Rewriting RNA: RSRT Funds Genetic Engineers in the AbuGoot Lab
Scientists at Harvard Medical School are developing an RNA Trans-splicing technology that could potentially address all Rett mutations.
DNA and RNA editing tools have the possibility to fix the mutations that cause Rett syndrome, with the potential to reduce or even reverse symptoms. Since 2010, RSRT has been funding scientists working to develop and refine genomic medicines. The latest researchers to join the RSRT family are Omar Abudayyeh and Jonathan Gootenberg who are working together to create an RNA-based genetic medicine for Rett syndrome.
Omar is an Assistant Professor at Harvard Medical School and also an Investigator at Brigham and Women’s Hospital and the Mass General Brigham Gene and Cell Therapy Institute. Jonathan is also an Assistant Professor at Harvard Medical School and an Investigator at Beth Israel Deaconess Medical Center.
Auspicious Beginnings
Omar and Jonathan met 15 years ago as undergraduate bioengineering students at MIT. What started as an email exchange about homework developed into working on research projects for a capstone course.
A shared passion for cutting-edge technology led them to the same graduate lab at the Broad Institute in Boston. There, working under Feng Zhang, the pair did research on CRISPR and other new genomic technologies.
“We published nine papers together,” says Jonathan. “It was a very exciting time, a really awesome time to be doing science. We saw each other so much; I’m surprised we didn’t get sick of each other. And after that, we decided to keep working together. We started a lab together at MIT, and the rest is kind of history.”
Complementary Collaborators
They now co-lead the Abudayyeh-Gootenberg lab at Harvard Medical School, where they bring different but complimentary backgrounds and experiences to the lab.
“We have different skill sets we can bring to the problems,” says Omar. “I did mechanical and bioengineering as part of my training. I also spent 2 years in medical school, so I have background medical knowledge as well.
These days, our lab is 50/50 computational and traditional ‘wet lab’ experiments. Having both of our backgrounds really allows us to be interdisciplinary, which is powerful. We also think very differently and that’s hard to quantify. But because of those very different viewpoints, I think that leads to really interesting solutions.”
New Innovations with Promising Potential
The Abudayyeh-Gootenberg lab is targeting DNA and RNA inside of cells to treat both rare disorders like Rett, and more common conditions.
“We have been working on genome editing and nucleic acid editing technologies for over a decade now,” says Jonathan. “We’re starting to see the ways we can have very powerful manipulations of these different pieces of biological information and translate that to patients.”
“All of our projects at some point have a eureka moment where you know it’s actually going to start to work,” says Omar. “It’s built on the back of thousands of failed experiments and slow improvements that eventually add up over time to be something.”
Rett Connection
Jonathan and Omar were introduced to Rett syndrome in graduate school, where they collaborated with long-time RSRT researcher Gail Mandel on an RNA-editing project to target a mutation in MECP2, the gene associated with Rett syndrome. They also crossed paths with another Boston-based RSRT researcher, Guoping Feng, exchanging ideas on RNA-editing technologies.
Their connection with RSRT began last year, just after they released a version of one of their research papers on bioRxv, a website that scientists commonly used to share research manuscripts before their official publication. Their manuscript detailed a technology they developed for editing RNA using a CRISPR-associated protein. They showed how RNA editing could be used to replace a large segment of the MECP2 RNA sequence in cells.
DNA holds the master copy of all the genes a cell might need. The cell makes copies of individual genes from the DNA sequence in the form of a related molecule, RNA. The cell’s protein factories attach to the RNA directly and use its instructions to make the protein specified by a given gene. Edits to either DNA or RNA could be used to correct Rett-causing mutations. Because the technology that Omar and Jonathan are developing would replace a large section of the MECP2 RNA sequence, rather than editing a specific mutation, it could actually be used to treat Rett syndrome in people regardless of the type of mutation.
After seeing Jonathan and Omar’s manuscript, Monica Coenraads quickly reached out to discuss possibilities for collaborating with RSRT on creating cures for Rett syndrome.
“It was incredible that Monica reached out to us,” says Jonathan. “It shows just how much RSRT is looking for new potential ways to treat and cure Rett syndrome. It’s really a testament to how proactive they are. We had a great initial conversation with Monica and it’s really blossomed into a working relationship.”
RSRT recently awarded the Abudayyeh-Gootenberg lab $858,000 to advance an RNA-based cure for Rett syndrome.
“Instead of treating each of the individual mutations that can cause Rett syndrome, we’re hoping to replace parts or even the entire gene with a single treatment that would actually apply to all patients with the disease,” says Omar. “And RNA trans-splicing is a way to do that.”
