A genome-wide screen for genes crucial to the immune response has taken Richard Cornall of the University of Oxford, UK, and Christopher Goodnow of the Australian National University in Canberra beyond the confines of immunology. The work, described on page 686, shows that exhaustion of stem cells due to accumulating DNA damage could be a key mechanism in ageing — a long-held hypothesis that had, until now, been difficult to assess.

“The project had its beginnings five years ago,” says Cornall, who worked with Goodnow before establishing his own group in Oxford. At that time, Goodnow had just set up a facility for creating point mutations throughout the mouse genome using the chemical ethyl nitrosourea and then screening the resulting mice for immunological phenotypes. The point-mutation approach has the advantage that it can find subtle defects, whereas knocking out a gene might result in death of the embryo.

One of the immunological strains generated from the screen caught the attention of Cornall's graduate student, Anastasia Nijnik. The strain had stood out because the mice were small, failed to thrive and had no antibodies or lymphocytes in their bloodstream. The collaborators mapped the mutation to the gene for ligase IV, an enzyme involved in fixing double-stranded breaks in DNA, a type of damage that accumulates in cells as they age. Embryos that do not have this gene die before birth. At about the same time that Nijnik identified the mutant gene, a flurry of papers were published that described patients with immunodeficiency and stunted growth caused by a mutation in the human ligase IV gene. “All these things together made us think the gene was interesting,” says Cornall.

To understand the consequences of the mutation, Cornall and Goodnow sought the advice of Penelope Jeggo from the University of Sussex, UK — an expert in double-strand DNA repair. Jeggo's group found that cells from the ligase IV mutant mice do not grow as well as wild-type cells, especially when they are exposed to oxygen, which increases the number of double-strand breaks. Jeggo also showed that the growth defect was due to a failure to repair the DNA breaks.

While analysing the lack of lymphocytes, the collaborators discovered that haematopoietic stem cells — the common precursor for lymphocytes and other blood cells — could not be transplanted from the tiny mice to another mouse; they failed to survive or grow. Because haematopoietic stem cells become less effective as people age, the group's findings suggested that the loss of function could be due to a defect in DNA repair.

The team also found that the number of stem cells in the tiny mice declined with age compared with wild-type mice, presumably because they were not surviving long-term. The stem cells that did remain divided more rapidly in an apparent effort to compensate for those that were lost. “This shows that repair of DNA damage is particularly critical for maintaining the stem-cell population that replenishes our blood as we age, and for transplanting these cells,” says Cornall.

He now wonders what role subtle changes in DNA repair have in stem-cell survival in other tissues, and in memory cells of the immune system, which also need to remain in a stem-like state long-term. “This study illustrates how a student with keen observation, and an interdisciplinary team of collaborators, can together leap beyond the boundaries of an individual discipline or question,” Cornall says. “Sometimes things go where the student wants to go.”