BioUpdates for December, 1998

Two teams of researchers from Europe and the United States have linked a mutated form of the gene SH2D1A (a protein encoder for the immune system) and an always fatal complication of Epstein-Barr syndrome, known as X-linked lymphoproliferative disease (or Duncan's disease). Epstein-Barr and related viral diseases, such as mononucleosis, entail immune system cells multiplying excessively, but with the normal SH2D1A gene, the proliferation of immune cells is halted. However, when a mutated form of the gene is present, B cells and T cells reproduce indefinitely because a surface protein, signaling lymphocyte-activation molecule or SLAM, does not know when to quit. This over activity leads to a failure to kill off infected cells and the development of Duncan's disease and its intensification. Both teams linked incidents of the mutation with incidents of Duncan's disease in their study groups, and its absence among healthy participants in the studies. This condition, almost always associated with boys, leads to a 70% mortality rate before the age of 10, with no known sufferers living beyond 40.

Reference: Coffey, A.J., et al. 1998. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genetics 20(October) p129.

Visit the following sites for more information:

• Nature Genetics: Outline of Coffey reference. Free registration required. Full text available to subscribers to Nature

• Nature: Outline of Sayos reference. Free registration required. Full text available to subscribers to Nature.

• Science News Online - Epstein-Barr deaths tied to faulty protein: A useful list of further reading and contacts.

Medicine, biotechnology and the understanding of human development took a huge leap forward this month, as did stock prices of the Geron corporation. Geron has financed research at the University of Wisconsin and Johns Hopkins University that has just culminated in both teams announcing the identification, isolation and culturing of human embryonic stem and germ cells. The discovery has enormous implications for the treatment of diseased tissues, drug testing, genetic engineering, and the understanding of fetal development and birth defects. The teams took different approaches. The Wisconsin group, led by James Thomson, took cells from human embryos created by in vitro fertilization. Specifically, embryos were cultured to the blastocyst stage then cell masses were removed and grown separately. Using mouse feeder cells, the researchers were able to maintain embryonic stem cells without any specialization developing or cells dying. Some were even successfully stored cryogenically. Indications are that all the cells can be maintained indefinitely. Meanwhile, John Gearhart at Johns Hopkins extracted embryonic germ cells from the 8 week old fetuses of aborted pregnancies. Although not as versatile as stem cells, the germ cells still have the ability to develop into a variety of different tissues. The next step in the process is to discover and understand the mechanisms which trigger cell differentiation into specialized tissue. It is at this stage that the medical applications of the discovery truly multiply. Of course, such research raises some complex ethical issues. Should embryos be used this way? Will it lead to a market for discarded fetuses?. To date, the federal government will not support research using human embryos. Furthermore, what does the future hold if we begin to determine how fetal development progresses? Are we about to see "designer babies"? The issues are many and complex.

References: Thomson, J.A. et al. 1998. Embryonic Stem Cell Lines Derived from Human Blastocysts Science Vol. 282 (November 6) p1145.

Visit the following sites for more information:

• Science : Complete copy of Thomson's report listed above.

• Complete copy of Gearhart's article listed above

• Proceedings of the National Academy of Sciences: Abstract of Gearhart's report listed above.

• Geron Corporation - Special Report: Geron's perspective on the research they have funded.

The heart bypass surgery procedures that have evolved over the decades may soon be obsolete, superseded by something as simple as an injection. Researchers at Cornell Medical School headed by Dr. Ronald Crystal announced to the American Heart Association the results of their work concerning heart gene therapy. They have been able to inject a gene into diseased cardiac tissue which prompts the production of a protein known as vascular endothelial growth factor or VEG-F. Normally, this protein only works during fetal development. The results have been impressive. Researchers have witnessed the development of new blood vessels which nourish the once starved tissue with subsequent relief from excruciating chest pain. Those treated with the gene therapy were patients at St. Elizabeth's Medical Center in Boston. All the patients have experienced significant improvement, with a significant number being entirely pain free. Treatment is still experimental with work still required to see how effective the direct gene therapy is compared to administering doses of the VEG-F protein. Doctors from the University of Minnesota reported success earlier this year treating angina sufferers with the protein. However, what does seem clear is that both methods of treatment show great potential for reducing the need for risky, intrusive and expensive heart surgery. We can all take heart from such prospects and the likelihood of lower medical bills for all of us!

