Volume 17 Issue 12, December 2011

Since its launch in 2001, the Center for Global Development (CGD) has been instrumental in convening working groups and issuing reports that shape the agenda for a range of topics that affect global poverty and people of the developing world. At the helm of its global health effort is Amanda Glassman. In recognition of CGD's ten-year anniversary last month, Elie Dolgin spoke to Glassman about how the think tank turns its words into actions.

The path to drug approval is long, hard and often perplexing. In recent months, the US Food and Drug Administration (FDA) has promised to bolster 'regulatory science', which aims to transform its decision-making process to be more efficient, transparent and accountable. However, diverse stakeholders, including patients, drug developers and the US Congress, will have to rise to the challenge of coordinating their priorities if this endeavor is to succeed.

Scientists had long assumed that any genetic mutation that does not alter a protein sequence should have no impact on human health. But recent research has shown that such synonymous DNA changes can trigger disease in a number of ways. Alla Katsnelson talks to scientists and biotech companies who are speaking up about 'silent' mutations.

We list key people who made headlines this year, either by standing up for what they saw as right or by stopping what they felt was wrong.

We look back on some of the key insights into biomedicine published this year.

Here we present the in-gene-ious cancer drugs, sanguine blood thinners and others of 2011 as we look back on this year's major headlines related to medications.

IgA regulates intestinal homeostasis by maintaining appropriate communities of bacteria within the gut. A new study shows that intestinal bacteria regulate metabolism via IgA (pages 1585–1593).

Although protein-polysaccharide conjugate vaccines provide notable clinical benefits, it is still not fully understood how they work. A new mechanism of action for these vaccines has been identified in which T cells can recognize sugar epitopes in the context of the major histocompatibility complex (MHC) provided they are bound to a protein 'anchor', which allows binding of the sugar epitope to the MHC (pages 1602–1609).

miR-200 family expression results in highly proliferative ovarian cancer cells. Yet this expression is also linked to longer overall survival in women with ovarian cancer. A new study sheds light into this apparent paradox showing that two members of this family—miR-141 and miR-200a—not only boost tumor growth but also sensitize tumor cells to chemotherapy (pages 1627–1635).

The nuclear factor-κB (NF-κB) family of regulators is well known for mediating dendritic cell (DC) maturation—that is, the acquisition of the functions required for full activation of T cells. Paradoxically, a key member of this family, NF-κB1, is now also implicated in maintaining DCs in an immature state (pages 1663–1667).

Cellular production of nitric oxide (NO) by nitric oxide synthase (NOS) in the face of limiting pools of arginine requires the intracellular citrulline-to-NO pathway, catalyzed by the enzyme argininosuccinate lyase (ASL). People with the urea cycle disorder argininosuccinic aciduria, caused by a deficiency of ASL, have systemic NO deficiency, which can be rescued by the use of an alternative, NOS-independent, nitrite-to-NO pathway.

The discovery that skin cells from an adult human can be reprogrammed back to their embryonic stage and then differentiated to produce neuron-like cells in culture opens an opportunity to study disease pathogenesis and screen potential therapeutic drugs. A new study provides an example of this approach for the neuropsychiatric disorder Timothy syndrome (pages 1657–1662).

Chemotherapy can save the lives of many individuals with cancer. Unfortunately, it usually causes infertility after treatment, posing a concern for these people who will face a lifetime condition that considerably limits the quality of their lives. Advances in the field of oncofertility have brought hope to cancer survivors who long to plan a family; however, standard approaches only rely on cryopreservation of sperms and eggs before treatment and do not prevent infertility. In 'Bedside to Bench', Min Xu, Mary Ellen Pavone and Teresa Woodruff examine a study where individuals treated with gonadotropin-releasing hormone (GnRH) agonists before cancer therapy showed a decreased risk of infertility. How these agonists work to suppress and protect ovarian function and increase fertility in women after treatment is still unclear and begs further investigation at the bench. In 'Bench to Bedside', Amander Clark, Bart Phillips and Kyle Orwig discuss potential experimental options to preserve and restore male fertility after chemotherapy. These approaches will shed light into mechanisms of male fertility and spermatogenesis and may be the alternative to sperm freezing, which is not suitable for prepubertal boys and men unable to make sperm.

This review provides a guide to the conceptual and practical issues to consider when trying to generate an iPSc model that accurately recapitulates the features of a human genetic disease. The authors highlight recent successes in modeling genetic diseases using iPSCs and offers a perspective on the next steps that will be needed to improve current iPSC-based disease models.

It is well regarded that insulin receptor signaling in the liver is key to proper metabolic control. Reza Zarnegar and his colleagues now show that the hepatocyte growth factor receptor, Met, physically interacts with the insulin receptor signaling complex, potentiating the latter's signaling. They also show that Met signaling restores insulin responsiveness in a mouse model of insulin resistance, suggesting a potentially new therapeutic avenue to treat prediabetes.

Polly Matzinger and her colleagues have shown that in the absence of B cells, and in the presence of the microbiota, the intestinal epithelium launches its own immune defense mechanisms. However, this comes at the expense of metabolic programs involved in fat absorption by the gut. These results could explain the lipid malabsorption often seen in humans with common variable immunodeficiency or with HIV infection.

