Genetic testing of IVF embryos for Intelligence and Disease susceptibility

[Angelica Cheng]

Polygenic Embryo Screening: Ethical and Legal Considerations

Polygenic Embryo Screening: Ethical and Legal Considerations

Last month, Bloomberg reported on what seems to be the first child born following a new kind of genome-wide screening. Four embryos were screened, and the embryo selected for implantation was the one given the best genetic odds of avoiding heart disease, diabetes, cancer, and schizophrenia in...

www.thehastingscenter.org

Last month, Bloomberg reported on what seems to be the first child born following a new kind of genome-wide screening. Four embryos were screened, and the embryo selected for implantation was the one given the best genetic odds of avoiding heart disease, diabetes, cancer, and schizophrenia in adulthood. The test, called polygenic embryo screening, was performed by Genomic Prediction, a company in New Jersey.

The news has been met with concerns about the degree of control we may now have over future generations. While Genomic Prediction did not screen for intelligence or other non-disease traits, it is possible to do so, and this raises questions about eugenics and designer babies.

In this essay, we consider the ethical case for using polygenic scoring to select embryos that possess the best chance of a healthy life, as well as the need for regulation.

Polygenic embryo screening uses an algorithm to summarize the estimated effect of hundreds or thousands of genetic variants associated with an individual’s risk of having a particular condition or trait. It differs from more routine forms of embryo screening such as preimplantation genetic diagnosis (PGD), which detects single gene variants associated with a disease or trait. Polygenic scoring is not as precise as PGD, since it only represents an embryo’s risk of a particular condition or trait.

Polygenic embryo screening is essentially unregulated in most countries and is, therefore, available to prospective parents. Many countries that regulate genetic testing in general permit it only it for genetic disorders and conditions. In South Africa, for example, embryonic screening is governed by the regulations of the National Health Act. However, these regulations only specifically refer to one genetic trait – sex – and state that it can only be identified for purposes relevant to the health of the embryo. Since polygenic embryo screening itself is not regulated, parents may request it as an add-on the in vitro fertilization based on their right to make decisions concerning reproduction, or reproductive autonomy, which is guaranteed by the South African constitution.

Most European countries have legislation that restricts genetic testing to major diseases, such as beta thalassaemia. It is not clear whether an elevated probability of a disease would count. For example, in the United Kingdom, embryonic screening falls under the purview of the Human Fertilisation and Embryology Authority, which issues licences for preimplantation genetic testing. Licences are permitted to screen embryos against serious genetic diseases and sex-linked diseases, to identify tissue-compatible embryos, or to establish biological parentage.

Some concerns over using polygenic embryo screening are based on science. For instance, the score indicates the probable risk of a future child developing a certain condition, but it does not guarantee that this will be the case. Other concerns are based on ethics. If we consider one disease that polygenic embryo screening has been used for – heart disease – it is arguable that such screening is an extreme intervention. Heart disease is treatable and preventable; individuals can reduce their risk of heart disease through environmental management such as monitoring their diet. This raises the question of whether it is ethical to select against embryos with an increased probability of developing heart disease later in life when the condition can be managed. On the other hand, it can be argued that polygenic embryo screening would impact public health positively by reducing the burden on health care systems. It could be considered unethical not to use this technology as it would offer future generation the prospect of healthier lives. We may be morally obligated to check the polygenic risk scores of embryos and select the embryos with genetic traits that indicate the best prospect of quality of life.

Polygenic testing of embryos is currently offered by Genomic Prediction, MyOMe, and Orchid. It is available only to those with the ability to pay thousands of dollars. This raises the possibility of increasing inequality as the rich have babies with greater odds of good health and, potentially, other gifts and talents. However, increasing inequality is not inevitable. It is essential that, just as people have a right to basic health care, they also have a right to basic reproductive selection that is important to health and well-being. European countries are well placed to position this new revolution within state funded universal health care, but the demands of justice may be more difficult to meet elsewhere in the world.

Polygenic embryo screening has the potential to give babies a health advantage, but it may also be used to “score” embryos for social, or non-disease-based advantages. This raises the spectre of eugenics. For this reason, and to guard against misuse of the technology, broad discussion is needed around what advantages we would be prepared to allow to proliferate in future people. Some favor a regulatory model that would permit polygenic screening if it is correlated with increased odds of greater well-being. This would require a philosophical and ethical analysis of what constitutes well-being and a scientific analysis of the correlation between polygenic screening and that outcome. Societal discussion about these issues is necessary, too. Should genetic variants associated with diseases and non-disease traits be considered? Is there a difference, ethically, between justifying the selection of physical traits, such as eye color, and functional traits, such as intelligence, based on their potential to increase the well-being of a future person?

