A little more than 50 years ago, a man named Sydney Brenner introduced the world to a nematode worm called Caenorhabditis elegans. Brenner went on to win the Nobel Prize in 2002 for his findings in the “genetic regulation of organ development and programmed cell death.” However, the discovery of the worm itself was almost equally significant.
The C. elegans worm was transparent, had all the specialized cell types, was easily manipulated, and reproduced quickly. It was the ideal organism for genetic research. As such, it’s no surprise that two postdoctoral students on different continents became obsessed with it.
The Story of an Obsession
Image: Victor Ambros (2008)
In the early 1980s, Victor Ambros and Gary Ruvkun met in Robert Horvitz’s lab (also a 2002 Nobel laureate) while working on a perplexing problem: Why do some “mutant” worms display abnormal structures, shapes, and behaviors?
For years, their research focused on the seemingly simple task of cloning and manipulating various types of mutant nematodes, but they were unable to make progress. Their postdoctoral fellowships ended without success, and they eventually went their separate ways.
Ambros ended up at Harvard University and Ruvkun at Massachusetts General Hospital. They weren’t far from each other, but it didn’t seem so. Each continued to work alone on a problem everyone thought was impossible to solve. Ambros discovered that there were some very short pieces of RNA, but he didn’t know what they were for. Ruvkun, on the other hand, identified when genes were turned on but didn’t understand what could turn them on or block them.
On June 11, 1992, almost a decade after they began collaborating, they met again and shared the progress each had made over the course of that afternoon.
That’s when the magic happened.
The Great (Dis)order of Life
To fully grasp Ambros and Ruvkun’s discovery, it’s helpful to understand the problem they were tackling. DNA serves as an instruction manual for all the cells and processes in the human body. What’s fascinating is that every cell contains the same manual, yet each cell only uses a portion of it. The crucial question they sought to answer was: What ensures that only the right set of genes is active in each type of cell?
This was an incredibly challenging question for Ambros and Ruvkun to address, particularly since one of the crucial components of these gene regulatory mechanisms is much smaller than previously thought. While specialized regulatory proteins have been known since the 1960s, by the 1980s, it became evident that these proteins alone weren’t enough.
They Discovered microARN
Ambros had the missing piece to Ruvkun’s jigsaw puzzle. Together, they discovered a previously unknown level of regulation that would later prove to be of enormous importance. However, their discovery initially went unnoticed by most experts, not because it wasn’t interesting, but because they believed the mechanism was likely specific to C. elegans.
It took Ruvkun’s lab nearly another decade to find another case of microRNA, this time in a gene common to all living things. This discovery sparked widespread interest, and in recent years, research has revealed that “abnormal regulation by microRNAs can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, eye and skeletal disorders.”
Ambros and Ruvkun’s work has led to major therapeutic breakthroughs. Today, they were awarded a Nobel Prize for their discovery.
Image | Mattias Karlén
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