by Emily Mullinarchive page
April 21, 2021
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A new startup called Orchid is offering the chance for couples planning a pregnancy to learn their odds of passing on risks for common conditions like Alzheimer’s, heart disease, type 1 and 2 diabetes, schizophrenia, and certain cancers to their future child.
Existing pre-conception tests, which are widely available, can tell parents whether their children could have certain inherited disorders that are caused by mutations in a single gene. But such single-gene disorders, which include cystic fibrosis, sickle-cell disease, and Tay-Sachs, are relatively rare.
Orchid’s test, by contrast, looks at far more common diseases that are influenced by some combination of multiple genes, often numbering in the hundreds. Couples take the test at home by spitting into a tube and mailing it in. The company sequences the genomes of each parent and uses data sets of people with and without these diseases to calculate their risks. The result is known as a polygenic risk score.
Later this year, the startup also plans to begin offering embryo testing, which will involve extracting a few cells from embryos created by in vitro fertilization, sequencing their DNA, and generating similar risk reports. Couples undergoing IVF can already get their embryos tested for chromosomal abnormalities and single-gene disorders, but the Orchid test would greatly expand the list.
The company launched this month with backing from Stanford scientists and $4.5 million in funding from investors, including from Anne Wojcicki, the CEO of 23andMe, which supplies consumer genetic tests.
“Having children is the most consequential choice most of us make, yet parents go into pregnancy with zero visibility into how genetic risks could impact their future child,” Noor Siddiqui, Orchid’s founder and CEO, said in a press release.
Siddiqui, a Stanford graduate and computer scientist, sees it working this way: A couple learns that they’re at high risk of having a baby with diabetes. They can then use that information to mitigate their child’s risk. That could mean adopting a low-sugar diet or getting regular health screenings. Another option would be to pursue IVF and use Orchid’s test to select the embryo with the lowest risk of diabetes.
The testing could be an attractive prospect, especially for couples with a family history of diabetes, schizophrenia, or one of the other conditions that Orchid looks for. But the genetics behind many of these conditions are complex and still poorly understood.
For that reason, many experts think polygenic risk scores aren’t yet ready for prime time, and they worry that companies like Orchid may be overselling the technology to anxious couples.
Beyond single genes
The introduction of polygenetic consumer tests seems all but inevitable: generating risk scores for schizophrenia and other complex conditions is getting better thanks to an explosion in the amount of DNA data available. Using vast genetic databases of hundreds of thousands of people, researchers are developing algorithms to estimate a person’s risk for diabetes, depression, obesity, and certain cancers.
Another startup, Genomic Prediction, began offering polygenic risk reports in 2019, testing embryos for couples undergoing IVF. The company provides risk reports for some of the same multi-gene conditions as Orchid.
Amit V. Khera, a cardiologist at Massachusetts General Hospital and the Broad Institute who’s developed polygenic risk scores for heart disease and other conditions, says these scores could help adults mitigate their own risks by doing things like changing their diet or exercising more. But he doesn’t think the scores are ready to be deployed for preconception and embryo screening without further consideration.
For one thing, Khera says, there’s only so much risk you can eliminate when choosing among embryos that come from the same parents.
“For any two parents, the difference in risk between embryos is not going to be that big,” he says. “If my score is 0 and my wife’s score is 1, on average my kid’s score is going to be around 0.5. You might be able to find a 0.4 or 0.6 embryo, but they’re not going to be that different.”
Plus, Khera says, there are lots of genetic variants that researchers just don’t understand yet. His group has found variants that seem to protect against heart attacks but increase the risk of diabetes. In other words, there are genetic trade-offs.
Orchid’s test could also lure parents into a false sense of security that their future children won’t develop a particular disease. For instance, Patrick Sullivan, director of the Center for Psychiatric Genomics at the University of North Carolina, Chapel Hill, says that while genetics play a role in schizophrenia, the disease is often not inherited.
