To hear Kian Sadeghi tell it, his genetic testing company just might upend health care. The 23-year-old college dropout began working on Nucleus in 2020, from his bedroom in his parents’ Brooklyn home. From a swab of genetic material, he says, his company can glean insights into which drugs a person should be prescribed, which diet will best help them lose weight, and how concerned they should be about getting Alzheimer’s, among many other health considerations.
Sadeghi has received millions of dollars in financial backing from some of the most influential figures in Silicon Valley, including venture capital firms led by Reddit co-founder Alexis Ohanian and billionaire Peter Thiel. “It’s an inevitability that every single person has their entire human genome on their iPhone,” Sadeghi told Ohanian in a promotional video released on X, the platform formerly known as Twitter, in July 2022. “Who’s going to analyze it? Who’s going to store it? Who’s going to maintain it?” he said. “It’s going to be Nucleus.”
Sadeghi, who studied computational biology during his year-and-a-half as an undergraduate, asserts that he can provide more accurate, more extensive genetic analysis than anyone else in the industry. And as he describes it, he is under no obligation to the U.S. Food and Drug Administration, the agency charged with ensuring the safety and efficacy of commercial genetic tests, to demonstrate that any of it works as well as he’s claimed.
In that regard, he is not alone. Nucleus is part of a brewing industry that seeks to broaden the scope of consumer genetic testing — to move beyond the mere detection of rare genetic variants known to cause serious disorders and into a more slippery realm of probabilities. They capitalize on tools that mine huge DNA databases in search of genetic signatures for a virtually endless range of human characteristics: the odds that a person will develop a certain cancer, for example, or the likelihood that they’ll go far in school or obtain a high-paying job.
The companies commercializing these techniques have largely escaped regulatory scrutiny, despite doubts about the health benefits their analyses can provide and worries about the risks they could pose to customers, health care systems, and society at large. The commercial push has created tension between academic researchers who toil to uncover new genetic associations, and the entrepreneurs who repurpose the results for profit.
Some ethicists also express a darker anxiety: a worry that companies will be tempted to test the blurry line that separates genetic prediction of disease risk from attempts to divine more complex traits laden with social stigmas. They portray it as a slippery slope that could lead to new modes of discrimination and bias.
Whether Sadeghi himself will test that line remains unclear, but the 23-year-old CEO has hired as his chief scientific officer Lasse Folkersen, who once ran a site offering genetic scores for intelligence and other scores seen as controversial in genetics research, taking extraordinary steps to shield some of the offerings from public view.
A sobering question emerges: Is the world ready to be awash in genetic scores? “No,” said Lucas Matthews, an assistant professor of psychiatry at Columbia University who has studied some of the technology’s social ramifications. “But I don’t know if it ever can be.”
“It’s already out there,” Matthews added. “It’s happening, whether we’re ready or not.”
In a March 2022 video interview with the 20 Somethings Podcast — a show that features young people making their way in tech, business, sports, and entertainment — Sadeghi gave listeners a preview of how Nucleus will work. “You just basically go on our website,” he said, and “if you haven’t done genetic testing before, you can just order a kit off of it.” According to Sadeghi, once a customer has collected a DNA sample and sent it back to Nucleus, the company then processes and analyzes it, unlocking a hidden world of personal genetic insights. “We have this beautiful kind of disease and trait panel,” he said. “You can click on any disease.”
Sadeghi, dressed plainly in a black t-shirt, his bedroom providing a backdrop, then reeled off a half dozen or so examples of the many diseases and traits Nucleus will analyze: Alzheimer’s, cancer, depression, extroversion, and longevity among them. More analysis on more diseases and more traits, he promised.
The idea that someone could divine, from a DNA sample, a person’s odds of developing Alzheimer’s might seem like a fantasy. There is, after all, no “Alzheimer’s gene” — no single snippet of genetic code that determines whether or not a person will develop the disease.
But in recent decades, scientists have come to appreciate that there are, in fact, many genes that each seem to have some bearing on a person’s Alzheimer’s risk. To identify them, they can perform what are known as genome-wide association studies — data-intensive efforts that trawl vast human genetic databases to tease out correlations between genetic variants and human characteristics. One recent study, which examined the genetic information of nearly 800,000 people, found 75 points on the genome that have genetic variants associated with changes in Alzheimer’s risk.
