BIOE THICS AND THE NE W EMBRYOLOGY When Does Human … · 2014-10-10 · these cells, known as gametes, set apart from the rest of the body’s cells to form the next generation,

When Does Human Life

Begin?

The history of a man for the nine months preceding his birth would

probably be more interesting, and contain events of far greater

moment, than the three-score and ten years that follow it.

SAMUEL TAYLOR COLERIDGE (1885)

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UNIT 1B I O E T H I C S A N D T H E N E W E M B R Y O L O G Y


The eminent Victorian Samuel Taylor Coleridge got it right. The con-cept of an embryo is a staggering one. To become an embryo, youhad to build yourself from a single cell. You had to respire beforeyou had lungs, digest before you had a gut, build bones when youwere pulpy, and form orderly arrays of neurons before you knew

how to think. One of the critical differences between you and a machine isthat a machine is never required to function until after it is built. Everyanimal has to function as it builds itself.

The only way for an animal to grow from a single cell—the fertilizedegg—into a complex, many-celled adult is by first developing an embryo.Fertilization gives each animal a genome, a set of genes found in every cellof the animal’s body. The genome contains most of the instructions need-ed by the embryo to grow in particular ways—it specifies the individual’sgenotype. Some of these instructions define the species: a pregnant dogwill give birth to puppies, while her pregnant owner will give birth to ahuman baby. Other instructions encoded in the genotype produce varia-tions within the species—a chocolate lab or an Australian shepherd;blonde, red, or black hair; a wide nose or a narrow nose. The set of observ-able traits produced by the genotype (and influenced by environmentalfactors) is called the phenotype. The embryo is the link between the geno-type and the phenotype.

The branch of biomedical science that studies the development andtransformation of embryos is called either embryology or by its more recentname, developmental biology. Whereas most of biology studies the struc-ture and function of adult organisms, the interests of developmental biolo-gy lie in the transient stages leading up to the adult. Developmental biology

An Outline of Human Development

This material cannot be copied, disseminated, or used in any way without the express written permission of the publisher.

Copyright © 2005 Sinauer Associates Inc.

B I O E T H I C S A N D T H E N E W E M B R Y O L O G Y

C H A P T E R 1

studies the initiation and construction of organisms. It is a science of becom-ing, a science of process. To say that a mayfly lives but one day is profound-ly inaccurate to a developmental biologist. A mayfly may be a winged adultfor only a day, but it spends the other 364 days of its life developing intothat adult beneath the waters of a pond or stream.

The Questions of Developmental BiologyThe development of an animal from an egg has been a source of wonderthroughout history. The simple procedure of cracking open a chick egg oneach successive day of its three-week incubation provides a remarkable

experience as you watch a thin band of cellsgive rise to an entire bird. Aristotle, the firstnaturalist known to have recorded embry-ological studies, performed this procedureand noted the formation of the bird’s majororgans. Anyone can wonder at this remark-able—yet commonplace—phenomenon, butthe scientist seeks to discover how develop-

ment actually occurs. And rather than dissipating wonder, the scientist’snew understanding increases it.

Development is a relatively slow process of progressive change thataccomplishes two major objectives: (1) it generates cellular diversity andorder within each individual organism, and (2) it ensures the continuity oflife from one generation to the next. Thus, embryologists deal with two fun-damental questions: How does the single-celled fertilized egg give rise tothe many different cells of the adult body? And how does that adult bodyproduce yet another body? These two huge questions have been tradition-ally subdivided into four general questions scrutinized by developmentalbiologists:

1. The question of differentiation. A single cell, the fertilized egg, gives rise tohundreds of different cell types—muscle cells, skin cells, neurons, lenscells, lymphocytes, blood cells, fat cells, and so on (Figure 1.1). This gen-eration of cellular diversity is called differentiation. Since each cell of thebody (with very few exceptions) contains the same set of genes, we needto understand how this same set of genetic instructions can produce dif-ferent types of cells. How can the fertilized egg generate so many differ-ent cell types? How does one part of the gut tube become the pancreaswhile the part next to it becomes the liver? How does one particular cellgive rise to all the many different types of blood cells, while another cellgives rise to many different types of nerve cells?

2. The question of morphogenesis. Our differentiated cells are not randomlydistributed, but are organized into intricate tissues and organs. During

4 Unit 1: When Does Human Life Begin?


It is owing to wonder that people began tophilosophize, and wonder remains the begin-ning of knowledge.

ARISTOTLE (350 BCE)

development, cells divide, migrate, aggregate, and die; tissues fold andseparate. The organs are formed and arranged in a particular way: ourfingers are always at the tips of our hands, never in the middle; our eyesare always in our heads, not in our toesor gut. This creation of ordered form iscalled morphogenesis. How do mil-lions of individual cells form suchordered structures?

3. The question of growth. How do our cellsknow when to stop dividing? If eachcell in our face were to undergo just onemore cell division, we would be horribly malformed. If each cell in ourarms underwent just one more round of cell division, we could tie ourshoelaces without bending over. Our arms are generally the same size onboth sides of the body. How is cell division so tightly regulated?

4. The question of reproduction. In humans and other vertebrates, only certainvery specialized cells—the sperm and the egg—can transmit the instruc-tions for making an organism from one generation to the next. How are

Chapter 1: An Outline of Human Development 5


My dear fellow … life is infinitely stranger thananything which the mind of man could invent.Wewould not dare to conceive the things which arereally mere commonplaces of existence.

ARTHUR CONAN DOYLE, A CASE OF IDENTITY (1891)

(A) (B)

(D)

(C)

FIGURE 1.1 Some differentiated cells of the human body. (A) Red andwhite blood cells. Red blood cells carry oxygen to the rest of the body’scells.White blood cells, such as the single one in this picture, are part ofthe body’s immune system and play an important role in fighting bac-teria and other disease-causing organisms. (B) Epithelial cells form asheet lining the small intestine. Epithelial cells are found throughoutthe body; these particular digestive-tract cells secrete enzymes thatdigest food. (C) Skeletal muscle cells form fibers.The individual cells arenot visible here, but this micrograph gives a sense of how muscleswork as the fibers slide past one another to create movement. (D) Aneuron, or nerve cell.The long, thin structures radiating from the cen-tral cell transmit and receive sensory information that is processed bythe brain. (Micrographs © SPL/Photo Researchers, Inc.)

these cells, known as gametes, set apart from the rest of the body’s cellsto form the next generation, and what special instructions do they carrythat allow them to unite and form another embryo?

