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Victor Ambros, PhD, a researcher at the University of Massachusetts Chan Medical School, Worcester, and Gary Ruvkun, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts, discovered microRNAs, a new class of RNA molecules.
“Their groundbreaking discovery in the small worm Caenorhabditis elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans,” said the Nobel Assembly in a statement.
Protein Expression
Genetic information flows from DNA during transcription to messenger RNA (mRNA) and then to protein biosynthesis. In that stage, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA.
Different cell types or tissues express unique sets of proteins, however. This specialized expression results from precise regulation of gene activity, so that in each cell type, only the correct set of genes is active. In this way, for example, muscle cells, intestinal cells, and various types of nerve cells can fulfill their functions.
Furthermore, gene activity must constantly be fine-tuned to adapt cell functions to changing conditions in our body and environment. When gene regulation goes awry, it can lead to serious outcomes such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulation of gene activity has been an important goal for many decades.
In the 1960s, researchers had shown that specialized proteins called transcription factors bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since that time, thousands of transcription factors have been identified. For a long time, scientists thought that the main principles of gene regulation were understood.
Roundworm Research
In the late 1980s, Dr. Ambros and Dr. Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, PhD, who received the Nobel Prize in 2002 with Sydney Brenner and John Sulston. In Dr. Horvitz’s laboratory, they studied the relatively inconspicuous, 1-mm long roundworm C elegans.
Despite its small size, C elegans has many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals. These features make it a popular animal model.
Dr. Ambros and Dr. Ruvkun were interested in genes that ensure that different cell types develop at the right time. They examined two mutated worm strains, lin-4 and lin-14, that exhibited defects in the temporal activation of specific genes during development. The laureates wanted to identify mutated genes and understand their function.
Dr. Ambros had previously shown that lin-4 appeared to be a negative regulator of lin-14. But how lin-14 activity was blocked was unknown.
Collaboration Yields Breakthrough
After his postdoctoral years, Dr. Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Systematic mapping allowed the cloning of the gene and led to an unexpected result: lin-4 produced an unusually short RNA molecule that lacked a code for protein synthesis. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14.
At the same time, Dr. Ruvkun, in his newly founded laboratory at Massachusetts General Hospital and Harvard Medical School, studied the regulation of lin-14. In contradiction to the current understanding of gene regulation, he showed that it was not the production of lin-14 mRNA that was inhibited by lin-4. The regulation seems to occur at a later stage in the gene expression process, namely through the shutdown of protein synthesis. In addition, a section in lin-14 mRNA was discovered to be necessary for inhibition by lin-4.
The two laureates compared their results, leading to a groundbreaking discovery. The short lin-4 sequence matched complementary sequences in the relevant section of the lin-14 mRNA. Dr. Ambros and Dr. Ruvkun conducted further experiments showing that the lin-4 microRNA silences lin-14 by binding to the complementary sequences of its mRNA, thus blocking the production of the lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, the microRNA, had been discovered.
Subdued Initial Response
The results were published in Cell in 1993 and initially received little attention. However, interest grew in 2000 when Dr. Ruvkun’s research group published the discovery of another microRNA encoded by let-7.
In contrast to lin-4, let-7 was highly conserved and present throughout the animal kingdom. The article sparked great interest. In the following years, hundreds of microRNAs were identified. Today, researchers know that there are more than 1000 genes for various microRNAs in humans and that gene regulation by microRNAs is found in all multicellular organisms.
In addition to mapping new microRNAs, experiments by several research groups have elucidated fundamental mechanisms. Their binding leads to inhibition of protein synthesis or degradation of mRNA. Interestingly, a single microRNA can regulate the expression of many genes. Conversely, a single gene can be regulated by multiple microRNAs, thus coordinating and fine-tuning entire gene networks.
The cellular machinery for producing functional microRNAs is also used to produce other small RNA molecules in plants and animals, for example, as a means of protecting plants from viral infections. Andrew Z. Fire and Craig C. Mello, who were awarded the Nobel Prize in 2006, described RNA interference, in which specific mRNA molecules are inactivated by the addition of double-stranded RNA molecules to cells.
Small RNAs, Great Importance
Gene regulation by microRNA has likely existed for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.
From genetic research, it is known that cells and tissues do not develop normally without microRNAs. Abnormal regulation can lead to cancer. Mutations in genes encoding microRNAs cause, among other things, congenital deafness and eye and skeletal diseases. And mutations in one of the proteins required for microRNA production lead to the DICER1 syndrome, a rare but severe syndrome associated with cancer in various organs and tissues.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Victor Ambros, PhD, a researcher at the University of Massachusetts Chan Medical School, Worcester, and Gary Ruvkun, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts, discovered microRNAs, a new class of RNA molecules.
