Zigzagging for 15,000 miles across 42 states, more than 10,000Americans are handing the Olympic Torch from hand to hand on its84-day passage from Los Angeles to Atlanta. There, on July 20th, theflame, which began its journey in Greece, will kindle the start of thecentenary Olympic Games.
In a way, this relay race has points in common with the way nervestransmit their messages to muscles.
Instead of a flaming torch, microscopic sacs, or vesicles, pass achemical messenger called acetylcholine (ACh) across a nanometers-wide gap between nerve and muscle, called the neuromuscularjunction (NMJ), or synapse. There it binds to a receptor protein.
Medical school students must memorize the 507 muscles of thehuman body, ranging from the minute musculus dilator iridis, whichwidens and narrows the pupil of the eye, to the massive musculusrector femoris, which bulges in the thighs of Olympic athletes.
Neuromuscular junctions command and activate every movement ofevery muscle. Early in fetal gestation, motor neurons stop growingand start differentiating, to construct NMJs as mission controls forthe future body's lifelong and life-preserving muscular activity.
"Loss of muscle mass, and muscle atrophy, are huge clinicalproblems," observed molecular neuroscientist George Yancopoulos."Muscle loss affects particularly elderly patients, immobilized inhospital beds, who are already at the brink of having sufficientmuscle mass to support normal life."
Yancopoulos is vice president, discovery, at RegeneronPharmaceuticals Inc. in Tarrytown, N.Y.
"Our company," he told BioWorld Today, "is very interested in thepossibility of maintaining muscle mass in situations where it declines,as well as in muscle diseases, such as myopathies and dystrophies."
Regeneron abandoned a Phase III trial of ciliary neurotrophic factor(CNTF) in 1994 (see BioWorld Today, June 24, 1994, p. 1), andturned to other factors for motor neuron disease. "We have sincebeen seeking," Yancopoulos said, "a growth-factor receptor that wasspecifically expressed _ and upgraded in muscle-injury situations."
Last summer, he and his Discovery Group were able to announcethey had cloned "an exquisitely muscle-specific-receptor kinase(MuSK)," which filled their bill.
In normal muscle, they found that MuSK is only expressed at the siteof the NMJ, "apparently poised perfectly to receive a crucial nerve-derived signal."
"So we said," Yancopoulos continued, "if only we had the growthfactor for this receptor, it could be very interesting in adult nerveinjury."
As a step in this direction, the researchers constructed transgenicmice in which they had knocked out the MuSK receptor gene. "Loand behold, we had this incredible developmental defect _ completeabsence of NMJ formation.
"The animals were born, they looked rather normal, but since theyhad no NMJ, the nerves could never tell the muscles to move. Theynever took their first breath of life, and so they died in minutes."
Thus clued in, the group determined that MuSK was part of areceptor complex for a protein discovered a decade ago in fetal nervegeneration, and named agrin. "People had been looking for the agrinreceptor ever since," Yancopoulos said, "but nobody previously hadever imagined that agrin had a role in adults."
"So we're thinking, that in that situation, the agrin is playing a verydifferent role, providing a growth or maintenance signal to the muscleat risk. Now we want to test the possibility that we can start injectingsystemic agrin to treat a variety of muscle-wasting and diseasestates."
The company has "gone through the stages of cloning human agrin,and filing all the necessary patents," Yancopoulos said.
His group has begun testing the product in rodents "to show we canmaintain stable levels and get receptor activation."
Regeneron's research on agrin and MuSK commanded a triad ofarticles in Cell dated May 17, 1996, plus that issue's cover and a"Minireview" editorial.
But that was just the beginning. Science for the following week,dated May 24, 1996, devoted its opening editorial page to thediscoveries, headlined: "Synapse-making molecules revealed." Andthe current issue of Nature, dated June 6, played catch-up with a"News and Views" commentary, "Agrin signals at the junction."
Finally, Tuesday's Proceedings of the National Academy of Sciences,dated June 11, weighed in with an article, "Substrate-bound agrininduces expression of acetylcholine receptor e-subunit gene incultured mammalian muscle cells."
Yancopoulos compares Regeneron's clinical potential for agrin totreat neurons with "what people had been doing with erythropoietin[EPO] for anemia. The reason EPO is a big drug," he observed, "isbecause EPO receptors are expressed only in red blood cells _ thecells at risk in anemia.
"So we want to give growth factors for particular nerve and musclecells at risk of neurological and muscle diseases." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.