Metagenomics As a Tool To Diagnose and Understand COVID-19

Throughout the current COVID-19 pandemic, testing has been highlighted as a critical component of the response, enabling rapid identification and isolation of infected individuals. Most of this testing is PCR-based, detecting the presence of the SARS-CoV-2 virus only.

By comparison, clinical metagenomics analyzes the whole community of microbes present in a sample. To learn about some of the advantages of this approach and how clinical metagenomics can be used as a tool to diagnose and understand pathogens such as SARS-CoV-2, Technology Networks recently spoke with Robert Schlaberg, co-founder and CMO of IDbyDNA.

Anna MacDonald (AM): For our readers who may be unfamiliar, please can you give us an overview of what metagenomics is?

Robert Schlaberg (RS): Clinical metagenomics involves sequencing all DNA/RNA in a sample from a patient with an infection. This includes pathogen genetic material – be that from bacteria, fungi, parasites or viruses. Next, the genetic material is sequenced (or decoded) using the same technology that allows us to read the human genome and has revolutionized our understanding of cancer. The DNA sequence data is analyzed by comparison to databases of pathogen genomes. This allows clinicians to identify any known pathogen, and also discover new ones by looking for genetic signatures of thousands of pathogens in parallel. Rather than taking a hypothesis-driven view with a test that looks for a specific pathogen, as traditional infectious disease tests do, clinical metagenomic sequencing is used to analyze all the genetic material within a sample at once. Metagenomics gives doctors and scientists the ability to identify a pathogen from a broad spectrum instead of testing a sample and seeing whether or not it contains one specific microorganism.

AM: What are the benefits of analysing all the pathogens in a sample?

RS: Clinical metagenomics allows us to see a deeper, more complete picture of the pathogens, but also good microorganisms, found in or on the patient. Because the content of the patient’s sample is converted into genetic information, powerful analytical methods such as machine learning can now be used to solve the testing challenge. This allows us to generate insight and more actionable information for better triage and treatment of patients. By testing for all potential pathogens at once, time spent running tests, waiting for results, and running more tests can be reduced. In addition, cutting-edge sequencing technology, such as next-generation sequencing (NGS) is constantly improving the accuracy, speed, sensitivity and specificity of detection – the more data we gather through metagenomic sequencing, the more detailed and precise our results become.

AM: How can clinical metagenomics be used as a tool to diagnose and understand pathogens such as SARS-CoV-2?

RS: As we know, increasing contact between people and wildlife, global connectivity, healthcare disparities, and delays in broadly available tests have exacerbated the rapid spread of emerging infectious diseases, such as COVID-19. This pandemic has underscored the need for new tools to detect, surveil and monitor emerging pathogens, inform public health responses, reduce transmission, and develop effective treatment. Now more than ever, universally applicable, future-proof, and scalable solutions are needed to provide comprehensive and reliable information to local healthcare providers and global public health officials. Besides broad pathogen detection, clinical metagenomics also provides pathogen genome information. In the case of SARS-CoV-2, this led to the virus’ initial discovery, and can be used to monitor how it changes over time, and how it moves through communities and across the globe. This information can be used to track down where transmission occurs and limit the virus’ spread. Clinical metagenomics is changing the diagnostic landscape and will be a key tool in preparing for future transmission. Its wider adoption by routine diagnostic laboratories will allow surveillance to improve dramatically by sharing and monitoring pathogen genomic sequences around the globe in real time. This allows researchers to monitor the virus so that healthcare resources can be deployed most effectively. When a new pathogen is detected, metagenomic tests can be much more quickly tailored to a new virus as only a software update may be needed with the rest of the testing remaining unchanged. In simple terms, metagenomic analysis brings a giant magnet to the search for the needle in the haystack.

AM: Why is it advantageous to be able to develop a detailed DNA signature of a pathogen?

RS: There is more to identifying pathogens than just their names. Metagenomic analysis allows us to compare viral mutations to construct the pathogen’s family tree and transmission patterns, identify antibiotic resistance in bacteria, differentiate harmful pathogens from innocent bystanders more accurately, and monitor patients with infections for signs of new or unusual pathogens, to name just a few advantages. Knowing the full story of an infection is important in delivering quality care to patients.

AM: Why is increased global testing and monitoring of pathogens such as SARS-CoV-2 so important?

RS: This pandemic has shown how important it is to understand the risks posed by novel viruses, often ones that exist in animals but can make the jump to infect people. We need to know where they are lurking, what types of viruses they are, and how to be better prepared by preventing transmission, designing vaccines, and developing treatment. There is still much that we are learning about SARS-CoV-2, including the spectrum of disease it can cause, modes of transmission, what a protective immune response looks like, and even how to best test for it. At this time, it is essential to use our resources as best we can to curb further spread of the virus, and metagenomics is one of the most powerful tools we have. Diagnostic testing of patients suspected to have COVID-19 should include the detection of other respiratory pathogens. Additional information is valuable both if the patient tests positive or negative for SARS-CoV-2. If the patient has COVID-19, metagenomics can quickly identify any other pathogen the patient may be infected with in addition to SARS-CoV-2. This is more common than initially thought and in contrast to SARS-CoV-2, many of those infections can be treated with drugs we already have, helping reduce disease severity. If a patient tests negative for SARS-CoV-2, their disease may be caused by another pathogen that a COVID-19 test cannot find as it is only looking for SARS-CoV-2. The doctor needs to know the cause so they can provide effective treatment. Metagenomics can find those other pathogens, helping to make a diagnosis and selecting appropriate treatment.

AM: What barriers are there to greater adoption of NGS technologies for infectious disease testing?

RS: The cost and time to perform metagenomic testing have traditionally been barriers to adoption of NGS technologies, but these have dropped precipitously over the past several years. By removing these and other barriers such as eliminating the need for expert knowledge, bioinformatics expertise, and computational resources, the user-friendly and diagnostic-grade Explify Platform empowers diagnostic laboratories to offer cutting edge testing without prior experience. NGS-based pathogen detection is on its way to becoming part of routine infectious disease workup and the Explify Platform will accelerate this trend by democratizing metagenomic testing. Already the cost of metagenomic testing has been reduced much in the same way human DNA genome sequencing has become commonplace through services such as 23andme and Ancestry.com. This means that in the near future, widely available metagenomic testing will allow for much better tracking of the spread of infectious diseases, faster response to emerging new pathogens and, as a result, much more effective deployment of public health resources.

AM: Can you tell us more about your partnership with Illumina and current COVID-19 work?

RS: IDbyDNA and Illumina partnered to accelerate NGS adoption for clinical infectious disease testing. Our Explify Platform can detect over 50,000 microorganisms, including over 6,000 common and rare pathogens such as SARS-CoV-2, with quantification capabilities and the ability to detect anti-microbial resistance. By combining this with Illumina’s NGS systems and library preparation capabilities, we are developing a range of complete, streamlined workflow solutions. Recently, we jointly announced our research-use-only Respiratory Virus Oligos Panel, which can detect SARS-CoV-2 along with 35 other viral respiratory pathogens like the flu and other human coronaviruses. This test provides more information on the virus than a qPCR panel – in addition to identifying the virus’ complete genomic fingerprint, we can use the test to track transmission and identify co-infections. With a targeted enrichment approach, we believe that we can make metagenomic sequencing the future of testing for pathogens like SARS-CoV-2. In addition, we are expecting to launch more target enrichment products for a broader respiratory panel later this year.
Robert Schlaberg was speaking to Anna MacDonald, Science Writer, Technology Networks.