Volume 19 Issue 7, July 2013

The ability to patent human genes has been costly to researchers and patients, and has restricted competition in the biotech marketplace. The recent US Supreme Court decision making isolated human genes unpatentable will bring freedom of choice to the patient, and level the playing field for research and development.

Doris Meder and Geert Van Minnebruggen had a dream to team up core facilities across the EU so that institutes could pool resources to buy state-of-the-art machines as soon as the tools became available. To that end, they founded Core for Life (C4L), a pan-European project that formally launched on 14 May. Katharine Sanderson spoke with Meder and Van Minnebruggen about how they hope to democratize access to the very latest technologies for life scientists.

The resource-poor countries of Africa have traditionally relied on Western nations for their drug supply, but a new drug development center with a promising antimalarial agent could pave the way for a homegrown pharmaceutical pipeline. Linda Nordling investigates how this one facility at the southern tip of the continent promises to embolden an entire African drug industry.

Most research prizes in biomedicine, from the Nobels to the Laskers, are restricted to three recipients. But in an age of big science, when much larger teams are generally needed to make important research discoveries, all the people who provide seminal contributions deserve to be awarded.

Metabolic alterations, such as those caused by mutations in the enzyme isocitrate dehydrogenase (IDH), define a clinically distinct subset of primary brain cancers. Expression of BCAT1 is now reported as a new metabolic change defining brain cancers without IDH mutations (pages 901–908).

A new study provides an example of the delicate balance between stem cell migration, differentiation and maintenance in the context of skin wounding. In mice, wounding or ultraviolet irradiation induces melanocyte stem cells in the hair follicle to leave their niche before cell division and migrate up the follicle to differentiate into functional melanocytes, thus providing a protective pigmented barrier (pages 924–929).

Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease.

There is much interest in the area of cardiac regeneration to replace cardiomyocytes lost in a heart attack. A number of recent studies have shown the feasibility of direct reprogramming, which allows one cell type to be directly converted into another cell type without going through a pluripotent intermediate step. In this Review, the authors review developments in direct reprogramming to cardiac cells in vitro and in vivo and compare the utility of these methods with pluripotent stem cell–mediated approaches.

A new wave of antivirals to fight hepatitis C infection has helped patients achieve a good quality of life, but drug resistance, side effects and a lack of pan-viral genotype coverage still remains a problem. This Review discusses current clinical studies and potential targets of the virus life cycle to tackle these issues and puts forward a paradigm to develop second-generation effective antivirals and drug combinations for achieving the ideal regimen of an all-oral, interferon-free therapeutic cocktail.

In this Review, David L. Thomas discusses how recent therapeutic and diagnostic advances could be implemented in public health strategies to prevent viral hepatitis infections and treat existing infected patients. Despite the still increasing incidence and prevalence of hepatitis C infection, available tools may bring viral eradication a step closer toward becoming a reality.

During chronic infection caused by hepatitis C and B viruses, effector adaptive immune cells are exhausted and incapable of clearing the virus, but they can still contribute to liver inflammation in this setting. This Review discusses the regulatory role of nonspecific immune natural killer (NK) cells, which, along with other immune regulatory signals, help the host counteract liver disease progression and immunopathology by controlling virus-specific immunity.

Ongoing investigational studies aim to uncover new strategies to develop an effective vaccine to prevent hepatitis C infection. Advances have moved forward vaccine candidates, but technical and biological barriers posed by the virus still exist. This Review discusses how to better design vaccine trials and evaluate key components of protective immunity to achieve a working preventive vaccine.

Persistence of hepatitis C virus contributes to chronic infection, which can lead to liver fibrosis and even liver cancer. Different factors, such as host genetics and immunity and viral immune evasion strategies, account for the outcome of the infection and the patient response to antivirals. This Perspective discusses how the interaction of these factors modulates viral immunity and how they might be used to identify the key targets to mount an effective immune response that will clear the virus and improve drug response.

An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice.

This study identifies miR-30c as a regulator of both microsomal triglyceride transfer protein, needed for the secretion of APOB-containing lipoproteins such as low-density lipoproteins, and a number of other genes involved in lipid biosynthesis. In mice, miR-30c regulates hepatic lipid biosynthesis and lipoprotein secretion such that hepatic overexpression of miR-30c reduces plasma cholesterol and triglyceride concentrations and decreases atherosclerotic plaque burden.

Branched-chain amino acid transaminase 1, the enzyme that initiates the catabolism of branched-chain amino acids, is involved in glioma pathogenesis, making it a potential therapeutic target.

Activation of inflammasomes has been implicated in sensing pathogens. Now Dario Zamboni and colleagues report that the Nlrp3 inflammasome has a key role in restricting replication of Leishmania parasites in macrophages and in mice by triggering interleukin-1A–dependent induction of nitric oxide, a crucial mediator of defense against Leishmania.

Humans lack robust regeneration of hair follicles after skin wounding. George Cotsarelis and colleagues now show that γδ T cells are not present at high levels in human skin, that in mice they are a key initial source of the protein fibroblast growth factor 9 and that this factor modulates hair follicle regeneration during skin wound healing. These results suggest a possible topical clinical treatment to regrow hair after wounding and perhaps for other conditions of hair loss.

Mayumi Ito and her colleagues show that during skin wounding in mice, melanocyte stem cells in the hair follicle are induced by melanocortin 1 receptor (Mc1r) signaling to migrate towards the epidermis and differentiate into mature pigment-producing cells. This mechanism allows for protection of the healing skin from ultraviolet light–induced damage.

CD8⁺ T cell responses have been associated with control of HIV replication, but the role of CD4⁺ T cells in protecting against this virus is unclear. In an analysis of HLA class II–restricted CD4⁺ T cell responses in HIV-infected individuals, Hendrik Streeck and his colleagues now report that certain HLA-DRB1 variants are associated with low viremia and can present a wide breadth of peptides, suggesting that CD4⁺ T cell responses in infected individuals may help control HIV.

Depression is a debilitating condition for which new treatments are sorely needed. Now, Erich Gulbins and his colleagues report that reducing ceramide levels in the brain has antidepressant effects in mouse models of the disease.

Building on earlier work, Dekkers et al. describe the first application of their intestinal organoid culture technology to the study of human disease, in this case cystic fibrosis. These so called 'mini-guts', which recapitulate the essential in vivo intestinal tissue architecture in vitro, are used to develop a rapid and quantitative assay to measure mutant cystic fibrosis transmembrane conductance regulator (CFTR) function, as well as test the efficacy of correctors and potentiators of mutant CFTR.