Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Resistance to antibiotics is the not-so-secret weapon promiscuously deployed against the human race by bacteria and other organisms. But, as bacteriologists have recognized in recent years, their pathogenic foes field a quite separate and equally insidious scourge the laying on of biofilms. These slimy, intractable coatings of bacteria and other living microorganisms form on moist surfaces from wet rocks to unbrushed teeth. The health threats they cause range from dental cavities to the lethal biofilms laid on infected lungs in cystic fibrosis patients by Pseudomonas aeruginosa. Biofilms also curse hard-to-sterilize medical instruments and artificial implants. For reasons unknown, biofilms themselves by their own unique mechanisms strongly resist antibiotics. (See BioWorld Today, Oct. 25, 2001, p. 1.)
Now molecular biologists at Princeton University have laid bare a previously unknown molecular pathway inside bacterial cells that is critical for biofilm formation. Their report in the Proceedings of the National Academy of Sciences (PNAS), released online Feb. 5, 2002, is titled: “Surface sensing and adhesion of Escherichia coli controlled by the Cpx-signaling pathway.” (Cpx, a synthetic xanthine derivative, carries the chemical name, 8-cyclopentyl-1,3-dipropylxanthine thus accounting for its acronym.)
The paper’s authors suggest that this pathway might be a target for which new antibiotics can be developed to treat these biofilm infections. They describe finding a protein near the bacterial cell surface that detects a stimulus outside the cell such as a chemical or physical contact. This protein then can modify other proteins inside the cell, triggering a cascade of molecular interactions. These eventually activate certain genes, and spread the biofilm.
The PNAS paper reports that one such pathway involving the Cpx protein family enabled the common intestinal bacterium Escherichia coli to sense when it has contacted a surface, causing it to adhere and launch a biofilm. Gene activation normally controlled by the Cpx pathway greatly increased when E. coli initially attached to a solid surface. However, this process required enlisting another essential molecule, NlpE, which perches on the bacterial cell surface.
The co-authors made the salient point that “bacterial adhesion is an important initial step in biofilm formation.” They showed that “the expression of Cpx-regulated genes is induced during initial adhesion of E. coli to abiotic surfaces.” Their paper concludes: “In this study, we show by using gene fusions that the Cpx system is activated upon attachment of E. coli to hydrophobic surfaces. In addition . . . we also provide evidence that an initial CpxRA signaling system and the outer membrane lipoprotein NlpE are required for productive cell-surface interactions leading to stable adhesion.”
New Study Refutes Dogma That Copper Chaperoning Of Superoxide Dismutase Plays Role In Familial ALS
Lou Gehrig’s disease amyotrophic lateral sclerosis (ALS) arises from the death of certain motor neurons in the central nervous system. Dysfunctional hands and feet are early signs of ALS, leading to muscle weakness and wasting. The disease usually afflicts its victims in their prime of adult life. Within three years of diagnosis typically around age 40 half of ALS patients are dead of their disease. Some 70,000 people worldwide suffer amyotrophic lateral sclerosis, half of them in the U.S. Though widely differing in their symptoms, the neurodegenerative diseases Alzheimer’s, Parkinson’s Huntington’s and ALS have one feature in common: Their dying neurons in spinal cord, motor cortex or brain stem in ALS are choked with accumulations of aggregated mutant proteins.
An estimated 80 percent of all ALS cases are sporadic striking out of the blue, with no hint of familial origin. The other 20 percent inherit the disease from their forebears. Both forms have similar clinical and pathological features. The mutant gene responsible for 25 percent of inherited Lou Gehrig’s disease kills motor neurons by taking on a new, lethal function unrelated to the normal protective role of these proteins. Those inherited mutations were previously believed to kill neurons by a process related to their normal function.
The advance online edition of Nature Neuroscience (scheduled for the journal’s April issue) carries an article titled: “Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading.” Its lead and senior authors are at The Johns Hopkins University School of Medicine in Baltimore. The co-authors used a transgenic ALS mouse model to examine whether the normal function of the affected gene was involved in the disease. The normal gene encodes an enzyme, superoxide dismutase (SOD), which protects cells from damage caused by toxic reactive oxygen species (ROS). Until now, the damage due to its mutations was blamed on a change in this function, resulting in production of ROS.
The new study finds that complete loss of the mutant protein’s ability to interact with ROS had no effect on onset or progression of ALS symptoms. In contrast, abnormal aggregates of the mutated protein were still present in these transgenic mice, indicating that this in vivo model of ALS may be a useful tool for further study of the disease.
International Genome Project Challenges Originality Of Celera Genomics Gene Sequencing Approach
There were two ways to sequence the human genome one employed by Celera Genomics Group, the other, by the Human Genome Project’s International Consortium. Since February 2001, when both published their results, there has been controversy.
An article in the Proceedings of the National Academy of Sciences, dated March 19, 2002, carries the title: “On the sequencing of the human genome.” Its authors, the three leaders of the public consortium, lead off: “Two different papers using different approaches reported draft sequences of the human genome. The International Human Genome Project [HGP] used the hierarchical shotgun approach, whereas Celera Genomics adopted the whole-genome shotgun [WGS] approach. In the Celera paper, the authors did not analyze their own WGS data . . . Instead, they used an unorthodox approach to incorporate simulated data from the HGP.”