Volume 15 Issue 3, March 2009

Biological innovation typically takes place within the walls of academia and industry. But a new grassroots movement to organize hobby scientists is afoot. Mac Cowell and Jason Bobe, co-founders of the organization DIYBio, spoke with Prashant Nair about their plans for amateur biology.

For many years, textbooks portrayed nerve communication as a straightforward process in which a signal simply hopped from one cell to the next. This traditional view also cast cells known as glia as passive bystanders to the signaling action between neurons. But scientists increasingly regard glia as influential third players in the space where signals pass between neurons, a space they have termed the 'tripartite synapse'. On the basis of this concept, some have begun to study the involvement of glia in nervous system disorders and to develop therapeutic compounds that target these cells. David Gruber reports.

A remote, downstream event in the pathology of muscular dystrophy may have a key role in the disease (pages 325–330). It seems that induction of nitric oxide synthase causes calcium to leak inside the cell through ryanodine receptors. The findings provide new options for therapeutic interventions.

An experimental simian immunodeficiency virus vaccine boosts production of memory T cells at the site where the virus first contacts the body—in the mucosa (pages 293–299). The approach has the potential to result in more effective HIV vaccines than those currently under development.

Activation of hypoxia-inducible factor, a molecule central to oxygen sensing, can promote the survival and growth of tumor cells. New experiments dissect a pathway behind this effect—upregulation of the epidermal growth factor receptor (pages 319–324).

Findings in knockout mice indicate that hypoxia-sensitive pathways modulate the glucose-sensing machinery of pancreatic beta cells. Conditions that mimic hypoxia severely impair glucose-stimulated insulin release.

Three studies implicate Kindlin-3, a molecule that mediates signaling through integrins, in a rare disorder characterized by spontaneous bleeding and susceptibility to infection (pages 300–305, 306–312 and 313–318).

Inherited neurodegenerative conditions such as Huntington's disease have proximal causes (a defective gene) and downstream causes (pathological events caused by that gene). Albert R. La Spada examines efforts to target bad genes with gene knockdown approaches on the eve of a clinical trial designed to silence the causative gene in familial amyotrophic lateral sclerosis. Masahisa Katsuno, Hiroaki Adachi and Gen Sobue examine the possibility of targeting a potentially damaging downstream event in Huntington's disease—dysregulated cholesterol metabolism in the brain.

Bone is resorbed by osteoclasts, and too much activity by these cells leads to disease, such as osteoporosis. Here Kyoji Ikeda and colleagues show that the combined action of iron uptake and a key transcription factor involved in mitochondrial biogenesis are required for the proper functioning of these cells and that in cases of increased bone loss, iron chelation may be beneficial by inhibiting these cells.

During autophagy, cytosolic proteins and damaged organelles are delivered via autophagosomes to lysosomes, where they are degraded before presentation at the cell surface. Agents that induce autophagy have previously been shown to boost antigen presentation in vitro. Here Chinnaswamy Jagannath and colleagues show in mice that autophagy can be exploited to boost the efficacy of a dendritic cell vaccine for Mycobacterium tuberculosis.

Interleukin-10 is known to dampen immune responses and contribute to the persistence of chronic viruses and parasites. Thomas Braciale and his colleagues show in mice that the anti-inflammatory cytokine is produced, along with proinflammatory cytokines, by effector CD4⁺ and CD8⁺ T cells during an acute virus infection of the lung, thereby helping to regulate the extent of inflammatory lung damage in response to the virus.

The first phase 2 gene therapy trial for HIV-1 has shown some promising signs. There's a long way to go before this would be a viable approach in people with HIV—this trial did not show a statistically significant difference in viral load at the primary end point–but other analyses did reveal that the gene therapy seemed to have a modest, but statistically significant, effect at reducing viral load in the treated subjects versus the placebo arm. The study also provides some clues about what to improve in the future.

Issue:Vaccines that induce T cell responses to simian immunodeficiency virus are able to reduce virus load in infected macaques. Such vaccines typically induce central memory T cells that must expand before gaining full antiviral functions. Picker and his colleagues show that a new replicating anti-SIV vaccine, based on the persistently infecting cytomegalovirus, which preferentially induces effector memory T cells in mucosal tissues, can reduce the likelihood that the macaques become infected in the first place (pages 244–246).

Kindlin-3 interacts with β₁ and β₃ integrins on platelets, and Kindlin-3–deficient mice have defects in platelet activation and blood clotting. Moser et al. now show that these mice also have defects in β₂ integrin activation on leukocytes, leading to severely compromised leukocyte adhesion to the endothelium. The combined platelet and leukocyte defects of these mice resemble those seen in individuals with the leukocyte adhesion deficiency syndrome LAD-III. Other papers in this issue by Malinin et al. and Svensson et al. provide evidence that KINDLIN-3 dysfunction does indeed underlie this type of human disease syndrome (pages 249–250, 306–312 and 313–318).

In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation (pages 249–250, 300–305 and 313–318).

In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation (pages 249–250, 300–305 and 306–312).

Hypoxia promotes tumor growth by stimulating angiogenesis, glycolysis, resistance to apoptosis and cell invasion. Wang et al. now report that hypoxia also increases the duration of growth factor signaling in tumor cells. They show that hypoxia-inducible factor downregulates the expression of an effector of early endosome fusion, slowing the endocytic recycling of epidermal growth factor receptor and thereby extending its activation and potential to enhance tumor cell proliferation and survival (pages 246–247).

Increased calcium levels in dystrophic muscle have damaging consequences. In this report, Bellinger et al. show that nitrosylation of the ryanodine receptor calcium channel, leading to calcium leak through the channel, is an underlying cause of increased calcium levels in the muscle of dystrophic mdx mice. Treatment of the mice with a compound that inhibits calcium leak increases their muscle function and physical activity, pointing to a potential new treatment for muscular dystrophy (pages 243–244).

Mark Tuszynski and his colleagues show that brain-derived neurotrophic factor is neuroprotective and can improve cognition in rodent and primate models of Alzheimer's disease.

A research team led by Renier Brentjens offers a new approach to monitor in vivo trafficking of T cells by tagging them for bioluminescence imaging using a membrane-anchored form of the humanized Gaussia luciferase enzyme. The set-up provides a high bioluminescent signal and should be useful for studying in vivo T cell function in mouse models of disease investigating mouse or human primary T cells.