Embryo selection

Embryo selection is the practice of testing embryos created by in vitro fertilisation and choosing which ones to transfer to a uterus. It is the only form of genetic choice over offspring in routine clinical use anywhere, and it is the concrete reality behind most of what is discussed under the heading of Designer babies. What it can deliver depends almost entirely on whether a trait is determined by a single locus or by thousands, a distinction public debate consistently underweights.

§The four tests

Preimplantation genetic testing is now named by what it looks for. The current names were standardised in the late 2010s and replaced the older PGD and PGS labels.

• PGT-M, for monogenic disease. Where the parents' variants are known, embryos can be genotyped for the disease allele alongside linked markers from family members, which guards against amplification failure. Accuracy is high, and PGT-M is the uncontested core of the technique.
• PGT-SR, for structural rearrangements. Carriers of balanced translocations produce a high proportion of unbalanced embryos; testing identifies them.
• PGT-A, for aneuploidy. It screens for the wrong number of chromosomes, on the assumption that transferring euploid embryos raises live-birth rates. It is widely sold and the least well supported of the four.
• PGT-P, for polygenic scores. It ranks embryos by predicted risk of common disease or by the predicted value of a complex trait. A small number of commercial laboratories offer it, and no major professional society endorses it for clinical use. It has its own article at Polygenic embryo screening.

The physical procedure is the same in each case: five to ten cells are removed from the trophectoderm of a day-5 or day-6 blastocyst, the portion that becomes placenta rather than fetus, and their DNA is amplified and sequenced. The embryo is vitrified while the result is awaited.

§Origins

The first births followed embryo biopsy in 1990, when a team led by Alan Handyside amplified a Y-specific sequence to identify female embryos for couples carrying X-linked disorders.¹ Sex was a proxy. Testing for the disease allele itself followed within a few years, as PCR and later array and sequencing methods improved.

Two cases did more to shape public understanding than the technique itself. In 2000, preimplantation testing was used both to avoid Fanconi anaemia and to select an embryo whose tissue type matched an affected sibling, so that cord blood from the resulting child could treat her.² In 2008 the United Kingdom legislated on the practice explicitly, permitting tissue-type matching under licence and prohibiting the deliberate preference of an embryo known to carry a serious abnormality over one that does not.

§Why PGT-A is contested

PGT-A is performed on a large share of IVF cycles in some markets, yet the evidence that it improves outcomes is weak. A multicentre randomised trial published in 2019 found no improvement in ongoing pregnancy rate per patient randomised, with a possible benefit in a subgroup of older patients in per-protocol analysis.³ A subsequent randomised trial in China, restricted to patients with several good-quality blastocysts, likewise failed to show superiority over conventional morphological selection on cumulative live-birth rate.⁴

The mechanistic explanation is that a biopsy samples only part of the embryo. Trophectoderm cells can be aneuploid while the inner cell mass is not, and blastocysts classified as mosaic have produced healthy children after transfer.⁵ Because the test leads to some embryos being discarded, a screen with imperfect predictive value can reduce the number of transfers without improving the odds of any one of them. Overdiagnosis in cancer screening and in direct-to-consumer testing has the same statistical structure.

A test's accuracy is not its clinical value

PGT-A reliably measures chromosome copy number in the sampled cells. Whether acting on that measurement produces more babies is a separate claim. It is what patients are paying for, and the randomised evidence does not support it.

§The arithmetic that caps the gain

Selection can only choose among embryos that exist, and each embryo recombines two genomes the parents already have. Two constraints follow from this.

The first is supply. A stimulation cycle in a patient under 35 commonly yields a handful of usable blastocysts; the number falls with age, and many cycles in patients over 40 yield none. Selection therefore operates on a small sample.

