Thursday, 21 November, 2024
The cellular components that turn DNA directions into a body’s building blocks are akin to pieces of a Swiss watch: tiny, delicate, specialized — and complicated. If any part is missing or broken, the watch stops working.
The scientists who received the 2024 Nobel Prize in Physiology or Medicine discovered and characterized a component of that “watch” that no one previously understood — microRNA. Before its discovery by the laureates Victor Ambros of the University of Massachusetts Chan Medical School in Worcester and Gary Ruvkun of Massachusetts General Hospital in Boston, scientists had an incomplete understanding of the process that controls how cells make proteins.
They knew that DNA contains the “instructions” in the chemical equivalent of a computer code. They also knew that messenger RNA (mRNA) carries those instructions to the cell’s “protein factory” called the ribosome. But they didn’t understand when, why, or how that process could be interrupted.
That’s where microRNA comes in. The molecule gets its “micro” prefix because the thousand or so different versions in the human body have significantly fewer chemical “letters” than mRNA. But those small letters play a big role. By binding to mRNA, they essentially “gum up the gears” and stop protein production. That seemingly simple act allows them to play an outsize role. This means that microRNA helps control when and how much a particular protein should be made.
That essential task helps fine-tune protein production. This is key because although each cell contains the same genetic instructions in its DNA, each cell can also create many highly specialized proteins when microRNA turns protein production “on” or “off,” altering both the type and amount made. As a result, our bodies produce a staggeringly complex and diverse amount of proteins based on the same set of instructions but tailored through microRNA’s essential “on/off” function.
As with many big discoveries, Ambros and Ruvkun started small. They were working on a tiny worm called C. elegans, that scientists use as a research “model” because its relatively small number of genes give them enough different functions to examine, but not so much that they are overwhelmed with complexity.
In the late 1980s, Ambros and Ruvkun were research fellows in Robert Horvitz’s MIT lab. Horvitz, alongside Sydney Brenner and John Sulston, was awarded the Nobel Prize in 2002. They were especially interested in genes that act as “timer switches” for different genetic programs that control when specific cell types develop. Two mutant strains of worms — lin-4 and lin-14 — demonstrated defects in turning such genetic programs on and off. But they didn’t know how or why.
They each continued to ask those questions, starting in their own research labs. Ambros, who had moved to Harvard, “mapped” the genes that made the lin-4 mutant. In doing so, he discovered something unexpected. The lin-4 gene made a very short RNA molecule that lacked a code for protein production. This finding suggested that the small RNA was somehow inhibiting it. But he didn’t know how.
Meanwhile, Ruvkun, who had established a lab at Massachusetts General Hospital and Harvard Medical School, conducted experiments that showed that — unlike what he expected — lin-4 did not shut down production of mRNA from lin-14. Some other unknown mechanisms must be at work at a later stage in the protein-making process.
When Ambros and Ruvkun compared notes, they made an important breakthrough: they noticed that the short lin-4 sequence matched specific, complementary segments in the lin-14 mRNA, fitting together like a lock and key. Further experiments showed that lin-4 microRNA binds to these segments, blocking lin-14 protein production. In doing so, they demonstrated a new method of gene regulation — which was met with indifference after their key publications.
That changed in 2000 when Ruvkun discovered another microRNA encoded by the let-7 gene. Unlike lin-4, the let-7 gene was present in more than just C. elegans, so it drew wider interest. Since then, scientists have discovered more than a thousand genes that produce different microRNAs in humans and have shown that all multicellular organisms use microRNA to control protein production.
Scientists are also learning more about the role microRNAs play in diseases. For example, defects in their function may play a role in many types of cancer. That makes sense because cancer is essentially cell production run amok, and microRNAs can play an outsize role in that process. Work has been underway to pinpoint what microRNA molecules are involved in particular cancers, such as the thyroid.
As scientists continue to learn more about the specific role each of the thousand or so microRNA molecules play in controlling protein production, they will come closer to finding ways to understand — and, hopefully, treat — more diseases, including cancers. To repair a watch, one must first understand what each of its minute parts does. The discovery and ongoing research of microRNA provides such knowledge.
