By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
Sensations of burning, tickling, pricking or tingling - neurologists call them paresthesias - are typical early symptoms of multiple sclerosis (MS). These central nervous system disturbances reflect the destruction of myelin protein, which wraps around the axons on nerve cells - like insulation around an electrical wire. Loss of myelin sheathing degrades nerve conduction, which marks the slow, intermittent but escalating effects of MS.
Three types of cells in the brain and peripheral nervous system, notably the spinal cord, form myelin. They are oligodendrocytes, Schwann cells and olfactory ensheathing cells (OEC). Therapeutic efforts to replace the missing myelin in MS focus mostly on Schwann cells.
A recent Journal of Neuroscience, dated Feb. 1, 2001, reports, "Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord." Its authors are neuroscientists at the Yale University School of Medicine in New Haven, Conn.
They obtained the myelin-making Schwann cells from the amputated legs of patients with diabetes or vascular disease, and transplanted these cells with a fine glass needle into the lesioned spinal cords of immunosuppressed rats. After three to five weeks of extensive remyelination, they observed a typical Schwann cell pattern in the lesion zone.
"The spinal columns displayed improved nerve conduction velocity," they found. "Their action potentials conducted over a greater distance into the lesion, suggesting that conduction block was overcome. This data suggest that a large subpopulation of axons in the demyelinated lesion was remyelinated by cell transplantation and the remaining axons were not."
MS is an autoimmune disease in which the arms of the immune system denude nerve axons of their myelin. Therefore, besides experimental recombinant interferon therapy, its patients require immunosuppressive drugs against the autoimmune assault. The co-authors presumed that "Schwann cells are not as antigenically predisposed to the immunological attack seen in multiple sclerosis as are oligodendrocytes. Our results indicate," their paper concludes, "that anatomical and electrophysiological repair of demyelinated axons by adult human Schwann cells is an important prerequisite for future considerations of these cells as candidates for autologous transplantation studies in humans."
The co-authors speculate that possibly in the future, Schwann cells could be harvested and, with a nerve biopsy directly from the MS patient who needs the transplant treatment, grown in large numbers - making immunosuppressive drugs unnecessary.
New 'Phenotype-Based Gene-Trap' Screen
Elucidates Normal Wiring Of Mammalian Brain
Elsewhere on the axonal front, an article in Nature, dated March 8, 2001, is headed, "Defining brain wiring patterns and mechanisms through gene trapping in mice." Its authors, at the University of California, San Francisco, make the initial point that "the search to understand the mechanisms regulating brain wiring has relied on biochemical purification approaches in vertebrates and genetic approaches in invertebrates to identify molecular cues and receptors for axon guidance."
Their paper describes "a phenotype-based gene-trap screen in mice designed for the large-scale identification of genes controlling the formation of the trillions of connections in the mammalian brain." They conclude: "We are directed to the relevant axons by the histochemical marker; the 'needle in the haystack' problem is, in effect, solved through the molecular tagging of the 'needle.'"
Computational Method Predicts How Individual
Patients Will Respond To The Same Medicine
"One man's meat is another man's poison." That venerable epigram reflects a modern truth: A drug the doctor prescribes may not work the same in every patient.
A paper in the monthly Journal of Molecular Biology, dated March 23, 2001, announces a new departure in pharmacogenomics - the science that correlates genetic variation with drug response. Its title tells its story: "Predicting the functional consequences of non-synonymous single nucleotide polymorphisms [nsSNP]: Structure-based assessment of amino acid variation." Its co-authors are bioinformatics researchers at Variagenics Inc. in Cambridge, Mass.
"Recent surveys of human genetic diversity," their paper points out," have estimated that there are about 250,000 to 400,000 common single nucleotide polymorphisms in protein-coding sequences of the genome. Some of them," it added, "introduce amino acid polymorphisms into their encoded proteins."
The company's computational approach, said its vice president for research and genomics, Colin Dykes, "is a powerful tool for prioritizing the SNPs and haplotypes most likely to affect drug response. It reinforces our recommendations to drug developers regarding patient populations to study in clinical trials."
Crystal Structures Of Two Enzymes Elucidate
Jaundice Mechanism Of Bilirubins In Yellow Babies
Newborn babies often turn a light yellow on day one following birth. This infant jaundice may spread downward from head to feet, reflecting increasing levels of bilirubin.
Jaundice in premature or otherwise sickly infants calls for attention. The deepening yellow color signifies abnormally high levels of bilirubins in their bloodstream. These proteins can be neurotoxic, and their build-up in an infant's brain may cause irreversible damage. Phototherapy is a treatment of choice, in which the yellow baby is exposed to selected wavelengths of light. This illumination produces isomers of bilirubin in and under the skin, which can be more readily excreted than the initial protein.
Bilirubins are the breakdown products of heme - the oxygen-binding factor of hemoglobin - released from red blood cells that have been destroyed, or simply outdated. However, bilirubins are not waste products that are all bad. In fact, they are potent antioxidants made by the body.
Heme converts to bilirubins in two steps. First, it is cleaved to produce unstable intermediates called biliverdins. Then biliverdin reductase enzymes complete their conversion to bilirubins. The March issue of Nature Structural Biology contains an article reporting the crystal structures of two different biliverdin reductases. Its title: "Structure of human biliverdin IXb reductase, an early fetal bilirubin IXb-producing enzyme." Its authors are at Trinity College, Ireland; the Institute of Molecular Biology in Barcelona, Spain; and Japan's Riken Harima Institute. n