Oct 3, 2018 | Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations
Next step is to design Web portal offering low-cost ‘polygenic risk score’ to people willing to upload genetic data received from DNA testing companies such as 23andMe
Pathologists and other medical professionals have long predicted that multi-gene diagnostics tests which examine thousands of specific gene sequences might one day hold the key to assessing disease risk, diagnosing diseases, and guiding precision medicine treatment decisions. Now, a research team from the Broad Institute, Massachusetts General Hospital (MGH) and Harvard Medical School have brought that prediction closer to reality.
Their study, published last month in Nature Genetics, found that a genome analysis called polygenic risk scoring can identify individuals with a high risk of developing one of five potentially deadly diseases:
- Coronary artery disease;
- Atrial fibrillation;
- Type 2 diabetes;
- Inflammatory bowel disease; and,
- Breast cancer.
Polygenic Scoring Predicts Risk of Disease Among General Population
To date, most genetic testing has been “single gene,” focusing on rare mutations in specific genes such as those causing sickle cell disease or cystic fibrosis. This latest research indicates that polygenic predictors could be used to discover heightened risk factors in a much larger portion of the general population, enabling early interventions to prevent disease before other warning signs appear. The ultimate goal of precision medicine.
“We’ve known for long time that there are people out there at high risk for disease based just on their overall genetic variation,” senior author Sekar Kathiresan, MD, co-Director of the Medical and Population Genetics Program at the Broad Institute, and Director, Center for Genomic Medicine at Massachusetts General Hospital, said in a Broad Institute news release. “Now, we’re able to measure that risk using genomic data in a meaningful way. From a public health perspective, we need to identify these higher-risk segments of the population, so we can provide appropriate care.”
“What I foresee is in five years, each person will know this risk number—this ‘polygenic risk score’—similar to the way each person knows his or her cholesterol,” Sekar Kathiresan, MD (above), Co-Director of the Medical and Population Genetics Program at the Broad Institute, and Director, Center for Genomic Medicine at Massachusetts General Hospital, told the Associated Press (AP). He went on to say a high-risk score could lead to people taking other steps to lower their overall risk for specific diseases, while a low-risk score “doesn’t give you a free pass” since an unhealthy lifestyle can lead to disease as well. (Photo copyright: Massachusetts General Hospital.)
The researchers conducted the study using data from more than 400,000 individuals in the United Kingdom Biobank. They created a risk score for coronary artery disease by looking for 6.6 million single-letter genetic changes that are more prevalent in people who have had early heart attacks. Of the individuals in the UK Biobank dataset, 8% were more than three times as likely to develop the disease compared to everyone else, based on their genetic variation.
In absolute terms, only 0.8% of individuals with the very lowest polygenic risk scores had coronary artery disease, compared to 11% for people with the highest scores, the Broad Institute news release stated.
“The results should be eye-opening for cardiologists,” Charles C. Hong, MD, PhD, Director of Cardiovascular Research at the University of Maryland School of Medicine, told the AP. “The only disappointment is that this score applies only to those with European ancestry, so I wonder if similar scores are in the works for the large majority of the world population that is not white.”
In its news release, the Broad Institute noted the need for additional studies to “optimize the algorithms for other ethnic groups.”
The Broad Institute’s results suggest, however, that as many as 25 million people in the United States may be at more than triple the normal risk for coronary artery disease. And millions more may be at similar elevated risk for the other conditions, based on genetic variations alone.
Reanalyzing Data from DNA Testing Companies
The researchers are building a website that would enable users to receive a low-cost polygenic risk score—such as calculating inherited risk score for many common diseases—by reanalyzing data users previously receive from DNA testing companies such as 23andMe.
Kathiresan told Forbes his goal is for the 17 million people who have used genotyping services to submit their data to the web portal he is building. He told the magazine he’s hoping “people will be able to get their polygenic scores for about as much as the cost of a cholesterol test.”
Some Experts Not Impressed with Broad Institute Study
But not all experts believe the Broad Institute/MGH/Harvard Medical School study deserves so much attention. Ali Torkamani, PhD, Director of Genomics and Genome Informatics at the Scripps Research Translational Institute, offered a tepid assessment of the Nature Genetics study.
