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.
Teams from multiple Swedish organizations are investigating the relationship of protein-coding genes to antibodies
Scientists in Sweden are discovering new ways to map the expression of genes in cells, tissues, and organs within the human body thanks to advances in molecular profiling. Their study has successfully combined the analysis of single-cell transcriptomics with spatial antibody-based protein profiling to produce a high-resolution, single-cell mapping of human tissues.
The data links protein-coding genes to antibodies, which could help researchers develop clinical laboratory tests that use specific antibodies to identify and target infectious disease. Might this also lead to a new menu of serology tests that could be used by medical laboratories?
This research is another example of how various databases of genetic and proteomic information—different “omics”—are being combined to produce new understanding of human biology and physiology.
In a Human Protein Atlas (HPA) project press release, Director of the HPA consortium and Professor of Microbiology at Royal Institute of Technology in Stockholm, Mathias Uhlén, PhD, said, “The [Science Advances] paper describes an important addition to the Human Protein Atlas (HPA) which has become one of the world’s most visited biological databases, harboring millions of web pages with information about all the human protein coding genes.”
“We are excited that the new open-access Single Cell Type section constitutes a unique resource for studying the cell type specificity and exact spatial localization of all our proteins”, said Cecilia Lindskog, PhD (above), Head of the HPA Tissue Atlas and Associate Professor, Experimental Pathology, Uppsala University, in the Protein Atlas press release. Medical laboratories may soon have new serology tests to perform that were developed based on HPA data. (Photo copyright: Human Uterus Cell Atlas.)
Distinct Expression Clusters Consistent to Similar Cell Types
To perform their research, the scientists mapped the gene expression profile of all protein-coding genes across different cell types. Their analysis showed that there are distinct expression clusters which are consistent to cell types sharing similar functions within the same organs and between organs of the human body.
The scientists examined data from non-diseased human tissues and organs using three main criteria:
Publicly available raw data from human tissues containing good technical quality with at least 4,000 cells analyzed and at least 20 million read counts by the sequencing for each tissue.
High correlation between pseudo-bulk transcriptomics profile from the scRNA-Seq data and bulk RNA-Seq generated as part of the Human Protein Atlas (HPA).
High correlation between the cluster-specific expression and the expected expression pattern of an extensive selection of marker genes representing well-known tissue- and cell type-specific markers, including both markers from the original publications and additional markers used in pathology diagnostics.
According to the HPA press release, “across all analyzed cell types, almost 14,000 genes showed an elevated expression in particular cell types, out of which approximately 2,000 genes were found to be specific for only one of the cell types.”
The press release also states, “cell types in testis showed the highest numbers of cell type elevated genes, followed by ciliated cells. Interestingly, only 11% of the genes were detected in all analyzed cell types suggesting that the number of essential genes (‘house-keeping’) are surprisingly few.”
Omics-based Biomarkers for Accurate Diagnosis of Disease
The Human Protein Atlas is the largest and most comprehensive database for spatial distribution of proteins in human tissues and cells. It provides a valuable tool for researchers who study and analyze protein localization and expression in human tissues and cells.
Ongoing improvements in gene sequencing technologies are making research of genes more accurate, faster, and more economical. Advances in gene sequencing also could help medical professionals discover more personalized care for patients leading to improved outcomes. A key goal of precision medicine.
One of the conclusions to be drawn from this work is that clinical laboratories and anatomic pathology groups will need to be able to handle immense amounts of data, while at the same time having the capabilities to analyze that data and identify useful patterns that can help diagnose patients earlier and more accurately.
Ongoing research at the University of Washington promises new methods for identifying and cataloging large numbers of cells quickly, which could lead to more individualized treatments in support of precision medicine initiatives
Researchers have found a new method for identifying specific cell types by groups, a breakthrough that some experts say could lead to new and more accurate methods for diagnosing and treating disease in individual patients, and new tools for fighting cancer and other chronic diseases. If this happens, both clinical laboratories and anatomic pathology labs would benefit from this technology.
A study published in the journal Science titled, “Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism,” describes advances in cataloging cells that are much faster than the traditional method of using a microscope. The research is still in the experimental stage, but it is being hailed as both exciting and promising by experts in the field.
Barcoding Large Numbers of Cells for Viewing Simultaneously
To test their method, researchers from the University of Washington (UW) sequenced each cell of an individual Caenorhabditis elegans (nematode). Nematodes are transparent roundworms that have been extensively studied making them ideal for the UW study, since much information exists about their cellular structure.
“We came up with this scheme that allows us to look at very large numbers of cells at the same time, without ever isolating a single cell,” noted Jay Shendure, PhD, MD, Professor of Genome Sciences at the University of Washington.
