Clinical laboratory managers should note that this company’s new diagnostic offering involving screening embryos for specific genetic conditions is not without controversy
Is the world ready for whole genome sequencing (WGS) of preimplantation embryos to help couples undergoing in vitro fertilization (IVF) treatments know if their embryos have potential genetic health problems? Orchid Health, a clinical preimplantation genetic testing (PGT) laboratory that conducts genetic screening in San Francisco, believes the answer is yes! But the cost is high, and the process is not without controversy.
According to an article in Science, Orchid’s service—a sequencings of the whole human genome of preimplantation embryos at $2,500 per embryo tested—“will look not just for single-gene mutations that cause disorders such as cystic fibrosis, but also more extensively for medleys of common and rare gene variants known to predispose people to neurodevelopmental disorders, severe obesity, and certain psychiatric conditions such as schizophrenia.”
However, Science also noted that some genomics researchers “claim the company inappropriately uses their data to generate some of its risk estimates,” adding that the “Psychiatric Genomics Consortium (PGC), an international group of more than 800 researchers working to decode the genetic and molecular underpinnings of mental health conditions, says Orchid’s new test relies on data [PGC] produced over the past decade, and that the company has violated restrictions against the data’s use for embryo screening.”
There are some who assert that a whole genome sequence of an embryo—given today’s state of genetic technology and knowledge—could generate information that cannot be interpreted accurately in ways that help parents and doctors make informed prenatal testing decisions. At the same time, criticisms expressed by the PGC raise reasonable points.
Perhaps this is a sign of the times. Orchid Health is the latest genetic testing company that is looking to get ahead of genetic testing competitors with its diagnostics offerings. Meanwhile, knowledgeable and credible experts question the appropriateness of this testing, given the genetic knowledge that exists today.
“This is a major advance in the amount of information parents can have,” Orchid’s founder and CEO Noor Siddiqui (above) told CNBC. “The way that you can use that information is really up to you, but it gives a lot more control and confidence into a process that, for all of history, has just been totally left to chance.” Should Orchid Health’s analysis prove useful, pediatricians could order further clinical laboratory prenatal testing to confirm and diagnose potential genetic diseases for parents. (Photo copyright: General Assembly.)
Orchid Receives World-class Support
Regardless of the pushback from some genetic researchers, Orchid has attracted several world-class geneticists and genetics investors to its board of advisors. They include:
Jacques Cohen, PhD, embryologist, co-founder and former director for genetics laboratory Reprogenetics LLC (now CooperGenomics).
Anne Wojcicki, co-founder and CEO of direct-to-consumer genetic testing company 23andMe.
and others.
The WGS test, according to Orchid, detects genetic errors in embryos that are linked to severe illnesses before a pregnancy even begins. And by sequencing 99% of an embryo’s DNA, the test can spot potential health risks that could affect a future baby.
According to its website, the PGT lab company uses the WGS data to identify both monogenic (single-gene) and polygenic (multiple-gene) diseases, including:
Orchid is not without its critics. Knowledgeable, credible experts have questioned the appropriateness of this type of genetic testing. They fear it could become a modern-day form of eugenics.
Andrew McQuillin, PhD, Professor of Molecular Psychiatry at University College London, has concerns about Orchid’s preimplantation genetic testing. He maintains that it is difficult to control how such data is used, and that even the most accurate sequencing techniques do not predict disease risk very well.
“[Polygenic risk scores are] useful in the research context, but at the individual level, they’re not actually terribly useful to predict who’s going to develop schizophrenia or not,” McQuillin told Science. “We can come up with guidance on how these things should be used. The difficulty is that official guidance like that doesn’t feature anywhere in the marketing from these companies.”
McQuillin also stated that researchers must have an extensive discussion regarding the implications of this type of embryo screening.
“We need to take a look at whether this is really something we should be doing. It’s the type of thing that, if it becomes widespread, in 40 years’ time, we will ask, ‘What on Earth have we done?’” McQuillin emphasized.
Redefining Reproduction
It takes about three weeks for couples to receive their report back from Orchid after completing the whole genome sequence of a preimplantation embryo. A board-certified genetic counselor then consults with the parents to help them understand the results.