In an article in GEN that noted polygenic risk scores were receiving “the type of attention reserved for groundbreaking science,” Torkamani said the recent news is “not particularly” a big leap forward in the field of polygenic risk prediction. He described the results as “not a methodological advance or even an unexpected result,” noting his own group had generated similar data for type 2 diabetes in their analysis of the UK dataset.
Nevertheless, Kathiresan is hopeful the study will advance disease treatment and prevention. “Ultimately, this is a new type of genetic risk factor,” he said in the news release. “We envision polygenic risk scores as a way to identify people at high or low risk for a disease, perhaps as early as birth, and then use that information to target interventions—either lifestyle modifications or treatments—to prevent disease.”
This latest research indicates healthcare providers could soon be incorporating polygenic risking scoring into routine clinical care. Not only would doing so mean another step forward in the advancement of precision medicine, but clinical laboratories and pathology groups also would have new tools to help diagnose disease and guide treatment decisions.
—Andrea Downing Peck
Related Information:
Genome-wide Polygenic Scores for Common Diseases Identify Individuals with Risk Equivalent to Monogenic Mutations
Predicting Risk for Common Deadly Diseases from Millions of Genetic Variants
Multigene Test May Find Risk for Heart Disease and More
A Harvard Scientist Thinks He Has a Gene Test for Heart Attack Risk. He Wants to Give It Away Free
Why Do Polygenic Risk Scores Get So Much Hype?
Sep 28, 2018 | Laboratory Pathology
Even in its early stages the Human Cell Atlas project is impacting the direction of research and development of RNA sequencing and other genetic tests
No one knows exactly how many cell types exist in the human body. Though traditional texts place numbers in the hundreds, recent studies have found ranges from thousands to tens of thousands. Anatomic pathologists and clinical laboratory scientists know that the discovery of new types of human cells could lead to the creation of new medical laboratory tests.
So, it’s an important development that leaders of the Human Cell Atlas Consortium, a project comparable to the Human Genome Project, have set out to determine the exact numbers of cell types. And their findings could open up an entirely new field of diagnostic testing for clinical laboratories and anatomic pathology and lead to advances in precision medicine.
With the ability to identify cell types and sub-types associated with human disease and health conditions, medical labs could have a useful new way to help physicians make diagnoses and select appropriate therapies.
Begun in 2016, the group’s mission according to the Human Cell Atlas website 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.”
The ambitious project aims to catalog every cell type in the human body and “account for and better understand every cell type and sub-type, and how they interact.”
Striving for Deeper Understanding of the Basics
Cells are the basic building blocks of life, but scientists don’t know exactly how many different types of cells there are.
In an NPR interview, Aviv Regev, PhD, Professor of Biology and a core member at the Broad Institute of MIT and Harvard, investigator at the Howard Hughes Medical Institute, and co-leader of the Human Cell Atlas Consortium, said, “No one really knows how many [cells types] there will be,” adding, “People guess anything from the thousands to the tens of thousands. I’m not guessing. I would rather actually get the measurements done and have a precise answer.”
In an innovative move, Regev and her team improved the method they were already using to sort cells—single-cell RNA sequencing. “All of sudden we moved from something that was very laborious—and we could do maybe a few dozen or a few hundred—to something where we could do many, many thousands in a 15- to 20-minute experiment,” she told NPR.
Dark Daily covered a similar advance in single-cell RNA sequencing in “‘Barcoding’ Cells in Nematodes Could Bring Advances and New Medical Laboratory Tools for Treatment of Cancer and Other Chronic Diseases.”
But the project is massive. A typical human body contains about 37.2 trillion cells. So, the Human Cell Atlas scientists decided to complete preliminary pilot projects to identify the most efficient and effective strategies for sampling and analyzing the various cells to create the full atlas.
“It’s kind of like we’re trying to find out what are all the different colors of Lego building blocks that we have in our bodies,” Sarah Teichmann, PhD, Head of Cellular Genetics and Senior Group Leader at Wellcome Sanger Institute in the UK, and co-leader of the Human Cell Atlas Consortium, told NPR. “We’re trying to find out how those building blocks—how those Lego parts—fit together in three dimensions within each tissue.”
