I. DEVELOPMENT FROM FERTILIZATION TO BIRTH

The ethical relevance of studying human development appears when one asks which stages of the human life cycle embody significant ethical concerns. Between birth and death, the human organism is a person, equipped with the full measure of basic human rights. This much is not really controversial, and the debate primarily concerns the prenatal phase of development. Do human rights accrue to the unborn all at once, for instance at fertilization? Do they instead arise in a gradual manner, based on the various progressive steps through which the prenatal human organism acquires significant person–like properties? Besides personal rights, are there other ethically–significant values and properties that would justify a respectful treatment of embryos and fetuses? An understanding of prenatal development is a necessary, albeit in no way sufficient, condition for addressing these issues successfully.

To understand the basic biology of any sexually reproducing organism, one needs to grasp the primary concept of the life cycle. The life cycle of humans includes fertilization, cleavage, gastrulation, organogenesis, fetal development, birth, child development and puberty, gametogenesis and again fertilization. It is through the germ–line that the life cycle persists from generation to generation. On the other hand, the somatic cells (which comprise all the cells of the fetus, child, and adult that are not directly involved in reproduction) belong to an inherently mortal entity, the human organism, whose fate is senescence and death. One turn of the life cycle defines one generation. Fertilization and birth define the beginning and end of the prenatal phase of development, which is comprised of two stages: embryonic and fetal.

The embryonic phase initiates with fertilization, the meeting of the male (sperm) and female (oocyte) gametes, giving rise to the zygote. At fertilization, a new, diploid genome arises from the combination of the two haploid genomes included in the gametes. The zygote divides several times (cleavage stage) to form a blastocyst. The cells of the blastocyst, called blastomeres, are separated into two parts: an outer layer, called the trophoblast, that eventually contributes to the placenta; and an inner cell mass that contributes to the future embryo. About six days after fertilization, the blastocyst attaches to the endometrium (the epithelial lining of the uterus). This marks the beginning of pregnancy and further development depends on intricate biochemical exchanges with the woman's body. While the trophoblast invades the uterine wall, the inner cell mass undergoes further stepwise differentiation processes that lead to the formation of the embryonic epiblast (the precursor of the actual human individual) and several extraembryonic structures (Figure 1). The embryo then undergoes gastrulation, the process that starts with the formation of the primitive streak. This is the crucial developmental step, common to all animals but the most primitive invertebrates, by which the three basic germ layers of the embryo are formed. These are called ectoderm, mesoderm, and endoderm.

From the third to the eighth week, the process of organogenesis involves the differentiation of the three germ–layers into specific tissues and primordial organs. The earliest stage in organogenesis is called neurulation and starts when a specific area of ectoderm turns into the primordium of the nervous system. During organogenesis, many genes that are crucial to development are activated, and complex cell–to–cell signals insure the proper differentiation of various cell types, as well as the movement and migration of cells to their proper places in the developing embryo. For some cell types, this involves long–range navigation. For instance, the gamete precursors must travel from their initial position near the yolk sac to the primordial gonads.

At the end of the embryonic phase, many important organ systems are in place, at least in rudimentary form. The fetal phase is characterized by further differentiation and maturation of tissues and organs, as well as considerable growth, especially towards the end of pregnancy. In the late fetal phase, the nervous system undergoes an acceleration of synapse formation and maturation of the brain, which is increasingly sensitive to outside cues. This process continues well after birth.

Specific Developmental Stages in Detail

Especially in early development, specific developmental processes seem more meaningful than others in the ethical debate about the moral status of human prenatal life. These are described in more detail.

GAMETOGENESIS AND FERTILIZATION. The embryo is usually defined as coming into existence at fertilization and becoming a fetus when organogenesis is completed (eight weeks after fertilization). These borders are not sharply defined. The definition of an embryo thus cannot avoid being operational and context–dependent. The term conceptus is useful to denote any entity resulting from fertilization, when no reference to a more specific stage is intended. An additional complication results from the significant overlap between the final stages of female gametogenesis, fertilization, and initial cleavage.