These questions are among the most exciting in all science because they arefundamental to how we come into being. They are also among the mostexciting questions in medicine, because birth defects and cancers involveerrors in the processes of growth, differentiation, and morphogenesis. Andcoupled with recent advances in biotechnology, knowledge of how cellsgrow, differentiate, and order themselves may lead to new procedures forregenerating damaged organs or enhancing existing ones.

Human Embryonic StagesAll animals come from a common ancestral origin, and the basic structureof our life cycle is not much different from those of earthworms, eagles,flies, or beagles. Some people come out of embryology classes with a newphilosophy of life. Others come out of the same class merely knowing a lotmore Greek than when they went in. Here is the Greek part—the vocabu-lary by which biologists name the stages of human development.

The generation of a new organism is initiated (but not completed) by thefusion of genetic material from two specialized cells—the sperm and theegg (Figure 1.2). This fusion, called fertilization (or, in humans, concep-tion), combines the parents’ genes and stimulates the egg to begin develop-

ment. The products of human con-ception are sometimes called theconceptus. These products includethe zygote, the embryo, the embry-onic sacs (amnion, chorion, yolksac, and allantois), and the fetus.



FIGURE 1.2 Human egg and sperm.Thismicrograph has been artificially coloredso that the egg (blue) and sperm (white)can be distinguished. Notice how muchlarger the egg is than the sperm; theactual size of the egg is about one-tenthof a millimeter, barely visible to thehuman eye. Although many sperm canattach to the egg’s surface, as shownhere, normally only one sperm enters andfertilizes the egg. (Photograph by D. M.Phillips/Photo Researchers, Inc.)

FertilizationWe will discuss fertilization in detail inChapter 3. Here we will simply say that thesperm brings to the egg 23 chromosomescontaining the genes that the father will passon to the new person. The sperm also pro-vides a structure called the centriole that willbe needed for cell division. The egg con-tributes its own genes in a set of 23 chromo-somes, giving the new individual a completecomplement, or karyotype, of 46 chromo-somes (Figure 1.3). The egg—which is thou-sands of times bigger than the sperm—alsocontributes a large amount of cellular mate-rial called cytoplasm. In the egg cytoplasmare structures called mitochondria that willprovide energy for embryonic development,along with other biochemical factors thatinstruct the early division and differentiationof the cells.

The fertilized egg is called the zygote(Greek for “tethered together”). The humanzygote is only 100 μm (100 microns, or one-tenth of a millimeter) in diameter—barelyvisible to the eye.

EmbryogenesisThe processes that comprise development between fertilization and birth

are collectively called embryogenesis. In humans, the period between fer-tilization and birth is called the gestation period, and it usually lasts 38weeks (just over 9 months; an average of 266 days).

During the first 8 weeks of gestation, the conceptus is called an embryo.During this embryonic period, the organ systems begin to form and theircells differentiate. This crucial 60-day period has been divided into 23 spe-cific stages, called “Carnegie stages” after the Carnegie Institute at JohnsHopkins University (the location of the laboratory that first described thesestages in the early 1900s) (Figure 1.4). The events that take place during theCarnegie stages are intricate and sensitive; even slight biochemical or genet-ic aberrations can have massive effects on the emerging embryo. The vastmajority of miscarriages occur during the embryonic period, often beforethe woman even realizes she is pregnant.



FIGURE 1.3 A human karyotype. Every human bodycell has two copies each of 23 chromosomes, for atotal of 46 chromosomes in its nucleus. Each of the 23chromosomes can be stained a different colorbecause the different genes present on them giveeach a distinct biochemical composition.The X and Ychromosomes determine the individual’s sex, as dis-cussed at length in Chapter 5; this person has two Xchromosomes and is thus female. (Courtesy of Drs.T.Ried and E. Schröck, National Institutes of Health).



1 (Zygote)(1 day)

2 (2–3 days)

3 (Blastocyst) (4–5 days)

8 (Late gastrula) (17–19 days)

9

(19–21 days)10

(21–23 days)11

(23–26 days)12

(26–30 days)

Male and female nuclei

Diploid nucleus

16 cells

2 cells

Placenta (partial)

Embryo

Inner cell mass (embryonic stem cells)

Dorsal (back) view

(A)

Lateral (side) views

Trophoblast cells

FIGURE 1.4 The Carnegie stages of the human embryonic period (the 60 days imme-diately following conception). (A) Stages 1–13 (approximately 30 days) cover the eventsof fertilization, implantation, cleavage, gastrulation, and neural tube formation. Note thatthe images are not to scale. Stage 1: The fertilized egg is 0.1–0.15 mm in diameter(about half the size of the period at the end of this sentence). Stage 2: Early cleavage,from the 2- to the 16-cell embryo. Stage 3: The blastocyst has an inner cell mass and tro-phoblast; is no more than 0.2 mm in diameter.This is the stage from which embryonicstem cells are obtained. At stages 4–7 (not shown), the blastocyst implants in the uterusand begins gastrulation. Stage 8: This model depicts embryo toward the end of gastru-lation; it is now about 2 mm long. Stage 9: Model showing the neural folds, which indi-cate the beginning of neural tube formation. Stages 10 & 11: The neural tube fuses.Theembryo at this point is no more than 3 mm long. Stage 12: The rostral (head) and cau-dal (tail) regions of the embryo are discernible.



13(30–32 days)

14 (31–35 days)

15 (35–38 days)

16 (37–42 days)

17

(42–44 days)18

(44–48 days)19

(48–51 days)20

(51–53 days)

21

(53–54 days)22

(54–58 days)23

(56–60 days)

Actual size = 3 mm

Actual size = 30 mm

(B)

(B) Stages 14–23 (days 30–60).The body’s major organs form over the remainder of theembryonic period, as the embryo grows from approximately 3 mm to about 35 mmlong. After 60 days, development becomes primarily a matter of growth and maturationrather than organ formation, and the conceptus is referred to as a fetus rather than anembryo. (A, photographs and models from the Louisiana State University Heirloom Col-lection, courtesy of the National Library of Medicine; B, photographs from the Kyoto Col-lection, Kyoto University Graduate School of Medicine, courtesy of Dr. Kohei Shiota.)



