Volume 20 Issue 6, June 2014

In April, the US Defense Advanced Research Projects Agency (DARPA) launched the Biological Technologies Office. The man picked to lead the BTO is Geoffrey Ling, a physician-scientist with training in neurology and pharmacology who spent 27 years in the US Army Medical Corps. Ling spoke with Brendan Borrell about what the BTO will mean for the medical research community.

About 90% of the people in the world carry a latent virus known to cause cancer. On the fiftieth anniversary of its discovery, researchers are considering joining up their experimental treatments against these malignancies. David Holmes reports.

The mentorship of early-career scientists is necessary to their individual career success and the future of the biomedical research enterprise as a whole. Recently launched NIH programs and tools aim to facilitate this important type of training.

Regulatory B cells exert an immunosuppressive role by secreting the cytokine interleukin-10 (IL-10). Two studies have now identified B cell–derived IL-35 as both an inducer and a mediator of regulatory B cell function. IL-35 switched off inflammation in mouse models of autoimmunity, whereas its absence in B cells in mice enhanced survival after Salmonella enterica serovar Typhimurium infection. IL-35 could therefore be targeted for treating human autoimmune and infectious disease.

Age-related cognitive decline occurs in many mammals, including humans, resulting from a decline in hippocampal function, and it is associated with reduced synaptic plasticity in hippocampal circuits. In this issue of Nature Medicine, a new study shows that cognitive impairment observed in aged mice is largely reversible following exposure to the blood of young mice.

A new study in infants shows that broadly neutralizing antibodies (bNAbs) against HIV can be found early in life, demonstrating for the first time that these antibodies can be induced by the infant immune system.

Barth syndrome is a rare X-linked genetic disorder caused by mutations in the tafazzin (TAZ) gene that result in dilated cardiomyopathy, skeletal myopathy and neutropenia. Tafazzin has a mitochondrial function, and a new study using cardiomyocytes derived from induced pluripotent stem cells (iPSCs) from humans with Barth syndrome identifies increased mitochondrial reactive oxygen species (ROS) production as a key intermediate causing cardiac contractile dysfunction (pages 616–623).

Although hematological cancers are genomically unstable, the mechanisms by which they evade DNA damage–induced cell death are largely unknown. A current study has revealed that the Hippo signaling pathway transcriptional regulator YAP1 activates an ABL1/p73-mediated proapoptotic effect in response to DNA damage, suggesting that YAP1 has a tumor suppressor function and that the Hippo pathway is a potential therapeutic target in human cancers.

The development of new therapies is an arduous, time-consuming and costly task. Furthermore, the development of many compounds runs into issues related to safety. Drug repurposing, where drugs with established safety in humans are tested and developed for efficacy in a disease other than the one for which they were developed, is gaining traction because of its potential to overcome an initial bottleneck in the drug development process. In “Bedside to Bench,” Stephen Strittmatter discusses the types of scenario in which drug repurposing may be of benefit, such as when a drug is repurposed for a new molecular target or for the same target in a different disease. In “Bench to Bedside,” Michael Pollak focuses on a recent study that suggest that biguanides that are normally used in the treatment of diabetes could have direct cyotoxic action on cancer cells with mutations in respiratory complex I. The pharmacokinetic hurdles that may need to be overcome for this to be translated to the clinic are also discussed.

Pancreatic adenosquamous carcinomas are rare but highly aggressive tumors, and our understanding of them is limited. In a new study, Miles Wilkinson and colleagues now report that they have identified somatic mutations in an RNA helicase encoded by UPF1 in some pancreatic adenosquamous carcinomas. UPF1 is required for nonsense-mediated RNA decay, suggesting that the aberrant accumulation of altered RNA transcripts may contribute to the malignant phenotype of these tumors and could be a target of diagnostic and therapeutic approaches for this tumor type.

Tumor cells of epithelial origin present rampant DNA damage but do not undergo apoptosis due to inactivation of TP53. Understanding the mechanisms by which tumor cells are protected from cell death is crucial for identifying new therapeutic targets. Cottini et al. report that hematological malignancies also present DNA damage and a distinct, TP53-independent mechanism for evading cell death: low levels of the Hippo pathway coactivator YAP1 prevent apoptosis induced by nuclear relocalization of ABL1 triggered by DNA damage. A serine-threonine kinase, STK4, downregulates YAP1 levels; notably, STK4 inhibition increases YAP1 and related p73-mediated apoptosis in hematological malignancies.

