CST Researchers Take on Coronavirus

CST Researchers Take on Coronavirus

BY BRUCE E. BEANS AND GREG FORNIA

From computational analyses that indicate the novel coronavirus

is genomically stable, to recruiting idle home computers to aid researchers, to creating predictive epidemiological models, College of Science and Technology faculty are actively engaged in the worldwide effort to beat back the pandemic.

PHOTO: RYAN S. BRANDENBERG

TRACKING A GENOME’S STABILITY

SARS-CoV-2, the virus that causes COVID-19, appears to be very stable in terms of its genomic, or complete DNA, makeup.

“At least at the moment, the SARS-CoV-2 virus is very homogenous and stable globally as it passes through the human population,” said Sergei Pond, professor of evolutionary genomics and a researcher with Temple University’s Institute for Genomics and Evolutionary Medicine.

Pond, who is also a member of the Department of Biology, bases that conclusion partly on data gathered by the Global Initiative on Sharing All Influenza Data (GISAID), a German-based, public-private partnership that, as of Aug. 24, had nearly 85,000 SARS-CoV-2 genome sequences available to researchers.

Pond’s big-data analysis of the GISAID genome database indicates that, even though each virus genome contains approximately 30,000 different positions, any two randomly selected individual genomes have only eight to 10 different positions—an extremely small number—that indicate evidence of mutations.

In addition, the top two positions that indicated such potential for change in late August were also the top two in late March. The third was discovered in April, and the fourth and fifth in early summer.

“Given that most mutations have no effect and often aren’t transmitted, this should make it relatively easier to create an effective vaccine,” said Pond. “That’s great news because the vaccines being trialed now (in late summer) are likely to be able to stimulate the correct immune response because they were designed based on genomic information that was available in March and April.

“If there had been a lot of change since then, we might have to worry that those early vaccine designs, as well as potential treatments and diagnostics, might not be as effective. But that’s not the case.”

Further underscoring the virus’ apparent stability, Pond is also the co-author—with four UK collaborators—of a related study that is awaiting peer review. They concluded that the SARS-CoV-2 virus underwent most of its adaptive evolutionary steps in bats, not humans. “Bats seem to have had the novel coronavirus for thousands, if not millions, of years, which allows time for lots of evolution,” says Pond. “As a result, our hypothesis is that it didn’t have to do much to spread to humans and result in immediate human-to-human transmission.”

Since 2007, Pond has contributed to the ongoing development of the Galaxy Project. Partially funded by the National Science Foundation, the open, web-based platform for computational biological research is a joint project of Pennsylvania State University, Johns Hopkins University and the Oregon Health & Science University.

Using the Galaxy Project’s powerful software tools, Pond says he and his research collaborators will be watching for any changes in the virus during the next six to 12 months that could indicate it is evolving in a clinically significant way. “We will continue to look for any evidence that, in the wake of defensive responses by the human body, the virus is adapting or changing,” said Pond, who this fall has revised his genomics in medicine class to focus on COVID-19 phenomena.

PHOTO: RYAN S. BRANDENBERG

COVID-19 Assistance Team

BY GREG FORNIA

The Temple University COVID-19 Assistance Team—a task force of faculty, students and staff from across the university—supported Temple University Hospital (TUH) medical personnel on the front lines of COVID-19 care during the winter and spring of 2020. The wide-ranging effort included designing and fabricating stronger materials to hold N95 masks in place to 3-D printed ventilator manifolds that enable a single unit to support two patients.

Tonia Hsieh, associate professor of biology, led a face shield design and production. To date, more than 15,000 were produced and distributed to TUH medical staff. A small number of shields were also sent to Temple’s Maurice H. Kornberg School of Dentistry.

“The team developed a novel CNC milling and molding method,” explains Hsieh, using the abbreviation for computer numerical control. “That has the potential to increase production speed from about two hours to produce one face shield holder through 3D printing, towards the goal of making approximately 100 shield holders every 15 minutes.”

The face shield team included, among many others: William Wohl, a TUH transplant coordinator who organized prototype testing; Andrew Wit, assistant professor in the Tyler School of Art and Architecture; Timothy Rusterholz, TYL ’11, an assistant professor of instruction at Tyler; David Ross, manager of the Charles Library makerspace; and Kyle Schwab, ENG ’19, currently a master’s student in biomedical engineering.

For Hsieh, she is amazed by the talent and creativity present on the COVID-19 task force. “The staff and faculty on this effort made major sacrifices in all aspects of their lives to push this forward at the rapid pace necessary to combat the ferocity of this virus,” she says. “Temple students are impressive, but the students on this endeavor have a dedication that far exceeds anything I ever could have imagined. It’s a humbling and inspiring experience.”

CREATING PREDICTIVE EPIDEMIOLOGICAL MODELS

Rob Kulathinal, an associate professor of biology who spent the past academic year on sabbatical at the College de France in Paris, unexpectedly found himself during COVID-19 confinement helping to develop new epidemiological models that can predict the spread and control of the disease.

As part of a team of mathematical biologists, Kulathinal helped to generate a new random variable model that “includes direct population-based clinical features taken from the recent literature, including SARS-CoV-2 incubation period and generation time, as well as the fraction of asymptomatics in a population and duration times between infection, symptom establishment, hospitalization, recovery and death,” explains Kulathinal. “From our simulations we have also been able to infer the effective days of confining a population and the effects of such lockdowns on deaths.”

The model, which has been submitted for peerreviewed publication, suggests several strategies to guide both local and global policies—including monitoring, surveillance and population controls—in reducing the spread of this deadly virus.

