have certitude beyond a reasonable doubt (i.e., moral certitude) that the entity created through ANTOAR is not an embryo. Reasonable doubt is expelled through a process of rigorous material and temporal analysis of the product of the technique. If there is sufficient evidence in animal experimentation to rule out a reasonable doubt that an embryo comes into existence through ANT-OAR, then we proceed to human cell experimentation.

Another related question might be asked: having established that the expression of a desired transcription factor or factors is categorically incompatible with embryonic existence, what is the possibility that in testing for the expression of that transcription factor the method will deliver false positives? This too will need to be addressed during experimentation using nonhuman animal cells. Rigorously testing the products of ANT-OAR will enable us to reliably establish the probability of methodological test failure. If failure rates are statistically negligible, and testing otherwise consistently establishes that the entity produced from ANT-OAR is not an embryo but a pluripotent cell; and the firm intention is to protect the value of human life by never producing a human organism; then it may be reasonable to proceed with testing in human cells knowing that a very remote possibility exists that an embryo may result; that 31 possibility is accepted as an unwanted and unintended side effect of an otherwise morally justifiable act. By analogy, women are sometimes prescribed estrogen pills for the regulation of the menstrual cycle. One activity of orally administered estrogen can be to render a woman’s uterine lining inhospitable to a nidating embryo, in the rare instance of a breakthrough ovulation and subsequent fertilization. Knowing this, many Catholic moral theologians agree that for serious reasons the choice of a woman, even a sexually active married woman, to take estrogen pills for purposes of cycle regulation can be legitimate, if a contraceptive intent is excluded.

E. CHRISTIAN BRUGGER is assistant professor of theology at the Institute for the Psychological Sciences in Arlington, Virginia.

1 Hurlbut published an expanded version of the essay with the same title in Perspectives in Biology and Medicine 48, no. 2 (Spring 2005): 211–228; for a synopsis of the idea, see Hurlbut’s interview with Jennifer Lahl, National Director of the Center for Bioethics and Culture Network, entitled “Altered Nuclear Transfer: Is it the Answer for the Embryonic Stem Cell Research Debate?” available at www.cbc-network.org.

I would like to acknowledge the assistance of Dr. Hurlbut; Dr. Maureen Condic of the Department of Neurobiology and Anatomy at the University of Utah School of Medicine; Thomas Berg, L.C., Executive Director of the Westchester Institute; and Dr. Michael Augros of the Center for Higher Studies of the Legion of Christ for their assistance in preparing this essay.

2 “Pluripotency” is the capacity of a cell to develop into all the various tissue types of the human body. It is important to note that presently no useful embryonic stem cell-based therapies exist. Nonetheless, many scientists believe that embryonic stem cells, because of their pluripotency, promise to provide important tools for the study of disease, and possibly to provide cells and tissues for groundbreaking medical therapies.

3 The joint statement was published as: “Production of Pluripotent Stem Cells by Oocyte-Assisted Reprogramming: Joint Statement with Signatories,” National Catholic Bioethics Quarterly 5, no. 3 (Autumn 2005): 579–583. It should be emphasized that the proposal called for initial research using only nonhuman animal cells. Only in the case that such research established beyond a reasonable doubt that ANT-OAR could reliably be used to create pluripotent stem cells without creating embryos would its signatories support research using human cells. Signatories include: Hadley Arkes, Ph.D., Amherst College; Rev. Nicanor Pier Giorgio Austriaco, O.P., Ph.D., Providence College; Rev. Thomas Berg, L.C., Ph.D., The Westchester Institute for Ethics and the Human Person; E. Christian Brugger, D. Phil., Institute for Psychological Sciences; Nigel M. de S. Cameron, Ph.D., Institute on Biotechnology and the Human Future and Chicago-Kent College of Law, Illinois Institute of Technology; Joseph Capizzi, Ph.D., Catholic University of America; Maureen L. Condic, Ph.D., University of Utah, School of Medicine; Samuel B. Condic, M.A., University of Houston; Rev. Kevin T. FitzGerald, S.J., Ph.D., Georgetown University Medical Center; Rev. Kevin Flannery, S.J., D.Phil., Pontifical Gregorian University; Edward J. Furton, Ph.D., The National Catholic Bioethics Center; Robert P. George, J.D., D.Phil., Princeton University; Timothy George, Th.D., Samford University; Alfonso Gómez-Lobo, Dr. phil., Georgetown University; Germain Grisez, Ph.D., Mount Saint Mary’s University; Markus Grompe, M.D., Oregon Stem Cell Center; John M. Haas, Ph.D., The National Catholic Bioethics Center; Robert Hamerton-Kelly, Th.D., Stanford University; John Collins Harvey, M.D., Ph.D., Georgetown University Medical Center; Paul J. Hoehner, M.D., M.A., FAHA, The University of Virginia Graduate School of Arts and Sciences; William B. Hurlbut, M.D., Stanford University; John F. Kilner, Ph.D., The Center for Bioethics and Human Dignity; Patrick Lee, Ph.D., Franciscan University of Steubenville; William E. May, Ph.D., John Paul II Institute for Studies on Marriage and Family at The Catholic University of America; Rev. Gonzalo Miranda, L.C., Ph.L., S.T.D., Regina Apostolorum Pontifical Athenaeum; C. Ben Mitchell, Ph.D., Trinity International University; Most Reverend John J. Myers, J.C.D., D.D., Roman Catholic Archbishop of Newark, New Jersey; Chris Oleson, Ph.D., Center for Higher Studies Thornwood, New York; Rev. Tad Pacholczyk, Ph.D., The National Catholic Bioethics Center; Rev. Peter F. Ryan, S.J., S.T.D., Mount St. Mary’s University; William L. Saunders, J.D., The Family Research Council; David Stevens, M.D., M.A., Christian Medical & Dental Associations; Rev. Msgr. Stuart W. Swetland, S.T.D., The Newman Foundation; M. Edward Whelan III, J.D., Ethics and Public Policy Center; Rev. Thomas Williams, L.C., Ph.L., S.T.D., Regina Apostolorum Pontifical Athenaeum.

