Researchers at UC San Francisco have successfully developed a genomic test that allows for the swift identification of nearly any type of pathogen, whether it be a virus, bacteria, fungus, or parasite, after a decade of application.
This test has the capacity to significantly enhance the treatment of neurological infections resulting in illnesses such as meningitis and encephalitis, while simultaneously accelerating the identification of emerging viral pandemic threats. It utilizes an advanced genomic sequencing method known as metagenomic next-generation sequencing (mNGS).
Unlike traditional methods that focus on one pathogen at a time, mNGS examines all nucleic acids—both RNA and DNA—within a given sample.
“Our approach may seem straightforward,” stated Charles Chiu, MD, PhD, a professor of laboratory medicine and infectious diseases at UCSF and the senior author of the study. “By consolidating several tests into one, we can eliminate the prolonged uncertainty involved in diagnosing and treating infections.”
The researchers initially created a clinical mNGS test to evaluate cerebrospinal fluid (CSF), which is the clear liquid that surrounds the brain and spinal cord.
Since then, the test has been administered to thousands of patients with unexplained neurological issues, both at UCSF and at various hospitals throughout the nation.
In a study published on November 12 in Nature Medicine, it was shown that the mNGS test accurately identified 86% of neurological infections.
In a related study published concurrently in Nature Communications, the team employed mNGS to detect pathogens in respiratory fluid linked to pneumonia and automated the process for quicker results.
The researchers anticipate that the automated version of the test will be capable of identifying new viral pathogens that could lead to respiratory pandemics similar to COVID-19.
A major advancement in diagnosing rare infectious neurological diseases
Neurological diseases often pose significant diagnostic challenges, particularly when caused by rare or unknown pathogens. Usually, each day that passes without a diagnosis results in a further decline in the patient’s health.
In the early 2010s, Chiu, along with UCSF colleagues Joe DeRisi, PhD, and Michael Wilson, MD, pioneered a metagenomic sequencing technique to examine CSF for possible pathogens responsible for neurological infections.
The innovation involves sequencing the entirety of genetic material found in CSF and employing a computational analysis to distinguish human sequences from those originating from bacteria, viruses, fungi, or parasites.
In 2014, this technology assisted doctors in Wisconsin in treating a young boy who was critically ill in the ICU with an unidentified infection.
Despite a lengthy series of tests failing to provide answers, UCSF’s test managed to pinpoint that the boy had leptospirosis in just 48 hours, a condition treatable with penicillin. Following treatment, he made a complete recovery.
Following this success, the mNGS test became a standard procedure at UCSF, with hospitals and clinics across the country sending samples for analysis by the UCSF Clinical Microbiology Laboratory, which Chiu directs.
Between 2016 and 2023, the UCSF team evaluated nearly 5,000 CSF samples through this testing method, detecting infections in 14.4% of cases, with an accurate identification of pathogens in 86% of those instances.
“Our mNGS test outperforms any other testing categories for neurological infections,” Chiu remarked. “The findings bolster its role as an essential component in the diagnostic toolkit for physicians dealing with infectious diseases.”
To broaden access to this technology, Chiu, DeRisi, Wilson, and others established Delve Bio, currently the sole provider of the mNGS CSF test designed at UCSF.
“These results endorse integrating mNGS as a fundamental instrument in the clinical evaluation of CNS infections,” said Steve Miller, MD, PhD, chief medical officer of Delve Bio. “mNGS provides the most unbiased, comprehensive, and definitive means for pathogen detection. Its rapid diagnostic capabilities offer guidance for the management and treatment of patients with meningitis and encephalitis, potentially lowering future healthcare expenses.”
Preparing for the next pandemic
For mNGS to act as a timely warning for potential pandemics, it must be efficient. Chiu and his research team have modified it to analyze respiratory fluid and have developed automation processes.
While the CSF testing includes over 100 steps and can require 2 to 7 days for processing, the respiratory test involves just 30 minutes of manual intervention before transferring control to robots and algorithms.
“We aimed to complete the entire procedure within 12 to 24 hours, providing results either the same day or the next,” Chiu stated.
In the Nature Communications study, the researchers showed that the test could spot respiratory viruses with pandemic potential, such as SARS-CoV-2, influenza A and B, and RSV, in under a day, even at minimal virus concentrations in a sample.
They also assessed the technology’s capacity to recognize divergent viruses or new strains, concluding it could hypothetically identify any new variants that may appear in the future.
Both the CSF and respiratory variants of the mNGS test have received breakthrough device designation from the U.S. Food and Drug Administration (FDA).
Authors: Additional authors from UCSF for the Nature Medicine paper include Patrick Benoit, MD, Noah Brazer, Mikael de Lorenzi-Tognon, MD, PhD, Emily Kelly, MD, MS, Venice Servellita, MS, Miriam Oseguera, Jenny Nguyen, MD, MA, Jack Tang, MHS, Charles Omura, Jessica Streithorst, PhD, Melissa Hillberg, Danielle Ingebrigtsen, MHS, Kelsey Zorn, MHS, and Michael R. Wilson, MD. For all authors, see the paper.
For the Nature Communications paper, additional contributing authors from UCSF include Jessica Karielle Tan, PhD, Venice Servellita, MS, Doug Stryke, Emily Kelly, MD, MS, Jessica Streithorst, PhD, Nanami Sumimoto, Abiodun Foresythe, Hee Jae Huh, Jenny Nguyen MD, MA, Miriam Oseguera, Noah Brazer, Jack Tang, MHS, Danielle Ingebrigtsen, MHS, Becky Fung, Helen Reyes, Melissa Hillberg, Peter M. Mourani, Charles R. Langelier, MD, PhD, Mikael de Lorenzi-Tognon, MD, PhD, and Patrick Benoit, MD. For all authors, see the paper.
Funding: The support for the Nature Medicine paper was partly provided by a BARDA EZ-BAA award 75A50122C00022, US CDC grants 75D30122C15360 and 75D30121C12641 and the Chan Zuckerberg Biohub San Francisco.
Funding for the Nature Communications paper was also partially funded by a BARDA EZ-BAA 494 award 75A50122C00022, US CDC grants 75D30122C15360 and 75D30121C12641, Abbott Laboratories, and the Chan Zuckerberg Biohub San Francisco.
Disclosures: Chiu is a founder of Delve Bio and participates on its scientific advisory board, along with those of Flightpath Biosciences, Biomeme, Mammoth Biosciences, BiomeSense, and Poppy Health. He also holds a US patent (509 11380421) for “Pathogen detection using next generation sequencing.” Wilson is a co-founder and serves on the scientific advisory board and board of directors for Delve Bio.