Nuclear membrane

Nucleus

Centriole (replicated)

Equatorial(metaphase) plateTwo copies of

chromosomeCentromere

Original cell Interphase/Prophase Metaphase

DNA replicates, creating newcopies of each chromosome

Chromosomes align on their centromeresat the equatorial (metaphase) plate

Cytoplasm

Centrioles migrate to opposite poles

Microtubules pull chromosomes apart

Nuclear membrane disintegrates

EarEarEarEar

1 2 3

CNS CNSCleavage and implantation

Brain,spinal cord

Heart Heart

Limbs Limbs

4 5 6 7 8

9 16 27-36 38 (full term)

Eye Eye Teeth PalateEar Ear

Embryonic period (weeks 1–8)

External genitalia

Embryo

Placenta

(A)

(B) Fetal period (weeks 9–38)

Third trimester(fetus viable)

Brain, spinal cord

Ear

Externalgenitalia

FIGURE 1.5 The periods of human development.(A) The embryonic period lasts the first 8 weeks andincludes the period before the embryo implantsinto the uterus, as well as the stages where themajor organs begin to form. (B) The fetal period,beginning on week 9 and extending to the full-term infant at approximately week 38, is mainly oneof growth and maturation.The labeled dots indi-cate critical times for the formation of some majororgan systems. During these time frames, theorgans are particularly susceptible to drugs andother external agents that can cause birth defects(see pages 23–25).The central nervous system, orCNS, includes the brain and spinal cord (red dots)and develops over the full term of gestation.

During the 30 weeks following the embryonic period, the conceptus iscalled a fetus. During the fetal period, the organ systems mature and theconceptus grows enormously.

Physicians often divide human gestation into three trimesters of threemonths each. The first trimester subsumes the embryonic period and earlyfetal limb and organ formation. The second and third trimesters are prima-rily periods of growth and maturation (Figure 1.5). The third trimester,beginning at around week 27, is historically the time when the fetus, if bornprematurely, would have a reasonable chance of independent survival (i.e.,survival without modern technological support).

CleavageThe first stage of embryogenesis is cleavage. During cleavage, the cellsdivide by a process called mitosis (Figure 1.6). In almost all of the body’scells, there are two copies of each chromosome—one copy from the moth-er and one from the father (see Figure 1.3). During mitosis, the chromo-somes first duplicate themselves so that the cell has four copies of eachchromosome. Then the cell divides in two in such a way that each new cellcontains one copy of each chromosome—that is, each of the two new cellscontains the same two chromosomes as the original cell. Thus, almost every



Anaphase Two daughter cells, identical to original cell

Centromeres divide and chromosomes separate, becoming daughter chromosomes

Telophase

Nuclear membrane re-forms

FIGURE 1.6 During mitotic cell division, a chromosome doubles by replicating its DNA.The centriole has also duplicated, and the two centrioles now migrate to anoppositesides of the nucleus.The duplicated chromosomes become attached to the centriolesby microtubules, which pull the chromosomes apart so that one chromosome goes intoeach new cell.To make it easier to visualize, the process is diagrammed here for only onechromosome; however, in humans all 46 chromosomes will duplicate and then divide inthe same mitotic cycle, so that the number of chromosomes in each cell remains 46.

cell in your body has the same genome as every other cell.* Indeed, eachbody cell (somatic cell) is the mitotic descendant of the zygote.

Humans follow the typical mammalian pattern of cleavage, which takesmuch longer than those of most other animals. Given that mammaliancleavage takes place inside the mother’s body, it has been very difficult tostudy; however, the knowledge we now possess was worth waiting for.

One of the most amazing things about mammalian cleavage is that itmust be synchronized with the migration of the embryo into the uterus.The young, unfertilized mammalian egg is released from the ovary andswept into the oviduct (also called the Fallopian tube) by fingerlike projec-tions of the oviduct called fimbriae (Figure 1.7). The fimbriae have a proteinthat recognizes the protein matrix surrounding the egg, and they transferthe egg into the tube adjacent to the ovary. Fertilization occurs in a regionof the oviduct that is close the ovary. This is important, because if fertiliza-tion occurs too close to the uterus (womb), the zygote won’t have enough



Uterus

Morula (Day 4)

Ovary

Ovulation(egg leaves ovary)

Oviduct (Fallopian tube)First cleavage

Zona pellucida2 cells

Fimbriae

FertilizationBlastocyst(Days 5–6)

4 cells8 cells

Cleavage (days 1–4)

Implantation(Day 7)

FIGURE 1.7 Development of a human embryo from fertilization to its implantation intothe uterus. Compaction of the human embryo into a morula occurs on day 4, shortlyafter each cell has divided three times.The embryo “hatches”from the protective zonapellucida upon reaching the uterus (see Figure 1.12).

*Red blood cells (Figure 1.1A) and lymph cells do not carry the same genetic informationfound in other somatic cells. Red blood cells (also known as erythrocytes) “toss out” theirgene-bearing nuclei and become full of hemoglobin, the protein that carries oxygen mole-cules. Lymph cells (lymphocytes) alter the genes that produce antibodies as part of ourimmune response.

time to make the cells that stick to the lining of the uterus and allow theembryo to implant into it.

Immediately after fertilization, the cells divide once every 12–18 hours.Each cleavage-stage cell is called a blastomere.

CompactionIn mammals, the first cell type differentiation occurs during the cleavagestage. This differentiation creates the cells by which the embryo will attachto the uterus, so it has to take place in the oviduct, before the embryo reach-es the womb. In the oviduct, hairlike projections called cilia gently push theembryo toward the uterus; the embryonic cells continue to divide duringthis 5-day journey (see Figure 1.7).

