Newly-defined Cardiovascular-Kidney-Metabolic Syndrome (CKM) means physicians will be in close collaboration with clinical laboratories to make accurate diagnoses
In a presidential advisory, the AHA defines a newly described systemic health disorder called Cardiovascular-Kidney-Metabolic Syndrome (CKM). The syndrome “is a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD (chronic kidney disease), and the cardiovascular system leading to multi-organ failure and a high rate of adverse cardiovascular outcomes.”
A CKM diagnosis, which is meant to identify patients who are at high risk of dying from heart disease, is based on a combination of risk factors, including:
weight problems,
issues with blood pressure, cholesterol, and/or blood sugar,
reduced kidney function.
CKM is a new term and doctors will be ordering medical laboratory tests associated with diagnosing patients with multiple symptoms to see if they match this diagnosis. Thus, clinical laboratory managers and pathologists will want to follow the adoption/implementation of this new recommendation.
“The advisory addresses the connections among these conditions with a particular focus on identifying people at early stages of CKM syndrome,” said Chiadi Ndumele, MD, PhD (above), Associate Professor of Medicine at Johns Hopkins University and one of the authors of the AHA paper, in a news release. “Screening for kidney and metabolic disease will help us start protective therapies earlier to most effectively prevent heart disease and best manage existing heart disease.” Clinical laboratories will play a key role in those screenings and in diagnosis of the new syndrome. (Photo copyright: Johns Hopkins University.)
Stages of CKM Syndrome
In its presidential advisory, the AHA wrote, “Cardiovascular-Kidney-Metabolic (CKM) syndrome is defined as a health disorder attributable to connections among obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD), including heart failure, atrial fibrillation, coronary heart disease, stroke, and peripheral artery disease. CKM syndrome includes those at risk for CVD and those with existing CVD.”
The five stages of CKM syndrome, which the AHA provided to give a framework for patients to work towards regression of the syndrome, are:
Stage 0: No CKM risk factors. Individuals should be screened every three to five years for blood pressure, cholesterol, and blood sugar levels, and for maintaining a healthy body weight.
Stage 1: Excess body fat and/or an unhealthy distribution of body fat, such as abdominal obesity, and/or impaired glucose tolerance or prediabetes. Patients have risk factors such as weight problems or prediabetes and are encouraged to make healthy lifestyle changes and try to lose at least 5% of their body weight.
Stage 2: Metabolic risk factors and kidney disease. Includes people who already have Type 2 diabetes, high blood pressure, high triglyceride levels, and/or kidney disease. Medications that target kidney function, lower blood sugar, and which help with weight loss should be considered at this stage to prevent diseases of the heart and blood vessels or kidney failure.
Stage 3: Early cardiovascular disease without symptoms in people with metabolic risk factors or kidney disease or those at high predicted risk for cardiovascular disease. People show signs of disease in their arteries, or have heart function issues, or may have already had a stroke or heart attack or have kidney or heart failure. Medication may also be needed at this stage.
Stage 4: Symptomatic cardiovascular disease in people with excess body fat, metabolic risk factors or kidney disease. In this stage, people are categorized as with or without having kidney failure. May also have already had a heart attack, stroke or heart failure, or cardiovascular conditions such as peripheral artery disease or atrial fibrillation.
“We now have several therapies that prevent both worsening kidney disease and heart disease,” said Chiadi Ndumele, MD, PhD, Associate Professor of Medicine at Johns Hopkins University and one of the authors of the Circulation paper, in a news release. “The advisory provides guidance for healthcare professionals about how and when to use those therapies, and for the medical community and general public about the best ways to prevent and manage CKM syndrome.”
According to an AHA 2023 Statistical Update, one in three adults in the US have three or more risk factors that contribute to cardiovascular disease, metabolic disorders, or kidney disease. While CKM affects nearly every major organ in the body, it has the biggest impact on the cardiovascular system where it can affect the blood vessels, heart muscle function, the rate of fatty buildup in the arteries, electrical impulses in the heart and more.
“There is a need for fundamental changes in how we educate healthcare professionals and the public, how we organize care and how we reimburse care related to CKM syndrome,” Ndumele noted. “Key partnerships among stakeholders are needed to improve access to therapies, to support new care models, and to make it easier for people from diverse communities and circumstances to live healthier lifestyles and to achieve ideal cardiovascular health.”