Founder and CEO Noor Siddiqui hopes Orchid will be able to scale up its operations and introduce more automation to the testing process to the cost per embryo.
“We want to make this something that’s accessible to everyone,” she told CNBC.
“I think this has the potential to totally redefine reproduction,” she added. “I just think that’s really exciting to be able to make people more confident about one of the most important decisions of their life, and to give them a little bit more control.”
Clinical laboratories have long been involved in prenatal screening to gain insight into risk levels associated with certain genetic disorders. Even some of that testing comes with controversy and ambiguous findings. Whether Orchid Health’s PGT process delivers accurate, reliable diagnostic insights regarding preimplantation embryos remains to be seen.
By analyzing strains of the bacterium from a hospital ICU, the scientists learned that most infections were triggered within patients, not from cross-transmission
Tracking the source of Hospital-acquired infections (HAI) has long been centered around the assumption that most HAIs originate from cross-transmission within the hospital or healthcare setting. And prevention measures are costly for hospitals and medical laboratories. However, new research puts a surprising new angle on a different source for some proportion of these infections.
The study suggests that most infections caused by Clostridioides difficile (C. Diff), the bacterium most responsible for HAIs, arise not from cross-transmission in the hospital, but within patients who already carry the bacterium.
A researcher performed whole genome sequencing on 425 strains of the bacterium isolated from the samples and found “very little evidence that the strains of C. diff from one patient to the next were the same, which would imply in-hospital acquisition,” according to a UM news story.
“In fact, there were only six genomically supported transmissions over the study period. Instead, people who were already colonized were at greater risk of transitioning to infection,” UM stated.
Arianna Miles-Jay, PhD, a postdoctoral fellow in The Snitkin Lab at the University of Michigan and Manager of the Genomic Analysis Unit at the Michigan Department of Health and Human Services, performed the genomic sequencing. “By systematically culturing every patient, we thought we could understand how transmission was happening. The surprise was that, based on the genomics, there was very little transmission,” she said in the UM news story.
“Something happened to these patients that we still don’t understand to trigger the transition from C. diff hanging out in the gut to the organism causing diarrhea and the other complications resulting from infection,” said Evan Snitkin, PhD (above), Associate Professor of Microbiology and Immunology, and Associate Professor of Internal Medicine, Division of Infectious Diseases at University of Michigan, in a UM news story. Medical laboratories involved in hospital-acquired infection prevention understand the importance of this research and its effect on patient safety. (Photo copyright: University of Michigan.)
Only a Fraction of HAIs Are Through Cross-Transmission
In the study abstract, the researchers wrote that “despite enhanced infection prevention efforts, Clostridioides difficile remains the leading cause of healthcare-associated infections in the United States.”
Citing data from the US Centers for Disease Control and Prevention (CDC), HealthDay reported that “nearly half a million C. diff infections occur in the United States each year. Between 13,000 and 16,000 people die from the bacterium, which causes watery diarrhea and inflammation of the colon. Many of these infections and deaths have been blamed on transmission between hospitalized patients.”
The new study, however, notes that 9.3% of the patients admitted to the ICU carried toxigenic (produces toxins) C. diff, but only 1% acquired it via cross-transmission. The carriers, the study authors wrote, “posed minimal risk to others,” but were 24 times more likely to develop a C. diff infection than non-carriers.
“Our findings suggest that measures in place in the ICU at the time of the study—high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms —were effective in preventing C. diff transmission,” Snitkin told HealthDay. “This indicates that to make further progress in protecting patients from developing C. diff infections will require improving our understanding of the triggers that lead patients asymptomatically carrying C. diff to transition to having infections.”
Recognizing Risk Factors
Despite the finding that infections were largely triggered within the patients, the researchers still emphasized the importance of taking measures to prevent hospital-acquired infections.
“In fact, the measures in place in the Rush ICU at the time of the study—high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms—were likely responsible for the low transmission rate,” the UM news story noted.
One expert not involved with the study suggested that hospitals’ use of antibiotics may be a factor in causing C. diff carriers to develop infections.