Shortly after the formation of 8 cells (that is, after the third cell division,around four days after fertilization), the blastomeres remain loosely connect-ed to one another. However, soon afterward, the blastomeres undergo a spec-tacular change in their behavior. They suddenly huddle together, maximiz-ing their contact with one another and forming a compact ball of cells (Figure1.8). This tightly packed arrangement is stabilized by tight junctions that formbetween the outside cells of the ball, sealing off the inside of the sphere.

The cells of the compacted embryo divide to produce a 16-cell morula(Latin for “mulberry,” which it vaguely resembles; see Figure 1.8E). Themorula consists of a small group of internal cells surrounded by a largergroup of external cells. Most of the descendants of the exterior cells become



(A) (B) (C)

(D) (E) (F)

Blastomeres

Compaction Morula

Inner cell mass (ICM)

Blastocyst

Trophoblast (outer layer of cells)

FIGURE 1.8 Cleavage of amammalian embryo.Thesemicrographs of a mouseembryo show a sequence simi-lar to that of humans. (A) 2-cellstage. (B) 4-cell stage. (C) Early8-cell stage. (D) Compacted 8-cell stage. (E) Morula. (F) Blasto-cyst. (Photographs courtesy ofJ. G. Mulnard.)

trophoblast cells. Trophoblast cells produce no embryonic structures.Rather, they form the tissue of the chorion, the embryonic portion of theplacenta (Figure 1.9). The chorion enables the embryonic blood vessels tocome into contact with the mother’s blood vessels, thus allowing theembryo to receive oxygen and nourishment from its mother. The chorionalso secretes hormones that cause the uterus to remain soft and to retainthe fetus as it grows. In addition, the chorion produces chemicals thatblock the mother’s immune system so that the mother will not reject theembryo.*

The embryo proper is derived from the descendants of the inner cells ofthe 16-cell stage. These cells generate the inner cell mass (ICM), which willgive rise to the embryo and its associated yolk sac, allantois (waste sac), andamnion (water sac) (Figure 1.9). The distinction between trophoblast andinner cell mass represents the first differentiation event in mammaliandevelopment. The trophoblast cells must be made first, since these are thecells that will adhere to the uterus. Once the trophoblast adheres to theuterus, the trophoblast and uterus interact to make the placenta. Duringthis time, the cells of the inner cell mass secrete proteins that help the tro-



Chorionic villi

Chorion

Embryo

Yolk sac

Amnion

FIGURE 1.9 A human conceptus at50 days of gestation (the end ofweek 6).The embryo lies within theamnion, and its placental blood ves-sels can be seen extending into thechorionic villi (fingerlike projectionsof the chorion).This remarkable clas-sic photograph shows the conceptusslightly larger than its actual size. Atthis point in development theembryo is in fact about 2 centime-ters (less than 1 inch) long. (Photo-graph from the Carnegie Institutionof Washington, courtesy of C. F.Reather.)

*Because approximately half of the embryo’s genes come from its father, the embryo’s tissuesare different from (“foreign to”) the mother’s tissues. Without the chemical blockade pro-duce by the chorion, the mother’s system would reject the embryo, just as it would reject adonated organ if immunosuppressant drugs were not administered.

phoblast grow. Only later will the inner cell mass start to make the embryo.This stage, when the conceptus has an inner cell mass surrounded by tro-phoblast cells, is called a blastocyst (see Figure 1.8F).

The inner cell mass: Twins and stem cellsBefore the blastocyst is formed, each of the early blastomeres (2-, 4-, or 8-cell stage) is thought to be able to form an entire embryo, including the tro-phoblast. This amazing ability is called regulation, and it stunned earlyembryologists. It means that if you were to take a single blastomere out ofthe 8-cell embryo and place that cell into a glass dish full of nutrients, thatcell by itself would generate a complete blastocyst. This blastocyst could beplaced into a uterus and develop into an entire organism. The isolated blas-tomere doesn’t make one-eighth of an embryo—it can make all the cells ofthe body. Thus, blastomeres are said to be totipotent (Latin, “capable ofbecoming anything”).

During the blastocyst stage, each blastomere of the inner cell mass hasthe ability to form any type of cell in the embryo proper, but the isolatedICM cells probably cannot form trophoblast cells. Thus, cells of the innercell mass are said to be pluripotent (Latin, “capable of becoming manythings”; see Chapter 7). In other words, each of the cells of the inner cellmass is not yet determined to become any specific type of cell, and whatcell type they will become depends largely upon interactions betweencells. These experiments have been done with mouse embryos, butwhether this restriction in potency applies to human embryos is not yetknown. However, the regulative capacity of the ICM cells is seen in humantwinning.

Human twins are classified into two major groups: monozygotic (Greek,one-egg) or identical twins, and dizygotic (two-egg), or fraternal twins. Fra-ternal twins are the result of two separate fertilization events and have sep-arate and distinct genotypes, whereas identical twins are formed from a sin-gle embryo whose cells somehow dissociated from one another, and thusshare a common genotype (Figure 1.10). Identical twins may be producedby the separation of early blastomeres, or even by the separation of theinner cell mass into two smaller clusters within the same blastocyst.

Identical twins occur in roughly 0.25 percent (i.e., 1 in 400) of humanbirths. About 33% of identical twins have two complete and separate chori-ons, indicating that separation occurred before the formation of the tro-phoblast tissue at day 5 (Figure 1.11A). The remaining two-thirds of identi-cal twins share a common chorion, suggesting that the split occurred withinthe inner cell mass after the trophoblast formed.

By day 9, the human embryo has completed the construction of anotherextraembryonic layer, the lining of the amnion. This tissue forms theamnionic sac (or water sac), which surrounds the embryo with amnionic



fluid that protects it from drying out and cushions it against impacts. If theseparation of the embryo occurs after the formation of the chorion on day5 but before the formation of the amnion on day 9, the resulting embryoshave a single chorion but separate amnions (Figure 1.11B). A very small per-centage of identical twins are born within a single chorion and amnion (Fig-ure 1.11C). This means that the division of the embryo into two individualscame after the amnion formed at day 9. Such twins are at risk of being con-joined (“Siamese twins”).

