Best of all, the researchers say the test could provide an inexpensive means of early diagnosis. This assay could also be used to monitor how well patients respond to cancer therapy, according to a news release.
The protein had previously been identified as a promising biomarker and is readily detectable in tumor tissue, they wrote. However, it is found in extremely low concentrations in blood plasma and is “well below detection limits of conventional clinical laboratory methods,” they noted.
To overcome that obstacle, they employed an ultra-sensitive immunoassay known as a Simoa (Single-Molecule Array), an immunoassay platform for measuring fluid biomarkers.
“We were shocked by how well this test worked in detecting the biomarker’s expression across cancer types,” said lead study author gastroenterologist Martin Taylor, MD, PhD, Instructor in Pathology, Massachusetts General Hospital and Harvard Medical School, in the press release. “It’s created more questions for us to explore and sparked interest among collaborators across many institutions.”
“We’ve known since the 1980s that transposable elements were active in some cancers, and nearly 10 years ago we reported that ORF1p was a pervasive cancer biomarker, but, until now, we haven’t had the ability to detect it in blood tests,” said pathologist and study co-author Kathleen Burns, MD, PhD (above), Chair of the Department of Pathology at Dana-Farber Cancer Institute and a Professor of Pathology at Harvard Medical School, in a press release. “Having a technology capable of detecting ORF1p in blood opens so many possibilities for clinical applications.” Clinical laboratories may soon have a new blood test to detect multiple types of cancer. (Photo copyright: Dana-Farber Cancer Institute.)
Simoa’s Advantages
In their press release, the researchers described ORF1p as “a hallmark of many cancers, particularly p53-deficient epithelial cancers,” a category that includes lung, breast, prostate, uterine, pancreatic, and head and neck cancers in addition to the cancers noted above.
“Pervasive expression of ORF1p in carcinomas, and the lack of expression in normal tissues, makes ORF1p unlike other protein biomarkers which have normal expression levels,” Taylor said in the press release. “This unique biology makes it highly specific.”
Simoa was developed at the laboratory of study co-author David R. Walt, PhD, the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard Medical School, and Professor of Pathology at Harvard Medical School and Brigham and Women’s Hospital.
The Simoa technology “enables 100- to 1,000-fold improvements in sensitivity over conventional enzyme-linked immunosorbent assay (ELISA) techniques, thus opening the window to measuring proteins at concentrations that have never been detected before in various biological fluids such as plasma or saliva,” according to the Walt Lab website.
Simoa assays take less than two hours to run and require less than $3 in consumables. They are “simple to perform, scalable, and have clinical-grade coefficients of variation,” the researchers wrote.
Study Results
Using the first generation of the ORF1p Simoa assay, the researchers tested blood samples of patients with a variety of cancers along with 406 individuals, regarded as healthy, who served as controls. The test proved to be most effective among patients with colorectal and ovarian cancer, finding detectable levels of ORF1p in 58% of former and 71% of the latter. Detectable levels were found in patients with advanced-stage as well as early-stage disease, the researchers wrote in Cancer Discovery.
Among the 406 healthy controls, the test found detectable levels of ORF1p in only five. However, the control with the highest detectable levels, regarded as healthy when donating blood, “was six months later found to have prostate cancer and 19 months later found to have lymphoma,” the researchers wrote.
They later reengineered the Simoa assay to increase its sensitivity, resulting in improved detection of the protein in blood samples from patients with colorectal, gastroesophageal, ovarian, uterine, and breast cancers.
The researchers also employed the test on samples from 19 patients with gastroesophageal cancer to gauge its utility for monitoring therapeutic response. Although this was a small sample, they found that among 13 patients who had responded to therapy, “circulating ORF1p dropped to undetectable levels at follow-up sampling.”
“More Work to Be Done”
The Simoa assay has limitations, the researchers acknowledged. It doesn’t identify the location of cancers, and it “isn’t successful in identifying all cancers and their subtypes,” the press release stated, adding that the test will likely be used in conjunction with other early-detection approaches. The researchers also said they want to gauge the test’s accuracy in larger cohorts.
“The test is very specific, but it doesn’t tell us enough information to be used in a vacuum,” Walt said in the news release. “It’s exciting to see the early success of this ultrasensitive assessment tool, but there is more work to be done.”
More studies will be needed to valid these findings. That this promising new multi-cancer immunoassay is based on a clinical laboratory blood sample means its less invasive and less painful for patients. It’s a good example of an assay that takes a proteomic approach looking for protein cancer biomarkers rather than the genetic approach looking for molecular DNA/RNA biomarkers of cancer.
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.
