Tiny RNA molecules have a big impact
RNA – regarded as a humble carrier of messages and fetcher of protein building information – has been living in DNA’s shadow for ages. The twinned spiral strands of DNA, which contain all the genetic information for making an organism, have come to represent the molecule of life, and the central dogma of biology has been that this genetic information is passed by rote transcription through DNA’s single-stranded cousin, RNA, to make proteins. Fifty years on, RNA has finally stepped into the limelight – revolutionizing ideas about how genes are regulated.
This so-called “RNA revolution” in molecular biology follows a series of recent discoveries of new types of RNA. These RNA molecules are not produced to be mere messengers; rather, the RNA molecules themselves are the end product, and they play a key role in the development of the organism. One such family of RNA molecules is the microRNAs (miRNA). Smaller than the well-known messenger RNA, these molecules help regulate the process by which genetic information is turned into proteins – gene expression. They do this by binding to messenger RNA molecules, preventing them from carrying out protein synthesis. RNA interference, as this process is called, provides the cell with a way of controlling the levels of hundreds of different proteins by turning genes off at the appropriate times.
Dr. Eran Hornstein of the Weizmann Institute’s Molecular Genetics Department and his team investigate how miRNAs help to regulate the various kinds of gene expression that lead to normal development as well as to disease. “We know that when some protein-coding genes acquire mutations, the result is disease. What we don’t know is what happens when miRNAs acquire mutations. Could faulty miRNAs also result in disease? Would their different mechanism of action imply a different set of diseases? If miRNAs are indeed involved in the emergence of genetic diseases, then new cures could be developed that target these miRNA genes,” says Hornstein.
Hornstein’s research specifically focuses on the role of miRNAs in the development of the pancreas, bone and cartilage, and how malfunctions in their genetic programs may contribute to such common diseases in these organs as diabetes mellitus, cleft palate and osteoporosis. “Cancer, too, begins when genetic programs go awry, so studies of the faulty regulation of miRNAs might provide new insights into the role of small RNAs in this devastating disease,” he says.
The team employs various types of research tools to identify the different miRNAs as well as their effects. The lab mainly uses mouse models in which they are able to “knock out” a whole miRNA pathway or specific miRNA genes. These perturbations in a live context enable the scientists to deduce the miRNAs’ role in normal development.
So far, the group has discovered that if miRNAs are inactivated in pancreatic beta cells – the cells that secrete the hormone insulin, which regulates blood glucose levels – the mice exhibit hallmarks of diabetes mellitus. Hornstein’s team is now characterizing the molecular mechanisms by which miRNAs regulate the balance of glucose and insulin in the body.
Another avenue of research undertaken by the lab is uncovering the contribution of miRNAs to the development of skeletal tissues. Genetically removing miRNAs from skeletal tissues, for example, results in such striking deformities as complete loss of the skull, dwarfism and cleft palate. The team is now deciphering which genetic pathways go wrong in each instance and the specific miRNAs involved.
Hornstein: “Scientists are only now beginning to understand the true impact of miRNAs, both in the normal development of an organism and in disease. This newfound knowledge may one day lead to the development of new therapeutics that could target previously unknown mechanisms.” Indeed, scientists have already created synthetic versions of miRNAs that are both important research tools for biologists and possible new therapies for a number of diseases. Further research will no doubt revolutionize the way doctors treat certain diseases in the future.
Dr. Eran Hornstein was born in Jerusalem in 1971. After a five-year army service, Hornstein attended the Hebrew University-Hadassah School of Medicine in Jerusalem. “I initially went to med school with the aim of becoming a physician. But I was also interested in science, so I decided to conduct basic research in parallel, in the lab of Prof. Oded Meyuhas of the Hebrew University’s Biochemistry Department.” Although medical training was exciting, Hornstein felt more attracted to basic research and thus, after completing his internship, he went on to postdoctoral studies with Prof. Cliff Tabin at Harvard Medical School, focusing on developmental biology.
“I feel that my medical training influences my world of associations and my inclination to study the basic molecular genetic mechanisms underlying disease states – especially as it ultimately has a significant impact on humans.”
Hornstein joined the Weizmann Institute as a senior scientist in 2006 and works with a team of seven students and three postdocs.
Dr. Eran Hornstein’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Kekst Family Center for Medical Genetics; and the Kirk Center for Childhood Cancer and Immunological Disorders. Dr. Hornstein is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair.