W&M iGEM engineers possible COVID-19 therapeutic using mathematical models
As the race for a COVID-19 vaccine presses on throughout the globe, a team of budding synthetic biologists at William & Mary are researching another equally critical tool in the fight against the novel coronavirus – therapeutics.
“It’s clear that a vaccine is absolutely essential for us to return back to anything resembling normal, but vaccines are not 100% effective and distribution to the world’s population will likely take time,” said Margaret Saha, Chancellor Professor of Biology. “As advised by health professionals, it is essential that research on therapeutics continues in parallel, because even if we have a vaccine, we're not likely going to see the disappearance of SARS-CoV-2 any time soon.”
SARS-CoV-2 is the virus that causes the disease known as COVID-19, and Saha is the faculty advisor to William & Mary’s iGEM team. The acronym stands for International Genetically Engineered Machine. The group of undergraduates is preparing to compete in the world’s largest synthetic biology competition for the seventh year in a row. Saha has served as the iGEM faculty advisor for all seven years.
The team consists of ten students from a variety of different majors: Beteel Abu-ageel ’22, Avery Bradley ’23, Matt Dennen ’22, Riya Garg ’23, Min Guo ’23, Josh Hughes ’22, Adam Oliver ’21, Julia Urban ’20, Wei Wang ’22 and Hantao Yu ’23.
{{youtube:medium:center|4-iBGKR3wzg,Video created by the W&M iGEM team to promote their research project}}
“This year, our project seems more relevant than ever,” said Dennen. “We are working to solve a problem that has forced its way to the front of everyone's mind for most of the past year. For this reason, it is obvious that our work can have an important impact, and the stakes are much higher.”
Given that the team did not have access to the lab this iGEM season, they decided to use this situation to their advantage and make lemonade from lemons. They chose to pursue a challenging two-part project that entailed: 1.) the design of a novel type of therapeutic – a probiotic that uses lipids as bioactive molecules that can possibly treat a variety of RNA viral infections, including COVID-19, and 2.) the development of a complex mathematical model to test the feasibility of the design.
While many approaches to antiviral therapeutics focus on inhibiting key proteins in the viral infection cycle, there is growing interest in the role of lipids. This year, W&M iGEM is focused on lipids. The organic compounds comprise fatty acids or their derivatives that are involved in the body’s energy storage, membrane structure and chemical signaling – and, as recent research is showing, the response of the innate immune system to pathogens. Lipids are important in modulating the body’s initial immune response to SARS-CoV-2, Saha explained.
One of the prominent aspects of COVID-19 infections in many individuals is the presence of a cytokine storm. This is when the body produces an excessive amount of pro-inflammatory cytokines that often lead to widespread tissue damage and increased mortality. It is essential to develop therapeutics that are able to modulate an excessive pro-inflammatory response, but not completely suppress the response, since it is required to clear the viral infection, Saha explained. Using the power of synthetic biology, developing a “smart drug” would be potentially very useful.
“The lipid-based therapeutic is called a ‘smart probiotic,’” Saha said. “It's smart, because it responds to the physiology of the environment in which it finds itself.”
In simple terms, the team’s project is to design and computationally evaluate a living drug, explained Urban, who is in her third year on the team and serving her second year as co-captain. The team has designed the probiotic to monitor and respond to inflammation and immune response in a way that modern drugs, including Remdesivir and Dexamethasone, are not capable of doing.
“Living materials can regenerate and self-heal; they can respond to their environment in a way that non-living materials cannot,” Urban said.
When it comes to drug development, a medication that could interact and respond to the needs of the patient on a cellular level would be an important advancement, she explained.
Abu-ageel, also a co-captain on the team, explained further.
"Our project this year explores the future of therapeutics. We have designed a probiotic that can sense the amount of inflammation in the nasal cavity and respond by producing antiviral fatty acids," she said. “This concept of 'sense and respond' therapeutics could be transformative for the medical field. Rather than relying on medications that are unable to differentiate between different conditions that patients may have, which often makes them less effective, we need to move into the age of personalized medicine.”
The W&M project will be judged against other projects from major research institutions throughout the world at the iGEM Giant Jamboree in a virtual conference from Nov. 14-22. The winner will take home what’s been called the “World Cup of Science.”
It’s a championship title the university has claimed before. A William & Mary team won the iGEM Grand Prize in 2015, and was first runner-up in 2017. The competition requires students to be engineers, chemists, biologists, mathematicians and computer scientists all at once. It’s how science is done in the 21st century — team-based, multidisciplinary, quantitative and focused on finding solutions to difficult problems.
To be sure, this year’s team is in no position to go out and start doing clinical trials. In fact, the team will not begin constructing the probiotic in the lab, and will instead focus on mathematical modeling. The first stage of any engineering project is to design the construct and then perform the extensive mathematical modeling to show that it’s achievable, Saha explained.
“The bottom line of our project is to design this system using a variety of modular genetic parts and to show that at least the design is feasible,” Saha said. “We use a complex mathematical model to predict our outcomes and show if and how this drug would actually work in vivo.”
She also remarked that modeling work would not have been possible without the continual collaboration of Mainak Patel, assistant professor of mathematics, and a co-advisor to the team. His insight and expertise have been invaluable, she said.
Changing course
In January, the team had just selected its final roster of 10 students. All of the students were living on campus and had been brainstorming a wide range of lab-based projects. Then came COVID-19.
“We were watching what was happening throughout the world,” Saha said. “We have three students on our team who are from China, so they were even more aware of how serious this was. We are a cohesive team and we were worried for them and their families. By late February, early March, the writing was on the wall that things were not going to be normal anymore.”
Following spring break, when the university made the decision to pivot to remote teaching, the iGEM team was forced to scrap all of their work and start from scratch on a new project. This meant a complete restructuring of roles as well, Urban explained.
In past years, William & Mary’s iGEM team contained a group primarily focused on wetlab work, and another group primarily focused on the in silico mathematically modeling necessary to inform the wetlab. In the absence of a wetlab project, the team has become more interdisciplinary than ever, with all members contributing to genetic part design as well as computational analysis.
“Usually, I oversee wetlab progress, which includes constructing and characterizing genetic parts in our lab,” Urban said. “I train the new members in wetlab procedures, which has been one of my favorite things about iGEM. The closure of our lab eliminated those opportunities, so my responsibility shifted to leading the team in remote work, which includes lots of mathematical modeling and Zoom meetings.”
The team has been working entirely remotely since March, meeting virtually as often as 15 times per week. The change in format, from lab-based to design- and model-based work, had allowed for multiple subgroups to develop, Saha said.
One subgroup is attempting to develop an algorithm using machine learning techniques to predict likely virus sequences that have the probability of spillover or host-jumping to humans.
“That is going to be applicable, hopefully, to a number of different possible pandemics that may develop,” Hughes said. “It is a resource for investigators in the field, who determine if there is going to be a recombination event among two viruses that enable that virus to jump species. Our team is looking at trying to develop an algorithm that will predict that.”
Another subgroup has been regularly contributing to an outreach project called "Modeling for the Masses," explaining COVID-19 epidemiological models to people of all backgrounds who may be confused by the often conflicting information presented and what it means for them.
“I hope that the judges are able to see the effort that all members of our team have put into this work,” said Bradley. “While I certainly hope that we perform well in the competition, I have learned so much through this process that I will feel like I will have won no matter what the judges decide.”
