Lots of people did their own canning during the inflation years in Germany after the first World War. They saved money but for quite a few there was a terrible consequence because canned food can be deadly if it has not been heated well enough to kill all bacteria in it. Poorly canned vegetables, fish, and meat killed many people. The Germans initially blamed bad sausages (natürlich!), which gave the illness the name botulism (from the Latin word for sausage: botulus). The lethal agent is a toxin produced by the bacterium Clostridium botulinum that exists in the soil in many parts of the world and that grows and excretes toxin in closed containers regardless of the absence of air. Animals that have eaten botulinum-contaminated material also die.
The stories sound grisly. For instance, the guests at a wedding party were taken ill a day or two after the wedding feast, became nauseous, weak, and paralyzed in sequence according to how much they had eaten, and all died after a few days. The bride and groom who had only tasted the meal a little became ill last but then also died.
This particularly awful tale cautions us always to boil canning and preserving food for at least 10 min, never ever to open a sealed can that is bulging because gas has developed in it or to open a jar with bubbles under the lid, and not even to sniff or taste anything that has a rancid odor or taste. It may well kill you. Botulinum toxin is the most potent poison on earth.
Why am I writing about this dreadful stuff? It has been part of my life. I begin with the scientific work, tell you a little more about the toxin, and end with a bit of Medicine.
Nancy and I were married on the strength of my first job at McGill University where I was slated to work with Arnold Burgen who had published a paper the year before that showed that botulinum toxin was so potent because it shut off the outflow of the neural transmitter acetylcholine (ACh, that transmits messages in the cholinergic part of the autonomic system and from nerves to skeletal muscles). My job was to determine the detail of this action. So I worked on it from ‘50 to’ 52 in a chemically secure room fixed up with acid/base resistant floor and bench surfaces to permit flooding everything with strong base, protective goggles, rubber clothing and gloves and a secure box with glove inlets in which to handle the toxin. Most importantly, Nancy and I, and my technician Heinz Weiner, were protected by immunizations with toxoid.
(I suppose unborn baby Martin may have absorbed some of this while in utero.) Nancy typed the last bits of the resulting Ph. D. thesis, finishing in the afternoon just as the contractions started to come on regularly. We drove the 45 min from Chateaugay Village to the Royal Victoria Hospital in Montreal at some speed. Martin arrived in the small hours of the morning.
The research had gone well: I had shown that the toxin acted by shutting down the nerve endings before the impulse reached the transmittter release site rather than the transmitter release mechanism as such. This was a neat result and I got a paper out in Science in ‘53. and also reported it at the Int. Congr. of Physiol. Scis, held at McGill in ‘53 that was singled out for favorable mention in the review of the Congress in Nature. The full paper was published in J. Physiol in ‘54. I was launched with McGill as the benevolent springboard after an aborted start at Toronto (from where I received the degree, but that is a separate story). We went on to Canberra, Australia where I worked with Jack Eccles to learn about the central nervous system. After a while, however, he made me start on an additional project to study the toxin action further with the new method of intracellular recording. This refined my previous extracellular results and was reported in J. Physiol in ‘56. [Our main experiments were about the central action of tetanus toxin to follow up Sherrington’s interest in tetanus that had moved Jack to bring me in as the toxin ‘expert’ in the first place. We confirmed Sherrington’s suspicion that it depresses inhibition in the spinal cord, by showing that it interferes with transmission near inhibitory synaptic junctions (Nature ‘55, J. Physiol. ‘57).]
Montreal and Canberra led me to New York. In science that is a straight line although it is circuitous geographically. Actually first we returned to Montreal where I taught one academic term to fulfill the requirement of my postdoctoral travel grant from the Medical Committee of the National Research Council of Canada (MRC was split off from NRC only some years later). The year before we went abroad, I had been invited, after returning, by David Lloyd to join his Laboratory at the Rockefeller Inst. for Medical Research. This was a great honor which I accepted, of course. Later I discerned the unseen connections, David’s father had been Prof. of Botany at McGill, and David had had Jack Eccles as his immediate supervisor when he worked in Sherrington’s lab at Oxford. In New York I set up my lab, and also imported the two toxins that I had studied in Canberra, botulinum and tetanus. We used tetanus toxin once more as a tool in a study of inhibition in the cerebral cortex (Am. J. Physiol. ‘65) but botulinum was not used again; it just sat in the freezer, and both moved up Fifth Ave when I joined the New York Medical College.
