Novel anti-angiogenic biologics

Because many tumors types can develop resistance to current anti-angiogenic therapies, an urgent need exists to discover alternative therapies addressing new vascular targets. Carmeliet and colleagues show that an antibody against placental growth factor (PlGF)—a homolog of vascular endothelial growth factor (VEGF)—inhibits the growth and metastasis of more than a dozen tumor models, including some that are resistant to drugs inhibiting the VEGF–VEGF receptor 2 pathway. PlGF stimulates endothelial cell growth and migration and attracts bone marrow progenitors and macrophages by selectively binding to VEGF receptor 1. The anti-PlGF antibody reduces not only tumor angiogenesis, like drugs inhibiting the VEGF-VEGF receptor 2 pathway, but also macrophage recruitment, which can confer resistance against anti-VEGF treatment. The authors also show that the anti-PlGF antibody enhances the efficacy of chemotherapeutics and anti-VEGF therapeutics. In another study, Ferrara and colleagues show that an antibody against Bv8, an endothelial cell–specific cytokine, suppresses tumor angiogenes, inhibits the growth of several tumor models and reduces the number of CD11+ Gr1+ myeloid cells in peripheral blood and tumor tissue. Anti-Bv8 antibody also increases the efficacy of chemotherapy and anti-VEGF therapy. These two studies illustrate the potential of combination therapies in attenuating the recruitment of bone marrow–derived cells to the tumor niche. (Cell 131, 463–475, 2007; Nature 450, 825–831, 2007) JWT

Gut reaction fuels biofuel research

Converting lignocellulose to biofuel material has become a national priority, as lignin could provide a more energy-efficient source of ethanol than feed crops such as corn. Because chemical approaches for degrading lignin are expensive and environmentally unfriendly, attention is turning to a natural wood degrader—the termite—as a source of enzymes. Recently, the role of microbiota in this process has come to light, and now, using metagenomic and metaproteomic analysis, Ledbetter and colleagues have put together a picture of a unique community of bacteria that together produce a diverse array of cellulases and hemicellulases. The group analyzed over 71 million base pairs of DNA isolated from the microliter-sized hindgut of the higher termite Nasutitermes, collected from the forests of Costa Rica. Among sequences for 12 different phyla, those from spirochetes and fibrobacter predominated. The presence of fibrobacter was expected, as these bacteria occur in the lumens of cows and other ruminants; more surprising was the presence of spirochetes, which may be contributing enzymes for generating acetate, the major carbon source of the host termite. In addition to genes for the hydrolytic enzymes, the researchers uncovered others related to nitrogen fixation and chemotaxis, as well as 34 groups of genes previously undescribed. (Nature 450, 560–565, 2007) LD

Wrapping up the human genome

Despite the completion of the Human Genome Project four years ago, closing the more than 340 leftover gaps and reaching consensus about the total number of protein-coding genes remain critical challenges. Bovee et al. report in Nature Genetics how use of paired-end-sequence fosmid libraries reveals 2.5 Mb of new sequence that closes 26 of 250 euchromatic gaps in the human genome. Eight of the closed gaps are polymorphic. Writing in the Proceedings of the National Academy of Sciences, Clamp et al. tackle the equally important goal of distinguishing protein-coding genes from non-coding open reading frames (ORFs). By comparing the human, mouse and dog genomes, and then studying the properties of nonconserved ORFs in primates, they pare the number of putative protein-coding genes from 24,500 to 20,500. This methodology should facilitate annotation of new additions to the human gene catalog, such as those provided by Bovee et al. (Nat. Genet., published online December 23, 2007, doi:10.1038/ng.2007.34; Proc. Natl. Acad. Sci. USA 104, 19428–19433, 2007) PH

iPS cells for sickle cell disease

Induced pluripotent stem (iPS) cells are differentiated cells that have been returned to a pluripotent state by the introduction of a few select genes. In the first therapeutic application of this technology, Jaenisch and colleagues have used iPS cells to correct sickle cell anemia in a knock-in mouse homozygous for the human βS (sickle) globin allele. Tail-tip fibroblasts were collected from a 12-week-old afflicted mouse. For reprogramming to iPS cells, Oct4, Sox2, Klf4 and c-Myc flanked by loxP sites were delivered by viral vectors; Cre recombinase expression was then used to delete the tumorigenic c-Myc. The faulty globin gene was repaired by homologous recombination following transfection of the wild-type gene, with a targeting efficiency of 1 in 72 iPS cell colonies. Finally, the corrected iPS cells were induced to differentiate into hematopoietic progenitor cells in vitro and transplanted into irradiated, anemic mice. Compared with control animals, treated mice showed improvement in all disease parameters examined, including human b globin proteins A and S, elongated and normal red blood cells, reticulocytosis and body weight. (Science, 318, 1920–1923, 2007) KA

Gentler bone marrow transplantion

Although allogeneic bone marrow transplantation has the potential to ameliorate several hematological and autoimmune diseases, it usually requires intensive chemotherapy and/or irradiation to eradicate defective hematopoietic stem cells (HSCs) before donor HSCs replace them. Czechowicz et al. show that such drastic measures—which also destroy many other cells besides HSCs—can be avoided in immunodeficient mice by dosing them with an antibody against the HSC-specific receptor c-kit. Transient depletion of >98% of endogenous HSCs was associated with a 30- to 180-fold increase in stable engraftment of HSCs, relative to rates without conditioning. Besides providing evidence that donor HSC engraftment requires that host HSCs vacate the appropriate niches, the study could open the way for alternatives to current immunosuppressive drugs used in a raft of diseases. Identification of antibodies to human HSCs and verification using mouse models with engrafted human blood-forming systems may facilitate gentler treatment of maladies such as sickle cell anemia, severe combined immunodeficiency, multiple myeloma, thalassemia, type 1 diabetes, multiple sclerosis and lupus. (Science 318, 1296–1299, 2007) PH

Written by Kathy Ascheim, Laura DeFrancesco, Peter Hare & Jan-Willem Theunissen