The ability to screen developing human life for chromosomal
abnormalities and genetic disorders has been ours for some time.
Individuals and doctors have for many years been able to test
fetuses in utero, either through the genetic analysis of cells
obtained from amniotic fluid by amniocentesis (in the second trimester)
or through genetic analysis of chorionic villus samples obtained
from the placenta by biopsy (in the first trimester). The "selection"
that follows such testing is achieved by means of abortion; it
amounts to "selecting against" a developing fetus with a diagnosed
genetic disease or other unwanted trait (for example, maleness
or femaleness).
More recently, however, innovations in assisted reproduction and
molecular genetics have yielded new ways to test early-stage embryos in
vitro for genetic markers and characteristics. After such testing only
those embryos with the desired genetic characteristics are transferred
to initiate a pregnancy. By comparison with the older form of
screening, this approach is more "positively" selective; it amounts
more to "choosing in" rather than merely to "weeding out." Methods to
test or screen eggs and sperm before fertilization are also being
developed, and at least one type of sperm sorting-sorting by the
presence of X or Y chromosomes-is already in use in several clinical
trials. These two new techniques for testing early-stage
embryos-preimplantation genetic diagnosis (PGD) and sperm sorting-are
the subjects of the following discussion.
I. Uses and Techniques
A.Preimplantation Genetic
Diagnosis of Embryos
PGD is a technique that permits clinicians to analyze
embryos in vitro for certain genetic (or chromosomal) traits
or markers and to select accordingly for purposes of transfer.
The early embryo (six to eight cells) is biopsied by removal
of one or two cells, and the sample cell(s) is then examined
for the presence or absence of the markers of interest.
PGD is practiced in approximately fifty clinics worldwide,
the majority of them located in the United States. PGD was
first used in 1989 as an adjunct to in vitro fertilization
(IVF) for treating infertility. Official statistics do not
tell us how many children have been conceived following
PGD. Estimates vary widely; one recent report suggested
that "more than 1,000 babies have been born worldwide."1
PGD was initially used for sex identification to avoid transfer
of embryos with X-linked genetic diseases, such as Lesch Nyhan
syndrome, hemophilia, and X-linked mental retardation.2
PGD is now most commonly used to detect aneuploidies (that
is, an abnormal number of chromosomes, for example, trisomies
and monosomies).3
Some aneuploidies prevent the embryo from implanting, whereas
others are associated with disorders such as Down syndrome and
Turner syndrome. PGD is used also to detect monogenic diseases
such as cystic fibrosis and Tay-Sachs disease. More recently PGD
has been used to select embryos that would be compatible tissue
donors for older siblings in need of transplants.4
In still other cases PGD has been used for elective (non-medical)
sex selection.5
Today at least one-third of individuals who use PGD are otherwise
fertile, and this number may increase as the potential uses of
PGD expand.6
At present, PGD can identify genetic markers that correlate
with (or suggest a predisposition for) more than one hundred diseases,
including illnesses that become manifest much later in life, such
as early-onset Alzheimer disease.7
As genomic knowledge increases and more genes that correlate with
diseases are identified, the applications for PGD will likely
increase. In principle any known gene and its variants can be
tested for, and with improved methods for amplifying genetic screening
on small samples, it may some day be possible to test the single
cell removed from the embryo for hundreds of genetic markers.
Dr. Francis Collins, director of the National Human Genome Research
Institute, recently speculated that within five to seven years
the major contributing genes for diabetes, heart disease, cancer,
mental illness, Parkinson disease, stroke, and asthma will be
identified.8
Many couples with family histories of these diseases may be drawn
to PGD, even in the absence of infertility. Moreover, if genetic
associations with other, non-medical conditions are identified,
PGD might one day be used to screen for positive traits and characteristics
such as height, leanness, or temperament.i
PGD is a multi-step process requiring considerable technical
skill and expertise in the fields of genetics and reproductive
medicine. Because the testing is performed on early embryos in
vitro, individuals electing to use PGD must undergo all
of the phases of IVF described in Chapter 2.ii
Typically, embryo biopsy is performed three days after fertilization
when the embryo is at the six- to eight-cell stage. The researcher
makes a small hole in the zona pellucida (using a sharp pipette,
acidic solution, or laser), and then inserts a suction pipette
into the opening and removes one or two cells ("blastomeres").
Some researchers wait until the embryo reaches the blastocyst
stage (approximately five to six days after fertilization, when
the given embryo has grown to approximately one hundred cells)
to undertake this biopsy. The procedure is technically less demanding
at this stage and more cells can be removed and analyzed. Researchers
who biopsy blastocysts remove approximately ten cells from the
trophectoderm (the blastocyst's outer ring of cells that are the
precursors of the fetal portion of the placenta).
