Understanding why some mutations impair normal bodily functions and contribute to cancer may lead to new clinical laboratory diagnostics
New insight into the human genome may help explain the ageing process and provide clues to improving human longevity that can be useful to clinical laboratories and researchers developing cancer diagnostics. A recent study conducted at the Wellcome Sanger Institute in Cambridge, United Kingdom, suggests that the speed of DNA errors in genetic mutations may play a critical role in the lifespan and survival of a species.
To perform their research, the scientists analyzed genomes from the intestines of 16 mammalian species looking for genetic changes. Known as somatic mutations, these mutations are a natural process that occur in all cells during the life of an organism and are typically harmless. However, some somatic mutations can impair the normal function of a cell and even play a role in causing cancer.
“Aging is a complex process, the result of multiple forms of molecular damage in our cells and tissues. Somatic mutations have been speculated to contribute to ageing since the 1950s, but studying them had remained difficult,” said Inigo Martincorena, PhD (above), Group Leader, Sanger Institute and one of the authors of the study. Greater understanding of the role DNA mutations play in cancer could lead to new clinical laboratory tools and diagnostics. (Photo copyright: Wellcome Sanger Institute.)
Lifespans versus Body Mass
The mammalian subjects examined in the study incorporated a wide range of lifespans and body masses and included humans, giraffes, tigers, mice, and the highly cancer-resistant naked mole-rat. The average number of somatic mutations at the end of a lifespan was around 3,200 for all the species studied, despite vast differences in age and body mass. It appears that species with longer lifespans can slow down their rate of genetic mutations.
The average lifespan of the humans used for the study was 83.6 years and they had a somatic mutation rate of 47 per year. Mice examined for the research endured 796 of the mutations annually and only lived for 3.7 years.
Species with similar amounts of the mutations had comparable lifespans. For example, the small, naked mole-rats analyzed experienced 93 mutations per year and lived to be 25 years of age. On the other hand, much larger giraffes encountered 99 mutations each year and had a lifespan of 24 years.
“With the recent advances in DNA sequencing technologies, we can finally investigate the roles that somatic mutations play in ageing and in multiple diseases,” said Inigo Martincorena, PhD, Group Leader, Sanger Institute, one of the authors of the study in a press release. He added, “That this diverse range of mammals end their lives with a similar number of mutations in their cells is an exciting and intriguing discovery.”
The scientists analyzed the patterns of the mutations and found that the somatic mutations accumulated linearly over time. They also discovered that the mutations were caused by similar mechanisms and the number acquired were relatively similar across all the species, despite a difference in diet and life histories. For example, a giraffe is typically 40,000 times larger than a mouse, but both species accumulate a similar number of somatic mutations during their lifetimes.
“The fact that differences in somatic mutation rate seem to be explained by differences in lifespan, rather than body size, suggests that although adjusting the mutation rate sounds like an elegant way of controlling the incidence of cancer across species, evolution has not actually chosen this path,” said Adrian Baez-Ortega, PhD, postdoctoral researcher at the Sanger Institute and one of the paper’s authors, in the press release.
“It is quite possible that every time a species evolves a larger size than its ancestors—as in giraffes, elephants, and whales—evolution might come up with a different solution to this problem. We will need to study these species in greater detail to find out,” he speculated.
Why Some Species Live Longer than Others
The researchers also found that the rate of somatic mutations decreased as the lifespan of each species increased which suggests the mutations have a likely role in ageing. It appears that humans and animals perish after accumulating a similar number of these genetic mutations which implies that the speed of the mutations is vital in ascertaining lifespan and could explain why some species live substantially longer than others.
“To find a similar pattern of genetic changes in animals as different from one another as a mouse and a tiger was surprising. But the most exciting aspect of the study has to be finding that lifespan is inversely proportional to the somatic mutation rate,” said Alex Cagan, PhD, Postdoctoral Fellow at the Sanger Institute and one of the authors of the study in the press release.
