By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
The Gambia is a minuscule sliver of a country on the west coast of Africa; it¿s about twice the size of Delaware. A century ago, during its colonial past, The Gambia was known as ¿the white man¿s graveyard.¿ To this day it¿s where the largest number of lethal cerebral malaria infections take the lives of children. Among the country¿s population of some 1,250,000, infant mortality runs around 79 per 1,000 live births.
Adults, too, suffer debilitating bouts of malarial infection, almost entirely during the July-to-November rainy season, as do those in most sub-Saharan countries surrounding it. Such circumstances make The Gambia a favorite place for human tests of antimalarial vaccines.
One such extensive field trial reports its results in the current issue of The Lancet, dated Dec. 8, 2001. The article is titled: ¿Efficacy of RTS,S/ASO2 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomized trial.¿ The vaccine was developed by GlaxoSmithKline Biologicals, of Rixensart, Belgium.
Development of an effective vaccine against the P. falciparum malarial parasite is a major health priority for these African countries. Current R&D focuses on pre-erythrocytic vaccines, aiming to prevent infection of the blood stage, at which the disease leads to eruption of serious infections. Precursor symptoms feature chills and fever, malaise, headache, nausea, and muscle and joint pain.
From six Gambian villages, the vaccine team enrolled 306 volunteer men to receive three shots of either the RTS,S/ASO2 vaccine (the treatment group) or rabies vaccine ¿ an irrelevant but useful public health immunization (the control group). A fortnight before their third vaccine injection, both cohorts took antimalarial drugs to clear blood-stage infections. They were kept under health surveillance throughout the malaria transmission season. The primary endpoint was the time to first infection with the parasite.
The net number of cohorts who completed the course totaled 205 ¿ 131 in the treatment group, 119 controls. P. falciparum infections occurred much earlier among the controls than in the treatment contingent. The vaccine¿s protection seemed to wane as the overall incidence of infection reached its seasonal maximum. Overall vaccine efficiency was 34 percent, a figure that rose to 47 percent among 158 men who received a fourth booster shot. Vaccination induced strong antibody responses to the parasite¿s circumsporozoite protein, as well as strong T-cell reactions. The authors concluded that the RTS,S/ASO2 vaccine is safe, well tolerated and immunogenic. Their paper notes that it ¿is the first pre-erythrocytic vaccine to provide significant protection against natural P. falciparum infection in both malaria-naove and malaria-experienced individuals.¿
The paper¿s 19 co-authors, representing the ¿RTS,S Malaria Vaccine Trial Team,¿ include ¿ besides Gambian public health collaborators ¿ experts from Britain¿s Oxford University and London School of Tropical Medicine, as well as the Walter Reed Army Institute of Research in Washington.
Rare, Deadly Childhood Neurological Pathology Traced To Heat-Shock Loss Of White Matter In Brain
Regions of the brain and spinal cord come in two tints ¿ gray and white. Their gray matter consists mainly of cell bodies and neuronal dendrites, whereas white matter is largely or entirely composed of myelinated axons ¿ nerve fibers. When the white matter disappears, a rare but deadly inherited childhood disease ensues. It¿s called ¿leukoencephalopathy with vanishing white matter¿ ¿ VWM for short. First described in children with leukemia, it was ascribed to radiation and chemotherapy injury.
Now a paper in Nature Genetics, published online Nov. 12, 2001, attributes the etiology of VWM to a ubiquitous protein that targets the brain. When mutated, two genes that encode the complex elF2B cause the disease, according to neurologists and human geneticists at the Free University Medical Center in Amsterdam, the Netherlands. Their paper bears the title: ¿Subunits of the translation initiation factor elF2B are mutant in leukoencephalopathy with vanishing white matter.¿
Neurological deterioration in the disease usually begins in late infancy or early childhood, though juvenile and adult-onset cases may occur. Clinical signs include progressive loss of muscle coordination due to disorders of the cerebellum, muscle spasticity and optic atrophy, but without loss of mental abilities. As white matter vanishes, it is replaced by cerebrospinal fluid.
The elF2B complex normally initiates protein translation. Until now, genes encoding translation initiation had not been linked to human disease. By analyzing 41 affected individuals in 35 families, the co-authors identified two mutant genes in chromosomes 3 and 14 that encode elF2B components in VWM patients. They point out that the complex halts protein production when intracellular temperature rises too high. This heat-shock reaction may explain why VMW patients rapidly go down hill and often die, following a bout of fever and coma. Their findings, they suggest, might shed light on other temperature-sensitive brain disorders, such as multiple sclerosis.
Self-Assembled Artificial Bone Substance Aims To Repair Fractures, Treat Osteogenic Cancers
Getting right down to the nano-level, materials scientists and chemists at Northwestern University in Evanston, Ill., have designed a process and substance that mimics and repairs bones. Their report in Science, dated Nov. 23, 2001, bears the title: ¿Self-assembly and mineralization of peptide-amphiphile nanofibers.¿ (Amphiphile denotes a molecule, as in detergents, that contains groups of contrasting properties ¿ e.g., hydrophilic and hydrophobic.)
The authors¿ designer molecules promise development of a bone-like material to fix fractures and treat patients with bone cancer. Their molecules self-assemble into a 3-dimensional structure that imitates the key features of human bone at the nanoscale level. They include the collagen nanofibers that drive mineralization as well as the mineral nanocrystals. Collagen, the co-authors point out, is the most abundant protein in the human body ¿ from heart, eye and blood vessels to skin, cartilage and bone. It imparts structural strength to these tissues.
In their Science report, the researchers created self-assembled nanofibers that resemble the collagen fibrils of real bone in shape and size. When these were exposed to calcium and phosphate ions, the fibers became covered with hydroxyapatite crystals, which closely mimic the crystal lattice of bones and teeth.