Volume 18 Issue 10, October 2012

As the US presidential campaign heads into the final stretch before the Election Day, the nonpartisan alliance known as Research!America is working to put health research high on the political agenda. Mary Woolley, president and chief executive officer of the Washington, DC–based organization, spoke with Roxanne Khamsi about what it will take to catalyze support among lawmakers for biomedical research.

Synthetic biology has historically relied on bacteria as a testing ground for engineering cell behavior through genetic signals. But a small group of researchers have their sights set on redesigning mammalian cells, which have more complex genetic machinery. Daniel Grushkin meets the scientists aiming to reprogram our bodies' cells for a new generation of tailor-made treatments.

A new study in mice shows that sarcolipin, a small, regulatory protein of the intracellular calcium pump (SERCA) in skeletal muscle, is part of a nonshivering thermogenic mechanism for regulating both core body temperature and energy balance (pages 1575–1579).

Deficiency of the procoagulant cofactor factor VIII (FVIII) in hemophilia A is routinely treated by protein replacement therapy with plasma-derived or recombinant FVIII. Now, a humanized bispecific antibody has been demonstrated to perform the 'scaffold' function of FVIII and could potentially function as a FVIII substitute as a treatment for this inherited bleeding condition (pages 1570–1574).

Androgen withdrawal–based therapeutic strategies for spinal and bulbar muscular atrophy (SBMA) have shown limited benefit in clinical trials, and therapies for this disease still remain a considerable challenge. The finding that a class of migraine medications, the triptans, improve disease in a mouse model of SBMA suggests a new route for future investigations into SBMA therapies (pages 1531–1538).

Reactivation of 'metastasis suppressor' genes holds great promise for the treatment of incurable malignancies. To date, only a few of these genes have been identified. A new study shows that breast cancer metastasis can be blunted by leukemia inhibitory factor (LIF) signaling through regulation of the Hippo pathway, linking metastatic growth to the regulation of a pathway involved in building organs during development (pages 1511–1517).

Influenza viruses can cause a broad spectrum of disease severity, including devastating cases in some people. Several factors influence the epidemiological success of the virus; the mechanisms of transmission and the strategies for prevention and treatment have an impact on the disease outcome and the incidence of flu infection in the population. Understanding how and why the viruses spread so efficiently among people and determining possible ways to harness this transmission have been arduous tasks, given the limitations of flu animal models. In 'Bedside to Bench', Kanta Subbarao and Seema S. Lakdawala peruse a study that used a human challenge model to assess influenza transmission; this experimental approach shows how transmission can be studied in humans and emphasizes factors that are different compared to animals, such as distinct disease severity and incidence. Lessons can be taken to optimize animal studies. Another issue that dictates the severity of flu episodes is the potential emergence of drug-resistant strains in treated individuals. In 'Bench to Bedside', Anne Kelso and Aeron C. Hurt discuss another concern—the presence of drug-resistant viruses with additional permissive mutations that make them fit to infect and compete with wild-type strains. The fact that these strains can be found in untreated people and can spread poses a public health concern and a challenge for scientists to find new drugs and assess antiviral combinations.

NRAS-driven melanomas have limited therapeutic options. Combining genetically engineered models and oncogenic signaling inhibitors with rational systems-biology approaches, the authors compare the effects of genetic extinction of NRAS to that of chemical pathway inhibition targeting downstream MEK. The differences provide actionable targets by revealing that NRAS signaling operates as a gated output and that MEK inhibition, although inducing apoptosis, is not able to achieve further inhibition of NRAS-induced outputs such as cell-cycle progression. A combination of MEK and CDK4 inhibitors provides a more complete inhibition of NRAS signaling and a more effective antitumor effect in vivo.

The authors identify LIFR as a breast cancer metastasis suppressor by showing how its loss promotes metastasis without substantial effect on primary tumor growth. This function of LIFR involves promoting the membrane localization of Scribble and enabling the cytoplasmic sequestration of Hippo pathway transducers, thus involving this signaling pathway in metastasis control. LIFR loss is also observed in human breast tumors, where it correlates with poor prognosis.

