William & Mary’s undergraduate iGEM team won a Gold Medal and was nominated for a major award at the iGEM Giant Jamboree, the annual conference and award ceremony of the International Genetically Engineered Machine (iGEM) Foundation.
The William & Mary team joined some 6,000 participants from around the world in this year’s competition. The university has a history of iGEM achievement. A William & Mary team won the iGEM Grand Prize in 2015 and was first runner-up in 2017.
This year’s William & Mary iGEM project also drew considerable praise from the judges at the Giant Jamboree. One judge said, “I would like to recognize yours as one of the most challenging projects I saw this year.” A second judge weighed in, “I want to say this was a fantastic topic for a project and commend you all for trying to address this fundamental issue in the field.”
The leaders of the 2021 team are Avery Bradley ’23 and Beteel Abu-Ageel ’22, both biology majors, plus Bradley has a minor in CAMS — computational & applied mathematics & statistics. Both are iGEM veterans: it’s Bradley’s second competition and Abu-Ageel’s third.
“It’s an opportunity for a group of undergraduates to design their own research project and present that project to others from all over the world.” Bradley said. “As the field of synthetic biology really grew from iGEM, it’s amazing to think that I, as an undergraduate, could be part of this process and be at the forefront of a new field.”
The competition has been dubbed the World Cup of Science. Teams spend months brainstorming project ideas, researching and creating their project, which typically involves construction of complex genetic circuits along with extensive mathematical modeling. Circuits are created using a set of genetic parts — each of which is a sequence of DNA that encodes for RNA or proteins with specific functions.
“A genetic circuit is a construct made of DNA that can be used to engineer organisms and provide them with new functions,” Abu-Ageel said.
Synthetic biology is interdisciplinary by nature, and the 2021 William & Mary iGEM team reflects this. Other team members and their fields of concentration are Justin Berg ’24, undeclared major; Pinar Banu Caglayan ’23, neuroscience major, CAMS minor; KC David ’22, neuroscience major, CAMS minor; Matt Dennen ’22, biology major, CAMS minor, chemistry minor; Julia Drennan '24, biology and psychology major; Ubaid Kazianga ’23, physics major; Linda Ma ’22, applied mathematics and CAMS major; Alana Thomas ’24, biology major.
Faculty advisors included Margaret Saha, Chancellor Professor of Biology, who served as the lead PI of the team, and Mainak Patel, associate professor of mathematics who served as advisor for the mathematical modeling aspects of the project.
The 10-member William & Mary team spent countless hours and the better part of a year on their project, titled “Orthogonality.” In the context of synthetic biology, orthogonality is a term used to describe a genetic circuit that has no unintended interactions among its individual parts and with its host cell. Orthogonality is a guiding principle of synthetic biology. The team leaders note that without a proper understanding of these unintended interactions, one cannot ensure the safety of implementing a circuit in the real world.
“Many synthetic biology applications involve introducing exogenous DNA into a host cell. Often, in some way, you're altering the organism’s genetic material,” Abu-Ageel explained. “Unintended interactions between genetic circuits and the host can potentially have negative effects, not only on the functionality or efficiency of circuits, but also on the functionality of the host itself, and therefore on the environment in which it was designed to be placed.”
Despite the importance of orthogonality to synthetic biology, Bradley and Abu-Ageel say the concept is underassessed in scientific literature. The result is that genetic circuits are often assumed to be orthogonal without being tested. One goal of the W&M iGEM project this year, they explained, is to raise awareness about the lack of circuit-host orthogonality assessment within the field of synthetic biology. A second goal was to engineer a new, widely accessible way for synthetic biologists to quantify circuit-host orthogonality.
“Some of the current ways being used to measure orthogonality, such as RNA-sequencing, are very expensive, preventing most researchers from assessing the orthogonality of their circuits,” Bradley said.
She explained that their team designed a system of “sensor” circuits that can measure the orthogonality of circuits at a lower cost than existing assessment methods. These “sensor” circuits are able to quantify various aspects of a circuit’s orthogonality with the host, such as consumption of host resources and production of orthogonality markers. The measurements taken by these sensors can then be input into two mathematical models, which produce an orthogonality assessment for a particular circuit.
“To assess orthogonality using our project, iGEM teams and synthetic biologists can introduce one of our sensor circuits into a bacterial population. Our sensor circuit will then produce a fluorescence output which can be quantified using an instrument known as a plate reader,” Bradley said. “They can then take another bacterial population, and introduce our sensor circuit along with an additional ‘test’ circuit, whose orthogonality is being measured.”
She went on to explain that comparison of the fluorescence levels produced by the two populations can determine the impact of the test circuit on host functionality.
“These fluorescence outputs can then be converted into the number of fluorescent molecules being produced and plugged into two models designed by our team to produce an orthogonality assessment for that test circuit,” she said.
The team presented their project to a panel of judges at the iGEM Giant Jamboree. Their work on orthogonality was well received. It was one of four undergraduate projects nominated for one of iGEM’s Track Awards: Best Foundational Advance Project.
“Foundational Advance projects strive to improve the field itself by addressing technical problems, rather than addressing real world problems directly,” Abu-Ageel explained. “However, orthogonality assessment is critical to the implementation of all other synthetic biology applications, especially those that are addressing real-world problems directly.”
The two veteran iGEMers had high praise for their team, which put an immense number of hours into their project.
“Everyone was really passionate about the field of synthetic biology, especially when we were brainstorming what to do for our project,” Bradley said. “With the range of synthetic biology applications being so vast, it was difficult for our team to decide on just one project idea. Everybody came in with ideas and we were able to build off of each other, creating this year’s project.”
Saha, who has advised the William & Mary iGEM team from its first iGEM competition in 2014, concurred.
“I was so pleased that the team was willing to tackle an extremely challenging and difficult project, one that required developing multidisciplinary expertise,” she said. “The team did a fantastic job with the project, and this was recognized by our nomination in the Foundational Advance track. I am so impressed with the team and their accomplishments.”