Throughout their careers, the two Nobel laureates, Professor Victor Ambros, University of Massachusetts Medical School, Worcester, and Gary Ruvkun, Massachusetts General Hospital, Boston, Harvard Medical School, have shared a common interest in understanding how different cell types develop – and together they discovered a completely new principle of gene regulation, mediated by microRNAs. 

In a nutshell, MicroRNAs are snippets of genetic material that can turn genes off. Scientists previously believed that only proteins could do this, and in the 1960s it was shown that specialized proteins, transcription factors, controlled the flow of genetic information by determining which mRNAs are produced.However, findings by the two laureates published in Cell 1993 would change this fact.

This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types, and is essential for complex multicellular life.

“Whereas proteins in the nucleus regulate RNA transcription and splicing, microRNAs control the translation and degradation of mRNA in the cytoplasm. This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types, and is essential for complex multicellular life,” states Rickard Sandberg, Professor at the Department of Cell and Molecular Biology at Karolinska Institutet and Member of the Nobel Assembly at Karolinska Institutet.

From C. elegans to humans

In the 1980s the two laureates, as postdoctoral fellows in the Robert Horvitz lab, were studying the roundworm C. elegans to better understand the genes that control the timing of activation of different genetic programs. Ambros studied one mutant roundworm, lin-4, that could not advance past a particular developmental stage. He sought out to identify the gene altered in the lin-4 worms. Methodical mapping allowed the cloning of the gene and led to the finding that the lin-4 gene produced an unusually short RNA molecule that lacked a code for protein production. “This was a surprising discovery of a tiny non-coding RNA that could regulate mRNA translation and degradation through basepairing with sequences in mRNA untranslated regions. He discovered the first microRNA,” describes Sandberg. Ambros’ results suggested that this small RNA from lin-4 was responsible for inhibiting a gene called lin-14, but it was still unknown how this worked.

During the same period of time, Ruvkun had investigated the regulation of the lin-14 gene and he demonstrated that the critical region for lin-4’s effect is in the UTR (untranslated region). “Upon sharing the information, they discovered that the microRNA directly base-paired with the mRNA,” says Sandberg.

In 2000 Ruvkun’s research group also published the discovery of another microRNA. When the second microRNA was discovered and also found to be highly conserved across the animal kingdom, it spurred lots of cloning activities and soon it was realized that microRNAs are prevalent across multicellular organisms, with a subset being highly conserved across evolution.

Beautiful as it is

Today, thanks to Ambros’ and Ruvkun’s discoveries, we know the human genome codes for over one thousand microRNAs, and advances are being made in developing microRNA-based diagnostics and therapeutics for diseases. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, and eye and skeletal disorders. When asked about exciting, future applications of microRNA, Sandberg emphasizes that he thinks that the prize is already beautiful as it is. “They uncovered a regulatory system that has important functions in most, if not all, cell types of our bodies, and generally in multicellular organisms,” he says.

They uncovered a regulatory system that has important functions in most, if not all, cell types of our bodies, and generally in multicellular organisms.

Sandberg and his colleagues are currently not directly focusing on microRNAs in their lab, but he actually did so during his postdoctoral period he says. “I studied how alternative polyadenylation site usage, e.g. after T-cells gets activated, results in mRNAs with smaller 3’UTRs. This results in higher protein production since they can escape the microRNA mediated suppression.”

Uncovering principles and mechanisms of gene regulation

Rickard Sandberg’s lab at Karolinska Institutet focuses on uncovering the principles and mechanisms of gene regulation by developing strategies for more precise measurements of RNA in single cells.

Rickard Sandberg, Professor, Karolinska Institutet, and Member, the Nobel Assembly at Karolinska Institutet. Photo: Johannes Frandsén

“We have recently found several principles explaining how transcriptional bursting is encoded in the regulatory DNA sequences, demonstrating the importance of promoter regions for burst sizes and enhancers for burst frequencies,” he explains. “Moreover, we have demonstrated that in genes that generate more RNA molecules per burst, the synthesis rate is higher whereas the time period of the burst stays the same. This teases out fundamental principles for transcriptional regulation and dynamics in cells.”

Sandberg and his colleagues are currently working on how alternative splicing is regulated across cell types in the brain to specify cellular functions. Despite great efforts to molecularly characterize the brain in the past decade, very little data exist on alternative splicing.

“We would like to investigate the degree to which alternative splicing is used to diversify neuronal functions in the brain, e.g. molecular compatibilities between cell types and functional signal transmission through synapses. This has ramifications for understanding the extent to which neuronal wiring is hardwired by molecular cues, and gives better insights into disease progression, e.g. neurodegeneration and neuropsychiatry, that is intricately linked to splicing (or rather mis-splicing),” he explains.

