MIT iGEM team uses new CRISPR protein to target cancer-causing RNA splicing errors

Students’ novel construct could be a therapeutic for small cell lung cancer

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Left, during RNA splicing, introns are removed. Right, in alternative splicing, some exons can be removed. In the image, one spliced transcript has exons 1, 2, and 4, and the other has exons 1, 3, and 4.
Courtesy of the 2017 MIT iGEM Team

“This is the most authentic research experience you can get before grad school,” said Dr. Brian Teague, a research scientist in Professor Ron Weiss’s lab, about competing in the international genetic engineered machine (iGEM) competition.

Started by MIT as an IAP course in 2003, iGEM has grown into a large international competition of more than 300 schools around the world. iGEM teams use synthetic biology to solve real-world problems, and the competition culminates at the iGEM Jamboree, an event held in the fall with presentations, poster sessions, and opportunities for teams to interact with each other. In one well-known iGEM project from 2004 for example, students from the University of Texas engineered a bacterial system able to take a chemical photograph.

The 12-person MIT team project for 2017 was based on controlling alternative splicing. Genes consist of exons (coding DNA sequences) and introns (non-coding DNA sequences). When messenger RNA (mRNA) is initially transcribed from DNA, it contains both exons and introns. Before the mRNA transcript can be translated into a protein, the introns need to be removed in a process called RNA splicing. Alternative splicing occurs when some exons are not included in the processed mRNA transcript.

To illustrate this concept, the team compared a transcript to an English sentence. A spliced mRNA transcript with all exons included could be “The grass is always greener on the other side,” whereas an alternatively spliced transcript could be “The grass is on the other side,” changing the meaning of the sentence completely.

Mistakes in alternative splicing can lead to several diseases, including myotonic dystrophy, spinal muscular atrophy, retinitis pigmentosa, and forms of cancer. “Our main avenue for pursuing [control of alternative splicing] was to use a fairly new CRISPR protein: Cas13a,” said Molly Stephens ’18.

Like other CRISPR proteins, Cas13a can be guided to bind to and cut a specific nucleic acid sequence with a complementary RNA sequence. However, instead of targeting DNA like most CRISPR proteins, which would be a risky change to the genome, Cas13a binds to and cuts RNA. The team built a construct that has the potential to guide a mutated form of Cas13a to a particular mRNA sequence to prevent incorrect RNA splicing. Further testing is necessary, but if successful, this construct could be used therapeutically in small cell lung cancer, the team’s disease model.

It wasn’t all lab work. Nia Myrie ’20 said, “It’s a research experience, but I cannot even explain how much I’ve learned outside of the realm of science.” As part of the “human practices” component of their iGEM project, the team met with experts in synthetic biology from MIT and at miRagen Therapeutics. They also presented in an outreach event at the MIT Museum, engaged with high school students, and helped high school teachers design a synthetic biology curriculum.

For the MIT team, one of the valuable opportunities at the iGEM Jamboree was to interact with other teams from around the world. Adil Yusuf ’18 said that one of his favorite projects was done by the team from the College of William and Mary. They had an innovative synthetic biology project, but what stood out to him was their approach to the human practices component of their project. Yusuf said that William and Mary’s team “assessed the outcomes of previous human practices projects and built a database for past and future projects.” This database will help future teams learn from the experiences of past ones when designing their projects.

One aspect of iGEM that stood out to the team was that their hard work does lead to real value for the research community. Stephens said, “One of the most important moments was when we were contacted by someone in the Weiss lab who was interested in what we had produced as an undergrad team.”

MIT teams typically start working over IAP, brainstorming ideas for projects. Students learn more about synthetic biology techniques in the spring semester, and do most of the experimental work of their project over the summer. They spend the fall semester preparing for the iGEM Jamboree. All of the information needed to apply for MIT’s 2018 iGEM team is available at The application deadline is Dec. 15.