The 2024 Nobel Prize in Physiology or Medicine: awarded jointly awarded to
- Victor Ambros at the University of Massachusetts Medical School
- Gary Ruvkun professor of genetics at Harvard Medical School
Discovery: microRNA mediated
post-transcriptional gene regulation.
Published their results in 1993 in the journal Cell, in 2
publications.
Experiment
Ambros and
Gary Ruvkun were interested in how different cell types develop?
Model Organism
Selection:
Chose C. elegans,
a small roundworm, as the model organism due to its simple structure and
well-defined developmental stages.
- Investigated two genes, lin-4 and lin-14 controlling the timing of developmental processes in C. elegans.
- They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development.
- They wanted to identify the mutated genes and understand their function.
- Ambros had shown that lin-4 appeared to be a negative regulator of lin-14. But how?
Hypothesis
Formation:
Proposed that the
lin-4 gene acted as a negative regulator or inhibits the lin-14 gene expression,
aiming to understand how this regulation occurred.
Gene Cloning
experiment:
- Ambros Cloned the
lin-4 gene and discovered that it produced a short RNA molecule that did not
code for proteins, termed microRNA. This was surprising. Then the next question
was how
this small RNA from lin-4 was responsible for inhibiting lin-14. How might this
work?
- Ruvkun cloned the lin-14 gene and found that the lin-4 microRNA matched complementary sequences in the lin-14 mRNA. Then they compared their findings and found complementary sequence matching
Experimental
Validation:
Conducted
experiments showing that lin-4 microRNA binds to lin-14 mRNA, inhibiting its
translation into protein rather than blocking mRNA production. A
new principle of gene regulation, mediated by a previously unknown type of RNA,
microRNA, had been discovered!
What is a microRNA?
Micro RNA is a class of small RNA molecules bind to complementary sequences in target mRNAs, leading to either inhibition of protein synthesis or degradation of the mRNA. This process is essential for fine-tuning gene expression.
What is the significance of the discovery?
Further studies by Ruvkun's research group (2000) discovered another microRNA, encoded by the let-7 gene. Unlike lin-4, the
let-7 gene was highly conserved and present throughout the animal kingdom. Subsequent research revealed that microRNA
regulation is conserved across many species, including humans, leading to the
identification of over a thousand microRNAs in the human genome.
Mutations in genes coding for
microRNAs have been found in humans, causing conditions such as congenital
hearing loss, eye and skeletal disorders. Abnormal microRNA regulation can contribute to
diseases such as cancer and genetic disorders, emphasizing the importance of
their discovery in understanding cellular processes.
Ambros and Ruvkun’s seminal
discovery in the small worm C. elegans was surprising, and revealed a new dimension to gene regulation,
essential for all complex life forms.
Image credit: nobelprize.org
Reference:
Wightman, B., Ha, I., & Ruvkun, G. (1993). Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell, 75(5), 855-862.
Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. cell, 75(5), 843-854.