“These findings suggest that while we should continue our current infection prevention strategies, attention should also be given to identifying the individuals who are asymptomatic carriers and finding ways to reduce their risk of developing an infection, like carefully optimizing antibiotic usage and recognizing other risk factors,” Hannah Newman, Senior Director of Infection Prevention at Lenox Hill Hospital in New York City, told HealthDay.
Snitkin, however, told HealthDay that other factors are likely at play. “There is support for antibiotic disruption of the microbiota being one type of trigger event, but there is certainly more to it than that, as not every patient who carries C. diff and receives antibiotics will develop an infection.”
Another expert not involved with the study told HealthDay that “many patients are already colonized,” especially older ones or those who have been previously hospitalized.
“A lot of their normal flora in their GI tract can be altered either through surgery or antibiotics or some other mechanism, and then symptoms occur, and that’s when they are treated with antibiotics,” said Donna Armellino, RN, Senior VP of Infection Prevention at Northwell Health in Manhasset, New York.
This research also demonstrates the value of faster, cheaper, more accurate gene sequencing for researching life-threatening conditions. Microbiologists, Clinical laboratory scientists, and pathologists will want monitor further developments involving these findings as researchers from University of Michigan and Rush University Medical Center continue to learn more about the source of C. diff infections.
Clinical laboratories and pathology groups may soon have new assays for diagnosis, treatment identification, patient monitoring
It’s here at last! The human Y chromosome now has a full and complete sequence. This achievement by an international team of genetic researchers is expected to open the door to significant insights in how variants and mutations in the Y chromosome are involved in various diseases and health conditions. In turn, these insights could lead to new diagnostic assays for use by clinical laboratories and pathology groups.
Pathologists and clinical laboratories involved in genetic research will understand the significance of this accomplishment. The full Y chromosome sequence “fills in gaps across more than 50% of the Y chromosome’s length, [and] uncovers important genomic features with implications for fertility, such as factors in sperm production,” SciTechDaily noted.
This breakthrough will make it possible for other research teams to gain further understanding of the functions of the Y chromosome and how specific gene variants and mutations contribute to specific health conditions and diseases. In turn, knowledge of those genetic sequences and mutations would give clinical laboratories the assays that help diagnosis, identify relevant therapies, and monitor a patient’s progress.
“When you find variation that you haven’t seen before, the hope is always that those genomic variants will be important for understanding human health,” said Adam Phillippy, PhD, a senior investigator and head of the Genome Informatics Section at the National Human Genome Research Institute, in a press release. Clinical laboratories and anatomic pathology groups may soon have new assays based on the T2T study findings. (Photo copyright: National Human Genome Research Institute.)
Study Background and Recognition
Revolutionary thinking by the Telomere-to-Telomere (T2T) scientists led to the team’s breakthrough. The researchers “applied new DNA sequencing technologies and sequence assembly methods, as well as knowledge gained from generating the first gapless sequences for the other 23 human chromosomes,” SciTechDaily reported.
In 1977, the first complete genome of an organism was sequenced. Thus began the commencement of sequencing technology research. Twenty years ago the first human genome sequence was completed. The result was thanks to years of work through the preferred “chain termination” (aka, Sanger Sequencing) method developed by Fred Sanger and a $2.7 billion contribution from the Human Genome Project, according to a study published in the African Journal of Laboratory Medicine (AJLM).
By 2005, a new era in genomic sequencing emerged. Scientists now employed a technique called pyrosequencing and the change had great benefits. “Massively parallel or next-generation sequencing (NGS) technologies eliminated the need for multiple personnel working on a genome by automating DNA cleavage, amplification, and parallel short-read sequencing on a single instrument, thereby lowering costs and increasing throughput,” the AJLM paper noted.
The new technique brought great results. “Next-generation sequencing technologies have made sequencing much easier, faster and cheaper than Sanger sequencing,” the AJLM study authors noted.
The changes allowed more sequencing to be completed. Nevertheless, more than half of the Y chromosome sequence was still unknown until the new findings from the T2T study, SciTechDaily reported.
