News Feature

Reproducing with DNA

Finding partners through DNA profiles has yet to catch on, but the commercial sector for preconception and prenatal testing is booming. Malorye Allison Branca reports.

More than 5 million babies have now been born via in vitro fertilization (IVF). Women are having children later in life. Couples may be same sex or transgender. The use of sperm and egg donors as well as surrogate mothers is becoming increasingly common. In tandem with these societal shifts, DNA sequencing is increasingly being used to help people craft their personal and reproductive lives, as companies provide everything from gene-based partner matching to prenatal screening, and even a growing range of treatments for genetic conditions detected in utero.

Image: Jakarin2521/ iStock / Getty Images Plus

Not all these offerings have been market successes. The DNA-dating market, for example, has yet to take off. Gene-based fertility testing, meanwhile, is nascent. But preconception (carrier and pre-IVF) and prenatal testing are booming and expected to reach several billion dollars worldwide in the next decade. It's become one of the most competitive markets in the world, especially in countries such as China and India, which have huge numbers of births and where home-based firms have been slower to market than those in the US and Europe (Box 1).

Box 1: China's genetic play

Sijia Lu of Yikon Genomics estimates the current number of PGD and preimplantation genetic screening (PGS) procedures carried out in China at about 10,000 per year. For about half of those, the genetic analysis is carried out in some of the 39 infertility clinics or hospitals approved to do the procedure. For the other half, the genetic analysis is carried out by four companies, Lu's Yikon, Beijing-based Berry Genomics, Shenzhen-based BGI Diagnosis, and Jiaobarenhe, which partners with BGI. Lu says Yikon has about 2,000 cases per year.

This is only a fraction of the potential, says Lu. He reckons the potential market for PGD and PGS procedures in China is 200,000 (a number he got by multiplying the fraction of the population with birth defects (1%) by the average number of babies born each year (20 million)).

The procedure, while costing only a fraction of its price in the US, is still expensive to the average Chinese household, which partly explains why more don't opt for it. But the difficult approval process a clinic has to go through to get approved—achieved by only 39 of them in all of China to date—is also a bottleneck. The powerful National Development and Reform Commission is trying to push the technology, but the health ministry is putting on the brakes, appealing for more data before broadening access, according to sources contacted by Nature. Part of the reason for that is a lack of good embryologists who can carry out the delicate cell extraction procedure.

One major focus for Yikon is to do the tests using only the culture medium of the growing embryo, by picking up DNA of the dead cells that the embryo sheds8. “We are pushing the field that way, to be less invasive,” says Lu.

Such a noninvasive procedure would not only dispel any safety concerns associated with cell extraction but would also make it a procedure that anyone with basic medical training could do. Getting around the need for an embryologists could open up the door to more approved hospitals, says Lu.

Yikon was established in 2012 and produced its first baby in 2014.

David Cyranoski, Beijing

Love at first sniff

Though there's little evidence of momentum yet, DNA-based dating may still be 'a thing'. Several companies have taken a stab at the market believed to be worth $2 billion, with 50 million online dating users in the US alone (Table 1). What's more, there is a lot of unmet need out there. Brittany Barreto, co-founder and CSO of Pheramor, in Houston, Texas, says, “A recent market research study we did showed that only 2% of singles were satisfied with online dating sites.” Most DNA-related dating services have been based on research suggesting that women are attracted to men based on pheromones, which are genetically controlled through human leukocyte antigen (HLA) type. The theory is that women prefer partners with diverging HLA types to avoid inbreeding.

Table 1: Selected companies in the 'DNA-based coupling' field

The most cited report—often called the 'sweaty T-shirt experiment'—was carried out by Claus Wedekind and colleagues at the University of Bern and found that body odor, which is affected by pheromones, influences women's mate preference1. Women were asked to smell and then rate t-shirts men had worn for two consecutive nights. The women tended to rate the shirts more highly if the men had different HLA-A, -B, and -DR alleles from their own.

Toronto's Instant Chemistry, founded in 2013, was based in part on this study. Its website lists over 20 references supporting the science behind these claims. The company markets its services to established couples, helping them better understand their mutual 'chemistry', but it has also collaborated with dating services (such as Singld Out) and individual matchmaking consultants, providing them use of their tests. Instant Chemistry is also “still looking at the online dating space” says CSO Sarah Seabrook.