Once collected, the blastomeres or trophectoderm cells can be
analyzed by a variety of means depending on the purpose of the
test. PGD for detection of monogenic diseases is performed using
a technique called "polymerase chain reaction" (PCR). Sex identity
and chromosomal abnormalities are detected using a technique called
fluorescence in situ hybridization (FISH). PCR allows clinicians
to amplify sections of the DNA sequence, providing them with enough
DNA to detect specific gene mutations. In FISH, labeled markers
bind to chromosomes, permitting the researcher to observe and
enumerate such chromosomes.
In all these procedures, timing is critical. The clinician must
complete the analysis before the embryo develops beyond the stage at
which it can be successfully transferred. If the biopsy is performed on
Day 3, the practitioner has approximately forty-eight hours in which to
complete the analysis, verify results, and discuss options with the
patient or patients.
The error rate for PGD has been estimated between 1 and 10 percent,
depending on the assay used.9
Several technical difficulties maycompromise accuracy. Working
with so few cells-in many cases only one or two-leaves little
room for technical error. PCR can be problematic. In some instances,
for example, one allele fails to amplify to a detectable level.
This phenomenon, called "allele dropout," can lead to misdiagnosis.
Contamination of the PGD sample can also lead to misdiagnosis.
Technical difficulties associated with FISH may also affect accuracy
of diagnosis. Following the transfer of the selected embryos and
the initiation of pregnancy, clinicians routinely follow up with
chorionic villus sampling and amniocentesis to confirm the results
of PGD.
B.Genetic Analysis of Gametes
As well as testing early embryos, researchers are also
trying to test and screen gametes (ova and sperm) before
fertilization.
1. Preimplantation Genetic Diagnosis of Ova.
As an alternative to embryonic PGD, clinicians can now
perform a similar analysis on the developing oocyte, by
testing DNA from the polar bodies-nucleus-containing protrusions
that are ultimately shed from the maturing oocyte.10
As with cells obtained from embryo biopsy, PCR or FISH can
be used to test for, respectively, monogenic diseases or
chromosomal abnormalities (most aneuploidies are maternally
derived). The utility of polar body analysis is limited,
however, in that it reveals only the maternal contribution
to the child's genotype.
2. Sperm Selection.
Another form of gamete screening is sperm sorting. A number
of techniques are now under study, all of them aimed at
controlling the sexes of the children ultimately conceived
from these gametes. Most techniques to sort sperm have proven
unreliable. These have included albumin gradients, percoll
gradients, sephadex columns, and modified swim-up techniques.
One technique currently in clinical trials-commercially
called Microsort-has proven more successful. It exploits
the difference in total DNA content between X-chromosome
(female-producing) sperm and Y-chromosome (male-producing)
sperm. The researcher collects the sperm sample and stains
it with a fluorescent dye, bisbenzimide, which binds to
the DNA in each sperm. A female-producing sperm shines brighter
because it has 2.8 percent more DNA than the androgenic
sperm, owing to the larger size of the X-chromosome. Using
fluorescence-based separating equipment, the researcher
sorts the sperm into X-bearing and Y-bearing preparations.
The appropriate preparation is selected according to the
couple's preference and used to inseminate the woman. The
latest statistics report a 90 percent success rate for conceiving
female children and 72 percent success for conceiving male
children.
II. Ethical Considerations
PGD, when effective, enables parents to avoid
the deep grief and hardship that accompany the birth of
a child with dreaded and incurable diseases such as cystic
fibrosis and Tay-Sachs. And by screening out embryos with
genetic abnormalities before a pregnancy begins, it prevents
many women from having to decide whether to abort an abnormal
fetus. Yet PGD also raises a number of ethical concerns,
similar to but extending beyond the concerns attached to
assisted reproduction itself.
A. IVF-Related Concerns
IVF, and typically intracytoplasmic sperm injection (ICSI),
are essential to the practice of PGD. Thus, all of the ethical
concerns attending these practices of assisted reproduction (discussed
in Chapter 2) are likewise concerns here. But the prospect of
genetic selection creates a further reason, beyond infertility,
to seek and make use of assisted reproductive technologies. In
what follows we shall confine our attention to new issues
raised by genetic selection (though some of these issues may overlap
those raised by the established practice of prenatal diagnosis).
B. Well-Being of Children
PGD typically requires the removal of one or two cells from
a six- to eight-cell embryo. It is not known whether this embryo
biopsy affects the development of the child later born.11
PGD has entered clinical practice after only limited trial experience.
