A New Era for MicroRNA

Berta Strulovici, Vice-President Research, Automated Biotechnology Dept, Merck & Co. speaks with NGP, and provides some insight into the recent emergence of MicroRNA.

NGP. How does MicroRNA play a major role in normal tissue development and cellular differentiation?
BS. Well, it is worth mentioning that MicroRNAs (miRNA) have been somewhat neglected until recently, when it became clear that they have great promise in normal tissue development. Mature miRNA are small RNAs, about 22 nucleotides in length,that are encoded in the genomes of every organism. They bind to the 3'UTR of mRNAs serving the role of translational suppressors, thereby regulating protein production. Hundreds of miRNAs have been identified in humans, and there is emerging evidence that miRNAs regulate various physiological and pathological pathways such as cell differentiation, cell proliferation and tumorigenesis.

Although hundreds of miRNAs have been identified, much less is known about their biological function. However, recent work is starting to shed light on the importance of miRNA in hematopoiesis, with the revelation of tissue-specific expressed miRNAs which may have a critical role in normal hematopoiesis and hematopoietic malignancies. New studies combining gene expression data and functional assay results have identified roles for several miRNAs in adipocyte and skeletal muscle differentiation.

NGP. What are your thoughts on how miRNAs regulate biological function?
BS. Recent studies open the possibility that miRNAs may contribute to common metabolic diseases and to cancer, thus pointing to potential novel therapeutic opportunities based on targeting miRNAs. The question of how miRNAs regulate biological function is complex, as they appear to have very diverse roles. It is possible that functional specificity depends on whether a miRNA has more restricted expression or whether it silences a limited or broader number of mRNAs. The same miRNA may also serve different functions depending on the biological need in different cells/tissues.

NGP. How do you feel miRNAs represent a promising new class of cancer biomarkers?
BS. Cancer is a complex genetic disease involving expression abnormalities of both coding and noncoding genes (such as miRNAs). New evidence points to the fact that alterations in miRNAs are involved in the initiation and progression of human cancer. There appear to be widespread differential expression of miRNA genes in malignant compared with normal tissue or cells for many different reasons, such as their location in cancer-associated genomic regions and alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumors has identified signatures associated with diagnosis, stage of tumor, progression, prognosis and response to treatment. This, in fact, means that these miRNA expression signatures can be effectively used as cancer biomarkers. The unique pattern, resulting from the altered expression of specific miRNAs provides a diagnostic biomarker for the detection of the disease.

NGP. How does gene expression analysis move the drug discovery process towards a more genomic orientation?
BS. Drug discovery has traditionally started with a biochemical pathway implicated in a pathophysiological process. Through the advent of molecular biology and gene cloning techniques, drug discovery targets were produced and assayed against chemical libraries in order to identify compounds that had the potential to modulate the activity of the biochemical entity. The limitations to this process, which is still in place today, is that the number of potential targets is limited by the number of cloned genes, and the process of target validation (i.e. linking the target to therapeutic utility) is slow and it requires in depth knowledge of the pathophysiological process. The dream is to be able to link the Human Genome information to disease causality.

Gene expression analysis is being used routinely in many laboratories around the word. In drug discovery, they serve as powerful tools for investigating the mechanism of action of various drug candidates. Microarrays have the ability to contribute substantially to the analysis of metabolic pathways, the delineation and prediction of adverse drug events, serve as biomarkers for the selection of drug responders, and play a critical role in the strategies to identify genes involved in disease processes as new potential targets for drug intervention. The power of microarrays can be realized only with informatics tools such as the Rosetta Resolver System, which is a comprehensive gene expression analysis tool that combines data analysis with a powerful database.

NGP. What are your thoughts on the role of miRNA has in molecular biology and genetics?
BS. Ever since the recent discovery of miRNA as a major component of gene regulation, scientists have been racing to understand their function during the development of multicellular animals and plants. These small regulatory RNAs were first discovered in C. elegans as important regulators of development timing. Since then, they have been implicated in other aspects of development in vertebrates and invertebrates. The roles miRNA may be playing in cell signaling is still not being understood, and it is a matter of intense studies.

NGP. From your perspective, what is the future potential of miRNA for research?
BS. I believe that a lot more work needs to be done in order to gain a better understanding of the huge potential these small regulatory RNA molecules known as miRNAs may have. Like in any emerging field, when one opens a premier scientific journal such as Nature, Science, Cell, etc., there are hundreds of articles published on the subject. The dust will eventually settle and we will come to a better understanding of what miRNAs do in all their complexity. I believe that their potential for drug discovery is enormous, and data to this effect is already coming together, particularly in oncology research. This is a field that is actively being worked at within Merck, at the Rosetta site.