Regulation of polygenic embryo screening should explore these questions and address issues of justice and inequality. Crucially, regulators should make the technology broadly available, so that reaping its benefits does not depend on the ability to pay. Regulation should also ensure that screening that improves general health and well-being would be permitted.

 

[Angelica Cheng]

Polygenic Screening: What’s the use?

Polygenic Screening: What’s the use?

A theoretical framework predicts that using polygenic screening to select embryos against traits that depend on many genes has few benefits.

elifesciences.org

A theoretical framework predicts that using polygenic screening to select embryos against traits that depend on many genes has few benefits.

Using genetic tests to select ‘designer babies’ has been a subject of science fiction for generations, but it is now getting closer to becoming a reality. Like in many other areas of science, techniques are progressing much faster than ethical and policy discussions (Conley and Fletcher, 2017). Indeed, many parents already genetically screen embryos produced using in vitro fertilization (IVF) to avoid passing on genetic variants that are known to directly cause genetic disorders (Baruch et al., 2008).
However, the plummeting cost of genetic sequencing and the sophistication of the tools used to predict characteristics based on the genetics of an individual will soon make it possible to screen for ‘complex traits’ – this is, traits that depend on many genes. This type of analysis is called polygenic screening. In short, it assesses the probability of an embryo exhibiting a trait (such as a health condition) based on the collection of genetic variants it carries that are known to influence that trait. Polygenic screening could allow couples to produce several embryos through IVF, check how likely each one is to manifest one or several complex traits, and, based on that information, decide which embryo to implant. Unlike screening for conditions that depend on a single gene, however, polygenic screening cannot always guarantee that an embryo will manifest a condition. The traits that can be tested for using polygenic screening include many health outcomes, but also characteristics that are more controversial to target, such as the IQ of a future baby (Lázaro-Muñoz et al., 2021).
Now, in eLife, Todd Lencz (Zucker School of Medicine at Hofstra/Northwell and Northwell Health), Shai Carmi (Hebrew University of Jerusalem) and colleagues – including Daniel Backenroth (Hebrew University) as joint first author with Lencz – report on the usefulness of polygenic screening when testing for complex health traits, such as schizophrenia and Crohn’s disease (Lencz et al., 2021). Briefly, the utility of screening will depend on the predictive accuracy of the genetic tests performed and, more subtly, on the goal of the testing as well as the setting – that is, who specifically is being tested, and for what.
Lencz et al. largely take predictive accuracy as a given (but see Fletcher et al., 2021 for issues of accuracy), and employ a theoretical framework to ask deeper questions about the usefulness of several strategies that can be used when selecting embryos. First, Lencz et al. assume that a hypothetical couple produces several viable embryos via IVF. The probability of each of those embryos having a specific complex trait (for example, a given health condition) can be determined using polygenic screening. Based on these probabilities, the couple must then choose which embryo to implant. Starting from these assumptions, Lencz et al. compare the utility of different approaches to selection. Finally, Lencz et al. use genome data from schizophrenia and Crohn’s disease case-control studies to simulate virtual couples and their offspring and confirm their predictions.
Lencz et al. found that, in general, polygenic screening is not very useful when it targets complex health traits. This is because most selections occur between embryos with the same parents, which substantially limits both genetic and environmental variability. Thus, when selecting for specific characteristics, there is only a small number of possible outcomes, which reduces the usefulness of any selection regime. But, within this constraint, focusing on binary traits (for example, an embryo having or not having a disease) illuminates an important asymmetry in the utility of selection. Take, for example, the case of a couple having to select one of five embryos for implantation. The benefits of ruling out the one or two embryos with the highest risk scores, and then selecting from the remaining three or four embryos by chance are small. This is because although a couple is choosing at random between three embryos that do not have the highest risk of the disease, each of them could still be at a moderate risk of having the disease. Instead, a better strategy is to pick the embryo with the lowest risk score.
However, this result provides the first reason why parents, if they are well-informed, are unlikely to perform polygenic screening. Assuming that the negative attitudes most Americans have against enhancing traits through gene editing extend to genetic screening, parents are likely to want to screen embryos to avoid disease, but are probably against choosing the ‘best’ embryo (Scheufele et al., 2017).
Even if parents (counter to intuition) did want to choose the ‘best’ embryo, deciding which is the ‘best’ soon becomes an impossible task. Lencz et al. only consider the situation where parents are choosing between embryos more or less likely to exhibit one or two complex traits; but what happens when several traits, each dependent on many genes, are of interest? A decrease in the risk of one health condition, for example, could lead to an increase in the risk of another. Trading off risks between schizophrenia and Crohn’s disease would be difficult, but when other characteristics such as genetic risks for height, IQ, and eye color are thrown into the mix, the decision becomes impossible. This ‘paradox of choice’ is a second reason that parents will not choose polygenic screening if they are properly informed about it (Schwartz, 2004).
For both of these reasons, the analysis by Lencz et al. places critical focus on the lack of utility of genetic screening for complex traits, and the findings are an incredibly important contribution for science and for public and policy discussions. Nevertheless, a number of questions about the value of polygenic screening still remain. Lencz et al. answer the (constrained) question of which embryo to choose if you must choose one. Indeed, if there are five embryos with similar risks to pick from, Lencz et al. assume that parents will select one randomly. A related question is whether these parents should implant one of the five embryos they already have, or wait to use others. This may be answered using a method that predicts whether a couple are likely to produce a lower-risk embryo than the ones they already have, based on the parents’ genetic information (Chen et al., 2020).
An obvious next step will be to study actual couples (and not virtual couples as done by Lencz et al.) because couples in the real world are likely to be more genetically similar than couples chosen at random (Domingue et al., 2014; Conley et al., 2016). Like the selection question raised by Lencz et al., this use of polygenic screening opens a large set of ethical questions as well as questions about the utility of the approach that are not yet fully answered.