No comprehensive studies have been published on the effects of
PGD on the physical well-being of those involved. Some prospective
studies are currently underway in Europe, but it is unclear how
well-funded or comprehensive they will be.
C. Increased Control over the Characteristics
of Children
PGD gives prospective parents the capacity to screen and select
for specific genetic traits in their children. For now, that capacity
is limited. Technical limitations on the number of embryos that
can be produced in a single PGD cycle and on the number of tests
that can be performed on a single blastomere severely restrict
the number of characteristics for which practitioners can now
test. Similarly, the complexity of the relationship between identifiable
single genes and phenotypic characteristics will complicate the
development of genetic tests for many traits and characteristics
of interest (for example, where traits have polygenic contributions
or result from complex gene-environmental interactions). Moreover,
one cannot select for genes that are not brought to the embryos
by their genetic progenitors; efforts at positive selection will
be limited. Thus, the capacity to use PGD to select for a "superior
genotype"-a "designer baby"-is in our estimation not on
the horizon.iii
The present, more modest, applications of PGD-screening for
severe medical conditions, screening for genetic predispositions
or risk factors for a given disease, elective sex selection, and
selection with an eye to creating a matching tissue donor-do give
rise to ethical concerns about possible impacts on children and
families. PGD used for these purposes might in some cases treat
the resulting child as a means to the parents' ends. This concern
would be amplified should the reasons for embryo screening move
from "medical" purposes to non-medical or enhancement purposes,
from preventing the birth of a diseased child to trying to "maximize"
a child's genotype for desired characteristics. (This line is,
admittedly, hard to draw.)iv
Because the prospective child is deliberately selected on qualitative,
genetic grounds out of a pool of possible embryonic siblings,
PGD risks normalizing the idea that a child's particular genetic
make-up is quite properly a province of parental reproductive
choice, or the idea that entrance into the world depends on meeting
certain genetic criteria. Even if the prospective parents are
guided by their own sense of what would be a good or healthy baby,
their selection may in some cases serve their own interests more
than the child's (as in the case, for example, of a deaf couple
using PGD in an effort to produce a deaf child). The new technologies,
even when used only to screen out and eliminate the sick or "deficient,"
may change parents' attitudes toward their children, increasing
both the desire to control and the tacit expectation of certain
qualities-an attitude that might intensify as PGD becomes more
sophisticated. Children who are selected on non-medical grounds-such
as elective sex selection or trait selection-may experience increased
pressures to meet parental expectations.
The use of PGD to identify a prospective child as a tissue donor
match (currently a very rare practice) poses an additional ethical
concern: the deliberate creation and selection of a particular
child as a means for the benefit of another.v
It is, of course, likely that in most families such children would
be loved by their parents and by the siblings who would benefit
directly from their tissue donation. But even here there is a
dramatic shift in how the new PGD-selected donor-child is conceived
and regarded by the parents and family. Is it proper to assign
to an unconceived child the burden of being a savior of a sibling,
and then give that child life on condition that he or she fulfill
that role?
A closely related ethical concern is that this sort of selection
could reduce the scope of reproductive choice. As the aggregate
effect of parental choices reshapes society's understanding of
"normal" or "acceptable" phenotypes, parents might feel social
pressure to undergo PGD, as many pregnant women now are pressured
to undergo amniocentesis. In addition, parents might feel pressured
to use PGD for financial reasons; it is conceivable that HMOs
or health plans that cover IVF might someday require PGD for selection
against certain potentially costly diseases.
Some see these ethical concerns as unjustified or premature.
They believe that expanding our control over human reproduction
is an extension of the parental responsibility to care for one's
offspring, and that PGD will be used almost exclusively to prevent
the births of diseased children. They argue that the prospect
of using PGD for "enhancement" purposes is unlikely, since the
burdens of undergoing IVF and PGD would outweigh the limited possibility
of selecting an embryo that is genetically superior. The possibility
of so selecting will be limited both by the genetic complexity
of human traits like intelligence, and by the vast number of embryos
that would be required in order to make the choice for a "better"
genetic baby a meaningful one.
Whether and to what extent either the concerns or the reassurances
about PGD are justified is in many cases an empirical question, surely
worth considering and monitoring.
D. PGD for Late-Onset Disease
PGD can be used not only to identify abnormalities that would
lead to certain and immediate diseases (like Tay-Sachs or Down
syndrome), but can also be used to identify an increased susceptibility
to particular diseases later in life. Is PGD justified to avoid
the birth of a child who will be likely to live "only" thirty
years? Is it justified to avoid the birth of a child who is especially
susceptible to a late-onset disease like breast cancer or Alzheimer
disease? Questions like these will need to be confronted as the
ability to make biological and genetic predictions about unimplanted
embryos continues to grow.