Genome-wide association studies, or GWAS, are not limited to Alzheimer’s. For seemingly any human characteristic that can be measured, there are GWAS that have identified potentially relevant genes. A database maintained by the National Human Genome Research Institute and the European Bioinformatics Institute catalogs more than 88,000 such studies that have probed more than 9,000 traits. Studies have found genetic variants correlated with a tendency to develop diseases, like coronary artery disease and diabetes. Others have found correlations between genes and complex outcomes like the age at which a person loses their virginity, or their propensity for taking risks.
The techniques have become so routinized that even an automated bot can perform them: For the past five years, GWASBot, maintained by researchers in the U.S. and Finland, has conducted roughly one new GWAS every day, publishing its results on X. On different days in August, it identified genetic variants linked to people’s ability to solve an arithmetic problem, their tendency to feel fed up, and their penchant for taking naps during the day.
The biological mechanisms underlying the genetic associations are, almost always, opaque. Often, it is impossible to know whether a variant identified in a GWAS causes — or is merely correlated with — a change in the observed characteristic. Sometimes, the associations may not have much biological meaning at all: A specific point on the genome can be correlated with a trait for all sorts of reasons that have little to do with the gene itself.
Despite that uncertainty, the GWAS boom has bred a prediction industry, of sorts. Anyone with enough technological savvy can take a list of the genetic variants identified in a GWAS — and their effect sizes — and cross reference it with a person’s genetic information to calculate a number, a so-called polygenic score, that reflects that person’s predisposition for a disease or trait. The score may be presented as a percentile ranking that describes the person’s standing compared to a broader population and — in some cases — as an absolute risk that estimates a person’s overall odds of developing the disease or trait.
The estimates are imperfect, in part because genetics aren’t the only factors that influence a person’s outcomes; environmental influences also matter. A 2022 study of Swedish twins found that polygenic scores for Alzheimer’s could explain about 11 percent of the variation in risk that researchers observed — even after specially accounting for a gene that encodes for the protein apolipoprotein E, thought to have an outsized influence on the disease. Much of the remaining variation was ascribed to lifestyle and other non-genetic factors. Scores for other traits paint a similar picture: A 2023 study found that polygenic scores for coronary artery disease explained about 7.4 percent of the observed risk variation in a population of European ancestry; in a 2018 study of breast cancer, the fraction was just 2.7 percent.
Taken alone, the scores typically reveal very little about a person’s likelihood for developing a trait. In a 2019 study that followed people aged 60 and older who initially showed no signs of cognitive impairment, just over 1 percent of people whose polygenic scores put them at relatively high Alzheimer’s risk went on to develop dementia during the study’s roughly 8-year observation period. Just 0.63 percent of people who scored at the lowest level of risk developed dementia in that same timeframe. The vast majority of people, whether their genetic risk was deemed high or low, didn’t develop the condition.
Although polygenic scores alone may not be powerful predictors of disease, many researchers are optimistic that they can be combined with other, more conventional methods of risk estimation to improve screening for common conditions like cancer, cardiovascular diseases, and diabetes.
In the United Kingdom, the health care company Genomics plc partnered with the National Health Service to integrate the scores into traditional risk calculators for cardiovascular disease based on factors like cholesterol levels and blood pressure. A study funded by the company found that estimates that combined polygenic scores with those traditional risk factors were about 6 percent more accurate than those produced with the traditional risk calculator alone. They predicted that around 2,400 deaths could be prevented annually in the U.S. if the modified risk tool were implemented, and if every person identified as high risk adopted and adhered to a regimen of drugs that reduce cholesterol, called statins.
Other studies, which were not funded by industry, have found more modest gains. But collectively, they have fueled optimism that clinicians may one day use the scores to detect some ailments earlier and more accurately, empowering preventative measures that could help patients ward off disease and serious illness.