Instant Chemistry tests for six genetic variants in the HLA system “that have been associated with increased physical attraction, longer lasting relationships, and better sex lives,” at least between heterosexuals, according to company literature. They also provide a 'neurocompatibility' assessment based on four neurotransmitter genes associated with “emotional responsiveness, empathy, risk-taking, and stress resilience.” Seabrook explains that this is partly related to the serotonin transporter gene: “There is a long and a short version, and if you carry the short version you have a stronger emotional response.” At least one study suggests that if both partners have the short version, they are less likely to be satisfied in their relationship2. Other genes possibly associated with neurocompatibility affect the oxytocin receptor, the dopamine receptor, and catechol-O-methyltransferase, an enzyme that breaks down dopamine in the brain. Finally, the company does a psychological assessment that is graded by clinical psychologists.

But why cater only to established couples? “It turns out that this information brings a unique closeness to their relationship,” Seabrook says.

DNA dating's rise

This single finding intrigued many, and just a few years ago, numerous DNA dating services were on the market. Jana Bayad, the CEO and co-founder of Singld Out in San Diego, explains that her company was novel because it targeted busy professionals who “don't have time to meet 100 people to find their match.” Bayad ran into her co-founder, a matchmaker, at a coffee shop. They learned about Instant Chemistry's DNA-based compatibility testing, and Singld Out was born. Whereas Instant Chemistry focuses on people currently in a relationship, Singld Out aimed to give singles that information up front, to help them find a good match.

Singld Out garnered lots of good press early on, and their market research suggested they were onto something: they found that only a small percentage of people surveyed were completely against DNA testing, but that “the general public is still very scared of DNA testing,” according to Bayad. There are privacy concerns and an overall lack of understanding of how DNA testing works. “I think we were too early,” she says. She adds that people in STEM fields were, however, generally positive about it, which reinforced the idea of targeting professionals. But that proved to be too small a market.

These setbacks haven't daunted recent start-up Pheramor. “I was in college when I learned in a genetics class that we could predict who would be attracted to us by genes,” says CSO Barreto. “I thought 'I'll start a geneharmony.com.'”

Barreto points out that since the pivotal 1995 paper by Wedekind, at least nine more papers have supported the idea that women are preferentially attracted to the odor of a man whose HLA types are different from theirs: a 2008 study, for example, found greater MHC dissimilarity between European American couples than between random pairs of individuals3, and a 2016 study found people were more satisfied in their relationships if their partner had a dissimilar HLA type4. Furthermore, Pheramor will use new sets of genes “never before used in match-making,” Barreto says—genes associated with personality types, derived from a 2015 report that found at least 40% of personality is determined by genetics5.

Pheramor is not a one-trick pony, though. “Our business is more than a good first connection,” says Barreto. They call what they are doing “contextual genetics,” and will also be pulling data from participants' social media activity to help make better matches. They are launching a dating app that will go live by the end of the year in Houston, Texas.

In addition, they are encouraging all their customers to also allow their DNA to be tested for bone marrow donation matching. “If you are not white, you have less than a 7% chance of finding a bone marrow donor,” she points out. So far, 80% of the singles they have asked to submit their DNA for bone marrow donation compatibility have consented. “We are not just curing heartache, we are saving lives,” Barreto says. “We are creating a dating app that connects people in multiple ways.”

Even if the science holds up, Pheramor must crack a market that has so far been unwelcoming. “It's true there have been a lot of failures in this field,” Barreto admits. “Singld Out almost made it, but we still see a lot of reason to be optimistic.” For one thing, she points out how wildly popular current dating apps are, even though they end up providing only a small fraction of people with permanent relationships. “I'm excited to bring this marketplace an app that actually matches people based on science, to decrease the number of bad first dates and increase authentic connection,” she says. She is also encouraged by the growth of direct-to-consumer (DTC) companies such as Mountain View, California–based 23andMe and Lehi, Utah–headquartered Ancestry.com, which she believes are making people more familiar with, and accepting of, genetics. In fact, Pheramor competitor DNA Romance hinges upon the success of DTC genomic companies; subscribers have to get their genotype from such a company to complete the matching process. 23andMe has also patented a tool it claims could predict what offspring might look like on the basis of DNA (Box 2).

