As many clinical laboratory scientists know, gene sequencing technology continues to become faster, more accurate, and less expensive per whole human genome sequenced
In February, Dark Daily reported that Personalis, Inc. (NASDAQ:PSNL) had delivered its 100,000th whole human genome sequence to the US Department of Veterans Affairs Million Veterans Program (VA MVP). Now, the Menlo Park, Calif.-based cancer genomics company has topped that achievement by delivering its 125,000 whole human genome sequence!
“This represents another important landmark for both the program and for Personalis,” said John West, Chief Executive Officer, Personalis, in a news release. “We congratulate the VA MVP for reaching this important milestone.
“We strongly believe that the research projects being performed today will enable precision medicine in healthcare systems in the future across a wide range of disease areas,” he added. This is a positive development for clinical laboratories, as personalized medicine services require a lab to sequence and interpret the patient’s DNA.
Personalis was contracted with the US federal government to perform genetic research in 2012 and has delivered 50,000 genomes to the VA MVP during the past twelve months.
The Personalis and VA MVP researchers seek to gain a better understanding of how genetic variants affect health. Before the COVID-19 pandemic hit the US, the VA was enrolling veterans in the Million Veterans Program at 63 VA medical centers across the country. There are currently about 830,000 veterans enrolled in the venture and the VA is expecting two million veterans to eventually sign up for the sequencing project.
“As a global leader in genomic sequencing and comprehensive analytics services, Personalis is uniquely suited to lead these population-scale efforts and we are currently in the process of expanding our business operations internationally,” West added.
According to the press release, “the VA MVP provides researchers with a rich resource of genetic, health, lifestyle, and military-exposure data collected from questionnaires, medical records, and genetic analyses. By combining this information into a single database, the VA MVP promises to advance knowledge about the complex links between genes and health.”
NIH All of Us Research Program Supports Precision Medicine Goals Another genetic research project being conducted by the US National Institutes of Health (NIH) is the All of Us Research Program. Using donated personal health information from thousands of participants, the NIH researchers seek to “learn how our biology, lifestyle, and environment affect health,” according to the program’s website.
“We’re changing the paradigm for research,” said Josh Denny, MD (above), Chief Executive Officer of the All of Us Research Program, in an NIH news release. “Participants are our most important partners in this effort, and we know many of them are eager to get their genetic results and learn about the science they’re making possible. We’re working to provide that valuable information in a responsible way,” he added. Clinical laboratories may soon see new precision medicine biomarkers derived from this type of research. (Photo copyright: Vanderbilt University.)
The All of Us Research Program intends to have at least one million US participants take part in the research. The researchers hope to help scientists discover new knowledge regarding how biological, environmental, and behavioral factors influence health, and to learn to tailor healthcare to patients’ specific medical needs, a key component of precision medicine.
Participants in the project share personal information via a variety of methods, including surveys, electronic health records, and biological samples.
A Better Sampling of Under-Represented Communities
Since opening enrollment in 2018, more than 270,000 people have contributed blood, urine, and saliva samples to the All of Us Research Program. More than 80% of the participants come from communities that are traditionally under-represented in biomedical research.
“We need programs like All of Us to build diverse datasets so that research findings ultimately benefit everyone,” said Brad Ozenberger, PhD, Genomics Program Director, All of Us, in the NIH news release. “Too many groups have been left out of research in the past, so much of what we know about genomics is based mainly on people of European ancestry. And often, genomic data are explored without critical context like environment, economics, and other social determinants of health. We’re trying to help change that, enabling the entire research community to help fill in these knowledge gaps.”
The All of Us Research Project’s analysis of the collected data includes both whole-genome sequencing (WGS) and genotyping and is taking a phased approach in returning genetic data to participants.
Participants initially receive data about their genetic ancestry and traits. That is followed later by health-related results, such as how their genetic variants may increase the risk of certain diseases and how their DNA may affect their reaction to drug therapies.
Genetic researchers hope programs like these will lead to improved in vitro diagnostics and drug therapies. Genetic sequencing also may lead to new diagnostic and therapeutic biomarkers for clinical laboratories.
