List also includes precision oncology, liquid biopsies, and early diagnosis of pancreatic cancer
Pathologists and clinical laboratory managers will be interested to learn that in a recently updated article the World Economic Forum (WEF) identified a dozen important recent breakthroughs in the ongoing fight to defeat cancer, including some related to pathology and clinical laboratory diagnostics.
The article noted that approximately 10 million people die each year from cancer. “Death rates from cancer were falling before the pandemic,” the authors wrote. “But COVID-19 caused a big backlog in diagnosis and treatment.”
The Swiss-based non-profit is best known for its annual meeting of corporate and government leaders in Davos, Switzerland. Healthcare is one of 10 WEF “centers” focusing on specific global issues.
Here are four advances identified by WEF that should be of particular interest to clinical laboratory leaders. The remaining advances will be covered in part two of this ebrief on Wednesday.
“Our study represents a major leap in cancer screening, combining the precision of protein-based biomarkers with the efficiency of sex-specific analysis,” said Novelna founder and CEO Ashkan Afshin, MD, ScD (above), in a company press release. “We’re not only looking at a more effective way of detecting cancer early but also at a cost-effective solution that can be implemented on a large scale.” The 12 breakthroughs listed in the World Economic Forum’s updated article will likely lead to new clinical laboratory screening tests for multiple types of cancer. (Photo copyright: Novelna.)
Novelna’s Early-Stage Cancer Test
Novelna, a biotech startup in Palo Alto, Calif., says it has developed a clinical laboratory blood test that can detect 18 early-stage cancers, including brain, breast, cervical, colorectal, lung, pancreatic, and uterine cancers, according to a press release.
In a small “proof of concept” study, scientists at the company reported that the test identified 93% of stage 1 cancers among men with 99% specificity and 90% sensitivity. Among women, the test identified 84% of stage 1 cancers with 85% sensitivity and 99% specificity.
The researchers collected plasma samples from 440 individuals diagnosed with cancers and measured more than 3,000 proteins. They identified 10 proteins in men and 10 in women that correlated highly with early-stage cancers.
“By themselves, each individual protein was only moderately accurate at picking up early stage disease, but when combined with the other proteins in a panel they were highly accurate,” states a BMJ Oncology press release.
The company says the test can be manufactured for less than $100.
“While further validation in larger population cohorts is necessary, we anticipate that our test will pave the way for more efficient, accurate, and accessible cancer screening,” said Novelna founder and CEO Ashkan Afshin, MD, ScD, in the company press release.
Precision Oncology
According to the National Institutes of Health’s “Promise of Precision Medicine” web page, “Researchers are now identifying the molecular fingerprints of various cancers and using them to divide cancer’s once-broad categories into far more precise types and subtypes. They are also discovering that cancers that develop in totally different parts of the body can sometimes, on a molecular level, have a lot in common. From this new perspective emerges an exciting era in cancer research called precision oncology, in which doctors are choosing treatments based on the DNA signature of an individual patient’s tumor.”
“These advanced sequencing technologies not only extend lifespans and improve cure rates for cancer patients through application to early screening; in the field of cancer diagnosis and monitoring they can also assist in the formulation of personalized clinical diagnostics and treatment plans, as well as allow doctors to accurately relocate the follow-up development of cancer patients after the primary treatment,” Wang wrote.
Based in China, Genetron Health describes itself as a “leading precision oncology platform company” with products and services related to cancer screening, diagnosis, and monitoring.
Liquid and Synthetic Biopsies
Liquid biopsies, in which blood or urine samples are analyzed for presence of biomarkers, provide an “easier and less invasive” alternative to conventional surgical biopsies for cancer diagnosis, the WEF article notes.
These tests allow clinicians to “pin down the disease subtype, identify the appropriate treatment and closely track patient response, adjusting course, if necessary, as each case requires—precision medicine in action,” wrote Merck Group CEO Belén Garijo, MD, in an earlier WEF commentary.
The WEF article also highlighted “synthetic biopsy” technology developed by Earli, Inc., a company based in Redwood City, Calif.