“This suggests that somatic mutations may play a role in ageing, although alternative explanations may be possible. Over the next few years, it will be fascinating to extend these studies into even more diverse species, such as insects or plants,” he noted.
Benefit of Understanding Ageing and Death
The scientists believe this study may provide insight to understanding the ageing process and the inevitability and timing of death. They surmise that ageing is likely to be caused by the aggregation of multiple types of damage to the cells and tissues suffered throughout a lifetime, including somatic mutations.
Some companies that offer genetic tests claim their products can predict longevity, despite the lack of widely accepted evidence that such tests are accurate within an acceptable range. Further research is needed to confirm that the findings of the Wellcome Sanger Institute study are relevant to understand the ageing process.
If the results are validated, though, it is probable that new direct-to-consumer (DTC) genetic tests will be developed, which could be a new revenue source for clinical laboratories.
In fact, the UB study suggests traditional anatomical methods for determining the evolutionary relationships between species may not be as accurate as once thought, an article in SciTechDaily reported.
Nevertheless, the UB’s research into convergent evolution is unlocking new insights into how genes evolve over time and this new knowledge may help researchers develop genetic tests that more accurately identify different diseases and health conditions.
Additionally, studies that bring a better understanding of how beneficial genetic mutations work their way into a species’ genome might also aid researchers in developing personalized clinical laboratory testing and therapies based on manipulating a patient’s genetic sequences in ways that would be beneficial.
Gene Sequencing More Accurate at Determining Evolutionary Relationships
The UB study suggests that existing evolutionary (phylogenetic) trees may need to be reconsidered. To put a finer point on the findings, a UB news release on the study states, “determining evolutionary trees of organisms by comparing anatomy rather than gene sequences is misleading.”
The UB scientists used genetic sequencing to quickly—and more cost effectively—determine evolutionary relationships as compared to traditional morphology (anatomy and structure), according to the news release.
They found genetic data that revealed surprising relationships about where the sequenced species originated, and which differed with prior conclusions that were drawn based on the species’ appearance. The findings suggest there may be need to “overturn centuries of scientific work in classifying relation of species by physical traits,” the UB scientists said.
“For over a hundred years, we’ve been classifying organisms according to how they look and are put together anatomically, but molecular data often tells us a rather different story,” said Matthew Wills, PhD (above), Professor of Evolutionary Paleobiology, Milner Center for Education at the University of Bath, in the news release. “Our study proves statistically that if you build an evolutionary tree of animals based on their molecular data, it often fits much better with their geographical distribution.” This new use of genetic sequencing could lead to improved precision medicine treatments and clinical laboratory testing. (Photo copyright: University of Bath.)
Molecular Data Leads to New Insights into Convergent Evolution
The UB study’s use of genetic sequencing led the researchers to a greater understanding of convergent evolution, defined by “a characteristic evolving separately in two genetically unrelated groups of organisms,” according to UB.
For example, wings are a widely developed characteristic. But they are not necessarily a sign of relatedness when it comes to birds, bats, and insects.
“Now with molecular data, we can see that convergent evolution happens all the time—things we thought were closely related often turn out to be far apart on the tree of life,” Wills said, adding, “Individuals within a family don’t always look similar; it’s the same with evolutionary trees, too.”
Family Trees: Morphology Versus Molecular
In their paper, the UB researchers acknowledged the importance of phylogenies (evolutionary history of species) in areas of biology, including medicine. They aimed to study a better way to produce accurate phylogenetic trees.
“Phylogenetic relationships are inferred principally from two classes of data: morphological and molecular,” they wrote, adding, “The superiority of molecular trees has rarely been assessed empirically.”
So, they set out to compare the two approaches to building evolutionary trees:
Traditional morphology analysis, and
Phylogenetic trees developed using molecular data.
Using 48 pairs of morphological and molecular trees, they mapped data geographically.
“We show that, on average, molecular trees provide a better fit to biogeographic data than their morphological counterparts, and that biogeographic congruence increases over research time,” the researchers wrote.
