The Earth emerged 4.5 billion years ago, and life less than a billion years after that. Although life as we know it depends on four major macromolecules – DNA, RNA, proteins and lipids – it is believed that only one was present at the beginning of life: RNA.
It’s no surprise that RNA probably came first. It is the only one of those large macromolecules that can replicate itself and catalyze chemical reactions, both of which are essential for life. Like DNA, RNA is made of individual nucleotides connected in chains. Scientists initially understood that genetic information flows in one direction: DNA is transcribed into RNA and RNA is translated into proteins. That principle is called the central dogma of molecular biology. But there are many deviations.
A major example of an exception to the central dogma is that some RNAs are never translated or encoded into proteins. This fascinating derivation of the central dogma has led me to devote my scientific career to understanding how it works. Indeed, research into RNA has lagged behind other macromolecules. Although several classes of these so-called non-coding RNAs exist, researchers like me have begun to pay close attention to short stretches of genetic material called microRNAs and their potential to treat various diseases, including cancer.
MicroRNAs and diseases
Scientists consider microRNAs to be master regulators of the genome because of their ability to bind to and alter the expression of many protein-coding RNAs. Indeed, a single microRNA can regulate 10 to 100 protein-coding RNAs. Instead of translating DNA into proteins, they can instead bind to protein-coding RNAs to silence genes.
The reason microRNAs can regulate such a diverse collection of RNAs stems from their ability to bind to target RNAs to which they do not match perfectly. This means that a single microRNA can often regulate a collection of targets that are all involved in similar processes in the cell, leading to an enhanced response.
Because a single microRNA can regulate multiple genes, many microRNAs can contribute to disease when they become dysfunctional.
In 2002, researchers first identified the role that dysfunctional microRNAs play in diseases in patients with a type of blood and bone marrow cancer called chronic lymphocytic leukemia. This cancer results from the loss of two microRNAs that are normally involved in blocking the growth of tumor cells. Since then, scientists have identified more than 2,000 microRNAs in humans, many of which are altered by various diseases.
The field has also developed a fairly good understanding of how microRNA dysfunction contributes to disease. Changing one microRNA can alter several other genes, resulting in a plethora of changes that can collectively reshape the cell’s physiology. For example, more than half of all cancers have significantly reduced activity in a microRNA called miR-34a. Because miR-34a regulates many genes involved in preventing the growth and migration of cancer cells, loss of miR-34a may increase the risk of developing cancer.
Researchers are exploring the use of microRNAs as therapies for cancer, heart disease, neurodegenerative diseases and others. Although results in the laboratory are promising, bringing microRNA treatments into the clinic has faced several challenges. Many are related to inefficient delivery into target cells and poor stability, limiting their effectiveness.