Throughout their careers, the two Nobel laureates, Professor Victor Ambros, University of Massachusetts Medical School, Worcester, and Gary Ruvkun, Massachusetts General Hospital, Boston, Harvard Medical School, have shared a common interest in understanding how different cell types develop – and together they discovered a completely new principle of gene regulation, mediated by microRNAs. 

In a nutshell, MicroRNAs are snippets of genetic material that can turn genes off. Scientists previously believed that only proteins could do this, and in the 1960s it was shown that specialized proteins, transcription factors, controlled the flow of genetic information by determining which mRNAs are produced.However, findings by the two laureates published in Cell 1993 would change this fact.

This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types, and is essential for complex multicellular life.

“Whereas proteins in the nucleus regulate RNA transcription and splicing, microRNAs control the translation and degradation of mRNA in the cytoplasm. This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types, and is essential for complex multicellular life,” states Rickard Sandberg, Professor at the Department of Cell and Molecular Biology at Karolinska Institutet and Member of the Nobel Assembly at Karolinska Institutet.

From C. elegans to humans

In the 1980s the two laureates, as postdoctoral fellows in the Robert Horvitz lab, were studying the roundworm C. elegans to better understand the genes that control the timing of activation of different genetic programs. Ambros studied one mutant roundworm, lin-4, that could not advance past a particular developmental stage. He sought out to identify the gene altered in the lin-4 worms. Methodical mapping allowed the cloning of the gene and led to the finding that the lin-4 gene produced an unusually short RNA molecule that lacked a code for protein production. “This was a surprising discovery of a tiny non-coding RNA that could regulate mRNA translation and degradation through basepairing with sequences in mRNA untranslated regions. He discovered the first microRNA,” describes Sandberg. Ambros’ results suggested that this small RNA from lin-4 was responsible for inhibiting a gene called lin-14, but it was still unknown how this worked.

During the same period of time, Ruvkun had investigated the regulation of the lin-14 gene and he demonstrated that the critical region for lin-4’s effect is in the UTR (untranslated region). “Upon sharing the information, they discovered that the microRNA directly base-paired with the mRNA,” says Sandberg.

In 2000 Ruvkun’s research group also published the discovery of another microRNA. When the second microRNA was discovered and also found to be highly conserved across the animal kingdom, it spurred lots of cloning activities and soon it was realized that microRNAs are prevalent across multicellular organisms, with a subset being highly conserved across evolution.

Beautiful as it is

Today, thanks to Ambros’ and Ruvkun’s discoveries, we know the human genome codes for over one thousand microRNAs, and advances are being made in developing microRNA-based diagnostics and therapeutics for diseases. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, and eye and skeletal disorders. When asked about exciting, future applications of microRNA, Sandberg emphasizes that he thinks that the prize is already beautiful as it is. “They uncovered a regulatory system that has important functions in most, if not all, cell types of our bodies, and generally in multicellular organisms,” he says.

They uncovered a regulatory system that has important functions in most, if not all, cell types of our bodies, and generally in multicellular organisms.

Sandberg and his colleagues are currently not directly focusing on microRNAs in their lab, but he actually did so during his postdoctoral period he says. “I studied how alternative polyadenylation site usage, e.g. after T-cells gets activated, results in mRNAs with smaller 3’UTRs. This results in higher protein production since they can escape the microRNA mediated suppression.”

Uncovering principles and mechanisms of gene regulation

Rickard Sandberg’s lab at Karolinska Institutet focuses on uncovering the principles and mechanisms of gene regulation by developing strategies for more precise measurements of RNA in single cells.

Rickard Sandberg, Professor, Karolinska Institutet, and Member, the Nobel Assembly at Karolinska Institutet. Photo: Johannes Frandsén

“We have recently found several principles explaining how transcriptional bursting is encoded in the regulatory DNA sequences, demonstrating the importance of promoter regions for burst sizes and enhancers for burst frequencies,” he explains. “Moreover, we have demonstrated that in genes that generate more RNA molecules per burst, the synthesis rate is higher whereas the time period of the burst stays the same. This teases out fundamental principles for transcriptional regulation and dynamics in cells.”

Sandberg and his colleagues are currently working on how alternative splicing is regulated across cell types in the brain to specify cellular functions. Despite great efforts to molecularly characterize the brain in the past decade, very little data exist on alternative splicing.

“We would like to investigate the degree to which alternative splicing is used to diversify neuronal functions in the brain, e.g. molecular compatibilities between cell types and functional signal transmission through synapses. This has ramifications for understanding the extent to which neuronal wiring is hardwired by molecular cues, and gives better insights into disease progression, e.g. neurodegeneration and neuropsychiatry, that is intricately linked to splicing (or rather mis-splicing),” he explains.