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.
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.
Genetic data captured by this new technology could lead to a new understanding of how different types of cells exchange information and would be a boon to anatomic pathology research worldwide
What if it were possible to map the interior of cells and view their genetic sequences using chemicals instead of light? Might that spark an entirely new way of studying human physiology? That’s what researchers at the Massachusetts Institute of Technology (MIT) believe. They have developed a new approach to visualizing cells and tissues that could enable the development of entirely new anatomic pathology tests that target a broad range of cancers and diseases.
Scientists at MIT’s Broad Institute and McGovern Institute for Brain Research developed this new technique, which they call DNA Microscopy. They published their findings in Cell, titled, “DNA Microscopy: Optics-free Spatio-genetic Imaging by a Stand-Alone Chemical Reaction.”
Joshua Weinstein, PhD, a postdoctoral associate at the Broad Institute and first author of the study, said in a news release that DNA microscopy “is an entirely new way of visualizing cells that captures both spatial and genetic information simultaneously from a single specimen. It will allow us to see how genetically unique cells—those comprising the immune system, cancer, or the gut for instance—interact with one another and give rise to complex multicellular life.”
The news release goes on to state that the new technology “shows
how biomolecules such as DNA and RNA are organized in cells and tissues,
revealing spatial and molecular information that is not easily accessible
through other microscopy methods. DNA microscopy also does not require
specialized equipment, enabling large numbers of samples to be processed
simultaneously.”
The images above, taken from the MIT study, compares optical imaging of a cell population (left) with an inferred visualization of the same cell population based on the information provided by DNA microscopy (right). Scale bar = 100 μm (100 micrometers). This technology has the potential to be useful for anatomic pathologists at some future date. (Photo and caption copyrights: Joshua Weinstein, PhD, et al/Cell.)
New Way to Visualize Cells
The MIT researchers saw an opportunity for DNA microscopy to
find genomic-level cell information. They claim that DNA microscopy images
cells from the inside and enables the capture of more data than with
traditional light microscopy. Their new technique is a chemical-encoded
approach to mapping cells that derives critical genetic insights from the
organization of the DNA and RNA in cells and tissue.
And that type of genetic information could lead to new precision medicine treatments for chronic disease. New Atlas notes that “ Speeding the development of immunotherapy treatments by identifying the immune cells best suited to target a particular cancer cell is but one of the many potential application for DNA microscopy.”
In their published study, the scientists note that “Despite enormous progress in molecular profiling of cellular constituents, spatially mapping [cells] remains a disjointed and specialized machinery-intensive process, relying on either light microscopy or direct physical registration. Here, we demonstrate DNA microscopy, a distinct imaging modality for scalable, optics-free mapping of relative biomolecule positions.”
How DNA Microscopy Works
The New York Times (NYT) notes that the advantage of DNA microscopy is “that it combines spatial details with scientists’ growing interest in—and ability to measure—precise genomic sequences, much as Google Street View integrates restaurant names and reviews into outlines of city blocks.”
And Singularity Hub notes that “ DNA microscopy, uses only a pipette and some liquid reagents. Rather than monitoring photons, here the team relies on ‘bar codes’ that chemically tag onto biomolecules. Like cell phone towers, the tags amplify, broadcasting their signals outward. An algorithm can then piece together the captured location data and transform those GPS-like digits into rainbow-colored photos. The results are absolutely breathtaking. Cells shine like stars in a nebula, each pseudo-colored according to their genomic profiles.”
“We’ve used DNA in a way that’s mathematically similar to photons in light microscopy,” Weinstein said in the Broad Institute news release. “This allows us to visualize biology as cells see it and not as the human eye does.”
In their study, researchers used DNA microscopy to tag RNA
molecules and map locations of individual human cancer cells. Their method is
“surprisingly simple” New Atlas reported. Here’s how it’s done,
according to the MIT news release:
Small synthetic DNA tags (dubbed “barcodes” by the MIT team) are added to biological samples;
The “tags” latch onto molecules of genetic material in the cells;
The tags are then replicated through a chemical reaction;
The tags combine and create more unique DNA labels;
The scientists use a DNA sequencer to decode and reconstruct the biomolecules;
A computer algorithm decodes the data and converts it to images displaying the biomolecules’ positions within the cells.
The visualization above was created from data gathered by DNA microscopy, which peers inside individual cells. It demonstrates how DNA microscopy enables scientists to identify different cells (colored dots) within a sample—with no prior knowledge of what the sample looks like. (Photo and caption copyright: Joshua Weinstein, PhD, et al./Cell.)
“The first time I saw a DNA microscopy image, it blew me away,” said Aviv Regev, PhD, a biologist at the Broad Institute, a Howard Hughes Medical Institute (HHMI) Investigator, and co-author of the MIT study, in an HHMI news release. “It’s an entirely new category of microscopy. It’s not just a technique; it’s a way of doing things that we haven’t ever considered doing before.”
Precision Medicine Potential
“Every cell has a unique make-up of DNA letters or genotype. By capturing information directly from the molecules being studied, DNA microscopy opens up a new way of connecting genotype to phenotype,” said Feng Zhang, PhD, MIT Neuroscience Professor,
Core Institute Member of the Broad Institute, and
Investigator at the McGovern Institute for Brain Research at MIT, in the HHMI
news release.
In other words, DNA microscopy could someday have applications in precision medicine. The MIT researchers, according to Stat, plan to expand the technology further to include immune cells that target cancer.
The Broad Institute has applied for a patent on DNA
microscopy. Clinical laboratory and anatomic pathology group leaders seeking
novel resources for diagnosis and treatment of cancer may want to follow the MIT
scientists’ progress.
The National Institute of Health’s ClinVar public database of genetic variation is demonstrating good accuracy, and a handful of clinical labs are learning to share and review this relatively small genetic database
Accessible databases like ClinVar, which was launched by the National Institute of Health (NIH) in 2013, have emerged to aggregate genetic sequencing with acceptable results. ClinVar exists to meet the needs of the medical genetics community. It collaborates with organizations to make pertinent genetic information available.
ClinVar is an archive of compiled data relating to genotype and phenotype variations among humans. Through this database, individuals can present and peruse submissions regarding variants found in patient samples.
ClinVar is averaging about 6,000 submissions per month by both commercial laboratory companies and reference labs. Major contributors to the database include: (more…)
At Human Longevity, Inc. and the United Kingdom’s 100,000 Genome Project, knowledge gained from whole-genome sequencing is starting to be used to improve patient care
NEW ORLEANS, LA—Whole-human gene sequencing is poised to provide significant contributions to improving clinical care. That was one conclusion from expert speakers at the 21st annual Executive War College on Medical Laboratory and Pathology Management that happened here this week.
How fast knowledge from whole-human gene sequencing finds its way into clinical diagnostics and healthcare can be debated. But what is unquestioned, based on these presentations, is that insights gained from the analysis of large numbers of human genomes will trigger a revolution in how pathologists and physicians diagnose, treat, and care for patients. (more…)
