The big turn-off: RNAi goes clinical 1/10/05. By Barry Gardner RNA interference (RNAi) is now in every geneticist's toolbox – and may soon be in every doctor's surgery.

If ever there was a case for shooting the messenger, RNAi is surely it. Strings of ribonucleic acid (messenger RNA) are the go-betweens that carry the instructions encoded in our DNA to ribosomes, the cell's proteinbuilding machines. So, if you can block RNA en route, you can effectively disable specific genes. This is just what many researchers investigating gene function want to do – and it may also be an entirely new way of tackling disease.

RNAi was first discovered in the 1990s, but hit the big time in 2002 when it was 'Breakthrough of the Year' in the journal Science. Since then it has been lauded as a potential method of treating every ailment from cancer to coronary heart disease. In an astonishingly short time, RNAi has gone from discovery to human clinical trials.

Acuity Pharmaceuticals in Philadelphia has completed safety tests on the first ever RNAi treatment for a health problem. Fifteen people have undergone injections into the eye to treat macular degeneration, the leading cause of blindness in the elderly.

Other companies are also looking to harness RNAi to treat Alzheimer's disease, motor neurone disease, Parkinson's disease, hepatitis and even HIV. Benitec in Australia is working on a way of delivering a 'multiple warhead' that cripples several genes at once, which could aid the treatment of type 2 diabetes.

"The prospects for RNAi treatment really are tremendous," says Andy Fraser, who uses RNAi at the Wellcome Trust Sanger Institute. "It's been one of the most important scientific developments of the last two decades and I am confident in the next five to ten years we will see something positive come from it." And Professor Phillip Sharp, a Nobel Laureate at the Massachusetts Institute of Technology, adds: "The broader science of RNAi is just absolutely spectacular. This is not hype. The biggest science prizes in the world will fall to RNAi."

Blooming marvelous
RNAi may be exciting biomedical scientists, but its origins lie somewhere else entirely: in plant breeding. In 1990, Richard Jorgensen and colleagues in Amsterdam were trying to improve the colours of petunias by introducing extra copies of genes to boost pigmentation. But instead of bold reds and purples, their flowers turned white. The bemused scientists discovered that they had somehow managed to switch off pigmentation genes in the plants.

Then in 1998, two US researchers – Andrew Z Fire from Stanford University School of Medicine and Craig C Mello from the University of Massachusetts Medical School – discovered a similar phenomenon in nematode worms. They found that short double-stranded RNA molecules were rapidly degraded inside cells – but also triggered the culling of all single-stranded RNA molecules of the same type.

Fire and Mello realised that they had a tool to eliminate, very specifically, the activity of a particular gene. Not only that, but if you knew the sequence of all an organism's genes, you could systematically knock them out one by one. Researchers were quick to spot the potential of this approach. RNAi is now routinely used in organisms such as the nematode worm and the fruit fly Drosophila. But medical scientists also spotted an opportunity. Many diseases are caused by the action of defective genes. If such a gene could be turned off, its damaging effects might be overcome.

Interfering with humans
In Cleveland, Ohio, Dr Lawrence J Singerman is trying to do just that on behalf of Acuity Pharmaceuticals. "As far as I know we were the first to inject any RNAi into humans for any medical Macular degeneration in the retina; ribosome-studded endoplasmic reticulum; petunia; nematode worm; hepatitis C virus; dividing cancer cells.