By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
From needle injection to nasal inhalation to pump to pill, novel systems proliferate for delivering insulin to the body. Besides being cumbersome, all these modes of administering the hormone to diabetes mellitus patients miss the main point: Native insulin is generated on demand ¿ the body¿s own metabolic demand ¿ to perform its 24/7 task of balancing too much glucose (hyperglycemia) against too little (hypoglycemia). When these two metabolic conditions get out of kilter, and high blood sugar ensues, a diabetic patient may suffer severe symptoms, from nausea leading up to coma and death.
Exogenous insulin is the mainstay of therapy in all patients with Type I (juvenile) diabetes and in many with Type II (adult-onset) diabetes.
But that¿s just the half of it. Over time, as diabetologists have only recently confirmed, the off-again-on-again dosing with store-bought insulin, however assiduously titrated, cannot avoid the horrendous complications of diabetes that flare up after many years. These side effects include diabetic retinopathy, a leading cause of blindness, and circulatory disorders that result in a principal reason for limb amputations.
Now scientists at the University of California at San Diego have developed and tested in vivo a strategy whereby an insulin prodrug deposited in the body in a state of latency becomes active automatically in response to the body¿s ever-changing need for normoglycemia ¿ optimum glucose balance. Their report in The Proceedings of the National Academy of Sciences (PNAS) dated Nov. 20, 2001 (but released online Nov. 13), bears the title: ¿Synthesis of an organoinsulin molecule that can be activated by antibody catalysis.¿
Essentially, their method consists in modifying the insulin hormone so that it can hibernate, as it were, in the body until called upon. That wake-up call comes from an associated catalytic antibody, which cleaves the restraining molecules in the prodrug, thus reviving the sleeping hormone to bind its receptor and go into full, functional action.
In preliminary tests, the co-authors found that the modified insulin¿s ability to bind its receptor was reduced by 90 percent, and its transport of glucose by 96 percent in vitro, and 55 percent in rats. Adding the catalytic antibody reversed this defect completely by removing the chemical modifications, and unleashing insulin to do its job. When they tried their approach in rats, the results mirrored their therapeutic in vitro experiments.
Immunologists Indict A Molecular War Criminal In Friendly Fire¿ Aimed At Lupus Autoimmune Disease
There¿s nothing friendly about the ¿friendly fire¿ often cited to describe the self-wounding effects of autoimmune diseases. And like the battlefield attacks against one¿s own forces, the court martial often can¿t get to the root cause of the baseless onslaught.
Similarly, the researchers who sit in judgment on the causes of autoimmunity haven¿t yet been able to reach a verdict. All they know is that in autoimmune diseases, such as systemic lupus erythematosus (SLE or lupus), the victim¿s immune system has turned against its own body, because it ¿sees¿ its self-tissues as the enemy. Hence, the only current therapy for SLE is to disarm the patient¿s entire immune defenses with immunosuppresant drugs. This draconian treatment has its own backlash: The defenseless body is exposed to viral, bacterial, fungal and parasitic infections.
SLE attacks multiple organ systems in its patients, especially skin, kidneys and the central nervous system. A cure for the disease is urgently needed, particularly for children, in whom the disease often progresses to chronic renal failure and death. The search for such therapy logically takes off from trying to pin down the names and serial numbers of the specific troops and weapons deployed by the immune system in its unfriendly fire.
Immunologists at the Baylor Institute for Immunology Research in Dallas have just announced a step in this direction. Their report in Science dated Nov. 16, 2001, is titled: ¿Induction of dendritic cell differentiation by IFN-a in systemic lupus erythematosus.¿ The paper¿s findings indicate that ¿hyperactivation¿ of immune system cells that help regulate the body¿s tolerance of its own ¿self¿ proteins may have a hand in the more serious form of lupus. ¿Our results suggest,¿ the report concludes, ¿that IFN-a [interferon-alpha, the cytokine that triggers the hyperactivation] might represent a potential target for therapeutic intervention in SLE.¿
Spiny Female Fish Choose Future Fathers Based On Their Male Odor, Signifying Parental Fitness
Sticklebacks (Gasterosteus aculeatus) are small fish, 2 to 6 inches long, that are equally at home in freshwater lakes, saltwater seas and domestic glass tanks. The Dutch animal behaviorist Niko Tinbergen put sticklebacks on the map of reproductive research, for which ethological work he shared a Nobel prize in 1973. The fish owe their name to three sharp spines rising in a row from their backs. In the springtime, sticklebacks signal that they are ready for courtship and breeding by turning their bellies bright red.
In the 1940s, Tinbergen observed that when the fish in his glass tank saw a red truck go by, they lunged at it as if trying to break the windowpane. A male stickleback in breeding conditions will often attack another male.
Female sticklebacks are choosy about the future fathers they mate. They prefer the odor of males that carry the most array of genes in their major histocompatibility complex (MHC). This olfactory fussiness is related to the smell a male gives off when infested with parasites.
A new study in Nature dated Nov. 15, 2001, suggests that a finely tuned immunological sign allows female fish in heat, as it were, to sniff out the male that will give them the fittest offspring. The paper is titled: ¿Female sticklebacks count alleles in a strategy of sexual selection explaining MHC polymorphism.¿ Its authors are at the Max Planck Institute for Limnology in Plvn, Germany.