Sarah Teichmann, PhD (left), and Aviv Regev, PhD (right), are co-leaders of the Human Cell Atlas Consortium, an ambitious project of MIT/Harvard Broad Institute that seeks 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.” Such an advance could lead to significant advances in clinical laboratory and pathology testing and move healthcare closer to true precision medicine. (Photo copyrights: University of Cambridge and MIT/Broad Institute.
Some of the early pilot projects include a partnership with the Immunological Genome Project (ImmGen) to study and map the cells in the immune system. According to the Human Cell Atlas website, the partnership “will combine:
- “deep knowledge of immunological lineages;
- “clinical expertise and infrastructure needed to procure and process diverse samples;
- “genomic and computational expertise to resolve the hundreds of finely differentiated cell types that compose all facets of the immune system; and,
- the genomic signatures that define them.”
Other areas the pilot projects will address include:
Progress So Far
In the two short years since the Human Cell Atlas project began much work has already been accomplished, according to a news release. In addition to organizing the consortium and obtaining funding, the collaborators have published a white paper describing their goals and a framework for reaching them, as well as launching the pilot projects.
Such an ambitious project, however, is not without barriers and challenges. Regev and Teichmann, along with other collaborators, outlined some of those challenges in an article published in Nature.
The complexity of the human body combined with rapidly changing technology make simply agreeing on the scope of the project challenging. In order to meet that particular challenge, the collaborators plan to work in phases and drafts, which will allow for some flexibility and increasing focus on specifics as they go.
Other challenges include:
- keeping the entire project open and fair;
- procuring samples with consent and in an appropriate manner; and,
- organizing in an efficient and effective manner.
The collaborators have developed and detailed strategies for meeting each of these challenges.
The Human Cell Atlas could impact treatments for every disease that affects humans and bring healthcare closer to accomplishing precision medicine goals. By knowing what cells exist in what parts of the human body—and how they typically behave at their most basic levels—the MIT/Harvard/Broad Institute scientists hope to understand what’s happening when those cells “misbehave” in expected ways. The knowledge garnered from the Human Cell Atlas is likely to be invaluable to anatomic pathologists and clinical laboratories.
—Dava Stewart
Related Information:
Ambitious ‘Human Cell Atlas’ Aims To Catalog Every Type of Cell in the Body
‘Barcoding’ Cells in Nematodes Could Bring Advances and New Medical Laboratory Tools for Treatment of Cancer and Other Chronic Diseases
International Human Cell Atlas Initiative
The Human Cell Atlas White Paper
A Revised Airway Epithelial Hierarchy Includes CFTR-Expressing Ionocytes
Single-Cell Transcriptomes from Human Kidneys Reveal the Cellular Identity of Renal Tumors
The Human Cell Atlas: from Vision to Reality
‘Barcoding’ Cells in Nematodes Could Bring Advances and New Medical Laboratory Tools for Treatment of Cancer and Other Chronic Diseases
Jun 13, 2018 | Instruments & Equipment, Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing
Access to vast banks of genomic data is powering a new wave of assessments and predictions that could offer a glimpse at how genetic variation might impact everything from Alzheimer’s Disease risk to IQ scores
Anatomic pathology groups and clinical laboratories have become accustomed to performing genetic tests for diagnosing specific chronic diseases in humans. Thanks to significantly lower costs over just a few years ago, whole-genome sequencing and genetic DNA testing are on the path to becoming almost commonplace in America. BRCA 1 and BRCA 2 breast cancer gene screenings are examples of specific genetic testing for specific diseases.
However, a much broader type of testing—called polygenic scoring—has been used to identify certain hereditary traits in animals and plants for years. Also known as a genetic-risk score or a genome-wide score, polygenic scoring is based on thousands of genes, rather than just one.
Now, researchers in Cambridge, Mass., are looking into whether it can be used in humans to predict a person’s predisposition to a range of chronic diseases. This is yet another example of how relatively inexpensive genetic tests are producing data that can be used to identify and predict how individuals get different diseases.