 

[Angelica Cheng]

Polygenic risk scores: lowering a child’s odds of disease, or a slippery slope to designer babies?

https://www.scmp.com/magazines/post-magazine/long-reads/article/3182739/polygenic-risk-scores-lowering-childs-odds

Simone Collins knew she was pregnant the moment she answered the phone. She was on her sixth round of in vitro fertilisation (IVF) treatments and had grown used to staffers at a Main Line Fertility clinic in the United States starting this kind of call with the words “Oh, hi, Simone,” in a subdued tone, voices brimming with sympathy.
This time, though, on Valentine’s Day, the woman on the other end belted out a cheery “Oh, hi, Simone!”
Embryo 3, the fertilised egg that Collins and her husband, Malcolm, had picked, could soon be their daughter – a little girl with, according to their tests, an unusually good chance of avoiding heart disease, cancer, diabetes and schizophrenia.
But this is not a story about designer babies. No genes were edited in the creation of Collins’ embryo. The promise, from dozens of fertility clinics around the world, is just that the new DNA tests they are using can assess, in unprecedented detail, whether one embryo is more likely than the next to develop a range of illnesses long thought to be beyond DNA-based predictions.

It’s a new twist on the industry-standard testing known as preimplantation genetic testing, which for decades has checked embryos for rare diseases, such as cystic fibrosis, that are caused by a single gene.

One challenge with leading killers like cancer and heart disease is that they are usually polygenic: linked to many genes with complex interactions. Patients such as Collins can now take tests that assess thousands of DNA data points to decode these complexities and compute the disease risks.

Genomic Prediction, the five-year-old New Jersey company that handled the tests for her fertility clinic, generates polygenic risk scores, predicting in percentage terms an embryo’s chances of contracting each disease in the panel, and providing a composite score for overall health. Parents with multiple embryos can weigh the scores when deciding which one to implant. They just might need to add a few grains of salt to the scale.

In general, the percentage differences from embryo to embryo are slight and could well be outweighed by the effects of environmental factors. But Genomic Prediction adds up all the genetic data into overall health scores that start at a baseline for average risk of zero, with risk declining as the score rises.
The embryo Collins and her husband selected had a score of 1.9, compared with a – 0.96 for their lowest-scoring embryo. Collins says that doesn’t feel minor to her. “It’s using the cutting edge of science to give your future children every advantage you can,” she says. “It’s giving kids a better roll of the dice.”

This new form of genetic embryo testing appears to move humanity one step closer to control of its evolution. The US$14 billion IVF industry brings more than 500,000 babies into the world each year, and with infertility rates rising, the market is expected to more than double this decade.


Companies including Genomic Prediction bet many going into that process have seen enough loved ones suffer from a polygenic disease to want risk scoring. “Everyone has someone in their family,” says CEO Laurent Tellier, whose mother has faced down multiple cancers. “Everyone.”