New AHA Risk Calculator
In November, the AHA announced PREVENT (Predicting risk of cardiovascular disease EVENTs), a tool that doctors can use to assess a person’s risk for heart attack, stroke, and heart failure. The new risk calculator, which incorporates CKM, allows physicians to evaluate younger people as well, and examine their long-term risks for cardiovascular issues.
Doctors can use PREVENT to assess people ages 30 to 79 and predict risk for heart attack, stroke, or heart failure over 10 to 30 years.
“Longer-term estimates are important because short-term or 10-year risk in most young adults is still going to be low. We wanted to think more broadly and apply a life-course perspective,” Khan said. “Providing information on 30-year risk may reveal earlier opportunities for intervention and prevention efforts in younger people.”
According to CDC data, about 695,000 people died of heart disease in the US in 2021. That equates to one in every five deaths. Clinical pathologists will need to understand the AHA recommendations and how doctors will be ordering clinical laboratory tests to determine if a patient has CKM. Then, labs will play a role in helping doctors monitor patients to optimize health and prevent acute episodes that put patients in the hospital.
If validated, study findings may result in new biomarkers for clinical laboratory cholesterol tests and for diagnosing dementia
Researchers continue to find new associations between biomarkers commonly tested by clinical laboratories and certain health conditions and diseases. One recent example comes from research conducted by the University of California San Francisco. The UCSF study connected cholesterol biomarkers generally used for managing cardiovascular disease with an increased risk for dementia as well.
The researchers found that both high and low levels of high-density lipoprotein (HDL)—often referred to as “good” cholesterol—was associated with dementia in older adults, according to a news release from the American Academy of Neurology (AAN).
UCSF’s large, longitudinal study incorporated data from 184,367 people in the Kaiser Permanente Northern California health plan. How the findings may alter cholesterol biomarker use in future diagnostics has not been determined.
“The elevation in dementia risk with both high and low levels of HDL cholesterol was unexpected, but these increases are small, and their clinical significance is uncertain,” said epidemiologist Maria Glymour, ScD (above), study author and Professor of Epidemiology and Biostatistics at UCSF School of Medicine, in a news release. This is another example of how researchers are associating common biomarkers tested regularly by clinical laboratories with additional health conditions and disease states. (Photo copyright: University of California San Francisco.)
HDL Levels Link to Dementia Risk
The UCSF researchers used cholesterol measurements and health behavior questions as they tracked Kaiser Permanente Northern California health plan members who were at least 55 years old between 2002 and 2007, and who did not have dementia at the time of the study’s launch.
The researchers then followed up with the study participants through December 2020 to find out if they had developed dementia, Medical News Today reported.
“Previous studies on this topic have been inconclusive, and this study is especially informative because of the large number of participants and long follow-up,” said epidemiologist Maria Glymour, ScD, study author and Professor of Epidemiology and Biostatistics at UCSF School of Medicine, in the AAN news release. “This information allowed us to study the links with dementia across the range of cholesterol levels and achieve precise estimates even for people with cholesterol levels that are quite high or quite low.”
According to HealthDay, UCSF’s study findings included the following:
More than 25,000 people developed dementia over about nine years. They were divided into five groups.
53.7 milligrams per deciliter (mg/dL) was the average HDL cholesterol level, amid an optimal range of above 40 mg/dL for men and above 50 mg/dL for women.
A 15% rate of dementia was found in participants with HDL of 65 mg/dL or above.
A 7% rate of dementia was found in participants with HDL of 11 mg/dL to 41 mg/dL.
“We found a U-shaped relationship between HDL and dementia risk, such that people with either lower or higher HDL had a slightly elevated risk of dementia,” Erin Ferguson, PhD student of Epidemiology at UCSF, the study’s lead study author, told Medical News Today.
What about LDL?
The UCSF researchers found no correlation between low-density lipoprotein (LDL)—often referred to as “bad” cholesterol”—and increased risk for dementia. But the risk did increase slightly when use of statin lipid-lowering medications were included in the analysis.
“Higher LDL was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL was associated with a slightly greater risk of Alzheimer’s disease-related dementia for statin users,” the researchers wrote in Neurology.
“We found no association between LDL cholesterol and dementia risk in the overall study cohort. Our results add to evidence that HDL cholesterol has similarly complex associations with dementia as with heart disease and cancer,” Glymour noted in the AAN news release.
Australian Study also Links High HDL to Dementia
A separate study from Monash University in Melbourne, Victoria, Australia, found that “abnormally high levels” of HDL was also associated with increased risk for dementia, according to a Monash news release.