Biogeography a Better Gauge of Relatedness than Anatomy
The study also found animals on molecular trees lived geographically closer as compared to groups on morphological trees.
For example, molecular studies put aardvarks, elephants, golden moles, swimming manatees, and elephant shews in an Afrotheria group, named for Africa, which is where they came from. Therefore, the biogeography matches, however the appearances of these mammals clearly do not, the UB scientists point out.
“What’s most exciting is that we find strong statistical proof of molecular trees fitting better not just in groups like Afrotheria, but across the tree of life in birds, reptiles, insects, and plants,” said Jack Oyston PhD, UB Department of Biology and Biochemistry Research Associate and first author of the study, in the news release.
The researchers believe their findings support the accuracy of genetic-themed trees.
“It being such a widespread pattern makes it much more potentially useful as a general test of different evolutionary trees. But it also shows just how pervasive convergent evolution has been when it comes to misleading us,” Oyston added.
Advantages of Molecular Data
In their Nature Communications Biology paper, the UB scientists wrote that molecular data offer up these advantages over morphology:
Widely available in vast quantity.
Opportunity exists to “search, repurpose, and reanalyze sequenced data alongside novel sequences.”
Less subjectivity in researchers’ analysis.
Well-developed data at the ready and “still in their infancy.”
The University of Bath’s study of convergent evolution, phylogenetic trees, and comparison of molecular data versus morphology, has implications for medical laboratories. Should their research lead to new insights into how genes evolve over time, diagnostics professionals may have new information to identity diseases and work with others to precisely treat patients.
Supplychain shortages involving clinical laboratory products may not ease up any time soon, as China’s largest shipping province is once again in COVID-19 lockdown
Following two years of extremely high demand, pathology laboratories as well as non-medical labs in the United Kingdom (UK) and Europe are experiencing significant shortages of laboratory resources as well as rising costs. That’s according to a recently released survey by Starlab Group, a European supplier of lab products.
In its latest annual “mood barometer” survey of around 200 lab professionals in the UK, Germany, Austria, Italy, and France, Starlab Group received reports of “empty warehouses” and a current shortage of much needed lab equipment, reportedly as a result of rising costs, high demand, and stockpiling of critical materials needed by pathology laboratories during the COVID-19 pandemic, according to Laboratory News.
The survey respondents, who represented both medical laboratories and research labs, noted experiencing more pressure from staff shortages and insufficient supplies required to meet testing demands in 2021 as compared to 2020. For example, only 23% of respondents said they had enough liquid handling materials—such as protective gloves and pipettes—in 2021, down from 39% who responded to the same question in 2020.
“The entire laboratory industry has been in a vicious circle for two years. While more and more materials are needed, there’s a lack of supplies. At the same time, laboratories want to stockpile material, putting additional pressure on demand, suppliers, and prices,” Denise Fane de Salis, Starlab’s UK Managing Director and Area Head for Northern Europe, told Process Engineering. “Institutes that perform important basic work cannot keep up with the price competition triggered by COVID-19 and are particularly suffering from this situation,” she added.
“COVID-19 is the largest, but by no means the only challenge facing Europe’s laboratories,” Denise Fane de Salis (above), Starlab’s UK Managing Director and Area Head for Northern Europe, told Laboratory News. “The mood barometer we commissioned once again clearly shows that we need to look at the entire range of laboratory work. The laboratory sector is not only essential in medicine and research. Diagnostics have long since encompassed almost all areas of life and the economy.” Those in this country responsible for clinical laboratory supply chains should consider what Salis is advising. (Photo copyright: Starlab UK.)
Lab Supply Shortages Worsen in 2021
With a UK office in Milton Keynes, Starlab’s network of distributors specialize in liquid handling products including pipette tips, multi-channel pipettes, and cell culture tubes, as well as PCR test consumables and nitrile and latex gloves.
According to Laboratory News, Starlab’s 2021 annual survey, released in March 2022, found that:
64% cited late deliveries contributing to supply woes.
58% noted medical labs getting preference over research labs, up from 46% in 2020.
