The 2024 Nobel prize in physiology or medicine goes to two researchers, Victor Ambros and Gary Ruvkun, for their work on microRNA. They began their research in the same lab in the late 1980s as postdoctoral fellow, and then continued to collaborate after they each started their own labs.
Their research involves a key question about multicellular life. Every cell in the body of a multicellular creature has the same complete DNA code for all the genes and proteins that organism makes. And yet, brain cells and kidney cells, for example, are very different. Each expresses a different subset of the total complement of genes. Multicellular creatures, therefore, had to have evolved mechanisms by which gene expression is controlled, so that brain cells produce brain proteins and kidney cells produce kidney proteins.
The early research of Ambros and Ruvkun focused on C. elegans, a simple roundworm. This was a good target for research because it is a small creature but is multicellular and therefore has the same issue of gene expression as all other multicellular creatures. They were using three strains of C. elegans, a wild-type, and a strain with a mutation in the lin-4 gene, and a third with a mutation in the lin-14 gene. Lin-14 is a “heterochronic” gene that controls the timing of different stages of development across different cell types in C. elegans.
Ambros had previously shows that lin-4 is a regulator of the activity of lin-14, but the mechanism of this regulation was unknown. In his own lab he was able to determine that lin-4 coded for a very short RNA molecule, but did not code for any protein. He then hypothesized that this short RNA – called a microRNA – may be what’s regulating lin-14.
For background, in eukaryotes (like all multicellular life) DNA is kept in the nucleus, and contains all the genes of the entire organism. From genes in the DNA there is transcribed messenger RNA, which then travels outside the nucleus where the machinery is to translate that mRNA into a protein (with each triplet of base pairs in the RNA equaling one amino acid in the protein chain).
So Ambros established that microRNA produced by lin-4 was regulating, and specifically inhibiting, production of the lin-14 protein from the lin-14 gene, but did not yet know the mechanism. Meanwhile Ruvkun’s lab was finding that this inhibition did not occur at the transcription stage (the production of mRNA from DNA) but at the translation stage (the production of protein from mRNA).
When the two researchers compared their research they made the key discovery – that sequences on the microRNA produced by lin-4 matched (were complimentary to) sequences on the lin-14 mRNA. What was happening was that the microRNA was binding to the lin-14 mRNA and inhibiting its translation. They published their results in 1993, outlining an entirely new mechanism of regulation of gene expression.
Their work was largely ignored by the broader scientific community – not because it wasn’t solid work, but because it was assumed that this was likely a mechanism unique to C. elegans, or at least very limited evolutionarily. In any case it was likely not relevant to humans. But then, in 2000, Ruvkun’s group found microRNA produced by the let-7 gene. This gene is highly conserved in animals, including humans, which then suddenly sparked a lot of interest.
Over the ensuing years hundreds of microRNAs have been discovered, and it is now clear that this is a universal and important regulatory mechanism in multicellular creatures. MircoRNA can be coded for by their own genes, which are considered noncoding genes because they do not code for any protein. They can also derive from the introns of genes that do code for proteins – introns are the parts of a gene that are spliced out, with the exons connected together to form the mRNA that codes for the protein. But in some genes some of the introns can code for a microRNA.
Further is has been discovered by microRNA have two primary mechanisms by which they inhibit translation – they can directly block translation, so essentially make the mRNA non-functional, and/or they can cause the mRNA to be degraded much more quickly than it otherwise would be. As is usually the case, the more microRNAs are researched, the more complicated the picture becomes. Some microRNAs can interact with gene promoters – regions that are necessary for a gene to be active. Some can also regulate gene transcription, not just translation. One microRNA can regulate the translation of multiple genes, and one gene can be regulated by multiple microRNAs. Their function appears to be dynamic and dependent on many conditions within the cell.
Perhaps even more interesting, microRNA have been found in the extracellular space. They can, in fact, be packaged into little containers – vesicles – so they can be secreted outside the cell to act as cell-to-cell messengers. So one cell can make microRNAs that then inhibit the translation of a protein in another cell.
All this means that microRNAs are part of a complex network of regulation of gene expression in multicellular creatures. Over 1000 microRNA genes have been discovered to date. Further, microRNAs have been implicated in many disease states, including cancer, heart disease, lupus, and several neurodegenerative diseases. MicroRNAs are now considered a promising therapeutic target in some forms of cancer and potentially other diseases.
Also, because microRNA can be secreted outside of cells to act as a cell-to-cell messenger, this means that we may be able to detect microRNAs as a diagnostic tool for early detection of cancer, ALS, Alzheimer’s disease, and potentially other diseases.
The story of microRNA is a great example of how basic science can lead to an understanding of the fundamental mechanisms of biology that give us the tools to diagnose and treat diseases. It also shows the potential value of scientists just following their curiosity – Ambros and Ruvkun wanted to know how the lin-4 gene in C. elegans regulated the lin-14 gene. It was entirely possible that their research had no implications beyond this small roundworm. But it turns out they revealed a fundamental mechanism by which all multicellular life regulates gene expression. So here were are, over three decades later, with the Nobel Prize.
