Viral sequencing can reveal how SARS-CoV-2 spreads and evolves

The SARS-CoV-2 genome consists of a single RNA strand that is 30,000 letters long. Sequencing is a technique that provides a read-out of these letters.

By Carol Clark

The emergence of SARS-CoV-2 virus variants that are adding twists in the battle against COVID-19 highlight the need for better genomic monitoring of the virus, says Katia Koelle, associate professor of biology at Emory University. 

“Improved genomic surveillance of SARS-CoV-2 across states would really help us to better understand how the virus causing the pandemic is evolving and spreading in the United States,” Koelle says. “More federal funding is needed, along with centralized standards for sample collection and genetic sequencing. Researchers need access to such metadata to better track how the virus is spreading geographically, and to identify any new variants that may make it harder to control, so that health officials can respond more quickly and effectively.” 

Koelle studies the interplay between viral evolution and the epidemiological spread of viral infectious diseases. She is senior author of a “Viewpoint” article published in Science on the importance of SARS-CoV-2 sequencing to control the COVID-19 pandemic. 

Michael Martin, a PhD student in Emory’s Population, Biology and Ecology Program and a member of Koelle’s lab, is first author of the Science article. David VanInsberghe, a post-doctoral fellow in Koelle’s lab, is co-author. 

“Research into SARS-CoV-2 has been going at lightning speed,” Martin says. “This acceleration has provided us with one of the largest datasets ever so quickly assembled for a disease. We’ve learned a lot so far about how this virus spreads and adapts, but we still have many blind spots that need to be addressed.” 

The article summarizes key insights about SARS-CoV-2 that have already been gained by sequencing of its genome from individual patient samples. It also cites challenges that remain, including the collection and integration of metadata into genetic analyses and the need for the development of more efficient and scalable computational methods to apply to hundreds of thousands of genomes. 

A genome is an organism’s genetic material. Human genomes are made up of double-stranded DNA, coded in four different nucleotide base letters. A single human genome consists of more than 3 billion base pairs. In contrast, the genome of coronaviruses, including SARS-CoV-2, are made of RNA, which can have a simpler structure than DNA. The SARS-CoV-2 genome, for instance, consists of a single RNA strand that is only 30,000 letters long. Sequencing is a technique that provides a read-out of these letters. 

If the SARS-CoV-2 virus is found in a sample swabbed from someone’s nose or mouth, it confirms the likelihood that the person is carrying the virus, whether they have symptoms of COVID-19 or not. The virus in the sample can also be sequenced. 

“Sequencing the virus is like fingerprinting it,” Koelle explains. “And based on how close the fingerprints match between samples — that is, how close they are genetically — you can at times learn who is infecting whom. Analyzing sequences from samples taken from infected individuals in a given region over time can provide even more information.” 

Analyses of SARS-CoV-2 sequencing data have enabled researchers to estimate the timing of SARS-CoV-2 spillover into humans; identify some of the transmission routes in its global spread; determine infection rates and how they change within a region; and identify the emergence of some new variants of concern. 

Viral genomes can mutate during replication, changing letters as they spread to new people. Most of these random mutations will likely not affect the transmissibility or virulence of a virus — but a few may make it even more difficult to fight. Early evidence, for instance, suggests that a SARS-CoV-2 variant that recently emerged in the UK may be more easily transmitted and potentially more severe. A South African variant shows signs that it may reduce the efficacy of existing vaccines, while a variant first detected in Brazil also contains mutations that health officials worry may make the virus spread more quickly. 

“It can be difficult to identify which variants actually change how the virus replicates, spreads and causes disease because of confounding factors,” Martin explains. “If a variant spreads more quickly, for instance, you have to tease apart whether that was due to it becoming more transmissible or if someone who was infected with it attended a large gathering.” 

The better data researchers have, the faster they can solve such puzzles, he adds. 

Technological advances during recent years have made it more efficient and less costly to generate sequencing data. Barely a year after it emerged, more than 400,000 sequences of SARS-CoV-2 are now available in public databases, such as the GISAID platform which was launched in 2008 to share information among National Influenza Centers for the WHO Global Influenza Surveillance and Response System. 