As explained in a Wired story, “Earli’s approach essentially forces the cancer to reveal itself. Bioengineered DNA is injected into the body. When it enters cancer cells, it forces them to produce a synthetic biomarker not normally found in humans.”
The biomarker can be detected in blood or breath tests, Wired noted. A radioactive tracer is used to determine the cancer’s location in the body.
“Pancreatic cancer is one of the deadliest cancers,” the WEF article notes. “It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years.”
The test is based on a technology known as high-conductance dielectrophoresis (DEP), according to a UC San Diego press release. “It detects extracellular vesicles (EVs), which contain tumor proteins that are released into circulation by cancer cells as part of a poorly understood intercellular communication network,” the press release states. “Artificial intelligence-enabled protein marker analysis is then used to predict the likelihood of malignancy.”
The test detected 95.5% of stage 1 pancreatic cancers, 74.4% of stage 1 ovarian cancers, and 73.1% of pathologic stage 1A lethally aggressive serous ovarian adenocarcinomas, they wrote.
“These results are five times more accurate in detecting early-stage cancer than current liquid biopsy multi-cancer detection tests,” said co-senior author Scott M. Lippman, MD.
Look to Dark Daily’s ebrief on Wednesday for the remainder of breakthroughs the World Economic Forum identifies as top advancements in the fight to defeat cancer.
New vaccine could give clinical laboratories and antimicrobial stewardship programs the tool they need to dramatically reduce hospital-acquired infections
The innovative approach focuses on bolstering the patient’s immune system itself, rather than relying on proteins to fight infections, according to a USC Today article.
Developed by senior study author Brad Spellberg, MD, Chief Medical Officer at the Los Angeles General Medical Center, and colleagues, “The experimental vaccine takes an entirely different approach: It gooses the body’s preexisting supply of pathogen-gobbling immune cells called macrophages, which engulf and digest bacteria, fungi, and other bad actors. These activated fighters, found in all tissues, quickly neutralize incoming invaders which might otherwise multiply rapidly and overwhelm the body’s defenses,” USC Today reported.
“This is very different from developing new antibiotics,” Jun Yan, a doctoral student at Keck School of Medicine and the study’s first author, told USC Today. “This is using our own immune system to fight against different superbugs, which is a different approach than everybody else.”
To develop the vaccine [the USC researchers] formed a biotechnology startup called ExBaq LLC in Bethesda, Md.
“The pandemic stimulated unprecedented innovation in vaccine development, where federal funding and university-industry partnerships were game changers for translating promising discoveries from academic labs for the good of all,” said Ishwar K. Puri, PhD (above), senior vice president of research and innovation at USC. “We are both pleased and proud of the critical support the USC Stevens Center provided to enable the development of ExBaq’s experimental vaccine that protects vulnerable populations from serious infections.” Clinical laboratories that work with hospitals in the fight against hospital-acquired infections understand the importance of this discovery. (Photo copyright: University of Southern California.)
USC Vaccine Details
The USC team developed a “protein-free vaccine, composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan, that stimulates the innate immune system and confers protection,” the researchers wrote in Science Translational Medicine.
“Tested in two independent labs, the vaccine works within 24 hours and lasts for up to 28 days. In lab models, the number of pathogen-eating immune cells in the blood increased dramatically, and survival time of invasive blood and lung infections improved. Early data suggest that a second dose could extend the window to prevent infection,” USC Today reported.
Unlike anything currently available, the new vaccine focuses on boosting the body itself instead of creating antibodies against certain pathogens. A mere dose of the vaccine is described to “provide rapid protection against nine different bacteria and fungi species,” USC Today noted.
“It’s an early warning system. It’s like Homeland Security putting out a terror alert. Everybody, keep your eyes open. Keep an eye out for suspicious packages. You’re alerting the soldiers and tanks of your immune system. The vaccine activates them,” Spellberg told USC Today.
“The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant healthcare-associated infections,” the researchers wrote in Science Translational Medicine.