The Monash study—which was part of the ASPREE (ASPpirin in Reducing Events in the Elderly) trial of people taking daily aspirin—involved 16,703 Australians and 2,411 Americans during the years 2010 to 2014. The researchers found:
850 participants had developed dementia over about six years.
A 27% increased risk of dementia among people with HDL above 80 mg/dL and a 42% higher dementia risk for people 75 years and older with high HDL levels.
These findings, Newsweek pointed out, do not necessarily mean that high levels of HDL cause dementia.
“There might be additional factors that affect both these findings, such as a genetic link that we are currently unaware of,” Andrew Doig, PhD, Professor, Division of Neuroscience at University of Manchester, told Newsweek. Doig was not involved in the in the Monash University research.
Follow-up research could explore the possibility of diagnosing dementia earlier using blood tests and new biomarkers, Newsweek noted.
Cholesterol Lab Test Results of Value to Clinical Labs
If further studies validate new biomarkers for testing and diagnosis, a medical laboratory’s longitudinal record of cholesterol test results over many years may be useful in identifying people with an increased risk for dementia.
Clinical pathologists and laboratory managers will want to stay tuned as additional study insights and findings are validated and published. Existing laboratory testing reference ranges may need to be revised as well.
As well, the findings of this UCSF research demonstrate that, in this age of information, there will be plenty of opportunities for clinical lab scientists and pathologists to take their labs’ patient data and combine it with other sets of data. Digital tools like artificial intelligence (AI) and machine learning would then be used to assess that large pool of data and produce clinically actionable insights. In turn, that positions labs to add more value and be paid for that value.
If further research confirms these findings, clinical laboratory identification of cancer cells could lead to new treatments for certain childhood cancers
Can cancer cells be changed into normal healthy cells? According to molecular biologists at the Cold Spring Harbor Laboratory (CSHL) in Long Island the answer is, apparently, yes. At least for certain types of cancer. And clinical laboratories and anatomic pathologists may play a key role in identifying these specific cancer cells and then guiding physicians in selecting the most appropriate therapies.
The cancer cells in question are called rhabdomyosarcoma (RMS) and are “particularly aggressive,” according to ScienceAlert. Generally, and most sadly, the cancer primarily affects children below the age of 18. It begins in skeletal muscle, mutates throughout the body, and is often deadly.
“Treatment usually involves chemotherapy, surgery, and radiation procedures. Now, new research by scientists at Cold Spring Harbor Laboratory demonstrates differentiation therapy as a new treatment option for RMS,” Genetic Engineering and Biotechnology News (GEN) reported.
For those young cancer patients, this new research could become a lifesaving therapy as further studies validate the approach, which has been in development for six years.
“Every successful medicine has its origin story,” said Christopher Vakoc, MD, PhD (above), a molecular biologist at Cold Spring Harbor Laboratory, who led the team that develop the method for converting cancer cells into healthy cells. “And research like this is the soil from which new drugs are born.” As these findings are confirmed, it may be that clinical laboratories and anatomic pathologists will be needed to identify the specific cancer cells in patients once treatment is developed. (Photo copyright: Cold Spring Harbor Laboratory.)
Differentiation Therapy
According to an article in the Chinese Journal of Cancer on the National Library of Medicine website, “Differentiation therapy is based on the concept that a neoplasm is a differentiation disorder [aka, differentiation syndrome] or a dedifferentiation disease. In response to the induction of differentiation, tumor cells can revert to normal or nearly normal cells, thereby altering their malignant phenotype and ultimately alleviating the tumor burden or curing the malignant disease without damaging normal cells.”
Vakoc and his team first pursued differentiation therapy to treat Ewing sarcoma, a pediatric cancer that forms in soft tissues or in bone. In January 2023, GEN reported that the researchers had discovered that “Ewing sarcoma could potentially be stopped by developing a drug that blocks the protein known as ETV6.”
“This protein is present in all cells. But when you perturb the protein, most normal cells don’t care,” Vakoc told GEN. “The process by which the sarcoma forms turns this ETV6 molecule—this relatively innocuous, harmless protein that isn’t doing very much—into something that’s now controlling a life-death decision of the tumor cell.”
The researchers discovered that when ETV6 was blocked in lab-grown Ewing sarcoma cells, the cells became normal, healthy cells. “The sarcoma cell reverts back into being a normal cell again,” they told GEN. “The shape of the cell changes. The behavior of the cells changes. A lot of the cells will arrest their growth. It’s really an explosive effect.”