Why the TDT Breakthrough Is So Important
“The biggest surprise was how organized the repeats are,” said Adam Phillippy, PhD, a senior investigator and head of the NHGRI. “We didn’t know what exactly made up the missing sequence. It could have been very chaotic, but instead, nearly half of the chromosome is made of alternating blocks of two specific repeating sequences known as satellite DNA. It makes a beautiful, quilt-like pattern.”
Much can be gained in knowing more about the Y chromosome. Along with the X chromosome, it is significant in sexual development. Additionally, current research is showing that genes on the Y chromosome are linked to the risk and severity of cancer.
Might What Comes Next Give Clinical Labs New Diagnostic Tools?
The variety of new regions of the Y chromosome that the T2T team discovered bring into focus several areas of new genetic research. For instance, the “azoospermia factor region, a stretch of DNA containing several genes known to be involved in sperm production” was uncovered, and “with the newly completed sequence, the researchers studied the structure of a set of inverted repeats or palindromes in the azoospermia factor region,” SciTechDaily reported.
“This structure is very important because occasionally these palindromes can create loops of DNA. Sometimes, these loops accidentally get cut off and create deletions in the genome,” said Arang Rhie, PhD, a staff scientist at NHGRI and first author of the Nature study.
Missing regions would challenge the production of sperm, impacting fertility, so being able to finally see a complete sequence will help research in this area.
Scientists are only just beginning to recognize the value of this breakthrough to future genetic research and development. As genetic sequencing costs continue to drop, the T2T research findings could mean new treatment options for pathologists and diagnostic assays for clinical laboratories are just around the corner.
Genetic scientists show how rapid WGS is helping doctors determine best treatments for patients with life-threatening conditions
Clinical laboratory scientists will recall that last year, Dark Daily covered how researchers at Stanford University School of Medicine had developed a method for performing rapid whole genomic sequencing (WGS) in as little as five hours. We predicted that their new ultra-rapid genome sequencing approach could lead to significantly faster diagnostics and improved clinical laboratory treatments for cancer and other diseases. And it has.
The research scientist responsible for that breakthrough is cardiologist and Associate Dean of Stanford University School of Medicine, Euan Ashley, MD, PhD. Ashley is also a professor of genomics and precision health, cardiovascular medicine, genetics, and biomedical data science and pathology.
Ashley’s success demonstrates that the drive to reduce the diagnostic time to answer is a market dynamic encouraging research companies to continue finding ways to make WGS faster to accomplish, cheaper to perform, and the DNA sequences generated more accurate.
It is precisely these developments that will provide clinical laboratories and anatomic pathology groups with new means for improving diagnosis and the identification of the most appropriate therapies for individual patients—a core element of precision medicine.
Ashley’s team is now looking at how faster genetic sequencing results could help physicians make life-and-death treatment decisions, STAT reported.
“There’s just never been a better time to be doing genomics,” cardiologist Euan Ashley, MD, PhD, Associate Dean of the Stanford University School of Medicine, told STAT. “Now there are lots of choices. If you’re a genome center and you need to do half a million genomes, you’re going to be extremely price-sensitive. If you’re a clinical lab, where you get a few exomes and a few genomes every day, and what really matters to you is the highest possible accuracy for diagnosis, then you’re definitely going to make a different choice,” he added. (Photo copyright: euanangusashley.com.)
Getting Crucial Genetic Information Faster
Ashley believes that if doctors who work with rare and deadly diseases get crucial genetic information faster, they can more precisely determine which surgical procedures are best for their patients during life-or-death situations.
Already, his work is proving highly successful. In a letter his team published in the New England Journal of Medicine (NEJM), the researchers reported 12 cases of sequencing seriously ill patients, five of whom were diagnosed in seven hours and 18 minutes. Every single case resulted in tangible changes in treatments given to the patients.
“We continue to be interested in sequencing genomes faster and more accurately, for a broader range of clinical applications. We’re recruiting from intensive care units similar kinds of patients to the ones we did before, but with every aspect of the pipeline upgraded, which helps both from a speed but also from an accuracy perspective,” he told STAT.