“Patients who acquire infections from surgery spend, on average, an additional 6.5 days in the hospital, are five times more likely to be readmitted after discharge and twice as likely to die. Moreover, surgical patients who develop infections are 60% more likely to require admission to a hospital’s intensive care unit. Surgical infections are believed to account for up to 10 billion dollars annually in healthcare expenditures,” the CDC reports.
“All hospitalized patients are susceptible to contracting a [hospital-acquired] infection. Some patients are at greater risk than others: young children, the elderly, and persons with compromised immune systems are more likely to get an infection. Other risk factors are long hospital stays, the use of indwelling catheters, failure of healthcare workers to wash their hands, and overuse of antibiotics,” the CDC notes.
Therefore, USC’s new vaccine may be just what the doctor ordered to protect patients in hospitals and other healthcare settings from deadly HAIs.
Looking Ahead
There are currently no vaccines that are FDA-approved that treat “the most serious antibiotic resistant infections,” USC Today reported.
“Even if there were such vaccines, multiple vaccines would have to be deployed simultaneously to protect against the full slate of antibiotic-resistant microbes that cause healthcare-acquired infections,” Brian Luna, PhD, assistant professor of molecular microbiology and immunology at USC’s Keck School of Medicine, told USC Today.
Thus, USC’s new vaccine could be a boon to hospital antimicrobial stewardship programs. But so far, it has only been tested on mice.
“The next step is getting guidance from the US Food and Drug Administration (FDA) on the design of a clinical trial. The first such trial would be done in healthy volunteers to find the right dose of vaccine that is safe and triggers the same kind of immune response in people as seen in the mice,” USC Today reported.
ExBaq LLC has begun talking with potential larger partners who might be willing to help develop the vaccine into clinical testing.
For years hospitals and other healthcare settings—such as long-term care facilities, urgent care clinics, and clinical laboratories—have fought an uphill battle against superbugs. So, for a vaccine to be on the horizon that can prevent life-threatening hospital-acquired infections would be a game changer.
With antimicrobial stewardships being a requirement in all hospitals, medical laboratory managers and microbiologists may celebrate this new development and its potential to be a useful tool in fighting antimicrobial resistant bacteria in their facilities.
The St. Louis-based in vitro diagnostics (IVD) developer is making PrecivityAD available to physicians while awaiting FDA clearance for the non-invasive test
Clinical laboratories have long awaited a test for Alzheimer’s disease and the wait may soon be over. The first blood test to aid physicians and clinical laboratories in the diagnosis of patients with memory and cognitive issues has been released by C₂N Diagnostics of St. Louis. The test measures biomarkers associated with amyloid plaques in the brain—the pathological hallmark of Alzheimer’s.
In a news release, PrecivityAD describes the laboratory-developed test (LDT) as “a highly sensitive blood test using mass spectrometry and is performed in C₂N’s CLIA-certified laboratory. While the test by itself cannot diagnose Alzheimer’s disease … the test is an important new tool for physicians to aid in the evaluation process.”
PrecivityAD provides physicians with an Amyloid Probability Score (APS) for each patient. For example:
A low APS (0-36) is consistent with a negative amyloid PET scan result and, thus, has a low likelihood of amyloid plaques, an indication other causes of cognitive symptoms should be investigated.
An intermediate APS (37-57) does not distinguish between the presence or absence of amyloid plaques and indicates further diagnostic evaluation may be needed to assess the underlying cause(s) for the patient’s cognitive symptoms.
A high APS (58-100) is consistent with a positive amyloid positron-emission tomography (PET) scan result and, thus, a high likelihood of amyloid plaques. Presence of amyloid plaques is consistent with an Alzheimer’s disease diagnosis in someone who has cognitive decline, but alone is insufficient for a final diagnosis.
The $1,250 test is not currently covered by health insurance or Medicare. However, C₂N Diagnostics has pledged to offer discounts to patients based on income levels.
Jeff Cummings, MD, ScD (above) Research Professor, Department of Brain Health, University of Nevada, Las Vegas, said in a C₂N Diagnostics press release, “A blood test for Alzheimer’s is a game changer.” While there is no cure for Alzheimer’s, a non-invasive blood test can help providers diagnose patients when their symptoms are mild and often misdiagnosed. “Advances in Alzheimer’s diagnostics are key to more effective identification, diagnosis, and clinical trial recruitment,” he added. Currently, brain changes caused by the disease are most commonly identified through PET scans. (Photo copyright: University of Nevada Las Vegas.)