Assessing Heart Disease Risk through Genome-Wide Analysis
Sekar Kathiresan, MD, Co-Director of the Medical and Population Genetics program at Broad Institute of MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital (Mass General); and Amit Khera, MD, Cardiology Fellow at Mass General, told MIT Technology Review “the new scores can now identify as much risk for disease as the rare genetic flaws that have preoccupied physicians until now.”
“Where I see this going is that, at a young age, you’ll basically get a report card,” Khera noted. “And it will say for these 10 diseases, here’s your score. You are in the 90th percentile for heart disease, 50th for breast cancer, and the lowest 10% for diabetes.”
However, as the MIT Technology Review article points out, predictive genetic testing, such as that under development by Khera and Kathiresan, can be performed at any age.
“If you line up a bunch of 18-year-olds, none of them have high cholesterol, none of them have diabetes. It’s a zero in all the columns, and you can’t stratify them by who is most at risk,” Khera noted. “But with a $100 test we can get stratification [at the age of 18] at least as good as when someone is 50, and for a lot of diseases.”
Sekar Kathiresan, MD (left), Co-Director of the Medical and Population Genetics program at Broad Institute at MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital; and Amit Khera, MD (right), Cardiology Fellow at Mass General, are researching ways polygenic scores can be used to predict the chance a patient will be prone to develop specific chronic diseases. Anatomic pathology biomarkers and new clinical laboratory performed genetic tests will likely follow if their research is successful. (Photo copyrights: Twitter.)
Polygenic Scores Show Promise for Cancer Risk Assessment
Khera and Kathiresan are not alone in exploring the potential of polygenic scores. Researchers at the University of Michigan’s School of Public Health looked at the association between polygenic scores and more than 28,000 genotyped patients in predicting squamous cell carcinoma.
“Looking at the data, it was surprising to me how logical the secondary diagnosis associations with the risk score were,” Bhramar Mukherjee, PhD, John D. Kalbfleisch Collegiate Professor of Biostatistics, and Professor of Epidemiology at U-M’s School of Public Health, stated in a press release following the publication of the U-M study, “Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative.”
“It was also striking how results from population-based studies were reproduced using data from electronic health records, a database not ideally designed for specific research questions and [which] is certainly not a population-based sample,” she continued.
Additionally, researchers at the University of California San Diego School of Medicine (UCSD) recently published findings in Molecular Psychiatry on their use of polygenic scores to assess the risk of mild cognitive impairment and Alzheimer’s disease.
The UCSD study highlights one of the unique benefits of polygenic scores. A person’s DNA is established in utero. However, predicting predisposition to specific chronic diseases prior to the onset of symptoms has been a major challenge to developing diagnostics and treatments. Should polygenic risk scores prove accurate, they could provide physicians with a list of their patients’ health risks well in advance, providing greater opportunity for early intervention.
Future Applications of Polygenic Risk Scores
In the January issue of the British Medical Journal (BMJ), researchers from UCSD outlined their development of a polygenic assessment tool to predict the age-of-onset of aggressive prostate cancer. As Dark Daily recently reported, for the first time in the UK, prostate cancer has surpassed breast cancer in numbers of deaths annually and nearly 40% of prostate cancer diagnoses occur in stages three and four. (See, “UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service,” May 23, 2018.)
An alternative to PSA-based testing, and the ability to differentiate aggressive and non-aggressive prostate cancer types, could improve outcomes and provide healthcare systems with better treatment options to reverse these trends.
While the value of polygenic scores should increase as algorithms and results are honed and verified, they also will most likely add to concerns raised about the impact genetic test results are having on patients, physicians, and genetic counselors.
And, as the genetic testing technology of personalized medicine matures, clinical laboratories will increasingly be required to protect and distribute much of the protected health information (PHI) they generate.
Nevertheless, when the data produced is analyzed and combined with other information—such as anatomic pathology testing results, personal/family health histories, and population health data—polygenic scores could isolate new biomarkers for research and offer big-picture insights into the causes of and potential treatments for a broad spectrum of chronic diseases.
