Pioneering RNA interference library completed

Cancer Research UK and the Netherlands Cancer Institute have completed the first stage of a landmark initiative to systematically uncover the function of our genes, the charities announce.

Their pioneering RNA interference library – a collection of 24,000 designer molecules, created to inactivate a total of 8,000 different human genes – will now be rolled out to research groups across the Netherlands and the UK.

The library exploits the unique ability of RNA interference to switch off a single one of a cell’s 35,000 genes. Scientists will now begin the second phase of the initiative: working out what individual genes do by studying how cells are affected by their loss.

Cancer Research UK put over a quarter of a million pounds into the RNA interference library, which also received funding from the Netherlands Cancer Institute and a number of other Dutch partners.

Building on the huge success of the Human Genome Project, scientists will use the library to help identify the cluster of genes representing ‘the essence of cancer’. These genes, crucial for the development of the disease, are likely to be ideal targets for the future generation of anti-cancer drugs.

Scientists produced designer molecules of DNA called vectors, each of which codes for a piece of interference RNA and selectively inactivates a single gene. To ensure that gene inactivation was possible in a range of different conditions and in different types of cells, they developed three vectors for each gene they were targeting – adding up to the total of 24,000.

The library is the first in the world to focus on cancer and among the first to use vectors, which allow genes to be switched off more stably than with other systems and for longer periods of time. Completion of the first phase of the project comes fourteen months after its launch and just over two years after Cancer Research UK was formed.

Cancer Research UK’s Dr Julian Downward, leading the project at the charity’s London Research Institute, says: “The incredible power of RNA interference will allow us to make sense of the jumble of information produced by the Human Genome Project.

“We have the DNA sequence for every single human gene, but what we really need to know is what these genes are doing and in particular, which of them are contributing to cancer. With our library now completed, we should be able to answer some fundamental questions about the function of our genes and how they work together to produce a healthy cell or a cancerous one.”

Dr René Bernards, overall project leader at the Netherlands Cancer Institute, says: “This library will be a fantastic new tool to help us dissect out the functions of the hundreds, perhaps even thousands, of genes which play a role in cancer. It will greatly accelerate research into the genetic origins of the disease.”

Cancer Research UK’s technology transfer subsidiary, Cancer Research Technology (CRT), will license copies of the library to a number of pharmaceutical companies, with the proceeds being ploughed back into the charity’s research budget.

Harpal Kumar, Chief Executive of CRT, says: “The library is a fantastic innovation and one which will make it far easier to explore the mysteries of how our genes work together and why their malfunction can lead to cancer.

“Not only will the library be a major boost to public sector research, but it will also be extremely valuable within the commercial sector. It has the potential to transform the study of gene function and accelerate drug development.”

Scientists from the two charities will use the RNA interference library to create cells in which all genes are fully functional bar one. They will engineer cells with one of the library’s DNA vectors – coding for a specific piece of interference RNA – in order to permanently block a particular gene. Researchers will study the behaviour of cells in detail and particularly how they respond to losing individual genes.

They will also bombard cancer cells with numerous vectors simultaneously, in order to answer one of the ultimate questions in cancer biology – what is the genetic basis of a malignant cell? They will screen the treated cells for the handful that 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.

Cancer Research UK’s Chief Executive, Professor Alex Markham, says: “The word breakthrough is used much too often in connection with science, but the discovery of RNA interference may well justify the term.

“With the completion of this library, our researchers will be able to select any one of 8,000 genes and turn it off, if not at the flick of a switch then certainly with the squeeze of a pipette.

“For the first time, we’ll be able to quickly and easily dissect out the function of individual genes from the 35,000 in the human genome, which will be of huge benefit in identifying targets for the anti-cancer drugs of the future.”

ENDS

Note to editors:

Since its discovery, in the mid nineties, RNA interference has had a huge impact on medical research. It is a natural process and was first found in the humble nematode worm, which uses tiny pieces of double-stranded RNA to switch off potentially harmful rogue genes.

In 2002 researchers discovered that synthetically produced RNA sequences could be used to target genes in human cells – widely considered to be the most important scientific advance of the last decade.

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 has been created. Scientists can now transfer these vectors to cells to create ‘knock-downs’ for individual genes.

The first functional studies using RNAi vectors from the new library were recently reported in Nature (Berns et al., 428 (6981) pp.431-7)