The UW researchers used sci-RNA-seq to measure the activity in 42,035 cells at the same time. Once all of the cells were tagged, or barcoded, the researchers broke them open so the sequences of tags could be read simultaneously.
“We defined consensus expression profiles for 27 cell types and recovered rare neuronal cell types corresponding to as few as one or two cells,” wrote the researchers in their published study.
Because such a rich body of research on nematodes exists, the researchers could easily compare the results that got to those procured in previous studies.
Jay Shendure, MD, PhD (above), Professor of Genomic Sciences at the University of Washington, and an Investigator at the Howard Hughes Medical Institute, was just a graduate student when his work with genetics led to the development of today’s next-generation gene sequencing technologies. His new cell-type identification technology could eventually be used by clinical laboratories and anatomic pathology groups to diagnose disease. (Photo copyright: Howard Hughes Medical Institute.)
One Giant Leap for Medical Diagnostics
Identifying cell types has been a challenge to the medical community for at least 150 years. It is important for scientists to understand the most basic unity of life, but it has only been in the last few years that researchers have been able to measure transcriptomes in single cells. Even though the research so far is preliminary, the scientific community is excited about the results because—should the methods be refined—it could mean a great leap forward in the field of cell-typing.
However, the study did not identify all of the cell types known to exist in a nematode. “We don’t consider this a finished project,” stated Shendure in a New YorkTimes article.
Nevertheless, researchers not associated with the study feel confident about the promise of the work. Cori Bargmann, PhD, a neurobiologist and Torsten N. Wiesel Professor at The Rockefeller University, and an Investigator for the Howard Hughes Medical Institute from 1995 to 2016, states that the results “will be valuable for me and for the whole field,” adding, “Of course, there’s more to do, but I am pretty optimistic that this can be solved.”
“The ability to measure the transcriptomes of single cells has only been feasible for a few years, and is becoming an extremely popular assay,” wrote Valentine Svensson, predoctoral fellow et al, of EMBL-EBI in the UK, in a paper titled, “Exponential Scaling of Single-Cell RNA-Seq in the Last Decade.” He added, “Technological developments and protocol improvements have fueled a consistent exponential increase in the numbers of cells studied in single cell RNA-seq analyses.” The UW research represents another such improvement.
Human Cell Atlas—Understanding the Basis of Life Itself
There are approximately 37-trillion cells in the human body and scientists have long believed there are 200 different cell types. Thus, there is an enormous difference between a nematode and a human body. For medical science to benefit from these studies, massive numbers of human cells must be identified and understood. Efforts are now underway to catalog and map them all.
The Human Cell Atlas (HCA) is an effort to catalog all of those disparate cell types. The mission of HCA is “To create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.”
According to HCA’s website, having the atlas completed will impact our understanding of every aspect of human biology, from immunologic diseases to cancer. Aviv Regev, PhD, of the Broad Institute at MIT, who also is an Investigator with the HHMI and is co-chair of the organizing committee at the Human Cell Atlas notes, “The human cell atlas initiative will work through organs, tissues, and systems.”
One of the many complications of creating the atlas is that the locations of cells vary in humans. “The trick,” Regev noted in the New York Times article, “is to relate cells to the place they came from.” This would seem to be at the heart of the UW researchers’ new method for “barcoding” groups of cells.
Just as sequencing the entire human genome has brought about previously unimagined advances in science, so too will the research being conducted at the University of Washington, as well as the completion of the Human Cell Atlas Project. It is possible that pursuing the goal of quickly identifying and cataloging cells will lead to advances in anatomic pathology, and allow medical laboratory scientists to better interpret genetic variants, ultimately bringing healthcare closer to the delivery of true precision medicine.
Researchers have found that isolating a particular gene within the oral microbiome can reveal a huge amount of useful diagnostic information about a person’s health
Most people don’t think of dental plaque when they think about clinical laboratories. For the vast majority of people, the only diseases that dental plaque bring to mind are those of the mouth:
Samples that are sent to medical labs and pathology laboratories are more often blood or tissue. However, that could be changing, thanks in part to the work being done at the Oral Microbiome and Metagenomics Research Lab (OMMR) at the University of Toronto. (more…)
The human proteome map provides a catalog of proteins expressed in nondiseased issues and organs to use as baseline in understanding changes that occur in disease
Given the growing importance of proteins in medical laboratory testing, pathologists will want to know about a major milestone recently achieved in this field. Researchers have announced that drafts of the complete human proteome have been released to the public.
Experts are comparing this to the first complete map of the human genome that was made public in 2000. Clinical laboratory managers and pathologists know how the availability of this information provided the foundation for rapid advances in understanding different aspects involving DNA and RNA. (more…)
