Covid-19 arrived in Cambodia on January 23, a year ago, when a Chinese arrived from Wuhan, the city where the disease was first discovered, and soon became ill with fever. The PCR test to detect the genetic material of SARS-CoV-2, the coronavirus responsible for Covid-19, returned positive. In the news, the disease officially broke the borders of other countries.
For Cambodia, a developing country with a rudimentary health system and multiple direct flights from Wuhan, this new illness seemed to pose a particularly high risk.
Dr. Jessica Manning, a public health researcher at the National Institute of Allergy and Infectious Diseases, who has worked in Cambodia for many years, also saw the opportunity to help the country participate in global efforts to monitor new diseases. ..
Dr. Manning analyzed nose and mouth samples from patients via a genetic sequencer, a device that reads the letters that make up the organism’s genome. The sequencer was recently added to her laboratory in the Department of Parasitology of the Government of Cambodia in Phnom Penh. “I couldn’t wait for the sequence to come off the sequencer,” recalled Dr. Manning. “It was a totally dazzling excitement.”
The sequencer uploaded the raw data to an online software package called IDseq. IDseq can stitch the genomes in a sample and compare them to other known organisms. The system confirms that it carries a virus with a genome that is substantially identical to the new coronavirus identified in Wuhan, without hints from Dr. Manning’s group on what the sample contains. Did. Of the approximately 30,000 characters in the viral genome, only one character differed between the two sequences.
In the early days of Covid-19, researchers were unaware of how accurate the PCR tests were, or whether the virus was creating new strains with potentially different properties. The Cambodian report helped confirm the accuracy of the PCR test and revealed that only minor changes in the sequence were shown. The virus did not appear to be substantially mutated — showing that the disease would be easier to test, treat, and vaccinate.
For Dr. Manning, this exercise proved that even small research bases in developing countries could successfully detect new or unexpected pathogens and collect important information about them from the genome. As such, her lab and other labs could serve as an early warning system for the next potential pandemic.
Open black box
Dr. Manning, 40, began his career investigating known illnesses that primarily afflict developing countries, rather than new illnesses.
In 2008, while earning a medical degree from Emory University, she went to Mali to study and treat malaria as part of a project at the University of Bamako. “I lived in the bush for six months to collect samples,” she said. “Severe malaria cases occur at night, but no one told me. I really couldn’t sleep all night for months. Within 10 seconds of walking through the door, we evaluated It was horrifying, as many children die while they are. “
For the first time, she remembered giving a young and severely ill patient a new malaria drug called artesunate. “She was almost dead and after two days she was fine,” said Dr. Manning. “It was like Lazarus.” Dr. Manning puts his picture in the office with a patient, a girl named Fatumata.
She liked the work that combined research and patient care. “It brings this whole new dimension when you’re at the bedside and on the bench,” she said, meaning the laboratory. “Doing this kind of work attacks all your senses. It’s overwhelming, but that’s where we should work.”
Dr. Manning received a master’s degree in epidemiology in 2014 after carrying out public health projects in Haiti, Malawi and Rwanda, and assumed the position of doctoral researcher at the National Institute of Allergy and Infectious Diseases led by Dr. Anthony S. did. .Fauci.
In the lab, she sought to find a way to develop a universal mosquito vaccine that would protect people from the many mosquito-carrying diseases. Vaccines provoke an immune response to mosquito saliva and prevent mosquito-infected pathogens from infecting bitten people. Dr. Manning began a study in Cambodia to study how mosquito exposure to saliva and the diseases it carries alter human immune markers. So far, the project has discovered five molecules that may help develop vaccines against mosquito saliva.
The study also revealed that many illnesses remain a mystery in Cambodia. “Diagnosis is difficult, and some bugs are more difficult to diagnose than others,” said Dr. Manning. “We tend to focus on big things like malaria. If the patient has a very fever, use malaria as a trash can diagnosis.” When the doctor doesn’t know exactly what’s wrong , They often treat patients with grab bags of antibiotics and anti-malaria drugs.
In 2018, Dr. Manning learned about the Global Grand Challenge from the Bill & Melinda Gates Foundation. This allows researchers to use genomics to learn more about infectious diseases in developing countries. Dr. Manning saw it as a way to “elucidate what’s happening in this black box in Cambodia” — find out exactly which pathogen caused the many unexplained illnesses.
In 2019, Dr. Manning won one of the grants and immediately flew with three colleagues to the San Francisco research center Chan Zuckerberg Biohub. There, they learned how to use tools that help them pry open the black box.