Twin formation thus demonstrates that the cells of the inner cell mass areundifferentiated and can become any part of the embryo. When undiffer-entiated cells from the inner cell mass are isolated and grown in certain con-



Two separate fertilizations:

Two implantations:

(A) Dizygotic (two-egg) twins

Blastomeres

Zona pellucida

Inner cell mass

Blastocyst cavity

Trophoblast cells

2-cell stage

One fertilization:

Single implantation,inner cell mass splits

(B) Monozygotic (one-egg) twins

2-cell stage2-cell stage

Sperm

Egg

Fraternal twins(full siblings; notgenetically identical)

Identical twins(two genetically identical individuals)

FIGURE 1.10 Twinning inhumans. (A) Dizygotic (two-egg)twins are formed by two separatefertilization events. Each embryoimplants separately into theuterus, and the resulting twinsare no more closely relatedgenetically than any two full sib-lings. (B) Monozygotic (one-egg)twins are formed from a singlefertilization event. Sometimebefore day 14, the embryo splitsin such a way that the cells of theinner cell mass are separated intotwo groups. Each ICM groupforms a complete fetus, resultingin two individuals with identicalgenomes.

trolled laboratory conditions, they remain undifferentiated and continue todivide in their flasks. Such cells are called embryonic stem cells (ES cells).As we will detail in Chapter 9, embryonic stem cells can be directed to formthe precursor cells that give rise to blood cells, nerve cells, and other celltypes. This gives them enormous potential value for repairing damagedorgans.



Amnion

2 Amnions

1 Chorion

1 Chorion

2-cellembryo 2 Amnions

1 Amnion

Chorion

(A) ICM splits prior to day 5 (33%)

(C) ICM splits after day 9 (rare); risk of conjoined twins

(B) ICM splits days 5–9 (66%)

Trophoblast

Inner cell mass

Blastocoel

Blastocoel

Embryo Yolk sac2 Chorions

FIGURE 1.11 The timing of human monozygotic twinning with relation to extraembry-onic tissues. (A) Splitting occurs before the formation of the trophoblast, so each twinhas its own chorion and amnion; this occurs in approximately one-third of twin occur-rences. (B) In most of the remaining cases of identical twins, splitting occurs after tro-phoblast formation but before amnion formation, resulting in individual amnionic sacsbut a single shared chorion. (C) Splitting after amnion formation leads to twins in oneamnionic sac and a single chorion, a rare situation where there is a risk of conjoined(“Siamese”) twins.

Escape from the zona pellucida and implantation into the uterusWhile the blastocyst moves through the oviduct on its trek to the uterus, itgrows within a protein coat called the zona pellucida. The proteins in thiscoat were essential for sperm binding during fertilization; once fertilizationhas occurred, the zona pellucida proteins prevent the blastocyst fromadhering to the oviduct walls. If such adherence does take place, it resultsin an ectopic, or tubal, pregnancy—a dangerous condition, because a blas-tocyst implanted in the oviduct will grow, rupturing the oviduct and caus-ing life-threatening hemorrhaging.

When the embryo does reach the uterus, some 5–6 days after fertiliza-tion, it releases an enzyme that digests a hole in the zona pellucida (Figure1.12A). Once out, the blastocyst makes direct contact with the uterus. Theendometrial cells lining the inside of the uterus “catch” the blastocyst on amat that the endometrial cells secrete (Figure 1.12B). This mat contains asticky concoction of proteins that bind specifically to other proteins that arepresent on the embryo’s trophoblast, thus anchoring the embryo to theuterus. Once this “anchor” is in place, the trophoblast secretes another setof enzymes that digest the endometrial protein mat, enabling the blastocystto bury itself within the uterine wall.

At this point a complicated dialogue between the trophoblast cells andthe uterus begins. First the trophoblast cells “invade” the uterine tissue,


(A) (B)Zona pellucida

Blastocyst

Blastocyst

Uterine lining

FIGURE 1.12 Implantation of the mammalian blastocyst. (A) Once in the uterus, a mam-malian (mouse) blastocyst “hatches”from the zona pellucida, a protein coat that pre-vents the embryo from prematurely implanting in the oviduct before it reaches theuterus. (B) Initial implantation of a rhesus monkey blastocyst in the endometrial cells ofthe uterine lining. (A courtesy of E. Lacy; B from the Carnegie Institution of Washington,courtesy of Chester Reather.)


secreting a hormone called human chorionic gonadotropin, or hCG. (Thisis the hormone that is measured in pregnancy tests.) Human chorionicgonadotropin then instructs the mother’s ovaries to make another hor-mone, progesterone. Progesterone has a number of functions that are inte-gral to the continued success of the embryo’s development.* This hormoneallows the uterus to remain malleable (i.e., soft and pliable, so that theembryo can grow); it also prevents menstruation (which would destroy theembryo) by blocking muscle contraction; and finally, progesterone allowsthe blood vessels from the uterus to surround the embryo.

Under the influence of progesterone, the uterus makes new blood ves-sels and starts to form a new region, the decidua. The decidua will becomethe maternal portion of the placenta. The decidual region then tells the tro-phoblast cells of the embryo to become the chorion. Together, the deciduaand chorion form the placenta (Figure 1.13). Thus, the placenta is a singleorgan formed from two different organisms, the embryo and the mother.

GastrulationGastrulation refers to the series of cell movements by which the embryon-ic cells change their positions relative to one another. The embryo at thisstage is called a gastrula. Gastrulation beginsabout day 14 after fertilization (right around thetime of the woman’s first missed period). It isduring gastrulation that the embryonic cells losetheir ability to be pluripotent. They can nolonger regulate—i.e., they cannot regeneratemissing parts if some region of the embryo isremoved. Thus, at gastrulation, the embryo iscommitted to become a single organism. It can no longer give rise to twinsor other multiple births. This point is sometimes called “individuation.”

Early during the gastrula stage, some cells are set aside to become thegerm cells—the precursors of the sperm or eggs. The rest of the cells thatwill form the embryo begin to interact with one another to determine theirfates among the three major cell lineages. These lineages make up threegerm layers (Latin, germen, to bud or sprout), each of which will “germi-nate” into the different tissue and organ systems (Figure 1.14):• The ectoderm is the outermost layer of the embryo. It generates the surface

layer (epidermis) of the skin, and also forms the brain and nervous system.• The endoderm is the innermost layer of the embryo. It will give rise to the

lining of the digestive tube and its associated organs (including the lungs).