57% said demand for liquid handling products was the same as 2020.
30% of respondents said material requirements were up 50% in 2021, compared to 2020.
76% reported dealing with rising prices in lab operations.
29% expect their need for materials to increase by 25% in 2022, and 3% said the increase may go as high as 50%.
17% of respondents said they foresee challenges stemming from staff shortages, with 8% fearing employee burnout.
UK-European Medical Laboratories on Waiting Lists for Supplies
Could import of lab equipment and consumables from Asia and other areas outside UK have contributed to the shortages?
“A substantial portion of the world’s clinical laboratory automation, analyzers, instruments, and test kits are manufactured outside UK. Thus, UK labs may face a more acute shortage of lab equipment, tests, and consumables because governments in countries that manufacture these products are taking ‘first dibs’ on production, leaving less to ship to other countries,” said Robert Michel, Editor-in-Chief of Dark Daily and our sister publication The Dark Report.
Indeed, a statement on Starlab’s website describes challenges the company faces meeting customers’ requests for supplies.
“The pandemic also has an impact on our products that are manufactured in other countries. This particularly affects goods that we ship from the Asian region to Europe by sea freight. Due to the capacity restrictions on the ships, we expect additional costs for the transport of goods at any time. Unfortunately, the situation is not expected to ease for the time-being,” Starlab said.
Furthermore, economists are forecasting probable ongoing supply chain effects from a new SARS-CoV-2 outbreak in China.
Lockdown of China’s Largest Shipping Province Threatens Supply Chains Worldwide
According to Bloomberg News, “Shenzhen’s 17.5 million residents [were] put into lockdown on [March 13] for at least a week. The city is located in Guangdong, the manufacturing powerhouse province, which has a gross domestic product of $1.96 trillion—around that of Spain and South Korea—and which accounts for 11% of China’s economy … Guangdong’s $795 billion worth of exports in 2021 accounted for 23% of China’s shipments that year, the most of any province.”
Bloomberg noted that “restrictions in Shenzhen could inflict the heaviest coronavirus-related blow to growth since a nationwide lockdown in 2020, with the additional threat of sending supply shocks rippling around the world.”
“Given that China is a major global manufacturing hub and one of the most important links in global supply chains, the country’s COVID policy can have notably spillovers to its trading partners’ activity and the global economy,” Tuuli McCully, Head of Asia-Pacific Economies, Scotiabank, told Bloomberg News.
Wise medical laboratory leaders will remain apprised of supply chain developments and possible lockdowns in Asia while also locating and possibly securing new sources for test materials and laboratory equipment in anticipation of future supply shortages.
Though the variant poses low risk thanks to modern HIV treatments, the scientists stress the importance of access to early clinical laboratory testing for at-risk individuals
With the global healthcare industry hyper focused on arrival of the next SARS-CoV-2 variant, pathologists and clinical laboratories may be relieved to learn that—though researchers in the Netherlands discovered a previously unknown “highly virulent” strain of HIV—the lead scientist of the study says there’s “no cause for alarm.”
In a news release, researchers at the University of Oxford Big Data Institute said the HIV variant got started in the Netherlands in the 1990s, spread quickly into the 2000s, and that prior to treatment, people with the new virulent subtype B (VB variant) had exceptionally high viral loads compared to people with other HIV variants.
Fortunately, the scientist also found that around 2010, thanks to antiretroviral drug therapy, the severe variant began to decline.
In an interview with NPR, Chris Wymant, PhD, the study’s lead author, said, “People with this variant have a viral load that is three to four times higher than usual for those with HIV. This characteristic means the virus progresses into serious illness twice as fast, and also makes it more contagious.”
Fortunately, he added, “Existing medications work very well to treat even very virulent variants like this one, cutting down on transmission and reducing the chance of developing severe illness.
“Nobody should be alarmed,” he continued. “It responds exactly as well to treatment as HIV normally does. There’s no need to develop special treatments for this variant.”
