David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
In treating the rare but life-threatening pediatric infection called meningococcal septicemia, there are three overriding factors: Timing, timing and timing. That is why, in a large, recent clinical trial of an experimental therapeutic drug, 59 patients died within six hours of admission to intensive care - before they had a chance to receive the experimental compound.
The perpetrator of this greased-lightning angel of death is the bacterium Neisseria meningitidis, which lurks in the nasopharynx - the joint opening of gullet and windpipe - in humans, but in no other animals. Occurring in 0.4 to 4.0 per 100,000 of the population, it ranks among the commonest infectious causes of death in children and young adults. N. meningitidis executes its grim reaping by releasing a potent, fulminating endotoxin into the bloodstream. Its sudden symptoms include high fever, muscle pain, chills, vomiting, and tell-tale, purplish, hemorrhagic rashes under the skin.
Prompt antibiotics can often turn septic shock's corner, but recombinant antibodies to the toxin over the years have failed. Up to 30 percent die in eight to 12 hours before any symptoms occur. Survivors of the whole-body bacteria's exponential proliferation often suffer upper or lower limb amputations brought on by the blood's gangrenous intoxication of veins, arteries and capillaries. Higher concentrations of endotoxin are detected in meningococcal sepsis than in virtually any other human infection.
Now, a naturally occurring molecule secreted by certain blood cells of the immune system to fight bacterial infection is stepping up to the plate. Its self-explanatory name is bactericidal/permeability-increasing protein (BPI), which neutralizes endotoxin and kills their pathogen.
In its issue dated September 16, 2000, the journal Lancet reported on a randomized, double-blind, placebo-controlled efficacy trial of recombinantly-modified BPI at 22 centers in the U.S. and Britain. Its title: "Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomized trial."
This study enrolled children from 2 weeks of age to 18 years who showed evidence of severe meningococcal septic shock. Of 1,287 candidate patients screened, 897 were excluded, including 59 who died six hours before hospital admission, before receiving the drug. Of the remaining 393, 190 were treated with rBPI21, while 203 got placebos. During the 60-day study, 34 of the 393 died - 14 in the drug cohort, and 20 control patients.
Six of the 190 underwent severe, multiple amputations vs. 15 controls. "Results overall," the Lancet article concluded, indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease." An accompanying commentary termed the trial "disappointing," and suggested: "One likely explanation is that the drug, although pharmaceutically highly active, was given too late." It went on to caution: "Treatments that can be given only in intensive-care units will benefit only those patients who survive long enough to enter these units." It concluded: "Parents should be instructed to undress and inspect their febrile child regularly, especially at night."
Scientists At Stanford And Neurocrine In Hunt For Hypocretin Agonist Receptors To Treat Narcolepsy
If your body goes limp with laughter, what you're experiencing is cataplexy - a transient bout of extreme, generalized muscle weakness. Surprise, fear or anger can also bring it on. So can narcolepsy, a rare but devastating affliction in which its victims fall suddenly and frequently asleep during the day. Severely affected narcoleptic patients can have five to 20 cataleptic attacks a day. The only therapy is psychostimulants such as amphetamine, which treat narcolepsy's symptoms, not its cause.
A paper in Nature Medicine dated Sept. 1, 2000, casts light on that unknown etiology - a lack of recently discovered peptides called hyocretins. The article is titled, "A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains."
Its co-authors, scientists at Stanford University, carried out histopathological autopsies on the brains of six narcoleptic persons, and screened 74 patients for central nervous system mutations in their hypocretin genes. They suggest that a small-molecule receptor agonist should be able to offset the dearth of the anti-narcolepsy protective peptides, and provide a treatment for this untreatable malady. The Stanford co-authors are collaborating with San Diego-based Neurocrine Biosciences Inc. to develop such drugs. (See BioWorld Today, Aug. 10, 1999.)
In A Fountain-Of-Youth Simulation, Biologists Tweaked Brain Cells To Revert To Stem Cells
A current piece of folk wisdom warns, "You better go home with the guy what brung you!"
Current developmental biology holds that you can't go back to become the stem cells that synthesized you. A contrarian experiment reported in Science dated Sept. 8, 2000, reports: "Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells."
What's going on here?
Oligodendrocytes are non-neuronal glial cells in the brain that make their living by enwrapping neuronal axons in insulation-like myelin sheaths - the better to conduct their cerebral signals. These housekeeping cells owe their existence to their ancestral neural stem cells - grandfathers of all the cells in the central nervous system. These multipotential founder stem cells divide a limited number of times before turning into precursor cells, which end up differentiating into either neurons or glial cells.
Developmental biologists at Britain's University College, London, ran that process backwards. To paraphrase an old song, they made oligodendrocyte precursor cells (OPCs) become their own grandpas. To start this reversion trick, the co-authors isolated OPCs from the optic nerves of newborn rats, and cultured them in fetal calf serum or bone morphogenetic protein. That turned them into astrocyte-like cells. These they treated with basic fibroblast growth factor, a protein famous for stimulating stem cell proliferation. Nearly half started dividing, producing progeny that resembled stem cells to the point where they duly developed into neurons and astrocytes - as well as oligodendrocytes.