Beyond Vaccines: Can RNA Sense Gases?

By Savani Anbalagan, Ph.D., Principal Investigator, Adam Mickiewicz University, Poznan, Poland

For decades, RNA was considered to be in a supporting role, acting as a cellular intermediary that passes genetic instructions from DNA to proteins. However, as scientists discovered increasingly complex and unusual functional RNA molecules, it soon became clear that RNA plays a central role in cells. RNA is not just a static molecule; it can also sense.

We already know that certain messenger RNAs can act as primitive sensors, bending and shifting shape to detect shifts in temperature or ions. What if this isn't the exception, but the rule? I propose that a wide variety of RNAs act as "riboceptors"—direct cellular sensors capable of detecting everything from environmental stress to gaseous signaling molecules. If true, it could reshape our understanding of how RNA and metabolism are linked.

This idea of gas-sensing RNAs remains a hypothesis, and much work remains before it can be validated experimentally. Yet considering RNA as both an information carrier and an environmental sensor opens intriguing possibilities, not only for understanding fundamental biology but also for inspiring the next generation of RNA therapeutics.

Learning From Nature’s Molecular Toolkit

Biology rarely evolves redundant systems without purpose. Cells continuously monitor their surroundings, responding to fluctuations in temperature, oxygen availability, nitric oxide, carbon dioxide, pH, nutrients, and countless other signals. Receptors that sense molecules and factors, triggering a cellular response, are usually proteins. However, certain RNA can also sense and trigger a cellular response.

Bacterial riboswitches have long illustrated mRNA's remarkable ability to recognize metabolites or even temperature and regulate gene expression. More recently, researchers have uncovered increasingly sophisticated RNA structures that influence splicing, translation, localization, and RNA stability in response to cellular conditions.

These discoveries raise an important question: if mRNA can recognize metabolites, could evolution have also equipped other classes of RNA molecules to detect physical or chemical properties of the cellular environment, including gases?

Rather than viewing this possibility as a departure from established RNA biology, I believe it represents a logical extension of what we are already learning about RNA structure and function.

Could RNA Also Detect Gases?

We already know some microorganisms can use RNA thermometers in their mRNAs to detect temperature. Why stop there? Could evolution have extended this strategy to detect gases as well?

It is well known that hemoprotein-based gasoreceptors can sense gaseous molecules such as nitric oxide, oxygen, and carbon monoxide that play key roles in cellular physiology, metabolism, and signaling. Their concentrations can fluctuate continuously during development, inflammation, hypoxia, cardiovascular disease, and cancer.Even in plants, ethylene is a well known gaseous signaling molecule-sensed by copper-binding protein gasoreceptors that has functions in development, regeneration, and fruit ripening.

Thus, current models primarily describe metalloproteins as the molecules responsible for detecting these gases and initiating downstream signaling cascades. However, heme-binding RNA molecules too can exist within the same intracellular environment and possess highly dynamic three-dimensional structures that can respond to chemical interactions.

This raises another intriguing possibility: might such metal-RNA complexes directly recognize changes in gaseous molecules and alter their structure or regulatory activity accordingly? If metal-RNA complexes can sense and respond directly to gaseous molecules, it would represent an evolutionarily ancient gas-sensing mechanism that acts in parallel with, and perhaps independently of, protein-based signaling mechanisms.

For now, this remains speculative. However, history shows that, with adequate resources, speculative ideas can lead to novel discoveries.

Implications For RNA Therapeutics

Some RNA-based therapeutics have demonstrated increased stability and clinical efficacy. The challenge for the future may be to develop microenvironment-responsive RNA therapeutics. Promising progress in this area has been made using synthetic aptamers. If nature has indeed evolved endogenous riboceptors over millions of years, leveraging those highly complex, dynamic RNA structures could be beneficial.

The concept of riboceptors for all types of RNA may prove valuable for researchers developing RNA therapeutics, even if the underlying biology differs from current hypotheses. To the best of my knowledge, there are still no RNA therapeutics that can directly sense and respond to gaseous molecules. While this remains aspirational, studying endogenous gas-sensing riboceptors could provide engineering strategies with therapeutic applications.

Expanding The Functional RNA Landscape

Since the discovery of RNA, RNA biologists have made some of the most significant discoveries. These include the discovery of ribozymes, splicing, microRNAs, circular RNAs and RNA modifications, as well as riboswitches. Whether riboceptors will ultimately join this growing list remains to be seen.

The hypothesis of gas-sensing riboceptors is an invitation to address a burning question: If proteins can sense gases directly, can RNA also sense gases directly? If so, how can we benefit from that knowledge? Can such knowledge be applied to develop novel diagnostic assays, identify disease biomarkers, or microenvironment-responsive therapeutics? Can such knowledge help us to understand the origin of life or provide support for the RNA world hypothesis?

These questions will require well-controlled experiments, including in vitro RNA functional assays and in vivo experiments using diverse model organisms. These data can then be used to develop machine learning algorithms that predict other evolutionarily conserved riboceptor candidates in various naïve and disease cell types, as well as in pathogens.

Related Manuscript:

Gas-sensing riboceptors. Anbalagan S. RNA Biol. 2024 doi: 10.1080/15476286.2024.2379607.

About The Author

Savani Anbalagan, Ph.D., is a principal investigator in the Institute of Molecular Biology and Biotechnology at Adam Mickiewicz University in Poznań, Poland. His research explores fundamental mechanisms of cellular communication, with a particular focus on the role of cell signaling in zebrafish pituitary development. He has published foundational works defining the emerging discipline and field of gasocrinology. He has also published peer-reviewed manuscripts in journals affiliated to the American Physiological Society, Polish Biochemical Society and the Chinese Academy of Medical Sciences.