The birth of the first IVF baby, Louise Brown, in 1978 provoked a media frenzy. In comparison, a little girl named Aurea born by IVF in May 2020 went almost unnoticed. Yet she represents a significant first in assisted reproduction too, for the embryo from which she grew was selected from others based on polygenic screening before implantation, to optimise her health prospects.
For both scientific and ethical reasons, this new type of genetic screening is highly controversial. The nonprofit California-based organisation the Center for Genetics and Society (CGS) has called its use here “a considerable reach by the assisted-reproduction industry in the direction of techno-eugenics”.
The polygenic screening for Aurea was provided by a New Jersey-based company called Genomic Prediction. The gene-sequencing company Orchid Biosciences in California now also offers an embryo-screening package that assesses risks for common diseases such as heart disease, diabetes and schizophrenia.
Genetic screening of IVF embryos for health reasons, known as preimplantation genetic diagnosis or PGD, is not new in itself. In the UK, it is permitted by the Human Fertilisation & Embryology Authority (HFEA), which regulates assisted conception technologies, to look for specific gene variants associated with around 500 diseases, including cystic fibrosis and Tay-Sachs disease.
The diseases conventionally screened with PGD are mostly caused by a mutation in only a single gene. They can be nasty but are typically rare. In contrast, most common health problems, such as heart diseases or type 2 diabetes, are polygenic: caused by complex interactions among several, often many, genes. Even if particular gene variants are known to increase risk, as for example with the BRCA1/2 variants associated with breast cancer, such links are probabilistic: there’s no guarantee that people with that variant will get the disease or that those who lack it will not.
That’s simply how most genes work: in complex, interconnected and often poorly understood ways, so that the gene variants an individual carries don’t guarantee which traits they will develop. And environmental factors such as upbringing and diet, as well as unpredictable quirks of embryo development, also have a role. We’re products of (genetic) nature, nurture, chance and an interplay between all three.
Yet the availability today of genetic data for many thousands of individuals, thanks to the plummeting costs of genome sequencing and the popularity of genomic profiling companies such as 23AndMe and Orchid, has transformed our understanding of how genes relate to traits. The technique known as a genome-wide association study (GWAS) can sift through vast databanks to look for statistical associations between an individual’s gene variants and pretty much any trait we choose. Such studies have found that often substantial amounts of the differences between individuals can be linked to different variants (alleles) of many genes. Each gene might contribute only a tiny effect – too small to be apparent without plenty of data - but added together, the influence of the genes can be significant.
So someone’s genetic profile – the variants in their personal genome – can be used to make predictions about, say, how likely they are to develop heart disease in later life. They can be assigned a so-called polygenic risk score (PRS) for that condition. Aurea’s embryo was chosen because of low PRSs for heart disease, diabetes and cancer. PRSs can be used to predict other things too, such as a child’s IQ and educational attainment.
But such predictions are probabilistic, both because we can’t say exactly how our genes will “play out” in influencing that trait and because genes aren’t the only influence anyway. So there’s nothing inevitable or deterministic about a PRS. An individual with a high PRS for skin cancer might never develop it, while someone who scores low might do so. Someone with a genetic profile that predicts a modest IQ might turn out to be brilliant.
This is one reason why using PRSs in embryo screening – which is legal and largely unregulated in the US – is controversial. Unlike single-gene diseases, where the health outcome can be almost certain, it’s not clear how much faith we can put in predictions for polygenic traits. Yet we make choices based on probabilities all the time. We can’t be sure that a particular school will be best for our child’s education, but we may decide it will improve the chances of a good outcome. If one embryo has low PRSs for common diseases and another has high ones, doesn’t it make sense to pick the first? Aurea’s father, North Carolina neurologist Rafal Smigrodzki, has argued that part of a parent’s duty “is to make sure to prevent disease” in their child. Polygenic testing, he says, is just another way of doing that.
Embryo screening is already used for BRCA1 and 2, even though it is by no means certain that women who carry them will develop breast cancer. Advocates of PRS screening say that it merely improves the risk assessment by widening the genetic factors considered. “Most families with a history of breast cancer do not carry the BRCA allele and would benefit from polygenic screening,” says Genomic Prediction’s founder, Stephen Hsu, a professor of physics at Michigan State University. “The potential public health benefits are huge.” Ethics philosophers Sarah Munday and Julian Savulescu have argued in favour of allowing polygenic screening for any trait that can be shown to be “correlated with a greater chance of a life with more well-being”.
“There’s a scientific basis to the concept [of PRSs] and it’s a type of genetic assessment that has a future in medicine,” says bioethicist Vardit Ravitsky of the University of Montreal. Yet most regulators and many experts feel that there is not yet any justification for using them to try to improve the health outcomes of IVF children. “It’s not seen as ready for primetime use,” says Ravitsky. “It’s still at a research stage. So when you start jumping straight into implementation, especially in a reproductive context, you’re in a minefield.” An article in the New England Journal of Medicine in July pointed out that benefits of PRS embryo selection are likely to be very small, all the more so for people not of European heritage, for whom genomic data are less extensive and so less reliable for prediction.
