Volume 16 Issue 12, December 2010

In July, the global health financing mechanism UNITAID established an intellectual property–sharing scheme focused on scaling up access to new and lower-priced antiretroviral drugs in the developing world. Ellen 't Hoen, a lawyer who became executive director of the Medicines Patent Pool (MPP) last month, spoke with Asher Mullard about the challenges of encouraging companies to share their intellectual property in a normally guarded sector.

To truly know whether a stem cell has the developmental flexibility to give rise to new, therapeutic tissue types, the cells must undergo a definitive test in which they are injected into mice and observed. Yet many say this measure is too slow, too expensive and too unreliable. Elie Dolgin goes in search of a replacement.

The recent global campaign launched against a select number of neglected tropical diseases (NTDs) is a welcome development. But we should be as careful about measuring progress toward the control or elimination of these diseases as we are about choosing which ones to target.

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's the skinny on the weight loss drugs that disappointed, the hepatitis drugs that matched the hype and others as we look back on the major headlines relating to medications in 2010.

Sometimes the retraction of a paper can be as noteworthy as the publication of one. Here we list some of the take-backs of 2010 that left the biomedical community most taken aback.

Mesenchymal stem cells (MSCs) can form different cell types in culture, but their potential to build new tissue in various disorders where tissue is damaged has not been realized. A study now shows how mature cells from blood vessels are a new source of MSCs that may be used to regenerate cartilage and bone (pages 1400–1406).

The chromatin remodeling complex SWI-SNF is altered in cancer. New findings now show that the core component SNF5 can block a Hedgehog (Hh) effector, which promotes malignant rhabdoid tumor growth when SNF5 is lost (pages 1429–1433). Targeting this Hh effector may be a way to combat these aggressive childhood tumors.

The interaction between two proteins associated with a glutamate receptor can drive neuronal death mediated through this receptor after stroke. A small molecule, designed to specifically disrupt this deadly interaction, protects the brain in mice and rats against neuronal damage without undesirable side effects (pages 1439–1443).

Postoperative ileus complicates the recovery from intestinal surgery with a great economic burden. How this morbid condition spreads throughout the entire gut remains unknown, but new findings show that a T helper type 1 (T_H1)-mediated immune response is involved. Its components may be possible therapeutic targets (pages 1407–1413).

Understanding how the complex molecular mechanisms of the brain can be blighted, and what their role is in neurological disorders, can be an intricate task. The basis of mood alterations and how humans react to a damaged or altered brain circuit can provide clues for new therapies to target the root of these neurological glitches. In 'Bedside to Bench', Daniel Weinberger and Caroline Zink discuss how people with anorexia nervosa showed a connection between self starvation and motivational value—an opposite perspective to the traditional idea linking the absence of joy to the symptoms of this disorder and a new paradigm for developing the appropriate treatments. In 'Bench to Bedside', Dennis Charney and James Murrough peruse how the antidepressant action of ketamine in rats—a neurotrophic effect—can explain the rapid reduction in depression observed in the clinic with this drug. The receptors and signaling cascades involved may be used to develop therapies that may further enhance this rapid beneficial effect.

Dysfunction of the dopamine neurotransmitter system has long been implicated in depression. Now, Fang Liu and colleagues show that the interaction between two dopamine receptor subtypes is increased in the brain of subjects with major depression. Blocking this interaction in rodent models of depression can result in antidepressant-like effects.

Dry mucosal surfaces, such as the eyes and mouth, are a major clinical problem, particularly in the elderly or in individuals taking certain medications. Now, Carlos Belmonte and his colleagues show that cooling of the eye, caused by surface evaporation during eye opening, can induce tearing by stimulating TRPM8-expressing cold-sensing nerve endings.

Under certain conditions, endothelial cells can transform into mesenchymal cell types, a process known as endothelial-to-mesenchymal transition. Damian Medici et al. now provide evidence that this type of transition contributes to the generation of the ossified lesions of individuals with fibrodysplasia ossificans progressiva. Experiments in mice and in cultured endothelial cells indicate that activation of the ALK2 receptor in endothelial cells endows them with the ability to differentiate into a number of cell types.

One complication arising from gastrointestinal surgery is ileus, in which local manipulation of the intestine leads to dysmotility and paralysis of the entire intestine. Christian Kurts and his colleagues find that after surgery T helper type 1 memory cells are activated by intestinal dendritic cells via interleukin-12, and migration of memory T cells through the portal vein induces paralysis of unmanipulated sites. Inhibition of interleukin-12 or prevention of lymphocyte egress with FTY720 prevents ileus and suggests new targets for therapeutic intervention.

The transition from androgen-dependent to castration-resistant prostate cancer is a lethal event. N-cadherin seems to be a major cause underlying this transition, and targeting this adhesion molecule may have positive clinical benefit.

Physiological Stat3 signaling is temporally restricted. In cancer, Stat3 activity is often persistently elevated and fosters progression through its effects on tumor cells and their microenvironment. This report identifies the reciprocal positive regulation of S1PR1 and Stat3 in tumors as a mechanism by which tumor cells and their environment crosstalk to maintain Stat3 activity. This persistent loop is required for tumor progression and metastasis and could be a potential therapeutic target to block oncogenic Stat3 signaling.

The authors characterize a previously undescribed function of Snf5 that involves interaction with the transcription factor Gli1 and downregulation of its activity via chromatin remodeling. Snf5 is shown to restrict Hedgehog (Hh) signaling in normal development and cancer. Hh inhibition emerges as a potential therapeutic strategy for malignant rhabdoid tumors in which Snf5 is commonly lost.

By acting on the P2X₇ receptor, ATP released upon cell damage functions as a danger signal to promote acute graft-versus-host disease after bone marrow transplantation in mice.

Brain injury after stroke requires glutamate receptor activation of neuronal nitric oxide synthase (nNOS), but inhibiting either of these proteins can cause side effects. Now, Dong-Ya Zhu and colleagues show that a drug that blocks the interaction between nNOS and a glutamate receptor docking protein can reduce stroke damage in vivo, with no observed side effects.

Grazyna Palczewska and her colleagues use the noninvasive imaging modality of two-photon microscropy to study the retinoid cycle in the mammalian eye at the subcellular level. They perform spectral analyses of endogenous fluorophores, including fluorescent retinyl esters in subcellular structures called retinosomes, as well as their potentially harmful condensation products. This may prove useful in assessing retinal changes in the human eye at the earliest stage and long before retinal diseases become apparent and result in loss of vision.

Deficiencies with current in vitro methods to assess cancer invasion prompted Todd Ridky and his colleagues to design a three-dimensional human organotypic epithelial cancer model using primary epithelial cells from multiple stratified epithelial tissues. The model recapitulates many of the features of tumor progression, including epithelial invasion through the intact basement membrane and supporting stroma. Studying epithelial tumor cell invasion in a more physiologic manner may help identify potential therapeutic targets for a range of epithelial tumors.