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.
Platform could be next breakthrough in quest for painless technology to replace in-patient phlebotomy blood draws for many clinical laboratory tests
In a proof-of-concept study, scientists from Israel and China have developed a “smart” microneedle adhesive bandage that measures and monitors in real time three critical biomarkers that currently require invasive blood draws for medical laboratory tests commonly performed on patients in hospitals.
According to a Technion news release, the microneedles are short, thin, and relatively painless because they only extend through the outer layer of skin to reach the interstitial fluid underneath. The needle system attaches to the patient’s skin using an adhesive patch and transfers data wirelessly to both doctor and patient in real time through cloud and Internet of Things (IoT) technologies.
Such a novel technology that allows inpatients to be monitored for key biomarkers without the need for a phlebotomist to collect blood for testing will be attractive and would likely improve the patient’s experience.
It also could reduce the volume of specimen required, potentially eliminating the invasive specimen collection procedure altogether.
“To adapt the technology to daily life, we have developed a unique [adhesive bandage] made of a flexible and soft polymer that stretches and contracts along with the skin and therefore does not interfere with any action whatsoever,” said Hossam Haick, PhD (above), in a Technion news release. “Since it is important for us that the system is available to everyone, we made sure to use relatively inexpensive materials, so the final product will not be expensive. The technology we have developed represents a leap forward in diagnosing diseases and continuous physiological monitoring at home and in the clinic.” Such a real-time monitoring device could eliminate clinical laboratory testing for certain biomarkers that currently require invasive blood draws. (Photo copyright: Technion-Israel Institute of Technology.)
Leap Forward in Diagnostic Testing and Disease Monitoring
As pathologists and medical laboratory scientists are aware, sodium is a prominent prognostic biomarker for assessing certain blood conditions such as dysnatremia, the presence of too much or too little sodium. It’s an essential element found in blood cells and blood fluid that plays a vital role in transmitting signals to the nervous system, as well as in other biological functions.
Led by Hossam Haick, PhD, head of the LNDB (Laboratory for Nanomaterials-based Devices) group and Dean of Certification Studies at Technion, the team of scientists tested their device’s effectiveness at monitoring patients’ blood for both hypernatremia (high concentration of sodium in the blood) as well as hyponatremia (low concentration of sodium in the blood).
Both conditions can affect neurological function and lead to loss of consciousness and coma. Thus, early monitoring is critical.
“As of now, detection and monitoring of sodium levels in the human body is carried out by means of laborious and bulky laboratory equipment, or by offline analysis of various bodily fluids,” the study’s authors explained in the news release. Use of the smart microneedle patch, they added, allows the patient to continue about their day as normal, as well as gives their doctor time to attend to more patients.
The “innovative stretchable, skin-conformal and fast-response microneedle extended-gate FET (field-effect transistor) biosensor [integrated with] a wireless-data transmitter and the Internet-of-Things cloud for real-time monitoring and long-term analysis [could] eventually help [bring] unlimited possibilities for efficient medical care and accurate clinical decision-making,” noted the study’s authors in Advanced Materials.
More research will be needed to determine whether this latest medical technology breakthrough will lead to a viable minimally invasive method for measuring, diagnosing, and monitoring medical conditions, but Technion’s platform appears to be another step toward a long-sought alternative to painful blood draws.
Further, pathologists and clinical laboratory managers should expect more products to hit the market that are designed to collect a lab specimen without the need for a trained phlebotomist. Companies developing these products recognize that recruiting and retaining trained phlebotomist is an ongoing concern for medical labs. Thus, to have a method of collecting a lab specimen that is simple and can be done by anyone—including patients themselves—would be an important benefit.
Findings are ‘a vital first step in discovering potentially valuable targets for development of new [COVID-19] treatments,’ noted co-first author of the study
Researchers at King’s College London (KCL) have determined that levels of certain blood proteins specific to each person’s blood type can be “causally linked” to an increased risk of hospitalization and death from a COVID-19 infection. The scientists also found that a person’s genetics play a key role in establishing the levels of those proteins in the blood.
