Rewriting Heredity: RNA's Pivotal Role in Health, Evolution, and Environmental Adaptation

The Nature vs. Nurture Debate: Beyond the DNA Blueprint

Since the early 1980s, scientists have been trying to understand the extent to which our genes determine our risk for disease compared to environmental factors like lifestyle and diet. The completion of the Human Genome Project was a milestone, enabling the identification of genes responsible for rare inherited disorders. However, similar approaches to common diseases such as heart disease, diabetes, and mental health disorders revealed a perplexing gap: only 40% of the genetic effect could be mapped back to DNA. This "missing heritability" led to questions about heredity and whether other systems, beyond DNA, could transmit information across generations, especially concerning environmental exposures.

RNA's Emergence as a Key Player

Research on model organisms, including yeast, flies, worms, and mice, has demonstrated that environmental stresses experienced by parents can directly influence the health and behavior of their offspring. In each case, RNA emerged as a crucial molecule in mediating what is known as an epigenetic effect from environmental stress.

While DNA modifications as epigenetic effects are erased in sperm and eggs, making them non-heritable, RNA, like DNA, is directly heritable from parents to children, suggesting that they may work together as the heritable material. Monaco proposes a reconstructed model where both DNA and RNA contribute to heredity, but the environment primarily exerts its influence through changes in RNA.

Rewriting the Central Dogma: RNA's Adaptive Memory

The central dogma of biology posits DNA as the primary blueprint for life and heredity, capable of replicating itself and producing RNA to carry out various functions. Monaco suggests an update: RNA also functions as a heritable material, capable of changing its levels and genetic code in response to environmental stress, with some of these changes being passed down through generations. Drawing parallels from the COVID-19 pandemic, Monaco illustrates how rapidly RNA can evolve and mutate, causing long-lasting effects. Like viruses, environmental factors, exposures in parents such as diet, stress, bacterial infections, and substance misuse all contribute.

RNA molecules can form partnerships through a process called splicing, acting as a form of memory by connecting with older, established RNAs that previously fought off viral infections. This adaptability allows organisms to respond to rapidly evolving viruses and, over time, drive changes at the DNA level, leading to the co-evolution of RNA and DNA.

Jumbo Circles: RNA's Response to Environmental Stress

Researchers at Tufts University have discovered that RNA can produce a circular form, known as Jumbo circles, through splicing. These stable structures, found in all living organisms, are particularly important in fetal development, especially in the brain and heart, and can be edited to provide further flexibility in their genetic code. These Jumbo circles encompass many functionally related genes, enabling a coordinated and efficient response to environmental changes. One set of jumbo circles are produced after environmental stress caused by viral infection. The genes on these jumbo circles help the organism return to normal after the attack, acting as a cleanup process.

Turtles and tortoises, known for their longevity and negligible aging, exhibit a remarkable ability to form jumbo circles. This capability may help them withstand the stress of infection, preventing the accumulation of cellular waste that leads to aging and neurodegenerative diseases in humans.

Implications for Mental Health and Antiviral Treatments

Monaco suggests that understanding RNA's role could revolutionize the diagnosis and treatment of mental health disorders. Because mental health disorders are highly heritable, but DNA changes only account for a small portion of the risk, there is room for an RNA effect working alongside DNA. Studies have shown that individuals with neurodevelopmental disorders exhibit reduced RNA editing, possibly due to a reduction in circular RNAs. Since RNA mechanisms are transient and reversible, targeting RNA could offer new therapeutic avenues.

Furthermore, understanding how RNA fights and remembers viral infections through the formation of jumbo circles could lead to alternative antiviral treatments. Given that the virus that causes COVID-19 is an RNA virus, boosting our natural antiviral detection system could provide therapeutic potential and reduce severe illness and hospitalizations.

A New Frontier in Heredity and Evolution

Monaco's exploration into the role of RNA marks a significant shift in our understanding of heredity and evolution. By recognizing RNA as a dynamic and adaptable carrier of environmental information, scientists may unlock new strategies for preventing and treating a wide range of diseases, potentially extending human lifespan and improving overall health. Perhaps, one day, humans can live as long as turtles and tortoises if we can boost our jumbo circle making ability to overcome chronic inflammation from infections and slow down the aging process.