4 It should be noted that such reprogramming is highly inefficient, with typically only 0.1-1% of all transferred nuclei producing a live birth.

5 A transcription factor is a protein that helps regulate gene expression by binding to the gene and aiding and directing transcription of the gene’s DNA into RNA. For gene expression to be complete the RNA needs to be further translated into its corresponding protein.

6 Nanog is just one of a number of transcription factors that have been shown to be essential in maintaining the pluripotency of inner cell mass cells; for two essays on Nanog’s activity, see Hatano, Shin-ya, Masako Tada, et al., “Pluripotential competence of cells associated with Nanog activity,” Mechanisms of Development 122 (2005), 67–79; and Mitsui, Kaoru, Yoshimi Tokuzawa, et al., “The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells,” Cell 113 (30 May 2003): 631–642.

7 David L. Schindler, “A Response to the Joint Statement, ‘Production of Pluripotent Stem Cells by Oocyte Assisted Reprogramming,’” Communio: International Catholic Review 32, no. 2 (Summer 2005): 369-380. Part II of the Spring 2005 issue of Communio (vol. 32, no. 1) is dedicated to Hurlbut’s original ANT proposal; Schindler and Adrian J. Walker criticize Hurlbut’s proposal in two essays; Nicanor Pier Giorgio Austriaco, O.P., offers a reply. Although several of the arguments and concomitant errors leveled against ANT by Schindler and Walker correspond to those formulated in Schindler’s later essay, “A Response to the Joint Statement,” my intention in this essay is to criticize only Schindler’s later essay.

10 Nicanor Austriaco, O.P., writes: “if we follow Schindler’s logic, any human cell—a skin cell, a liver cell, or a kidney cell—regardless of its ‘phenotypical manifestation’ could be ontologically equivalent to a single-cell embryo” (“Are Teratomas Embryos or Non-Embryos? A Criterion for Oocyte-Assisted Reprogramming,” The National Catholic Bioethics Quarterly 5, no. 4 [Winter 2005]: 705f).

11 Austriaco discusses the concepts of active and passive potentialities in reference to ANT in “Altered Nuclear Transfer: A Critique of a Critique,” Communio: International Catholic Review 32, no. 1 (Spring 2005): 172–176.

12 Aristotle, Metaphysics, bk. VII, no. 10, 1035b14, tr. W. D. Ross, in The Complete Works of Aristotle, ed. Jonathan Barnes, vol. 2 (Princeton, N.J.: Princeton University Press, 1984), 1635. Aquinas will also say that one sense of “form” is the “what it is” of a thing, its essence or quiddity, which would include its matter taken universally, like “flesh and bones” in the case of man. Other times, however, Aristotle and Thomas will use “substantial form” to mean only one part of a thing’s essence. A natural substance is composed of both matter and form, and neither of these alone is what that substance is—a man is not just a soul. At Metaphysics VI, bk. 1, 1025b29–35, for example, Aristotle insists that the “what” of a natural thing must always include matter. I thank Dr. Michael Augros for pointing this out to me.

13 Aristotle, De Anima, bk. II, no. 1, 412a27, tr. J. A. Smith, in The Complete Works of Aristotle, ed. Jonathan Barnes, vol. 1 (Princeton, N.J.: Princeton University Press, 1984), 656.

14 Aquinas, Commentary on Aristotle’s De Anima, bk. II, lecture IV, par. 271, tr. Kenelm Foster, O.P., and Silvester Humphries, O.P. (Notre Dame, Ind.: Dumb Ox Press, 1994), 88.