Additional Research Requested
While C₂N’s PrecivityAD is the first test of its kind to reach the commercial market, it has not received US Food and Drug Administration (FDA) clearance, nor has the company published detailed data on the test’s accuracy. However, the PrecivityAD website says the laboratory-developed test “correctly identified brain amyloid plaque status (as determined by quantitative PET scans) in 86%” of 686 patients, all of whom were older than 60 years of age with subjective cognitive impairment or dementia.
But some Alzheimer’s advocacy groups are tempering their enthusiasm about the breakthrough. Eliezer Masliah, MD, Director of the Division of Neuroscience, National Institute on Aging, told the Associated Press (AP), “I would be cautious about interpreting any of these things,” he said of the company’s claims. “We’re encouraged, we’re interested, we’re funding this work, but we want to see results.”
Heather Snyder, PhD, Vice President, Medical and Scientific Relations at the Alzheimer’s Association told the AP her organization will not endorse a test without FDA clearance. The Alzheimer’s Association also would like to see the test studied in larger and diverse populations. “It’s not quite clear how accurate or generalizable the results are,” she said.
Braunstein defended the decision to make the test for Alzheimer’s immediately available to physicians, asking in the AP article, “Should we be holding that technology back when it could have a big impact on patient care?”
Howard Fillit, MD, Founding Executive Director and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation (ADDF), maintains the first-of-its-kind blood test is an important milestone in Alzheimer’s research. ADDF invested in C₂N’s development of the test.
“Investing in biomarker research has been a core goal for the ADDF because having reliable, accessible, and affordable biomarkers for Alzheimer’s diagnosis is step one in finding drugs to prevent, slow, and even cure the disease,” Fillit said in an ADDF news release.
C₂N is also developing a Brain Health Panel to detect multiple blood-based markers for Alzheimer’s disease that will aid in better disease staging, treatment monitoring, and differential diagnosis.
Second Alzheimer’s Test in Development
Soon medical laboratories may have two different in vitro diagnostic tests for Alzheimer’s disease. On December 2, Fujirebio Diagnostics filed for FDA 510(k) premarket clearance for its Lumipulse G β-Amyloid Ratio (1-42/1-40) test, which looks for biomarkers found in cerebral spinal fluid.
“Accurate and earlier intervention will also facilitate the development of new drug therapies, which are urgently needed as the prevalence of Alzheimer’s disease increases with a rapidly aging population globally,” Fujirebio Diagnostics President and CEO Monte Wiltse said in a news release.
The Lumipulse G β-Amyloid test, which is intended for use in patients aged 50 and over presenting with cognitive impairment, has received CE-marking for use in the European Union.
Clinical laboratory managers will want to keep a close eye on rapidly evolving developments in testing for Alzheimer’s disease. It is the sixth leading cause of death in the United States and any clinical laboratory test that could produce an early and accurate diagnosis of Alzheimer’s Disease would become a valuable tool for physicians who treat patients with the symptoms of Alzheimer’s.
The AI protein-structure-prediction system may ‘revolutionize life sciences by enabling researchers to better understand disease,’ researchers say
Genomics leaders watched with enthusiasm as artificial intelligence (AI) accelerated discoveries that led to new clinical laboratory diagnostic tests and advanced the evolution of personalized medicine. Now Google’s London-based DeepMind has taken that a quantum step further by demonstrating its AI can predict the shape of proteins to within the width of one atom and model three-dimensional (3D) structures of proteins that scientist have been trying to map accurately for 50 years.
Pathologists and clinical laboratory professionals know that it is estimated that there are around 30,000 human genes. But the human proteome has a much larger number of unique proteins. The total number is still uncertain because scientists continue to identify new human proteins. For this reason, more knowledge of the human protein is expected to trigger an expanding number of new assays that can be used by medical laboratories for diagnostic, therapeutic, and patient-monitoring purposes.