Wymant is senior researcher in statistical genetics and pathogen dynamics at the Big Data Institute (BDI).
Epidemiologist Chris Wymant, PhD (above), lead author of the Big Data Institute study at Oxford University, says today’s modern HIV antiretroviral drug therapies effectively treat for the “highly viral” HIV VB variant he and his team discovered. “Nobody should be alarmed,” he told NPR. “It responds exactly as well to treatment as HIV normally does.” Nevertheless, he stressed the importance of access to early clinical laboratory testing for at-risk individuals. (Photo copyright: Oxford Big Data Institute.)
In their published study, the BDI researchers reported that their analysis of genetic sequences of the VB variant suggested it “arose in the 1990s from de novo (of new) mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.
“By the time, they were diagnosed, these individuals were vulnerable to developing AIDS within two to three years. The virus lineage, which has apparently arisen de novo since around the millennium, shows extensive change across the genome affecting almost 300 amino acids, which makes it hard to discern the mechanism for elevated virulence,” the researchers noted.
The researchers analyzed a data set from the project BEEHIVE (Bridging the Epidemiology and Evolution of HIV in Europe and Uganda). They found 15 of 17 people positive for the VB variant residing in the Netherlands. That prompted them to focus on a cohort of more than 6,700 Dutch HIV positive people in the ATHENA (AIDS Therapy Evaluation in the Netherlands) cohort database, where they found 92 more individuals with the VB variant, bringing the total to 109.
According to a Medscape report on the study’s findings, people with the VB variant showed the following characteristics:
Double the rate of CD4-positive T-cell declines (indicator of immune system damage by HIV), compared to others with subtype-B strains.
Increased risk of infecting others with the virus based on transmissibility associated with variant branching.
Wymant says access to clinical laboratory testing is key to curtailing the number of people who contract the VB variant. “Getting people tested as soon as possible, getting them onto treatment as soon as possible, has helped reduce the numbers of this variant even though we didn’t know that it existed,” he told NPR.
The University of Oxford Big Data Institute study is another example of how constantly improving genome sequencing technology allows scientists to dig deeper into genetic material for insights that can advance the understanding of many diseases and health conditions.
Medical laboratory company’s patients in Southwest England previously had tested positive for COVID-19 ona Lateral Flow Device
If providing accurate test results is key to maintaining trust with healthcare consumers, a private COVID-19 testing laboratory in the United Kingdom (UK) may have permanently damaged its reputation after reporting an estimated 43,000 false negative COVID-19 RT-PCR (polymerase chain reaction) test results over a five-week span between September 8, 2021, and October 12, 2021.
For now, Immensa Health Clinic Ltd., a subsidiary of DNA testing company Dante Labs, had its testing operations suspended on October 15 while the UK Health Security Agency (UKSA) investigates the cause of false negative PCR test results from the company’s lab in Wolverhampton, England. The test results went out to people who previously had tested positive for COVID-19 on a lateral flow device (LFD).
“We have recently seen a rising number of positive LFD results subsequently testing negative on PCR. As a result of our investigation, we are working with NHS Test and Trace and the company to determine the laboratory technical issues which have led to inaccurate PCR results being issued to people. We have immediately suspended testing at this laboratory while we continue the investigation,” said Will Welfare, MBChB, Public Health Incident Director, UK Health Security Agency, in a UKHSA statement.
“There is no evidence of any faults with LFD or PCR test kits themselves and the public should remain confident in using them and in other laboratory services currently provided,” he added.
UK Government Officials Question How Lab Won Lucrative COVID-19 Testing Contracts
Immensa was awarded a £119 million (US$163.37 million) coronavirus testing contract by the British government in October 2020, just months after it was founded by Andrea Riposati, owner/CEO of Dante Labs, which has clinical laboratories in the UK, Italy, and the United Arab Emirates. The company’s corporate headquarters are in New York City while its scientific operations are based in the UK.