At the same time, however, a chorus of experts say that society should temper any expectations that polygenic scores will revolutionize health care. Among them is Amit Sud, who previously served as an academic clinical lecturer at the Institute of Cancer Research. In recent papers, Sud and coauthors have pointed out that the accuracy gains from using polygenic scores are modest and that, as with any screening tool, the possibility that a polygenic score will correctly flag a candidate for preventative treatment must be balanced against its potential for false positives — cases where someone is flagged as high risk for a disease that they will never develop.
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Those false positives, Sud and his colleagues have argued, could lead many people to undertake costly and unnecessary screening and treatment. In an analysis published this year in The BMJ, they estimated that a proposed U.K. policy to offer annual screening to women with moderate or high polygenic risk scores for breast cancer would detect 1,700 more cancers but produce more than 5,700 false positives, and they pointed to a separate study estimating that a proposal to incorporate polygenic scores in coronary artery disease prevention would cost around $140,000 in additional screening and treatment for every year of quality life that it saved.
To the extent that clinical benefits of polygenic scores do materialize, Sud and his coauthors argued, they are unlikely to be reaped equally. That’s because, for technical reasons, the scores tend to work best for people who are genetically similar to the populations studied in the genome wide association studies the scores were based on. And, to date, the vast majority of GWAS have used populations of European descent.
“When you hear people speak about polygenic scores,” he added, “it sounds very optimistic. It sounds like it’s going to solve a lot of problems. But from first principles, I don’t see how it can.”
If the benefits of introducing polygenic scores in controlled clinical contexts remain uncertain, some say there’s even less evidence to suggest that individual consumers will be able to reliably parlay scores into improved health outcomes on their own. Yet improved health outcomes are exactly what Nucleus and many other consumer-driven genetic companies are promising.
“I think it ultimately comes down to precision personal insight,” Sadeghi said when he was asked in the March 2022 podcast interview what actionable steps customers would be able to take based on the information that Nucleus provides. “What drugs should be used specifically for you, in the health care context? What diet should you have based off your DNA?”
Other companies have implied that they can deliver similar benefits. Nebula Genomics, a genetic testing and analysis company co-founded by Harvard University professor George Church, advertises that its analyses can help customers determine the best diet and supplements, find the right exercise plan to lose weight, and extend their lives. The company charges $249 — plus a $275 lifetime membership fee — for its whole genome sequencing package, which includes reports on ancestry and rare genetic mutations, as well as access to nearly 290 polygenic scores on different genetic predispositions.
However, Cathryn Lewis, a professor of genetic epidemiology and statistics at King’s College London, said she’s seen scant evidence that people react to their polygenic scores in ways that yield positive impacts on their health. She said the closest study she knows of is a 2022 randomized controlled trial that tracked patients with high polygenic risk for coronary artery disease.
The study found that patients who were informed and counseled about their polygenic scores were more likely to begin a regimen of statins, compared with patients who weren’t apprised of their scores. But after one year, the two groups showed no appreciable difference in their risk for cardiovascular disease, based on factors like blood pressure, cholesterol levels, and blood glucose levels. Learning about polygenic scores changed people’s behavior, Lewis said, but it didn’t have the intended effect on people’s health.
Absent clearer evidence of polygenic scores’ utility, some experts are leery about efforts to position them as consumer health products. In an email to Undark, Muin Khoury, the chief of the public health genomics branch at the Centers for Disease Control and Prevention, was blunt: There are no polygenic score tests, he wrote, “currently available for health, social or behavioral traits with sufficient scientific evidence to support their routine use in health practice.” Absent guidance from a health care professional, he added, “a consumer is on their own to determine whether a genetic test is valid and useful for examining health and other traits.”
Lewis told Undark that she worries the analyses will send customers rushing to their primary care providers to request unnecessary screening and tests. And because people with the means to purchase the analyses are likely to be more affluent and middle class, she added, the products could exacerbate inequalities in access to care. “It rolls into all sorts of downstream medical care,” Lewis said, “which is not appropriate for the individual. It’s not appropriate for society.”
Church acknowledged that many polygenic scores have not demonstrated an ability to deliver clinically significant health outcomes, but he indicated that Nebula Genomics’ reports are not intended for medical or pharmaceutical use, and that “the point of the exercise is to get people used to thinking probabilistically.” He said he hopes they will urge consumers to talk with their doctors and seek more diagnostics, and he suggested that fears that those patients will strain health care systems are overblown. “I think we complain too much about medical costs,” he said. “I think we’re underdiagnosed as a species, given the amazing technology.”