The scientists then turned their attention on Rhabdomyosarcoma to see if they could elicit a similar response.
“In this study, we developed a high-throughput genetic screening method to identify genes that cause rhabdomyosarcoma cells to differentiate into normal muscle. We used this platform to discover the protein NF-Y as an important molecule that contributes to rhabdomyosarcoma biology. CRISPR-based genetic targeting of NF-Y converts rhabdomyosarcoma cells into differentiated muscle, and we reveal the mechanism by which this occurs,” they wrote in PNAS.
“Scientists have successfully induced rhabdomyosarcoma cells to transform into normal, healthy muscle cells. It’s a breakthrough that could see the development of new therapies for the cruel disease, and it could lead to similar breakthroughs for other types of human cancers,” ScienceAlert reported.
“The cells literally turn into muscle,” Vakoc told ScienceAlert. “The tumor loses all cancer attributes. They’re switching from a cell that just wants to make more of itself to cells devoted to contraction. Because all its energy and resources are now devoted to contraction, it can’t go back to this multiplying state,” he added.
Promising New Therapies for Multiple Cancers in Children
Differentiation therapy as a treatment option gained popularity when “scientists noticed that leukemia cells are not fully mature, similar to undifferentiated stem cells that haven’t yet fully developed into a specific cell type. Differentiation therapy forces those cells to continue their development and differentiate into specific mature cell types,” ScienceAlert noted.
Vakoc and his team had previously “effectively reversed the mutation of the cancer cells that emerge in Ewing sarcoma.” It was those promising results from differentiation therapy that inspired the team to push further and attempt success with rhabdomyosarcoma.
Their results are “a key step in the development of differentiation therapy for rhabdomyosarcoma and could accelerate the timeline for which such treatments are expected,” ScienceAlert commented.
Developing New Therapies for Deadly Cancers
Vakoc and his team are considering differentiation therapy’s potential effectiveness for other types of cancer as well. They note that “their technique, now demonstrated on two different types of sarcoma, could be applicable to other sarcomas and cancer types since it gives scientists the tools needed to find how to cause cancer cells to differentiate,” ScienceAlert reported.
“Since many forms of human sarcoma exhibit a defect in cell differentiation, the methodology described here might have broad relevance for the investigation of these tumors,” the researchers wrote in PNAS.
Clinical laboratories and anatomic pathologist play a critical role in identifying many types of cancers. And though any treatment that comes from the Cold Spring Harbor Laboratory research is years away, it illustrates how new insights into the basic dynamics of cancer cells is helping researchers develop effective therapies for attacking those cancers.
Norwegian researchers reviewed large clinical trials of six common cancer screenings, including clinical laboratory tests, but some experts question the findings
Cancer screenings are a critical tool for diagnosis and treatment. But how much do they actually extend the lives of patients? According to researchers at the University of Oslo in Norway, not by much. They recently conducted a review and meta-analysis of 18 long-term clinical trials, five of the six most commonly used types of cancer screening—including two clinical laboratory tests—and found that with few exceptions, the screenings did not significantly extend lifespans.
The 18 long-term clinical trials included in the study were randomized trials that collectively included a total of 2.1 million participants. Median follow-up periods of 10 to 15 years were used to gauge estimated lifetime gain and mortality.
“The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy,” the researchers wrote in their published paper.
The researchers noted, however, that their analysis does not suggest all screenings should be abandoned. They also acknowledged that some lives are saved by screenings.
“Without screening, these patients may have died of cancer because it would have been detected at a later, incurable stage,” the scientists wrote, MedPage Today reported. “Thus, these patients experience a gain in lifetime.”
Still, some independent experts questioned the validity of the findings.
Gastroenterologist Michael Bretthauer, MD, PhD (above), a professor at the University of Oslo in Norway led the research into cancer screenings. In their JAMA Internal Medicine paper, he and his team wrote, “The findings of this meta-analysis suggest that colorectal cancer screening with sigmoidoscopy may extend life by approximately three months; lifetime gain for other screening tests appears to be unlikely or uncertain.” How their findings might affect clinical laboratory and anatomic pathology screening for cancer remains to be seen. (Photo copyright: University of Oslo.)
Pros and Cons of Cancer Screening
The clinical trials, according to MedPage Today and Oncology Nursing News covered the following tests:
Mammography screening for breast cancer (two trials).
