Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research.
For some brain tumors, the key to success is not who you know, but where you are. This semi-cynical observation is voiced by molecular virologists at Washington University School of Medicine in St. Louis. In trying to develop a mouse model of neurofibromatosis 1 - a genetic disorder that predisposes children to certain types of brain tumors - the team discovered that tumors developed only when all brain cells were genetically abnormal, not just the cell type that becomes cancerous. The study is featured on the cover of Cancer Research, dated Dec. 15, 2003. Its title: "Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity."
"We are quite excited by this report," said neurologist David Gutmann, the article's senior author, "as it represents the first model of this type of tumor. We've always assumed that cancer results from the loss of specific genes in a particular cell, but apparently that isn't always the case. Our findings suggest that, as in real estate, location is everything. A permissive environment may be the key to whether a tumor cell becomes cancerous or just sits dormant for a patient's entire life."
Neurofibromatosis is the most common neurological disorder caused by a single gene. The disorder can lead to a variety of complications, including skin, spine and brain cancer. Up to 20 percent of patients with Nf1 develop tumors in a type of support cell called an astrocyte, along the optic nerve and optic chiasm, which transmits information from the eye to the brain. Astrocytes that develop into tumors lack both copies of the Nf1 gene. So Gutmann's team first developed genetically engineered mice in which all cells were normal except astrocytes, which lacked both copies of the Nf1 gene. To their surprise, the mice did not develop brain tumors. Humans with Nf1 are born with one normal and one mutilated copy of the Nf1 in all cells in their bodies. The co-authors therefore hypothesized that genetic abnormalities in brain cells surrounding astrocytes might be essential for tumor formation. To test that theory, they developed mice with no functional copies of the Nf1 gene in their astrocytes and only one functional copy in all other brain cells - a scenario identical to that of human patients with the disease. Result: Every mouse developed astrocyte tumors along the optic nerve or chiasm within the first 10 months.
Gutmann proposed that understanding the events that lead to tumor growth is critical for learning how to predict, and hopefully prevent, tumors. "It's clear from our findings," he explained, "that if we figure out what external cues are necessary to trigger tumor growth, we could try to cut off that switch without having to correct the underlying gene defect. The potential for the mouse model used in this experiment to serve as a preclinical model of Nf1 is enhanced by our team's ability to detect tumors in their very early stages, using a powerful Tesla magnetic resonance imaging scanner. Their techniques and equipment enable them to detect tumors the size of a piece of thread."
Immunologists Find Classical & Non-canonical Kinases Vital To Innate Antiviral Defenses
How the body's immune system fights off viral infection is only a half-open book. Chapter 1 describes the "innate" defenses, dispatched as advance forces to engage attacking viruses before they have a chance to wreak their lethal intrusion. Behind the lines lies Chapter 2, a build-up of heavy-duty "specific adaptive immune" cells, ready to kill off the threatening viruses.
A team of research immunologists has garnered new clues about how chemical communication initiates the immune system's response to viral infection. The innate immune defenses recognize viral infection through various routes, including the binding of viral molecules to specific receptors. The recognition process triggers a network of chemical events that ultimately cause expression of antiviral genes.
The co-authors - all at Harvard University or University of Massachusetts Medical School at Worcester - report their preliminary findings in the Proceedings of the National Academy of Sciences (PNAS), released online Dec. 8, 2003, for subsequent print publication. Their paper reads: "IFN-regulatory factor 3-dependent gene expression is defective in Tbk-1 deficient mouse embryonic fibroblasts." The article shows how enzymes known as the non-canonical forms of I-kappa-B kinases (IKK) add phosphate groups to the immune transcription factor known as interferon regulatory factor-3 (IRF3).
After infecting the mice with either Sendai or Newcastle disease viruses, the cells failed to express antiviral genes that require IRF3. The results suggest that non-canonical IKKs are important mediators of IRF3-dependent antiviral gene expression. In mice, so far so good. But what about people? The PNAS paper allows, "Recent studies of human cell lines in culture have implicated two non-canonical IkB kinases [in the] phosphorylation of IRF3. This data provide strong genetic evidence," the PNAS paper concludes, "that TBK1 is an essential mediator of innate antiviral gene-expression programs that require IRF3."
Sophisticated, Flashlight-Toting Protein - Reflectin By Name - Carries Rare Amino-Acid Residues
The sea-going squid (Euprymna scolopes) has a built-in flashlight on its underside, which is beamed downward by reflective plates made of an unusual family of proteins. The plates might offer inspiration for nanotechnology designs in spectroscopy and optics. The squid's light organ is powered by luminescent bacteria and is surrounded by stacks of the silvery reflector plates. In addition to serving as a spotlight during feeding, the illumination may help reduce the squid's telltale shadow on the sea floor. Marine scientists have found that E. scolopes' reflector platelets are made of a previously undescribed group of proteins, which they named "reflectins." Their report appears in Science, dated Jan. 8, 2004, and is titled "Reflectins: The unusual proteins of squid reflective tissues." The co-authors are at the University of Hawaii-Manoa in Honolulu.