For better or worse, genetic testing of embryos offers a potential gateway into a new era of human control over reproduction. Couples at risk of having a child with a severe or life-limiting disease such as cystic fibrosis or Duchenne muscular dystrophy have used preimplantation genetic testing (PGT) for decades to select among embryos created through in vitro fertilization (IVF) for those that do not carry the disease-causing gene. But what new iteration of genetic testing could tempt healthy, fertile couples to reject our traditional time-tested and wildly popular process of baby making in favor of hormone shots, egg extractions and DNA analysis?
A California-based start-up called Orchid Biosciences claims it has an answer to that question. The company offers prospective parents genetic testing prior to conception to calculate risk scores estimating their own likelihood of confronting common illnesses such as heart disease, diabetes, and schizophrenia and the likelihood that they will pass such risks along to a future child. Parents-to-be can then use IVF, along with Orchid’s upcoming embryo screening package, to identify the healthiest of their embryos for a pregnancy.
Orchid aims to use PGT and IVF to expand what is already a thriving marketplace in screening tests for prospective parents. Initially, the only people offered tests to prevent genetic disease in the next generation were those whose ancestry put them at higher risk for a specific condition, such as Tay-Sachs disease in the Ashkenazi Jewish population. The first genetic screen intended for universal use and covering a wide range of diseases was introduced by Counsyl (now part of Myriad Genetics) in 2010. Today carrier screening is a $1.7-billion industry. These tests search for genetic problems that otherwise come to light only after the birth of an affected child. But diseases caused by a single gene are rare. Most children are born healthy, and most couples who do carrier screening come away reassured.
By contrast, Orchid’s risk assessment includes common diseases, ensuring that a high percentage of prospective parents who do this version of preconception testing will find something to worry about. Those who choose to act on their concerns will soon have the option of paying for IVF plus Orchid’s embryo-testing package. According to its promotional materials, the company will provide a scorecard intended to identify, among various embryos, the future children least likely to develop heart disease, breast cancer, prostate cancer, type 1 or 2 diabetes, and five other conditions that make up Orchid’s current common disease risk portfolio.
With a marketing strategy that encourages routine use of IVF for those who can afford it, Orchid breaks new ground in introducing the first—but likely not the last—consumer-driven model of human reproduction. The ambitions of this new Silicon Valley venture into health care are backed by the imprimatur of health-tech luminaries, including 23andMe co-founder and Orchid investor Anne Wojcicki. Orchid’s first product on the market is its “Couple Report,” at a cost of $1,100. Phase two, scheduled for launch later this year, examines embryos conceived by IVF, allowing the couple to pick and choose among potential children in a process that Orchid CEO Noor Siddiqui, speaking in an interview on the podcast Mendelspod in April, referred to as “embryo prioritization.” Siddiqui is a former Thiel Foundation Fellow whose interests lie in the use of technology in medicine. She did not respond to repeated requests for an interview from Scientific American.
Geneticists have greeted Orchid’s launch with skepticism, in large part because of objections to the company’s use of a technique called polygenic risk scores to assess an embryo’s lifetime risk of common diseases. Heart disease runs in families just like musical ability or height, but only in exceptional cases can the inherited risk be traced to a single gene. Hundreds or even thousands of genes each contribute in a small way. Polygenic risk scores attempt to sum up the overall likelihood of a particular outcome—such as getting a disease—by simply observing which patterns of variation in a genome are associated with a higher or lower probability of having the condition. In other words, this method gives us information about who might be more or less likely to get sick without explaining why. The statistical association is real but hardly definitive, and it tracks population-level trends that may not be relevant for the individual in question.
Researchers who work with polygenic risk scores are concerned about their use in this context. “We don’t know what these variants are doing biologically,” says Peter Kraft, a professor of epidemiology and biostatistics at the Harvard T. H. Chan School of Public Health. “Something that’s associated with a decreased risk of breast cancer could be associated with all other kinds of things, some of which might actually increase your risk of something else. We just don’t know enough yet.”
Some version of prenatal planning as envisioned by Orchid may be possible eventually, but few experts seem to share their optimism that today is that day. A July 1 special report in the New England Journal of Medicine pointed out the inherent weakness of using polygenic risk scores to distinguish among sibling embryos—which, unlike random individuals in a population, will be identical in 50 percent of the genetic variation that is examined to generate a score. The report concluded with recommendations on how to convey any purported benefits from polygenic scores in embryo selection responsibly—and the need to emphasize the underlying uncertainties in the data. “Any one of the issues discussed in this article would be difficult to communicate accurately—even to other scientists and clinicians,” the authors noted. “Collectively, these issues constitute a formidable challenge for [companies selling these services], which must ensure that their customers understand what they are doing.” The report also called for the Federal Trade Commission to look carefully at claims made by any company using polygenic scoring to pick embryos.