An odd thing happened in the winter of ‘69 when I was checking over my lab at the NY Med. College before the Christmas holidays. As I made sure that all was where it should be, I sensed something was amiss. I could not place that odd feeling until I recalled that an item was missing from the freezer. I looked again, and recognized with a shock that the locked metal box that contained tubes of pure botulinum toxin was gone. It could not be, surely! That box had been there for many years, unused but in good order, although the freezer itself had no lock. I searched everywhere but finally realized with at jolt that the box was truly gone. I am not sure exactly what I thought about it, but I locked the place up and went home. Finally I told Nancy who sat bolt upright in bed and inquired, with reason, whether I had really looked everywhere, and on talking about it some more we came to the conclusion that this was a major crisis. Advice and help was needed, and she suggested that I call Jimmy Rowen the next day.
He invited me to talk about this over supper near his office. An extraordinary night developed upon returning to Shearman Sterling. Jimmy worked calmly and purposefully, assistants came and went, and I sat opposite his desk like a rabbit petrified by dreadful visions. First he established the legal consequences of the various lethal disasters the missing stuff could cause if handled carelessly either in the building, the street, the garbage, or in the garbage dumps in the Jersey marshes. The answers were all awful, I remember hearing something that sounded like "fifteen years as perhaps obtainable" if people were killed. Since it seemed unlikely that the College would stand behind me as the negligent party, there followed a search for the best path to follow. Eventually the decision was to give notice in writing of the missing toxin to the Vice-President Research, coupled with my offer to help in any search he might wish to initiate.
But, in addition, we decided to give a copy of the letter first to a particular colleague who conceivably might have been involved in the mysterious disappearance, a person with an odd sense of mischief and an unreliable temper. If that was indeed the problem, the letter should defuse the whole thing. And so it devolved: after having delivered the letter to his office in the morning, his technician came forward to say that the toxin box was back in the freezer and allowed that he had been instructed to hide that box on a beam near the ceiling in my lab! There it was, in the freezer, locked and untouched. Some sense of mischief! And so the letter to the VP was never sent, the matter was never discussed with anyone; it was the crisis that never was. Jimmy had saved our family from disaster. The next week I took the box to a lab at Rockefeller where toxins were still studied by a former colleague from McGill, I never wanted to see it again. The person receiving it tossed it into a freezer chest with other deadly stuff, and as I walked out I noticed that his freezer had no lock either.
Well, what about the toxin, how did one get this stuff? The answer was from the "military" because botulinum toxin had already been studied as a possible biological-chemical weapon during the War in the forties (when it had been found unsatisfactorily unstable). We obtained pure, crystalline toxin from Edward Schantz, a research chemist at Fort Detrick, Md. Since it was so poisonous, neither the Post Office nor any courier would have carried it, so Ed used to send it (carefully encapsulated and padded) in a plain brown paper mailing package. That worked to Montreal, Canberra, and New York. Great, eh? Ed and I talked a lot about the toxin, how it works, and how one can study it. At McGill I had studied it by local injection of minute amounts into otherwise healthy cats.
In 1993 he reminded me in a letter of these conversations, and particularly of one when I visited him at Fort Detrick in which he reports I ..."said that that the toxin should be a good substance to quiet down overactive muscles". .. Ed had accepted this suggestion and passed it on to an eye surgeon, Alan Scott, who did use it for overactive eye muscles in experiments with monkeys, and later, after FDA clearance, on human volunteers. After 10 years of human trials, the FDA licensed this batch of toxin in 1989 as an orphan drug which is now packaged as "Botox" by Allergan Pharmaceuticals and used for the treatment of many dystonias and other involuntary muscle movements.
In a recent symposium book Therapy with Botulinum Toxin (Dekker ‘94) Ed Schantz led off with a ‘Historical Perspective’ in which he says .."The possible use of toxins for weakening a muscle was first suggested to me by Dr. Vernon Brooks, a physiologist to whom I furnished toxin for his studies and with whom I occasionally discussed the action of the toxin. He had shown in his publications that acetylcholine was formed at the nerve endings and paralysis resulted because the toxin blocked its release to the muscle. He suggested in the 1950s that the toxin would be good to reduce the activity of hyperactive muscle." ...
All this came back to me at the Neuroscience Meeting in Washington last month.
The (dystrophic) woman on duty in the Dystrophy Foundation booth nearly fell around my neck when I mentioned the above after she told me that she was being treated that way with Botox. She said "God bless you, I was completely bedridden until this treatment came along ". Of course she had never heard of me, but she knew of Scott and the story since then.
So we have come full circle two ways. First, there was the fun of the scientific sleuthing that in the end helped to beat a sword into a plowshare. And second, tied to the first, is my student history: I was a candidate for the double degree M.D. Ph.D., in Toronto and then at McGill, but that went out the window after I met Nancy so that we could get married soon.
What I needed was a job, and McGill obliged by taking me on as a Lecturer. I have never regretted any aspect of this and it is great to see that a useful medical treatment came out of some abstract research I once did. That is the way it always comes about anyway, I am happy to have had a hand in it.
12/1/96 © Vernon Brooks