Monday, February 15, 2021

NIH grant funds Emory work on indoor air sensor for SARS-CoV-2

"We hope our project will yield an important air-monitoring tool as we enter an era when pandemics will likely become more common," says Emory chemist Khalid Salaita, principal investigator of the NIH grant.

By Carol Clark

Emory University received a National Institutes of Health grant, for a total of $883,000 over two years, to develop a sensor capable of detecting SARS-CoV-2, the virus that causes COVID-19, in the air of indoor spaces. The grant is part of the NIH RADx Radical initiative, which aims to support new, non-traditional approaches for rapid detection devices that address current gaps in testing for the presence of SARS-CoV-2, as well as potential future pandemic viruses. 

“Our goal is to create a fully automated electronic sensor that continually measures for the presence of SARS-CoV-2 in the environment in real time,” says Khalid Salaita, principal investigator of the grant and an Emory professor of chemistry. “The sensor could be used in schools, airports or any high-traffic indoor areas.” 

The new sensor will potentially have the flexibility to be re-programmed to detect other dangerous strains of viruses that may emerge, he adds. “Even after we get the COVID-19 pandemic under control, the demand for viral sensing will remain,” Salaita says, noting that the new sensor will take at least two years to develop. 

Salaita, a leader in biophysics and nanotechnology, is also on the faculty of the Wallace H. Coulter Department of Biomedical Engineering, a joint program of Georgia Tech and Emory. 

Co-investigators of the grant include Gregory Melikian, a professor at Emory School of Medicine, in the Department of Pediatrics’ Division of Infectious Disease; and Yonggang Ke, assistant professor at Emory’s School of Medicine and the Wallace H. Coulter Department of Biomedical Engineering. 

The project will work to adapt the technology of a DNA micromotor, developed in 2015 by the Salaita Lab and further enhanced through collaboration with the Ke Lab. The Milikian Lab will generate harmless, engineered viral particles that mimic the real virus, and its potential mutants, to allow the team to test and validate the technology. 

Emory graduate Kevin Yehl (now on the faculty of Miami University) developed the micromotor with Salaita while he was a PhD student in the Salaita Lab. It is the first rolling DNA motor, and is capable of sensing, leading the researchers to dub it the “Rolosensor.” It won a bronze medal in the 2016 Collegiate Inventors Competition, the foremost program in the country encouraging invention and creativity in undergraduate and graduate students. 

Emory graduate Kevin Yehl, shown while he was a PhD student in the Salaita Lab demonstrating a prototype of the Rolosensor.

The Rolosensor, about the size of a human red blood cell, consists of hundreds of synthetic DNA strands, or “legs,” bound to a sphere. The DNA legs are placed on a glass slide coated with the reactant: RNA. The DNA legs are drawn to the RNA, but as soon as they set foot on it they destroy it through the activity of an enzyme called RNase H. As the legs bind and then release from the substrate, they guide the sphere along, allowing more of the DNA legs to keep binding and pulling. 

“When we first developed the motor it was initially out of pure curiosity,” Salaita says. “We wondered if we could convert chemical energy into mechanical work and make something move.” 

The researchers soon realized that anything that resists the motion of the rolling motor slows its speed. The speed of the motor can be monitored by attaching a clip-on microscope lens to the camera of a smart phone. They showed that the Rolosensor can detect a single DNA mutation by capturing videos of the particle motion to measure particle displacement. The team was awarded a patent in 2020 to use the simple, low-tech method for doing diagnostic sensing in the field, or anywhere with limited resources. 

Even during the few months early in the COVID-19 pandemic that his lab was temporarily shut down, Salaita began to think about how the Rolosensor might be adapted to detect SARS-CoV-2. 

He began discussing the idea with Melikian, a virologist who worked on HIV and other viruses but had also pivoted to take on the challenge of SARS-CoV-2. The Melikian Lab figured out a way to make “pseudo” viral particles with spikey proteins that mimic those of SARS-CoV-2. 

“These pseudo viruses, which are harmless and do not replicate, will provide a way for us to test and optimize the assay as we try to adapt our rolling motor to detect SARS-CoV-2,” Salaita explains. 

Graphic by the Salaita Lab demonstrates the plan for how the DNA motor will work to detect SARS-CoV-2.

The plan calls for the Ke Lab to help make the body of the rolling motor “sticky” to the SARS-CoV-2 viruses, but not to any other virus or material, by using DNA structures that function like Velcro. The Rolosensor will be embedded into a microchip, where it will roll across the surface unless it encounters viral particles that cause it to stick. A camera will continuously record the speed of the motors. If a motor stalls, it will trigger an electronic alarm signal at a central monitoring station. 

“Imagine an unobtrusive, encased device, similar to a smoke detector, that continuously samples the air,” Salaita says. “A central server on a cloud could collect data from numerous devices, in an airport, for example, and send out an alert for a SARS-CoV-2 detection event, including the GPS coordinates, whenever a motor stopped.” 

An additional key collaborator is Primordia Biosystems, Inc., a company that specializes in building microfluidic chips that can sample virus-containing aerosols in the air. 

The motors can run for up to 24 hours, allowing for fully automatic viral sensing, without the need for sample processing or other human intervention. 

Three Emory PhD chemistry students in the Salaita Lab have collected preliminary data and will conduct the experiments and tests needed to complete the project: Alisina Bazrafshan, Selma Piranej and Yuxin Duan. 

Many hurdles remain to develop a prototype for an indoor air sensor for SARS-CoV-2, Salaita says, including concerns such as sensitivity of the device and whether it would generate false positives. The longer-range goal is to adapt the rolling motor device so that it could be programmed to effectively detect high levels of any virus of concern in an indoor air space. 

“One thing is for certain, there is a need for viral-detecting devices for public indoor air spaces and many researchers are working to try to meet this challenge,” Salaita says. “We hope our project will yield another important air-monitoring tool as we enter an era when pandemics will likely become more common.”


Wednesday, February 3, 2021

Physics of snakeskin sheds light on sidewinding

The sidewinder rattlesnake (Crotalus cerastes) is found in the deserts of the Southwestern United States and northern Mexico. (Photo by Wolfgang Wuster)

Most snakes get from A to B by bending their bodies into S-shapes and slithering forward headfirst. A few species, however — found in the deserts of North America, Africa and the Middle East — have an odder way of getting around. Known as “sidewinders,” these snakes lead with their mid-sections instead of their heads, slinking sideways across loose sand. 

Scientists took a microscopic look at the skin of sidewinders to see if it plays a role in their unique method of movement. They discovered that sidewinders’ bellies are studded with tiny pits and have few, if any, of the tiny spikes found on the bellies of other snakes. The Proceedings of the National Academy of Sciences (PNAS) published the discovery, which includes a mathematical model linking these distinct structures to function. 

“The specialized locomotion of sidewinders evolved independently in different species in different parts of the world, suggesting that sidewinding is a good solution to a problem,” says Jennifer Rieser, assistant professor of physics at Emory University and a first author of the study. “Understanding how and why this example of convergent evolution works may allow us to adapt it for our own needs, such as building robots that can move in challenging environments.”

Thursday, January 28, 2021

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.


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

Tuesday, January 26, 2021

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.


Tuesday, January 12, 2021

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.”