*Chemically blocking the binding of progesterone to the uterine tissue prevents the implan-tation of the embryo and terminates the pregnancy. This blockade is the method of action bywhich the drug mifipristone—sometimes called RU486—produces an early abortion.

It is not birth, marriage, or death, but gastrulation, which is truly the most im-portant time in your life.

LEWIS WOLPERT (1986)

• The mesoderm is sandwiched between the ectoderm and endoderm. Itgenerates the blood, heart, kidneys, gonads, bones, muscles, and connec-tive tissues (e.g., ligaments and cartilage). Some of the mesodermextends outward from the embryo and into the trophoblast. These cellswill generate the blood vessels of the umbilical cord that connects theembryo to the placenta (see Figure 1.13).

In addition to the germ-layer cells that will form the embryo, the cells ofthe inner cell mass also form three sacs (see Figure 1.9): the amnion, theallantois, and the yolk sac. The function of the amnion was discussed earli-er in this chapter. The allantois is a waste storage sac for the by-products ofmetabolism. The early embryo cannot urinate or defecate; its waste prod-ucts are stored in the allantois until the placenta takes over these functions.

Unlike the prominent yolk sacs we associate with chicken eggs, the mam-malian yolk sac does not in fact store any yolk. Because mammalian embryos



FetusPlacenta

Uterus

Umbilical cord

Fetal capillaries

CO2and waste

O2 and nutrients

O2

CO2

CO2and waste

O2 and nutrients

O2

O2

CO2

Maternal vein Maternal artery

Umbilical arteries

Chorionicvillus

Umbilical vein

Fetal portion of placenta

Maternal portion of placenta

CO2

2 Months

FIGURE 1.13 The human placenta. Nutrients, oxygen, and waste materials (carbon diox-ide and urea) are exchanged between the maternal and fetal blood in the placenta.Theplacenta forms from the chorion (trophoblast) of the embryo and from the decidua(uterine lining) of the mother.The embryo is attached to the placenta by its umbilicalcord. Embryonic blood vessels enter the placenta and come into close proximity to themother’s blood vessels.

get nutrition through their placentas, our yolk sac is not needed for nutrition,as it is in bird and reptile eggs. The mammalian yolk sac, however, remainsimportant because it is the place where the embryo’s early blood cells aremade, and where the germ cells (sperm and egg precursors) first form.

OrganogenesisOnce the three germ layers are established, their cells interact with oneanother and rearrange themselves into tissues and organs. This process iscalled organogenesis. The first indication that organogenesis is occurringis the formation of the neural tube by ectodermal cells. The neural tube willbecome the brain and the spinal cord.

The ectodermal cells start as a flat sheet on the outside of the embryo (Fig-ure 1.15A). At the start of neural tube formation, a ridge of ectodermal cellsrises up on each side of the embryo and migrates toward the center (Figure1.15B,C). As these ridges, or neural folds, migrate, they push the central cells



Zygote Blastocyst Gastrula

Germ layers

Germ cells

Ectoderm (outer layer)

Epidermis (skin) and hair; central nervous system (brain and spinal cord); facial bones and tissues; sensory and other neurons; pigment cells

Mesoderm (middle layer)

Circulatory system (heart, blood, blood vessels); kidneys; gonads (testes, ovaries); muscle; bone; connective tissue (ligaments, cartilage)

Endoderm (internal layer)

Organs of the digestive tract (stomach, liver, pancreas, intestines); lungs and bronchii; thyroid

Precursors of the gametes (sperm and egg) are set aside early in gastrulation

Ectoderm

Mesoderm

Endoderm

Extraembryonicmesoderm

Amnion

FIGURE 1.14 Gastrulation and the germ layers. As cells differentiate during the courseof gastrulation, they are organized according to the germ layer from which they arise.Some organ systems contain cells from more than one germ layer.The germ cells (pre-cursors of the sperm or egg) are set aside early in gastrulation and do not arise from thegerm layers.

downward and then connect above them (Figure 1.15D,E). The cells thatwere at the center of the embryo are now the bottom (ventral or belly) cellsof the neural tube, while those cells at the tips of the neural folds are now thetop (dorsal, or back) cells of the neural tube.



Future neural tissue(neuroectoderm)

Neural crest

Neural plate

Neural crestcells

Neural crest cells (become cells of facial bones and tissues; pigment cells; peripheral nervous system cells)

Neural tube (becomes brain and spinal cord)

Future epidermal(skin) tissue

32415

32415

Plane of closure (see Figure 1.16)

Closure ofneural tube

(A)

(B)

(C)

(D)

(E)

FIGURE 1.15 Neural tube forma-tion is seen during the initialstages of organogenesis.Theupper cells of the ectoderm—theneural ectoderm or neuroecto-derm—fold inward , forming atube.This neural tube will even-tually become the central nerv-ous system (CNS)—the brain andspinal cord.The sheet of ecto-derm lying above the neural tubebecomes the epidermis of theback, and the transient column ofcells connecting the two is calledthe neural crest.The neural crestcells migrate to form the periph-eral nervous system (that is, allthe nerve cells that exist outsideof the brain and spinal cord), thebones of the face, and severalother cell types.



Birth DefectsAbout 2 percent of human infants are born withsome readily observable anatomical abnormality(Thorogood 1997).Those abnormalities seen atthe time of birth are called congenital anomalies

or, more commonly, birth defects.These abnor-malities may include missing limbs, missing orextra digits, cleft palate, eyes that lack certainparts, hearts that lack valves, and so forth.

Abnormalities caused by genetic events (suchas gene mutations or an abnormal number ofchromosomes) are called malformations. Malfor-mations often appear as syndromes (from theGreek,“running together”), where several abnor-malities are seen concurrently. For instance, a mal-formation called Down syndrome is caused by anextra copy of chromosome 21 in each cell. People

with an extra copy of this very small chromosomesuffer from mental retardation, the absence of anasal bone, heart defects, a characteristic slantingof the eyes, and often the closure of the intestine.