15 Aquinas asserts that at death, when life passes from the body, a substantial change takes place; the body is no longer, properly speaking, a human body, except in an equivocal sense; the eyes and flesh of a corpse are only equivocally referred to as human eyes and human flesh since neither possesses its proper operation qua human. He says this in response to Platonic dualism, which holds that since the soul is united to the body as a driver is to a machine, the body is what it is apart from the soul; therefore at death, when the soul departs, the body remains a human body and its parts human body parts; see Aquinas, Summa Contra Gentiles (SCG), bk. II, ch. 57, no. 10, tr. James F. Anderson (South Bend, Ind.: University of Notre Dame Press, 1975), 171.

17 The idea of materia apta is not that we have, in one instance, the proper organic matter, and then the soul that comes to inform it, but rather, evidence of a characteristically organismal disposition of the matter bespeaks the presence of the in-forming substantial human form.

20 In his original proposal for ANT, Hurlbut uses the term “biological artifact” to refer to the entity created by the method, an entity, he says, “with no inherent principle of unity, no coherent drive in the direction of the mature human form, and no claim on the moral status due to a developing human life” (William B. Hurlbut, “Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells,” 225).

21 Edward Furton makes this point against Schindler’s argument; see Edward J. Furton, “A Defense of Oocyte-Assisted Reprogramming,” The National Catholic Bioethics Quarterly 5, no. 3 (Autumn 2005): 467.

22 The idea that we know what a thing is by observing how it behaves is more fully developed in Maureen L. Condic and Samuel B. Condic, “Defining Organisms by Organization,” The National Catholic Bioethics Quarterly 5, no. 2 (Summer 2005): 331–353, esp. 339–340.

24 John Paul II rejects this view in his 1998 encyclical Fides et ratio; there he strongly affirms “the human capacity to know the truth, to come to a knowledge which can reach objective truth by means of that adaequatio rei et intellectus to which the Scholastic Doctors referred” (82, Vatican translation). Vatican II also teaches: “intelligence is not confined to observable data alone, but can with genuine certitude attain to reality itself as knowable, though in consequence of sin that certitude is partly obscured and weakened” (Gaudium et spes, 15, Vatican translation).

25 John Paul II, Veritatis splendor (1993), 48, Vatican translation. Emphasis original.

29 I am indebted to Maureen Condic for several of the ideas set forth in the preceding two paragraphs.

30 “Production of Pluripotent Stem Cells by Oocyte-Assisted Reprogramming: Joint Statement with Signatories,” The National Catholic Bioethics Quarterly 5, no. 3 (Autumn 2005): 579.

31 Women for Faith and Family, “Is Oocyte Assisted Reprogramming (OAR) A Moral Procedure To Retrieve Embryonic Stem Cells?” (15 August 2005, updated 22 September 2005), available at www.wf-f.org/OAR_StemCells.html .

REASONABLE DOUBTS.
A REPLY TO E. CHRISTIAN BRUGGER

E. Christian Brugger devotes a considerable portion of his essay”ANT-OAR: A Morally Acceptable Means for Deriving Pluripotent Stem Cells. A Reply to Criticisms” 2 to responding to David Schindler’s critique of the OAR proposal in the pages of Communio. 3 Brugger singles out for particular rebuttal Schindler’s claim that supporters of OAR have not yet given us sufficient assurance that the procedure would not produce human embryos. As Brugger reads him, Schindler is demanding more evidence on this score than he can reasonably ask for. His interrogation of OAR, lacking any sound scientific or philosophical foundation, rests instead on an irrational, ultimately dualistic unwillingness to let the physical evidence garnered in laboratory experiments decide whether OAR produces embryos or not:

It is absurd to claim that an entity is a human organism when it expresses itself neither materially nor temporally in ways characteristic of human organisms. As I said, this is dualist; it denies discernibly human material characteristics to something human; the entity looks, expresses itself, and behaves like a pluripotent stem cell; it does not express itself in a way characteristic of a human organism, nor does it have any peculiarly human organismic behavioral characteristics; but it just might be informed by a human soul. This is like claiming that a human soul might be trapped inside a stone. If we can distinguish between any cell and a zygote, we should be able to distinguish between an ANT-OAR cell and a zygote. 4

Brugger boils Schindler’s position down to this: there are serious grounds for thinking that OAR produces embryos even if the OAR product “looks, expresses itself, and behaves like a pluripotent stem cell.” Unfortunately, Brugger is setting up a straw man here, for Schindler’s actual contention is precisely that the OAR product does not and cannot look and act like a pluripotent stem cell in at least one decisive respect: its coming into being. For if we compare OAR with SCNT, Schindler insists, we find that OAR uses exactly the same event—exactly the same fusion of an enucleated egg and a somatic cell nucleus—that SCNT uses to clone a human embryo. What Schindler is really asserting, then, is that, even if the OAR product looks and acts more or less like a pluripotent stem cell in other respects, its coming into being looks and acts sufficiently like the coming into being of a human embryo to raise serious questions about OAR. Far from asserting that physical tokens in general are irrelevant to distinguishing embryos from stem cells, Schindler is simply insisting that there is one physical token that trumps all the others in the particular case of OAR: has the new entity come into being in a sufficiently human species-specific way? In the following essay, I would like to restate and defend Schindler’s reasons for thinking that OAR supporters have not yet ruled out a Yes answer.