Ten years ago, it wasn’t clear this kind of risk analysis would ever be possible, let alone practical. Over the past decade, advances in genetic testing have improved the technology’s efficiency at a pace faster than that of computer chips. Some lower-level DNA sequencing costs as little as US$40 now, and your whole genome could soon be mapped for US$100, a fraction of today’s cost.

Massive global DNA repositories allow researchers to draw connections between certain genes and all manner of life outcomes. Some studies correlate genes with height; others, with how far a person is likely to go in school.

Genomic Prediction doesn’t offer scores on attributes unrelated to health, nor does rival Orchid, which is backed by Anne Wojcicki, the CEO of genetic testing giant 23andMe. But there are ways for motivated parents to get those kinds of predictions, and Collins and her husband did just that.
Although choosing your embryo based on its odds of earning a graduate degree is still a long way off from eugenics, or even from the gene-editing tool Crispr, it is decidedly more fraught than efforts to minimise cancer risks.

There’s some real daylight between the solid science behind polygenic scoring for disease risks and parental desires to pick the “perfect kid”. So as the science makes its way into leading peer-reviewed journals, it is yielding much more spirited debates than are usually seen in publications with names such as Fertility and Sterility.

In general, the true believers say polygenic risk scoring should be available and clearly offered to everyone. Critics say it is a slippery slope towards designer babies. Sceptics say both camps are overselling how much we really know about what the testing can show and stress that genetic predispositions don’t lead to linear outcomes.
Choosing your healthiest-seeming embryo, after all, can only tell you so much about even the genetic influences on a child’s life.

 

[Angelica Cheng]

Last autumn, Shai Carmi, a statistical geneticist at the Hebrew University of Jerusalem, published a study in the biomedical journal eLife that found that selecting an embryo with the lowest polygenic score for schizophrenia could reduce a future child’s risk by almost 50 per cent – with several important caveats.
“There is accumulating evidence, based on modelling and simulation and some real data from families, that there is potential for risk reduction,” says Carmi. “But there are very serious limitations and practical problems.”

Scores may not be as accurate as believed for all kinds of reasons – complex diseases are complex – and risk reductions may be lower in practice than modelling suggests, especially if parents have few embryos to choose from.

And this finding on disease risks did nothing, he says, to challenge his research from a 2019 study published in the journal Cell, where he concluded that polygenic testing would likely have little effect on height (maybe an inch) or IQ (a couple of points).
Still, he says, the disease-risk correlations are solid. More conservative critics argue even that data shouldn’t be attached to any grand promises until more definitive studies can be conducted over decades.

Genomic Prediction says its testing simply builds on well-established methods. While it is tracking patient outcomes for a formal study, the underlying technology is widely accepted and the mass genetic data uncontested.
“It’s just DNA,” says Nathan Treff, the company’s chief scientific officer. “We don’t have to wait for embryos to turn into adults, because we have the same information on adults that we get from an embryo.”
If the scientific community can’t reach a consensus on these issues, is it possible for parents-to-be, who just want the best for their children, to separate the truth about the limitations of polygenic risk scores from the rosy promises? Well, let’s hope so, because the most important thing about the scores, and one that’s inarguable, is that polygenic scoring is already here.

The initial process of polygenic embryo testing looks pretty comparable to the single-gene tests that have been around much longer. First, cells are drawn from an embryo a few days old, and the DNA is processed. Then proprietary software analyses the material, using data on hundreds of thousands of people, from DNA projects such as the UK Biobank, to translate genetic variations into odds for diseases.
Since its founding in 2017, Genomic Prediction has used mathematical methods rooted in physics to draw information from even tiny quantities of embryo DNA.
“These fancy methods are shown to actually work by looking at tens of thousands of real-world brother or sister pairs,” Tellier says, “and proving able to accurately predict which one has schizophrenia, or cancer, despite both being in the same family environment.”

So far, one of the company’s more striking findings is that desirable health-related genes often appear to cluster in one embryo while risks of illness cluster in another.
“It’s very cruel,” says Tellier, who was previously head of bioinformatics for a lab at BGI, China’s leading genomics company with headquarters in Shenzhen. “Some people are just born with the cards stacked against them in a lot of ways, and other people are just born with a lot of luck. This is all we can do – help stack those odds.”
On a recent Monday at its pristine headquarters in North Brunswick, New Jersey, lab supervisor Heather Garnsey performs the final steps in the scientific equivalent of a four-day recipe to extract usable genetic information from embryo cells. Her processes amplify the DNA to thousands of times its original volume and fragment it into tinier pieces so it can hybridise (attach) to a glass slide.