As reported in these trials, “colorectal cancer screening with sigmoidoscopy prolonged lifetime by 110 days, while fecal testing and mammography screening did not prolong life,” the researchers wrote. “An extension of 37 days was noted for prostate cancer screening with prostate-specific antigen testing and 107 days with lung cancer screening using computed tomography, but estimates are uncertain.”
The American Cancer Society (ACS) recommends certain types of screening tests to detect cancers and pre-cancers before they can spread, thus improving the chances for survival.
The ACS advises screenings for breast cancer, colorectal cancer, and cervical cancer regardless of whether the individual is considered high risk. Lung cancer screenings are advised for people with a history of smoking. Men who are 45 to 50 or older should discuss the pros and cons of prostate cancer screening with their healthcare providers, the ACS states.
A CNN report about the University of Oslo study noted that the benefits and drawbacks of cancer screening have long been well known to doctors.
“Some positive screening results are false positives, which can lead to unnecessary anxiety as well as additional screening that can be expensive,” CNN reported. “Tests can also give a false negative and thus a false sense of security. Sometimes too, treatment can be unnecessary, resulting in a net harm rather than a net benefit, studies show.”
In their JAMA paper, the University of Oslo researchers wrote, “The critical question is whether the benefits for the few are sufficiently large to warrant the associated harms for many. It is entirely possible that multicancer detection blood tests do save lives and warrant the attendant costs and harms. But we will never know unless we ask,” CNN reported.
Hidden Impact on Cancer Mortality
ACS Chief Scientific Officer William Dahut, MD, told CNN that screenings may have an impact on cancer mortality in ways that might not be apparent from randomized trials. He noted that there’s been a decline in deaths from cervical cancer and prostate cancer since doctors began advising routine testing.
“Cancer screening was never really designed to increase longevity,” Dahut said. “Screenings are really designed to decrease premature deaths from cancer.” For example, “if a person’s life expectancy at birth was 80, a cancer screening may prevent their premature death at 65, but it wouldn’t necessarily mean they’d live to be 90 instead of the predicted 80,” CNN reported.
Dahut told CNN that fully assessing the impact of cancer screenings on life expectancy would require a clinical trial larger than those in the new study, and one that followed patients “for a very long time.”
“From its title, one would have expected this paper to be based on analysis of individual lifetime data. However, it is not,” he wrote in a compilation of expert commentary from the UK’s Science Media Center. “The paper’s conclusions are based on arithmetic manipulation of relative rates of all-cause mortality in some of the screening trials. It is therefore difficult to give credence to the claim that screening largely does not extend expected lifetime.”
He also questioned the inclusion of one particular trial in the University of Oslo study—the Canadian National Breast Screening Study—“as there is now public domain evidence of subversion of the randomization in this trial,” he added.
Another expert, Leigh Jackson, PhD, of the University of Exeter in the UK, described the University of Oslo study as “methodologically sound with some limitations which the authors clearly state.”
But he observed that “the focus on 2.1 million individuals is slightly misleading. The study considered many different screening tests and 2.1 million was indeed the total number of included patients, however, no calculation included that many people.”
Jackson also characterized the length of follow-up as a limitation. “This may have limited the amount of data included and also not considering longer follow-up may tend to underestimate the effects of screening,” he said.
This published study—along with the range of credible criticisms offered by other scientists—demonstrates how analysis of huge volumes of data is making it possible to tease out useful new insights. Clinical laboratory managers and pathologists can expect to see other examples of researchers assembling large quantities of data across different areas of medicine. This huge pools of data will be analyzed to determine the effectiveness of many medical procedures that have been performed for years with a belief that they are helpful.
FDA says the move will make it easier to gain authorization for other clinical laboratory tests to utilize at-home collection kits
In another sign of how diagnostic testing is responding to changing consumer preferences, the US Food and Drug Administration (FDA) granted marketing authorization to LetsGetChecked for the company’s Simple 2 test for chlamydia and gonorrhea, which includes at-home collection of samples sent to the test developer’s clinical laboratories in the US and in Ireland.
This marks the first time the FDA has cleared a diagnostic test for either condition in which samples are collected at home. It’s also the first test with at-home sample collection to be authorized for any sexually transmitted infection (STI) other than HIV, the FDA said in a new release.