As just noted, Schindler’s critique of OAR in the first part of his essay rests on the claim that OAR involves the same fusion of an enucleated oocyte and a somatic cell nucleus as cloning does. One element of Brugger’s response is based either on a misquotation of Schindler’s text or on Brugger’s reliance on a draft version of the article. His citation from Schindler refers in one place to a “fusion of an oocyte,” without the adjective “enucleated,” 5 which is duly present in the published text. Brugger tries to make the case that Schindler’s insistence on the notion of “fusion” betrays an ignorance of the basic scientific structure of OAR: “[i]t is not the ‘fusion’ of a somatic cell nucleus and an oocyte,” 6 Brugger reminds us. This is correct, of course, but it does not affect Schindler’s point in the least, which is that the fusion in question is the fusion of an enucleated egg cell and a somatic cell nucleus, as in SCNT. 7 In Schindler’s view, this fusion is prima facie a “mimicked conception,” not because its mechanics are the same as in natural conception, where “a sperm penetrates an egg, [and] the nuclei fuse, giving rise to a diploid zygote with a totipotent epigenetic state,” 8 but because its result is the same—as the (admittedly rare) successes of SCNT show can be the case. Obviously, OAR is not in vitro fertilization. Schindler’s question is simply whether, given its dependence on the same fusion of cellular materials as SCNT depends on, OAR might not be cloning. One may think that Schindler’s answer to this question is wrong, but one has to refute his arguments, rather than ruling them out of court as resting on flawed science. What, then, are these arguments?

Schindler’s claim that OAR involves “mimicked conception” is not a description of the stated intent of the OAR proposal, but rather the conclusion of an argument that goes like this. If SCNT fuses an enucleated oocyte and a somatic cell nucleus to produce an embryo—to “mimic conception” as to result, though not as to method—and if OAR can succeed only under the same conditions under which SCNT succeeds, then OAR prima facie involves a “mimicked conception,” too. The force of this argument rests on Schindler’s demonstration that epigenetic modification of the cellular materials, pre-transfer or no, is not sufficient to guarantee, beyond a reasonable doubt, that the procedure does not involve the creation and/or destruction of embryos. In his rebuttal, Brugger offers two arguments against this demonstration, one scientific and one philosophical. Both, I will suggest, do not suffice to vitiate the prima facie appearance that OAR is a form of cloning. In explaining why this is so, I will also be restating what I take to be the core of Schindler’s argument that “epigenetics is not enough.”

(1) Brugger’s scientific counter-argument is that the zygotic epigenetic state, while not a sufficient condition for the existence of a new human individual, is certainly a necessary condition of it. The zygotic epigenetic state is, or is co-essential with, the materia apta, the requisite material platform for the actualization of a new human individual (more on the materia apta below). By the same token, he would argue, if, prior to transfer, we can prevent the epigenetic reprogramming action of the enucleated oocyte from yielding a zygotic epigenetic state, then we can effectively remove this platform and, in so doing, prevent any human individual from ever coming into existence in the first place. Conversely, if we can ensure that the enucleated egg’s reprogramming action results in a pluripotent stem-cell-like epigenetic state, then we can create an entity that, ab initio, was never a human embryo, but always a human pluripotent stem cell:

A one-celled embryo is by definition totipotent. The entity created by ANT-OAR is ab initio pluripotent. It therefore cannot be an embryo. But might it not pass, ever so instantaneously, through a state of totipotency during reprogramming? In principle, no. If Nanog expression (or expression of some other transcription factor, or combination of transcription factors and precise gene modifications, etc.) is definitional of the state of pluripotency; and forced Nanog expression (or forced expression of . . .) characterizes ab initio the “biological artifact” that ANTOAR brings into existence, being intentionally made to do so before nuclear transfer, then the entity never was totipotent. 9

The main problem with Brugger’s argument here is that it overlooks the fact that there is an interval of time between (1) the fusion of the enucleated oocyte and the somatic cell nucleus and (2) the completion of the reprogramming process. 10 One implication of the existence of this interval is that the enucleated oocyte cannot carry out its epigenetic reprogramming without first fusing with the somatic cell nucleus into a new cell. Brugger notwithstanding, OAR is not literally a form of direct cellular dedifferentiation, but the creation of a new cell that is the suppositum, the “ontological subject,” both of the reprogramming process and of whatever epigenetic states that process eventually results in. 11 The fusion of the cellular materials results, in other words, in an entity that puts itself in the zygote epigenetic state through self-directed action. In other words, the simplest interpretation of the facts is that a new human being has come into existence and is running itself through the epigenetic reprogramming process. 12 But the OAR proposal aims to modify only the outcome of this process. For the same reason, it leaves completely open the possibility that the procedure has created a human embryo with a defective developmental path. The fact that OAR programs-in modifications in its product’s epigenetic state before nuclear transfer does not affect this situation in the least. Since these modifications would actually take effect only at the end of the logical sequence of fusion—new cell—initiation of reprogramming process, programming them in before nuclear transfer does not guarantee that there was no embryo at the beginning of that sequence. Brugger’s insistence that OAR modifies prior to nuclear transfer turns out to be something of a red herring. 13