E. Eugenics and Inequality
For some critics, PGD calls to mind the specter of "eugenics";
it is seen as a technology that facilitates the selection of "better"
children. Some worry that as PGD becomes more widespread, it will
serve to further stigmatize the disabled and promote the notion
that some lives are not worth living or are better off prevented
in the first place. This is in a sense nothing new-amniocentesis
and prenatal diagnosis are common and have already raised similar
concerns. What is novel about PGD, though, is that it can be used
to select "for" desirable traits, not just "against" markers for
disease.
Other commentators worry that widespread use of PGD (so long
as it is not covered by insurance or subsidized by taxpayers)
could widen and worsen the gap between the "haves" and the "have-nots"
in society, as access to PGD, like access to IVF itself, is restricted
to those who can afford it. Furthermore, techniques that permit
parents to screen and select their children's genetic make-up
might produce a new kind of inequality between parents and children.
Such techniques would allow parents not simply to give life to
their offspring, but to choose (or try to choose) what kind
of offspring they have. Of course, through education and upbringing
parents have always had an enormous influence on the lives of
their children, but inasmuch as the consequences of genetic screening
and selection are imposed before birth and are biologically permanent,
the inegalitarian effects of the new technology are novel and
potentially significant. Biology is not destiny, but one's genetic
make-up is surely crucial to one's life; if selected deliberately
in advance by others, it might shape or limit a child's self-understanding
and sense of future possibilities. The ability to affect the genetic
make-up of the next generation may also exacerbate the tendency
to assign too much importance to genetic make-up, and so may promote
an excessively reductionist view of human life. These new practices
may lend undue credence to the notion that human characteristics
and conditions are simply or predominantly genetically determined-a
too-narrow understanding of human freedom, agency, and experience,
and a simplistic understanding of human biology.
F. Parents and Children
The introduction of rigorous genetic screening into childbearing
might set a new standard for what counts as an acceptable birth.
The attitude of parents toward their child may be subtly shifted
from unconditional acceptance toward critical scrutiny: the very
first act of parenting could become not the unreserved welcoming
of an arriving child, but the judging of his or her fitness, while
still an embryo, to become one's child, all by the standards of
contemporary genetic screening. Moreover, as the screening technology
itself is further refined, becoming better able to pick out serious
but not life-threatening genetic conditions (from dwarfism and
deafness to dyslexia and asthma) and then to distinguish genetic
markers for desirable traits, the standards for what constitutes
an acceptable birth may grow more exacting.
III. Regulation
There is now no direct regulation of either PGD or sperm
sorting as such. There are, however, sources of regulation,
described below, that touch or might conceivably touch these
practices to some extent.
A. Federal Regulation
CLIA, the Clinical Laboratory Improvement Amendments, which
as previously noted regulates laboratories that perform diagnostic
tests for health assessment on human specimens, does not apply
to tests performed in the context of IVF including PGD. Because
these are the contexts in which PGD and related techniques for
selection are practiced, CLIA is inapplicable. If, in the future,
CLIA were deemed applicable to PGD and related activities, it
would function to ensure quality assurance and control, as described
in Chapter 2.
Similarly, the FDA has a limited role in the regulation of PGD and
related activities. The FDA governs any articles that may be used in
these activities, ensuring that they are safe and effective for their
intended uses. Specifically, the FDA regulates (as devices) any test
kits that are manufactured and sold for purposes of genetic testing.
However, it seems that there are today no such kits for PGD or the
related activities discussed above. Most labs use assays that they
develop themselves.
To the extent that PGD and related activities occur in the research
setting, they may be subject to the human-subjects protections
discussed in Chapter 5 (Institutional Review Board [IRB] approval,
informed consent, etc.). That is, under certain circumstances, the
donors of embryos or reproductive tissue for such experiments would be
considered "human subjects" and protected accordingly. But insofar as
PGD is regarded as part of standard medical practice, no such oversight
would obtain.
B. State Laws
There are currently no state laws that directly govern PGD or
related practices. Some statutes that govern embryo research may
touch these activities, as discussed in Chapter 5. In the main,
however, there is no significant state regulation.
C. Tort Litigation
As in the case of standard assisted reproduction, individuals
can use litigation as a means of regulating the practice of PGD
and related activities. To prevail on a theory of malpractice,
a plaintiff would have to demonstrate that a clinician owed a
duty to the plaintiff, which the clinician breached resulting
in injury. The viability of tort claims as an effective regulatory
mechanism remains to be seen, though one might imagine the difficulties
inherent in demonstrating causation and harm.
