Professor Dr. Elisa Izaurralde has made important contributions to the field of RNA biology in recent years. The managing director of the Max Planck Institute for Developmental Biology in Tübingen explores the complex mechanisms of cellular gene regulation. For her work on mRNA regulation she has now been honored with the prestigious Ernst Jung Prize for Medicine.
Donated by the Hamburg based merchant Ernst Jung, the Prize has been awarded every year since 1976 for major work in the field of human medicine. With a prize money of 300,000 Euros, it has become one of Europe's most important research awards. The jury honored Izaurraldes pioneering work in the field of RNA-mediated gene regulation. The relatively new research field has been considered for the second time already. Thomas Tuschl, who described the mechanism of RNA interference (RNAi) – originally identified in nematodes – for the first time in humans, received the award in 2008. Izaurralde got this year's prize now at a ceremony in Hamburg.
"This reflects the great hopes that now rest on RNA research," said Izaurralde, who shares the prize with the United States based cell biologist Professor Peter Walter. A surprising development, considering that RNA was neglected scientifically for a long time. Postulated in 1956 by Francis Crick, the dogma of molecular biology once centered on the view that RNA molecules represent just mere message transporters between DNA and functionally active proteins or components of the protein synthesis machinery. More attention was given to RNA only when it became apparent that they not only transport the encoded genetic information from DNA to the site of the protein synthesis, the so-called ribosomes, but also hold important regulatory functions in the cells.
"There are two discoveries that have revolutionized the RNA field," said Izaurralde. The first was to demonstrate that some cellular RNAs have catalytic activity. One stricking example is the ribosomal RNA, which is not only involved in the structural configuration of the ribosome, but is catalytically active itself by accomplishing the chemical linkage of the amino acids in protein synthesis. "Only enzymes had been granted this capability before," said Izaurralde.
The second breakthrough discovery was the identification of small regulatory noncoding RNAs. "These very short, only about 20 nucleotides long RNA fragments were originally held for cellular degradation products of mRNA", said Izaurralde. It was only in 1998 that Andrew Fire and Craig Mello created an entirely new field of research when they made the Nobel Prize-winning observation that in nematodes so-called short interfering RNA (siRNA) can shut down the function of whole genes.
"The siRNA has developed quickly into an important tool for basic research," said Izaurralde. So far, to investigate the function of genes and the effect of their product, knockouts in the organims or the cells of study had to be created in which the functional gene was inactivated or deleted from the genome. "Now, however, we can investigate the function of a protein without making any changes to the DNA content", says Izaurralde. This is possible because the siRNA induces mRNA degradation what subsequently prevents protein production. "This process represents rather a knockdown of a gene than a knockout", explains the scientist.
Izaurralde itself focuses her research on another group of small non-coding RNAs - the so-called microRNA (miRNA). These are short RNA molecules, comprising only about 21 to 22 nucleotides, that are produced within the cells of the organism. "The miRNA plays an important role in mRNA silencing, by a process that is closely related to RNA interference," says Izaurralde. Like siRNA the miRNA binds to mRNA and triggers their degradation or alternatively inhibits their translation into a functional protein.
In contrast to siRNA which binds only to fully complementary mRNA, the miRNA may also interact with incomplete complementary areas and target hundreds of different mRNA species. "In this way the cells have an efficient tool to fine tune the activity of their own genes - even after the transcription of the genetic information into mRNA," said Izaurralde. Approximately 30 percent of all human genes are regulated by miRNAs, including numerous transcription factors. "This form of RNA-mediated gene regulation, that is widespread among higher eukaryotes, is significantly faster and more sensitive than a regulation at the DNA level," Izaurralde explains.
Izaurralde, who is a scientific director at the Max Plack Institute in Tübingen since 2005, has contributed significantly to the elucidation of the exact mechanisms of RNA silencing in recent years. She showed that miRNA has to combine with proteins from the Argonaute family and a protein termed GW182 to be able to silence the target mRNA. "For the function of miRNA GW182 is essential," said Izaurralde, who identified the crucial protein in complex screening processes. The next step will now be the deciphering of the exact crystal structure of the protein. "Only then it will be possible for us to understand the process of miRNA-mediated gene regulation at the molecular level," said Izaurralde.
The post-transcriptional gene regulation by miRNAs is vital in the control of numerous fundamental biological processes. "It is therefore not surprising that the miRNA appears to play a role in the development of cancer as well," said Izaurralde. All malignant tumors examined to date exhibit altered miRNA expression patterns. "It is not always clear whether this reflects the cause or the consequence of the complex disease process," said Izaurralde. However, it was shown already that certain miRNA genes that promote tumorigenesis are mutated in different cancers or their expression is greatly altered. This makes miRNA not only a promising diagnostic and prognostic biomarker, but also provides a novel therapeutic approach in the treatment of cancer.
But the modulation of the function of mRNAs seems to be a promising therapeutic target for a variety of diseases. "It could be a tool for various metabolic disorders where the overexpression of certain genes is the primary cause," said Izaurralde. For now there are still some hurdles to overcome. In particular, the organ- and cell-specific uptake of small RNA molecules in the body is an unsolved problem. "But preliminary studies in animal models suggest that this procedure is feasible at least for organs such as the liver" said Izaurralde.
Max Planck Institute for Developmental Biology
Prof. Dr. Elisa Izaurralde
Tel.: +49 (0)7071/ 601 - 1350