Volume 17 Issue 5, May 2011

Singapore, the fastest growing economy in Asia last year, has enjoyed a decade of free-flowing research funding. Money is still pouring in, but the question remains whether money can buy international-class science. Sir George Radda, who was appointed chairman of the city-state’s Biomedical Research Council (BMRC) in 2009, talks with David Cyranoski about what’s ahead for Singapore.

Intellectual property isn't something you can see or touch. Yet some companies are trying to sell medical patents the same way antiques dealers sell ancient coins or fine art—at live auctions. Will this new model work? Cassandra Willyard explores the weird world of intellectual property auctions.

Facing dwindling product pipelines and looming patent cliffs, nearly all of the world's major drugmakers have recently overhauled their research and development activities. Brendan Borrell asks what difference these efforts have made.

Medical school faculty receiving remunerations from industry have financial incentives for promoting the products of the companies paying them. It's no surprise, then, that medical schools require disclosure and management of such relationships. Yet, despite their greater prevalence and more profound influence, the financial incentives offered by medical schools have gone largely unnoticed. A consistent standard for disclosure and management should be applied to both intramural and extramural financial relationships.

Although leukocyte activation in fat tissue promotes obesity-related insulin resistance, a role for B cells has been unclear. A new study in obese mice shows that they enter the fat tissue to activate T cell function and boost inflammation, exacerbating the metabolic disease (pages 610–617).

Although attention deficit hyperactivity disorder (ADHD) is a highly heritable and common psychiatric disorder, few susceptibility genes have been identified. A new multidisciplinary genetic study in humans and mice reveals GIT1 (encoding G protein–coupled receptor kinase–interacting protein-1) as a previously undescribed ADHD susceptibility gene in humans and provides new insights into the underlying mechanisms of this condition (pages 566–572).

Hepatitis C virus puts about 130 million people worldwide at risk for severe liver disease, but no vaccine or broadly effective therapy yet exists. A new study identifies receptor tyrosine kinases as host factors required for hepatitis C virus entry—potentially opening the door for new antiviral strategies (pages 589–595).

Thiazolidinediones (TZDs) target peroxisome proliferator–activated receptor-γ (PPAR-γ) and are widely prescribed to treat type 2 diabetes but are associated with substantial weight gain. This side effect of TZDs is now shown to be mediated via brain PPAR-γ. These findings suggest an important role for brain PPAR-γ in obesity and have major implications for the clinical use of TZDs (pages 618–622 and 623–626).

Interleukin-2 receptor-α (IL-2Rα) on antigen-presenting dendritic cells (DCs) is now shown to trans-present IL-2 to T cells during the earliest stages of T cell activation (604–609). The resulting T cell proliferation is blocked by daclizumab, an IL-2Rα–specific antibody used to treat multiple sclerosis and prevent transplant rejection, highlighting the importance of understanding individual variability in immune responses to daclizumab treatment.

Moderate to severe asthma is difficult to treat because recurring bouts of inflammation in the lungs induce fibrosis, which reduces lung elasticity, gas exchange and responses to conventional therapy. A recent study identifies the tumor necrosis factor family member LIGHT as an essential mediator of airway fibrosis in a mouse model of chronic asthma (pages 596–603).

Animal experiments using single organs as models of fibrosis spur therapeutic development toward promising targets, but testing of these therapies in human fibrosis yielded disappointing results and limited efficacy. Finding core pathways relevant in different organs that can become fibrotic will uncover molecules that will prove useful as therapeutic targets in many species, including humans. In 'Bench to Bedside', Scott Friedman, Wajahat Mehal and John Iredale discuss this new paradigm in fibrosis research and its potential as a new drug development approach. In 'Bedside to Bench', Alison Eddy peruses how the protein encoded by UMOD, a gene linked to variable risk for chronic kidney disease and hypertension in humans, may have a role in fibrosis and kidney disease. Uncovering the normal function of UMOD and its gene variants will shed light on the pathogenesis of chronic kidney disease and aid in the discovery of new targets for kidney fibrosis and hypertension.