Even among some researchers who are optimistic about using polygenic scores to screen for physical health conditions, there is one emerging application of polygenic scores that makes them uneasy: the prediction of risks for depression and other psychiatric conditions.
The genetic testing giant 23andMe has helped lead the way into this ethically fraught terrain. In recent years, the company has released more than three dozen health-related polygenic scores, including scores for depression, ADHD, and panic attacks, according to company white papers. Meanwhile, Nebula Genomics’ offerings include scores for depression, PTSD, bipolar disorder, and other mental health conditions. And although Nucleus has yet to disclose its full genetic testing lineup, Sadeghi has already indicated that depression will be on the menu of options.
For people like Lewis, who herself has helped conduct several genome-wide association studies on depression, part of the concern is that geneticists’ understanding of psychiatric traits is still immature. In a widely cited 2018 study, she and her coauthors found that polygenic scores could account at best for just about 2 percent of the variation in depression risk observed in general populations — though she says that figure has been as high as 6 percent in unpublished data. Still, “giving you information on that very small piece of information isn’t very useful when the rest of it is unknown,” said Lewis.
Experts also worry about the psychological harms that might come from receiving a high-risk determination for a disease like depression, with no clear course of action to take in response. “If someone’s at high genetic risk of heart disease, say, we can support them to lose weight, to change their diet, to have more exercise,” Lewis said. “But in psychiatric disorders, we don’t have those preventative options. And so we are at risk of giving someone the anxiety and the worry, without giving them anything to ameliorate that worry.”
In a 2021 paper, Brent Kious, an assistant professor of psychiatry at the University of Utah, and his colleagues warned that polygenic scores for psychiatric traits could be easily misinterpreted by the public, and could contribute to harmful self-stigma and anxiety. The researchers called on the FDA to specifically prohibit direct-to-consumer polygenic scores for suicide risk, saying it was unclear whether there were any beneficial actions a person at elevated risk could take that would “offset the social and psychological harms of the tests themselves.” (Kious clarified to Undark that, although he opposes the use of polygenic scores for suicide in direct-to-consumer settings, he thinks they should be allowed in clinical settings where they can be tied to genetic counseling.)
Echoing other experts who spoke with Undark, Kious stressed that some polygenic scores have a greater potential to cause harm than others. It’s one thing to misinterpret a polygenic risk score for the ability to curl one’s tongue, he suggests, “but, you know, dementia, suicide, major depressive disorder, schizophrenia — I tend to think in terms of psychiatric examples — I think, yeah, those could certainly be bad for people.”
There exists a school of thought that all genetic information should be free — that it should not, in fact cannot, be cordoned off from the lay public. Arguably, few people have embodied that ethos more than Lasse Folkersen, the geneticist who was hired in 2022 to be the chief scientific officer of Nucleus.
Before joining Nucleus, Folkersen worked as a genetics expert at the Danish National Genome Center, and before that as a scientist with a psychiatric hospital based in Copenhagen. During evenings, he ran a website called Impute.me, where users could upload their raw genetic data from companies such as 23andMe or Ancestry and receive polygenic scores for any of hundreds of traits, calculated based on publicly available data from published genome-wide association studies. The service was free, though users who donated five dollars were promised spots at the front of the processing queue. As Folkersen recalled in an interview with Undark, when he started out in 2015, his was probably one of the only sites in the world where people could get polygenic risk scores. He estimates that during the seven years he ran the site, he processed around 100,000 unique genomes.
Folkersen’s philosophy was to take in essentially every GWAS that academia produced. Impute.me offered polygenic scores for snoring, for coffee consumption, for adventurousness. Some scores rested on thin scientific footing. After a Reddit user complained that the site’s score for longevity was based on a study that had failed to identify even a single genetic association meeting a standard threshold for statistical significance, Folkersen removed the score from the site. At least one other score based on a study that failed to meet that threshold, for extroversion, appears to have remained live until Folkersen shuttered the site last year, a review of archived webpages suggests.
