Volume 16 Issue 8, August 2010

Peter Piot, formerly executive director of UNAIDS, will become director of the London School of Hygiene and Tropical Medicine next month. Speaking with Asher Mullard, he discusses the changing nature of global health research.

Salt has been humanity's great taste enhancer, preservative and all-around go-to food ingredient for 8,000 years. But the ubiquitous white crystal is now thought to have caused an epidemic of heart attacks and strokes. In response, many food manufacturers are devising new ways to curb sodium intake while trying to maintain food's saline-stoked good flavor. Stephen Strauss gets a taste of the leading technological solutions for cutting back on the tabletop seasoning.

IBM computers and Microsoft software have been mainstays of biomedical studies for years. But, in the past decade, software and technology companies have increasingly been taking a more active role in biological research. Monica Heger profiles four of the movers and shakers who have been leading the charge.

As concerns have emerged in recent years over medications such as Vioxx and now Avandia, the need to improve the surveillance of approved drugs has become increasingly apparent. To ensure the success of the drugs they develop, biomedical researchers should track a wider set of clinical endpoints in drug trials and prepare to distinguish between real and false risks suggested by long-term safety monitoring.

Blood coagulation protects from microbial infections. A recent study now shows that neutrophils fine tune the procoagulant response to invading pathogens (pages 887–896). Neutrophils degrade an inhibitor of coagulation, locally 'trapping' bacteria in small blood vessels. But they also increase blood clots in large vessels in the absence of infection, which may be relevant for the treatment of thrombosis.

The angiogenic switch, which leads to the activation of endothelial cell proliferation and the growth of new blood vessels, is a crucial step in tumorigenesis. A study now shows that this process is linked to a microRNA in endothelial cells (909–914). Blocking microRNAs may offer new avenues for antiangiogenesis therapy to treat cancer.

Vaccines can prevent infections by several pathogens. Success, however, has been limited for other chronic diseases, reflecting a constraint for effectively manipulating the human immune system. The results from four studies describe a novel dendritic cell (DC) subset in humans that may be crucial for the design of vaccines against cancer and other chronic diseases.

Elevated amounts of glutamate, which acts as a neurotransmitter but is also a neurotoxin, are a hallmark of the autoimmune neurological disease multiple sclerosis and may contribute to its pathology. The discovery that a receptor for glutamate can inhibit the development of autoimmunity and protect from neuroinflammation in a mouse model of multiple sclerosis suggests that glutamate may also have a protective role and that its receptor may represent a therapeutic target (pages 897–902).

Cancers can compromise the capacity of the host immune system to recognize tumor antigens. Recent findings now show that increased accumulation of lipids in dendritic cells in tumors can impair presentation of tumor antigens—which is crucial for activation of the immune system—providing a conceptual framework that may help increase the efficacy of therapeutic vaccines (pages 880–886).

Macrophages engulf microbes and cellular debris to protect us from disease and help repair wounded tissues. In cancer, they also infiltrate the tumor, but studies in humans and mice now uncover more sinister roles for these immune cells in cancer. In 'Bedside to Bench', Christiana Ruhrberg and Michele De Palma scrutinize a clinical study where the presence of macrophages correlates with a high risk of disease progression in people with Hodgkin's lymphoma, indicating a clinical value of macrophages as biomarkers of survival. The authors also emphasize how characterizing of the mechanisms by which subpopulations of macrophages promote tumor cell motility and angiogenesis might help in the development of antiangiogenic therapies to stop tumor progression. In 'Bench to Bedside', Joseph Qualls and Peter Murray examine a study that shows how stopping migration of macrophages into the tumor can impair tumor regrowth after radiation treatment.

Ethylmalonic encephalopathy is a metabolic disease affecting many organ systems that is caused by the inability to metabolize sulfide. Now, Zeviani and colleagues have discovered a dual drug regimen that can ameliorate disease in affected children.

Increased levels of Ca²⁺ in cardiomyocytes promote cell growth that, under stressful conditions, such as those caused by hypertension, can contribute to heart remodeling and failure. Joerg Heineke et al. identify a new regulator of this type of maladaptive cardiac muscle growth in mice, the calcium-binding protein CIB1, which they show regulates the membrane-association of calcineurin and downstream signaling.

Dendritic cells in individuals with cancer and in mouse tumor models show an increase in triacylglycerides that seems to impair their antigen-processing capability and could thus contribute to tumor immune tolerance. This aberrant lipid load results from tumor-induced elevation of the scavenger receptor Msr1 on dendritic cells, and it can be targeted therapeutically to improve the efficiency of anticancer vaccines.

Neutrophils release the serine proteases neutrophil elastase and cathepsin G, which have microbicidal activity and thereby contribute to the innate immune response. Steffen Massberg et al. now show that these neutrophil serine proteases, in association with extracellular nucleosomes, can also promote coagulation and thrombosis within large blood vessels. In a mouse model of systemic bacterial infection, these proteases spurred intravascular coagulation in the microcirculation of the liver, limiting bacterial tissue invasion. These findings point to a role for thrombosis in antimicrobial defense.

Excessive glutamate seen in multiple sclerosis leads to excitotoxicity and neuronal dysfunction. Fallarino et al. find that the clinical signs and neuroinflammation in experimental autoimmune encephalitis is worsened in mice deficient in the metabotropic glutamate receptor-4. Small molecules that enhance signaling through this receptor suppress neuroinflammation by promoting T regulatory cell development and suppressing T_H17 responses. This cross-talk between the nervous and immune system suggests an endogenous mechanism to suppress neuroinflammation in the context of multiple sclerosis.

The authors uncover a new role for the RNA-binding protein Msi2 in the regulation of hematopoietic stem cell homeostasis and leukemogenesis. Msi2 is required for the maintenance of the balance between progenitor renewal and differentiation, and its overexpression cooperates with oncogenic events to induce aggressive leukemia. Msi2 expression is also elevated in human myeloid leukemias and may be a new prognostic marker and therapeutic target in acute myeloid leukemia.

Sudarshan Anand et al. show that endothelial cell expression of the microRNA miR-132 targets a negative regulator of Ras pathway signaling and thereby releases a brake to new blood vessel formation. miR-132 expression is upregulated in the endothelium of human hemangioma and tumor samples, and an antagonist of miR-132, delivered specifically to tumor endothelium using an integrin-targeted nanoparticle, was able to inhibit tumor angiogenesis and growth in mice.

Sullivan and his colleagues describe a novel microneedle patch-based system for vaccine delivery that targets the skin's antigen-presenting cells, providing improved immunogenicity and eliminating the hazards associated with using hypodermic needles. The group demonstrates the feasibility of this approach for influenza prophylaxis, whereby vaccine is encapsulated within microscopic polymeric needles that dissolve in the skin in minutes.

Tarik Massoud and colleagues offer a new, noninvasive molecular imaging technique based on split reporter complementation for quantifying and imaging protein-protein interactions—cytoplasmic and nuclear—in vivo using positron emission tomography. They use a split reporter system based on the enzyme herpes simplex virus type 1 thymidine kinase, an approach designed to significantly improve the sensitivity and dynamic range of imaging protein-protein interactions.

Harald Ott and his colleagues build on their earlier work, based on reconstruction of a decellularized heart, to develop a new way to bioengineer a functioning lung. Through a process of decellularization, seeding with endothelial and epithelial cells, and maturation in an innovative bioreactor system, followed by transplantation into rats of the regenerated lungs in orthotopic position, the group was able to demonstrate adequate ventilation, blood flow and gas exchange in vivo for short periods of time.