Piecing Together the Next Pandemic

Kovid-19 arrived in Cambodia a year ago on 23 January, when a Chinese citizen flew in from Wuhan, the city in which the disease was first detected, and soon became ill with fever. A PCR test to detect the genetic material of SARS-CoV-2, coronovirus that causes covid-19, came back positive. With that news, the disease had officially pierced the borders of another nation.

For Cambodia, a developing country with an underdeveloped health care system and several direct flights from Wuhan, the new disease was particularly high risk.

Public health researcher with the National Institute of Allergy and Infectious Diseases, Drs. Jessica Manning, who had been working in Cambodia for years, also saw an opportunity: helping the country become involved in a global effort to see new diseases.

Dr. Manning took nasal and oral samples from the patient through a genetic sequencer, a device that reads the letters that make up an organism’s genome; The sequencer was recently in Phnom Penh in addition to its laboratory in the Parasitology Department of the Cambodian Government. Dr. “I couldn’t wait for the scenes coming from the sequencer,” Manning said. “It was sheer excitement.”

Sequencer uploaded the raw data into an online software package called IDSec, which could tie together genomes in samples and compare them to other known organisms. This system, Dr. Manning’s group verified without any indication what might have happened in the sample, that it is a virus with a genome, similar to the new coronovirus identified in Wuhan. There are differences between only two sequences out of about 30,000 characters in the virus’s genome.

In those early days of Kovid-19, researchers did not know how accurate PCR tests were or whether the virus was potentially generating new strains with different properties. The Cambodian report helped confirm the accuracy of the PCR test, and it was discovered that only minor changes were visible in the sequences. The virus was not mutated enough – a sign that the disease would be easier to test, treat, and vaccinate.

Dr. For Manning, the exercise was evidence that even a small research outpost in developing countries could successfully detect new or unexpected pathogens and important information about them from their genome. As such, his laboratory and others like him can serve as an early warning system for the next possible pandemic.

40 year old Dr. Manning did not start his career investigating new diseases, but he knows that most suffer from the developing world.

In 2008, earning his medical degree at Emory University, he went to Mali to study and treat malaria as part of a project at Bamako University. “I lived in the bush for six months to collect samples,” she said. “Severe malaria cases come at night, which nobody told me. I didn’t really get a full night of sleep for months. It was terrible, because many children died within 10 seconds of walking in the door.

She recalled for the first time that she had given a new malaria drug called artesunate, in a young, seriously ill patient. “Manning said,” she was almost dead, and then two days later she recovered and recovered. “It was like Lazarus.” Dr. Manning keeps a picture of himself with the patient, a girl named Fatoumata, in his office.

He liked how Kama researched and treated patients. “It brings this whole new dimension when you’re at the bedside and the bench,” she said, mean lab. “Working like this kills all your senses. It is heavy. But this is where we should work. “

After advancing public health projects in Haiti, Malawi and Rwanda, Drs. Manning received a master’s degree in epidemiology in 2014 and then held a position as a physician researcher at the National Institute of Allergy and Infectious Diseases, Drs. Agency headed by Anthony S. Fauci

At the institute, he tried to figure out how to develop a universal mosquito vaccine, which would protect people from many diseases caused by mosquitoes. This vaccine will work by creating an immune response in the mosquito’s saliva, preventing any mosquito pathogens from infecting the bitten person. Dr. Manning began a survey in Cambodia to study how immune markers in humans are altered by exposure to mosquito saliva and the diseases it causes. So far, the project has replaced five molecules that may be helpful in developing a vaccine against mosquito saliva.

The survey also revealed that many diseases in Cambodia remained mysterious. “Diagnostics are harder, and some insects are more difficult to diagnose than others,” Dr. Manning said. “We focus on big people like malaria. We use malaria as a waste diagnosis if a patient is very feverish. “When doctors don’t know what’s wrong,” he said, they often treat patients with grab bags of antibiotics and antimalarial drugs.

In 2018, Drs. Manning learned about a Global Grand Challenge from the Bill & Melinda Gates Foundation, which gave researchers a grant to use genomics to find out more about infectious disease in developing countries. Dr. Manning saw it as a way to “find out what’s happening in this black box of Cambodia” – to find out what pathogens caused many of his unexplained diseases.

In 2019, Dr. Manning won one of the grants and soon flew with three colleagues to Zuckerberg Biohub, a research center in San Francisco, where he learned how to use tools that could help open the black box.