This is relevant for clinical laboratories—particularly hospital/health system laboratories—because testing for specific proteins in the blood by medical laboratories could help flag incoming patients at higher risk for an acute COVID-19 infection.
Also, “By identifying this suite of proteins, the research has highlighted a number [of] possible targets for drugs that could be used to help treat severe COVID-19,” noted a KCL news release.
Identifying certain drugs that would be more effective for specific individuals or healthcare groups is a core goal of precision medicine.
“We have used a purely genetic approach to investigate a large number of blood proteins and established that a handful have causal links to the development of severe COVID-19,” said Alish Palmos, PhD (above), Postdoctoral Research Associate, King’s College London Social, Genetic and Developmental Psychiatry Center, and co-first author of the study. “Honing in on this group of proteins is a vital first step in discovering potentially valuable targets for development of new treatments.” Medical laboratories may soon be able to use this knowledge as a way to determine risk for severe COVID-19 hospitalization, as well as to guide decisions on how to use new precision medicine drugs for combating the infection. (Photo copyright: Twitter.)
Genetic Variants Linked to Causality
Since the COVID-19 pandemic began in late 2019, scientists and researchers have been vigorously trying to understand the SARS-CoV-2 coronavirus and determine why some patients have more severe symptoms than others.
To conduct their study, the KCL researchers screened more than 3,000 blood proteins to identify which proteins have a causal link to hospitalization risk, the need for respiratory support, and death from a severe COVID-19 infection.
“Causality between exposure and disease can be established because genetic variants inherited from parent to offspring are randomly assigned at conception similar to how a randomized controlled trial assigns people to groups,” said Vincent Millischer, MD, PhD, Medical University of Vienna and co-first author of the study in the KCL news release.
“In our study, the groups are defined by their genetic propensity to different blood protein levels, allowing an assessment of causal direction from high blood protein levels to COVID-19 severity whilst avoiding influence of environmental effects,” he added.
The scientists selected genetic variants, known as single nucleotide polymorphisms, that were strongly associated with blood protein levels. They then performed their analysis using Mendelian randomization to test the causal associations of those blood proteins with the development of severe COVID-19 infections.
“Mendelian randomization uses genetic variants associated with a trait [e.g., protein level] and measures their causal effect on disease outcomes, [avoiding] environmental confounding factors, such as lifestyle, being physically ill, etc.,” Alish Palmos, PhD, told Medical News Today. Palmos is a Postdoctoral Research Associate at King’s College London’s Social, Genetic, and Developmental Psychiatry Center and co-first author of the study.
Blood Groups Linked to COVID-19 Hospitalization, Death
One of the most important findings of the KCL research is a causal association between COVID-19 severity and an enzyme called ABO, which determines blood type. This discovery suggests that blood groups perform an instrumental role in whether individuals develop severe forms of the illness.
“The enzyme helps determine the blood group of an individual and our study has linked it with both risk of hospitalization and the need of respiratory support or death,” said Christopher Hübel, PhD, Postdoctoral Research Associate, King’s College and co-last author of the study in the press release. “Our study does not link precise blood group with risk of severe COVID-19, but since previous research has found that proportion of people who are group A is higher in COVID-19 positive individuals, this suggests that blood group A is more likely candidate for follow-up studies.”
The KCL researchers uncovered several compelling findings regarding blood proteins and COVID-19, including:
The discovery of six blood markers that were significantly associated with an elevated risk of hospitalization.
The discovery of nine blood markers that were significantly associated with a decreased risk of hospitalization.
Consistent results indicating hospitalization being significantly associated with decreased levels of macrophage inflammatory protein.
Five blood markers associated with the need for respiratory support or death.
Eight blood markers causally associated with a statistically significantly decreased risk of need for respiratory support or death.
Consistent results with respiratory support or death being significantly causally associated with decreased levels of neprilysin.
Developing New COVID-19 Treatments and Preventative Therapies
“What we have done in our study is provide a shortlist for the next stage of research,” said Gerome Breen, PhD, in the KCL news release. Breen is Professor of Psychiatric Genetics at King’s College London’s Institute of Psychiatry, Psychology and Neuroscience, and co-last author of the study.
