Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research
A genetic analysis technique that compared the gene expression pattern of humans to those of a fruit fly, a roundworm and species of yeast obtained new insights on gene function.
By comparing widely differing species, Stanford University researchers gazed across evolutionary time and identified interactions between genes that have remained intact despite evolution. Their findings appear in Sciencexpress dated Aug. 21, 2003, under the title "A gene co-expression network for global discovery of conserved genetic molecules."
Using evolution as a filter helped focus on genes involved in core, conserved biological processes such as protein degradation, ribosomal function and neuronal processes. Analyzing the number and types of gene interactions provided insights into the evolution of gene function, whether genes act in a single pathway or have multiple functions, and how densely they are connected to other genes. Laboratory data confirmed predictions of gene function in humans and the worm, Caenorhabditis elegans.
The genome sequences of humans and several model organisms have established a nearly complete list of genes needed to enact cell, developmental and behavioral processes in these organisms. The next major challenge is to elucidate the function of the genes and discover how they interact to perform specific biological processes, especially for the large fraction of genes in the genome for which functions are currently unknown. DNA microarrays (chips) supply a first step toward the goal of uncovering gene function on a global scale. Since genes encoding proteins that participate in the same pathway are co-regulated, clusters of genes often exhibit expression patterns that are correlated under a large number of DNA chip experiments.
Using experiments, it would be difficult or impossible to distinguish accidentally regulated genes from those that are physiologically important. However, evolutionary conservation is a powerful criterion to identify genes that are functionally significant.
The recent availability of large sets of DNA microarray data for humans, flies, worms and yeast makes it possible to measure evolutionarily conserved co-expression on a genome-wide scale. Because small and subtle changes in fitness can confer selective advantage during evolution, the test for related gene function using evolutionary conservation in the wild is more sensitive than scoring the phenotype resulting from strong loss-of-function mutants in the laboratory.
55 Percent To 75 Percent Of Antibodies Expressed By Naive B Cells React Against Own Body
It seems remarkable that autoimmune disorders aren't more common, considering that more than half of the body's developing B cells are "self-reactive," according to new findings. The immune system is constantly producing B cells, which carry antibodies that hook onto foreign particles. In each developing B cell, the antibody genes get chopped up and spliced back together.
That creates a hugely diverse assortment of antibodies. Some of the combinations, however, produce antibodies that bind to the body's own molecules. That event leads to autoimmune disorders such as systemic lupus erythematosus.
A recent Sciencexpress report, dated Aug. 14, 2003, carries the heading "Predominant autoantibody production by early human B cell precursors." Its senior author is a research immunologist at the Rockefeller University in New York. He and his colleagues have found that between 55 percent and 75 percent of all antibodies emerging from human bone marrow are self-reactive (attacking the body's own "self" cells and tissues). This proportion, they note, is much larger than previously appreciated.
The paper also identified two checkpoints in the development process, at which most of the autoantibodies were taken out of commission. Even small changes in the efficiency of those two checkpoints could increase a person's susceptibility to autoimmunity. To examine the development and silencing of autoreactive B cells, the co-authors cloned antibodies from single B cells derived from the bone marrow and blood of three healthy donors. They tested these samples for reactivity against cell lysates and a panel of defined antigens.
To determine whether individual antibodies cloned from different B-cell subsets were self-reactive, 248 of them were expressed in antigenic cells. Seventy-six percent of all antibodies cloned from early immature B cells tested high levels of reactivity. The paper concluded that "during normal human B cell development, a large number of self-reactive antibodies are removed from the repertoire during the immature B cell stage in the bone marrow and during transition from the new emigrant to the mature naive B cell stage in the periphery."
Transgenic Pro-Angiogenic Growth Factors Heal Skin Lacerations With Unanticipated Rapidity
Mice engineered to produce the protein named angiopoietin-related growth factor heal wounds extremely quickly. Transgenic mice that spawn AGF in epidermal keratinocytes (a type of cornified skin cell) exhibited swollen and reddish ears, noses and eyelids. In addition, they showed an increased number of vessels in the dermis, suggesting that AGF encourages blood vessel formation.
A report in the Proceedings of the National Academy of Sciences dated July 14, 2003, is titled "Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling and regeneration." Its co-authors are at Keio University in Tokyo.
Unexpectedly, the transgenic mice showed significantly thicker skin and more rapidly multiplying skin cells than did control animals. After excising small sections of the ear and tail, the co-authors observed unusually fast wound healing in the transgenic animals. Even 2-millimeter holes punched in their ear lobes completely closed within 28 days. Further AGF research may lead to novel therapies for wound care.