Box 2: The gamete mating game

In 2013, 23andMe was granted a patent entitled “Gamete donor selection based on genetic calculations” by the US Patent & Trademark Office (USPTO) (Nat. Biotechnol. 32, 8, 2014). The so-called 'build a baby' patent describes a “Family Trait Inheritance Calculator” that uses information on a variety of gene variants from different potential 'partners' to compute the probability of phenotypes in offspring (e.g., eye color, taste, predisposition to cancer). The patent describes a partner selection process that would “compare the probabilities of observing the phenotype of interest resulting from different combinations of the genotype of the recipient and the genotypes of the plurality of donors to identify the preferred donor.” Essentially, the idea is for a person to screen a group of gamete donors to identify a donor with the highest-ranked probability of producing desired traits in offspring—all without ever meeting them. The patent has been criticized as an instrumentalization of reproduction. The trait calculator, which was available for a time on the company website, was limited in what it offered compared to what was detailed in the patent. According to company spokesperson, Andy Kill, the company has no plans to implement it. According to the USPTO's PAIR database, however, as of September, the patent has not yet been abandoned, suggesting that patent maintenance fees have been paid up until now. And in some ways, the gamete selection approach is already being pursued in fertility clinics; for example, the California Cryobank (https://cryobank.com/search/) has a search tool that enables potential customers to pick sperm on the basis of donor similarity to celebrities as well as other physical and mental attributes.

Beat the clock

With more couples balancing careers and families, the timing of childbearing is becoming an issue for singles looking for partners as well as for couples. Celmatix, in New York, was formed so that women would not need to make decisions around fertility based just on their age. Founder and CEO Piraye Yurttas Beim, an embryologist, says the light bulb went off for her when she was sitting in a seminar about preimplantation genetic diagnosis (PGD) and she learned that some women were prone to failing multiple rounds of IVF for unexplained reasons: “I raised my hand and asked 'Who is applying personalized medicine to reproduction?', and of course, there are academics looking at everything, but there wasn't a company doing this.”

Reproductive medicine for men, she explains, has advanced by leaps and bounds. “Even men without sperm can reproduce now,” she says, via testicular sperm extraction, which can also include using spermatogonial stem cells. Celmatix aims to make the journey to conception smoother for women, using gene testing that will help them learn more quickly whether they are at higher risk of a fertility problem and whether it has a genetic basis.

The company has gathered clinical data on close to a million fertility treatment cycles from some of the US's largest reproductive health centers. They have also done a systematic analysis of more than 20,000 articles in PubMed on women's reproductive medicine, resulting in over 1.1 million annotations. In addition, they are doing a population-based study using whole-genome sequencing. Besides looking at genes that impede fertility, they are studying the genetics of women able to conceive spontaneously even in their 40s, who accounts for about 10% of women. “We are getting this information to women when they can still be proactive,” Beim says. “This test will be the next Pap smear, but it will give you insight into risks to your fertility.”

The current test, called Fertilome, costs $950 and covers 32 genes. The list of genes is only available to patients and their doctors. The test looks at genetic markers associated with recurrent pregnancy loss, primary ovarian insufficiency, endometriosis, and polycystic ovarian syndrome. It is recommended for women who want to delay childbearing beyond their 30s, or who have a family history or possible symptoms associated with infertility (such as hyperandrogenism or primary ovarian insufficiency). The test is also used by women undergoing fertility treatment. Most patients pay for these procedures themselves, and they are expensive. The decision of whether to keep trying or not is also emotionally difficult. Beim says that hundreds of patients have already been counseled based on the test and “our first Fertilome babies are due later this year.”

Not everyone is convinced such testing is advisable yet. “Traditionally, genetic testing for infertility has focused on screening for the FMR1 premutation (for Fragile X) and karyotype abnormalities, to identify patients either at risk for premature ovarian insufficiency or recurrent pregnancy loss,” says Irene Souter, director of the preimplantation genetic diagnostics program at the MGH Fertility Center, in Boston. Fertility panels are a new development. “This is a great area to do research,” Souter adds, as there is evidence that certain causes of infertility are at least partly genetic. “But these tests are not standard of care yet and I wouldn't get one.”

