The future of bioengineering is RNA and Amber Bio, founded by Jacob Borrajo, is leading the way in its approach to developing new modalities for editing RNA. Too add more depth to this episode, below I’ve written about:

• Why RNA editing is such a big deal

• What a spliceosome is and how useful they are

• Amber’s “genome book”

• Biology as an engineering discipline

The S³ bio blackout is sponsored by Pillar VC

This entire “bio blackout” we’re doing on S³ right now where episodes 15-19 are entirely biotech focused, is sponsored by Pillar VC. Pillar is single handedly increasing the number of biotech companies that exist in the world in a meaningful way. They’re founder first and are pioneering a “Founder-led bio” approach investing in teams that are founder led rather than brought about by large institutions. You should check out Pillar’s website here, the quality of their approach comes across in a meaningful way even over the web.

Why editing RNA is a big deal

Editing RNA represents a monumental leap in creating therapeutics. RNA editing doesn’t just patch up genetic mistakes; it intercepts the problem before these errors ever become part of the cellular machinery.

Unlike traditional therapies that might supplement enzyme deficiencies or modulate immune responses, RNA editing goes upstream, stopping diseases at the genetic source. This method sidesteps the need to directly manipulate the more permanent and complex DNA, offering a layer of safety and reversibility—if an edit has unintended consequences, the transient nature of RNA means the effects are not permanently written into the genome.

RNA editing is in sharp contrast with other common therapeutic approaches like small molecule drugs, which often alleviate symptoms or hinder disease progression but don’t address the underlying genetic cause. Even with the advent of gene therapy, which does target the root of certain genetic conditions, the actual process of altering DNA is laden with technical challenges and ethical debate, particularly with respect to off-target effects and long-term implications.

RNA editing offers a middle ground, a sort of genetic intervention without the permanence and weightiness of DNA editing, providing a precision tool in the medical arsenal that could be both potent in effect and graceful in application. It’s a precise, editable, and less invasive way to rewrite the biological script, offering a new chapter in the story of how we fight genetic diseases.

But, how is Amber is looking to make these RNA edits?

Spliceosomes

The primary way Amber is approaching the editing of RNA is through spliceosomes, large ribonucleoprotein complexes. Basically, spliceosomes work like tiny molecular scissors and glue inside of our cells. They cut out the bits of RNA that aren’t needed and stick the right bits back together.

Nature employs the spliceosome with remarkable proficiency all of the time. This complex molecular machinery acts as a meticulous editor, snipping out non-coding segments called introns and splicing together the remaining coding sequences known as exons.

This splicing process is much more complicated than my metaphor of scissors and glue; it's a sophisticated form of RNA editing that allows a single gene to generate multiple protein variants—a phenomenon known as alternative splicing.

Through this mechanism, nature exponentially increases the diversity of proteins a single gene can produce, enabling a vast array of biological functions and adaptations. From the development of complex organs to the fine-tuning of immune responses, the spliceosome plays a central role in the dynamic expression of genetic information, showcasing nature's economy and elegance in using the same genetic scripts to direct a multitude of biological outcomes.

Amber’s book metaphor

Jacob likens the human genome to an extensive, intricate book where the text encodes the instructions for building every protein our bodies need. Just as a book is composed of letters that form words and sentences, our genome is a compilation of chemical bases that sequence into genes.

However, sometimes there are typos—mutations in the genetic code—that can disrupt the story, leading to diseases.

Most current therapies painstakingly focus on these typos, attempting to correct them one at a time, akin to using a fine-tipped pen to fix each error as it's encountered. This method is precise but can be incredibly time-consuming and costly, given the vastness of genetic variations that can lead to disease.

Amber's approach, however, is more akin to replacing entire faulty pages in this genetic book rather than just single letters. Their tools don't just correct single-base errors; they have the potential to rework larger sections of genetic text, thereby addressing multiple mutations or errors at once. By leveraging the cell's own editing machinery—the spliceosome—along with the guiding precision of CRISPR-Cas systems, Amber envisions a therapeutic approach that is not limited to one mutation at a time but is adaptable to the myriad of ways genes can break.

It's as if they are not just fixing the existing text but also reformatting the pages, ensuring that the protein "story" unfolds as it should, ultimately maintaining the body's health. This not only streamlines the process of creating therapies but could also significantly reduce the development time and cost, making these treatments more accessible to patients.

Engineering as a biology discipline

While filming with Amber I was once again surprised by the unorthodox framing of their biotechnological endeavor. It was not the biology-rich experimental focused jargon I had braced for; instead, Jacob described their approach through engineering principles.

The complexity of gene editing, which I had assumed would be steeped in biological terms, was distilled into a language of systems, processes, and optimizations. This isn’t just rhetoric, this new age of founder-led biotechnology companies are approaching biology through the lens of systems.

By viewing the genome as an engineer looks at a malfunctioning circuit, Jacob and his team identified a systematic, scalable way to address genetic errors. Instead of targeting mutations individually, which would be like soldering each faulty connection in our circuit analogy, they engineered a way to rewrite larger sections of genetic code, akin to installing a new, error-free component to replace a series of faults. This mindset, borrowing from the iterative, problem-solving approach of engineering, allows Amber to not only tackle current genetic challenges but also to adapt swiftly to new ones, just as an engineer might update a system to handle new tasks or correct unforeseen issues.

Keep on building the future,

— Jason

Filmed in San Francisco, CA | Edited in Los Angeles & San Francisco, CA | Composed in Davis, CA