Folkersen acknowledges that some of the scores provided by Impute.me were poorly predictive. Still, he said, “I really still hate the idea of having some external arbiter saying, well, then you can’t have it. I much more like the idea of saying, ‘Well, here it is. It is less impactful, it is less predictive. It is of less consequence to you, basically. And we can explain why.’”
But a 2021 study, co-authored by Folkersen, suggests that Impute.me’s users often failed to grasp those limitations. The study found that only about one in four respondents could correctly answer eight questions assessing their understanding and interpretation of the polygenic scores they’d received. More than half reported negative reactions to receiving their scores, and around one in 20 scored over the threshold for potential post-traumatic stress disorder, according to one common self-reported measure of distress.
Folkersen found the results concerning, as did Jehannine Austin, a medical genetics professor at the University of British Columbia who collaborated on the study. Austin and other academics worked with Folkersen to devise ways to present scores in way that users could better understand, such as providing them in terms of absolute risk — the percentage chance that a person will develop a disease or trait. “That was a direct outcome of looking at that data and going, ‘Oh no, that’s, that’s not good,’” Austin said. In an email follow-up with Undark, Folkersen indicated that better communicating scores with users would be a priority at Nucleus.
Impute.me was not just a health site. Among the analyses the site offered were genetic scores relating to athletic ability, hypersexuality, intelligence, and other categories that geneticists and bioethicists have deemed of heightened concern due to their perceived ties to social status, their associations with harmful stereotypes, or their centrality to the identities of minoritized groups.
The intelligence scores Folkersen offered clandestinely — at a page hidden from the Impute.me homepage but accessible with a URL or direct link. Responding on Reddit after a user seemed to express disappointment at being ranked in the zeroth percentile for the trait, Folkersen explained his rationale: “This is exactly the reason why the intelligence module is unlisted,” he wrote. “People can’t handle it if they get a low score because they somehow take it more personal than a real IQ test. They are wrong.”
Folkersen argued that an IQ test is a far more accurate prediction of intelligence than a polygenic score. Indeed, many scientists have said that polygenic scores aren’t equipped to predict individual outcomes for traits like intelligence. The genetic variants identified in a large 2018 GWAS for intelligence, published in Nature Genetics, could account for around 5 percent of the variance observed in studied populations of European ancestry, and part of that may reflect factors that are only indirectly related to genetics.
Despite Folkersen’s efforts to keep them discreet, Impute.me’s intelligence scores garnered attention in internet forums and message boards, at times providing fodder for racist diatribes. Emil Kirkegaard — a right-wing blogger who has argued for innate intellectual differences between races — described the intelligence scores as the “juicy parts” of the site.
The hidden intelligence module likely remained live until 2022, when Impute.me shuttered and was acquired by Nucleus. Around the same time, Sadeghi appointed Folkersen as Nucleus’s chief scientific officer. The web address for Folkersen’s old site now redirects to the Nucleus homepage, and both Sadeghi and Folkersen have indicated that the new genetic testing company is, as Folkersen put it, “building on top of Impute.me.”
But it is not clear to what extent, if any, Nucleus will adopt Impute.me’s permissive stance toward controversial polygenic scores. Folkersen told Undark that Nucleus has not ruled anything out at the moment, and that the guiding principle will be to go with traits of which society approves.
“There’s no commitment to draw a line somewhere,” he said, though he added it’s not in the company’s interest to create a stir. “Our stated goal is not to cause controversy,” he said. “Our stated goal is to lower the bar for access to health care.”
When asked in a Zoom interview with Undark if he was aware of Impute.me’s hidden panel of intelligence scores, Sadeghi did not respond. After a few seconds of silence, Prabarna Ganguly, a communications officer who was monitoring the call, cut in to refer Undark to the following statement: “Nucleus plans to provide non-disease (trait) reporting on specific traits. We are spending a great deal of time to ensure we thoughtfully, rigorously, and beautifully construct reports that empower people to understand more about how their DNA helps shape who they are.”
Through Ganguly, Sadeghi declined to discuss with Undark any of the company’s plans to offer polygenic scores for non-disease related traits.