New York–based Phosphorus Diagnostics also offers gene-based fertility evaluations, among other genetic diagnostics. It is a spin-out of another New York genetic testing company, Recombine (acquired in 2016 by Pleasanton, California–based Cooper Surgical), which has long offered carrier testing. Phosphorus is partnered with Recombine to sell a test they call CarrierMap, which is based in part on data from their customers who volunteered their information to develop fertility risk evaluation tests. The company's female infertility panel tests for almost 80 genes related to a handful of conditions related to female infertility. But their panel also includes “emerging evidence genes...for which there is initial evidence” of association with a known fertility issue. The company's male fertility test includes just 20 genes and covers the handful of common causes of male infertility.

Sperm and egg screening

For those couples who can conceive, another question might be whether they have any risks of inherited diseases. Carrier testing has also grown in popularity, particularly among people who already know they are at high risk of carrying a certain disease

Probably the most striking example of carrier testing is the nonprofit organization Dor Yeshorim, which provides limited test panels that include some of the conditions most common among people of Jewish descent (http://doryeshorim.org/). These conditions, most of which are deadly and/or seriously debilitating, are thought to have become concentrated in this population, particularly among groups that were geographically isolated, because Judaism strongly encourages marriage within the faith. The testing service is specifically aimed at supporting traditional matchmaking, while avoiding hereditary conditions. On its website, the group states that its mission is to eliminate “the agonizing occurrence of fatal and debilitating genetic diseases in Jewish families worldwide.”

Thanks to donations, the group is able to offer their tests to Jews worldwide at a subsidized rate. Dor Yeshorim's standard Ashkenazi panel tests for nine diseases including Tay–Sachs disease, cystic fibrosis, and glycogen storage disease type 1A. They also have an extended Ashkenazi panel with an additional nine genes and a Sephardi panel that tests for 17 genes. (The Ashkenazi and Sephardi make up the largest subgroups of Jewish people.)

It is not just particular ethnic groups that can be carriers of mutations for lethal or debilitating conditions, however. “Most people will not know they are carriers of a genetic disease until their child is diagnosed,” says Eric Evans, a cofounder and CSO of Counsyl in S. San Francisco. “Only about 20% of affected kids are born to families with a known history of a hereditary condition.”

Counsyl and other companies offer carrier testing, through a physician, to anyone who can afford it. The challenge for these companies is which conditions to test for and how to design their test. Counsyl examined 650 genes to determine the severity and frequency of significant mutations and to see how to maximize detection of them. Their assay can test for 173 conditions with greater than 99% accuracy across multiple ethnicities, according to the company. “We are looking for conditions that are severe and profound,” Evans explains.

About a quarter of conditions they can test for are for diseases that would not be detected on a typical exome screen6. “You need a very special chemistry and bioinformatics pipeline to analyze things such as pseudogenes,” he says. In addition, they have custom assays for conditions like 21-hydroxylase-deficient congenital adrenal hyperplasia, which is not uncommon but is difficult to diagnose. This type of testing, Evans says, is about “balancing two paths: you want maximum ability to detect risk, but you also need to be confident about the negatives.” For Counsyl, that's meant designing a lot of custom assays and workflows.

Evans stresses that it's also necessary to have appropriate counseling available for parents. Because the expressivity of mutations vary, not every mutation is going to have the same effect, and would-be parents need to understand that. Another key element is education for physicians about this rapidly advancing field.

GenePeeks, in Cambridge, Massachusetts, does preconception screening with a computational genetics focus. They generate a “Variant Gene Dysfunction” (VGD) score for every variant found in each parent. This data is then mapped to “virtual progeny,” created based on the parents' genomes. This process is used to estimate the risk of approximately 1,000 genetic diseases. “We use all the data that exist on variants,” says cofounder and CSO Lee Silver. He points out that 100% of people carry some mutations, but the impact of mutations within a single gene varies significantly. “The question isn't whether you are positive for a mutation or not, it's whether or not that presents a risk to your future offspring.”

The company works with any patient planning a pregnancy, but a lot of their clients are undergoing IVF or using donor eggs: “We want to move the intervention from prenatal to preconception,” Silver says. If a couple is found to be at high risk for having an affected child, the company can refer them to experts in PGD. GenePeeks is working with partners in Japan and the Middle East, with plans to expand to Europe and Asia.