“The highest risk factors we get from schizophrenia are generally de novo variants, meaning neither parent has them,” he says. “This is a mutation that develops in the making of the child. It’s a random event.” These de novo mutations wouldn’t show up on a couple’s risk report generated by Orchid. They would on an embryo report, but that would require couples undergoing IVF and embryo screening.
Another limitation of current polygenic risk scores is that the data sets they rely on include mostly people of European ancestry. Historically, genetic studies haven’t included people of diverse backgrounds.
“You’re going to lose accuracy when you take those scores and try to use them on other groups,” says Genevieve Wojcik, a genetic epidemiologist at Johns Hopkins.
Picking your best embryo
As polygenic scores get more accurate, embryo selection may offer a chance to reduce the prevalence of certain common diseases. But there is a more controversial prospect.
The same techniques geneticists use to predict these diseases can be also be used to predict characteristics like intelligence or weight in adulthood. For now, Orchid is focused on providing disease risk reports to parents, but Genomic Prediction of New Jersey already screens embryos for “intellectual disability.”
Gabriel Lázaro-Muñoz, a bioethicist and lawyer at Baylor College of Medicine who has studied polygenic risk scores, says the ability to screen and select embryos for a wide range of traits veers into eugenics territory. “We have to have a serious conversation about how to use this technology in our society,” he says.
Negative attitudes about mental illness are already pervasive, and polygenic risk tests could further stigmatize these conditions. The idea that it’s possible to choose whether or not to reduce a future child’s risk of such conditions puts a lot of pressure on parents, he says. Beyond the issue of mental illness, should parents be able to choose their “smartest” embryo?
And even if couples wanted to pursue polygenic screening, the expense could be prohibitive. Orchid hasn’t publicly released the cost of its tests, but one source told MIT Technology Review that it charges $1,100 for its couple report. (Orchid did not respond to multiple interview attempts.) While the company is offering a financial assistance program to couples who can’t afford it, there’s still the price of IVF to consider. One IVF cycle costs $12,000 to $17,000, and getting pregnant often takes several cycles.
“This is reproduction for rich people,” says Laura Hercher, a genetic counselor and director of research in human genetics at Sarah Lawrence College. “What they seem to be saying is, everyone who can afford it should do IVF.”
Indeed, in a podcast interview Siddiqui suggested that more couples should use IVF to choose their healthiest embryos.
Hercher and others wonder whether that’s the best use of polygenic risk scores. “Are we comfortable with saying ‘Let the market decide what things we want to test embryos for’?” Hercher asks. “Or is time to step in and say ‘Are all uses of this justified?’”
Saving a life
That market for this technology is driven by demand from parents, and for some, knowing the genetic risks their child faces could be a godsend.
Laura Pogliano says having a test like Orchid’s could have helped her better support her son Zac, who was initially diagnosed with obsessive-compulsive disorder as a teenager in 2009. As his symptoms grew worse, doctors eventually determined that he had schizophrenia. Zac died from heart failure in 2015, at age 23. (An estimated 50% of sudden deaths in schizophrenia are from cardiovascular causes.)
Pogliano says if she had known about her son’s risk before he was born, she would have been able to look out for early signs and get him treatment sooner. Schizophrenia symptoms— hallucinations, delusions, confused speech, and disorganized thinking—generally start to appear in a person’s 20s, but changes in the brain can begin several years earlier.
She says Zac’s illness blindsided her family: “With schizophrenia, you think you have a healthy child, but you never actually did. The brain has been prepping for this disease for years.”
Pogliano says she would have raised her son differently if she’d known he was at high risk. She would have been more vigilant about his use of alcohol and marijuana, which can alter the nervous system and trigger psychosis in people with schizophrenia.
She hopes screening for schizophrenia will be routine someday. It’s different from guessing the risk of conditions like heart disease, breast cancer, or Alzheimer’s, she says: those diseases emerge much later in life, but parents have an opportunity to make a real difference in their kids’ lives if they know their schizophrenia risk.
“Designer babies isn’t the point,” she says. “All parents want is a path to health for their children.”
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