Tellier was previously head of bioinformatics for a lab at BGI. Photo: Genomic Prediction
Ultimately, she says, a laser reader interprets fluorescing spots on slides into the particular genetic codes present in the sample in each position.
Genomic Prediction charges US$1,000 in advance, plus US$400 per embryo analysed. When parents-to-be get the scorecard for their embryos, one of the company’s genetic counsellors talks them through what it means. The head counsellor, Jennifer Eccles, and her team begin by breaking down what the scores for overall health include.
They may also address specific risks tied to family histories of disease. In general, though, the early adopters who come their way are often less concerned about a specific disease and more about maximum data-gathering, she says. She calls this frame of mind “genetic forward”.

That certainly describes Collins and her husband. Both are authors whose education non-profit, the Collins Institute for the Gifted, promotes individualised teaching programmes for homeschool and boarding-school kids. They live in Pennsylvania with their two sons and want a big family. By the time they heard of polygenic risk scoring, they had spent US$20,000 a pop on five sets of IVF treatments.
“We actually did a new round of IVF after having already done five rounds just to get these tests,” Collins says. “That’s how desperately we wanted this data.”
They scrimped over months for treatments to generate many embryos and asked Genomic Prediction to analyse a dozen of them.

 

[Angelica Cheng]

Along with an overall health score, each embryo received a specific score rating its risk for both types of diabetes, several types of cancer, four heart-related conditions and schizophrenia. Genomic Prediction told them one of their embryos had a 1.61 per cent chance of schizophrenia, compared with a 1 per cent risk in the general population, while another embryo had just a 0.29 per cent risk.
Such data is useful not just for selection, Collins says, but for what many would consider an unusual style of parenting. “When you tell your kid not to smoke pot, it becomes a lot more meaningful when you can say, ‘You, personally, are way more at risk of developing schizophrenia than the general population,’” she says. “It’s about helping kids understand where they need to be careful.”
That wasn’t, however, where Collins and her husband wanted to stop. “What was most important to us was mental health and performance,” she says. “We have a lot more confidence in things like early cancer detection and treatment than in the ability to address things like brain fog and depression.”
https://www.scmp.com/news/hong-kong...nd-depression?module=hard_link&pgtype=article
Genomic Prediction doesn’t offer scores on cognitive function or height. It originally considered including findings on whether an embryo was likely to be intellectually disabled or in the bottom 1 per cent for height but dropped the idea. So the Collinses downloaded the raw embryo data from Genomic Prediction and exported it to the website of SelfDecode, a Florida company that analyses adult DNA, which they paid US$199 to use for a month.
Running the SelfDecode analysis on each of their embryos gave them assessments of far less tangible qualities, such as supposed capacity for stress management. They created a spreadsheet with each embryo’s scores, weighting them according to their desired mental health traits. Many differences were minuscule, but there were some outliers, according to the SelfDecode analysis.


It rated one embryo with a 91 per cent risk for chronically low mood, compared with a 21 per cent risk for another. All the cross-checking made the decision much easier, Collins says, because their top pick in terms of SelfDecode’s mental health assessment was also the embryo with the best Genomic Prediction scores for general health.
Collins says she and her husband didn’t seek to select against attention-deficit/hyperactivity disorder or autism because the conditions can correlate with some advantages, including raw intelligence.
“We’re a very neuro-atypical household,” says Collins, who’s been diagnosed with autism, as has one of her sons. “We feel like the world as it exists now is actually in some cases better adapted for autistic people.”
Genomic Prediction doesn’t encourage parents to seek outside insights on non-medical traits, Tellier says, but it is each customer’s right to have access to their embryos’ raw genetic data. He also wouldn’t discount the possible value of other correlations.
“A genome is a genome,” he says. “Almost any analysis is possible.” That includes analyses that raise more complex dilemmas. Studies suggest, for example, that higher odds of creativity correlate with higher odds for bipolar disorder. “Reducing the risk for one thing can also reduce the risk for good things that come with it,” says Eccles. “There’s a whole Pandora’s box we have yet to touch.”
Polygenic risk scoring is unlikely to face serious legal blowback in the US, where it would be generous to call the regulation of fertility treatments laissez-faire. That leaves parents-to-be vulnerable to companies that overpromise, says Michelle Meyer, a legal scholar and bioethicist at Geisinger Health System, in Pennsylvania. “At a minimum, you want people to know what they’re getting into,” she says.