“Out of 1000s of blood proteins we have whittled it down to about 14 that have some form of causal connection to the risk of severe COVID-19 and present a potentially important avenue for further research to better understand the mechanisms behind COVID-19 with an ultimate aim of developing new treatments but potentially also preventative therapies,” he added.
Further research and clinical investigation are needed to validate the King’s College London researchers’ findings. However, their insights could result in new clinical laboratory tests and personalized treatments for COVID-19.
Study shows that access to early childhood treatment could have lasting effects and prevent premature adult aging
Researchers in New Zealand have found that people who experienced “daily smoking status, obesity, or a psychological disorder diagnosis” beginning early in life were “biologically older” at midlife than those who did not. The findings suggest that early access to treatments for these health concerns could decrease risk for “accelerated biological aging,” according to the study published in JAMA Pediatrics.
Although these findings do not currently provide a path to a diagnostic test for clinical laboratories, this study is yet another example of how researchers are increasingly using broad swaths of healthcare data to help identify people at risk for certain healthcare conditions.
Such research often presents opportunities for medical laboratories to participate in healthcare Big Data analysis, which in turn helps healthcare providers make precision medicine diagnoses for individual patients.
Study Assessments and Clinical Laboratory Biomarkers
The scientists found that participants who had one of three health conditions as an adolescent—obesity, smoking daily, or psychological disorder (anxiety, attention deficit/hyperactivity disorder, depression)—showed advanced signs of aging at age 45 when compared to others without those conditions, CNN reported.
The signs included:
Walking 11.2 centimeters per second slower.
Brain appears 2.5 years older.
Face appears four years older.
At age 11, 13, and 15, the Dunedin Study participants were assessed by pulmonary specialists and others for asthma, cigarette smoking, and obesity, Fox News reported.
“There’s a long history of that kind of research in terms of how smoking is damaging at the cellular level but also can result in the kinds of health conditions that we associate with biological aging, like (chronic obstructive pulmonary disease), lung cancer, things like that,” the study’s first author Kyle Bourassa, PhD (above), told CNN. “The hope is if we were to study a cohort now, a much higher proportion of those children and adolescents are actually going to be treated for these things, which will reduce the risk of accelerated aging later in life,” he added. Results of the study may also lead to new clinical laboratory diagnostics. (Photo copyright: Duke University.)
According to an earlier DMHDRU statement, the biomarkers used at this point in the study included:
“Participants who had smoked daily, had obesity, or had a psychological disorder diagnosis during adolescence were biologically older at midlife compared with participants without these conditions. Participants with asthma were not biologically older at midlife compared with those without asthma,” the researchers wrote. These findings led the researchers to certain conclusions about receiving early treatments, CNN reported.
“No participants in this cohort were prescribed stimulants for attention-deficit/hyperactivity disorder, and selective serotonin reuptake inhibitors were not yet in use for adolescent depression and anxiety during the study period. Whereas 81.1% of the adolescents with asthma received some type of treatment, which could have mitigated the implications for biological aging,” the authors wrote in their study.
“Our paper reaffirms that those are important treatments and those kinds of investments younger in the lifespan could net big benefits in terms of both health and the cost of healthcare later on as well,” Kyle Bourassa, PhD, told CNN. Bourassa is the study’s First Author and a clinical psychology researcher and advanced research fellow at the Durham VA Health Care System.
Clinical Laboratories Curate Massive Amounts of Healthcare Data
For pathologists and medical laboratory scientists, the University of Otago study is a reminder that clinical laboratories provide a critical tool to diagnostics professionals: housing, sharing, and analyzing data that contribute to precision medicine diagnoses.
The DMHDRU researchers’ findings also highlight the importance of access to common treatments offered early in life for some people to reduce risk of accelerated aging and disease.
Should the test prove clinically viable, it could lead to new biomarkers for eye disease diagnostics and a new assay for clinical laboratories
Scientists at Flinders University in Australia have developed a genetic blood or saliva test that, they say, is 15 times more effective at identifying individuals at high risk of glaucoma than current medical laboratory tests.
If so, this discovery could lead to new biomarkers for diagnostic blood tests that help medical professionals identify and treat various diseases of the eye. Their test also can be performed on saliva samples. The researchers plan to launch a company later in 2022 to generate an accredited test that can be used in clinical trials.