Gametogenesis involves a special type of cell division called meiosis. When primordial germ cells (which are diploid—i.e., they have two complete sets of chromosomes) enter meiosis, their DNA is duplicated so that there are now four copies of each type of chromosome (a condition called tetraploidy). In the first meiotic division, there are genetic exchanges within each group of homologous chromosomes, which then separate into diploid daughter cells. In the second meiotic division, there is no further round of DNA duplication. Each chromosome in a pair is allotted to a separate daughter cell, now haploid. Each primordial germ cell thus gives rise to four daughter haploid cells.

In the male, all four cells resulting from meiosis ultimately become functional spermatozoa. In contrast, in the female, only one of the daughter cells becomes an oocyte, the other three cells are discarded as polar bodies. In addition, female meiosis is not completed until after fertilization has occurred. During each ovarian cycle of the sexually mature female, one oocyte progresses partially through meiosis but is arrested in the middle of the second meiotic division at the time it is discharged from the mature ovarian follicle into the oviduct. If the oocyte is fertilized, meiosis is completed. Within the newly fertilized egg, the male and female pronuclei undergo a protracted migration towards each other, while DNA is duplicated within both. Thereafter, both nuclear envelopes disappear and the chromosomes derived from the male and female gamete are involved in the first cleavage division. Thus the first genuine diploid nucleus is observed at the two–cell stage only (30 hours after initial contact of sperm and oocyte). While fertilization usually occurs close to the ovary, the conceptus is gently nudged towards the uterus, a voyage lasting about five days.

Both through recombination of gene segments during the first meiotic division, and through random assortment of homologous chromosomes in gametes, genetic novelty is generated. In other words, gametes are genetically distinctive in relation to their diploid progenitors and do not simply reflect the genetic structure of their parent organism. In a sense, gametes are distinctive "individuals" in relation to the organism that produces them. Fertilization creates genetic novelty of a different sort, by combining two independent paternal genomes. The zygote is genetically distinctive because it represents the meeting of two independent parental lineages. Thus genetic novelty appears twice per turn of the human life cycle.

CLEAVAGE, PLURIPOTENTIALITY, AND TWINNING. During cleavage, the zygote divides into smaller embryonic cells. At the 16–cell stage, the embryo is called a morula and a first differentiation into two cell types is initiated. The trophoblast is the cell layer that will soon connect with the uterine wall, whereas the inner cell mass includes the cells of the later stage embryo. At the blastocyst stage, a central cavity (blastocoel) is formed. If a blastomere is removed from the inner cell

FIGURE 1

mass of a blastocyst (as, for instance, in preimplantation diagnosis), the blastocyst is still able to produce a complete late embryo and fetus. This illustrates a fundamental principle called regulation, or regulative development. Within the early embryo, cell fates are not definitely fixed but largely depend on interactions with neighboring cells, so that development adjusts to the presence or absence of specific environmental cues. The molecular basis and the genes responsible for these cues are increasingly well known.

At the blastocyst stage, the inner mass cells are pluripotent (i.e., they have developmental plasticity) and are able to participate in the formation of most cell types of the adult organism, as shown for instance by experiments with cultured immortalized blastomeres, called embryonic stem cells. Recent research does suggest that individual blastomeres acquire some degree of molecular specificity quite early. However, this inherent "bias" that tends to drive every blastomere towards a specific cellular fate can easily be overridden at this stage.

Around day 6, the blastocyst has hatched from the surrounding zona pellucida (the outer envelope of the ovum) and is ready for implantation. As it attaches to the endometrium, two distinctive layers appear in the inner cell mass. The ventral layer (hypoblast) contributes to the primitive yolk sac. The dorsal layer soon differentiates between the embryonic epiblast that will contribute to the embryo–to–be, and the amniotic ectoderm lining the newly appearing amniotic cavity (day 7–8). This two–layered structure is called the embryonic disk. All this happens as the blastocyst burrows deeper into the uterus wall and the trophoblast comes into close contact with maternal blood vessels. The trophoblast also produces human chorionic gonadotropin (hCG), which is the substance detected in pregnancy tests and is essential to the maintenance of pregnancy. Abnormal conceptuses are very common until that stage and are eliminated, usually without detectable signs of pregnancy. Inversely, fertilization occasionally results in a hydatidiform mole. This structure consists of trophoblastic tissue and therefore mimics the early events of pregnancy (hCG is produced), without their being any actual embryonic tissue present.

