Nature Genetics pp 92 - 95

Leber congenital amaurosis (LCA) is a rare, inherited genetic disease that causes nearly total blindness in infancy. There is currently no treatment for the disease but LCA (and retinal degeneration in general) is a good candidate for gene therapy because the photoreceptor cells, which are typically affected, are relatively intact (in the short term) and accessible to injected agents. Most efforts have been focused on trying to slow retinal degeneration and eventual blindness in mice and rats. But, the restoration of sight to a blind eye has not been demonstrated—in rodents or any animal—until now. A team of scientists headed by Jean Bennett (of University of Pennsylvania, Philadelphia, USA) describes the first successful gene therapy that restores sight in blind dogs.

Mutations in at least three known genes can cause LCA. One gene, RPE65, encodes a protein that is involved in metabolizing retinoids to form retinal, the chromophore of the visual pigments in the photoreceptor cells. (These are responsible for 'translating' light into nerve impulses.) Mice with mutations in Rpe65 have nonfunctional photoreceptors and retinas that degrade over time.

Bennett and colleagues studied dogs that have a naturally occurring mutation in RPE65 and go blind or develop impaired vision, much the same way infants with LCA do. They used a common viral-based gene therapy vector to deliver a normal copy of RPE65 to the retinas of a cohort of these dogs. Following treatment, measurements of vision, such as sensitivity to electrophysiological stimuli, indicated that the eye that received treatment responded as well as eyes of seeing dogs. They also tested the treated animals for different behavioral tasks, such as the ability to avoid obstacles in dim light. As revealed by the supporting video (posted on the press web site) the dogs avoided bumping into objects placed on the same side as the treated eye.

This study provides hope that, despite the numerous and substantive obstacles to developing effective gene therapy, the correction of LCA arising from mutations in RPE65 is at least feasible.

Nature Genetics pp 42 - 45 and pp 7 - 9

Human cytomegalovirus (HCMV) is the leading cause of congenital (present at birth) viral disease and opportunistic infection of immunocompromised patients. This is due to the high prevalence of the virus, with up to 90% and 50% of the urban and rural populations infected, respectively. The virus's slow growth cycle allows co-survival of both infected cell and virus, so infection is generally asymptomatic. The virus, however, is never eliminated; rather, it remains latent in tissues of the host, and is reactivated in immunocompromised individuals such as people with HIV or allograft recipients. These people have impairments in both cell-mediated and antibody-mediated immunities. In rare instances, however, severe illness occurs in fetuses and newborns without known immunological impairment. It is thought that a type of blood cell, called the Natural Killer (NK) cell, controls viral infection, but definitive proof has been lacking. In this issue, Silvia Vidal (of University of Toronto, Canada) and colleagues provide support for this hypothesis: they identify a NK cell receptor that protects mice specifically against cytomegalovirus (CMV).

It was previously established that infection by CMV in the mouse is controlled by a gene or genes that lie in a region of chromosome 4 that contains a cluster of genes encoding NK cell receptors. In the current study, Vidal and colleagues show that a gene called Klra8 (also known as Ly49H) that encodes a stimulatory receptor expressed on the surface of NK cells allows the detection and destruction of CMV-infected cells. As Jean-Laurent Casanova and colleagues (of Necker Medical School, Paris, France) discuss in an accompanying News & Views article, Klra8 could have evolved to protect against CMV.

In contrast with T and B lymphocytes, NK cells produce a relatively modest repertoire of surface receptors and are not selected in response to specific infectious agents. The study provides the first genetic evidence for a specific role of NK cells in pathogen-specific immune response and provides some helpful pointers for studies of human immunity to HCMV.

Nature Genetics pp 21 - 28 and pp 9 - 10

The National Library of Medicine's MEDLINE citation database, the world's largest searchable collection of biomedical literature, has, since 1966, accumulated more than 11 million titles and abstracts from articles published in over 4,000 relevant journals. As a tool for retrieving information about a particular gene or protein, it is unsurpassed. As a tool for discovering new connections between particular genes and biological processes, it is also arguably the world's most underexploited (in silico) repository of data. A group led by Eivind Hovig (of The Norwegian Radium Hospital, Oslo, Norway) has now outlined a computational approach to extracting new information from this massive archive. Conducted on a large scale across the entire database, the analysis generates networks of related genes that reveal heretofore unknown aspects of biology.

A similar, if small-scale, approach was published last year by Benjamin Stapley and Gerald Benoit (of the University of Kentucky), who coined the term "biobibliometrics." The basic assumption is that genes that are mentioned in the same abstract are likely to have a biological relationship. By analogy to global approaches to understanding the genome, transcriptome and proteome, Hovig and colleagues have now searched the titles and abstracts of over 10 million MEDLINE citations—the 'biobibliome'—to produce a "gene-to-gene co-citation network" for 13,712 known human genes. By annotating this network with biological attributes such as medical subject heading (MeSH) terms, the authors have identified meaningful biological relationships between sets of genes that, though subsequently validated by experiment, had not been predicted. The computational tools to carry out these analyses have been deposited in a publicly available database called PubGene (http://www.PubGene.org). PubGene provides an opportunity to harvest at least some of the collective wisdom—as yet unrealized—that has been produced by thousands of scientists over the last 35 years.

Though powerful, the method by Hovig and colleagues is limited by difficulties in dealing rationally and systematically with the flood of information entering the literature. Many of these problems are of long-standing concern, including inconsistencies in nomenclature, the inaccessibility of the full text of most published articles, and the sheer complexity of biology itself. These issues are discussed in an accompanying News & Views article by Daniel Masys (of the University of California, San Diego), and in this month's Nature Genetics editorial.