By analyzing ancient poop, researchers have discovered how much the human microbiome has changed over the past millennium, what may have brought about the change, and how those changes formed today’s human microbiome
Two thousand year-old human poop has yielded new insights into the evolution of the microbial cells (microbiota) inhabiting today’s human gut—collectively known as the human microbiome—that could help pathologists and clinical laboratories better understand diseases that may be linked to gut bacteria.
A recent study conducted by an international team of scientists reveals that the gut bacteria of today’s humans may have been altered by the onset of modern processed foods, sanitation, and the use of antibiotics.
In “Reconstruction of Ancient Microbial Genomes from the Human Gut,” published in the journal Nature, the researchers wrote, “In this study, we establish that palaeofaeces [Paleofeces in the US] with well-preserved DNA are abundant sources of microbial genomes, including previously undescribed microbial species, that may elucidate the evolutionary histories of human microbiomes. Similar future studies tapping into the richness of palaeofaeces will not only expand our knowledge of the human microbiome but may also lead to the development of approaches to restore present-day gut microbiomes to their ancestral state.”
Ancient Poop Is a ‘Time Machine’ into the Human Microbiome
To perform the research for this study, scientists analyzed Deoxyribonucleic acid (DNA) from eight preserved, fossilized feces (coprolites) to gain insight into the gut bacteria of ancient communities. The samples used in the research were originally found in rock formations in Utah and Mexico and were preserved by dryness and stable temperatures. The coprolites were between 1,000 and 2,000 years old.
“These paleofeces are the equivalent of a time machine,” Justin Sonnenburg, PhD, Associate Professor, Microbiology and Immunology at Stanford University and co-author of the study, told Science. Tiny bits of food found in the coprolites indicated that the diet of the ancient people included:
The dried-out poop samples were first radiocarbon dated. Then, tiny fragments of the coprolites were rehydrated which allowed researchers to recover longer DNA strands than those found in previous, similar studies. This study compared the microbiome of the ancient populations to that of present-day individuals. The authors of the study suggest that during the past millennium, the human microbiome has lost dozens of bacterial species and has become less diverse.
Other research studies have linked lower diversity among gut bacteria to higher rates of modern diseases, such as diabetes, obesity, and allergies, Science noted.
“We really wanted to be able to go back in time and see when those changes [in the modern gut microbiome] came about, and what’s causing them,” Archeological Geneticist Christina Warinner, PhD, Assistant Professor of Anthropology at Harvard University and one of the authors of the study, told Science. “Is it food itself? Is it processing, is it antibiotics, is it sanitation?” Warinner is the Sally Starling Seaver Assistant Professor at the Radcliffe Institute, and a group leader in the Department of Archaeogenetics at the Max Planck Institute for Evolutionary Anthropology and affiliated with the faculty of biological sciences at the Friedrich Schiller University in Jena, Germany. (Photo copyright: The Game Changers.)
Ancient versus Modern Microbiome
The ancient microbiomes lacked markers for antibiotic resistance and included dozens of bacterial species that were previously unknown. According to the study, “a total of 181 of the 498 reconstructed microbial genomes were classified as gut derived and had extensive DNA damage, consistent with an ancient origin, and 39% of the ancient genomes offered evidence of being newly discovered species.”
The scientists also discovered that the gut bacteria of present-day people living in non-industrialized societies is more like that of the ancient people when compared to present-day humans living in industrialized societies. But there are still vast differences between the ancient and the modern microbiome.
For example, a bacteria known as Treponema is virtually unknown in the microbiome of current humans, even those living in non-industrialized societies. However, according to Kostic, “They’re present in every single one of the paleofeces, across all the geographic sites. That suggests it’s not purely diet that’s shaping things,” he told Science.
What Can Clinical Laboratories Learn from Ancient Poop?
The ancient poop study scientists hope that future research on coprolites from the past will reveal more information regarding when shifts in the microbiome occurred and what events or human activities prompted those changes.
Research on the human microbiome has been responsible for many discoveries that have greatly impacted clinical pathology and diagnostics development.
Microbiologists and other medical laboratory scientists may soon have more useful biomarkers that aid in earlier, more accurate detection of disease, as well as guiding physicians to select the most effective therapies for specific patients, a key component of Precision Medicine.
The findings of this study are another step forward in understanding the composition and functions of gut bacteria. The study of the microbiome could prove to be a growth area for clinical laboratories and microbiology labs as well. It is probable that soon, labs will be performing more microbiome testing to help with the diagnosis, and treatment selection and monitoring of patients.