“A large chunk of the public sequencing data for SARS-CoV-2 has come out of the UK,” Koelle notes. “That’s because the British government has an initiative to do high-density sampling of the SARS-CoV-2 genome.” 

The rich data set from the UK helped identify the emergence of the variant in Britain that is spreading rapidly. “There might be other variants of concern emerging in other places around the world besides the ones already identified, but we just don’t know because we don’t have as good of surveillance in those locations,” Koelle says. 

“While the United States has been slow in efforts to sequence SARS-CoV-2 from samples across the nation, there are several excellent viral sequencing efforts and phylogenetic analyses, primarily driven by academic researchers, that have helped to understand SARS-CoV-2 transmission more locally,” Koelle says. “We have the expertise in the U.S., but the effort is more piecemeal.” 

“We need a coordinated, nationally standardized program to do widespread sequencing of SARS-CoV-2 in the United States,” Martin says. “Much of the data collected now just has a state identifier but we need greater resolution while also protecting patient privacy. More county-level identifiers, for instance, would be one way to greatly improve the quality and the depth of the data.” 

Once the COVID-19 pandemic ebbs, it’s important to continue to build the national infrastructure and systems for infectious disease surveillance — including viral sequencing — and to keep it in place, both researchers stress. 

“There will be more infectious disease pandemics, and we need to be better prepared,” Martin says.

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Anonymous cell phone data can quantify behavioral changes for flu-like illnesses

Anonymous cell phone data can quantify behavioral changes for flu-like illnesses

 

A NASA satellite image of Iceland, superimposed with a heatmap of movement data of individuals during the 2009 H1N1 epidemic, drawn from cell phone metadata near the time they were diagnosed with a flu-like illness. (Graphic by Ymir Vigfusson, Rebecca Mitchell and Leon Danon).

By Carol Clark

Cell phone data that is routinely collected by telecommunications providers can reveal changes of behavior in people who are diagnosed with a flu-like illness, while also protecting their anonymity, a new study finds. The Proceedings of the National Academy of Sciences (PNAS) published the research, led by computer scientists at Emory University and based on data drawn from a 2009 outbreak of H1N1 flu in Iceland. 

“To our knowledge, our project is the first major, rigorous study to individually link passively-collected cell phone metadata with actual public health data,” says Ymir Vigfusson, assistant professor in Emory University’s Department of Computer Science and a first author of the study. “We’ve shown that it’s possible to do so without comprising privacy and that our method could potentially provide a useful tool to help monitor and control infectious disease outbreaks.” 

The researchers collaborated with a major cell phone service provider in Iceland, along with public health officials of the island nation. They analyzed data for more than 90,000 encrypted cell phone numbers, which represents about a quarter of Iceland’s population. They were permitted to link the encrypted cell phone metadata to 1,400 anonymous individuals who received a clinical diagnosis of a flu-like illness during the H1N1 outbreak. 

“The individual linkage is key,” Vigfusson says. “Many public-health applications for smartphone data have emerged during the COVID-19 pandemic but tend to be based around correlations. In contrast, we can definitively measure the differences in routine behavior between the diagnosed group and the rest of the population.” 

The results showed, on average, those who received a flu-like diagnosis changed their cell phone usage behavior a day before their diagnosis and the two-to-four days afterward: They made fewer calls, from fewer unique locations. On average, they also spent longer time than usual on the calls that they made on the day following their diagnosis. 

The study, which began long before the COVID-19 pandemic, took 10 years to complete. “We were going into new territory and we wanted to make sure we were doing good science, not just fast science,” Vigfusson says. “We worked hard and carefully to develop protocols to protect privacy and conducted rigorous analyses of the data.” 

Vignusson is an expert on data security and developing software and programming algorithms that work at scale. 

He shares first authorship of the study with two of his former students: Thorgeir Karlsson, a graduate student at Reykjavik University who spent a year at Emory working on the project, and Derek Onken, a Ph.D. student in the Computer Science department. Senior author Leon Danon — from the University of Bristol, and the Alan Turing Institute of the British Library — conceived of the study. 