There seem to be only two reported cases in which malpractice
suits have been brought against practitioners of PGD for negligence
and fraud. In one of the cases, Paretta v. Medical Offices
for Human Reproduction,12
a couple sued an IVF clinician for medical malpractice for his
failure to perform PGD on an embryo to test for cystic fibrosis,
when he knew that the ova donor was a carrier for the disease.
The defendant moved for summary judgment (that is, a ruling from
the court that, in light of undisputed material facts, the defendant
is entitled to judgment in his favor as a matter of law). The
court held that a right of recovery did not exist for the child's
birth with cystic fibrosis or for the parents for emotional distress,
because to rule otherwise would "give children conceived with
technology more rights and expectations than those conceived without
such assistance." However, the court ruled that a right of recovery
did exist for the monetary expenses incurred for the infant's
treatment and care. Remaining questions such as whether the clinician
was grossly negligent or fraudulent "in failing to prevent the
patient and her husband from bearing a child, conceived through
in-vitro fertilization, that had cystic fibrosis" involved disputes
of important facts that could not be resolved in the context of
a motion for summary judgment. The court refused to rule out,
however, the possibility that, if successful, the plaintiffs might
ultimately be entitled to monetary losses resulting from the mother's
decision to stay home to provide special care to the sick child.
D. Professional Self-Regulation
The chief sources of guidance and regulation for the practice
of PGD and related activities the guidelines propounded by professional
societies. The American Society for Reproductive Medicine (ASRM)
provides guidance to clinicians who practice PGD and related activities.
Its practice committee has published extensive guidelines on the
practice of PGD, indicating that it should be treated as a clinical
(rather than experimental) procedure.vi
Thus, it may be practiced without oversight by an institutional
review board (IRB) or the substantial equivalent. Additionally,
the ethics committee of ASRM has published a report entitled "Sex
Selection and PGD"13
that deems sex selection in this context as ethically acceptable
for medical indications, but discourages purely elective use on
the grounds that it might promote gender discrimination and other
harms. It is not clear what is meant by the injunction to "actively
discourage" this use, but at the time of this writing there are
Society for Assisted Reproductive Technology (SART) member clinics
that advertise the use of PGD for elective sex selection, even
though SART requires, as a condition for membership, adherence
to ASRM guidelines, including ethics opinions.
A related ASRM ethics opinion, entitled "Preconception Gender
Selection for Nonmedical Reasons,"14
deals with sperm sorting for sex selection. It discusses the same
ethical concerns as in "Sex Selection and PGD" but reasons to
a different conclusion, namely, that such practices (achieved
through techniques such as Microsort) are ethically acceptable
for couples seeking "gender variety in their family, i.e., only
to have a child of the gender opposite an existing child or children,"vii
15 provided
couples understand the risks and affirm that they will accept
a child of the opposite sex, should the procedure fail. ASRM notes,
however, that the techniques for preconception sex selection are
experimental, and should be treated accordingly. The American
College of Obstetricians and Gynecologists echoes the views of
ASRM, declaring PGD for sex selection acceptable if it is for
medical indications, but rejects as unethical its use for purely
elective purposes.
The American Medical Association's Code of Medical Ethics explicitly
states that it is "unethical to engage in selection on the basis of
non-disease related characteristics or traits." None of these opinions
have more than hortatory power. In the absence of public policy
governing the permissible uses of the sex selection of children, it is
likely that a small number of medical specialists will continue to
engage in and perhaps normalize this practice.
The American College of Medical Genetics provides voluntary
guidelines for quality control and quality assurance of laboratories
performing genetic testing. It does not, however, regulate PGD
or related activities as such.
IV. Conclusion
While its use is now limited, the advent of PGD is significant.
PGD represents the first fusion of genomics and assisted
reproduction and the first reproductive technology that
allows would-be parents to screen and select the genetic
characteristics of their potential offspring, to a limited
but growing degree. It is striking that this new capacity
arrived with little fanfare-entering into routine practice
essentially unmonitored, unstudied, and unregulated. There
is now no governmental body, state or federal, monitoring
or regulating PGD.viii
There are no regulatory efforts to address the well-being
of children born after PGD or to assess the risks presented
to them by embryo biopsy. There are practice guidelines
issued by professional societies on the use of PGD for elective
sex selection, but these are statements of principle rather
than enforced standards.ix
There are also neither governmental nor nongovernmental
guidelines regarding the boundary between using PGD in efforts
to produce a disease-free child and using it in efforts
to select genetic traits that go "beyond therapy"-that is,
traits that are useful to older siblings or simply desirable
to the would-be parent.
_________________
FOOTNOTES