Danvers, Massachusetts–based Veritas Genetics, meanwhile, wants to provide testing that is “out-of-pocket affordable,” says founder and CEO Mirza Cifric. The company's focus is whole genome sequencing and interpretation, which includes data on hereditary conditions. But it also offers prenatal and newborn genetic testing and is expanding into carrier testing. What's unique about Veritas is that while many companies are focused on the affluent customers in the US, Veritas is looking beyond that. The world market comprises millions of births in the US and many more millions outside it. “There are over 19 million births per year in China alone,” Cifric points out. Veritas has an office and a College of American Pathologists (CAP)-accredited lab in China that is in the process of becoming US CLIA (Clinical Laboratory Improvement Amendments) certified.

Veritas' products have now generated business in at least 30 countries. It's not clear if the company's carrier testing products will even be offered in the US at first, though, because there is so little room for price competition in this market now. But Veritas is charging forward overseas, and will be watching the US market closely. “Once you make something accessible and affordable, it catches on,” Cifric says.

Going forward, Counsyl, GenePeeks, Veritas, and their competitors are seeking to expand the number of conditions they can test for as well as the number of couples, or individuals, wishing to start a family that they can reach. Most of these companies also offer other services. Counsyl, for example, also provides prenatal and cancer risk testing. Veritas offers prenatal and newborn screening testing (the latter only in China), and will be aggressively competing on cost.

Selecting your baby

There is little to show yet that you can actually use DNA to find a compatible mate, but the options for would-be parents seeking to learn about potential health issues in their children make this one of the fastest-moving fields in reproductive medicine.

Although there has been a rapid uptake of prenatal testing, some feel that it's going to take time for all of this technology to become commonplace. “I think that in 20 to 40 years most babies will be made using PGD,” says Hank Greely, a professor and director of the Center for Law and the Biosciences at Stanford University and the author of the book The End of Sex and the Future of Human Reproduction (Harvard University Press, 2016). One of the key ethical issues that comes up is whether couples will practice sex selection or begin seeking 'designer' babies by selecting embryos for height, eye color, or other nonmedical related features, either based on prenatal testing or through the use of gene-editing technology.

Although sex selection is already going on, determining other human features is still not even technically possible. “It's important to make a distinction between 'designing' and 'selecting' embryos,” Greely says. “Right now we are at the selection stage; designing is a long way off.”

The biggest question, he says, will be access—whether families will be left out of the selection process because they simply cannot afford it. In the meantime, there will be an expansion in the use of noninvasive prenatal testing, or NIPT7, which is already increasingly being advised, even for pregnancies not considered at high risk of being affected by genetic conditions.

Stephen Kingsmore of Rady Children's Institute for Genomic Medicine, in San Diego, also foresees the growth of a new field: materno-fetal medicine. “There are more things we can do when we find a defect in utero,” he says, including surgery, transfusions, and drug treatments.

Rady recently purchased one of Illumina's new NovaSeq instruments, which are capable of rapid and highly accurate sequencing. The hospital plans to partner with children's hospitals around the country, offering up Rady's experience with such cases as well as their sequencing and analytical capabilities for prenatal testing and newborn screening. “The fastest diagnosis we've done so far took just 26 hours,” Kingsmore says. “We tested 114 families this year, and we plan to take it up to 900 now.”

This type of testing, from before conception through the newborn stage, appears to be in demand, based on worldwide sales of tests, which could lead price competition. It will be spreading around the world, potentially changing forever the way that babies are made and treated in their first months of life. Veritas's Cifric, however, says that the future lies in whole-genome sequencing. Veritas can already do a whole genome for under $1,000. “Everybody can do the same targeted tests,” he says. “The incremental value is [achieved] by doing the whole genome.”

“The science is zooming ahead,” says Genepeek's Silver. “Soon we will have a million human gene sequences and the clinical databases are growing exponentially.” That's plenty of fuel to fire up a boom.

Change history

  • Corrected online 14 December 2017

    In the version of this article initially published, on p.1019, Yurttas Beim's name was misspelled as “Biem,” and on p.1020, Hank Greely's last name was misspelled as “Greeley” twice. The errors have been corrected in the HTML and PDF versions of the article.

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