“Serious questions have to be asked about how this private firm—[which] didn’t exist before May 2020—was awarded a lucrative £120 million (US$164.64 million) contract to run this lab,” Member of Parliament (MP) Jonathan Ashworth (above), Labor Party Shadow Health Secretary, told The Guardian. “From duff PPE [personal protective equipment] to failing test kits, ministers have sprayed around tax money like confetti and utterly failed to deliver the service people deserve,” he added. (Photo copyright: The Mirror.)
NHS Test and Trace, the government program to track and help prevent the spread of COVID-19, has advised people who received the false test results, but who may still be infectious, to be retested.
In responding to the UKHSA’s action, Riposati pointed to Immensa’s track record and reiterated the laboratory’s emphasis on quality.
“We are fully collaborating with UKHSA on this matter. Quality is paramount for us,” Riposati said in the UKHSA statement. “We have proudly analyzed more than 2.5 million samples for NHS Test and Trace, working closely with the great teams at DHSC and UKHSA. We do not wish this matter or anything else to tarnish the amazing work done by the UK in this pandemic.”
Clinical Laboratories Not Accredited to Perform COVID-19 Testing
However, on October 18, 2021, The Guardian reported that the Immensa Health Clinic was not accredited by the UKAS, the UK’s independent accreditation service, before being appointed to perform COVID-19 testing. Dante Labs also has not been awarded UKAS accreditation, according to the newspaper report.
Government officials previously maintained that Immensa was “accredited to all of the appropriate standards.”
Immensa first made headlines in January 2021 when The Sun published an expose´ that included video of employees fighting, drinking, and bragging about watching porn while working at the clinical laboratory.
News of the testing failure at Immensa caused Tory MP Nigel Mills to tell The Sun, “This place should have been shut down for good when The Sun ran its [original] story. It is shocking it has been allowed to remain open and now there is an enormous mess.
“It’s a disgrace,” he added. “If shortcomings have emerged in the process here—which I strongly imagine they have—then heads should roll. The investigation should widen out and an audit should be carried out into other testing companies.”
Dante Labs Under Other Investigations
Immensa’s parent company, Dante Labs, is also under investigation in the UK due to concerns the company “may be treating its customers unfairly.”
A statement from the UK Competition and Markets Authority (CMA), outlined the UK government’s probe into Dante Labs. The statement cited the lab for:
Potentially not delivering PCR tests and/or results on time or at all,
Failing to respond to complaints or provide proper customer service,
Refusing or delaying refunds when requested, and
Providing terms and conditions that may unfairly limit consumers’ rights.
According to The Guardian, Dante Labs’ US operation also faced scrutiny in 2018 after the company admitting it had sent five used DNA test kits to people containing the saliva of other people. Dante Labs maintained its shipping company was the cause of the error.
US Labs Also Face Scrutiny over False Negative Test Results
Since the outbreak of SARS-CoV-2 in early 2020, there have been only a limited number of news accounts about clinical laboratories that reported a substantial number of inaccurate COVID-19 test results, either in the United States or the United Kingdom. In the US, there has been more news coverage of the federal Department of Justice (DOJ) prosecuting lab owners and related parties for submitting fraudulent claims for COVID-19 tests.
But the absence of those news accounts does not mean that there have been no incidents in the US where a lab testing company reported significant numbers of inaccurate COVID-19 test results.
In 2020, for example, Dark Daily reported on how Abbott Lab’s ID NOW COVID-19 rapid molecular test faced scrutiny over false negatives resulting in the FDA issuing a public warning about the point-of-care test’s accuracy after receiving 15 “adverse event reports” indicating some patients were receiving “false negative results.”
Then on June 22, 2020, KHN reported that the FDA had “received a total of 106 reports of adverse events for the Abbott test, a staggering increase. The agency has not received a single adverse event report for any other point-of-care tests meant to diagnose COVID-19.”
The UK lab’s failures are simply the latest example of how inaccurate test results erode the trust of healthcare consumers and draw the ire of politicians and government regulators. In this case, however, poor government oversight of a newly minted COVID-19 testing laboratory should face equal scrutiny.