Tumors use numerous mechanisms to escape detection and killing by the immune system. George Coukos and colleagues now report that cancer cells can also co-opt tumor-associated endothelial cells to prevent immune eradication. The researchers show that factors secreted by cancer cells induce increased expression of Fas ligand on the tumor endothelium, resulting in killing of CD8⁺ effector T cells and thereby facilitating immune escape and tumor growth.

Cardiomyocytes generated from induced pluripotent cells hold great promise for understanding and treating heart disease. William Pu and his colleagues apply new technologies for studying such cardiomyocytes from patients with Barth syndrome to explore how the mitochondrial defects characteristic of this syndrome lead to heart dysfunction.

In heart muscle cells, a region of the sarcolemmal membrane periodically invaginates to form T tubules, a specialized membrane domain that contains important ion channels regulating cell contraction. Robin Shaw and his colleagues describe how a cardiac-specific splice variant of the isoform of the protein BIN1 helps make folds in T tubules, which affects the ability of ions in the extracellular space to freely diffuse and protects the heart from arrhythmia.

Regulatory B (B_reg) cells producing interleukin-10 (IL-10) suppress autoimmune disease, but the mechanisms mediating their induction remain unclear. Charles E. Egwuagu and colleagues report that IL-35 induces B_reg cells and also promotes their production of IL-35. In vivo IL-35 suppresses autoimmune disease in an IL-35 receptor– and IL-10–dependent manner. Adoptive transfer of IL-35–induced B_reg cells inhibits established autoimmune disease, suggesting that IL-35 and IL-35–producing B_reg cells may be used to treat inflammatory disease.

The immune system matures during the neonatal period and is influenced by environmental factors. Benjamin J. Marsland and his colleagues show that the lung is colonized by microbes early in life. Formation of the lung microbiota is associated with the induction of regulatory T cells and the development of tolerance to allergens. Absence of microbial colonization leads to allergic airway disease later in life, suggesting that the lung microbiota promotes immune tolerance.

Although neutrophils have crucial functions in microbial killing, they can also trigger tissue damage via the release of reactive oxygen species and proinflammatory mediators. Robert Zeiser and colleagues now report that neutrophils also contribute to the severity of graft-versus-host disease following translocation of bacteria in the gut induced by the conditioning regimen for allogeneic hematopoietic cell transplantation.

Antibodies capable of neutralizing a broad array of HIV-1 viral isolates from different clades have been isolated from some chronically infected individuals, but their development is thought to require several years. In this issue, Julie Overbaugh and her colleagues report that HIV-infected infants also develop broadly neutralizing antibodies—some at 1 year of age—and their occurrence early in life may shed light on HIV vaccine efforts to induce these antibodies.

Aging is associated with cognitive impairment and degenerative processes in the brain. Here, Tony Wyss-Coray and colleagues report that exposure of aged mice to young blood improves learning and memory in aged mice. This effect is associated with structural improvements in dendritic spine density in the hippocampus and functionally with increased synaptic plasticity. These findings suggest that circulating factors in young blood can reverse impairments in learning, memory and synaptic plasticity in aged mice.

Lower levels of ω–3 fatty acid–derived resolution mediators have been linked to insulin resistance in obese mice. André Marette and his colleagues now show that treatment of obese mice with a resolution mediator (protectin DX (PDX)) results in IL-6 release from muscle and subsequent improvement in insulin sensitivity. PDX may represent a new class of antidiabetes medication.

Osteogenesis imperfecta (OI) is a debilitating illness marked by brittle bones and fractures, as well as extraskeletal abnormalities. Now, Ingo Grafe and colleagues show that both the dominant and recessive forms of this disease are caused by excessive TGF-β signaling and that targeting this pathway improves bone health in mouse models of OI.

Using an adapted competitive peptide phage display platform, Hong Qin and colleagues identify new candidate peptides specifically binding myeloid-derived suppressor cells (MDSCs), with which they generate peptide-Fc fusion proteins (peptibodies). The peptibodies deplete intra-umoral MDSCs in several mouse tumor models, in addition to those in blood and spleen, with limited off-target activity and superiority over standard depletion methods. Validation of this approach for cell type–specific surface marker discovery identified S100A9 as a target on the surface of MDSCs.

Whole-exome sequencing (WES) has emerged as a transformative technology for biological discovery, but technical difficulties have so far prevented its widespread clinical use. Here, Eliezer Van Allen and colleagues are able to perform production-scale WES on small amounts of clinically acquired formalin-fixed, paraffin-embedded tumor tissues. Using a newly created WES clinical interpretation algorithm, they apply the complete clinical WES framework prospectively to patients and demonstrate how it can be used to directly affect patient care.