(2) Brugger bases his philosophical argument againstSchindler on the Aristotelian-Thomistic notion of materia apta, the material organization required as a platform to sustain a given substantial form. According to Brugger, materia apta provides this platform because it is the seat of what he calls the “active potencies” that enable the substantial form to display its characteristic operations in the given matter. On Brugger’s account, however, the zygotic epigenetic state is definitive of the materia apta for humanness and so determines the “active potencies” for the behavior characteristic of human organisms. 14 By the same logic, suppressing the OAR product’s zygotic epigenetic state deprives it of the platform for the active potencies of humanness—and so deprives it of its human status. If this suppression can be made to coincide with the new entity’s coming into being through pre-transfer biochemical modification of what will be its initial epigenetic state, then, by the same logic, it will never have been a human organism at all. Since agere sequitur esse, Brugger reasons, the prevention of the materia apta for the active expression of a human being’s characteristic operations is necessarily the prevention of the genesis of any human being in the first place.

There are two main problems with Brugger’s argument here. (i) First, Brugger’s invocation of the Aristotelian-Thomistic doctrine of materia apta misses the point. Schindler is not denying this doctrine, but claiming that the fusion of the enucleated oocyte and the somatic cell nucleus itself already provides a sufficient materia apta for the existence of a human being. Brugger fails to address the crucial question, which is not whether or not OAR can modify the outcome of epigenetic reprogramming, but whether or not such modification is by itself sufficient to rule out the creation of a new human embryo. (ii) This brings me to the second problem with Brugger’s philosophical argument, which is that it comes perilously close to overturning the Aristotelian-Thomistic priority of act over potency, especially when Brugger faults Schindler for failing to understand that “it is precisely the character of the organic material, which includes inter alia the material’s genetic imprinting, that determines the possibilities for humanness.” 15 As far as I can tell—and it is difficult to tell because his argument is vague and tangled here—Brugger seems to be confusing the active potencies, as nature-rooted powers, with the material basis of their expression, and then taking the latter as quasi-constitutive for human identity. But if active potencies flow from actualized natures, and not vice versa, then the absence/modification of the zygotic epigenetic state is not by itself sufficient to dispose of the question Schindler has raised. It leaves completely open the possibility that OAR creates embryos with developmental defects set to go off already in the zygotic stage of their existence. And so we find ourselves back at square one.

The scientific and philosophical battering rams that Brugger deploys to knock down Schindler’s doubts against OAR leave them not only unbowed, but also unbloodied. Let me briefly explain why I do not think that any possible arguments would be enough to dispel them.

Normal conception follows a certain logical-temporal sequence: first, the process of fertilization and the concomitant coming-into-being of a new human individual, and then the initiation of the epigenetic reprogramming process. 16 SCNT also follows this process, except that it substitutes the fusion of an enucleated egg and a somatic cell nucleus for fertilization—which is why Schindler speaks of a “mock fertilization” in this context. 17 Now, OAR, as a form of SCNT, also replicates this pattern. It differs from normal SCNT in one respect only: it tries (prior to transfer) to get the epigenetic reprogramming process to move towards a pluripotent stem cell-like epigenetic state. Is this enough to distinguish OAR from cloning? Since, in the normal case, the zygotic epigenetic state logically presupposes the fertilization event that constitutes a new human being as the suppositum of that state, the mere premature forcing of transcription factors associated with the epigenetic state of pluripotent stem cells is not by itself sufficient to ensure that OAR involves no “mock fertilization,” and so cannot guarantee an affirmative answer to this question. In order to deliver a warranted Yes, OAR would have to change the entire pattern of fusion—new entity—reprogramming, rather than just modifying the outcome of the last element in the series.

The problem, of course, is that, if OAR hopes to get stem cells, it has to use nuclear transfer, and if it uses nuclear transfer, it can only modify the outcome of the reprogramming process, while working within the overall fusion—new entity—reprogramming pattern. Thus, whatever OAR may do to the terminus ad quem of the reprogramming process, the terminus a quo has to remain substantially what it is—and therefore what it would be in successful cloning as a “mock fertilization.” Yes, indeed: in SCNT, as in general, agere (the epigenetic reprogramming process/resulting zygotic epigenetic state) sequitur esse (the nature of the entity established through “mock fertilization”) and the problem with OAR—its inherent conceptual flaw—is that it tacitly relies on this sequitur while claiming to have dispensed with it. The only way to justify, or not notice, this contradiction is to make the fallacious inference that, since agere sequitur esse, any change in agere is automatically a change in esse. 18 To reason in this way—as Brugger appears to do—amounts either to question-begging or a mechanistic reduction of agere to esse. In either case, the principle gets turned on its head, and agere sequitur esse comes to mean esse sequitur agere.

