Metagenomics As a Tool To Diagnose and Understand COVID-19 / La metagenomica come strumento per diagnosticare e comprendere COVID-19
Metagenomics As a Tool To Diagnose and Understand COVID-19 / La metagenomica come strumento per diagnosticare e comprendere COVID-19
Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa
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.
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.
ITALIANO
Durante l'attuale pandemia di COVID-19, i test sono stati evidenziati come una componente critica della risposta, consentendo una rapida identificazione e isolamento delle persone infette. La maggior parte di questi test si basa sulla PCR, rilevando solo la presenza del virus SARS-CoV-2.
In confronto, la metagenomica clinica analizza l'intera comunità di microbi presenti in un campione. Per conoscere alcuni dei vantaggi di questo approccio e come la metagenomica clinica può essere utilizzata come strumento per diagnosticare e comprendere agenti patogeni come SARS-CoV-2, Technology Networks ha recentemente parlato con Robert Schlaberg, co-fondatore e CMO di IDbyDNA.
Anna MacDonald (AM): Per i nostri lettori che potrebbero non avere familiarità, ti preghiamo di darci una panoramica di cosa sia la metagenomica?
Robert Schlaberg (RS): la metagenomica clinica prevede il sequenziamento di tutto il DNA / RNA in un campione di un paziente con un'infezione. Ciò include materiale genetico patogeno, sia esso da batteri, funghi, parassiti o virus. Successivamente, il materiale genetico viene sequenziato (o decodificato) utilizzando la stessa tecnologia che ci consente di leggere il genoma umano e ha rivoluzionato la nostra comprensione del cancro. I dati della sequenza del DNA vengono analizzati confrontando i database dei genomi patogeni. Ciò consente ai medici di identificare qualsiasi agente patogeno noto e di scoprirne di nuovi cercando in parallelo firme genetiche di migliaia di agenti patogeni. Invece di prendere una visione basata sull'ipotesi con un test che cerca un patogeno specifico, come fanno i tradizionali test delle malattie infettive, il sequenziamento metagenomico clinico viene utilizzato per analizzare tutto il materiale genetico all'interno di un campione contemporaneamente. La metagenomica offre a medici e scienziati la capacità di identificare un patogeno da un ampio spettro invece di testare un campione e vedere se contiene o meno un microrganismo specifico.
AM: Quali sono i vantaggi dell'analisi di tutti i patogeni in un campione?
RS: La metagenomica clinica ci consente di vedere un quadro più profondo e completo dei patogeni, ma anche dei buoni microrganismi, presenti nel o sul paziente. Poiché il contenuto del campione del paziente viene convertito in informazioni genetiche, ora è possibile utilizzare potenti metodi analitici come l'apprendimento automatico per risolvere la sfida del test. Questo ci consente di generare intuizioni e informazioni più fruibili per una migliore valutazione e trattamento dei pazienti. Testando contemporaneamente tutti i potenziali patogeni, è possibile ridurre il tempo impiegato per l'esecuzione dei test, l'attesa dei risultati e l'esecuzione di più test. Inoltre, la tecnologia di sequenziamento all'avanguardia, come il sequenziamento di nuova generazione (NGS), migliora costantemente l'accuratezza, la velocità, la sensibilità e la specificità del rilevamento: più dati raccogliamo attraverso il sequenziamento metagenomico, più dettagliati e precisi diventano i nostri risultati.
AM: Come può la metagenomica clinica essere utilizzata come strumento per diagnosticare e comprendere agenti patogeni come SARS-CoV-2?
RS: Come sappiamo, l'aumento del contatto tra persone e fauna selvatica, connettività globale, disparità sanitarie e ritardi nei test ampiamente disponibili hanno esacerbato la rapida diffusione di malattie infettive emergenti, come COVID-19. Questa pandemia ha sottolineato la necessità di nuovi strumenti per rilevare, sorvegliare e monitorare i patogeni emergenti, informare le risposte della salute pubblica, ridurre la trasmissione e sviluppare un trattamento efficace. Oggi più che mai sono necessarie soluzioni universalmente applicabili, a prova di futuro e scalabili per fornire informazioni complete e affidabili agli operatori sanitari locali e ai funzionari globali della sanità pubblica. Oltre all'ampia rilevazione dei patogeni, la metagenomica clinica fornisce anche informazioni sul genoma dei patogeni. Nel caso di SARS-CoV-2, questo ha portato alla scoperta iniziale del virus e può essere utilizzato per monitorare come cambia nel tempo e come si muove attraverso le comunità e in tutto il mondo. Queste informazioni possono essere utilizzate per rintracciare dove avviene la trasmissione e limitare la diffusione del virus. La metagenomica clinica sta cambiando il panorama diagnostico e sarà uno strumento chiave nella preparazione per la trasmissione futura. La sua più ampia adozione da parte dei laboratori diagnostici di routine consentirà alla sorveglianza di migliorare notevolmente condividendo e monitorando sequenze genomiche patogene in tutto il mondo in tempo reale. Ciò consente ai ricercatori di monitorare il virus in modo che le risorse sanitarie possano essere impiegate nel modo più efficace. Quando viene rilevato un nuovo patogeno, i test metagenomici possono essere adattati molto più rapidamente a un nuovo virus in quanto potrebbe essere necessario solo un aggiornamento del software con il resto del test rimasto invariato. In termini semplici, l'analisi metagenomica porta un magnete gigante nella ricerca dell'ago nel pagliaio.