“Their groundbreaking discovery in the small worm Caenorhabditis elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans,” said the Nobel Assembly in a statement.
Protein Expression
Genetic information flows from DNA during transcription to messenger RNA (mRNA) and then to protein biosynthesis. In that stage, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA.
Different cell types or tissues express unique sets of proteins, however. This specialized expression results from precise regulation of gene activity, so that in each cell type, only the correct set of genes is active. In this way, for example, muscle cells, intestinal cells, and various types of nerve cells can fulfill their functions.
Furthermore, gene activity must constantly be fine-tuned to adapt cell functions to changing conditions in our body and environment. When gene regulation goes awry, it can lead to serious outcomes such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulation of gene activity has been an important goal for many decades.
In the 1960s, researchers had shown that specialized proteins called transcription factors bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since that time, thousands of transcription factors have been identified. For a long time, scientists thought that the main principles of gene regulation were understood.
Roundworm Research
In the late 1980s, Dr. Ambros and Dr. Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, PhD, who received the Nobel Prize in 2002 with Sydney Brenner and John Sulston. In Dr. Horvitz’s laboratory, they studied the relatively inconspicuous, 1-mm long roundworm C elegans.
Despite its small size, C elegans has many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals. These features make it a popular animal model.
Dr. Ambros and Dr. Ruvkun were interested in genes that ensure that different cell types develop at the right time. They examined two mutated worm strains, lin-4 and lin-14, that exhibited defects in the temporal activation of specific genes during development. The laureates wanted to identify mutated genes and understand their function.
Dr. Ambros had previously shown that lin-4 appeared to be a negative regulator of lin-14. But how lin-14 activity was blocked was unknown.
Collaboration Yields Breakthrough
After his postdoctoral years, Dr. Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Systematic mapping allowed the cloning of the gene and led to an unexpected result: lin-4 produced an unusually short RNA molecule that lacked a code for protein synthesis. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14.
At the same time, Dr. Ruvkun, in his newly founded laboratory at Massachusetts General Hospital and Harvard Medical School, studied the regulation of lin-14. In contradiction to the current understanding of gene regulation, he showed that it was not the production of lin-14 mRNA that was inhibited by lin-4. The regulation seems to occur at a later stage in the gene expression process, namely through the shutdown of protein synthesis. In addition, a section in lin-14 mRNA was discovered to be necessary for inhibition by lin-4.
The two laureates compared their results, leading to a groundbreaking discovery. The short lin-4 sequence matched complementary sequences in the relevant section of the lin-14 mRNA. Dr. Ambros and Dr. Ruvkun conducted further experiments showing that the lin-4 microRNA silences lin-14 by binding to the complementary sequences of its mRNA, thus blocking the production of the lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, the microRNA, had been discovered.
Subdued Initial Response
The results were published in Cell in 1993 and initially received little attention. However, interest grew in 2000 when Dr. Ruvkun’s research group published the discovery of another microRNA encoded by let-7.
In contrast to lin-4, let-7 was highly conserved and present throughout the animal kingdom. The article sparked great interest. In the following years, hundreds of microRNAs were identified. Today, researchers know that there are more than 1000 genes for various microRNAs in humans and that gene regulation by microRNAs is found in all multicellular organisms.
In addition to mapping new microRNAs, experiments by several research groups have elucidated fundamental mechanisms. Their binding leads to inhibition of protein synthesis or degradation of mRNA. Interestingly, a single microRNA can regulate the expression of many genes. Conversely, a single gene can be regulated by multiple microRNAs, thus coordinating and fine-tuning entire gene networks.
The cellular machinery for producing functional microRNAs is also used to produce other small RNA molecules in plants and animals, for example, as a means of protecting plants from viral infections. Andrew Z. Fire and Craig C. Mello, who were awarded the Nobel Prize in 2006, described RNA interference, in which specific mRNA molecules are inactivated by the addition of double-stranded RNA molecules to cells.
Small RNAs, Great Importance
Gene regulation by microRNA has likely existed for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.
From genetic research, it is known that cells and tissues do not develop normally without microRNAs. Abnormal regulation can lead to cancer. Mutations in genes encoding microRNAs cause, among other things, congenital deafness and eye and skeletal diseases. And mutations in one of the proteins required for microRNA production lead to the DICER1 syndrome, a rare but severe syndrome associated with cancer in various organs and tissues.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Victor Ambros, PhD, a researcher at the University of Massachusetts Chan Medical School, Worcester, and Gary Ruvkun, PhD, professor of genetics at Harvard Medical School in Boston, Massachusetts, discovered microRNAs, a new class of RNA molecules.
“Their groundbreaking discovery in the small worm Caenorhabditis elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans,” said the Nobel Assembly in a statement.