What I have called OAR’s conceptual flaw is not superficial, for it sits in the very attempt to get stem cells without embryos while using nuclear transfer to do it. Nor can scientific experimentation remedy this inner contradiction in the OAR proposal. The reason for this is not that experimental testing in itself is worthless. It is that the construction of the experiments for testing OAR will necessarily partake of the OAR proposal’s conceptual flaw, and so will either bypass the central issue—when is a human organism actually present?—or yield outcomes that can appear favorable only on the assumption of some form of mechanism. I am not suggesting, of course, that we should move the discussion to a purely theoretical plane, without any reference or deference to the empirical phenomena. I am rather suggesting that OAR—and so the experiments designed to test it—focuses on the wrong set of empirical phenomena and then justifies this wrong focus with untenable arguments. I am suggesting, in other words, that OAR has a built-in, fatal neglect of what may be the one decisive phenomenon in the present context: the fusion of the enucleated egg and the somatic cell nucleus that, very arguably, establishes a human esse whose agere OAR modifies in its expression, but not in its substantial basis. Even if OAR succeeds in producing a pluripotent epigenetic state, then, there remain serious reasons for doubting whether it has not obtained it on the back of an embryo. 19

If I am right, Schindler and Brugger, or, more generally, the editors of Communio and the signers of the Joint Statement in favor of OAR, do not disagree because the former foolishly deny the principle of agere sequitur esse, while the latter sensibly defend it. No, both parties agree about the centrality of agere sequitur esse, but differ as to when they think it starts to be relevant: with fertilization or its “mock” equivalent, the fusion of enucleated egg and somatic cell nucleus (the editors of Communio), or only on the completion of epigenetic reprogramming (OAR supporters)? Moreover, although the two answers are symmetrical in their intention to privilege the agere sequitur esse principle, they are not at all symmetrical in their respective fidelity to it. Interpreting epigenetic reprogramming as a teleological self-unfolding revelatory of an already-existing human organism, the first answer expresses the Thomistic principle to a tee, whereas the attempt to establish the second answer and vitiate the first ends up with an inversion of this principle that logically requires question-begging and/or mechanism. The tables, in other words, have been completely turned, and it turns out that Schindler, and not Brugger, is the real Aristotelian here. For Schindler is not, as Brugger asserts, dualistically ignoring the human body, 20 but arguing that proponents of OAR are—and, that, in so doing, they are unwittingly colluding in the erosion of respect for that body in the earliest stages of its existence.

In conclusion, I would like to point out that, even if the argument I have just outlined is shown to be mistaken, and the concept of OAR is not problematic from the point of view of natural philosophy and morality, the fact remains that the procedure will not be 100 percent reliable. Even if I am dead wrong in the foregoing essay, in other words, OAR will still occasionally mistakenly produce embryos. 21 Now, Brugger admits this, but he argues that, so long as the incidence of mistaken embryos is “statistically negligible,” there can be no reasonable doubts about the morality of OAR. Why not? Because the intention not to produce embryos can justify the risk of occasionally mistakenly producing some by the principle of double effect, as Brugger explains in the following passage:

If failure rates are statistically negligible, and testing otherwise consistently establishes that the entity produced from ANTOAR is not an embryo but a pluripotent cell; and the firm intention is to protect the value of human life by never producing a human organism; then it may be reasonable to proceed with testing in human cells knowing that a very remote possibility exists that an embryo may result; that possibility is accepted as an unwanted and unintended side effect of an otherwise morally justifiable act. 22

There are two serious problems with this argument, it seems to me. First of all, even if we were to suppose that it is statistically very unlikely that OAR would mistakenly produce an entity that even Brugger would call an embryo, a supposition that is not at all clear given the highly speculative nature of the OAR proposal, the fact of the matter is that no one could be sure that it would not produce such an entity—until it was too late. Imagine a parallel situation: a friend gives you a gun with 20,000 chambers and invites you to play Russian Roulette with the assurance that only two or three of the chambers are actually loaded. Since any given chamber might be loaded, you would be foolish to accept the challenge on the grounds that the odds were seemingly in your favor. After all, the first pull of the trigger might put one of the 3/20,000 bullets into your skull. Would it not be just as foolish to pursue human OAR, since on any given trial you might be making an embryo-producing mistake? Wouldn’t trying human OAR be tantamount to playing Russian Roulette with embryos?