—Jon Stone
Related Information:
Forecasts of Genetic Fate Just Got a Lot More Accurate
Polygenic Scores to Classify Cancer Risk
Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-Wide Study: Results from the Michigan Genomics Initiative
Polygenic Risk Score May Identify Alzheimer’s Risk in Younger Populations
Use of an Alzheimer’s Disease Polygenic Risk Score to Identify Mild Cognitive Impairment in Adults in Their 50s
New Polygenic Hazard Score Predicts When Men Develop Prostate Cancer
Polygenic Hazard Score to Guide Screening for Aggressive Prostate Cancer: Development and Validation in Large Scale Cohorts
UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service
Apr 18, 2018 | Instruments & Equipment, Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations
Three innovative technologies utilizing CRISPR-Cas13, Cas12a, and Cas9 demonstrate how CRISPR might be used for more than gene editing, while highlighting potential to develop new diagnostics for both the medical laboratory and point-of-care (POC) testing markets
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is in the news again! The remarkable genetic-editing technology is at the core of several important developments in clinical laboratory and anatomic pathology diagnostics, which Dark Daily has covered in detail for years.
Now, scientists at three universities are investigating ways to expand CRISPR’s use. They are using CRISPR to develop new diagnostic tests, or to enhance the sensitivity of existing DNA tests.
One such advancement improves the sensitivity of SHERLOCK (Specific High Sensitivity Reporter unLOCKing), a CRISPR-based diagnostic tool developed by a team at MIT. The new development harnesses the DNA slicing traits of CRISPR to adapt it as a multifunctional tool capable of acting as a biosensor. This has resulted in a paper-strip test, much like a pregnancy test, that can that can “display test results for a single genetic signature,” according to MIT News.
Such a medical laboratory test would be highly useful during pandemics and in rural environments that lack critical resources, such as electricity and clean water.
One Hundred Times More Sensitive Medical Laboratory Tests!
Co-lead authors Jonathan Gootenberg, PhD Candidate, Harvard University and Broad Institute; and Omar Abudayyeh, PhD and MD student, MIT, published their findings in Science. They used CRISPR Cas13 and Cas12a to chop up RNA in a sample and RNA-guided DNA binding to target genetic sequences. Presence of targeted sequences is then indicated using a paper-based testing strip like those used in consumer pregnancy tests.
MIT News highlighted the high specificity and ease-of-use of their system in detecting Zika and Dengue viruses simultaneously. However, researchers stated that the system can target any genetic sequence. “With the original SHERLOCK, we were detecting a single molecule in a microliter, but now we can achieve 100-fold greater sensitivity … That’s especially important for applications like detecting cell-free tumor DNA in blood samples, where the concentration of your target might be extremely low,” noted Abudayyeh.
“The [CRISPR] technology demonstrates potential for many healthcare applications, including diagnosing infections in patients and detecting mutations that confer drug resistance or cause cancer,” stated senior author Feng Zhang, PhD. Zhang, shown above in the MIT lab named after him, is a Core Institute Member of the Broad Institute, Associate Professor in the departments of Brain and Cognitive Sciences and Biological Engineering at MIT, and a pioneer in the development of CRISPR gene-editing tools. (Photo copyright: MIT.)
Another unique use of CRISPR technology involved researchers David Liu, PhD, and Weixin Tang, PhD, of Harvard University and Howard Hughes Medical Institute (HHMI). Working in the Feng Zhang laboratory at the Broad Institute, they developed a sort of “data recorder” that records events as CRISPR-Cas9 is used to remove portions of a cell’s DNA.
They published the results of their development of CRISPR-mediated analog multi-event recording apparatus (CAMERA) systems, in Science. The story was also covered by STAT.
“The order of stimuli can be recorded through an overlapping guide RNA design and memories can be erased and re-recorded over multiple cycles,” the researchers noted. “CAMERA systems serve as ‘cell data recorders’ that write a history of endogenous or exogenous signaling events into permanent DNA sequence modifications in living cells.”
This creates a system much like the “black box” recorders in aircraft. However, using Cas9, data is recorded at the cellular level. “There are a lot of questions in cell biology where you’d like to know a cell’s history,” Liu told STAT.
