For cancer researcher Todd Golub, the paper on page 335 of this issue represents a return to an early enthusiasm. Working as a postdoc at Brigham and Women's Hospital in Boston in 1990, Golub got interested in an unusual bone-marrow disorder called 5q– syndrome. The condition, characterized by defective red-blood-cell development, severe anaemia and a tendency to progress to acute myeloid leukaemia, had been linked to a gene somewhere in a 1.5-megabase common deleted region (CDR) on chromosome 5, says Golub, “but we just didn't have the tools to identify the gene”.

Things have changed a lot since then. “The tools available now are just spectacular,” says Golub, who is now director of the cancer programme at the Broad Institute, a genomic-medicine centre in Cambridge, Massachusetts, run jointly by the Massachusetts Institute of Technology and Harvard University. One of those tools, RNA interference, or RNAi, and the help of a particularly persistent postdoc led to the discovery that the 5q– syndrome is caused by a defect in a gene called RPS14, which makes a ribosomal protein.

Gene deletions associated with cancer are usually expected to be biallelic, meaning that the deletion results in both copies of a relevant tumour-suppressor gene being inactivated. But no one had been able to find biallelic inactivation in 5q– syndrome. “There was growing evidence in cancer generally that just having one allele affected has an impact,” Golub says. “We needed some way to test this hypothesis.”

Enter RNAi, which allows researchers to use short stretches of nucleic acid to reduce the expression of a target gene, mimicking, in effect, the 'haploinsufficiency' that Golub and his collaborators suspected was the cause of 5q– syndrome. Postdoc Benjamin Ebert developed a set of 189 short hairpin RNAs that would target each of the CDR's 40 genes.

Ebert and Golub were surprised that the partial disruption of RPS14 by several of these RNAs seemed to reproduce all the symptoms of 5q– in cultured cells. At first they thought the result was an error. “There were some amazing candidate genes” in the CDR, Golub says. “If we had ranked the genes from 1 to 40 on our level of excitement, I suspect that RPS14 would have been last.”

But a battery of additional tests confirmed that RPS14 was indeed the culprit. “Many a postdoc has disappeared into the black hole of studying 5q− syndrome, never to emerge,” Golub jokes. “A study like this requires an amazing and fearless champion, and Ben fearlessly took it on.”

The identification of RPS14 haploinsufficiency and the resulting reduced levels of protein as the cause of the 5q– syndrome links the condition to a variety of congenital bone-marrow disorders known to be related to disruptions in ribosomal proteins, leading the way to insights for their study and treatment.

The broader hope, according Golub, is that this study will pave the way for using RNAi screening as a general tool for gene discovery, especially for the many cancers and other diseases now thought to result from partial loss of gene function.