Volume 17 Issue 10, October 2011

In August, Mahendra Rao returned to the US National Institutes of Health (NIH) after a six-year hiatus to head the new Intramural Center for Regenerative Medicine. The $52-million center was launched in early 2010 by the agency to develop new therapies using stem cell approaches. Elie Dolgin spoke to Rao to find out how he plans to turn stem cell discoveries into cell-based therapies.

Many of today's most celebrated drugs are designed to hit only one biological target with great precision. But a novel clinical trial aims to turn this idea on its head by using 'network pharmacology' to more effectively tackle a common neurological disorder affecting limb movement. Claire Ainsworth looks into how medicine's proverbial 'magic bullet' might soon give way to a more sophisticated arsenal.

The new National Center for Advancing Translational Sciences planned for the US National Institutes of Health intends to help transform biological findings into new therapeutic products. But if taxpayer funding of risky biomedical research translates into lucrative new medicines, the public should share in the economic benefits as well.

Memory T cells can be maintained for a lifetime, but the underlying mechanism has been hard to pin down. A new study identifies a subset of memory T cells with stem cell properties in humans and shows that these cells mediate a superior antitumor response in a mouse model of adoptive T cell therapy (pages 1290–1297).

BRCA1 germline mutations lead to an increased risk of breast and ovarian cancer, but the mechanisms by which the product of this gene functions as a tumor suppressor have remained elusive. Now, analysis of a missense BRCA1 variant shows that it can epigenetically regulate an miRNA implicated in cancer, providing new mechanistic insights (pages 1275–1282).

In the search for an improved vaccine to combat tuberculosis, a potent candidate has unexpectedly emerged that induces potent efficacy against mycobacterial infection in mice (pages 1261–1268).

Mutations in the microsatellite of the chaperone heat shock protein 110 (HSP110) yield a mutant protein that counteracts oncogenic potential, enhances responsiveness to chemotherapy and associates with increased survival in individuals with colorectal cancers that arise through defective DNA mismatch repair (pages 1283–1289).

A study in a mouse model of immune-mediated glomerular disease and in people with rapidly progressive glomerulonephritis shows activation of epidermal growth factor receptor (EFGR) signaling in podocytes by a molecule expressed in the kidney (pages 1242–1250). Blocking this axis may open new doors to treat inflammatory kidney conditions.

Epilepsy complicates the clinical course of many patients with brain tumors, particularly gliomas. A mouse model of glioma now indicates that glioma cells release glutamate, causing tumor-related seizures (pages 1269–1274). Sulfasalazine, an approved therapeutic for Crohn's disease, can block glutamate release and improve seizures in these mice; therefore, this drug may also have potential antiepileptic effects in humans.

Despite remarkable advances in managing disease progression in people infected with HIV, an effective vaccine to prevent infectivity and stop the HIV epidemic remains an unmet clinical need. The genetic variability of the virus and the poor natural immune response—humoral and cellular—generated against HIV are hurdles that pose challenges to vaccine development. In 'Bench to Bedside', Bruce Walker, Rafi Ahmed and Stanley Plotkin examine a study in rhesus macaques where a vector-based viral vaccine that elicits a persistent and rapid T effector cell response to SIV antigens results in control of the infection. Although only 50% of the rhesus macaques controlled the infection, this in vivo finding stresses how outdoing the natural immune cellular response can prove effective to clear systemic viruses. But a humoral response will still remain the 'holy grail' to avoid HIV infection and transmission. In 'Bedside to Bench' Tom Hope peruses recent vaccine trials to propose how to best achieve an effective antibody response against HIV by discussing the perks and perils of non-neutralizing versus broadly neutralizing antibodies.

This report describes the isolation and in vitro expansion of human colon stem cells from normal tissues. Cells with high levels of the membrane receptor EPHB2 are shown to have characteristics of intestinal stem cells, and the authors optimize culture conditions that allow their in vitro expansion as multipotent cells capable of differentiation into several intestinal lineages.

The placebo response involves a perceived effect of a drug that was not really received by the subject. Fabrizio Benedetti and colleagues demonstrate that the placebo response to NSAIDs in reducing pain is mediated by the endocannabinoid system in humans.

To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.

To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.

Rapidly progressive glomerulonephritis (RPGN) is a form of severe kidney injury that can lead to promptly lethal renal failure. Pierre-Louis Tharaux and colleagues report that HB-EGF is upregulated in RPGN, resulting in activation of EGFR in podocytes and their dysfunction. They further show that genetic loss of expression of HB-EGF or EGFR in a mouse model is protective, whereas pharmacological inhibition of EGFR, even after disease onset, is therapeutic. These results suggest a possible avenue of treatment for this potentially devastating condition.