Courtesy: Discovermagazine.com
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The cellular components that turn DNA directions into a body’s building blocks are akin to pieces of a Swiss watch: tiny, delicate, specialized — and complicated. If any part is missing or broken, the watch stops working.
The scientists who received the 2024 Nobel Prize in Physiology or Medicine discovered and characterized a component of that “watch” that no one previously understood — microRNA. Before its discovery by the laureates Victor Ambros of the University of Massachusetts Chan Medical School in Worcester and Gary Ruvkun of Massachusetts General Hospital in Boston, scientists had an incomplete understanding of the process that controls how cells make proteins.
They knew that DNA contains the “instructions” in the chemical equivalent of a computer code. They also knew that messenger RNA (mRNA) carries those instructions to the cell’s “protein factory” called the ribosome. But they didn’t understand when, why, or how that process could be interrupted.
That’s where microRNA comes in. The molecule gets its “micro” prefix because the thousand or so different versions in the human body have significantly fewer chemical “letters” than mRNA. But those small letters play a big role. By binding to mRNA, they essentially “gum up the gears” and stop protein production. That seemingly simple act allows them to play an outsize role. This means that microRNA helps control when and how much a particular protein should be made.
That essential task helps fine-tune protein production. This is key because although each cell contains the same genetic instructions in its DNA, each cell can also create many highly specialized proteins when microRNA turns protein production “on” or “off,” altering both the type and amount made. As a result, our bodies produce a staggeringly complex and diverse amount of proteins based on the same set of instructions but tailored through microRNA’s essential “on/off” function.
As with many big discoveries, Ambros and Ruvkun started small. They were working on a tiny worm called C. elegans, that scientists use as a research “model” because its relatively small number of genes give them enough different functions to examine, but not so much that they are overwhelmed with complexity.
In the late 1980s, Ambros and Ruvkun were research fellows in Robert Horvitz’s MIT lab. Horvitz, alongside Sydney Brenner and John Sulston, was awarded the Nobel Prize in 2002. They were especially interested in genes that act as “timer switches” for different genetic programs that control when specific cell types develop. Two mutant strains of worms — lin-4 and lin-14 — demonstrated defects in turning such genetic programs on and off. But they didn’t know how or why.
They each continued to ask those questions, starting in their own research labs. Ambros, who had moved to Harvard, “mapped” the genes that made the lin-4 mutant. In doing so, he discovered something unexpected. The lin-4 gene made a very short RNA molecule that lacked a code for protein production. This finding suggested that the small RNA was somehow inhibiting it. But he didn’t know how.
Meanwhile, Ruvkun, who had established a lab at Massachusetts General Hospital and Harvard Medical School, conducted experiments that showed that — unlike what he expected — lin-4 did not shut down production of mRNA from lin-14. Some other unknown mechanisms must be at work at a later stage in the protein-making process.
When Ambros and Ruvkun compared notes, they made an important breakthrough: they noticed that the short lin-4 sequence matched specific, complementary segments in the lin-14 mRNA, fitting together like a lock and key. Further experiments showed that lin-4 microRNA binds to these segments, blocking lin-14 protein production. In doing so, they demonstrated a new method of gene regulation — which was met with indifference after their key publications.
That changed in 2000 when Ruvkun discovered another microRNA encoded by the let-7 gene. Unlike lin-4, the let-7 gene was present in more than just C. elegans, so it drew wider interest. Since then, scientists have discovered more than a thousand genes that produce different microRNAs in humans and have shown that all multicellular organisms use microRNA to control protein production.
Scientists are also learning more about the role microRNAs play in diseases. For example, defects in their function may play a role in many types of cancer. That makes sense because cancer is essentially cell production run amok, and microRNAs can play an outsize role in that process. Work has been underway to pinpoint what microRNA molecules are involved in particular cancers, such as the thyroid.
As scientists continue to learn more about the specific role each of the thousand or so microRNA molecules play in controlling protein production, they will come closer to finding ways to understand — and, hopefully, treat — more diseases, including cancers. To repair a watch, one must first understand what each of its minute parts does. The discovery and ongoing research of microRNA provides such knowledge.
Courtesy: Discovermagazine.com
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