The term pre–embryo was often used to mark the embryonic stages described so far. This term is sometimes shunned in contemporary discourse, as it has been suspected to be a semantic trick to downgrade the standing of the very early embryo. Yet even writers like Richard A. McCormick belonging to the Catholic tradition, sets great store by the moral standing of the earliest forms of prenatal development, have expressed doubts about the validity of this suspicion (1991). More importantly, doing away with the term "pre–embryo" does not solve the two underlying conceptual problems that this term addresses. The first ensues from the cellular genealogy linking the zygote to the later stage embryo and fetus. Only a small part of the very early embryo is an actual precursor to the late embryo, fetus, and born child. Whatever terminology one wishes to use, no account of early development can avoid sentences such as this, written by Thomas W. Sadler in 2000, "[t]he inner cell mass gives rise to tissues of the embryo proper," or terms such as the embryo–to–be. This is an inescapable consequence of the fact that the late embryo includes only a small subset of all the cells that originate with the zygote and blastocyst (Figure 1 shows the complex genealogy of embryonic and extraembryonic tissues in human development). The second problem arises from the fact that the early embryo has a degree of freedom as regards its final numerical identity. Until about 12 days after fertilization, twinning can occur. In other words, until that stage, a single embryo still has the potential to divide in two embryos, ultimately developing into two separate persons. Therefore there is no intrinsic one–to–one relationship between the zygote and the late embryo, as there is between the late embryo, the fetus, and the born human.

GASTRULATION. Gastrulation begins with a wave of cellular movements that start at the tail end of the embryo and extend progressively forward. Future endoderm and mesoderm cells slip inside the embryonic disk through a groove called the primitive streak (day 14). The anterior end of the streak is called the node. Of the cells that migrate inside the streak, some form the endoderm and others will lie atop the endoderm and form the mesoderm. Finally, those cells that remain in their initial position on the surface of the embryonic disk become the ectoderm. Gastrulation sets the overall organization of the embryo in a definitive way. The main axes (anterior–posterior, left–right) are defined under the control of two central signaling centers: the node (which is the equivalent of the organizer discovered by embryologists working on frog and chick embryos) and the anterior visceral endoderm.

Recent data from molecular genetics have partially uncovered the molecular basis of axis determination. The determination of the anterior–posterior axis involves the HOX genes, a set of four gene complexes. Since HOX genes located at the "front end" of a HOX complex are expressed at the "front end" of the embryo, the arrangement of the various genes within each complex remarkably reflects the place at which they are expressed in the embryo along the anterior–posterior axis. The four HOX complexes thus provide four "genetic images" of the lengthwise arrangement of embryonic structures. The left–right asymmetry of the embryo (and thus of the future body plan) is thought to originate with specific cells in the node. In a way that is not fully understood, these cells induce a cascade of protein signals that is different on the left and right side of the embryo. This results in the synthesis of controlling factors that are laterally restricted. It is supposed that these controlling factors and other factors direct the development of asymmetric organs accordingly.

Through gastrulation, the embryo arises as a defined entity endowed with a much higher level of organic unity than at any stage before. The laying down of the head–to–tail axis and other defined spatial features, as well as the loss of pluripotentiality in many cell lineages, mark the beginning of a single individual human organism and thus provide one of the first important dimensions of the ontological continuity typical of the born human.

LATER DEVELOPMENTAL STEPS. In the initial step in organogenesis, the midline axial section of mesoderm—the notochord—instructs the overlying ectoderm to turn into the neural plaque. This structure soon wraps around to form the primitive neural tube, out of which the central nervous system will eventually grow. By the beginning of the fetal period (eighth week), the rudiments of the heart, blood and blood vessels, the major segments of the skeleton and associated muscle groups, the limbs, and many other structures are in place. It is noteworthy that although the primordial nervous system is one of the earliest organ systems to emerge in development, it takes the longest time to mature. Synaptogenesis (the formation of–contacts between nerve cells) starts on a grand scale only late in pregnancy and continues well after birth. This is important to keep in mind when interpreting early movements of the fetus, visualized more and more accurately by ultrasonography. These movements reflect the maturation of local neuromuscular structures and are not due to significant brain function, since there is no "brain" in the sense of the later, much more developed anatomic and functional structure called by that name. This is different later in pregnancy, when fetal movement is more reactive to the environment and when it becomes arguably legitimate to interpret it as "behavior," insofar as it reflects the increased functional capabilities of the central nervous system. Finally, the concept of viability basically reflects the ability of fetal lungs and kidneys to support extrauterine life, which is impossible before the twenty-second week.