Ashley and his team continue to delve into the patient care aspects, striving to continue to make a big impact. In addition, the group is being sought out by cancer doctors who need faster diagnoses.
“We also have a lot of interest from cancer doctors saying it’s really important to make a cancer diagnosis quickly. And of course, there is no person who’s ever had the specter of cancer hanging over them for a moment that didn’t want some kind of an answer faster. If you can have it in the next minute, you would take it rather than waiting several weeks,” he noted.
As a result, the group has initiated pilot studies “to look at returning results faster in the same way that we were speeding up the intensive care unit with whole genome sequencing,” Ashley told STAT.
Though the work is in the early stages, the team has a few scenarios where access to genetic data changes medical decision making. For instance, when genetic test results showing a positive BRCA variant alter a doctor’s surgical plan.
“We don’t wait for a cardiac enzyme [test] if somebody’s having a heart attack. That comes back within 10 minutes to a few hours from the lab. I don’t see why you should have to wait for a test to tell you if you’re positive for BRCA variant,” he told STAT.
“Another very obvious place is acute leukemia. And there’s a number of actionable conditions where if they can be detected rapidly, then treatment can be started faster,” he added.
Improving Genetic Sequencing Accuracy while Lowering Costs
STAT asked Ashley about a claim that his team could cut their Guinness World Record sequencing time in half.
“It’s easy to throw that number around, harder to deliver on it. But I think we’re definitely on track to knock hours, not minutes, off that record,” he said.
Additionally, the team continues to work on decreasing cost per genome. In just the time since the record was set, there has already been great strides in this area. The market is filled with new companies and the competition has lowered costs.
“It has definitely come down,” Ashely noted. “In fact, by the time we ended up publishing the [NEJM] paper—as opposed to when we first did this calculation—the cost was already lower. And that was actually before the entry of these new companies to the market, which added downward pressure on costs of sequencing,” he added.
Getting Payers to Reimburse for Genetic Sequencing
Even though costs for WGS is dropping, getting health plans to reimburse for genetic testing remains difficult.
“The challenge now is persuading payers to the very obvious fact that this technology makes patients’ lives better and saves them money,” Ashley told STAT. “And that’s the amazing part. There are so many cost-effectiveness studies now for this technology and yet we are still paying people to sit on the phone all day long and debate with insurance companies.
“And in a world where we pay a very large amount of money for therapeutics, these diagnostics can be cost-saving and lifesaving. At some level, it’s hard to understand why it hasn’t been deployed much more readily,” he concluded.
Clinical laboratory leaders, pathologists, and research scientists should continue to monitor the development of rapid genetic sequencing for diagnostic purposes.
Research in the UK and US into how rapid WGS can prevent deaths and improve outcomes for kids with rare genetic diseases may lead to more genetic testing based in local clinical laboratories
Genetic scientists with the National Health Service (NHS) in England have embarked on an ambitious plan to offer rapid whole genome sequencing (rWGS) for children and babies with serious illnesses, as part of a larger initiative to embrace genomic medicine in the United Kingdom (UK).
The NHS estimates that the plan will benefit more than 1,000 children and babies each year, including newborns with rare diseases such as cancer, as well as kids placed in intensive care after being admitted to hospitals. Instead of waiting weeks for results from conventional tests, clinicians will be able to administer a simple blood test and get results within days, the NHS said in a press release.
The press release notes that about 75% of rare genetic diseases appear during childhood “and are responsible for almost a third of neonatal intensive care deaths.”
Here in the United States, pathologists and clinical laboratory managers should see this development as a progressive step toward expanding access to genetic tests and whole genome sequencing services. The UK is looking at this service as a nationwide service. By contrast, given the size of the population and geography of the United States, as this line of medical laboratory testing expands in the US, it will probably be centered in select regional centers of excellence.
“This strategy sets out how more people will be empowered to take preventative action following risk-based predictions, receive life-changing diagnoses, and get the support needed to live with genomically-informed diagnoses alongside improved access to cutting-edge precision [medicine] treatments. It also outlines how the NHS will accelerate future high-quality genomic innovation that can be adopted and spread across the country, leading to positive impacts for current and future generations,” the NHS wrote.