Bone marrow-derived mesenchymal stem cells (BMMSCs) have so far failed to live up to their potential as a treatment for the repair of large bone defects. Songtao Shi and his colleagues now show that this may be due to their apoptosis mediated by resident T cells in the wound as a result of excess IFN-γ and TNF-α signaling. They show that reducing the levels of these cytokines, including through the local administration of aspirin, markedly increases the survival of implanted BMMSCs and improves bone wound healing in a mouse model.

Glycoconjugate vaccines—such as those targeting some bacteria—couple a glycan to a protein to provide T cell help to B cells and induce polysaccharide-specific IgGs. T cell help has been thought to be conferred by recognition of the protein portion by T cells. Dennis Kasper and his colleagues now report that a glycan-peptide conjugate can induce T cells specific for the glycan moiety, which could help inform future glycoconjugate vaccine development.

The hormone aldosterone can damage the heart after myocardial infarction, such that drugs that inhibit its action are often prescribed. B. Julie He et al. now uncover a new pathway underlying the detrimental effects of aldosterone action: oxidation of the enzyme Ca²⁺/calmodulin-dependent protein kinase II leads to its activation and increased expression of the metalloprotease MMP9 in cardiac muscle cells, thereby promoting cardiac rupture.

The enzyme argininosuccinate lyase (ASL) generates the amino acid arginine, the precursor to both urea and nitric oxide. However, arginine supplementation is not sufficient to correct all of the symptoms of individuals with a congenital deficiency of this enzyme. Ayelet Erez et al. explain this paradox by showing that ASL has a role in nitric oxide synthesis that is independent of its catalytic activity and provide evidence that therapy with agents boosting nitric oxide levels might be beneficial in ASL-deficient individuals.

This report identifies a new contribution of members of the miR-200 family to tumorigenesis. miR-200a and miR-141 specifically regulate p38α, contributing to the cellular modulation of oxidative stress responses. In this role, the miRs can accelerate ovarian tumorigenesis but also endow cancer cells with increased sensitivity to ROS-inducing chemotherapy. This two-part effect is reflected on the distinct association of the miRs with patient survival and may be informative for treatment decisions.

b-AP15 is a novel inhibitor of proteasome activity, with a different mechanism of action than the available and widely used proteasome inhibitors such as bortezomib. b-AP15 inhibits the deubiquitinating activity of the regulatory subunit of the proteasome, necessary for protein degradation, and induces cytotoxicity impairing tumor growth in mouse models. The compound may represent an alternative therapeutic approach with a broader spectrum of applicability than current proteasome inhibitors.

Raf kinase activity is deregulated in cancers and is thought to promote tumor growth by inducing proliferation signaling through MEK/Erk. This report identifies a new role for c-Raf independent of MEK/Erk and relying on phosphorylation of Ser338. Phospho–C-Raf interacts with the mitotic kinases Aurora-A and Plk1, activating the latter to promote mitotic progression and increase cell division, and this pathway is a crucial mediator for the protumorigenic effect of c-Raf in vivo.

This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons. Now, Valentin Gribkoff and his colleagues show some preliminary evidence that the drug dexpramipexole may have clinical activity in a small placebo-controlled trial in patients with ALS.

Timothy syndrome is a neurodevelopmental disease that includes autism-like features. Using iPS-derived neurons from individuals with Timothy syndrome, Ricardo Dolmetsch and his colleagues identify changes in cortical neuron fate and neurotransmitter expression that may begin to explain the neural mechanisms that underlie this disorder.

Although maturation of dendritic cells can drive autoimmune responses in mice, it remains unclear whether intrinsic factors hold dendritic cells in a resting state. Pamela Ohashi and her colleagues identify a repressive mechanism requiring expression of nuclear factor-κB1 in dendritic cells. Loss of nuclear factor-κB1 results in CD8⁺ T cell activation, TNF-α production and autoimmune diabetes in mice.

Wound healing involves a transient regeneration of tissue, but, if this process continues unabated, pathology occurs in the form of fibrosis, which can prevent normal organ function and even death. Derek Mann and his colleagues have found that serotonin-responsive profibrogenic hepatic stellate cells inhibit the growth of neighboring liver cells during the termination phase of liver injury. They also found that inhibiting serotonin signaling during established disease improved liver fibrosis in various mouse models of liver injury.

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease.

The future of imaging is the integration of function and anatomy. Hongki Yoo et al. have successfully done just that by combining two existing intravascular imaging techniques into a single catheter-based system. Their dual-modality intra-arterial catheter uses a combination of optical frequency domain imaging and near-infrared fluorescence imaging to simultaneously provide molecular information in the context of the surrounding three-dimensional microanatomy of the artery wall.

Makoto Mitsunaga et al. have developed a new form of molecular-targeted cancer therapy that provides an alternative to current photodynamic approaches where damage to surrounding healthy cells and tissues can be a problem. They use a target-specific photosensitizer based on a near-infrared phthalocyanine dye, which is conjugated to monoclonal antibodies targeting human epidermal growth factor receptors (HER1 and HER2). Selective treatment using this approach was shown in vivo in subcutaneous cancer xenografts in mice.