Protein Expression
Genetic information flows from DNA during transcription to messenger RNA (mRNA) and then to protein biosynthesis. In that stage, mRNAs are translated so that proteins are produced according to the genetic instructions stored in the DNA.
Different cell types or tissues express unique sets of proteins, however. This specialized expression results from precise regulation of gene activity, so that in each cell type, only the correct set of genes is active. In this way, for example, muscle cells, intestinal cells, and various types of nerve cells can fulfill their functions.
Furthermore, gene activity must constantly be fine-tuned to adapt cell functions to changing conditions in our body and environment. When gene regulation goes awry, it can lead to serious outcomes such as cancer, diabetes, or autoimmune diseases. Therefore, understanding the regulation of gene activity has been an important goal for many decades.
In the 1960s, researchers had shown that specialized proteins called transcription factors bind to specific regions of DNA and control the flow of genetic information by determining which mRNAs are produced. Since that time, thousands of transcription factors have been identified. For a long time, scientists thought that the main principles of gene regulation were understood.
Roundworm Research
In the late 1980s, Dr. Ambros and Dr. Ruvkun were postdoctoral researchers in the laboratory of Robert Horvitz, PhD, who received the Nobel Prize in 2002 with Sydney Brenner and John Sulston. In Dr. Horvitz’s laboratory, they studied the relatively inconspicuous, 1-mm long roundworm C elegans.
Despite its small size, C elegans has many specialized cell types such as nerve and muscle cells that are also found in larger, more complex animals. These features make it a popular animal model.
Dr. Ambros and Dr. Ruvkun were interested in genes that ensure that different cell types develop at the right time. They examined two mutated worm strains, lin-4 and lin-14, that exhibited defects in the temporal activation of specific genes during development. The laureates wanted to identify mutated genes and understand their function.
Dr. Ambros had previously shown that lin-4 appeared to be a negative regulator of lin-14. But how lin-14 activity was blocked was unknown.
Collaboration Yields Breakthrough
After his postdoctoral years, Dr. Ambros analyzed the lin-4 mutant in his newly established laboratory at Harvard University. Systematic mapping allowed the cloning of the gene and led to an unexpected result: lin-4 produced an unusually short RNA molecule that lacked a code for protein synthesis. These surprising results suggested that this small RNA from lin-4 was responsible for inhibiting lin-14.
At the same time, Dr. Ruvkun, in his newly founded laboratory at Massachusetts General Hospital and Harvard Medical School, studied the regulation of lin-14. In contradiction to the current understanding of gene regulation, he showed that it was not the production of lin-14 mRNA that was inhibited by lin-4. The regulation seems to occur at a later stage in the gene expression process, namely through the shutdown of protein synthesis. In addition, a section in lin-14 mRNA was discovered to be necessary for inhibition by lin-4.
The two laureates compared their results, leading to a groundbreaking discovery. The short lin-4 sequence matched complementary sequences in the relevant section of the lin-14 mRNA. Dr. Ambros and Dr. Ruvkun conducted further experiments showing that the lin-4 microRNA silences lin-14 by binding to the complementary sequences of its mRNA, thus blocking the production of the lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, the microRNA, had been discovered.
Subdued Initial Response
The results were published in Cell in 1993 and initially received little attention. However, interest grew in 2000 when Dr. Ruvkun’s research group published the discovery of another microRNA encoded by let-7.
In contrast to lin-4, let-7 was highly conserved and present throughout the animal kingdom. The article sparked great interest. In the following years, hundreds of microRNAs were identified. Today, researchers know that there are more than 1000 genes for various microRNAs in humans and that gene regulation by microRNAs is found in all multicellular organisms.
In addition to mapping new microRNAs, experiments by several research groups have elucidated fundamental mechanisms. Their binding leads to inhibition of protein synthesis or degradation of mRNA. Interestingly, a single microRNA can regulate the expression of many genes. Conversely, a single gene can be regulated by multiple microRNAs, thus coordinating and fine-tuning entire gene networks.
The cellular machinery for producing functional microRNAs is also used to produce other small RNA molecules in plants and animals, for example, as a means of protecting plants from viral infections. Andrew Z. Fire and Craig C. Mello, who were awarded the Nobel Prize in 2006, described RNA interference, in which specific mRNA molecules are inactivated by the addition of double-stranded RNA molecules to cells.
Small RNAs, Great Importance
Gene regulation by microRNA has likely existed for hundreds of millions of years. This mechanism has enabled the evolution of increasingly complex organisms.
From genetic research, it is known that cells and tissues do not develop normally without microRNAs. Abnormal regulation can lead to cancer. Mutations in genes encoding microRNAs cause, among other things, congenital deafness and eye and skeletal diseases. And mutations in one of the proteins required for microRNA production lead to the DICER1 syndrome, a rare but severe syndrome associated with cancer in various organs and tissues.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.