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.
With 100% of the human genome mapped, new genetic diagnostic and disease screening tests may soon be available for clinical laboratories and pathology groups
Utilizing technology developed by two different biotechnology/genetic sequencing companies, an international consortium of genetic scientists claim to have sequenced 100% of the entire human genome, “including the missing parts,” STAT reported. This will give clinical laboratories access to the complete 3.055 billion base pair (bp) sequence of the human genome.
If validated, this achievement could greatly impact future genetic research and genetic diagnostics development. That also will be true for precision medicine and disease-screening testing.
Completing the First “End-to-End” Genetic Sequencing
In June of 2000, the Human Genome Project (HGP) announced it had successfully created the first “working draft” of the human genome. But according to the National Human Genome Research Institute (NHGRI), the draft did not include 100% of the human genome. It “consists of overlapping fragments covering 97% of the human genome, of which sequence has already been assembled for approximately 85% of the genome,” an NHGRI press release noted.
“The original genome papers were carefully worded because they did not sequence every DNA molecule from one end to the other,” Ewan Birney, PhD, Deputy Director General of the European Molecular Biology Laboratory (EMBL) and Director of EMBL’s European Bioinformatics Institute (EMBL-EBI), told STAT. “What this group has done is show that they can do it end-to-end. That’s important for future research because it shows what is possible,” he added.
In their published paper, the T2T scientists wrote, “Addressing this remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium has finished the first truly complete 3.055 billion base pair (bp) sequence of a human genome, representing the largest improvement to the human reference genome since its initial release.”
Tale of Two Genetic Sequencing Technologies
Humans have a total of 46 chromosomes in 23 pairs that represent tens of thousands of individual genes. Each individual gene consists of numbers of base pairs and there are billions of these base pairs within the human genome. In 2000, scientists estimated that humans have only 30,000 to 35,000 genes, but that number has since been reduced to just above 20,000 genes.
According to STAT, “The work was possible because the Oxford Nanopore and PacBio technologies do not cut the DNA up into tiny puzzle pieces.”
PacBio used HiFi sequencing, which is only a few years old and provides the benefits of both short and long reads. STAT noted that PacBio’s technology “uses lasers to examine the same sequence of DNA again and again, creating a readout that can be highly accurate.” According to the company’s website, “HiFi reads are produced by calling consensus from subreads generated by multiple passes of the enzyme around a circularized template. This results in a HiFi read that is both long and accurate.”
Oxford Nanopore uses electrical current in its sequencing devices. In this technology, strands of base pairs are pressed through a microscopic nanopore one molecule at a time. Those molecules are then zapped with electrical currents to enable scientists to determine what type of molecule they are and, in turn, identify the full strand.
The T2T Consortium acknowledge in their paper that they had trouble with approximately 0.3% of the genome, but that, though there may be a few errors, there are no gaps.
“You’re just trying to dig into this final unknown of the human genome,” Karen Miga (above), Assistant Professor in the Biomolecular Engineering Department at the University of California, Santa Cruz (UCSC), Associate Director at the UCSC Genomics Institute, and lead author of the T2T Consortium study, told STAT. “It’s just never been done before and the reason it hasn’t been done before is because it’s hard.” (Photo copyright: University of California, Santa Cruz.)
Might New Precision Medicine Therapies Come from T2T Consortium’s Research?
The researchers claim in their paper that the number of known base pairs has grown from 2.92 billion to 3.05 billion and that the number of known genes has increased by 0.4%. Through their research, they also discovered 115 new genes that code for proteins.
The T2T Consortium scientists also noted that the genome they sequenced for their research did not come from a person but rather from a hydatidiform mole, a rare growth that occasionally forms on the inside of a women’s uterus. The hydatidiform occurs when a sperm fertilizes an egg that has no nucleus. As a result, the cells examined for the T2T study contained only 23 chromosomes instead of the full 46 found in most humans.
Although the T2T Consortium’s work is a huge leap forward in the study of the human genome, more research is needed. The consortium plans to publish its findings in a peer-reviewed medical journal. In addition, both PacBio and Oxford Nanopore plan to develop a way to sequence the entire 46 chromosome human genome in the future.
The future of genetic research and gene sequencing is to create technologies that will allow researchers to identify single nucleotide polymorphisms (SNPs) that contain longer strings of DNA. Because these SNPs in the human genome correlate with medical conditions and response to specific genetic therapies, advancing knowledge of the genome can ultimately provide beneficial insights that may lead to new genetic tests for medical diagnoses and help medical professionals determine the best, personalized therapies for individual patients.
Is gut microbiota the fabled fountain of youth? Researchers at Valenzano Research Lab in Germany found it works for killifish. Could it work for other vertebrates as well?
Research into the microbiomes of humans and other animals is uncovering tantalizing insights as to how different microbes can be beneficial or destructive to the host. It is reasonable to expect ongoing research will eventually give microbiologists and clinical laboratories useful new medical laboratory tests that assess an individual’s microbiome for diagnostic and therapeutic purposes.
