Contribution of a snake venom toxin to myasthenia gravis: the discovery of alpha-bungarotoxin in Taiwan.

Myasthenia gravis (MG) is now recognized as an autoimmune disorder in which antibodies to acetylcholine (ACh) receptor lead to impairment of neuromuscular transmission. The discovery of alpha-bungarotoxin by Chang and Lee in 1963 has played a crucial role in establishing the new concept of MG. However, isolation of bungarotoxins from the venom of Taiwan banded krait, Bungarus multicinctus, was accomplished in the poorly funded and under equipped laboratory of the Department of Pharmacology, National Taiwan University, during the post-WWII period of economic depression and research isolation. Because alpha-bungarotoxin binds specifically and irreversibly with the muscle type nicotinic ACh receptor, it was used to localize ACh receptor and to isolate the ACh receptor protein, opening up a new era of receptor studies. It was also used to produce an antibody to ACh receptor and eventually an experimental autoimmune model of MG and clinical confirmation. The discovery of alpha-bungarotoxin has been considered the most important contribution to neurosciences from Taiwan.

Professor Chen-Yuan Lee, MD (1915-2001), pharmacologist: snake venom research at the Institute of Pharmacology, National Taiwan University.

Professor Chen-Yuan Lee was born in Tainan, Taiwan. In 1940, he joined the staff of the Institute of Pharmacology of the university, now named National Taiwan University. Dr Lee began a study of Daboia russelli formosensis venom under the direction of Professor Tsungming Tu who, in the 1930s, initiated the pharmacological studies of Formosan snake venoms carried out at the Institute. Under Professor Lee's direction, the Institute became known internationally for its work on the isolation, composition and characterization of the pharmacological properties of neurotoxins isolated from Formosan elapid venoms. Sophisticated use of the latest techniques revealed the mode of action of postsynaptic -bungarotoxin and presynaptic -bungarotoxin from Bungarus multicinctus venom, postsynaptic cobrotoxin, cytotoxic cardiotoxin and phospholipase A2 from Naja naja atra venom. Through work undertaken with colleagues at the Institute and in foreign countries, Professor Lee made an important contribution to our understanding of the mode of action of snake neurotoxins, and to their use in the elucidation of neuromuscular transmission. In the past decade, C.-Y. Lee was a prominent campaigner for social and political justice in Taiwan.

Looking back on the discovery of alpha-bungarotoxin.

This review is a personal narration by a retiring pharmacologist from Taiwan who looks back at his discovery of alpha-bungarotoxin from the historical perspective of Taiwan during the last 50 years, with accounts of his experiences and his efforts to overcome hardship. How the alpha-toxin was isolated and characterized as an irreversible specific nicotinic acetylcholine (ACh) receptor antagonist, and how it subsequently became a useful experimental probe are presented here. The dilemma of differentiating the actions of tubocurarine and alpha-bungarotoxin is analyzed. The author also outlines findings based on work done in his laboratory using alpha-bungarotoxin as a tool on particular aspects of synaptic transmission. These include presynaptic receptor for positive feedback of transmitter release, explosive release of ACh, up- and downregulation of ACh receptors after chronic drug treatment, autodesensitization of junctional ACh receptors, differences in action between natural transmitter and exogenous agonists and that between junctional and extrajunctional ACh receptors. Some experimental pitfalls, in which biomedical scientists are frequently trapped, are raised. Finally, some anecdotes are appended from which the reader may further understand scientific life in the 20th century, including its joys and regrets.