“Early diagnosis of glaucoma can lead to vision-saving treatment, and genetic information can potentially give us an edge in making early diagnoses, and better treatment decisions,” said lead researcher Owen Siggs, PhD, Associate Professor, College of Medicine and Public Health at Flinders University, in a university press release.
Flinders University researchers have been collaborating with scientists at the QIMR Berghofer Medical Research Institute and other research institutes worldwide for some time to identify genetic risk factors for glaucoma, the press release noted.
“In the cross-sectional study of monogenic and polygenic variants related to the disease, the new genetic test was evaluated in 2,507 glaucoma patients in Australia and 411,337 people with or without glaucoma in the UK. The test, conducted using a blood or saliva sample, could potentially detect individuals at increased risk before irreversible vision loss happens,” Medical Device Network reported.
“Genetic testing is not currently a routine part of glaucoma diagnosis and care, but this test has the potential to change that,” said Jamie Craig, PhD, (above), Distinguished Professor, College of Medicine and Health at Flinders University in Australia and senior author of the study, in a press release. “We’re now in a strong position to start testing this in clinical trials,” he added. This is yet another example of how new research is identifying a novel biomarker that could be incorporated into a clinical laboratory test. (Photo copyright: Flinders University.)
Who Is at Risk for Glaucoma?
Glaucoma is a group of eye diseases that are typically caused by a buildup of pressure within the eye. The eyeball contains and produces a fluid called aqueous humour which provides nutrition to the eye and keeps the eye in a proper pressurized state. Any excess of this fluid should be automatically released via a drainage canal called the trabecular meshwork.
But that’s not always the case. When the fluid cannot drain properly, intraocular pressure is created. Most forms of glaucoma are characterized by this pressure, which can damage the optic nerve and eventually cause vision loss and even blindness. Treatments for the disease include medications, laser treatments, and surgery.
Anyone can develop glaucoma, but according to the Mayo Clinic, individuals at higher risk of the disease include:
Individuals over the age of 60.
Those with a family history of glaucoma.
People of African, Asian, or Hispanic descent.
Patients with certain medical conditions, such as diabetes, heart disease, high blood pressure, and sickle cell anemia.
Those with corneas that are thin in the center.
Individuals who have had a past eye injury or certain types of eye surgery.
People who have taken corticosteroid medications, especially eyedrops, for an extended period of time.
Glaucoma is the second leading cause of blindness worldwide, particularly among the elderly. When diagnosed early, the condition is manageable, but even with treatment, about 15% of glaucoma patients become blind in at least one eye within 20 years.
According to the federal Centers for Disease Control and Prevention (CDC), approximately three million Americans are living with glaucoma. The disease often has no early symptoms, which is why it is estimated that about 50% of individuals who have glaucoma do not realize they have the illness.
Thus, a clinically-viable genetic test that is 15 times more likely to identify people at risk for developing glaucoma in its early stages would be a boon for ophthalmology practices worldwide and could save thousands from going blind.
More research and clinical trials are needed before the Flinders University genetic test for glaucoma becomes available. But the discovery alone demonstrates the importance of continuing research into identifying novel biomarkers that could be incorporated into useful clinical laboratory diagnostic tests.
Last-minute court injunction stopped a mass walkout, but allied health workers continue to push country’s District Health Boards for improvements
In New Zealand, the unprecedented surge in PCR COVID-19 testing due to the SARS-CoV-2 Omicron variant appears to have pushed the country’s 10,000 healthcare workers—including 4,000 medical laboratory scientists and technicians—to the breaking point.
On March 3, just 24 hours before the first of two walkouts was scheduled to begin, New Zealand’s Employment Court banned the strike that would have shut down medical laboratories in the country’s mixed public-private healthcare system. Medical laboratory workers make up 40% of the nation’s 10,000 healthcare workers who planned the nationwide strike to protest low pay and poor working conditions, according to 1News.
New Zealand’s Public Service Association (PSA) is the country’s largest trade union representing more than 80,000 workers across government, state-owned enterprises, local councils, health boards, and community groups.