As mentioned before, the differentiation and migration of early gametes also occurs during the embryonic phase. This separation of the germ cell lineage from all other cell lineages marks a bifurcation in the life cycle. Unlike somatic cells, gamete precursors have a chance of becoming gametes and participating in fertilization, thus contributing to the next generation. In a way, the germ cell lineage is eternal through successive turns of the life cycle, whereas the rest of the embryo, the sum total of somatic cells, is inherently mortal.

Extracorporeal Embryos

Science fiction fantasies about the artificial uterus notwithstanding, only the very first stages of human development can occur outside the female body. Since 1978, in vitro fertilization followed by embryo transfer has been a common treatment of fertility problems. The growth of ovarian follicles is stimulated by the administration of gonadotropins. Oocytes are then collected by laparoscopy and placed in an appropriate culture medium. Sperm is added and cleavage occurs in culture until the blastocyst is transferred in the uterus.

With in vitro fertilization, the early embryo became much more accessible to human intervention, and this has raised ethically perplexing possibilities. Interventional research on early embryos has become possible, raising the question of whether it is ethical to produce human embryos for research purposes, or whether research should be done, if at all, only on "spare" embryos. These occur when some embryos are no longer needed for fertility treatment, even though they resulted from in vitro fertilization performed with therapeutic intent. Additionally, progress in genetic testing techniques using very small amounts of DNA has made preimplantation diagnosis of genetic abnormalities possible. Single blastomeres are removed from in vitro blastocysts, their DNA amplified by polymerase chain reaction (PCR), and subjected to genetic tests with appropriate DNA probes. (Thanks to regulative development, the missing blastomere is soon compensated for.) In this way, embryos can be screened for certain genetic defects and only those free of defects chosen for embryo transfer. This procedure is sometimes suspected of being eugenic, and the controversy around it has led to it being outlawed in certain countries including Germany and Switzerland.

Developmental Steps and Moral Status

The biological processes around fertilization and early embryonic development are often accorded considerable relevance in ethical debates, making a detailed description of these processes necessary. This descriptive effort, however, is not based on the belief that "the facts speak for themselves." They emphatically do not. In fact, many ethical controversies about the ethics of in vitro fertilization, embryo research, therapeutic cloning, abortion and the like, are less about ethics in the strict sense as they are about expressing divergent interpretations of biology. The marshalling of biological fact to support apodictic statements of moral status involves many, usually unspoken, "bridge principles." These principles involve highly complex notions, such as unity, individuality, potentiality, and continuity. It is a common misconception that these theoretical concepts constitute stable, common–sense notions that are merely applied to biological entities and processes. In actuality, these concepts are themselves given new meanings and qualifications in the very process of using them to make sense of biological facts. Between the realm of ontological categories and the empirical domain of biology, there is a two–way street.

It is often said that "human life begins at fertilization." Strictly speaking, this statement is meaningless. Human life does not begin at any point of the human life cycle; it persists through successive generations. The ethically relevant question to ask is at what stage a human individual is first endowed with important ethical value and correlative rights against harm. The difficulty is that no particular step stands forth as a self–evident developmental marker, both because developmental events that appear as sharp discontinuities turn out to be protracted processes upon closer scrutiny (for instance, fertilization is a process, not an instantaneous event), and because the highlighting of one developmental process over another necessarily involves more or less plausible philosophical assumptions.

Three different concepts of individuality appear to be relevant:

• genomic individuality as established trough fertilization;
• numerical identity, defined once twinning is no longer possible;
• identity of the self, as sustained by a functional central nervous system.