While only about 40 percent of humanity has access to the Internet, cell phone ownership is ubiquitous, even in lower and middle-income countries, Vigfusson notes. And cell phone service providers routinely collect billing data that provide insights into the routine behaviors of a population, he adds.

“The COVID pandemic has raised awareness of the importance of monitoring and measuring the progression of an infectious disease outbreak, and how it is essentially a race against time,” Vigfusson says. “More people also realize that there will likely be more pandemics during our lifetimes. It is vital to have the right tools to give us the best possible information quickly about the state of an epidemic outbreak.” 

Privacy concerns are a major reason why cell phone data has not been linked to public health data in the past. For the PNAS paper, the researchers developed a painstaking protocol to minimize these concerns. 

The cell phone numbers were encrypted, and their owners were not identified by name, but by a unique numerical identifier not revealed to the researchers. These unique identifiers were used to link the cell phone data to de-identified health records. 

“We were able to maintain anonymity for individuals throughout the process,” Vigfusson says. “The cell phone provider did not learn about any individual’s health diagnosis and the health department did not learn about any individual’s phone behaviors.” 

The study encompassed 1.5 billion call record data points including calls made, the dates of the calls, the cell tower location where the calls originated and the duration of the calls. The researchers linked this data to clinical diagnoses of a flu-like illness made by a health providers in a central database. Laboratory confirmation of influenza was not required. 

The analyses of the data focused on 29 days surrounding each clinical diagnosis, and looked at changes in mobility, the number of calls made and the duration of the calls. They measured these same factors during the same time period for location-matched controls. 

“Even though individual cell phones generated only a few data points per day, we were able to see a pattern where the population was behaving differently near the time they were diagnosed with a flu-like illness,” Vigfusson says. 

While the findings are significant, they represent only a first step for the possible broader use of the method, Vigfusson adds. The current work was limited to the unique environment of Iceland: An island with only one port of entry and a fairly homogenous, affluent and small population. It was also limited to a single infectious disease, H1N1, and those who received a clinical diagnosis for a flu-like illness.

“Our work contributes to the discussion of what kinds of anonymous data lineages might be useful for public health monitoring purposes,” Vigfusson says. “We hope that others will build on our efforts and study whether our method can be adapted for use in other places and for other infectious diseases.” 

Co-authors include the late Gudrun Sigmundsdottoir, directorate of health for Iceland’s Center for Health Security and Communicable Disease Control; Congzhang Song (Cornell University); Atil Einarsson (Reykjavik university); Nishant Kishore (Harvard); Rebecca Mitchell (formerly with Emory’s Nell Hodgson Woodruff School of Nursing); and Ellen Brooks-Pollock (University of Bristol). 

The work was funded by the Icelandic Center for Research, Emory University, the National Science Foundation, the Leverhulme Trust, the Alan Turing Institute, the Medical Research Council and a hardware donation from NVIDIA Corporation.

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San Diego Zoo gorillas contract COVID, raising alarms for great apes in wild

A mountain gorilla mother and her baby in the wild in Rwanda. Great apes "are important not just to ecosystems but to giving us insights into understanding our own selves and our evolutionary past," says Emory disease ecologist Thomas Gillespie.

By Carol Clark

The news that some members of the gorilla troop at the San Diego Zoo have tested positive for the virus that causes COVID-19 ramps up the urgency for protecting great apes in the wild from exposure, warns Thomas Gillespie, an Emory disease ecologist. 

“This first known transmission to apes confirms what we strongly suspected — that one of our closest living relatives is susceptible to the novel coronavirus,” says Gillespie, an associate professor in Emory’s Department of Environmental Sciences and Rollins School of Public Health. “More than ever, it’s a race against time. If gorillas in the wild become infected it will be a much more dangerous scenario because we won’t have the ability to contain it.” 

In March, Gillespie co-authored a Nature commentary warning that non-human great apes are susceptible to human respiratory diseases and that COVID-19 could prove devastating to animals on the brink of extinction. 

The non-human great apes include chimpanzees, bonobos and gorillas, which live in equatorial Africa, and orangutans, which are native to the rainforests of Indonesia and Malaysia. The International Union for Conservation of Nature (IUCN) lists chimpanzees and bonobos as endangered species, while gorillas and orangutans are critically endangered. 