Congenital anomalies can also be the result ofthe fetus being exposed to exogenous (outside)agents, including certain chemicals, viruses, radia-tion, or high fevers.These anomalies are calleddisruptions.The agents responsible for disrup-tions are called teratogens (Greek, meaning“monster-formers”), and the study of how envi-ronmental agents disrupt normal development iscalled teratology.The table gives a partial list ofknown teratogens.

The summer of 1962 brought two portentousevents in the study of teratology.The first was thepublication of the book Silent Spring, in which biol-ogist Rachel Carson described how the insectici-dal chemical DDT, in widespread use around the

Some agents thought to cause disruptions in human fetal developmenta

Drugs and chemicalsAlcoholAntithyroid agents (PTU)BromineCortisoneDiethylstilbesterol (DES)DiphenylhydantoinGentamycinHeroinLeadMethylmercuryPenicillamineRetinoic acid (Isotretinoin, Accutane)StreptomycinTetracyclineThalidomideTrimethadioneValproic acidWarfarin

Source: Adapted from Opitz 1991.aThis list includes known and possible teratogenic agents and is not exhaustive.

Ionizing radiation (X-rays)

Hyperthermia (fever)

Infectious microorganismsCoxsackie virusCytomegalovirusHerpes simplexParvovirusRubella (German measles)Toxoplasma gondii (toxoplasmosis)Treponema pallidum (syphilis)

Metabolic conditions in the motherAutoimmune disease

(including Rh incompatibility)DiabetesDietary deficiencies, malnutritionPhenylketonuria



Birth Defects (continued)

world, was destroying bird eggs and preventingreproduction in several bird species.The secondwas the discovery that thalidomide, a sedativedrug used to help alleviate nausea in pregnantwomen, could cause limb and ear abnormalities inthe fetus.These two discoveries showed that theembryo was vulnerable to environmental insults.

Thalidomide is a powerful example of a terato-gen.Thalidomide is an effective drug with veryfew side effects for adults, and it was prescribed(mostly in Europe) as a mild sedative. However, inthe early 1960s, two scientists independently con-cluded that this drug was responsible for a dra-matic increase in a previously rare syndrome ofcongenital anomalies.The most noticeable ofthese anomalies was phocomelia, a condition inwhich the long bones of the limbs are severelyshortened (Figure A). Over 7,000 affected infants

were born to women who took the drug, and awoman need only have taken one tablet to pro-duce children with all four limbs deformed. Otherabnormalities induced by the ingestion of thalido-mide included heart defects, absence of the exter-nal ears, and malformed intestines.

That outside agents could affect the develop-ing fetus was underscored in 1964, when an epi-demic of rubella (German measles) spread acrossAmerica. Adults who contracted the diseaseexperienced relatively mild symptoms, but over20,000 fetuses infected by the rubella virus wereborn blind or deaf, or both. Many of these infantswere also born with heart defects and/or mentalretardation.

Teratogens do their damage during particulartimes, as the body is developing certain parts.Thistime is called the period of susceptibility.Thalido-mide, for instance, was found to be teratogeniconly during days 34–50 after the last menstruation

(about 20 to 36 days after fer-tilization). From day 34 to day38, no limb abnormalities areseen, but during this period,thalidomide can cause theabsence or deficiency of earcomponents (Figure B). Mal-formations of upper limbs areseen before those of the lowerlimbs because the arms formslightly earlier than the legsduring development.

It is during the embryonicperiod that most of the organsystems form, whereas thefetal period is generally oneof growth and modeling.Themaximum period of terato-gen susceptibility is betweenweeks 3 to 8, since that iswhen most organs are form-ing.The nervous system,

(A) PHOCOMELIA, THE LACK OF PROPER LIMB DEVELOPMENT, was themost visible of the birth defects that occurred in many childrenwhose mothers took the drug thalidomide during pregnancy. (Pho-tograph © Deutsche Presse/Archive Photos.)

In humans, this crucial formation of the neural tube begins early in thethird week of gestation. The nervous system grows throughout embryonicand fetal development, and connections between the neurons begin to inte-grate the parts of the body and the brain. Different parts of the nervous sys-tem “zip” together starting from several points (Figure 1.16A). Failure to closethe nervous system results in neural tube birth defects such as anencephaly(the anterior part of the neural tube remains open; Figure 1.16B) and spinabifida (the posterior end of the neural tube remains open; Figure 1.16C). Folicacid (also known as folate or vitamin B9) has been shown to be important in


Birth Defects (continued)though, is constantly forming, andremains susceptible throughout devel-opment (see Figure 1.5).

Before week 3, the embryo is notusually susceptible to teratogens. Dur-ing this time, a substance either dam-ages most or all of the cells, resulting inthe death of the embryo; or it damagesonly a few cells and the remaining cellsare able to compensate so that theembryo develops normally.

Absence of ear

Malformed or absent thumbs

Absence of arms

Severe shortness of arms

Dislocation of hip

Malformation of ear

Absence of legs

Severe shortness of legs

Malformed thumbs

34 38 42 46 50

Days after last menstruation(B) THALIDOMIDE DISRUPTS DIFFERENT STRUCTURESat different times of human development.

1

33 3

55

1 1

5

2 2 2

44

Normal Anencephaly Spina bifida

4

(A) (B) (C)

FIGURE 1.16 Closure of the humanneural tube. (A) Regions of neural tubeclosure (see Figure 1.15) superimposedon the body of a newborn.Theseregions are hypothesized to exist in thispattern on the basis of genetic evi-dence. (B) Anencephaly is caused by thefailure of neural plate fusion in region 2.(C) Spina bifida is caused by the failureof region 5 to fuse (or of the posteriorneuropore to close).


this zippering process, and obtaining sufficient amounts of this vitamin iscritical for pregnant women.

Many organs contain cells from more than one germ layer, and it is notunusual for the outside of an organ to be derived from one layer and theinside from another. For example, the outer layer of skin (epidermis) comesfrom the ectoderm, while the inner layer (the dermis) comes from the meso-derm. Also during organogenesis, certain cells undergo long migrationsfrom their place of origin to their final location. The germ cells (primordialeggs and sperm), for instance, do not form within the gonads (ovaries andtestes). Rather, they migrate from the base of the yolk sac into the develop-ing gonads—a long trip. The cells that form the facial bones migrate fromthe neural crest, a strip of cells originally seen between the newly formedneural tube and the skin of the back (see Figure 1.15E). Once these cellsmigrate, that connection between skin and neural tube vanishes.