AM: Perché è vantaggioso poter sviluppare una firma dettagliata del DNA di un agente patogeno?
RS: C'è di più nell'identificare i patogeni oltre ai loro nomi. L'analisi metagenomica ci consente di confrontare le mutazioni virali per costruire l'albero genealogico del patogeno e i modelli di trasmissione, identificare la resistenza agli antibiotici nei batteri, differenziare i patogeni dannosi da astanti innocenti e monitorare i pazienti con infezioni per segni di agenti patogeni nuovi o insoliti, per nominare solo pochi vantaggi. Conoscere l'intera storia di un'infezione è importante per fornire assistenza di qualità ai pazienti.
AM: Perché è così importante aumentare i test globali e il monitoraggio di agenti patogeni come SARS-CoV-2?
RS: Questa pandemia ha dimostrato quanto sia importante comprendere i rischi posti dai nuovi virus, spesso quelli che esistono negli animali ma che possono fare il salto per infettare le persone. Dobbiamo sapere dove si nascondono, quali tipi di virus sono e come prepararsi meglio prevenendo la trasmissione, progettando i vaccini e sviluppando il trattamento. C'è ancora molto da imparare sulla SARS-CoV-2, incluso lo spettro della malattia che può causare, le modalità di trasmissione, l'aspetto di una risposta immunitaria protettiva e persino come testarla al meglio. Al momento, è essenziale utilizzare le nostre risorse nel miglior modo possibile per frenare ulteriormente la diffusione del virus e la metagenomica è uno degli strumenti più potenti che abbiamo. I test diagnostici su pazienti sospettati di avere COVID-19 dovrebbero includere il rilevamento di altri agenti patogeni respiratori. Ulteriori informazioni sono utili sia se il paziente risulta positivo o negativo per SARS-CoV-2. Se il paziente ha COVID-19, la metagenomica può identificare rapidamente qualsiasi altro agente patogeno con cui il paziente può essere infettato oltre a SARS-CoV-2. Questo è più comune di quanto si pensasse inizialmente e, contrariamente a SARS-CoV-2, molte di queste infezioni possono essere trattate con farmaci che già abbiamo, contribuendo a ridurre la gravità della malattia. Se un paziente risulta negativo per SARS-CoV-2, la sua malattia può essere causata da un altro agente patogeno che un test COVID-19 non riesce a trovare poiché cerca solo SARS-CoV-2. Il medico deve conoscere la causa in modo che possano fornire un trattamento efficace. La metagenomica può trovare quegli altri agenti patogeni, aiutando a fare una diagnosi e selezionando un trattamento adeguato.
AM: Quali sono gli ostacoli alla maggiore adozione delle tecnologie NGS per il test delle malattie infettive?
RS: I costi e i tempi per eseguire i test metagenomici sono stati tradizionalmente ostacoli all'adozione delle tecnologie NGS, ma questi sono diminuiti precipitosamente negli ultimi anni. Rimuovendo queste e altre barriere come l'eliminazione della necessità di conoscenze specialistiche, competenze in bioinformatica e risorse computazionali, la piattaforma di ampliamento intuitiva e di livello diagnostico consente ai laboratori diagnostici di offrire test all'avanguardia senza precedenti esperienze. Il rilevamento di agenti patogeni basati su NGS sta per diventare parte del lavoro di routine sulle malattie infettive e la piattaforma Explify accelererà questa tendenza democratizzando i test metagenomici. Già il costo dei test metagenomici è stato ridotto molto nello stesso modo in cui il sequenziamento del genoma del DNA umano è diventato un luogo comune attraverso servizi come 23andme e Ancestry.com. Ciò significa che nel prossimo futuro, i test metagenomici ampiamente disponibili consentiranno un monitoraggio molto migliore della diffusione delle malattie infettive, una risposta più rapida ai nuovi agenti patogeni emergenti e, di conseguenza, un dispiegamento molto più efficace delle risorse sanitarie pubbliche.
AM: Puoi dirci di più sulla tua collaborazione con Illumina e l'attuale lavoro di COVID-19?
RS: IDbyDNA e Illumina hanno collaborato per accelerare l'adozione di NGS per i test clinici sulle malattie infettive. La nostra piattaforma Explify è in grado di rilevare oltre 50.000 microrganismi, inclusi oltre 6.000 agenti patogeni comuni e rari come SARS-CoV-2, con capacità di quantificazione e capacità di rilevare la resistenza antimicrobica. Combinando questo con i sistemi NGS di Illumina e le capacità di preparazione delle librerie, stiamo sviluppando una gamma di soluzioni di flusso di lavoro complete e ottimizzate. Di recente, abbiamo annunciato congiuntamente il nostro pannello Oligos del virus respiratorio, solo per uso di ricerca, in grado di rilevare SARS-CoV-2 insieme ad altri 35 agenti patogeni respiratori virali come l'influenza e altri coronavirus umani. Questo test fornisce più informazioni sul virus rispetto a un pannello qPCR. Oltre a identificare l'impronta genomica completa del virus, possiamo utilizzare il test per tracciare la trasmissione e identificare le coinfezioni. Con un approccio di arricchimento mirato, riteniamo di poter rendere il sequenziamento metagenomico il futuro dei test per agenti patogeni come SARS-CoV-2. Inoltre, prevediamo di lanciare più prodotti per l'arricchimento target per un pannello respiratorio più ampio entro la fine dell'anno.
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