My second problem is with Brugger’s invocation of the principle of double effect. While double effect does legitimate the knowing risk of side-effects otherwise impossible to be chosen ethically, it does not do so in just any situation. It confers this legitimacy only in view of abnormal circumstances that pressingly require or recommend the action to which the knowing risk of otherwise unchooseable side-effects is inevitably attached. Since the—let us be perfectly honest—remote possibility that the scientific community may one day give up conventional methods of embryonic stem cell research for something like OAR, or the less remote, but still distant, potential for medical advances, does not meet this test of urgency, the principle of double effect has no real relevance to Brugger’s case. But if double effect does not apply here, then what Brugger’s argument logically amounts to is this: a possible future good (the conversion of the scientific community; potential medical advances) justifies a present evil (the possibility of accidentally making a “statistically negligible” number of embryos). This sort of argument logically entails, or expresses, something less like traditional Catholic moral theology and more like proportionalism. Does Brugger really want to go this route?

Brugger’s precipitous appeal to double effect bears out, it seems to me, the pertinence of one of the central questions of Schindler’s essay that Brugger nowhere addresses: whence the haste to make ANT-OAR work—even at the (supposedly acceptable) risk of possibly sacrificing a few human lives? Is it really so important to assure embryonic stem cell researchers that they can have what they want, after all? Wouldn’t it be better to put the brakes on the ANTOAR project, at least for a while, and to ponder the implications of what, I hope to have shown, are not at all irrational cavils, but strong and serious reasonable doubts about its conceptual and moral viability? It strikes me that advocates of ANT-OAR have nothing to lose and everything to gain by doing so.

1 I would like to thank Dr. W. Malcolm Byrnes for invaluable criticisms of an earlier draft of this essay. Of course the claims I express here, as well as the mistakes I might make, are mine, and not Dr. Byrnes’s.

2 E. Christian Brugger, “ANT-OAR: A Morally Acceptable Means for Deriving Pluripotent Stem Cells. A Reply to Criticisms,” Communio 32, no. 4 (Winter, 2005): 753–769.

3 In particular, Brugger is replying to David L. Schindler, “A Response to the Joint Statement, ‘Production of Pluripotent Stem Cells by Oocyte Assisted Reprogramming,’” Communio 32, no. 2 (Summer, 2005): 369–380.

4 Brugger, “ANT-OAR: A Morally Acceptable Means,” 766–767. Emphasis original.

7 As Brugger insists, the egg used in nuclear transfer is an enucleated one, with only its cytoplasm left. But that is just the point: the egg is enucleated so that the somatic cell nucleus—which has been detached from its cytoplasm—can receive a new cytoplasm so as to form a single cell. If no such fusion of the enucleated egg and the somatic cell nucleus into a new cell took place, then OAR proponents would be in the difficult position of maintaining the—frankly absurd—claim that OAR has the (magical?) power to turn this nucleus, which is itself not a cell, but a part of one, into a whole cell complete with a new cytoplasm.

9 Brugger, “ANT-OAR: A Morally Acceptable Means,” 762–763. Emphasis original.

10 I am indebted for this valuable insight, as well as for much that I will say in the present paragraph, to José Granados, “ANT-OAR: Is Its Underlying Philosophy of Biology Sound?” in the present issue of Communio. It should be pointed out that, even if the time of the interval mentioned here is reduced to a seeming zero, the doubt that OAR produces an embryo remains as alive as before. Why? Because the time interval reflects a deeper logical sequence of defining events that come in the following order: fusion of the relevant cellular materials, initiation of the reprogramming process, formation of the “zygotic” epigenetic state. OAR has to work with this logical sequence, no matter how much it shortens the time between the stages: it needs the fusion of the cellular materials to have the reprogramming process, and it needs the reprogramming process to end up with (it hopes) pluripotent stem cells. According to Schindler, this shared sequence indicates enough identity with cloning to raise serious doubts whether OAR does not produce embryos, after all.

11 See Brugger, 756; 763. Brugger’s vagueness about the subject of epigenetic reprogramming is very telling: “[a]fter nuclear transfer into an enucleated oocyte,” he writes on pages 755–756, “the epigenetic state is reprogrammed from its formerly highly specialized state back to a state of totipotency. It goes through a process of epigenetic dedifferentiation. If it reaches its terminus, the reprogrammed cell is a zygote, a one-celled embryo, with the genotype of the donor of the somatic cell.” In the first sentence, and at the beginning of the second, the subject of the reprogramming is the epigenetic state of the somatic cell nucleus. In the middle of the second sentence, though, the subject suddenly shifts to the “reprogrammed cell.” This shift of subjects gives the impression that the cell resulting from SCNT is the same entity as the somatic cell nucleus—only reprogrammed epigenetically. This is wrong: the somatic cell nucleus is only part of a cell, not a whole cell. Consequently, if SCNT results in a whole cell, it can only be because it has made a new cell out of the somatic cell nucleus and the enucleated egg cytoplasm. As we will see in a moment, this fact has a huge bearing on the argument at hand.

12 If we do not follow this interpretation, then we have to deal with at least two problematic implications. First, we commit ourselves to saying that the process of fertilization is not the beginning of human life, but is itself an intermediate stage prior to the completion of the zygotic epigenetic state. Second, we have the difficulty of explaining what is the ontological subject of the obviously teleological, directed process of forming the zygotic epigenetic state. If this subject is not already a human being, then how can it direct itself into the epigenetic state of a human being?