DeepMind’s AI tool is called AlphaFold and the protein-structure-prediction system will enable scientists to quickly move from knowing a protein’s DNA sequence to determining its 3D shape without time-consuming experimentation. It “is expected to accelerate research into a host of illnesses, including COVID-19,” BBC News reported.
This protein-folding breakthrough not only answers one of biology’s biggest mysteries, but also has the potential to revolutionize life sciences by enabling researchers to better understand disease processes and design personalized therapies that target specific proteins.
In November, DeepMind’s AlphaFold won the 14th Community Wide Experiment on Critical Assessment of Techniques for Protein Structure Prediction (CASP14), a biennial competition in which entrants receive amino acid sequences for about 100 proteins whose 3D structures are unknown. By comparing the computational predictions with the lab results, each CASP14 competitor received a global distance test (GDT) score. Scores above 90 out of 100 are considered equal to experimental methods. AlphaFold produced models for about two-thirds of the CASP14 target proteins with GDT scores above 90, a CASP14 press release states.
According to MIT Technology Review, DeepMind’s discovery is significant. That’s because its speed at predicting the structure of proteins is unprecedented and it matched the accuracy of several techniques used in clinical laboratories, including:
Unlike the laboratory techniques, which, MIT noted, are “expensive and slow” and “can take hundreds of thousands of dollars and years of trial and error for each protein,” AlphaFold can predict a protein’s shape in a few days.
“AlphaFold is a once in a generation advance, predicting protein structures with incredible speed and precision,” Arthur D. Levinson, PhD, Founder and CEO of Calico Life Sciences, said in a DeepMind blogpost. “This leap forward demonstrates how computational methods are poised to transform research in biology and hold much promise for accelerating the drug discovery process.”
Science reported that AlphaFold, which scored a median of 87—25 points above the next best predictions—did so well that CASP14 organizers worried DeepMind may have been somehow cheated. To validate the results, they asked AlphaFold to complete a “special challenge”—modeling a membrane protein from an ancient species of microbes called archaea, which they had been unable to model satisfactorily using X-ray crystallography. AlphaFold returned a detailed image of a three-part protein with two long helical arms in the middle. “It’s almost perfect,” Andrei Lupas, PhD, Director at the Max Planck Institute for Developmental Biology, told Science. “They could not possibly have cheated on this. I don’t know how they do it.” (Graphic copyright: DeepMind/Nature.)
“Even tiny rearrangements of these vital molecules can have catastrophic effects on our health, so one of the most efficient ways to understand disease and find new treatments is to study the proteins involved,” Moult said in the CASP14 press release. “There are tens of thousands of human proteins and many billions in other species, including bacteria and viruses, but working out the shape of just one requires expensive equipment and can take years.”
Science reported that the 3D structures of only 170,000 proteins have been solved, leaving roughly 200 million proteins that have yet to be modeled. Therefore, AlphaFold will help researchers in the fields of genomics, microbiomics, proteomics, and other omics understand the structure of protein complexes.
“Being able to investigate the shape of proteins quickly and accurately has the potential to revolutionize life sciences,” Andriy Kryshtafovych, PhD, Project Scientist at University of California, Davis, Genome Center, said in the press release. “Now that the problem has been largely solved for single proteins, the way is open for development of new methods for determining the shape of protein complexes—collections of proteins that work together to form much of the machinery of life, and for other applications.”
Clinical laboratories play a major role in the study of human biology. This breakthrough in genomics research and new insights into proteomics may provide opportunities for medical labs to develop new diagnostic tools and assays that better identify proteins of interest for diagnostic and therapeutic purposes.
Clinical laboratories involved in genetic testing may find this welcomed news, after a pair of studies conducted in 2019 raised concerns about CRISPR base editing. The researchers of those studies observed that it “causes a high number of unpredictable mutations in mouse embryos and rice,” Chemical and Engineering News (C&EN) reported, adding, “Other groups have raised concerns about off-target mutations caused when the traditional CRISPR-Cas9 form of gene editing cuts DNA at a location that it wasn’t supposed to touch. The results of the new studies are surprising, however, because scientists have lauded base editors as one of the most precise forms of gene editing yet.”