Even exposure to viruses that have mild effects in people, such as those causing the common cold, have been associated with mortality events in wild primates. 

The San Diego Zoo Safari Park reported that it conducted tests for the presence of the SARS-CoV-2, the coronavirus that causes COVID-19, after two of its gorillas began coughing. On January 11, the test results confirmed the presence of the virus in some of its gorillas, the zoo announced in a release, adding that it suspects that the virus was transmitted by an asymptomatic staff member, despite the strict prevention protocols in place. 

Great apes, in particular, are at risk from many human diseases due to our close relationship. Chimpanzees and bonobos are our nearest living relatives, sharing about 99 percent of human DNA, while gorillas are our next closest relatives, sharing 98 percent of our DNA. 

The great apes also share key sites within the ACE2 receptor protein with humans that allow SARS-CoV-2 to bind onto cells and infect them. 

Gillespie is a member of an IUCN task force focused on mitigating the impact of COVID on great apes and other primates. He is working with governments and organizations in Africa, including the Jane Goodall Institute, to provide scientifically-informed guidance on protecting wild apes during the pandemic as tourism, research and other activities that lead to human-ape overlap resume. The IUCN Save Our Species Program provided funding to support communities impacted by the loss of great ape tourism, to help prevent people from resorting to poaching animals or logging their habitats. Some of those funds are set to run out soon. 

Gillespie’s lab is also developing a spatially-explicit model to investigate key factors that may affect the spread of the virus among wild primates, so that governments and organizations can prioritize efforts to protect the animals. 

“What’s happened in San Diego has brought the pandemic risks for great apes back into the spotlight,” Gillespie says. “Great apes are our closest relatives and many of them are critically endangered, on the verge of extinction. We’ve gained a lot of insights into our own health and biology by studying these animals. They are important not just to ecosystems but to giving us insights into understanding our own selves and our evolutionary past.”

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Movers and shakers: New evidence for a unifying theory of granular physics

Understanding the dynamics of granular materials — such as sand flowing through an hourglass or salt pouring through a shaker — is a major unsolved problem in physics. A new paper describes a pattern for how record-sized events affect the dynamics of a shaken granular material as it moves from an excited to a relaxed state, adding to the evidence that a unifying theory underlies this behavior. 

The Proceedings of the National Academy of Sciences (PNAS) published the work by Stefan Boettcher, an Emory theoretical physicist, and Paula Gago, an expert in modeling the statistical mechanics of granular matter in the Department of Earth Science and Engineering at the Imperial College of London. 

“Our work marks another small step forward to describing the behavior of granular materials in a uniform way,” says Boettcher, professor and chair of Emory’s Department of Physics. “A complete understanding of granular materials could have a huge impact on a range of industries,” he adds. 

“To name just a few examples, it’s relevant to the compaction of granules into pellets to make pills, the processing of grains in agriculture and to predict behaviors of all kinds of geophysical matter involved in civil engineering.”

Read the full story.

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Chemists invent shape-shifting nanomaterial with biomedical potential

Electron micrographs give a detailed view of the new nanomaterial. Arrows indicate layers that form in the tubes, leading to the hypothesis that the sheets form tubes by scrolling in at the corners.

Chemists have developed a nanomaterial that they can trigger to shape shift — from flat sheets to tubes and back to sheets again — in a controllable fashion. The Journal of the American Chemical Society published a description of the nanomaterial, which was developed at Emory University and holds potential for a range of biomedical applications, from controlled-release drug delivery to tissue engineering. 

The nanomaterial, which in sheet form is 10,000 times thinner than the width of a human hair, is made of synthetic collagen. Naturally occurring collagen is the most abundant protein in humans, making the new material intrinsically biocompatible. 

“No one has previously made collagen with the shape-shifting properties of our nanomaterial,” says Vincent Conticello, senior author of the finding and Emory professor of biomolecular chemistry. “We can convert it from sheets to tubes and back simply by varying the pH, or acid concentration, in its environment.” 

The Emory Office of Technology Transfer has applied for a provisional patent for the nanomaterial.

Read the full story here.

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