Genomics experts say this is a sign that clinical laboratory genetics testing is maturing into a powerful tool for population health
Faced with lagging sales and employee layoffs, genomics companies in the genealogy DNA testing market are shifting their focus to the healthcare aspects of the consumer genomics data they’ve compiled and aggregated.
Recent analysis of the sales of genetic tests from Ancestry and 23andMe show the market is definitely cooling, and the analysts speculate that—independent of the consequences of the COVID-19 pandemic on consumer behavior—the two clinical laboratory genetic testing companies may already have done testing for the majority of consumers who want to buy these tests.
“I think the consumer market is going to become more integrated into the healthcare experience,” Joe Grzymski, PhD, told GenomeWeb. “Whether that occurs through your primary care doctor, your large integrated health network, or your payor, I think there will be profound changes in society’s tolerance for using genetics for prevention.”
In February, Ancestry, the largest company in the home DNA testing space, announced it was laying off 6% of its workforce or approximately 100 people, across different departments due to a decline in sales, CNBC reported. Several weeks earlier, 23andMe, the second largest company in this market, also announced it was laying off about 100 people or 14% of its workforce due to declining sales.
“I wasn’t surprised by the news,” said Linda Avey, a 23andMe co-founder who is now co-founder and Chief Executive Officer at Precisely Inc., a genomics company headquartered in San Francisco. She was commenting to GenomeWeb on the recent restructuring at her former company. “The level of expensive advertising has been insane here in the US. Those [customer acquisition costs] are not a sustainable model.”
CNBC surmised that the lull in at-home genetic testing is due mainly to:
A drought of early adopters. Individuals who were interested in the testing for genealogical and health reasons, and who believed in the value of the tests, have already purchased the product.
Privacy concerns. Some potential customers may have reservations about having their DNA information collected and stored in a database due to concerns about how that data is safeguarded and its potential uses by outside companies, law enforcement, and governments.
COVID-19 May or May Not Be a Factor in Declining DNA Testing Sales
The COVID-19 pandemic may be playing a role in the decline in sales of at-home DNA testing kits. However, there are indications that the market was cooling before the virus occurred.
An article in MIT Technology Review reported that 26 million people had purchased at-home DNA testing kits by the beginning of 2019. The article also estimated that if the market continued at that pace, 100 million people were expected to purchase the tests by the end of 2020.
However, data released by research firm Second Measure, a company that analyzes credit and debit card purchases, may show a different story, reported Vox. The data showed a general decline in test kit sales in 2019. Ancestry’s sales were down 38% and 23andMe’s sales were down 54% in November 2019 compared to November 2018. The downward trend continued in December with Ancestry sales declining 15% and 23andMe sales declining 48% when compared to December 2018.
Second Measure, however, compiled data from the two companies’ websites only. They did not include testing kits that may have been purchased through other sources such as Amazon, or at brick and mortar locations.
Nevertheless, the measures being taken by genomics companies to shore up their market indicates the Second Measure data is accurate or very close.
Rise of Population-level Genomics
This decline in genealogical sales seems to be behind DNA-testing companies shifting focus to the healthcare aspects of consumer genomics. Companies like 23andMe and Ancestry are looking into developing health reports based on their customers’ data that can ascertain an individual’s risk for certain health conditions, or how they may react to prescription medications.
“We are seeing the next wave of maturity of the genetics market,” Othman Laraki, co-founder and CEO of Color Genomics, told CNBC. “If expensive diagnostic testing was genomics’ equivalent of mainframe computers, direct to consumer ancestry genetics was the hobbyist use. While the early adopter wave is petering out, we are seeing the real market (the equivalent of a PC in every home and a phone in every pocket), which is population-level use of genetics, taking hold.” (Photo copyright: San Francisco Business Times.)
For some genomics companies like 23andMe, the at-home DNA testing market was never specifically about selling testing kits. Rather, these companies envisioned a market where consumers would pay to have their DNA analyzed to obtain data on their ancestry and health, and in turn the testing companies would sell the aggregated consumer data to other organizations, such as pharmaceutical companies.
