1780-1794
In Italy, the physician and physicist L. Galvani uses frogs to demonstrate that muscles contract when stimulated by electricity. By touching the exposed muscle of one frog with the nerve of another, he proves that electric forces exist within living tissue.
1863-1866
In an Austrian monastery garden, G. Mendel studies the manner in which pea plants inherit traits ('factors'). He demonstrates numerically that a pair of these factors controls characteristics (e.g., tallness, shortness) that can be inherited either dominantly or recessively. Despite publication in natural science society journals, Mendel's peers ignore his work during his lifetime. We now recognize Mendel as the father of genetics.
1907
In England, pharmacologist R. Hunt isolates acetylcholine from adrenal gland extracts.
1911
In England, physiologist and pharmacologist H. Dale proposes that acetylcholine transmits nerve impulses.
1921
In Germany, the physician and pharmacologist O. Loewi proves that acetylcholine is involved in transmitting impulses from one nerve cell to another and from the nerve cell to the muscle.
1922
German-American biochemist O. Meyerhof and British physiologist and biophysicist A.V. Hill share the Nobel Prize for Physiology or Medicine for their discoveries that muscles produce heat from the cyclic breakdown of sugars into lactic acid.
1929
With H. Dudley, H. Dale isolates acetylcholine from animal tissues.
1936
In England, H. Dale and his collaborators show that by electrically stimulating the nerve, it releases acetylcholine, which provokes skeletal muscle contraction.
1938-1956
In England, physiologist and biophysicist A.V. Hill and colleagues work with frogs to demonstrate how muscle contraction releases energy in the form of mechanical work and heat.
1939-1946
In Hungary and America, biochemist A. Szent-Gyorgyi discovers actin, a muscle protein that, in combination with myosin, causes muscles to contract by using adenosine triphosphate (ATP) as the energy source.
1958
In Sweden, pharmacologists J. Axelsson and S. Thesslef show that a caffeine bath causes frog muscle fibers to contract even when electrical current has not affected the muscle membrane.
1960
In Australia, internist M.A. Denborough and colleagues determine the familial inheritance of deadly reactions to general anesthesia.
1967
In the United States, organic chemist H.R. Snyder and colleagues synthesize a new class of chemicals, including dantrolene, which appear to cause muscle relaxation in the anesthetized cat model.
1968
In South Africa, anesthesiologist G.G. Harrison and colleagues inadvertently discover that the pig can serve as an experimental model for malignant hyperthermia.
1969
In England, molecular biologist H.E. Huxley and physiologist A.F. Huxley propose the sliding-filament theory of muscle contraction: two muscle proteins, actin and myosin, arranged in partially overlapping filaments, slide past each other through the activity of the energy-rich compound, ATP, during muscle contraction.
1970
In Canada, anesthesiologist B.A. Britt and pharmacologist W. Kalow analyze the medical histories of U.S. and Canadian MH-susceptible families to help predict which anesthetic agents appear to trigger fatal episodes.
1970-1971
In Canada, W. Kalow, B.A. Britt, and colleagues develop a biopsy test to predict susceptibility to MH in humans. In Britain, anesthesiologist F.R. Ellis and neuropathologist D.G.F. Harriman suggest additional methods for performing this biopsy test.
1972-1973
In the United States, pharmacologists K.O. Ellis and S.H. Bryant determine that dantrolene relaxes goat skeletal muscle directly without affecting the other muscles of the body.
1975-1976
In South Africa, G.G. Harrison demonstrates that dantrolene aborts MH in pigs. In the U.S., G. Gronert and colleagues confirm and extend Harrison's findings.
1977-1979
In the United States, clinical research manager M.E. Kolb leads a multi-center study that uses dantrolene to treat human MH crises.
1980
The U.S. Food and Drug Administration (FDA) approves dantrolene for treating human MH.
1985
In the U.S., toxicologist I. Pessah and colleagues identify calcium channel receptors (ryanodine receptors) in rabbit skeletal muscle whose function can be affected by caffeine and calcium. Molecular biologist S. Fleischer and co-investigators isolate these receptors at the ends of the skeletal muscle sarcoplasmic reticulum (storehouses for calcium).
1990
In Canada and Ireland, research teams led by D.H. MacLennan and T.V. McCarthy, simultaneously link the gene for the skeletal muscle calcium release channel with MH susceptibility in humans.
1991
In Canada, D.H. MacLennan and P.J. O’Brien determine that malignant hyperthermia in pigs arises from a single incorrect amino acid, which codes for an abnormal calcium release channel.
1994
Led by North American MH Registry director M.G. Larach and biostatistician, A.R. Localio, international experts from the U.S., Australia, Canada, Denmark and the United Kingdom collaborate to produce an MH clinical grading scale.
1997-1998
European and North American MH research groups validate the MH muscle biopsy tests for predicting human susceptibility to MH.
2000
International researchers describe more than two dozen mutations in the genes for calcium release channels and slow calcium channels that are linked to human MH susceptibility.
Return to Making Anesthesia Safer: Unraveling the Malignant Hyperthermia Puzzle