RNA Interference 1998 – Silencing Target Gene Expression

Science journalist Kat Arney wrote:

“A small, transparent worm seems an unusual character in one of the most exciting science stories of the late twentieth century. Yet without these tiny worms, known to scientists as Caenorhabditis elegans, American biologists Andrew Fire and Craig Mello would not have won the 2006 Nobel Prize in Physiology or Medicine.”

As background, genes are determined by  DNA  (deoxyribonucleic acid) on chromosomes in our cells. DNA information can be copied into  mRNA (messenger ribonucleic acid), and proteins can then be synthesised using the information in mRNA. In 1998, Fire, Mello and colleagues described how they could selectively suppress specific gene activity after exposing worms to suitable RNA sequences, in a process called RNA interference (RNAi).

• In organisms such as plants, fruit flies and worms, RNAi can be initiated in the laboratory using long double-stranded RNAs (dsRNAs) corresponding to a target gene to be inactivated. 
• After entering cells, dsRNAs are broken down by the cellular enzyme  Dicer  into smaller interfering RNAs, called siRNAs. 
• The siRNAs assemble into RNA-induced silencing complexes (RISCs), a protein complex containing  Argonaute. 
• With the help of Argonaute, RISCs then attack mRNAs matching the siRNA sequences, break them down and destroy them, thereby silencing expression of the target gene. 

Scientists do not use long dsRNAs in mammals because they are recognised as foreign genetic material and trigger a strong immune response. However, they can experiment with RNAi in mammals by bypassing Dicer and using shorter, appropriate siRNAs.

Normal human cells probably use RNAi to defend against viruses, as seen in plants and invertebrates, and to regulate gene expression and cell development. MicroRNAs are short RNA fragments produced naturally within cells. Researchers hope RNAi could be used in medical treatments, including cancer control through silencing genes in tumour cells, treatment of neurodegenerative diseases and antiviral therapies.

Description of the article image: Researchers first described using RNA interference to selectively suppress specific genes in the worm Caenorhabditis elegans. In the image, fluorescence confocal microscopy demonstrates the presence of two proteins in a living specimen.

Historical figures mentioned in the article: Andrew Zachary Fire (b. 1959), Craig Cameron Mello (b. 1960)

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