“This global first is an incredible moment for the NHS and will be revolutionary in helping us to rapidly diagnose the illnesses of thousands of seriously ill children and babies—saving countless lives in the years to come,” said NHS chief executive Amanda Pritchard (above) in a press release announcing the program. (Photo copyright: Hospital Times.)
New Rapid Whole Genome Sequencing Service
The NHS announced the plan following a series of trials last year. In one trial, a five-day old infant was admitted to a hospital in Cheltenham, Gloucester, with potentially deadly levels of ammonia in his blood. Whole genome sequencing revealed that changes in the CPS1 gene were preventing his body from breaking down nitrogen, which led to the spike in ammonia. He was given life-saving medication in advance of a liver transplant that doctors believed would cure the condition. Without the rapid genetic test, doctors likely would have performed an invasive liver biopsy.
Using a simple blood test, the new newborn genetic screening service in England is expected to benefit more than 1,000 critically ill infants each year, potentially saving their lives. “The rapid whole genome testing service will transform how rare genetic conditions are diagnosed,” explained Emma Baple, PhD, Professor of Genomic Medicine at University of Exeter Medical School and leader of the National Rapid Whole Genome Sequencing Service in the press release. “We know that with prompt and accurate diagnosis, conditions could be cured or better managed with the right clinical care, which would be life-altering—and potentially life-saving—for so many seriously unwell babies and children,” Precision Medicine Institute reported.
According to The Guardian, test results will be available in two to seven days.
Along with the new rWGS testing service, the NHS announced a five-year plan to implement genomic medicine more broadly. The provisions include establishment of an ethics advisory board, more training for NHS personnel, and an expansion of genomic testing within the existing NHS diagnostic infrastructure. The latter could include using NHS Community Diagnostics centers to collect blood samples from family members to test for inherited diseases.
UK’s Longtime Interest in Whole Genome Sequencing
The UK government has long been interested in the potential role of WGS for delivering better outcomes for patients with genetic diseases, The Guardian reported.
In 2013, the government launched the 100,000 Genomes Project to examine the usefulness of the technology. In November 2021, investigators with the project reported the results of a large pilot study in which they analyzed the genomes of 4,660 individuals with rare diseases. The study, published in the New England Journal of Medicine (NEJM) titled, “100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care—Preliminary Report,” found “a substantial increase in yield of genomic diagnoses made in patients with the use of genome sequencing across a broad spectrum of rare disease.”
The study’s findings suggest that use of WGS “could save the NHS millions of pounds,” The Guardian reported.
Whole Genome Sequencing System for Newborns in the US
“This NBS-rWGS [newborn screening by rapid whole genome sequencing] system is designed to complement the existing newborn screening process and has the potential to eliminate the diagnostic and therapeutic odyssey that many children and parents face,” Kingsmore said in a press release. “Currently, only 35 core genetic disorders are recommended for newborn screening in the United States, but there are more than 7,200 known genetic diseases. Outcomes remain poor for newborns with a genetic disease because of the limited number of recommended screenings. With NBS-rWGS, we can more quickly expand that number and therefore potentially improve outcomes through precision medicine.”
A more recent 2023 study which examined 112 infant deaths at Rady Children’s Hospital found that 40% of the babies had genetic diseases. In seven infants, genetic diseases were identified post-mortem, and in five of them “death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission,” the authors wrote.
“Prior etiologic studies of infant mortality are generally retrospective, based on electronic health record and death certificate review, and without genome information, leading to underdiagnosis of genetic diseases,” said Christina Chambers, PhD, co-author of the study, in a press release. “In fact, prior studies show at least 30% of death certificates have inaccuracies. By implementing broad use of genome sequencing in newborns we might substantially reduce infant mortality.”
Pioneering work with whole genome sequencing for newborns, such as that being conducted by the clinical laboratory and genetic teams at Rady Children’s Hospital and the UK’s NHS, could allow doctors to make timely interventions for our most vulnerable patients.