Samples are collected through a vaginal swab or urine sample. “Results are delivered online in approximately 2-5 days with follow-up virtual consultations and treatment available if needed,” the company press release states.
Previously authorized tests for the conditions required sample collection at the point of care. The company also offers telehealth and online pharmacy services.
“This authorization marks an important public health milestone, giving patients more information about their health from the privacy of their own home,” said Jeff Shuren, MD, JD (above), Director of the FDA’s Center for Devices and Radiological Health. “We are eager to continue supporting greater consumer access to diagnostic tests, which helps further our goal of bringing more healthcare into the home.” With this emphasis on at-home testing from the FDA, clinical laboratories in the US and Ireland will likely be processing more at-home collected samples. (Photo copyright: FDA.)
Simple 2 Process and Costs
Prior to collecting the sample, the user goes online to complete a questionnaire and activate the kit, the FDA news release notes.
LetsGetChecked, headquartered in New York City and Dublin, Ireland, says its US labs are CLIA– and CAP-certified. The company currently offers more than 30 at-home tests covering STIs, men’s health, women’s health, and COVID-19, at prices ranging from $89 to $249 per test.
The Simple 2 test costs $99, and is not covered by insurance, Verywell Health reported. Consumers can get discounts by subscribing to quarterly, semiannual, or annual tests.
New Regulatory Pathway
The FDA said it reviewed the test under its De Novo regulatory pathway, which is intended for “low- to moderate-risk devices of a new type,” according to the news release.
“Along with this De Novo authorization, the FDA is establishing special controls that define the requirements related to labeling and performance testing,” the agency stated. “When met, the special controls, in combination with general controls, provide a reasonable assurance of safety and effectiveness for tests of this type.”
This creates a new regulatory classification, the agency said, that will make it easier for similar devices to obtain marketing authorization.
Citing data from the federal Centers for Disease Control and Prevention (CDC), the FDA news release states that chlamydia and gonorrhea are the most common bacterial STIs in the US. The CDC estimates that there were 1.6 million cases of chlamydia and more than 700,000 cases of gonorrhea in 2021.
“Typically, both infections can be easily treated, but if left untreated, both infections can cause serious health complications for patients, including infertility,” the news release states. “Expanding the availability of STI testing can help patients get quicker results and access to the most appropriate treatment, ultimately helping to curb the rising rates of STIs.”
Experts Praise the FDA’s Authorization of the Lab Test
STI experts contacted by STAT said they welcomed the FDA’s move.
“There are many people who would like to be tested for STIs who may not know where to go or who have barriers to accessing medical care,” said Jodie Dionne, MD, Associate Professor of Medicine in the University of Alabama at Birmingham (UAB) Division of Infectious Diseases. “If we are going to do a better job of reaching more sexually active people for STIs … we need to be creative about how to get them tested and treated in a way that is highly effective and works for them.”
Family physician Alan Katz, MD, a professor at the University of Hawaii John A Burns School of Medicine, told STAT that the Hologic assay is also used by clinicians who treat people in remote locations to diagnose STIs and is regarded as being highly accurate.
“This option is exceptionally useful for individuals who live in rural areas or are geographically distanced from a clinic where STI testing can be done and there is no telehealth option available,” he told STAT.
With this latest move, the FDA is recognizing that it is time to give consumers more control over their healthcare. This is a signal to clinical laboratories that they should be developing their own strategies and offerings that serve consumers who want to order their own tests. Of course, many states still require a physician’s signature on lab test orders, but that is likely to change over time.
Scientists believe useful new clinical laboratory assays could be developed by better understanding the huge number of ‘poorly researched’ genes and the proteins they build
Researchers have added a new “-ome” to the long list of -omes. The new -ome is the “unknome.” This is significant for clinical laboratory managers because it is part of an investigative effort to better understand the substantial number of genes, and the proteins they build, that have been understudied and of which little is known about their full function.
The Unknome Database includes “thousands of understudied proteins encoded by genes in the human genome, whose existence is known but whose functions are mostly not,” according to a news release.
The database, which is available to the public and which can be customized by the user, “ranks proteins based on how little is known about them,” the PLOS Biology paper notes.
It should be of interest to pathologists and clinical laboratory scientists. The fruit of this research may identify additional biomarkers useful in diagnosis and for guiding decisions on how to treat patients.