Were Nucleus to offer its customers genetic scores for intelligence or other social and behavioral traits, it would not the be the first company to venture into that territory. Nebula Genomics offers scores for several traits that are considered by ethicists to be of heightened concern, including a score for intelligence based on a 2017 Nature Genetics study. (As recently as Oct. 25, one page on the website listed same-sex sexual behavior as an available score.) Genome Link, a site where users can upload DNA data obtained from other companies, also offers scores for a plethora of social and behavioral traits, including those that purport to measure a person’s genetic predispositions to math ability, vengefulness, and violence.
Like many experts, Columbia University’s Matthews — who’s studied implications of using polygenic scores to predict intelligence-related traits — has mixed feelings about the rise of these consumer-focused polygenic scores. He is sympathetic with the idea that people should have access to information about their genes. But he told Undark that the use of polygenic scores to predict genetic propensities to social and behavioral traits could be prone to misuse, misinterpretation, and abuse.
Among other things, he said, such scores could lead people to “geneticize” social behaviors — to view them primarily through a genetic lens, whether or not the science justifies it. In a 2021 study, Matthews and his colleagues saw glimpses of how that could play out in the real world. The team assembled participants and asked some of them to imagine receiving a low polygenic score for educational attainment, or how many years of schooling a person finishes. Others, they asked to imagine receiving a high score. The participants who imagined low scores seemed to internalize those judgements, creating a sort of self-fulfilling prophecy: They later reported lower self-assessments of academic potential, self-esteem, competence, and academic efficacy.
“You can imagine ways in which this might interact with not just attitudes of people towards themselves, but attitudes towards others, like educators towards their students, or students towards their peers,” Matthews said. “Believing this person might have limited potential can maybe influence the behavior towards the person.”
Yet another concern with polygenic scores for social and behavioral traits, experts told Undark, is that they can paint a misleading picture of the role genetics plays in shaping human behavior. That is, statistical associations that on their face appear to be purely genetic may in reality stem from a confluence of biological and social factors, including effects of discrimination that may have been at play in a society over generations.
“I think we need to be careful about using genetics to try to make any predictions for things that are that are primarily social,” said Amy McGuire, who leads Baylor College of Medicine’s Center for Medical Ethics and Health Policy. “It really becomes confounded to the point that it’s misleading.”
To the extent that for-profit companies are offering controversial scores on social and behavioral traits, it is largely because academics, many of them supported by public institutions and public funding, are undertaking controversial research. Scientists have performed at least 20 genome-wide association studies for intelligence since 2011, and dozens more on traits like educational attainment, sexual preference, gender, and aggressive behavior. Many genetic testing companies draw directly from these published academic studies to compute their polygenic scores.
That dynamic has at times generated tension between the academic scientists who perform genome wide association studies and the companies who repurpose the studies’ results for profit. In 2019, a tech entrepreneur marketed and sold a “How Gay are You App” based on GWAS of same-sex sexual behavior, eliciting an uproar from scientists in the field.
Yet researchers typically have little say in how their data is used once they publish it. And for Daphne Martschenko, an assistant professor of biomedical ethics at Stanford University, some of the uses are troubling. Of particular concern, she said, are companies that have begun offering polygenic scores as part of their embryo screening services for in-vitro fertilization patients.
The scores attempt to predict an embryo’s lifetime odds of developing certain diseases and conditions, to aid prospective parents in deciding which among a selection of embryos they would like to implant to begin a pregnancy. But it’s far from clear that polygenic scores are powerful enough to inform such decisions, and questions swirl about which, if any, scores might be ethical to use. One company offering embryo screening services, Genomic Prediction, drew backlash when it advertised a polygenic screening for low cognitive ability, which its co-founder suggested was based on a 2018 GWAS on educational attainment. The Los Angeles Times has since reported that the company, now known as LifeView, no longer screens for cognitive disability.
It can be tricky to convey to customers the limitations and uncertainty inherent in polygenic scores, Martschenko said. “I think that there’s a lot of potential for people to misunderstand what this information is actually telling them.”
