In Time for ASH, Treasure Trove of Red Blood Cell Genes
The umbrella term "anemia" encompasses diseases that range from merely annoying to fatal. But overall, a multinational consortium led by researchers from the British Imperial College London, the German Helmholtz Center, and the Dutch University of Groningen wrote that it is "a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity." The consortium published results of a genomewide association study in more than 135,000 people that identified 121 new candidate genes important for red blood cell formation. Those candidates were expressed preferentially in red blood cell precursors, and more than a third of them were expressed in blood stem cells. "Our results," the authors wrote, "provide new insights into the genes and gene variants that may influence hemoglobin levels and related red blood cell indices, and will underpin a deeper knowledge of the biological mechanisms involved in hematopoiesis and red blood cell function." The paper appeared in the Dec. 6, 2012, advance online edition of Nature.
Getting Heart Cells Back on the Merry-Go-Round
Scientists from the Italian International Centre for Genetic Engineering and Biotechnology identified two microRNAs that can entice adult heart muscle cells, which have normally stopped dividing, back into the cell cycle. Heart muscle cells normally stop dividing shortly after birth in mammals, and any growth is due to existing cells getting bigger, which is most often not a good thing. The authors screened microRNAs for their ability to induce heart muscle cell proliferation in newborn mice, and then tested those same microRNAs on adult heart cells. Two such microRNAs were able to stimulate adult heart muscle cells to proliferate when treated in cell culture. When mice were injected with those two miRNAs after suffering a heart attack, the treatment reduced the area of damage and promoted repair and functional recovery. The authors contended "the miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss." Their findings appeared in the Dec. 6, 2012, issue of Nature.
Separating Bad from Good Stem Cells
Researchers from the Japanese Kyoto University discovered a marker that differentiates normal from tumor stem cells in the intestine. Targeting cancer stem cells might make it possible to truly eradicate tumors, but finding markers that can distinguish tumor from normal stem cells has been challenging. The researchers looked at one marker, Dclk-1, that is expressed in some intestinal cells and has been suggested as a marker for both regular intestinal stem cells and specific types of adult intestinal cells. The authors used lineage tracing experiments to show that Dclk-1 is expressed in polyps, where they were an ongoing source of tumor progenitor cells. In mice genetically engineered to develop colon tumors; specifically killing cells that expressed Dclk-1 led to regression of polyps, which are precursors of tumors. The authors concluded that their data "suggest the potential for developing a therapy for colorectal cancer based on targeting Dclk-1 positive tumor stem cells." Their work was published in the Dec. 2, 2012, online issue of Nature Genetics.
Autophagy: Don't Kill Bacterium, Make it Stronger
A team from Ohio State University has shown that Anaplasma phagocytophilum, which causes the tick-borne disease anaplasmosis, hijacks the autophagy machinery in its quest to infect cells. Autophagy, which cells use to digest large protein complexes, is one mechanism for clearing infections. But the team showed that in their experiments, A. phagocytophilum activated the autophagosome to provide itself with building blocks for its own replication. In doing so, the bacterium managed to turn the infection-fighting capacity of autophagic processes on its head, with the extra bonus that because autophagy is a normal cellular process, it does not set off any alarm bells in the form of inflammatory responses, which allowed the bacterium to get a jump start on replication. The work appeared in the Nov. 29, 2012, issue of the Proceedings of the National Academy of Sciences.
Linking Autophagy to Obesity
Meanwhile, scientists from the Korean Sungkyunkwan University School of Medicine uncovered a role for autophagy in obesity and insulin resistance. In their studies, the authors found that mice with the autophagy gene Atg-7 knocked out in either muscles or liver, both of which are major targets of insulin, were protected from developing diet-induced obesity or insulin resistance. The autophagy deficiency led to mitochondrial deficiency and the conversion of energy-storing white fat to energy-burning brown fat. One of the large intracellular components that autophagy recycles is mitochondria, which gives it a de facto contributing role in regulating energy balance. "These findings," the authors concluded, "suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine,' and together these processes promote protection from diet-induced obesity and insulin resistance." Their paper appeared in the Dec. 2, 2012, advance online edition of Nature Medicine.
