Cancer Research UK today launches a major international initiative to use RNA interference – hailed as the biggest scientific breakthrough in a decade – to systematically uncover the functions of our genes.
The project will take advantage of the extraordinary ability of RNA interference to specifically switch off individual genes while leaving all others unaffected.
Details of the initiative – a collaboration with the Netherlands Cancer Institute – are announced on Cancer Research UK’s first anniversary.
Scientists will build on the huge success of the Human Genome Project, inactivating almost 10,000 genes, one at a time, in order to find out precisely what they do and how they might contribute to cancer’s development.
Their ultimate aim will be to identify the cluster of genes which constitute the essence of cancer – likely to be ideal targets for new anti-cancer drugs.
Speaking at Cancer Research UK’s National Supporters’ Day conference, Chief Executive Sir Paul Nurse says: “Despite the massive advances in sequencing the DNA in the human genome, the function of most of our genes remains a mystery. The next big challenge for scientists is to find out exactly what they’re all doing, so we can work out which of them are playing important roles in cancer and other diseases.
“Such an endeavour has never before been possible, because dissecting out the function of a single gene from around 35,000 is extremely difficult. But thanks to the incredible discovery of RNA interference, we think we should now be able to crack the problem.”
RNA interference is a natural process discovered in the obscure nematode worm. The nematode uses tiny pieces of double-stranded RNA to specifically switch off certain rogue genes that would otherwise cause it harm.
Researchers have found that synthetically produced RNA sequences can be used to target genes in human cells – a finding lauded as 2002’s ‘breakthrough of the year’ by Science magazine and widely considered to be the most important discovery of the last decade.
Scientists from Cancer Research UK and the Netherlands Cancer Institute plan to use RNA interference to create cells in which all genes are fully functional bar one. They will genetically engineer cells with DNA coding for a specific piece of interference RNA, permanently blocking a particular gene. The library of cells will be available for use throughout both organisations, allowing researchers to study the behaviour of cells in detail, and particularly how they respond to losing individual genes.
Researchers will also bombard cancer cells with 30,000 pieces of interference RNA in order to answer one of the ultimate questions in cancer biology – what is the genetic essence of a malignant cell?
They will screen the treated cells for the handful which have reverted to type and become normal again. The set of genes switched off by RNA interference in these cells may represent the most crucial group of cancer genes in the human genome and are likely to be extremely good targets for future anti-cancer drugs.
Dr Julian Downward of the Cancer Research UK London Research Institute is leading the initiative together with Dr René Bernards at the Netherlands Cancer Institute.
Dr Downward comments: “This project will help move forward the frontiers of medical science, from knowing the sequences of DNA that make up our genome, to knowing how these sequences work together to form a functional human being.
“Using RNA interference, we should be able to find out precisely what we need to take away from a cancerous cell in order to make it normal again – essentially we will be dismantling cancer at the level of its genes.”
An initial pilot study will look at 300 genes. If, as expected, it proves successful, the project will be rolled out to cover a further 8,000 or so genes, at the cost of over half a million pounds. Eventually, the research may be extended to cover the entire human genome.
Dr Downward adds: “In times gone by, it took a few years before the very latest technologies filtered down to charities and academic laboratories, so it’s really exciting to be among the pioneers of the use of RNA interference for cancer research.”
Sir Paul adds: “The entire scientific community is tremendously excited at the potential of RNA interference. It’s really pleasing that a result of the merger to form Cancer Research UK, we’ve now got the financial clout and expertise to use such a powerful new technology for research into cancer.”
He adds: “This initiative will further push forward our understanding of the way our genetic information functions in healthy tissue and in disease.”
Scientists have recently begun to gain a good understanding of how RNA interference works. To use the information contained in a gene to make a protein molecule, a cell first has to make an intermediate molecule called a messenger RNA. But interference RNA latches onto specific molecules of messenger RNA and seems to direct their destruction – selectively switching off the targeted gene.
In the new project, a library of different vectors containing interference RNA for each chosen gene will be created. Scientists will transfer these vectors to cells to create ‘knock-downs’ for individual genes.
Cancer Research UK’s Prof David Glover made one of the early contributions to the development of RNA interference for use in mammalian cells. CRT, the charity’s technology transfer organisation, is managing a patent covering this application and is in discussions with a number of interested parties to enable this technology to be utilised over a wide range of applications.