Nathan Treff is the chief scientific officer of Genomic Prediction. Photo: Genomic Prediction
Critics of polygenic embryo testing argue that it could add unnecessary stress and confusion to the already difficult IVF process, leading parents to discard embryos unnecessarily.
This spring, the non-profit European Society of Human Genetics called polygenic risk scoring “premature at best”, noting that environment can dramatically affect genetic expression. It said more research is needed to understand how polygenic risk scores might be useful in medical treatment, including for adults.
“It will be vital that a societal debate takes place before any potential application of the technique,” the group wrote, “and this should be focused on what would be considered acceptable with regard to the selection of individual traits, in particular.”

In other words, the writers weren’t sure about the accuracy of the results but were nonetheless worried about eugenics-style selection – a concern The New England Journal of Medicine also flagged in a call for “an urgent society-wide conversation” on the subject last summer.
Treff says he’s game for broader debate. “It does require these big conversations,” he says. “There’s a lot of work there.”
In the May issue of Fertility and Sterility, he and Oxford ethicist Julian Savulescu argue that the real crime would be not offering their scores to everyone, because a lower chance of disease means a better life for a future child. “The lesson of the Nazi eugenics programme is that couples, not the State, should make their decisions about reproduction,” they wrote.

In December, Genomic Prediction doubled its venture funding to about US$25 million and says it will use the cash to expand and add to its testing panel. Boston IVF, one of the biggest fertility networks in the US, recently started offering Genomic Prediction’s polygenic testing to its patients, says CEO David Stern.
“Like anything else, you have early adopters,” he says. “We have had patients who worked in the biotech field or the Harvard milieu who came in and asked for it.”
Stern predicts that, like egg freezing, polygenic embryo testing will grow slowly at first, but steadily, and eventually demand will reflect the powerful appeal of lowering a child’s odds for disease.
https://www.scmp.com/news/people-cu...-window-world?module=hard_link&pgtype=article
The technology’s potential to exacerbate inequality isn’t lost on him. He already sees the gaps between a state such as Massachusetts, where fertility treatments are often covered by insurance, and California, where they often aren’t.
“That’s not fair,” he says, “and the same applies to this, where you create the potential that people who can afford it can now have children without this disease, but people who can’t afford it, can’t.”
The analysis also might not be as reliable for non-white people, because genomic data collected to date has tended to skew heavily towards people with European ancestry.
Believers such as Collins and her husband support government subsidies for fertility and parenthood but aren’t interested in any conversation about slowing down.
“This is about the people who care about giving their children every opportunity,” she says. “I do not believe that law or social norms are going to stop parents from giving their kids advantages.”

 

[Angelica Cheng]

Polygenic screening of embryos is here, but is it ethical?

Polygenic screening of embryos is here, but is it ethical?

The first child born using the technique arrived last year. But can it really help reduce diseases in a new generation, or is it ‘techno-eugenics’?

www.theguardian.com

A light micrograph showing embryo selection for in vitro fertilisation. Photograph: Science Photo Library/Alamy
The first child born using the technique arrived last year. But can it really help reduce diseases in a new generation, or is it ‘techno-eugenics’?

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.

Louise Brown, the first person conceived by in vitro fertilisation, in 1980. Once controversial, the use of IVF and PRSs to select certain traits may soon be seen as just another aspect of parenthood. Photograph: Jane Bown/The Observer
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.

Orchid Biosciences’ preconception screening kit, which can give couples thinking of having a baby some idea of what their offspring’s predisposition to certain conditions and diseases might be. Photograph: guides.orchidhealth.com
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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.

 

[Angelica Cheng]

“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.

Prof Stephen Hsu (right) with Boris Johnson’s former adviser Dominic Cummings on the steps of No 10 Downing Street. Photograph: Stephen Hsu/Twitter
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 in our hyper-competitive societies

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”.

 

[AVeryHonestPerson]

I was at KKH and I asked about some genetic testing, I was a step from Embro transfer.
The nurses seems frustrated and told me that all these tests were not necessary and only for those with genetic defect history, or under special conditions.

Where are all these tests done anyway?

 

[Angelica Cheng]

I was at KKH and I asked about some genetic testing, I was a step from Embro transfer.
The nurses seems frustrated and told me that all these tests were not necessary and only for those with genetic defect history, or under special conditions.

Where are all these tests done anyway?

Any reason why you want to do genetic tests - like to avoid Down syndrome in older mothers?