Nevertheless, UC Berkeley’s latest breakthrough is expected to drive development of new and more accurate CRISPR-Cas genome-editing tools, which consist of base editors as well as nucleases, transposases, recombinases, and prime editors.
Understanding CRISPR Base Editors At a ‘Deeper Level’
Harvard University Chemistry and Chemical Biology Professor David Liu, PhD, who co-authored the study, explained the significance of this latest discovery.
“While base editors are now widely used to introduce precise changes in organisms ranging from bacteria to plants to primates, no one has previously observed the three-dimensional molecular structure of a base editor,” he said in a UC Berkeley news release. “This collaborative project reveals the beautiful molecular structure of a state-of-the-art highly-active base editor—ABE8e—caught in the act of engaging a target DNA site.”
UC Berkeley Professor Jennifer Doudna, PhD (above), who served as senior author of the study, says scientists may now have the information necessary to refine base editors and improve their precision and genome-targeting ability. “This structure helps us understand base editors at a much deeper level,” she said in the UC Berkeley statement. “Now that we can see what we’re working with, we can develop informed strategies to improve the system.” (Photo copyright: UC Berkeley.)
Jennifer Doudna, PhD, UC Berkeley Professor, Howard Hughes Medical Institute Investigator, and senior author of the study, has been a leading figure in the development of CRISPR-Cas9 gene editing. In 2012, Doudna and Emmanuelle Charpentier, PhD, Founding, Scientific and Managing Director at Max Planck Unit for the Science of Pathogens in Berlin, led a team of researchers who “determined how a bacterial immune system known as CRISPR-Cas9 is able to cut DNA, and then engineered CRISPR-Cas9 to be used as a powerful gene editing technology.” In a 2017 news release, UC Berkeley noted that the work has been described as the “scientific breakthrough of the century.”
Viewing the Base Editor’s 3D Shape
CRISPR-Cas9 gene editing allows scientists to permanently edit the genetic information of any organism, including human cells, and has been used in agriculture as well as medicine. A base editor is a tool that manipulates a gene by binding to DNA and replacing one nucleotide with another.
According to the recent UC Berkeley news release, the research team used a “high-powered imaging technique called cryo-electron microscopy” to reveal the base editor’s 3D shape.
Genetic Engineering and Biotechnology News notes that, “The high-resolution structure is of ABE8e bound to DNA, in which the target adenine is replaced with an analog designed to trap the catalytic conformation. The structure, together with kinetic data comparing ABE8e to earlier ABEs [adenine base editors], explains how ABE8e edits DNA bases and could inform future base-editor design.”
The graphic above, taken from the UC Berkeley news release, shows the “3D structure of a base editor, comprised of the Cas9 protein (white and gray), which binds to a DNA target (teal and blue helix) complementary to the RNA guide (purple), and the deaminase proteins (red and pink), which switch out one nucleotide for another.” (Image and caption copyright: UC Berkeley.)
Knowing the Cas9 fusion protein’s 3D structure may help eliminate unintended off-target effects on RNA, extending beyond the targeted DNA. However, until now, scientists have been hampered by their inability to understand the base editor’s structure.
“If you really want to design truly specific fusion protein, you have to find a way to make the catalytic domain more a part of Cas9, so that it would sense when Cas9 is on the correct target and only then get activated, instead of being active all the time,” study co-first author Audrone Lapinaite, PhD, said in the news release. At the time of the study, Lapinaite was a postdoctoral fellow at UC Berkeley. She is now an assistant professor at Arizona State University.
“As a structural biologist, I really want to look at a molecule and think about ways to rationally improve it. This structure and accompanying biochemistry really give us that power,” added UC Berkeley postdoctoral fellow Gavin Knott, PhD, another study co-author. “We can now make rational predications for how this system will behave in a cell, because we can see it and predict how it’s going to break or predict ways to make it better.”
Clinical laboratory leaders and pathologists will want to monitor these new advances in CRISPR technology. Each breakthrough has the power to fuel development of cost-effective, rapid point-of-care diagnostics.