To identify unknown pathogens, Drs. Manning’s project employs an approach called metagonomic sequencing. More traditional techniques of genomic diagnosis, such as commonly used PCR tests to detect coronoviruses, look for a specific genetic sequence of a single pathogen. Those tests are accurate, fast, and relatively cheap – but they can only find one pathogen that you already know you’re looking for.

Instead, metagonomic sequencing reads all of the genomic material in a sample and identifies all organisms present: accessory bacteria, common pathogens, pathogens that have never been seen before. Dr. “Metaganomics can show that we don’t know what we know,” Manning said. Said former US Secretary of Defense Donald H., Manning. A popular quote from Rumsfeld.

But identifying the truly unknown is complex. Common sequencing machines cut DNA and RNA molecules into small blocks, each containing dozens to hundreds of genetic building blocks, and read sequences of blocks in each. This creates billions of short sequences without any knowledge of how they were originally organized.

To make sense of all that data, Drs. Manning’s lab uses IDSec, a free online, open-source software package that reverse-engineers how all short segments can fit together to form any number of genomes, and to identify known genomes. Let’s compare these with Public Database.

“It’s like a giant puzzle,” said Joseph Derici, a biochemist at the University of California, San Francisco, and IDSec’s lead developer. “Where the edges of the pieces match, you can snap them together and assemble a picture of the genome.” This analysis is computationally demanding, relying on hundreds or thousands of powerful processors. But IDseq runs on servers in the cloud, allowing researchers in developing countries to analyze remotely at any cost.

After receiving his training in metagonomics, Drs. Manning and his colleagues returned to Cambodia and set up an sequencing project at a hospital in the city of Chabar Mon. Now, when patients with unexplained fever come to the hospital, workers take blood samples and they are referred to Dr. Ph.D. in the Department of Parasitology of the Cambodia Government in Phnom Penh. Manning’s lab, where researchers try to find out what the patient is? .

Such a patient appeared in May. 13-year-old Phoon Falla was sick for eight months with fever, pain and chills and no one was sure what went wrong with him.

After Fella’s parents agreed to let her participate in the metagonomic study, medical staff drew her blood and transported it from the car to the lab in Phnom Penh. Technicians there took samples through the sequencer and uploaded the data to IDSec.

The scan revealed that the fella was taking a form of malaria that could lapse into a patient’s liver and then flow into the bloodstream, causing fever, fatigue, and headache. Standard antimalarial drugs are of limited use; The parasite retracts from the liver, only to flare up again after weeks or months.

With a firm diagnosis in hand, the hospital prescribed primaquine, one of the few drugs that could kill the malarial parasites lurking in the liver. Fela soon recovered again, cooking and playing with her young relatives. “People here feel that she has been taken care of,” her mother said. “I’m so relieved that she’s getting better.”

Watching for novel pathogens in Southeast Asia has recently become an important part of a global effort to understand the Kovid-19 epidemic and prevent the next one before it occurs. In late January, a group of researchers, at the Pasteur Institute in Cambodia, Announced that it used metagenomic sequencing In 2010 to find a coronavirus belonging to SARS-CoV-2 in a bat caught in Cambodia. This finding suggests that Southeast Asia represents an important area to consider in the ongoing search for the origin of SARS-CoV-2, and for future monitoring of coronavir, ”the researchers wrote.

“This is what we were looking for, and we found it,” Dr. Visna Duong, study leader, Told nature in November. “It was exciting and surprising at the same time.”

That discovery has attracted the attention of researchers who want to better understand how and when viruses cross between species.

Dr. Duong is particularly looking at places where people come in close proximity with fruit bats. “Such exposure may allow the virus to mutate, which may cause an epidemic,” He told the BBC last month.

Dr. Manning plans to work with Cambodia’s Communicable Diseases Center to begin monitoring animals in two local wet markets, where pathogens can jump to humans. And his group recently expanded its fever-monitoring project to two Timing hospitals in Phnom Penh, aiming to give early warning about the spread of new and unknown diseases.

A small Cambodian lab alone is unlikely to catch the next possible pandemic, but it has given Dr. Has provided a strong proof of concept for Manning’s approach.

“Cambodia-based project has really shown the value of metagonomic sequencing,” Dr. Farhad Imam, a genomics expert and a program officer of the Gates Foundation who received Dr. Helped to choose Manning’s proposal.

“You can set up an early detection network for the next outbreak,” he said. “The faster we know what it is, the faster we can build tools to defeat it.”

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