“These uncharacterized genes have not deserved their neglect,” said Sean Munro, PhD (above), MRC Laboratory of Molecular Biology in Cambridge, England, in a press release. “Our database provides a powerful, versatile and efficient platform to identify and select important genes of unknown function for analysis, thereby accelerating the closure of the gap in biological knowledge that the unknome represents.” Clinical laboratory scientists may find the Unknome Database intriguing and useful. (Photo copyright: Royal Society.)
Risk of Ignoring Understudied Proteins
Proteomics (the study of proteins) is a rapidly advancing area of clinical laboratory testing. As genetic scientists learn more about proteins and their functions, diagnostics companies use that information to develop new assays. But did you know that researchers tend to focus on only a small fraction of the total number of protein-coding DNA sequences contained in the human genome?
The study of proteomics is primarily interested in the part of the genome that “contains instructions for building proteins … [which] are essential for development, growth, and reproduction across the entire body,” according to Scientific American. These are all protein-coding genes.
Proteomics estimates that there are more than two million proteins in the human body, which are coded for 20,000 to 25,000 genes, according to All the Science.
To build their database, the MRC researchers ranked the “unknome” proteins by how little is known about their functions in cellular processes. When they tested the database, they found some of these less-researched proteins important to biological functions such as development and stress resistance.
“The role of thousands of human proteins remains unclear and yet research tends to focus on those that are already well understood,” said Sean Munro, PhD, MRC Laboratory of Molecular Biology in Cambridge, England, in the news release. “To help address this we created an Unknome database that ranks proteins based on how little is known about them, and then performed functional screens on a selection of these mystery proteins to demonstrate how ignorance can drive biological discovery.”
In the paper, they acknowledged the human genome encodes about 20,000 proteins, and that the application of transcriptomics and proteomics has “confirmed that most of these new proteins are expressed, and the function of many of them has been identified.
“However,” the authors added, “despite over 20 years of extensive effort, there are also many others that still have no known function.”
They also recognized limited resources for research and that a preference for “relative safety” and “well-established fields” are likely holding back discoveries.
The researchers note “significant” risks to continually ignoring unexplored proteins, which may have roles in cell processes, serve as targets for therapies, and be associated with diseases as well as being “eminently druggable,” Genetic Engineering News reported.
Setting up the Unknome Database
To develop the Unknome Database, the researchers first turned to what has already come to fruition. They gave each protein in the human genome a “knownness” score based on review of existing information about “function, conservation across species, subcellular localization, and other factors,” Interesting Engineering reported.
It turns out, 3,000 groups of proteins (805 with a human protein) scored zero, “showing there’s still much to learn within the human genome,” Science News stated, adding that the Unknome Database catalogues more than 13,000 protein groups and nearly two million proteins.
The researchers then tested the database by using it to determine what could be learned about 260 “mystery” genes in humans that are also present in Drosophila (small fruit flies).
“We used the Unknome Database to select 260 genes that appeared both highly conserved and particularly poorly understood, and then applied functional assays in whole animals that would be impractical at genome-wide scale,” the researchers wrote in PLOS Biology.
“We initially selected all genes that had a knownness score of ≤1.0 and are conserved in both humans and flies, as well as being present in at least 80% of available metazoan genome sequences. … After testing for viability, the nonessential genes were then screened with a panel of quantitative assays designed to reveal potential roles in a wide range of biological functions,” they added.
“Our screen in whole organisms reveals that, despite several decades of extensive genetic screens in Drosophila, there are many genes with essential roles that have eluded characterization,” the researchers conclude.
Clinical Laboratory Testing Using the Unknome Database
Future use of the Unknome Database may involve CRISPR technology to explore functions of unknown genes, according to the PLOS Biology paper.
Munro told Science News the research team may work with other research efforts aimed at understanding “mysterious proteins,” such as the Understudied Proteins Initiative.
The Unknome Database’s ability to be customized by others means researchers can create their own “knownness” scores as it applies to their studies. Thus, the database could be a resource in studies of treatments or medications to fight diseases, Chemistry World noted.
According to a statement prepared for Healthcare Dive by SomaLogic, a Boulder, Colorado-based protein biomarker company, diagnostic tests that measure proteins can be applied to diseases and conditions such as:
“The 27-protein model has potential as a ‘universal’ surrogate end point for cardiovascular risk,” the researchers wrote in Science Translational Medicine.
Proteomics definitely has its place in clinical laboratory testing. The development of MRC-LMB’s Unknome Database will help researchers’ increase their knowledge about the functions of more proteins which should in turn lead to new diagnostic assays for labs.
