Volume 15 Issue 1, January 2009

Merck's newly appointed chief strategy officer, Mervyn Turner speaks with Prashant Nair about the future promise of drug development and about how pharmaceutical companies can cope with the current economic downturn.

A growing body of evidence supports the idea that some infectious diseases have a heritable component, a notion put forth by none other than Louis Pasteur. As scientists begin to catalog the genetic changes that predispose people to specific illnesses, they are also exploring how to prevent sickness by replacing the missing parts of the immune system's defensive armor. Laura Spinney reports.

Mental retardation and epilepsy can result from the aberrant migration of neurons during development. An experimental treatment in prenatal mice restores normal patterns of migration and eases symptoms (pages 84–90).

A new approach to the treatment of sepsis relies on the infusion of mesenchymal stem cells, multipotent cells used experimentally to treat a range of medical conditions. In mouse models, the cells seem to reprogram immune cells that can contribute to sepsis (pages 42–49).

γ-secretase inhibitors inhibit Notch, a transmembrane receptor that drives many cases of T cell acute lymphoblastic leukemia—but there are safety concerns with such drugs. Combining these inhibitors with glucocorticoids could provide a more effective and safer approach (pages 50–58).

A trial of a childhood vaccine against a common respiratory virus went terribly wrong in the early 1960s. Instead of protecting children, the vaccine exacerbated disease in response to infection. We now have a better understanding as to why (pages 34–41).

Numerous drugs have been invented to counteract heart failure, but some have not lived up to their initial promise. As David Kass explains, the development of drugs to increase cardiac contractility has been particularly frustrating—but failure is also leading to new biological insights and new experimental approaches. Mark Anderson and Peter Mohler explore new ways of targeting calcium-mediated signaling in the heart—with a focus on combating heart failure by targeting 'local' forms of signaling in heart muscle.

Studies of hepatitis C virus replication in cell culture have suggested that certain microRNAs are required for efficient virus replication and that they may be involved in the antiviral effect of interferon. A study in humans infected with the virus provides a new perspective.

A formalin-inactivated vaccine from the 1960s against respiratory syncytial virus (RSV) failed to protect children. Although scientists thought that its failure resulted from formalin disruption of protective antigens, it is now shown that it resulted from low antibody avidity for protective epitopes after poor Toll-like receptor (TLR) stimulation. RSV vaccines could therefore become effective by including TLR agonists in their formulation (pages 21–22).

Mesenchymal stem cells have therapeutic effects in various different models of disease, but how they work is not always clear. Eva Mezey and her colleagues now propose that such cells may prove beneficial in sepsis—and they work by reprogramming innate immune cells (pages 18–20).

Notch signaling has a crucial role in T cell acute lymphoblastic leukemia (T-ALL), but γ-secretase inhibitors (GSIs), which block the Notch pathway, cause intestinal toxicity that limits their use. Adolfo Ferrando and his colleagues now report that glucocorticoids can reverse the gut toxicity of GSIs, and GSIs can restore sensitivity of T-ALL cells to glucocorticoids, suggesting that this combination may have clinical utility in T-ALL and other diseases (pages 20–21).

Early identification of individuals with colorectal cancer who are at high risk of metastasis might help guide treatment choice and improve outcome. Stein et al. now report that MACC1, a previously undescribed gene, is a prognostic indicator of colorectal cancer and describe its role as a transcriptional regulator of MET, which encodes the hepatocyte growth factor receptor and promotes metastasis of a variety of cancers.

Identifying factors that influence response to cancer chemotherapy is crucial for improving its efficacy. Mauro Delorenzi and his colleagues report that a stromal gene expression signature predicts resistance to a commonly used chemotherapy regimen in individuals with estrogen receptor–negative breast tumors. These findings underline the potential of the tumor microenvironment to modulate tumor phenotype and the clinical response to treatment.

Mitogen-activated protein (MAP) kinases are known to promote cardiac hypertrophy, but how upstream hypertrophic signals induce these kinases to cause hypertrophy has not been clear. Lorenz et al. now uncover a new mechanism of MAP kinase activation and demonstrate the crucial role that this mechanism has in the hypertrophic response.

Aberrant neuronal migration during development leads to defects in cortical development and to an increased seizure susceptibility. Now, Joseph LoTurco and his colleagues show that it is possible to re-invoke neuronal migration perinatally in rodents and reposition neurons into their correct cortical location (pages 17–18).

Children born to mothers with lupus have a higher rate of learning disorders. Now, in mouse studies, Betty Diamond and her colleagues show that neurotoxic antibodies found in mothers with lupus are transferred to the brains of their offspring. This leads to abnormalities in cortical formation during development and in cognitive function when the pups become adults.

The chemokines CCL5 and CXCL4 promote monocyte recruitment to atherosclerotic plaques. Recent findings in vitro have shown that heteromerization of CCL5 and CXCL4 increases their potency in stimulating monocyte adhesion and chemotaxis. Koenen et al. now show that this heteromerization has functional consequences in vivo. Treatment of atherosclerotic mice with a cyclic peptide that specifically disrupts the CCL5-CXCL4 interaction inhibited monocyte recruitment to atherosclerotic plaques. Moreover, selective inhibition of heteromer formation may offer therapeutic advantages compared to complete blockade of chemokine function.

A goal of cancer research is to develop specific and sensitive tumor-imaging techniques for early detection while minimizing background signals from nontarget, 'normal' tissues. The authors have designed a 'pH-activatable' probe, consisting of a targeted macromolecule (monoclonal antibody) and a fluorescence probe, which is activated after internalization in the lysosomes of targeted cancer cells. The utility of this approach for imaging HER2-positive lung cancer cells in mice is shown.

There is a need for mouse tumor models that more closely recapitulate the pathophysiology of human cancers. Here, a mouse model of glioblastoma multiforme (GBM) is generated with Cre-loxP controlled, lentiviral-mediated delivery of the oncogenes H-Ras and AKT. Transduction of the oncogenes in a small number of cells in adult immunocompetent mice led to the formation of GBM-like tumors, particularly when combined with loss of p53.