From circular RNA to next-generation cell therapies, academic innovations are bridging the gap between lab benches and patient bedsides.
In the dynamic world of biotechnology, some of the most transformative innovations begin not in corporate R&D labs, but in the bustling academic research centers of universities and institutes. Each year, Nature Biotechnology conducts a systematic survey to identify the most promising startups emerging from this academic crucible—companies poised to turn groundbreaking scientific discoveries into real-world therapies and technologies 1 .
The class of 2019 showcased a cohort tackling medicine's most persistent challenges with novel approaches.
These spinouts represent the vital bridge between fundamental research and commercial application.
The annual Nature Biotechnology survey spotlights R&D-intensive startups that have secured significant Series A financing and demonstrate exceptional scientific innovation 1 .
Novel approaches to tackle intractable viruses
Engineering reliable sources of platelets and universalizing cell therapies
New technologies for accurate cancer screening
Foundational platforms like RNA-editing and targeting protein-RNA interactions 1
While numerous technologies showed promise in 2019, one particularly intriguing approach came from Orna Therapeutics, a company spun out of MIT based on pioneering work in circular RNA (circRNA) 5 .
Before the COVID-19 pandemic made "mRNA" a household term, scientists were already wrestling with limitations of linear mRNA therapeutics:
Orna's technology addressed these challenges by reimagining the RNA structure:
The breakthrough came when Orna co-founder Alex Wesselhoeft, then a PhD student in Daniel Anderson's lab at MIT, adapted an elegant enzymatic approach from cyanobacteria 5 .
Cyanobacterial ribozyme split and placed around therapeutic gene
DNA template transcribed into linear RNA with ribozyme sequences
Ribozymes excise themselves and ligate therapeutic sequence
Created circRNAs over 10 kb in length with high efficiency
A significant obstacle for circRNA was translation—the process by which the cellular machinery reads the RNA code to build proteins. Linear mRNA uses a 5' cap structure to recruit ribosomes, but circRNAs, being endless, lack this cap.
The Orna team addressed this by screening and identifying highly efficient internal ribosome entry sites (IRESs)—RNA elements that recruit ribosomes to internal regions of the RNA. Surprisingly, with the right IRES, circRNA could actually produce more protein over a longer period than heavily modified linear mRNA 5 .
Orna's most advanced application of its circRNA platform is a revolutionary approach to cancer treatment called "in situ CAR" (isCAR) therapy 5 .
| Disease Model | Experimental Approach | Key Results | Significance |
|---|---|---|---|
| Acute Lymphoblastic Leukemia 5 | Multiple injections of anti-CD19 isCAR (circRNA) in mouse xenograft model | Complete tumor eradication | Demonstrated potent anti-cancer activity of in vivo CAR expression |
| Duchenne Muscular Dystrophy 5 | Intravenous delivery of circRNA-LNPs encoding shortened dystrophin protein | Limited but detectable protein expression in muscle tissue | Showed potential for protein replacement therapy in muscular diseases |
The development of advanced RNA therapies like Orna's circRNA platform relies on a specialized set of tools and reagents.
| Research Reagent / Tool | Function in Development | Specific Example/Application |
|---|---|---|
| Lipid Nanoparticles (LNPs) 5 | Delivery vehicles that protect RNA and facilitate cellular uptake | Immunotropic LNPs for T-cell targeting; hepatropic LNPs for liver delivery |
| Ionizable Lipids 7 | Critical LNP component that enables endosomal escape | Key to releasing RNA payload into cell cytoplasm |
| Phosphorothioate Backbone Modifications 7 | Chemical modification that increases oligonucleotide stability against nucleases | Used in divalent siRNAs to prolong activity in central nervous system |
| Internal Ribosome Entry Sites (IRES) 5 | RNA elements enabling cap-independent translation initiation | Essential for protein production from circular RNAs lacking 5' caps |
| Ribozymes 5 | Catalytic RNA molecules that perform biochemical reactions | Self-splicing introns used to circularize linear RNA transcripts |
| N-Acetylgalactosamine (GalNAc) Conjugates 7 | Targeting ligand for hepatocyte-specific delivery | Enables efficient siRNA delivery to liver cells with minimal off-target effects |
While Orna's circular RNA platform represented a significant innovation, it was far from the only promising technology emerging from academia in 2019. The year's cohort included companies tackling everything from cancer virotherapy to epigenome editing, demonstrating the remarkable diversity of biotech innovation 1 5 .
Developing protein-based therapeutics that bind irreversibly to their targets.
Using very small cityRNAs to broaden the range of siRNA therapeutics.
Developing cancer virotherapy using arenaviruses.
Creating non-hallucinogenic psychedelics for neuropsychiatric disorders.
Epigenome editing (founded by Jonathan Weissman, David Liu, and others).
Epigenome editing (founded by Fyodor Urnov, Charles Gersbach).
The academic spinouts of 2019, from Orna's circular RNA to next-generation epigenetic editors, demonstrate the incredible vitality of basic scientific research and its power to spawn transformative new therapies. These companies represent more than just promising science—they embody a crucial pathway through which abstract biological concepts become concrete solutions for patients.
The journey from an academic lab's discovery to a company's therapeutic candidate is long and fraught with challenges. Yet, as the continued progress of these 2019 startups shows—with many having secured substantial additional funding and advanced toward clinical trials—this translation process is essential for realizing the full potential of our scientific investments. They remind us that today's seemingly obscure academic discovery may well become tomorrow's medical breakthrough, proving that when it comes to innovation, the most important shape might just be the full circle from academic insight to patient impact.
This article was based on the annual academic spinouts survey published in Nature Biotechnology 1 and additional information from the Nature family of journals.