The activation of stress kinases, such as p38 MAPK, is believed to be detrimental to normal cellular processes. However, Umut Ozcan and his colleagues now show that p38 MAPK is actually beneficial, as in mice it increases the mRNA stability and nuclear localization of Xbp1s, a crucial factor in resolving endoplasmic reticulum stress and improving glucose homeostasis. These results suggest a possible indirect way of targeting XBP1s in the treatment of type 2 diabetes.

New vaccine candidates are urgently needed for the control and prevention of Mycobacterium tuberculosis (Mtb) infection. Kari Sweeney and her colleagues now report that an attenuated strain of Mycobacterium smegmatis expressing the esx-3 genes from Mtb induces effective CD4⁺ T cell dependent immunity against infection with Mtb in mice. The study offers a new avenue for the identification of protective immunogens in Mtb infection and a candidate vaccine platform warranting further study.

People with brain cancers called gliomas often have seizures due to secretion of the excitatory neurotransmitter glutamate from the tumor. Now, Harald Sontheimer and his colleagues report that blockade of a cystine-glutamate transporter in tumor cells by an FDA-approved drug can reduce glioma-induced epilepsy in mice.

BRCA1 loss of function is considered to promote tumorigenesis through impairment of the protein's role in DNA damage repair. By studying BRCA1 mutations that do not affect this function but still confer cancer predisposition, this report identifies a new function of BRCA1, the repression of miR-155 through modulation of HDAC activity. miR-155 increase correlates with BRCA1 loss or mutation in humans, and it likely to mediate some of the oncogenic effects of BRCA1 deficiency.

Microsatellite instability (MSI) due to alterations in DNA repair genes leads to carcinogenesis, but it also correlates with better prognosis and therapy response. Little is known of the contribution of altered noncoding sequences to MSI tumorigenesis. This report identifies a deletion in an MSI intronic region leading to the expression of a truncated chaperone, which shows dominant-negative effects on its wild-type counterpart. Acting as an endogenous inhibitor of a protumorigenic chaperone, the expression of the truncated variant associates with better prognosis in humans and may contribute to the overall limited malignancy of MSI tumors.

Whether there exists a human memory T cell population with stem cell–like properties of self-renewal and multipotency is under active investigation. Here Gattinoni et al. characterize a subset of human T cells that phenotypically resemble naive T cells yet have properties associated with memory T cells. These T cells show enhanced ability to self renew and to give rise to differentiated memory cell subsets, suggesting a stem cell–like functionality.

Loss of mismatch repair (MMR) genes is associated with poor cancer prognosis and has been reported to occur through genetic alterations that directly affect the expression of MMR genes such as MSH2. This report identifies a subset of leukemia patients with reduced levels of MSH2 protein but without alterations in the MSH2 gene, and it identifies concurrent deletions in regulators of MSH2 stability as potential contributors to the MSH2 deficiency and associated drug resistance in this and other cancers.

Calcineurin inhibitors, such as tacrolimus, are widely used immunosuppressive agents, but they can cause hypertension. In studies of tacrolimus-treated mice, the authors show that hypertension is due to activation of the sodium chloride transporter NCC in the kidney, causing sodium retention. They found that NCC activation also occurred in kidney transplant recipients receiving tacrolimus. The authors suggest that thiazide diuretics, which are NCC inhibitors, might counteract the hypertensive effects of this class of immunosuppressants.

Staphylococcus aureus produces pore-forming toxins, such as α-hemolysin, that damage epithelial cell layers, causing disease. In this issue, Inoshima et al. report that the cellular receptor for α-hemolysin—the metalloprotease ADAM10—is essential for lethal pneumonia caused by S. aureus infection in mice. The authors suggest that the combined effect of α-hemolysin on pore formation and in activating ADAM10 cleavage of the adherens junction protein E-cadherin disrupts the barrier function of the lung epithelium.

The prognosis for patients with advanced stage ovarian cancer is poor. Here, Gooitzen van Dam and colleagues demonstrate the first human application of a tumor-specific intraoperative fluorescence imaging methodology using a folate receptor-α (FR-α)-targeted fluorescent agent that exploits the overexpression of FR-α in the majority of epithelial ovarian cancers. It is hoped this approach may lead to improved intraoperative staging and more radical cytoreductive surgery.