Volume 19 Issue 12, December 2013

This year saw the launch of the Global Health Innovative Technology (GHIT) Fund—a new public-private partnership between five Japanese pharmaceutical companies, two government ministries and the Bill & Melinda Gates Foundation. In November, the Tokyo-based fund announced its first round of awards totaling $5.7 million. Leading the new $120 million, five-year initiative is BT Slingsby, a US-born scholar of the Japanese healthcare industry. He met with Cassandra Willyard to discuss the new fund and how Japan can help drive the development of medicines and vaccines for diseases of the developing world.

Co-working spaces in which many entrepreneurs share a common environment have been a hallmark of the computer startup industry for decades. Now, the life sciences sector is beginning to do the same. Elie Dolgin talks with the pioneers helping to bring affordable wet-lab space—plus the infrastructure and support needed to launch a successful commercial enterprise—to the next generation of biotech innovators.

Enabling women to serve at the highest leadership levels in pharmaceutical R&D will help advance science to offer a broader array of medicines to patients. But in an industry dominated by men in the most senior-level roles, women have a long way to go to get to the top.

Biomedical research in 2013 saw some dramatic developments, with unprecedented government action in the US ranging from the budget sequester in the spring to a dramatic government shutdown in autumn. But throughout the year, bright spots in science around the globe continued to dazzle, including multimillion-dollar partnerships to advance drug discovery and the go-ahead for highly anticipated trials of regenerative medicine.

Our list of newsmakers this year includes everyone from thought leaders with brainy plans for the future to individuals who influenced rules and regulations—even from beyond the grave.

As immunotherapies and even newer strategies such as antisense therapy march ahead, the drug development pipeline took an interesting turn this year. Here, we look back at the compounds that made the cut, as well as those that got cut.

From the microbiome to the microenvironment, certain areas of biomedicine saw fast-paced discovery this year. Here's a rundown of the papers that helped these fields advance quickly in 2013.

Cell-mediated activation of latent TGF-β1 is a key promoting event in fibrosis in all organs. A new study shows that specific targeting of the αv subunit of integrins in fibrogenic myofibroblasts effectively reduces developing and established fibrosis in liver, kidneys and lungs (pages 1617–1624).

Recurrent disease after apparent 'cure' of primary tumors is a common factor that contributes to cancer-associated mortality. A new study suggests that an inflammatory cytokine signature may provide a clinical indication of emergent recurrent disease and, accordingly, may suggest how to select and deliver therapy targeted against the secondary tumor (pages 1625–1631).

Despite metformin being one of the most commonly prescribed drugs for the treatment of diabetes, how it elicits its therapeutic effects has remained mysterious. A new study in mice shows that inhibitory phosphorylation of acetyl-coA carboxylases Acc1 and Acc2 by the AMP-activated protein kinase (AMPK) is essential for the ability of metformin to improve insulin sensitivity and lower blood glucose in obesity (pages 1649–1654).

High blood ammonia, as seen in severe liver disease and urea cycle disorders, is neurotoxic and difficult to treat. A new study shows that the toxic effects are caused by impaired astrocyte potassium buffering—not astrocyte swelling, as previously thought—and can be partially blocked by the diuretic bumetanide (pages 1643–1648).

Although stem cells were initially thought to be the magic bullet for numerous diseases, translation of a stem cell–based cure into the clinic is still a work in progress. Basic research is shedding light into the potential of stem cells, and different research fronts are now exploring how to exploit this potential to tackle diverse conditions. In 'Bench to Bedside', Akemi Tanaka, Mark Sauer, Dieter Egli and Daniel Kort discuss how genome transfer from eggs of mothers with mutated mitochondria into an enucleated egg from a healthy female donor at an early developmental stage can eliminate mitochondrial disease. The negligible mutant mitochondrial DNA carryover and the differentiation of subsequent embryonic stem cells into various cell types with healthy mitochondrial DNA content suggest this could be used to prevent transmission of mitochondrial disease to the offspring. The authors discuss safety concerns and remaining technical questions that need to be resolved to make way for this new technology in the clinic. In 'Bedside to Bench', Nan Yang and Marius Wernig peruse a small study of children with a myelin disorder showing that transplantation of human neural stem cells leads to engraftment and donor cell–derived myelination.