Fragile X mental retardation is caused by mutations in the FMRP gene. Now, Xinyu Zhao and her colleagues show that deletion of Fmrp specifically in adult neural progenitor cells is sufficient to induce learning deficits in mice, whereas restoration of Fmrp only in neural progenitor cells in Fmrp-deficient mice restores learning.

ADHD is characterized by hyperactivity and deficits in learning and memory. Now, Eunjoon Kim and colleagues report that a polymorphism in the gene that encodes the adaptor protein GIT1 is linked to ADHD in humans. This polymorphism reduces GIT1 expression, and GIT1-deficient mice show ADHD-like behaviors that can be alleviated with the psychostimulant drugs used to treat human ADHD.

By studying the effects of salt intake in mice and rats, ShengYu Mu et al. unravel the mechanisms by which dietary salt contributes to hypertension. Salt's prohypertensive effect required the activity of the glucocorticoid receptor in the kidney, which together with sympathetic nervous system activation led to decreased expression of the protein kinase WNK4, a key regulator of sodium channels that regulate blood pressure, via epigenetic regulation.

Inflammatory cell recruitment to injured tissues is needed for repair, but an excessive inflammatory response can exacerbate injury. Tibor Kempf et al. now identify the cytokine GDF-15 as a new anti-inflammatory factor that dampens leukocyte recruitment in the setting of myocardial infarction in mice, thereby preventing cardiac rupture. GDF-15 blocks leukocyte extravasation from the blood into injured tissue by inhibiting the activation of cell surface integrin receptors.

Treatment options for hepatitis C virus (HCV) infection have limited efficacy and high toxicity, resulting in poor adherence and, thus, viral resistance. Identifying previously unrecognized pathways involved in HCV infection may aid the development of new therapeutics. Using an RNAi screen, Lupberger et al. have identified cellular kinases involved in HCV infection of liver cells and have tested the ability of approved inhibitors to block viral entry both in vitro and in vivo.

Chronic inflammation of the airways is associated with remodeling and fibrosis, leading to a progressive decline in lung function in people with severe asthma. Michael Croft and his colleagues report that in mouse models of allergic lung inflammation expression of the TNF family member LIGHT is induced. Blockade of LIGHT prevents remodeling, providing a therapeutic strategy to prevent asthmatic airway remodeling.

Dendritic cells produce interleukin-2 (IL-2) and express the IL-2 receptor subunit CD25. Bibiana Bielekova and her colleagues show that dendritic cells, upon interacting with cognate T cells, secrete IL-2 into the immune synapse and use their CD25 to trans-present IL-2 to T cells, facilitating early IL-2 signaling in T cells. Inhibition of CD25 by the monoclonal antibody daclizumab prevents T cell activation and may partly account for the therapeutic effects of daclizumab in patients with multiple sclerosis.

Edgar Engleman and his colleagues show that B cell production of pathogenic IgG antibodies is involved in obesity-induced insulin resistance. They also show that B cell depletion in obese mice ameliorates metabolic disease, and that obese, insulin-resistant humans have a unique profile of IgG autoantibodies. These results suggest a possible new therapeutic target to treat insulin resistance.

Although the use of thiazolidinediones in the treatment of type 2 diabetes is controversial, they still comprise an important class of insulin-sensitizing drugs. In two reports, new evidence emerges that these drugs rely on the activation of their target, PPAR-γ, in the brain to improve hepatic insulin sensitivity and increase food intake and reduce energy expenditure.

Although the use of thiazolidinediones in the treatment of type 2 diabetes is controversial, they still comprise an important class of insulin-sensitizing drugs. In two reports, new evidence emerges that these drugs rely on the activation of their target, PPAR-A, in the brain to improve hepatic insulin sensitivity and increase food intake and reduce energy expenditure.

Studies of the recently discovered human rhinovirus species C (HRV-C) virus have been hampered by an inability to propagate the virus in standard cell culture. Yury Bochkov et al. have now developed a tissue culture system for HRV-C using human organ culture of sinus mucosa. This, together with development of a reverse genetics system for HRV-C, should provide a better understanding of HRV-C biology and facilitate discovery of an HRV-C receptor.