Reference: The work just reported to the American Heart Association has not been published yet. However, the follwoing reference is particularly relevant.

Visit the following sites for more information:

• Gene Therapy forCoronary Artery Disease: A review of research in the heart gene therapy field. Includes a number of useful references.

Paleontology has grabbed headlines a number of times this November, but perhaps the most significant find for evolutionary studies was in Argentina's Patagonian badlands, at a place now known as Auca Maheuvo (heuvo is Spanish for eggs). Luis Chiappe and his fellow researchers from the American Museum of Natural History and the Argentinean Museo Municipal Carmen Funes were literally walking on eggshells when they uncovered an extensive dinosaur nesting ground, a site that has provided paleontology with a number of firsts and plenty of material to work with. The site, which dates back some 70 to 90 million years to the late Cretaceous, is strewn with the fossilized eggs of an undetermined sauropod. What is more, some of the eggs still contain unhatched embryos that reveal bone, teeth and skin remains. These finds mark the first dinosaur embryos showing fossilized soft tissue (skin); the first known embryos of sauropods; and the first dinosaur embryos found in the southern hemisphere. Although, no definite identification has been made so far, all indications are that these are the eggs of the massive titanosaurs. The tooth remains have the same shape as those of titanosaurs, and adult remains of this particular species are also common in the region. The evidence is circumstantial, but convincing. The morphology of the embryos also suggests that the distinct armored plates of the titanosaur do not develop until after hatching, a similar pattern to that of current day crocodiles and armored lizards. Despite the extent and richness of the finds, few clues have yet to be found indicating how these sauropods cared for their eggs and young.

Reference: Chiappe, L.M., et al. 1998. Sauropod dinosaur embryos form the Late Cretaceous of Patagonia. Nature 396 #6708 (November 19) 258-261.

Visit the following sites for more information:

• Nature: Outline of Chiappe reference. Free registration required. Full text available to subscribers of Nature.

• American Museum of Natural History: Museum press release announcing discovery.

An Old Enemy: Could Alzheimer's have Infectious Origins?

Even though the cause of Alzheimer's disease has remained elusive, researchers have dismissed the possibility of any connections to infectious agents, a position that has persisted even in the face of data to suggest otherwise and the fact that anti-inflammatory drugs appear to slow the advance of the condition. But work by Brian Balin of the Philadelphia College of Osteopathic Medicine and Alan Hudson of Wayne State University School of Medicine is causing other scientists to rethink their position on infectious agents. Comparing the autopsied brains of Alzheimer sufferers with those free of the ailment, they revealed a startling correlation with an old enemy, the bacterium Chlamydia pneumoniae (C. pneomoniae is associated with severe respiratory illness and artherosclerosis). Balin and Hudson found presence of the bacteria in a variety of ways: antibodies that bind only to the bacteria stained regions of the brain affected by Alzheimer's disease were detected; an electron microscope showed images of the bacteria in brain cells; and the microbe was also cultured from samples of brain tissue.

Why has the bacteria avoided detection until now? It would appear to be a case of mistaken identity and looking in the wrong place. Firstly, it is possible that the bacteria were mistaken for cellular structures known as lysosomes. Secondly, it is not found in the nerve cells whose degeneration leads to Alzheimer's disease, but rather in the neighboring glia cells, whose inflammation can lead to damage of the nerve cells.

Reference: Balin, B.J. and Hudson, A.P. 1998. Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Medical Microbiology and Immunology Vol. 187 (August):23.

Visit the following sites for more information:

• Science News Online - Microbe linked with Alzheimer's disease

• Medical Microbiology and Immunology: Abstract of above reference.