Findings could lead to deeper understanding of why we age, and to medical laboratory tests and treatments to slow or even reverse aging
Can humans control aging by keeping their genes long and balanced? Researchers at Northwestern University in Evanston, Illinois, believe it may be possible. They have unveiled a “previously unknown mechanism” behind aging that could lead to medical interventions to slow or even reverse aging, according to a Northwestern news release.
Should additional studies validate these early findings, this line of testing may become a new service clinical laboratories could offer to referring physicians and patients. It would expand the test menu with assays that deliver value in diagnosing the aging state of a patient, and which identify the parts of the transcriptome that are undergoing the most alterations that reduce lifespan.
It may also provide insights into how treatments and therapies could be implemented by physicians to address aging.
“I find it very elegant that a single, relatively concise principle seems to account for nearly all of the changes in activity of genes that happen in animals as they change,” Thomas Stoeger, PhD, postdoctoral scholar in the Amaral Lab who led the study, told GEN. Clinical laboratories involved in omics research may soon have new anti-aging diagnostic tests to perform. (Photo copyright: Amaral Lab.)
Possible ‘New Instrument’ for Biological Testing
Researchers found clues to aging in the length of genes. A gene transcript length reveals “molecular-level changes” during aging: longer genes relate to longer lifespans and shorter genes suggest shorter lives, GEN summarized.
The phenomenon the researchers uncovered—which they dubbed transcriptome imbalance—was “near universal” in the tissues they analyzed (blood, muscle, bone, and organs) from both humans and animals, Northwestern said.
According to the National Human Genome Research Institute fact sheet, a transcriptome is “a collection of all the gene readouts (aka, transcript) present in a cell” shedding light on gene activity or expression.
The Northwestern study suggests “systems-level” changes are responsible for aging—a different view than traditional biology’s approach to analyzing the effects of single genes.
“We have been primarily focusing on a small number of genes, thinking that a few genes would explain disease,” said Luis Amaral, PhD, Senior Author of the Study and Professor of Chemical and Biological Engineering at Northwestern, in the news release.
“So, maybe we were not focused on the right thing before. Now that we have this new understanding, it’s like having a new instrument. It’s like Galileo with a telescope, looking at space. Looking at gene activity through this new lens will enable us to see biological phenomena differently,” Amaral added.
In their Nature Aging paper, Amaral and his colleagues wrote, “We hypothesize that aging is associated with a phenomenon that affects the transcriptome in a subtle but global manner that goes unnoticed when focusing on the changes in expression of individual genes.
“We show that transcript length alone explains most transcriptional changes observed with aging in mice and humans,” they continued.
In tissues studied, older animals’ long transcripts were not as “abundant” as short transcripts, creating “imbalance.”
“Imbalance” likely prohibited the researchers’ discovery of a “specific set of genes” changing.
As animals aged, shorter genes “appeared to become more active” than longer genes.
In humans, the top 5% of genes with the shortest transcripts “included many linked to shorter life spans such as those involved in maintaining the length of telomeres.”
Conversely, the researchers’ review of the leading 5% of genes in humans with the longest transcripts found an association with long lives.
Antiaging drugs—rapamycin (aka, sirolimus) and resveratrol—were linked to an increase in long-gene transcripts.
“The changes in the activity of genes are very, very small, and these small changes involve thousands of genes. We found this change was consistent across different tissues and in different animals. We found it almost everywhere,” Thomas Stoeger, PhD, postdoctoral scholar in the Amaral Lab who led the study, told GEN.
In their paper, the Northwestern scientists noted implications for creation of healthcare interventions.
“We believe that understanding the direction of causality between other age-dependent cellular and transcriptomic changes and length-associated transcriptome imbalance could open novel research directions for antiaging interventions,” they wrote.
While more research is needed to validate its findings, the Northwestern study is compelling as it addresses a new area of transcriptome knowledge. This is another example of researchers cracking open human and animal genomes and gaining new insights into the processes supporting life.
For clinical laboratories and pathologists, diagnostic testing to reverse aging and guide the effectiveness of therapies may one day be possible—kind of like science’s take on the mythical Fountain of Youth.
But even though the College of American Pathologists (CAP) and nine other organizations signed a December 12 stakeholder letter to leaders of key House and Senate committees urging passage of legislation that would enable some regulation of LDTs, the VALID Act was ultimately omitted from the year-end omnibus spending bill (H.R. 2617).
That may be due to pressure from organizations representing clinical laboratories and pathologists which lobbied hard against the bill.
Responding to criticism of its stance on FDA oversight of LDTs, in a May 2022 open letter posted on the organization’s website, anatomic pathologist and CAP president Emily Volk, MD, said “we at the CAP have an honest difference of opinion with some other respected laboratory organizations. … We believe the VALID Act is the only viable piece of legislation addressing the LDT issue. … the VALID Act contains many provisions that are similar to policy the CAP has advocated for regarding the regulation of laboratory tests since 2009. Importantly, the current version includes explicit protections for pathologists and our ability to practice medicine without infringement from the Food and Drug Administration (FDA).” (Photo copyright: College of American Pathologists.)