In addition, since April Kulathinal has been part of an international scientific group based in Paris that has been translating and summarizing the gist of thousands of COVID-19 research papers to present to the public via the website, adioscorona.org. The goal: to help non-scientists navigate through what Kulathinal calls the “increasing tide of new COVID-19 papers” in order to inform them about safe practices for the general public and to help guide household, workplace and governmental policy. Kulathinal oversees the translation of French. “Translating the conclusions gleaned from scientific studies has been an interesting lesson in how different cultures integrate science and society and how it is ultimately communicated,” he says.

PHOTO: RYAN S. BRANDENBERG

TAPPING THE POWER OF IDLE COMPUTING POWER

Besides doing their part to stop the virus’s spread through social distancing and other measures, citizens are also helping develop new therapeutics by running simulations on their computers. Performing specific calculations by coordinating and distributing the work across thousands of separate computers is called distributed computing.

Along with graduate students in his lab, Associate Professor of Chemistry Vincent Voelz has been working with an international team of researchers to computationally screen potential inhibitors of the coronavirus’s main protease, an attractive target for new antiviral drugs. And they’re using the distributed computing network Folding@home to do it. Folding refers to the processes by which a protein structure assumes its shape so that it can perform its biological functions.

“Our group uses the tools of molecular simulation and statistical mechanics to investigate the structure and function of biomolecules,” says Voelz, who has worked with Folding@home since 2007 while he was a postdoc at Stanford University, where the distributed computing network started. “It’s a quick jump from that work to using our expertise in biomolecular simulation to help fight COVID-19.”

For the coronavirus research, Voelz is partnering with researchers at Memorial SloanKettering Cancer Center and Diamond Light Source. An X-ray crystallography group in the U.K., Diamond Light Source has done groundbreaking work in solving more than a thousand different crystal structures of the coronavirus main protease and discovering several drug fragments that bind to sites on the protein.

“When the virus gets inside a cell, it co-opts the machinery of the cell to assemble more copies of itself and replicate,” explains Voelz. “If you can inhibit the protease, you can inhibit a necessary step in the virus’s lifecycle.”

The combined computing power of Folding@home’s thousands of users is being used to virtually screen a huge number of potential drug compounds. These simulations will help prioritize which molecules will be synthesized and analyzed by researchers aiming to rapidly develop new therapies against the coronavirus.

“We now know that there are many drug fragments that bind to specific places on the coronavirus’s protein structure,” says Voelz. “These are leads for further drug

development. The dynamical information that we get from the Folding@home simulations is really hard to measure experimentally in a lab.”

In early March, about 30,000 users had downloaded the Folding@home software and were active participants in the COVID-19 project. By June 1, that number had grown to 1.25 million. “Combined, we are now the largest supercomputer in the world,” says Voelz, who notes that the online gaming community is a big contributor. “We’ve broken the exaFLOP barrier, a measurement of operations per second that is the equivalent of ten times the compute power of the world’s fastest supercomputer.”

According to Voelz, the speed of the coronavirus’s spread around the world has inspired many researchers to remove “bottlenecks” in how scientific knowledge is developed, analyzed and shared.

“Scientific organizations are sharing information in an unprecedented way, and people around the world are banding together to solve a very difficult problem,” says Voelz. “Folding@home’s kind of citizen science or crowdsourced science can be very powerful. The more people get turned on to this idea, the more vitally important basic science we can do.”

Want to help find new drug therapies to fight COVID-19? Go to foldingathome.org to download the software.

Victoria Cantoral (BS ’17, Bio; ACHS ’19)

Tracking COVID-19 Clinical Trial Data

Victoria Cantoral is the clinical research coordinator for Temple University Hospital’s Department of Dermatology. In mid-March, when the pandemic shut down the dermatology studies, she responded to an urgent request from the Thoracic Medicine and Surgery Department.

“The moment I learned that Temple Hospital was in urgent need of clinical research coordinators to help coordinate the clinical trials, I jumped on the opportunity to give back to my ‘second home,’” says Cantoral. “They were so overwhelmed with COVID-19 clinical research studies that they needed help with individual patient data entry.”

Cantoral was involved in collecting extensive real-time data entry for a clinical drug trial. She recorded all the daily laboratory values, including metabolic chemistries and hematology panels, chest imaging impressions and adverse events of patients who had, at least initially, been on ventilators. The Temple patients were part of the randomized, double-blind phase 2/3 trial of sarilumab—a human monoclonal antibody against the interleukin-6 receptor that, according to previous studies, may help treat inflammation.

“Even though I wasn’t checking their temperature but was just entering data, I became so involved with these patients every day that I felt like I knew them,” says Cantoral. “When I saw some of my patients had been discharged, I rejoiced with them.”

However, on July 2, Sanofi and Regeneron Pharmaceuticals Inc., French- and U.S.-based pharmaceutical firms, stopped the Phase 3 trial. “The sarilumab trial was a phenomenal experience as a young pre-health professional,” says Cantoral, who completed CST’s Post Baccalaureate Program, Advanced Core in Health Sciences track, in 2019 and is now applying for admission next summer to medical school, including Temple’s Lewis Katz School of Medicine. “I had the opportunity to work with outstanding clinicians, experienced research coordinators and the most deserving population of patients at Temple Hospital.”

Cantoral recently signed on to coordinate another phase 3 COVID vaccine clinical trial at Temple Hospital. “I am beyond excited to take part in this unprecedented time of scientific advancements,” says Cantoral. “I know these experiences will pay off tremendously when I am training as a physician in the future.”