Immune Deficiencies in MeCP2 Syndrome
Scientists from the Baylor College of Medicine have uncovered new details about the immunodeficiency that is one consequence of MeCP2 gene duplication. Such gene duplication results in an ultimately fatal genetic syndrome characterized by nervous system degeneration and severe respiratory infections that can kill them. In their work, the authors showed that this susceptibility to infections was not due to a general immunodeficiency. Mice with MeCP2 overexpression were vulnerable to parasitic infections, but were able to control fungal infections. Further experiments showed that MeCP2 overexpression blocks the secretion of interferon-gamma from helper T cells, which leads to functional problems with specific helper T-cell subsets. The results, the authors wrote, "establish a rational basis for identifying, treating, and preventing infectious complications potentially affecting children with MECP2 duplication." They appeared in the Nov. 6, 2012, issue of Science Translational Medicine.
Host Responses against Malaria . . .
Platelets are turning out to have many functions besides the one they are best known for, that is to say, blood clotting. To wit, they also help fight infections, including malaria. A group of researchers from the Australian Maquarie University has identified platelet factor 4 or CXCL4 and the red blood cell Duffy-antigen receptor as key molecular players in that response. Platelets release platelet factor 4 when they come into contact with malaria-infected red blood cells, and the platelet factor 4 is then taken up into red blood cells, where it kills the parasite, via the Duffy antigen receptor. That antigen receptor, however, is not expressed by everyone, and is in fact expressed by only a minority of individuals in Western and Central equatorial Africa. The authors concluded that "an obvious implication of our findings is the potential lack of platelet mediated protection against malaria in these individuals and the possibility that this has an impact on disease severity and outcome. Although the available epidemiological and clinical data are insufficient to directly compare disease severity and outcome in humans with different Duffy alleles, [malaria] infections are most common in equatorial Africa and result in the highest global rates of death. They published their results in the Dec. 7, 2012, issue of Nature.
. . . And the Malaria Mosquito Response
Researchers from the Portuguese University of Porto, in the meantime, have reported crystal structure data on anophelin, an anti-clotting protein that the Anopheles mosquitoes that transmit malaria use to prevent blood clotting as they feed. Anophelin inhibits the clotting protein thrombin with nearly unparalleled efficiency. The authors looked at the crystal structure of anophelin bound to thrombin and discovered that it binds to thrombin in the opposite orientation of thrombin's natural substrates – that is, with the C-terminus rather than the N-terminus near the active site. The findings, which could be used to guide the design of better anti-clotting drugs, appeared in the Dec. 7, 2012, issue of Science.
Cancer Cell Targeting: Only Skin Deep
Scientists from the Whitehead Institute for Biomedical Research have demonstrated that it is possible to target transporters that tumor cells overexpress to specifically deliver toxic therapies to them. The authors were looking at resistance mechanisms to 3-bromopyruvate, which targets the glycolytic metabolism that cancer cells heavily depend on to meet their energy needs. The protein that determined whether a tumor was sensitive or resistant to 3-bromopyruvate was monocarboxylate transporter 1; it delivers the drug (and other molecules) preferentially into tumor cells because it is highly expressed on them. The authors said their findings "provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors." They published their work in the Dec. 2, 2012, issue of Nature Genetics.
JNK in Macrophages Critical for Diabetes
A team from the University of Massachusetts Medical School has discovered that knocking out the JNK gene specifically in macrophages also protected mice from the consequences of a high-fat diet. The Jnk signaling pathway contributes to inflammation, and that inflammation is what ultimately leads to the development of diabetes. The team found that when they knocked Jnk1 and Jnk2 in proinflammatory macrophages, animals became obese on a high-fat diet, but macrophages did not accumulate in their fat tissues and they did not develop diabetes. "Drug-mediated targeting of macrophage-expressed JNK therefore represents a potential therapeutic approach to suppress inflammation that may be applicable to the treatment of inflammatory disorders," including diabetes. Their work appeared in the Dec. 6, 2012, advance online edition of Science.
– Anette Breindl, Science Editor