In This Issue
APPLIED BIOLOGICAL SCIENCES
Hen eggs produce therapeutic proteins
Current methods for producing therapeutic proteins, such as monoclonal antibodies used to treat cancer, arthritis, and other inflammatory disorders, are expensive and time-consuming. Using farm animals for the mass production of such drugs is potentially cheaper, faster, and more efficient than standard methods, but so far researchers have been unable to optimize the technology. Simon Lillico et al. report the development of transgenic hens that produce functional protein drugs in the whites of their eggs. Production of these therapeutic proteins in eggs showed no evidence of transgene silencing or ectopic expression, which were problems encountered in previous attempts at this technology. The authors used a lentiviral vector to insert genes for the desired pharmaceutical proteins (miR24, a monoclonal antibody with potential for treating malignant melanoma, and human interferon β-1a, an antiviral drug) into the hen's gene for ovalbumin, a protein that makes up 54% of egg whites. All of the egg whites from these hens were found to contain functional therapeutic proteins. With the demand for therapeutic drugs increasing, the efficient generation of transgenic hens producing high levels of functional therapeutic proteins in eggs may mark an important step in the development of this technology, the researchers report. — M.M.
Hen eggs for therapeutic protein production.
“Oviduct-specific expression of two therapeutic proteins in transgenic hens” by S. G. Lillico, A. Sherman, M. J. McGrew, C. D. Robertson, J. Smith, C. Haslam, P. Barnard, P. A. Radcliffe, K. A. Mitrophanous, E. A. Elliot, and H. M. Sang (see pages 1771–1776)
APPLIED BIOLOGICAL SCIENCES
Global picture of the human metabolic network
Metabolism involves a complex web of genes, enzymes, and chemical reactions. Despite decades of research on many network components, a “global” picture of human metabolism has never before been assembled. To create a comprehensive representation, Natalie Duarte et al. reconstructed the human metabolic network from vast amounts of genomic and experimental data compiled from the literature. The authors identified missing components in the metabolic network and provided a framework for computer models. Their reconstruction, called Homo sapiens Recon 1, was established as a freely available database that accounts for the functions of thousands of genetic open reading frames, proteins, metabolites, and transport reactions. By transforming the reconstruction into an in silico model, Duarte et al. demonstrated its utility in identifying both potential drug targets and poorly understood aspects of metabolism, such as the intracellular transport of metabolites. Because the malfunction of human metabolism is a major contributor to disease, the model may be a useful tool for determining disease mechanisms and could play an important role in fulfilling the potential of individualized medicine. — M.M.
Glutathione reaction set mapped to disease associations.
“Global reconstruction of the human metabolic network based on genomic and bibliomic data” by Natalie C. Duarte, Scott A. Becker, Neema Jamshidi, Ines Thiele, Monica L. Mo, Thuy D. Vo, Rohith Srivas, and Bernhard Ø. Palsson (see pages 1777–1782)
DEVELOPMENTAL BIOLOGY
Fetal cells contribute to maternal angiogenesis
During human pregnancy, fetal cells enter the mother's blood and persist in her body, both in the circulation and in a range of other tissue types, decades after delivery. The differences in histocompatibility between mother and fetus have led researchers to hypothesize that this mismatch can trigger graft-versus-host immune reactions in the mother. Although evidence for this causation remains sparse, previous studies show that women afflicted with a pregnancy-linked inflammatory skin disease called polymorphic eruptions of pregnancy harbor fetal cells in 60% of skin lesions. Sau Nguyen Huu et al. used a mouse model to test whether inflamed skin actually recruits the fetal cells. The authors found that pregnant mice with contact dermatitis had inflamed skin enriched with fetal cells. Genetic markers revealed that these cells were concentrated in new blood vessels, suggesting that the cells participated in angiogenesis. The authors suggest that these fetal cells are endothelial progenitor cells and that they may also play a role in maternal vessel formation during wound healing or tumor growth. These fetal endothelial progenitor cells may also be useful as cell therapies for various vascular diseases, the authors say. — B.T.
Fetal cells express marker in maternal inflamed ear during pregnancy.
“Maternal neoangiogenesis during pregnancy partly derives from fetal endothelial progenitor cells” by Sau Nguyen Huu, Michèle Oster, Serge Uzan, Fabrice Chareyre, Sélim Aractingi, and Kiarash Khosrotehrani (see pages 1871–1876)
MEDICAL SCIENCES
Malaria DNA activates innate immunity
Malaria infects hundreds of millions of people annually, but little is known about innate immune responses to malarial infection. Peggy Parroche et al. studied the role that hemozoin, an insoluble crystal formed in the food vacuole of the malarial Plasmodium parasite, plays in activating Toll-like receptors. Toll-like receptors are central components of the innate immune response. Natural hemozoin stimulated dendritic cells to produce proinflammatory cytokines and chemokines such as IL-12p40 and Rantes via Toll-like receptor 9 (TLR9). This stimulatory ability, which pure synthetic hemozoin could not illicit, was abolished by nuclease treatment, although the hemozoin crystal remained intact. In addition to binding TLR9, natural hemozoin was found to bind Plasmodium DNA. In turn, this DNA triggered an immune response in dendritic cells. The authors' research suggests that TLR9 inhibitors, currently being developed for other immune disorders including lupus, may be effective against malaria. — F.A.
Hemozoin crystal.
“Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9” by Peggy Parroche, Fanny N. Lauw, Nadege Goutagny, Eicke Latz, Brian G. Monks, Alberto Visintin, Kristen A. Halmen, Marc Lamphier, Martin Olivier, Daniella C. Bartholomeu, Ricardo T. Gazzinelli, and Douglas T. Golenbock (see pages 1919–1924)
MICROBIOLOGY
Soil bacterium yields clues to tuberculosis' survival
Mycobacterium tuberculosis, the bacterium that causes tuberculosis, can survive for long periods of time and replicate in the hostile environment of host macrophages, immune system cells that engulf debris, germs, and other cells. Robert Van der Geize et al. identified a complete suite of genes necessary to break down cholesterol in the closely related soil bacterium Rhodococcus. Cholesterol and other steroids comprise important energy sources for saprophytic bacteria, including some mycobacteria. The 28 genes conserved in M. tuberculosis encoded proteins that take up cholesterol into the cell, oxidize the steroid's branched side chains, and catabolize its structural rings. At least 11 of these genes appear to be essential for M. tuberculosis survival in macrophages under conditions that model the immune response. Because many of these enzymes have no human homologs, these proteins may serve as attractive targets for antituberculosis therapeutics, which are increasingly important as drug-resistant strains of M. tuberculosis proliferate. — F.A.
Heat map of cholesterol ring-degrading gene activities.
“A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages” by Robert Van der Geize, Katherine Yam, Thomas Heuser, Maarten H. Wilbrink, Hirofumi Hara, Matthew C. Anderton, Edith Sim, Lubbert Dijkhuizen, Julian E. Davies, William W. Mohn, and Lindsay D. Eltis (see pages 1947–1952)