13 It is also worth pointing out that Brugger is vague on just how the transcription factors like Nanog involved in OAR are “characteristic of the pluripotent state” (Brugger, 756). Sometimes he seems to suggest that they are definitive of what a pluripotent stem cell is. But then he also acknowledges that they are just necessary conditions for the appearance of pluripotency. Which is it? It seems to me that the latter alternative must be the correct one, since, as Brugger says, the factors in question “appear to be essential for establishing and maintaining the state of pluripotency” (ibid.)—which means that they are (so far as we know based on the current state of the research) effective/instrumental causes of pluripotency, not the sum and substance of it. But if the mere presence of Nanog (or whatever) is not what defines a stem cell as such, but only what helps it establish and maintain its stem-cellness, then the premature forcing of its expression is perfectly compatible with the possibility that we have created an embryo with a developmental defect, rather than a pluripotent stem cell.

17 One of the connotations of the term “mock” or “mimicked conception/ fertilization” is that even SCNT, which alters the natural event of conception, still has to rely on it in some sense. Whatever else it does, SCNT relies on the same logical-temporal sequence as nature does: fusion of the relevant cellular materials—coming into being of a new individual—epigenetic reprogramming. The fact that the relevant cellular materials are no longer sperm and egg, but somatic cell nucleus and enucleated oocyte, does not change this fact, for if the fusion of the enucleated oocyte and the somatic cell nucleus did not have by nature at least some of the powers that the fusion of the egg and the sperm does, then SCNT would never produce embryos. The fact that, in spite of this, most trials of SCNT fail to produce viable embryos is no argument against this consideration.

18 Cloning failures are better explained by the unnatural conditions to which it subjects the cellular materials than by the assumption that they retain nothing of the natural teleology inherent in the sperm-egg fusion. SCNT does not replace nature, but mutilates it—while keeping just enough of it to lend it whatever (limited) efficacy it has.

18 Of course, Brugger might retort that there are certain characteristic attributes that, like the “inseparable accidents” of Scholastic philosophy, cannot be lacking to a human organism, so that their non-appearance always and necessarily signifies that no human organism is present, either. Now, this retort is partly correct, in that there are such “inseparable accidents” that, while being accidents, are nonetheless necessarily entailed by the essence of the species homo. Nevertheless, this retort overlooks the fact that an entity can have the specific essence of man, and so be “owed” the attributes that follow inseparably from that essence, while failing to have the actual physical wherewithal to instantiate those attributes. For example, a child born with a neck disease that made it physically impossible for him to laugh would still be a human being who, by virtue of his sharing in the specific essence “man,” ought to be able to laugh. Put more simply, the child is naturally a “laughing animal,” even if he cannot laugh because of a grave physical impediment. I recognize, of course, that a typical physical equipment goes with the essence of the human being; my point is simply that the equipment can be defective in individual cases without this meaning that there is no human being present who, by virtue of his human status, ought to have that equipment ceteris paribus and, indeed, would have it if not for the defect. It seems to me that Brugger’s position logically undermines this all-important distinction between abnormal humans and non-humans, and so amounts to the absurd claim that the physical impediment to our hypothetical child’s ability to laugh—at least if it is engineered prior to the child’s conception—means that the child is not by nature a “laughing animal,” that is, a human organism.

19 Let me record, however, my skepticism about the likelihood of OAR’s really managing to produce pluripotent stem cells. The OAR concept supposes, after all, the theoretical possibility of sufficiently replicating the conditions under which a pluripotent stem cell normally arises—in what is in fact an abnormal environment, whose distinctive commonality with the normal one is the presence of certain pluripotency-related transcription factors, such as, for example, Nanog. This decision to treat the normal environment and process in which stem cells arise as if it were cleanly replaceable or simply irrelevant seems logically to entail the mechanistic assumption that, for all practical purposes, a stem cell is nothing but a nucleus+cytoplasm+active Nanog (and/or other similar factors). Unless we live in a mechanistic universe, however, such a decision is very likely to have visible consequences that will render the claim that OAR has directly created stem cells suspect even from a (sufficiently perceptive) empirical point of view. We just do not, and probably never will, have the sort of control over the nature of human origins which OAR seems to bank on. If we did, then, as I said just now, there would be no need for nuclear transfer, and direct cellular dedifferentiation would be firmly within our grasp.

20 Indeed, it is Brugger who risks dualism when he argues that the zygotic epigenetic state must already be present in “active potency” before humanity can be instantiated, forgetting that the organization of matter required for that state is itself logically dependent on the instantiation of humanity already having happened.

21 I leave aside the fact that the transition from animal to human experimentation will also require a certain number of trials before a reliable experimental protocol for human OAR is established—a time in which similar mistakes are also very likely.

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