By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
In the early decades of the 20th century, a favorite laboratory animal model was the Wistar rat, bred at the prestigious Wistar Institute of Biological Research in Philadelphia. Then in 1938 a researcher named C. K. Gunn described a mutant Wistar rat with very yellow eyeballs, and symptoms of severe jaundice.
Fast forward to 1952. In that year, two pediatricians, J. F. Crigler and V. A. Najjar, reported in the journal Pediatrics, "Congenital familial nonhemolytic jaundice with kernicterus [brain involvement]." In three families extensively related through intermarriage, they found six newborn infants who developed severe jaundice on the first to third day of life. Five of them died of cerebral jaundice within 15 months; the sixth succumbed 15 years later to the rare disorder, now known as Crigler-Najjar syndrome (CNS).
It results from a functional defect in the gene that encodes the enzyme glucuronsyltransferase, which facilitates excretion of bilirubin from the liver into the bile. When bilirubin, the reddish byproduct of red blood cell turnover, builds up in the liver, it may cause CNS - or gallstones.
In its severe form, CNS type I spreads through the nervous system, subjecting its young victims to the ever- present danger of lethal brain damage. There is no definitive cure, but affected children must sleep nude for 10 to 12 hours a day under intense blue light, which breaks down the bilirubin. Unfortunately, this phototherapy loses its effectiveness with time. Then liver transplant becomes the remaining curative option.
CNS type I is an autosomal recessive inherited disease, which strikes an infant when both its parents carry the defective gene. In that respect, it parallels the jaundice that afflicts the Gunn rat, now the preferred animal model for studying Crigler-Najjar syndrome.
The current issue of The Proceedings of the National Academy of Sciences (PNAS), dated Aug. 31, 1999, reports a DNA-repairing experiment that permanently cured a Gunn rat of its look-alike type I CNS. The paper is titled: "Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide." Its senior author is hepatologist Clifford Steer, at the University of Minnesota, Minneapolis. He estimates at 300 the number of CNS type I patients in the world today. (See BioWorld Today, Mar. 4, 1998, p.1; and May 19, 1999, p. 1.)
The DNA defect in rat and human produces a premature stop codon in the gene sequence that encodes the bilirubin-excreting enzyme. As reported in PNAS, the co-authors achieved permanent correction of this defect in the Gunn rat's liver by site-specific replacement of the absent nucleotide residue. They used an RNA/DNA oligonucleotide designed to promote endogenous repair of genomic DNA. This genetic surgery technology, which Steer, its inventor, calls chimeroplasty, was developed by Kimeragen Inc., of Newtown, Pa.
The company's president and CEO, Gerald Messerschmidt, observed, "This study heralds a new way to treat disease by repairing the causative gene. The next step," he added, "is to gain approval from the U.S. Food and Drug Administration to initiate a human trial for Crigler-Najjar, anticipated for early next year." And John Crigler, professor of pediatrics at Harvard University, who co- discovered the eponymic syndrome nearly half a century ago, stated: "This [study] is the first direct attack on the basic genetic defect."
Zebrafish Elucidate Olfactory Neurons' Link To Immune Cells' Antigen-Detection Upbringing
In the research zoo of animal models - from fruit fly (Drosophila melanogaster) to nematode (Caenorhabditis elegans) to clawed frog (Xenopus laevis) to baby chick (Gallus gallus) to mouse (Mus musculus), the newest organism - and smallest vertebrate - in this in vivo lineup is the zebrafish (Brachydanio rerio). The gaily striped, 3-centimeter-long piscine member is better known to pet shops than to laboratories. One of B. rerio's advantages is that it's optically transparent.
At the Medical College of Georgia in Augusta, molecular geneticist Shuo Lin and colleagues enlisted zebrafish to help unravel a knotty problem of how the immune system does its thing. Specifically, how the body's antibody-generating B lymphocytes equip their future antigen-sensing army to recognize in advance every immunogenic intruder they will ever encounter.
This cell-boggling process, called V(D)J recombination, relies on two genes, rag1 and rag2, to mix and match the virtually infinite permutations involved in assembling the separate DNA segments that will arm each individual antigen-briefed antibody. These V, D and J segments stand for "variable" and "diversity," plus the element that "joins" them. Both rag genes are expressed in thymus and kidney, the sites where immune cells multiply and mature. Rag stands for "recombination activation gene."
The Georgia researchers' paper in Nature Genetics for September 1999 bears the title: "Artificial chromosome transgenesis reveals long-distance negative regulation of rag1 in zebrafish." The co-authors found that rag1 and rag2 also are expressed in the olfactory neurons of B. rerio. Zebrafish have 100 or so rag genes encoding various olfactory receptors, but only one gene, the group reported, is expressed in each odorant receptor neuron.
New 'Cosmeceutical' Skin Care Product Launch Employs Therapeutic Microsponge Polymer
A microsponge delivery system to enhance the appearance of skin discolored by blood vessel damage or inflammation is going public.
Advanced Polymer Systems Inc. (APS), of Redwood City, Calif., said Friday in a news release that "entertainer and child advocate Kathie Lee Gifford will serve as national spokeswoman" for the company's new microsponge-based retinol skin-care system, via a 30-minute TV "infomercial."
In a more therapeutic vein, APS noted that new polymeric products under development "include site-specific systems for delivering oral medications to the lower gastrointestinal tract, and bioerodible microspheres and polymers for oral or implantable drug delivery."