Organizations on Both Sides Brought Pressure to Bear on Legislators
The AAMC and AMP were especially influential, Bucshon told ProPublica. In addition to spending hefty sums on lobbying, AMP urged its members to contact legislators directly and provided talking points, ProPublica reported.
“The academic medical centers and big medical centers are in every state,” Bucshon said. As major employers in many locales, they have “a pretty big voice,” he added.
Discussing CAP’s reasoning behind its support of the VALID Act in a May 26 open letter and podcast, CAP president Emily Volk, MD, said the Valid Act “creates a risk-based system of oversight utilizing three tiers—low, moderate and high risk—in order to target the attention of the FDA oversight.”
While acknowledging that it had room for improvement, she lauded the bill’s three-tier risk-based system, in which tests deemed to have the greatest risks would receive the highest level of scrutiny.
She also noted that the bill exempts existing LDTs from an FDA premarket review “unless there is a safety concern for patients.” It would also exempt “low-volume tests, modified tests, manual interpretation tests, and humanitarian tests,” she wrote.
In addition, the bill would “direct the FDA not to create regulations that are duplicative of regulation under CLIA,” she noted, and “would require the FDA to conduct public hearings on LDT oversight.”
Pros and Cons of the VALID Act
One concern raised by opponents relates to how the VALID Act addressed user fees paid by clinical laboratories to fund FDA compliance activities. But Volk wrote that any specific fees “would need to be approved by Congress in a future FDA user fee authorization bill after years of public input.”
During the May 2022 podcast, Volk also cast CAP’s support as a matter of recognizing political realities.
“We understand that support for FDA oversight of laboratory-developed tests or IVCTs is present on both sides of the aisle and in both houses of Congress,” she said. “In fact, it enjoys wide support among very influential patient advocacy groups.” These groups “are very sophisticated in their understanding of the issues with laboratory-developed tests, and they do have the ear of Congress. There are many in the laboratory community that believe the VALID Act goes too far, but I can tell you that many of these patient groups don’t believe it goes far enough and are actively pushing for even more restrictive paradigms.”
Also urging passage of the bill were former FDA commissioners Scott Gottlieb, MD, and Mark B. McClellan, MD, PhD. In a Dec. 5 opinion piece for STAT, they noted that “diagnostic technologies have undergone considerable advances in recent decades, owing to innovation in fields like genomics, proteomics, and data science.” However, they wrote, laws governing FDA oversight “have not kept pace,” placing the agency in a position of regulating tests based on where they are made—in a medical laboratory or by a manufacturer—instead of their “distinctive complexity or potential risks.”
In their May 22 letter, opponents of the legislation outlined broad areas of concern. They contended that it would create “an onerous and complex system that would radically alter the way that laboratory testing is regulated to the detriment of patient care.” And even though existing tests would be largely exempted from oversight, “the utility of these tests would diminish over time as the VALID Act puts overly restrictive constraints on how they can be modified.”
CLIA Regulation of LDTs also Under Scrutiny
The provision to avoid duplication with the Clinical Laboratory Improvement Amendments (CLIA) program—which currently has some regulatory oversight of LDTs and IVCTs—is “insufficient,” opponents added, “especially when other aspects of the legislation call for requirements and activities that lead to duplicative and unnecessary regulatory burden.”
Opponents to the VALID Act also argued that the definitions of high-, medium-, and low-risk test categories lacked clarity, stating that “the newly created definition of moderate risk appears to overlap with the definition of high risk.”
The opponents also took issue with the degree of discretion that the bill grants to the US Secretary of Health and Human Services. This will create “an unpredictable regulatory process and ambiguities in the significance of the policy,” they wrote, while urging the Senate committee to “narrow the discretion so that stakeholders may better evaluate and understand the implications of this legislation.”
Decades ago, clinical laboratory researchers were allowed to develop assays in tandem with clinicians that were intended to provide accurate diagnoses, earlier detection of disease, and help guide selection of therapies. Since the 1990s, however, an industry of investor-funded laboratory companies have brought proprietary LDTs to the national market. Many recognize that this falls outside the government’s original intent for encouragement of laboratory-developed tests to begin with.
Genomic sequencing continues to benefit patients through precision medicine clinical laboratory treatments and pharmacogenomic therapies
EDITOR’S UPDATE—Jan. 26, 2022: Since publication of this news briefing, officials from Genomics England contacted us to explain the following:
The “five million genome sequences” was an aspirational goal mentioned by then Secretary of State for Health and Social Care Matt Hancock, MP, in an October 2, 2018, press release issued by Genomics England.