“Like a giant jigsaw puzzle”
To identify unknown pathogens, Dr. Manning’s project employs an approach called metagenomic sequencing. More traditional techniques of genomic diagnosis, such as the PCR test commonly used to detect coronavirus, look for characteristic gene sequences of a single pathogen. These tests are accurate, fast, and relatively inexpensive, but they can only find pathogens that you already know you are looking for.
Instead, metagenomic sequencing reads all genomic material in the sample and identifies all living organisms: useful bacteria, common pathogens, and previously undiscovered microorganisms. “Metagenomics can show that we don’t know what we don’t know,” said Dr. Manning, paraphrasing a popular quote from former US Secretary of Defense Donald H. Rumsfeld. ..
However, in reality, identifying unknown unknowns is complicated. A typical sequencing machine divides DNA and RNA molecules into short segments, each with tens to hundreds of gene building blocks, and reads the sequence of each block. This produces billions of short sequences with no information about how they were initially placed.
Dr. Manning’s lab uses IDseq, a free online open source software package, to understand all the data. It reverse-engineers how all short segments are combined to form any number of genomes and compares them to known genomes. Public database.
“It’s like a giant jigsaw puzzle,” said Joseph DeRisi, a biochemist at the University of California, San Francisco and lead developer of IDseq. “Where the edges of the pieces meet, you can snap them together to assemble a picture of the genome.” This analysis is computationally intensive and relies on hundreds or thousands of powerful processors. .. However, IDseq runs on a server in the cloud, allowing researchers in developing countries to perform remote analysis for free.
After training in metagenomics, Dr. Manning and her colleagues returned to Cambodia to launch a sequence project at a hospital in the town of Chbar Mon. Currently, when a patient with an unexplained fever comes to the hospital, workers take a blood sample and send it to Dr. Manning’s laboratory in the Department of Parasitology, Cambodian Government in Phnom Penh. Researchers then perform metagenomic analysis to try to pinpoint what is sick in the patient. ..
Such a patient appeared in May. 13-year-old Phoun Phalla suffered from fever, pain and chills for eight months, but no one knew what was wrong with her.
After Fara’s parents agreed to participate in a metagenomic study, medical staff took her blood and drove it to a laboratory in Phnom Penh. The technician there passed her sample through a sequencer and uploaded the data to IDseq.
Scans showed that Fara was lurking in the patient’s liver, flooding the bloodstream and carrying malaria, which could cause fever, malaise, and headaches. The use of standard antimalarial drugs is limited. The parasite retreats to the liver, but reignites after weeks or months.
With a definitive diagnosis, the hospital prescribed primaquine, one of the few drugs that can kill malaria parasites hidden in the liver. Fara quickly got well and cooked and played with her young relatives. “People here feel like she was taken care of,” her mother said. “I’m very relieved that she’s getting better.”
Early warning system
Monitoring of new pathogens in Southeast Asia has recently become an important part of global efforts to understand the Covid-19 pandemic and prevent the next pandemic before it occurs. In late January, a group of researchers, mostly at the Pasteur Institute in Cambodia, Announced the use of metagenomic sequences A coronavirus closely related to SARS-CoV-2 is discovered in bats caught in Cambodia in 2010. The findings suggest that Southeast Asia is an important area to consider in the ongoing investigation of the origin of SARS-CoV-2. Future surveillance of the coronavirus, the researchers write. ..
“This is what we were looking for, and we found it,” said research leader Dr. Veasna Duong. Speaking naturally In November. “It was exciting and surprising at the same time.”
The discovery has attracted attention from researchers who want a better understanding of when and how viruses cross between species.
Dr. Duong pays particular attention to where people approach fruit bats. “This type of exposure can mutate the virus and cause a pandemic.” He told the BBC last month..
Dr. Manning will work with the Infectious Diseases Center in Cambodia to begin monitoring animals at two local fresh markets where pathogens can infect humans using metagenomics. Her group recently expanded a fever monitoring project to two packed hospitals in Phnom Penh with the aim of early warning of the spread of a new undiagnosed illness.
It is unlikely that one small Cambodian lab will capture the next potential pandemic, but it provided a powerful proof of concept for Dr. Manning’s approach.
“The Cambodia-based project really demonstrates the value of metagenomic sequencing,” said Genomics expert and Gates Foundation Program Officer, who helped select Dr. Manning’s proposal to receive a grant. Dr. Farhad Imam said.
“In effect, you can set up an early detection network for the next outbreak,” he said. “The sooner we find out what it is, the faster we can build the tools to defeat it.”
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