Fertilization is important because it newly connects two parental lineages that were independent until then. The meeting of sperm and oocyte gives rise to a uniquely novel diploid genome that is not subject to further change. It will be the genome of the future person or persons arising from this particular fertilization. This fact is often misinterpreted according to a hylomorphic interpretation of the genome, where the latter becomes the formal cause of the future human being (Mauron). (Hylomorphism is the aristotelian and scholastic teaching that concrete objects, especially living things, result from a combination of form [morphê] and substance [hylê].) This interpretation suggests the notion that fertilization is the single crucial step, since the new genome appears at that point. This interpretation fails, not only because of the inherent conceptual problems of the hylomorphic view, but also because there exist biological facts such as twinning and genetic mosaicism that show that there is little connection between genomic individuality as such and personal identity. Monozygotic or identical twins are separate persons, even though they share "the same" genome, that originated from "the same" fertilization. This shows that genomic individuality does not provide any basis for the most essential property of personal identity, namely numerical identity through time. To be one and same person through changes in one's biography is an essential ingredient of any workable concept of the person, and the biological basis for this property does not originate before gastrulation. In fact, much of the organic singularity and coordinated functioning as one organism (rather than several potential organisms) is established only at that stage.

However, one may want a richer interpretation of this basic criterion of personal identity. Having a biography of one's own is not just being the same individual through time, but also experiencing a continuity of mental states, which is linked to an at least minimally–functioning central nervous system. In fact, nothing is more central to the modern conception of the self than the functional persistence of a central nervous system that provides the material substrate of an individual subjective biography. For this biographical, or subjective, identity, it is difficult to quote a definitive starting point. It is plausible to place it in late pregnancy, when the earliest possibility of a continuing self seems to be given, but there is no absolute certainty in this claim.

Conclusion

Ethical reasoning on this topic often shows a common pattern: one takes moral concepts that belong to uncontroversial persons (such as grown humans) and tries to apply them backwards to the fetus and embryo. However, importing intuitions pertaining to the ethics of personal rights and interests onto various forms of prenatal life is increasingly fraught with conceptual difficulties as one moves towards earlier stages. Indeed, the most perplexing problem in bridging human developmental biology and statements of moral standing is perhaps that traditional moral categories tend to be "all–or–none" concepts (either one is a person or not, and if so, one is equal in basic rights to all persons), whereas developmental biology shows mostly gradual change and tends to resolve what appear to be discrete borders into continuities. One obvious and popular answer to this quandary is to make ethical standing a gradually increasing property of the developing human organism. On the other hand, one may query the underlying assumption that there is a one–dimensional measure of ethical concern. Further reflection may benefit from a recognition that ethical concerns about human prenatal life are multidimensional, and sometimes qualitatively, not just quantitatively, different from the person–centered systems of ethical values and duties.

alexandre mauron

SEE ALSO: Abortion: Medical Perspectives; Alcoholism and Other Drugs in a Public Health Context; Cloning; Death, Definition and Determination of: Criteria for Death; Feminism; Infants; Infanticide; Maternal-Fetal Relationship; Moral Status;Reproductive Technologies: Ethical Issues; and other Embryo and Fetus subentries

BIBLIOGRAPHY

Ford, Norman M. 1988. When Did I Begin? Conception of the Human Individual in History, Philosophy and Science. Cambridge, Eng.: Cambridge University Press.

Gilbert, Scott F. 2000. Developmental Biology, 6th edition. Sunderland, MA: Sinauer Associates.

Green, Ronald M. 2001. The Human Embryo Research Debates: Bioethics in the Vortex of Controversy. Oxford: Oxford University Press.

Mauron, Alex. 2001. "Is the Genome the Secular Equivalent of the Soul?" Science 291: 831–832.

McCormick, Richard A. 1991. "Who or What Is the Preembryo?" Kennedy Institute of Ethics Journal 1: 1–15.

Robertson, John A. 1991. "What We May Do with the Preembryos: A Response to Richard A. McCormick." Kennedy Institute of Ethics Journal 1: 293–302.

Sadler, Thomas W. 2000. Langman's Embryology, 8th edition. Baltimore, MD: Lippincott Williams & Wilkins.

INTERNET RESOURCES

Gilbert, Scott F. 2000. "When Does Human Life Begin?" Website to accompany Developmental Biology, 6th edition. Available from <www.devbio.com/chap02/link0202a.shtml>.