As of this date a spokesman for Genomics England confirmed to Dark Daily that, with the initial goal of 100,000 genomes now attained, the immediate goal is to sequence 500,000 genomes.
This goal was confirmed in a tweet posted by Chris Wigley, CEO at Genomics England.
In accordance with this updated input, we have revised the original headline and information in this news briefing that follows.
What better proof of progress in whole human genome screening than the announcement that the United Kingdom’s 100,000 Genome Project has not only achieved that milestone, but will now increase the goal to 500,000 whole human genomes? This should be welcome news to clinical laboratory managers, as it means their labs will be positioned as the first-line provider of genetic data in support of clinical care.
Many clinical pathologists here in the United States are aware of the 100,000 Genome Project, established by the National Health Service (NHS) in England (UK) in 2012. Genomics England’s new goal to sequence 500,000 whole human genomes is to pioneer a “lasting legacy for patients by introducing genomic sequencing into the wider healthcare system,” according to Technology Networks.
The importance of personalized medicine and of the power of precise, accurate diagnoses cannot be understated. This announcement by Genomics England will be of interest to diagnosticians worldwide, especially doctors who diagnose and treat patients with chronic and life-threatening diseases.
Building a Vast Genomics Infrastructure
Genetic sequencing launched the era of precision medicine in healthcare. Through genomics, drug therapies and personalized treatments were developed that improved outcomes for all patients, especially those suffering with cancer and other chronic diseases. And so far, the role of genomics in healthcare has only been expanding, as Dark Daily covered in numerous ebriefings.
Genomics England, which is wholly owned by the Department of Health and Social Care in the United Kingdom, was formed in 2012 with the goal of sequencing 100,000 whole genomes of patients enrolled in the UK National Health Service. That goal was met in 2018, and now the NHS aspires to sequence 500,000 genomes.
“The last 10 years have been really exciting, as we have seen genetic data transition from being something that is useful in a small number of contexts with highly targeted tests, towards being a central part of mainstream healthcare settings,” Richard Scott, MD, PhD (above), Chief Medical Officer at Genomics England told Technology Networks. Much of the progress has found its way into clinical laboratory testing and precision medicine diagnostics. (Photo copyright: Genomics England.)
Genomics England’s initial goals included:
To create an ethical program based on consent,
To set up a genomic medicine service within the NHS to benefit patients,
To make new discoveries and gain insights into the use of genomics, and
To begin the development of a UK genomics industry.
To gain the greatest benefit from whole genome sequencing (WGS), a substantial amount of data infrastructure must exist. “The amount of data generated by WGS is quite large and you really need a system that can process the data well to achieve that vision,” said Richard Scott, MD, PhD, Chief Medical Officer at Genomics England.
In early 2020, Weka, developer of the WekaFS, a fully parallel and distributed file system, announced that it would be working with Genomics England on managing the enormous amount of genomic data. When Genomics England reached 100,000 sequenced genomes, it had already gathered 21 petabytes of data. The organization expects to have 140 petabytes by 2023, notes a Weka case study.
Putting Genomics England’s WGS Project into Action
WGS has significantly impacted the diagnosis of rare diseases. For example, Genomics England has contributed to projects that look at tuberculosis genomes to understand why the disease is sometimes resistant to certain medications. Genomic sequencing also played an enormous role in fighting the COVID-19 pandemic.
Scott notes that COVID-19 provides an example of how sequencing can be used to deliver care. “We can see genomic influences on the risk of needing critical care in COVID-19 patients and in how their immune system is behaving. Looking at this data alongside other omics information, such as the expression of different protein levels, helps us to understand the disease process better,” he said.
What’s Next for Genomics Sequencing?
As the research continues and scientists begin to better understand the information revealed by sequencing, other areas of scientific study like proteomics and metabolomics are becoming more important.
“There is real potential for using multiple strands of data alongside each other, both for discovery—helping us to understand new things about diseases and how [they] affect the body—but also in terms of live healthcare,” Scott said.
Along with expanding the target of Genomics England to 500,000 genomes sequenced, the UK has published a National Genomic Strategy named Genome UK. This plan describes how the research into genomics will be used to benefit patients. “Our vision is to create the most advanced genomic healthcare ecosystem in the world, where government, the NHS, research and technology communities work together to embed the latest advances in patient care,” according to the Genome UK website.
Clinical laboratories professionals with an understanding of diagnostics will recognize WGS’ impact on the healthcare industry. By following genomic sequencing initiatives, such as those coming from Genomics England, pathologists can keep their labs ready to take advantage of new discoveries and insights that will improve outcomes for patients.