The PSA’s 10,000 health workers (which includes 4,000 medical laboratory workers) had planned to strike on March 4-5 and March 18-19, but, according to the New Zealand Herald the Employment Court stopped the walkouts due to the rise in COVID-19-related hospitalizations.
The Herald noted, however, that PSA union members in Auckland had already postponed their walkout after county District Health Boards (DHB) expressed concern over patient safety.
“Striking has always been our last resort, and our members in Auckland continue to demonstrate their commitment to providing quality healthcare to New Zealanders by working tomorrow,” PSA Organizer Will Matthews told the Herald.
He insisted, however, that DHBs need to respond to workers’ concerns. “The depth of feeling from our members, and the support for industrial action nationwide is unprecedented,” Matthews told 1News. “We are now in a position where strike action is our only remaining option to get the DHBs and the government to listen.”
In an interview with Stuff, medical laboratory scientist Terry Taylor (above), president of the New Zealand Institute of Medical Laboratory Science, acknowledged laboratory workers’ commitment to doing the work, but he is concerned about the next big testing surge. “Goodwill only goes a certain distance in the end when people are knackered and not getting what they need. At the moment, we have the capability to do 50,000 to 60,000 [tests] per day throughout the whole country, but we couldn’t run that for more than a week. We’d be dead, we’d be overrun,” he said. Clinical laboratory leaders in this country may want to make note of Taylor’s concerns, as laboratory conditions in this country become stressed as well. (Photo copyright: Newshub.)
While no new strike dates have been set, Matthews said striking workers would include contact tracers and laboratory staff as well as nearly 70 other groups of healthcare workers, many of whom “don’t even earn a living wage.” According to Peoples Dispatch, allied health workers are working under the terms of a contract that expired in 2020.
The starting salary for a DHB medical laboratory scientist after completing a four-year degree is NZ$56,773 (US$39,519), while lab assistants and technicians start out at less than NZ$50,000 (US$34,804), Stuff reported.
In an interview with 1News, Taylor maintained that diagnostic labs in New Zealand have long been understaffed, undervalued, and their workers poorly treated. The COVID-19 pandemic, he says, has exacerbated an ongoing problem. Issues such as space constraints, for example, have become even more problematic.
“We’ve got extra machinery that’s come into the labs, we don’t get any more space, all these consumables sitting all over hallways and corridors, extra staff coming in to do the stuff,” Taylor told RNZ. “So, we’ve lost all our tearooms, we’ve lost all our office space, our conditions are markedly less than they should be.”
1News points out that the country’s medical laboratory scientists and technicians are processing more than 20,000 PCR COVID-19 tests per day in addition to running 120,000 other samples and 200,000 diagnostic tests. At the end of March 2020, the average number of COVID-19 tests processed per day was 1,777.
While New Zealand has preached to its citizens the need for widespread PCR testing, Taylor argued in February 2022 that the country must change its approach to offering PCR testing only to symptomatic individuals and close contacts.
“To run our diagnostic laboratories into the ground with endless irrelevant testing is a direct reflection of poor foresight, planning, and respect for the role of this critical health workforce,” Taylor told Newshub.
Necessity of Rewarding All Medical Laboratory Personnel
Medical laboratory scientist Bryan Raill is president of Apex, a specialist union of allied, scientific and technical employees. Raill told 1News the long-term solution is for the government to address pay equity, staffing levels, and worker wellbeing in the country’s historically undervalued medical laboratories.
“Medical laboratory scientists and technicians have to be fairly rewarded for the training, skill, and expertise they bring to the health system,” Raill said. “Medical laboratory scientists need a timely, fair, and equitable process to determine their worth.”
While the stresses on New Zealand medical laboratory workers are not identical, US clinical laboratory leaders will want to monitor the lengths to which New Zealand’s laboratory workers are willing to go to force improvements in their working conditions, staffing, and pay.
As the noted above, the government-funded health system is continually strapped for funds. Consequently, the health districts often defer capital investment in hospitals and medical laboratories. That is one reason why lab staff can find themselves working in space that is inadequate for the volume of specimens which need to be tested daily.