Human T cell function declines with age, reducing the ability of vaccines to protect the elderly against infectious disease. In this issue, Jörg Goronzy and his colleagues shed light on the mechanism by which naive CD4⁺ T cell responses are impaired in elderly individuals. The researchers show that miR-181a is reduced in these cells in older individuals. This results in increased expression of DUSP6, a phosphatase that dampens ERK signaling, which is necessary for optimal T cell receptor sensitivity to antigen.

Recurrent infections with respiratory syncytial virus (RSV) early in life increase susceptibility to asthma. Nandini Krishnamoorthy et al. show that RSV infection of young mice impairs maternally transferred tolerance to allergens. Regulatory T (T_reg) cells in infected mice have impaired suppressor function and adopt a T_H2-like phenotype.

Spinal and bulbar musclar atrophy (SBMA) is caused by expanded polyglutamine repeats in the androgen receptor, leading to motor neuron degeneration. Gen Sobue and his colleagues describe a molecular cascade whereby mutant androgen receptor upregulates CGRP in neuronal cells, promoting JNK activation and degeneration. The 5-HT1B/1D receptor agonist naratriptan, which is approved for the treatment of migraine, decreases CGRP expression and improves motor performance in a mouse model of SBMA, suggesting a novel therapeutic strategy for SBMA.

Obesity is often associated with mitochondrial dysfunction. What is not clear, however, is whether this is a cause or a consequence of the condition and its detrimental effects on metabolic health. Phil Scherer and colleagues now show that by manipulating a key protein involved in mitochondrial function specifically in adipocytes the mitochondria is crucial in maintaining proper lipid levels and whole-body insulin sensitivity.

In congenital neutropenia, myeloid-lineage differentiation in response to the cytokine G-CSF is defective. Julia Skokowa et al. now show that an interplay among three proteins—the adapter proteins HCLS1 and HAX1 and the transcription factor LEF-1—is required for G-CSF–triggered granulocytic differentiation, and they provide evidence that this pathway is dysregulated in both congenital neutropenia and acute myeloid leukemia.

Although type I phosphatidylinositol 3-kinases (PI3Ks) are well studied signaling proteins, the functions of other PI3Ks are more enigmatic. Kazuaki Yoshioka et al. find that the type II PI3K-2α isoform regulates endosomal trafficking and cell signaling in endothelial cells. Angiogenic and vascular permeability responses are attenuated in mice lacking PI3K-2α, pointing to this enzyme as a potential target for treating vascular disease.

Individuals with hemophilia A lack the coagulation factor FVIII and are treated with frequent intravenous injections of FVIII agents. However, many individuals develop antibodies to FVIII and can no longer be treated by FVIII injection. Takehisa Kitazawa and his colleagues report the development of a bispecific antibody to FIXa and FX that mimics the function of FVIII. This antibody reduces bleeding in a nonhuman primate model of hemophilia A, is resistant to the inhibitory effects of FVIII-specific antibodies and has a long half-life after subcutaneous injection.

Animals use their muscles to shiver to generate heat when exposed to the cold. But this is a short-term adaptation. Long term, it is believed the body relies on the brown adipose tissue (BAT) to generate heat in a nonshivering fashion. New work from Muthu Periasamy and colleagues challenge this BAT-centric view by showing that the muscle is also a key site of nonshivering thermogenesis.

A limitation of photodynamic therapy (PDT) is the depth of penetration of visible light needed for activation of the photosensitizers, restricting treatment to tumors on or just under the skin’s surface or those lining internal organs and cavities. Niagara Muhammad Idris and colleagues have addressed this issue by developing upconversion fluorescent nanoparticles (UNCs) that convert deeper penetrating near-infrared light to visible wavelengths without sacrificing efficacy for singlet oxygen (1O2) production. The group tested the UNCs in vivo in a subcutaneous mouse tumor model using a dual-sensitizer approach for greater PDT efficacy.

By exploiting the relationship between the transcription factor MYC and the transferrin receptor, where the level of transferrin receptor 1 expression may indicate activation of the MYC oncogenic pathway, Jason Holland and his colleagues have developed a novel PET radiotracer to quantitatively and noninvasively measure MYC activity. The ⁸⁹Zr-desferrioxamine transferrin PET radiotracer was tested in several murine models of inflammation and MYC-driven prostate cancer.