The blood-brain barrier (BBB) has a key role in maintaining brain homeostasis and, thus, brain function. This Review outlines recent advances in understanding the development and maintenance of the BBB and the contribution of BBB disruption to various neurological diseases. It also discusses how such insights might be used to design new therapeutic strategies for BBB repair.

Adjuvants play an important part in vaccines, as they can enhance and shape antigen-specific immune responses. This Review discusses the benefits of adjuvants and recent advances in understanding their mechanisms of action. The authors also set out the clinical barriers to development of new adjuvants and offer suggestions for overcoming these hurdles to the advancement of next-generation vaccines.

In exploring the possibility that racial differences in platelet function might exist, Paul Bray and his colleagues report that platelets from blacks have a greater propensity to aggregate than those from whites in response to activation of the PAR4 thrombin receptor. Mechanistically, this difference in platelet function seems to reflect differences in the expression of the microRNA miR-376c and its target, the enzyme phosphatidylcholine transfer protein.

Dean Sheppard and his colleagues show that genetic or pharmacological inhibition of α_v integrin signaling ameliorates fibrosis in several solid organs.

Detecting tumor recurrences early and developing therapies capable of targeting recurrences that resist frontline therapy could be of enormous benefit to patients with cancer. Using mouse tumor models, Richard Vile and colleagues find a cytokine signature associated with very early stage recurrences, as well as evidence that the recurrent tumors are resistant to innate immune responses. By targeting the altered phenotype of the recurrent tumors, the researchers cured the mice of cancer, suggesting new avenues for research into human cancer recurrence.

Autoimmunity is triggered by trafficking of self-reactive T cells into tissues. Joonsoo Kang and colleagues show that the kinase ITK regulates T cell trafficking. ITK inhibition or genetic ablation prevents homing of autoreactive T cells into tissues and reduces islet destruction in models of type 1 diabetes without affecting T cell activation or antiviral T cell responses, suggesting that this kinase may be targeted in autoimmune disease.

T cells specific for hepatitis C virus (HCV) have been reported in some individuals who have been repeatedly exposed to virus, yet have never had detectable HCV or HCV-specific antibodies. These findings suggest that T cells in these individuals may protect against infection by HCV. Barbara Rehermann and colleagues now test this assumption in a nonhuman primate study exposing animals to a very low dose of HCV.

Excess ammonia in the blood can cause neurologic dysfunction and seizures. Although previous studies have suggested astrocyte swelling and brain edema are associated with hyperammonemia, the authors show that ammonia compromises potassium buffering by astrocytes, increasing extracellular potassium concentrations and resulting in cortical disinhibition. Pharmacological or genetic inhibition of NKCC1 attenuates ammonia-induced neurologic impairment and seizures, suggesting hyperammonemia may be treated by targeting NKCC1.

Metformin is one of the most widely prescribed therapeutics for type 2 diabetes. But exactly how it works is still unclear. Gregory Steinberg and colleagues now show that it does so by activation of the enzyme AMP-activated protein kinase (Ampk) and Ampk's obligate targeting of two key enzymes involved in lipid homeostasis.

Variation in the promoter of the gene encoding uromodulin, the most abundant protein in urine, affects the individual risk of developing hypertension or chronic kidney disease. Luca Rampoldi, Olivier Devuyst and their colleagues show that the uromodulin risk alleles are associated with higher levels of uromodulin expression. This can promote hypertension, by stimulating sodium reabsorption by the loop of Henle in the kidney, and kidney damage in both mice and humans.

Matthias Hackl and his colleagues developed a new serial multiphoton microscopy approach to track migrating podocytes and parietal epithelial cells over time in vivo in the intact kidney. Use of this new approach is demonstrated in several mouse models and should help answer questions surrounding podocyte proliferation and migration to other (peri)glomerular regions, thus shedding light on the mechanisms of glomerular injury and regeneration.

There is an urgent need for quantitative magnetic resonance approaches for assessing brain development, as well as for studying the effects of drugs on neural tissue inflammation. Aviv Mezer and colleagues have developed a neuroimaging method for the quantification of local tissue volume and tissue-surface interaction, producing reliable quantitative measurements across a range of scanners. They apply their method to both the healthy brain and individuals with relapsing-remitting multiple sclerosis.