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Cells engage in their development by selecting the genetic information needed for their growth. This selection is controlled by the microRNA molecules, which bond to other molecules inside the cells, called messenger RNA.
Recently, Victor Ambros and Gary Ruvkun were awarded the 2024 Nobel Prize in physiology or medicine for their discovery of microRNA.
The human genome contains a set of instructions that essentially provide the roadmap for a person to develop and function. One of the questions that has occupied biological inquiries is how the genome can lead to such different outcomes in the body.
Messenger RNA brings DNA information from the genome to the gene products within the cells. Interference with messenger RNA molecules can determine whether microRNA produces proteins.
MicroRNA consists of tiny molecules that direct the cells in our bodies to turn certain genes on or off. Scientists discovered microRNA while working in the field of developmental biology, looking specifically at animal development.
In the 1980s, Ambros and Ruvkun began working together in the Robert Horvitz lab at the Massachusetts Institute of Technology (MIT). At the time, they were studying genetic approaches using Caenorhabditis elegans, also known as C. elegans.
The C. elegan was selected because although they are small, simple organisms comprised only of about 1,000 cells, all of which can be seen microscopically, they also have systems and parts that are integral to all animals.
C. elegans are a roundworm that have two sexes: a self-fertilizing hermaphrodite and a male. They have been used in studies to understand which mutations caused developmental abnormalities.
At that time, scientists already knew that proteins interceded changes in gene expressions, meaning how information in our DNA is turned into a final product, as the cells divide.
It was when looking at the gene product, the biochemical material that results from the gene expression, of the lin-4 gene that microRNA was identified.
An earlier study had already identified that worms with a mutated lin-4 gene lacked an important physiological composition. Others appeared "heavily disturbed," according to the International Journal of Life Science Methods.
This revelation led scientists to believe that lin-4, a protein, otherwise known as a gene product, played a key role in development.
Nearly a decade later, scientists reported a mutation of the lin-14 gene. With that information, Ambros was able to identify that the mutation of lin-14 seemed to have the opposite defects, in other words function as a negative regulator, of the lin-4 mutation.
Positive regulators essentially check that cells are meeting their necessary criteria throughout the cell cycle, giving the green light to advance. Negative regulators stop a cell’s progression through the cell cycle until the cell can meet specific criteria.
The identification of negative regulators can help scientists understand where, for example, there can be an intervention in the progression of disease.
Ambros was able to clone lin-4. Through various experiments, Ambros identified that lin-4 could produce a non-coding RNA. RNA refers to ribonucleic acid. It’s a molecule that exists in the majority of living organisms and viruses.
A non-coding RNA refers to when an RNA molecule performs its function but doesn’t turn into a protein. This has influence on a number of biological functions, such as cell survival and proliferation.
Ruvkun conducted his own set of experiments, ultimately discovering that a gene’s expression is controlled between its two key steps: transcription and translation. Hence, the breakthrough of a new principle of gene regulation, called microRNA.
These validations demonstrated that it is microRNA that controls the process of producing proteins. Not enough or too much of a protein can lead to the development of disease.
A significant amount of research has since emerged on the basis of Ambros and Ruvkun’s findings, contributing toward advancements of opinions on gene regulations and RNA functions.
Scientists now know that the human genome contains instructions for over 1,000 microRNA forms, which are critical to the development of organisms.
On the basis of this work, scientists have been able to investigate complex diseases and their treatments, such as heart disease, cancer, and diabetes, among many others.
While a number of clinical trials are ongoing, particularly by small initiatives, no microRNA-based drugs have been approved by the US Food and Drug Administration yet. Although scientists in the field expect renewed interest following the Nobel Prize win.
Scientists that conducted the first trial on a microRNA called miR-34 were eager of the potential to delay cancer onset. A molecule similar to miR-34 was administered to mice with lung cancer. The study showed early disease intervention slowed tumor growth.
When transferred to human trials, very high doses of the drug were administered to participants. Ultimately, this triggered a dangerous immune response, and four of the trial’s participants died as a result.
Since that first trial, researchers were able to modify the delivery of RNA molecules at lower, safer doses.
Companies like Alnylam Pharmaceuticals and Cardior Pharmaceuticals are making advancements in the development and trial of microRNA-based therapies to treat cardiovascular, neurologic, metabolic, infectious, and rare diseases.
While microRNA treatments are still under investigation, there is strong precedent for their potential success. RNA-based drugs targeting genetic disorders have been approved and take effect with mechanisms that are akin to microRNA drugs.
Sources: (The Conversation) (BBC) (The New York Times) (The Economist) (Northwestern University) (National Human Genome Research Institute) (ScienceDirect) (Nature)
See also: Is it possible to bring humans back from extinction?
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The discovery of microRNA is changing how we understand diseases such as cancer and Alzheimer’s. Instead of igniting genes to make proteins, microRNA regulates which genes are active by breaking down certain gene messages (mRNA). So, how does microRNA’s role open up new possibilities for treatments and research?
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