Organs form rapidly during the first trimester. The heart forms duringweek 4, and the first rudiments of the limbs (legs and arms) can be seenthen, too. The eyes start to form on week 5, on the sides of the head; byweek 7, the eyes are in the front of the face. By the end of the first trimester,all the major anatomical parts are present, although many of them are notcomplete. Although the embryo’s sex has been determined by its genotype,its sex organs are still rudimentary and “bipotential” (see Chapter 5). Thesex organs don’t become specifically male or female until the fetal period(around week 11).

The embryo at the end of first trimester is about 4 inches long andweighs about 1 ounce. By the end of second trimester, the fetus is about 12inches long and weighs between 1 and 1.5 pounds. The nervous systemcontinues to develop during the fetal period; the human electroencephalo-gram (EEG) pattern, a marker that the brain is functioning, is firstdetectable at around week 25 (that is, around the beginning of the seventhmonth of pregnancy).

BirthThe human baby is born as soon as its last critical organ system—the lungs—mature. If development were to go on too long inside the mother’s body, thebaby’s head would grow bigger than the birth canal. However, if the fetus isborn before the lungs mature, the baby cannot breathe on its own.

To coordinate the timing of birth with fetal lung development, humanshave evolved an intricate system whereby the fetus can send a signal to theuterus, telling the uterus that it’s time to start contractions. Once the fetallung has matured, it secretes a type of protein called surfactant* into the



*Surfactant is a product of mature mammalian lung cells. Surfactant protein coats the inter-nal cells of the lung and keeps them moist in the presence of the air the lungs inhale.

amnionic fluid. This surfactant protein causes an immune response (similarto an inflammation) in certain fetal cells. These “inflamed” fetal immunecells migrate into the uterus, where they secrete proteins that in turn causethe uterine muscles to contract. In this way, a “protein cascade” from thefetus signals its mother that the lungs have matured and the baby is readyto “go it alone.”

Like fertilization, birth is a process, and it is called (for good reason) labor.During the first stage of labor, contractions pull the cervix open and push thebaby forward (Figure 1.17A–C). In the second stage of labor, the baby is born(Figure 1.17D,E). The third stage of labor pushes out the placenta (the “after-birth”; Figure 1.17F), and the fourth stage is the recovery period.

When the baby takes its first breath, the air pressure closes a flap in theheart. This flap separates the blood circulation to the lungs from the bloodcirculation to the rest of the body. The baby can now breathe on its own,and the umbilical cord, which had been the source of oxygen for the grow-ing fetus, can now be cut.

A human infant is born very immature. It cannot walk, and it cannot findits mother’s breast without help. Even its eyes function only poorly. It isthought that this condition is brought about as an evolutionary compromisebetween the growing head and the size of a woman’s pelvis. The humanbrain keeps growing throughout childhood, making millions of new nervecells each day. If humans were born at the same stage of brain developmentas their ape relatives, a baby would probably be born at around 18 months,and its head would be far too large to pass through the birth canal. So itcould be said that we spend the first few years of our lives as “extrauterinefetuses,” totally dependent on parental care. We are still forming our nerv-ous system during this time, and it has been hypothesized that our abilityto think and interact with others is derived from the fact that we are beingsocialized during a time when we are rapidly forming neurons and canlearn extremely rapidly.

ConclusionThis brief overview should have left you with at least the sense that thedevelopment of a human being comprises thousands of steps and finelycoordinated interactions. At the cellular level, the embryo is a constantlygrowing and changing mass of cells that change from the single, totipotentzygote into a bewildering array of highly specializedcell types, including the many types of nerve cellsthat we blithely take for granted in our daily activi-ties of working, playing, learning, and communicat-ing. At the cellular level, thousands of proteins andsmaller chemicals are involved in sculpting thehuman being from the masses of cells. A foreign



The amazing thing about developmentis not that it sometimes goes wrong,but that it ever succeeds.

VERONICA VAN HEYNINGEN (2000)



(A) (B)

(C) (D)

(E) (F)

Umbilical cord

Pubis (bone)Urinary bladder

Vagina

Cervix

Rectum

Placenta

Urethra

Amniotic sac

Cervicalcanal

Rupturedamniotic sac

Umbilical cordPlacenta (partially

detached from uterus)

Mother's spine

chemical getting in the way, or the lack of the right protein at the necessarytime, can cause development to go tragically wrong. At the genetic level, theinstructions in our nuclei cause us to look more like our biological parentsthan we look like our friends and neighbors.

Until recently, we could only marvel at the intricacies and constancy ofhuman development. However, the incredible accumulation of moleculartechniques and new knowledge in developmental biology has drasticallychanged both the science of developmental biology and the role of that sci-ence within society. Questions that were undreamed of outside of sciencefiction are now very real and are demanding answers every day. Findinganswers, whether they apply to individual medical cases or affect societyas a whole, demands not only an understanding of the science but also anappreciation and respect for the spiritual and philosophical ideals andfoundations of human societies. The United States—faced not only withaccess to the most sophisticated technologies, but also with a populationwhose widely diverse religious, intellectual, and philosophical beliefs stemfrom virtually all the world’s cultures—is especially embattled by thesequestions.



FIGURE 1.17 The major movements of labor initiated by contractions of the uterus.(A) Engagement, during which the head goes below the pelvic inlet. (B) Flexion, wherethe head enters the birth canal. (C) Descent and internal rotation during the first stagesof labor.The cervix dilates (widens). (D) Extension of the fetal head (“crowning”).(E) External rotation of the body after the head is delivered. (F) After the baby is deliv-ered, the placenta, or “afterbirth,”separates from the uterus and will be expelled fromthe mother’s body.

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BIOE THICS AND THE NE W EMBRYOLOGY When Does Human … · 2014-10-10 · these cells, known as gametes, set apart from the rest of the body’s cells to form the next generation,