The second is variance. Full siblings share about half their genomes, so the spread of any polygenic trait within one couple's embryos is much narrower than the spread across the population. Modelling by Ehud Karavani and colleagues estimated that choosing the top-scoring of ten embryos would shift adult height by roughly two and a half centimetres and a cognitive test score by a comparable number of points on average, with the realised gain in any individual case varying widely and sometimes being negative.⁶ Predictive scores also perform substantially worse within families than across populations, because much of their apparent accuracy comes from population structure and indirect parental effects rather than from the embryo's own genotype.⁷

Better technology would not remove these limits. Improved prediction narrows the gap between realised and theoretical gain, but sibling similarity and the number of embryos set the theoretical gain itself. Only In vitro gametogenesis, by supplying far more embryos, would loosen the second constraint, and even then the return diminishes sharply: a hundredfold increase in the number of embryos available is worth less than a doubling of the expected shift. The consequences of that ceiling for cognitive traits specifically are worked through in Genetic enhancement of cognition.

Embryo supply also interacts with a separate question about what an embryo is. Stem-cell-derived structures of the kind described in Stem-cell-based embryo models are not products of fertilisation and could not be transferred, but they are increasingly used to study the developmental stages that selection is implicitly betting on.

§Objections

Disability rights. The expressivist objection, developed most fully by Adrienne Asch, holds that selecting against an embryo on the basis of a trait expresses a judgement about existing people with that trait. The judgement is not that a particular life would be bad; it is that a life like theirs is not worth starting.⁸ The counterargument distinguishes preventing an impairment from devaluing a person, and points out that parents routinely act to reduce their future children's risks without insulting anyone. Deaf and autistic community positions on screening are among the sharpest cases and are examined in Disability rights and enhancement.

Scope creep. Jurisdictions differ on non-medical sex selection, on testing for adult-onset and incompletely penetrant conditions such as BRCA1 variants, and on saviour-sibling matching. Each extension has been argued for as a small step from the last. Critics call that structure a slippery slope; defenders call it ordinary case-by-case reasoning. The licensing model used in the United Kingdom, where a regulator approves conditions one at a time, is the main institutional alternative to leaving the question to clinics; the broader regulatory picture is set out in Governance of human genome editing.

Whether choosing is obligatory. Julian Savulescu's principle of Procreative beneficence holds that parents who are already selecting have reason to select the embryo expected to have the best life, which turns a permission into a weak duty. Critics within Bioethics of enhancement object both to the ranking this requires and to the assumption that expected welfare can be read off a genotype.

Access. An IVF cycle with genetic testing costs more than most health systems will reimburse for a non-infertile couple, which places selection among the technologies analysed in Access and inequality. Unlike heritable Human germline editing, it is legal nearly everywhere, so cost rather than law is the binding constraint.

Information asymmetry. Reports generated by commercial polygenic services convey risk reductions that are small in absolute terms and are difficult to interpret without training. Professional societies are concerned less that a transfer decision will harm patients than that patients will make it on a misunderstanding of what the number means, a problem that also runs through Genetic discrimination and consumer genomics generally.

§Where it sits among the alternatives

Selection is often discussed as an early form of embryo editing, but the two are different capabilities. Selection cannot introduce an allele neither parent carries and cannot exceed the best combination those two genomes can produce. Editing can in principle do both, at the cost of the mosaicism and off-target damage demonstrated badly in the He Jiankui affair. For the narrow set of couples where selection fails outright, such as one parent homozygous for a dominant disease allele or both homozygous for a recessive one, editing is the only genetic option, and that is the strongest medical argument for it.

Mitochondrial replacement therapy occupies a third position, replacing an organelle rather than selecting or editing nuclear DNA, and for many mitochondrial conditions selection among embryos with variable heteroplasmy is a competing and simpler option.

A further consideration is timing. Testing an embryo competes with testing a fetus, and non-invasive prenatal screening from maternal blood already detects common aneuploidies in ordinary pregnancies at far lower cost, which is why embryo selection remains concentrated among couples who are using IVF anyway or who carry a known variant.

The technical direction most likely to change practice is non-invasive testing rather than more sensitive sequencing. In non-invasive testing, cell-free DNA is recovered from the medium the embryo was cultured in, using the same chemistry that underpins the liquid biopsies described in Nanoscale diagnostics. It would remove the biopsy, which is not risk-free, but its concordance with trophectoderm biopsy has so far been too inconsistent for it to move beyond research use into the clinic.

§See also

• Polygenic embryo screening
• Designer babies
• In vitro gametogenesis
• Human germline editing
• Mitochondrial replacement therapy
• Procreative beneficence
• Disability rights and enhancement
• Reproductive longevity

§References