Martschenko also expressed worry that the proliferation of polygenic scores could pave new pathways to discrimination. Although the Genetic Information Nondiscrimination Act of 2008 prohibits the use of genetic information in employment and health insurance decisions, Martschenko said that many other arenas — life insurance, education, banking — aren’t covered by the law. “There aren’t protections against lending institutions deciding that, you know, someone with a low polygenic score for income is, is a higher risk individual to give a loan to.”
Kian Sadeghi first came across Impute.me when he was researching computational genomics during the pandemic. He says he thought it was a good tool — a very good tool — and even used it to analyze his own DNA. But he also recalls thinking that he knew he could make the site much better.
He cold-emailed Folkersen in 2021, and the two hit it off. “We had probably an email chain that ran more than 250 emails long,” he recalled to Undark. Soon they were crafting plans to transform the site into Nucleus.
They decided that instead of merely offering customers the option to upload 23andMe or Ancestry data, Nucleus would do its own whole-genome sequencing. That would likely drive up costs, but it would allow them to capture rare genetic variants that cheaper, genotyping techniques can miss. Sadeghi and Folkersen also set out to incorporate non-genetic factors — age, for instance — to help refine their polygenic risk estimates. And they developed a strategy to communicate those estimates in terms of percentage risks, to aid user interpretation.
These features aren’t exactly new. 23andMe also incorporates demographic information to improve its risk estimates, and it presents those estimates as percentage risks. Nebula Genomics, meanwhile, offers whole genome sequencing. Ultimately, it is difficult to know precisely how Nucleus will differ from existing companies because Sadeghi has yet to disclose details about how his company’s risk models will work, and how he and his colleagues will ensure their accuracy.
As Sadeghi tells it, the company is under no obligation to disclose that information to the FDA either. “We’re an LDT,” he said, referring to a regulatory class of devices known as laboratory developed tests, defined as diagnostic tests that are designed, manufactured, and used within a single laboratory. “We’re not under their jurisdiction.”
Instead, Sadeghi noted that Nucleus is certified by the Centers for Medicare and Medicaid Services’ Clinical Laboratory Improvement Amendments program, or CLIA. But CLIA does not assess the accuracy with which genetic tests measure or predict clinical conditions and predispositions. Those tasks fall to the FDA exclusively. As a matter of policy, however, the FDA has generally opted not to review laboratory developed tests that are prescribed by a health care provider. Under Nucleus’s model, which Sadeghi describes as a consumer-initiated approach, customers will request genome sequencing test on the company’s app and, in most cases, directly receive the results and analyses. But a physician from Nucleus’s partner network will review, approve, and order the test, with Nucleus footing the bill for the services.
The FDA has pushed back against the notion that laboratory developed tests are beyond its regulatory reach — especially those that lack meaningful involvement by a licensed health care professional. In April 2019, the agency reprimanded a Virginia-based laboratory that, without seeking FDA approval, had touted the ability of its genetic tests to help patients discern which drugs they should be prescribed. “Although FDA has generally exercised enforcement discretion for LDTs,” the agency’s letter read, “the Agency always retains discretion to take action when appropriate.” Days later, the laboratory withdrew the tests from the market. According to FDA guidance, even computational analyses of a genetic sequence — performed separately from the sequencing itself — may be subject to the agency’s oversight.
Still, companies offering polygenic scores have managed to avoid the agency’s scrutiny. Church says that Nebula Genomics has not subjected any of its products to FDA review, and none of the 38 health-related polygenic scores offered by 23andMe have been authorized or approved by the agency. Some experts have called for stricter oversight of polygenic scores, suggesting current regulatory gaps leave consumers vulnerable.
Meanwhile, Nucleus is pressing forward. The company’s app is still in beta testing, but Sadeghi is buoyed by what he sees as an unstoppable downward trend in the cost to sequence a human genome. Since 2003, when the first sequence of the human genome was completed, the sequencing cost per genome has fallen from about $50 million to around $500 last year, according to data from the National Human Genome Research Institute. It is that plummeting curve that has convinced Sadeghi that people everywhere will one day store their entire genomes on their smart phones, and that Nucleus will be the app they choose.
In August, after news surfaced that a new technology, from the biotech company Illumina, may soon bring genome sequencing costs down to $200, Sadeghi posted on X “Yes,” and then added, “we will sequence billions of people in next decade.”