“Remember that 23andMe was never in the consumer genomics business, they were in the data aggregation business,” Spencer Wells, PhD, founder and Executive Director of the Insitome Institute, a US-based 501(c)3 nonprofit think tank focused on key areas in the field of personal genomics, told GenomeWeb. “They created a database that should in principle allow them to do what they promised, which is to improve people’s health through genomic testing.”
Even with clinical laboratory testing currently focused on COVID-19 testing, there remains an opportunity to sequence large numbers of people through at-home DNA testing and then incorporate those findings into the practice of medicine. The hope is that sales will again accelerate once consumers feel there is a compelling need for the tests.
Pathologists and clinical laboratory managers will want to watch to see if the companies that grew big by selling ancestry and genealogy tests to consumers will start to send sales reps into physicians’ offices to offer genetic tests that would be useful in diagnosing and treating patients.
Half of the genes identified were found to be singletons, unique to specific individuals, offering the possibility of developing precision medicine therapies targeted to specific patients, as well as clinical laboratory tests
Microbiologists and other medical laboratory scientists may soon have more useful biomarkers that aid in earlier, more accurate detection of disease, as well as guiding physicians to select the most effective therapies for specific patients, a key component of Precision Medicine.
The scientists also found that more than half of the bacterial genes examined occurred only once (called “singletons”) and were specific to each individual. A total of 11.8 million of these singletons came from oral samples and 12.6 million of them derived from gut samples, a Harvard news release noted.
In a paper published in Cell Host and Microbe the researchers state, “Despite substantial interest in the species diversity of the human microbiome and its role in disease, the scale of its genetic diversity, which is fundamental to deciphering human-microbe interactions, has not been quantified.”
To determine this quantity, the researchers conducted a meta-analysis of metagenomes from the human mouth and gut among 3,655 samples from 13 unique studies. Of their findings, they wrote, “We found staggering genetic heterogeneity in the dataset, identifying a total of 45,666,334 non-redundant genes (23,961,508 oral and 22,254,436 gut) at the 95% identity level.”
The scientists also found that while genes commonly found in
all the samples seemed to drive the basic functions of a microbe’s survival,
the singletons perform more specialized functions within the body, such as
creating barriers to protect the micro-organisms from external onslaughts and
helping to build up resistance to antibiotics.
“Some of these unique genes appear to be important in solving evolutionary challenges,” said Braden Tierney, a PhD student at Harvard Medical School and one of the authors of the study, in the news release. “If a microbe needs to become resistant to an antibiotic because of exposure to drugs, or suddenly faces a new selective pressure, the singleton genes may be the wellspring of genetic diversity the microbe can pull from to adapt,” he concluded.
‘More Genes in the Human Microbiome than Stars in the
Universe’
According to their published paper, the team of microbiologists and bioinformaticians pinpointed more than 46 million bacterial genes contained within 3,655 Deoxyribonucleic acid (DNA) samples. They identified 23,961,508 non-redundant genes in the oral samples and 22,254,436 non-redundant genes in the intestinal samples.
While similar research in the past has targeted bacteria in
either the gut or the mouth, the scientists believe their study is the first
that analyzed DNA collected from both areas simultaneously.
The graphic above, taken from the Harvard Medical School study, illustrates the ratio of singleton vs. non-singleton bacteria contained in human microbiome. The sheer amount of diversity seems to have impressed the scientists. “There may be more genes in the collective human microbiome than stars in the observable universe, and at least half of these genes appear to be unique to each individual,” the Harvard news release states. This diversity could lead to new precision medicine treatments and clinical laboratory diagnostics. (Graphic copyright: Harvard Medical School.)
“Just like no two siblings are genetically identical, no two bacterial strains are genetically identical, either,” said study co-author Chirag Patel, PhD, Assistant Professor of Biomedical Informatics at Harvard’s Blavatnik Institute. “Two members of the same bacterial strain could have markedly different genetic makeup, so information about bacterial species alone could mask critical differences that arise from genetic variation.”
The scientists also endeavored to determine the number of
genes that reside in the human microbiome but found the precise number difficult
to identify. One calculation estimated that number to be around 232 million,
while another suggested the number could be substantially higher.
“Whatever it may be, we hope that our catalog, along with a
searchable web application, will have many practical uses and seed many directions
of research in the field of host-microbe relationships,” stated Patel in the
news release.