Human microbiota (AKA, microbiome) have been identified as having a key role in several different health conditions. In previous ebriefings, Dark Daily reported on several breakthroughs involving the microbiome that bring the promise of precision medicine ever closer. Research and clinical studies are contributing to more accurate diagnoses, identification of best drugs for specific patients, and, enhanced information for physician decision-making, to name just a few benefits.
Valenzano Lab published its study online in August. The team of scientists and researchers led by Dario Valenzano, PhD, focused on the longevity of the turquoise killifish (Nothobranchius furzeri), a tiny fish native to the African countries of Mozambique and Zimbabwe. They found that when older killifish ate the fecal matter of younger killifish they lived longer. The fecal matter carried the microbiota to the older fish and extended their lifespans.
Moving Microbiome from One Gut to Another
To perform the research, Valenzano and his team first treated killifish that were nine and a half weeks old (considered middle-aged) with antibiotics to cleanse their gut flora. The fish were then placed in a sterile aquarium containing the gut contents of young adult killifish that were just six weeks old. Although killifish won’t typically eat feces, they would nip at the gut contents in the water and swallow some of the microbes from the younger fish in the process. The researchers discovered that the transplanted microbes were able to successfully colonize the stomachs of the older fish.
Dario Valenzano, PhD (above), gazes at an older Killifish, the subject in his research into increased aging at the Valenzano Research Lab in Cologne, Germany. Studies of the microbiomes of different species is expected to eventually give microbiologists new and useful clinical laboratory tests. (Photo copyright: Max Planck Institute for Biology of Aging.)
When the middle-aged killifish reached the age of 16 weeks—considered elderly—their gut microbiomes were still similar to that of a six-week-old fish. The process had a noticeable effect on the lifespan of the killifish that received the microbiome transplants from the young fish. They lived 41% longer than killifish that received microbes from middle-aged fish and their longevity increased by 37% over fish that were not exposed to any treatment at all. In addition, at 16 weeks, the killifish who had received the transplants were much more active than fish of the same age who had not received the transplants.
“These results suggest that controlling the composition of the gut microbes can improve health and increase life span,” the study paper noted. “The model system used in this study could provide new ways to manipulate the gut microbial community and gain key insights into how the gut microbes affect aging. Manipulating gut microbes to resemble a community found in young individuals could be a strategy to delay the onset of age-related diseases.”
Transferring Fecal Microbiota to Save/Extend Human Lives
Previous research has indicated there may be a connection between microbiomes and aging in some animals, and that the diversity of gut microbes decreases with age. This study proved that this same pattern is true in turquoise killifish.
However, Valenzano does not know how the microbes are affecting the lifespans of the older killifish. “It is possible that an aging immune system is less effective at protecting the micro-organisms in the intestines, with the result that there is a higher prevalence of pathogens in older guts. The gut microbiota in a young organism could help to counter this and therefore support the immune system and prevent inflammation. This could lead to longer life expectancy and better health,” he stated in a press release.
“You can really tell whether a fish is young or old based on its gut microbiota,” Valenzano told Nature. He noted, however, that it is too early to determine if fecal transplants can be used in humans to extend life. “I wouldn’t go that far. This is really early evidence that this has a potential positive effect.”
There is, however, a similar procedure used in humans called Fecal Microbiota Transplant or FMT that has demonstrated promising results in treating certain illnesses.
In a fecal transplant, fecal matter is collected from an approved donor, treated, and placed in a patient during a colonoscopy, endoscopy, sigmoidoscopy, or enema. The purpose of the transplant is to replace good bacteria in a colon that has undergone an event that caused the colon to be inundated with bad bacteria, such as Clostridium difficile, resulting in C. diff. infection, a life-threatening illness that, according to the Centers for Disease Control and Prevention (CDC), kills tens of thousands of people each year.
“The challenge with all of these experiments is going to be to dissect the mechanism. I expect it will be very complex,” stated Heinrich Jasper, PhD, in the Nature article. Jasper is a professor at the Buck Institute for Research on Aging in Novato, California. His lab is working on similar research with microbiome transplants in fruit flies. He predicts this type of longevity research will be performed on other animals in the future.
Valenzano’s and Jasper’s research may eventually create new diagnostic tools for microbiologists to assess the microbiome of individual patients. This technology may also enable microbiologists to advise pathologists and clinical laboratories regarding what specific microbes may be harmful and what microbes may be therapeutically beneficial to patients.
Disruptive technology drops the cost of DNA methylation sequencing by 100-fold
As sequencing of individual human genomes becomes more affordable and useful, the next big hurdle in genetic science will be to map the human epigenome. While DNA provides the blueprint for building a human being, the epigenome determines the details of how that blueprint is expressed in an individual. Pathologists and clinical laboratory administrators will want to track efforts to map and understand the human epigenome.
The epigenome is a set of chemical modifications to the genome that are not encoded in the DNA but which modulate how and when genes are expressed. Methylation is only one marker in the complex epigenetic map, but it is an important one. Methylation suppresses gene activity, and is thought to be responsible for suppressing some genes that prevent cancer. Though researchers are a long way from using this knowledge to cure cancer or other diseases, faster, more affordable DNA methylation sequencing will help move that research forward.