While researchers acknowledge that any medical applications are in the far future, the technology holds the potential to capture and replay activity on the cellular level—a potentially powerful tool for oncologists, pathologists, and other medical specialists.
Using CRISPR to Detect Viruses and Infectious Diseases
Another recently developed technology—DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR)—shows even greater promise for utility to anatomic pathology groups and clinical laboratories.
Also recently debuted in Science, the DETECTR system is a product of Jennifer Doudna, PhD, and a team of researchers at the University of California Berkeley and HHMI. It uses CRISPR-Cas12a’s indiscriminate single-stranded DNA cleaving as a biosensor to detect different human papillomaviruses (HPVs). Once detected, it signals to indicate the presence of HPV in human cells.
Despite the current focus on HPVs, the researchers told Gizmodo they believe the same methods could identify other viral or bacterial infections, detect cancer biomarkers, and uncover chromosomal abnormalities.
Future Impact on Clinical Laboratories of CRISPR-based Diagnostics
Each of these new methods highlights the abilities of CRISPR both as a data generation tool and a biosensor. While still in the research phases, they offer yet another possibility of improving efficiency, targeting specific diseases and pathogens, and creating new assays and diagnostics to expand medical laboratory testing menus and power the precision medicine treatments of the future.
As CRISPR-based diagnostics mature, medical laboratory directors might find that new capabilities and assays featuring these technologies offer new avenues for remaining competitive and maintaining margins.
However, as SHERLOCK demonstrates, it also highlights the push for tests that produce results with high-specificity, but which do not require specialized medical laboratory training and expensive hardware to read. Similar approaches could power the next generation of POC tests, which certainly would affect the volume, and therefore the revenue, of independent clinical laboratories and hospital/health system core laboratories.
—Jon Stone
Related Information:
Multiplexed and Portable Nucleic Acid Detection Platform with Cas13, Cas12a, and Csm6
Rewritable Multi-Event Analog Recording in Bacterial and Mammalian Cells
CRISPR-Cas12a Target Binding Unleashes Indiscriminate Single-Stranded DNase Activity
Researchers Advance CRISPR-Based Tool for Diagnosing Disease
CRISPR Isn’t Just for Gene Editing Anymore
CRISPR’s Pioneers Find a Way to Use It as a Glowing Virus Detector
With New CRISPR Inventions, Its Pioneers Say, You Ain’t Seen Nothin’ Yet
New CRISPR Tools Can Detect Infections Like HPV, Dengue, and Zika
Breakthrough DNA Editing Tool May Help Pathologists Develop New Diagnostic Approaches to Identify and Treat the Underlying Causes of Diseases at the Genetic Level
CRISPR-Related Tool Set to Fundamentally Change Clinical Laboratory Diagnostics, Especially in Rural and Remote Locations
Harvard Researchers Demonstrate a New Method to Deliver Gene-editing Proteins into Cells: Possibly Creating a New Diagnostic Opportunity for Pathologists
Nov 17, 2017 | Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations
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.
The researchers developed a strategy they dubbed “single-cell combinatorial indexing RNA sequencing,” or “sci-RNA-seq” for short, to profile the transcriptomes of nuclei. A New York Times article on the study describes sci-RNA-seq as a kind of barcoding that shows which genes are active in each cell.
“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 York Times 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.
—Dava Stewart
Related Information:
Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism
A Speedier Way to Catalog Human Cells (All 37 Trillion of Them)
Exponential Scaling of Single-Cell RNA-Seq In the Last Decade
Human Cell Atlas
Genetic Fingerprint Helps Researchers Identify Aggressive Prostate Cancer from Non-Aggressive Types and Determine if Treatment Will Be Effective
Big Data Projects at Geisinger Health Are Beginning to Help Physicians Speed Up Diagnosis and Improve Patient Care
Biomarker Trends Are Auspicious for Pathologists and Clinical Laboratories
Pathologists and Clinical Laboratories May Soon Have a Test for Identifying Cardiac Patients at Risk from Specific Heart Drugs by Studying the Patients’ Own Heart Cells