Current polygenic risk scores have limited predictive strength and reflect the shortcomings of genetic databases, which are overwhelmingly Eurocentric. Alicia Martin, an instructor at Massachusetts General Hospital and the Broad Institute of the Massachusetts Institute of Technology and Harvard University, says her research examining polygenic risk scores suggests “they don’t transfer well to other populations that have been understudied.” In fact, the National Institutes of Health announced in mid-June that it will be giving out $38 million in grants over five years to find ways to enhance disease prediction in diverse populations using polygenic risk scores. Speaking of Orchid, Martin says, “I think it is premature to try to roll this out.”
In an interview about embryo screening and ethics featured on the company’s Web site, Jonathan Anomaly, a University of Pennsylvania bioethicist, suggested the current biases are a problem to be solved by getting customers and doing the testing. “As I understand it,” he said, “Orchid is actively building statistical models to improve ancestry adaptation and adjustments for genetic risk scores, which will increase accessibility of the product to all individuals.”
Still, better data sets will not allay all concerns about embryo selection. The combined expense of testing and IVF means that unequal access to these technologies will continue to be an issue. In her Mendelspod interview, Siddiqui insisted, “We think that everyone who wants to have a baby should be able to, and we want our technology to be as accessible to everyone who wants it,” adding that the lack of insurance coverage for IVF is a major problem that needs to be addressed in the U.S.
But should insurance companies pay for fertile couples to embryo-shop? This issue is complicated, especially in light of the fact that polygenic risk scores can generate predictions for more than just heart disease and cancer. They can be devised for any trait with a heritable component, and existing models offer predictions for educational attainment, neuroticism and same-sex sexual behavior, all with the same caveats and limitations as Orchid’s current tests for major diseases. To be clear, tests for these behavioral traits are not part of Orchid’s current genetic panel. But when talking about tests the company does offer, Siddiqui suggested that the ultimate decision makers should be the parents-to-be. “I think at the end of the day, you have to respect patient autonomy,” she said.
Despite Orchid’s hard lean into parental free choice, bioethicists such as Gabriel Lázaro-Muñoz of the Center for Medical Ethics and Health Policy at Baylor College of Medicine worry that Orchid’s system of ranking embryos may unduly influence prospective parents and replace a very necessary broader societal debate on what qualifies as a good life. It is problematic for that reason, according to Lázaro-Muñoz, to have these companies “bias the conversation.”
Lurking in the background of every discussion on embryo selection and ethics is the specter of eugenics. “I think we have to be very aware of our history,” Lázaro-Muñoz says, “in terms of sterilization and state-mandated programs in the past that were aimed at ... exterminating individuals with some of these conditions.”
Clearly Orchid anticipates pushback. The company’s promotional materials include guides to fertility planning and the genetics of irritable bowel disease but also a set of talking points for concerned relatives described as “How to respond to your family skeptics—playing God, designer babies, and genetic enhancement.”
“Yes, we’re going there,” the guide says. Ethics? Bring it on. This is not a company in a defensive crouch. The “Our Principles” section of its Web site positions genetic testing as a human right. “From a reproductive freedom perspective, we stand for a couple’s right to have access to information that enables them to mitigate disease risk for their future child,” it says. Like other Silicon Valley health care technology pioneers, Orchid presents itself less as a product than as a social justice movement with a little commercial venture on the side, like a gift shop.
Orchid dismisses suggestions from detractors that its marketing oversells what polygenic risk scores have to offer in the context of screening embryos. “Parents are asking for this information and deserve to know it,” Siddiqui told Mendelspod, warning that those who stand in the way are “frankly being a little bit paternalistic.” And if prospective parents are not asking, Siddiqui suggested, perhaps they should be. When it comes to the next generation, “we’ve been sort of just rolling the dice,” Siddiqui said, while “the ability to actually stack the odds against disease is ... sort of a new capability that humanity has just gotten online.”
The suggestion that embryo selection is not only something people can do but something they should do raises perhaps one of the thorniest ethical issues of all. In the Mendelspod interview, Siddiqui drew a contrast between “earned” and “unearned” bad luck. “You can get hit by a car, right? That’s totally out of your control. But what is earned bad luck?” she asked before answering her own question. “I mean, that’s the idea of … you’re going base jumping constantly, and then you break your leg…. You kind of exposed yourself to higher risk there.”
Ultimately, if technology allows Orchid to offer a product that meaningfully reduces the risk of disease susceptibility in the next generation, does that mean that anyone who can’t or won’t use it deserves their bad luck? If the basic, no-frills version of human reproduction comes to be seen as a form of careless parenting, it invites a callous parsing of who does and does not deserve their fate—and, by extension, who does and does not deserve resources and support.