New Diagnostics for Clinical Laboratories?
This type of research could have lasting effects on clinical
laboratories. As the volume of data generated by diagnostic testing of microbes
in patients opens new understanding of how these factors affect human disease
and create differences from one individual to another, the increased number of
genes and gene mutations mean that microbiology laboratories will increase
their use of information technology and analytical software tools.
“Ours is a gateway study, the first step on a what will
likely be a long journey toward understanding how differences in gene content
drive microbial behavior and modify disease risk,” said Tierney in the Harvard
news release.
That’s good news, because new biomarkers derived from such
research will help microbiologists and other clinical laboratory scientists
more accurately detect disease and identify the best therapies for individual
patients.
‘Prime editing’ is what researchers are calling the proof-of-concept research that promises improved diagnostics and more effective treatments for patients with genetic defects
Known as Prime Editing, the scientists developed this technique as a more accurate way to edit Deoxyribonucleic acid (DNA). In a paper published in Nature, the authors claim prime editing has the potential to correct up to 89% of disease-causing genetic variations. They also claim prime editing is more powerful, precise, and flexible than CRISPR.
The research paper describes prime editing as a “versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit.”
And a Harvard Gazette article states, “Prime editing differs from previous genome-editing systems in that it uses RNA to direct the insertion of new DNA sequences in human cells.”
Assuming further research and clinical studies confirm the
viability of this technology, clinical laboratories would have a new diagnostic
service line that could become a significant proportion of a lab’s specimen
volume and test mix.
In that e-briefing we wrote that Liu “has led a team of scientists in the development of a gene-editing protein delivery system that uses cationic lipids and works on animal and human cells. The new delivery method is as effective as protein delivery via DNA and has significantly higher specificity. If developed, this technology could open the door to routine use of genome analysis, worked up by the clinical laboratory, as one element in therapeutic decision-making.”
Now, Liu has taken that development even further.
“A major aspiration in the molecular life sciences is the ability to precisely make any change to the genome in any location. We think prime editing brings us closer to that goal,” David Liu, PhD (above), Director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, told The Harvard Gazette. “We’re not aware of another editing technology in mammalian cells that offers this level of versatility and precision with so few byproducts.” (Photo copyright: Broad Institute.)
Cell Division Not Necessary
CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. It is considered the most advanced gene editing technology available. However, it has one drawback not found in Prime Editing—CRISPR relies on a cell’s ability to divide to generate desired alterations in DNA—prime editing does not.
This means prime editing could be used to repair genetic mutations in cells that do not always divide, such as cells in the human nervous system. Another advantage of prime editing is that it does not cut both strands of the DNA double helix. This lowers the risk of making unintended, potentially dangerous changes to a patient’s DNA.
The researchers claim prime editing can eradicate long lengths of disease-causing DNA and insert curative DNA to repair dangerous mutations. These feats, they say, can be accomplished without triggering genome responses introduced by other forms of CRISPR that may be potentially harmful.
“Prime editors are more like word processors capable of
searching for targeted DNA sequences and precisely replacing them with edited
DNA strands,” Liu told NPR.
The scientists involved in the study have used prime editing to perform over 175 edits in human cells. In the test lab, they have succeeded in repairing genetic mutations that cause both Sickle Cell Anemia (SCA) and Tay-Sachs disease, NPR reported.
“Prime editing is really a step—and potentially a significant step—towards this long-term aspiration of the field in which we are trying to be able to make just about any kind of DNA change that anyone wants at just about any site in the human genome,” Liu told News Medical.
Additional Research Required, but Results are Promising
Prime editing is very new and warrants further
investigation. The researchers plan to continue their work on the technology by
performing additional testing and exploring delivery mechanisms that could lead
to human therapeutic applications.
“Prime editing should be tested and optimized in as many cell types as researchers are interested in editing. Our initial study showed prime editing in four human cancer cell lines, as well as in post-mitotic primary mouse cortical neurons,” Liu told STAT. “The efficiency of prime editing varied quite a bit across these cell types, so illuminating the cell-type and cell-state determinants of prime editing outcomes is one focus of our current efforts.”
Although further research and clinical studies are needed to
confirm the viability of prime editing, clinical laboratories could benefit
from this technology. It’s worth watching.