“If PRS gives you the power to reduce your offspring’s lifetime risk of type 2 diabetes from 30% to 27%, is that worth the time, money, and emotional investment?” asks bioethicist Hank Greely of Stanford University in California. “And to whom?” That’s very different, he says, from the confidence with which single-gene diseases can be screened and avoided.
And once such screening methods are permitted, where does it stop? Already, American couples can screen embryos for gender, complexion and eye colour. What’s to stop a company offering to screen for a non-disease trait such as height or intelligence? “There’s no reason to think polygenic embryo screening will end with conditions like heart disease and diabetes,” says Katie Hasson, associate director of the CGS. “Screening for schizophrenia and other mental illnesses is already on offer. These directly echo eugenic efforts to eliminate ‘feeble-mindedness’. We are talking about deciding who should be born based on ‘good’ and ‘bad’ genes.”
Genomic Prediction has previously offered to screen for gene variants associated with “intellectual disability”, but Hsu stresses that now the company only offers the service for serious disease risks. “We decided that traits like height and cognitive ability are too controversial and detract from our ability to help families reduce disease risk,” he says.
It’s not clear that screening for such non-disease traits would work anyway. “I think the things that parents are most interested in, like intelligence, sports and musical ability, will have extremely small to nonexistent convincing PRS results,” says Greely. A study in 2019 suggested that using polygenic screening to select embryos for height and IQ would be likely to make only a tiny difference on average – and there’s a fair chance you wouldn’t end up picking the “best” embryo.
So what should be permitted? Hsu says: “We hope that in the future, society as a whole, perhaps on a nation-by-nation basis, will reach a consensus on which non-disease traits are acceptable for embryo screening.” Some have objected to his implication that, say, welfare dependence or criminality are “in the genes”. Hsu has also attracted controversy because of his comments on whether there are genetically based differences in IQ between racial groups, although he says he is “agnostic” on the issue. An outcry about his remarks on such matters compelled him to resign in 2020 as his university’s senior vice-president of research and innovation.
Hsu was also one of the scientists suggested by Dominic Cummings to run the UK’s new Advanced Research and Invention Agency. In 2014, Cummings blogged about how the NHS should cover the cost of selecting embryos for IQ; in 2019, he was pictured outside 10 Downing Street with Hsu.
To avoid any Gattaca-style genetic stratification of society, Hsu has expressed the hope that “progressive governments will make this procedure free for everyone”. But Hasson believes that this wouldn’t solve the problems of inequality that such techniques could exacerbate. Even if PRSs for smartness, say, have little real predictive value, she says that “belief in genomic predictions can itself be a driver of intense inequalities in society” by reinforcing ideas of genetic determinism. “Families that invest their money, time and hopes in this kind of screening and selection will have children they believe are genetically superior and those children will be treated as superior by their parents, care-givers and educators.”
Social pressure could make it hard to resist polygenic screening if it’s on offer in our hyper-competitive societies. “Once you do IVF, you feel pressure to use any add-on service or test that the clinic offers you,” says Ravitsky. “Look at what happens today when a woman declines prenatal screening or amniocentesis. Many women feel judged, not just by peers but by healthcare providers.” The idea that it’s all about autonomy of choice can be an illusion, she says.
Even if PRSs have little real value in forecasting the prospects of a child, evidently a market exists for them. In countries such as the US where assisted conception is weakly regulated, companies can make unrealistic and exploitative promises. Couples might even elect to have a child via IVF specifically to avail themselves of such opportunities. It’s a gruelling process that carries risks in itself, but women might feel compelled to use it, even though Ravitsky thinks that allowing someone to do so for this reason alone would be “borderline malpractice”.
Yet the genie is out of the bottle. “I believe that polygenic screening will become very common in the near future,” Hsu says. “Reasonable people will wonder why the technology was ever controversial at all, just as in the case of IVF.” The HFEA is still considering its implications, says its chief executive, Peter Thompson, who stresses that it is currently illegal in the UK. Even if there were more scientific consensus about the value of PRSs, he adds, “there is an important distinction between embryo selection to avoid serious harm and for so-called ‘enhancement’, like greater intelligence. The latter would represent a fundamental public policy shift.” It raises a range of ethical concerns and could only be contemplated if it has the backing of society more generally, he says.
“We urgently need public and policy conversations about polygenic embryo screening,” says Hasson. Finding the right balance between autonomy and social responsibility is the fundamental dilemma of liberal democracies. “We let people spend their money, and make decisions powerfully affecting their kids, on far more clearly bogus information than PRS,” says Greely.
“As a society, we’re very far from knowing how we want to use these potential technologies,” says Ravitsky, but, she adds, “we are already living in the grey zone”.