Excerpt 3 – Monkey Experiments – 1987
My Journey to a
Next Generation Treatment
Donald E. Moss, Ph.D.
[Setting and Summary by Jim Summerton, Ph.D.]
[ Setting and Summary: Moss had run biochemical experiments and experiments in rats which provided compelling evidence that his wonder drug, MSF, had the chemical and biological properties expected to provide unprecedented activity (efficacy) in renewing the acetylcholine concentrations needed for functional memory, while lacking the many undesired side effects which plagued the other drugs designed for this same purpose (and still widely perscribed for Alzheimer's patients today). However, at that time virtually all scientists working in this field discounted Moss' results because he still had no experimental tests in primates (monkeys and humans). As described in this chapter, the El Paso chapter of ADRDA (Alzheimer's Disease and Related Disorders Association) kindly stepped in with a $3,000 grant which allowed Dr. Moss to purchase four monkeys, and these allowed him to run the crucial safety tests in primates. Just as predicted from his earlier studies on rats, these studies in monkeys demonstrated that MSF is also safe to use in primates. ]
Whenever I got the chance to go to an Alzheimer’s conference or the Society for Neuroscience annual meeting, I talked about the possible use of MSF. I extolled the virtues of my wonder drug to anyone who would listen. I spoke from platforms in formal auditoriums. And I shouted to colleagues sitting on bar stools who had to hunch close to hear what I was saying over the din of clinking glasses, laughter, and other conversations.
If the conversation didn’t end with “What are you going to do about the patent?” it ended with “You couldn’t ever give something like that to humans – that stuff was made as a military nerve agent – it’ll be too toxic – if it’s such a good idea, why hasn’t a big drug company taken it over?” The answer to the question about a drug company made the circle complete. They weren’t interested because I didn’t have a patent. I felt like I was trapped in purgatory.
My colleagues’ new questions about toxicity encouraged me. It suggested that they were thinking about MSF being used in patients. And they were right that MSF had originally been made as a potential nerve poison after World War II. All I could say as a rebuttal was that the sulfonyl fluorides had failed the tests because they weren’t toxic enough.
I was damning myself with faint praise. The fact that MSF couldn’t be used as a nerve gas on a battle field did little to convince people that it could be used to treat dementia. My critics didn’t find my rat studies compelling evidence of safety. I needed something new.
My efforts on behalf of the ADRDA chapter in El Paso paid off in many ways. The most important was that I made friends with many fine people and I developed a first-hand appreciation of the desperate situation faced by Alzheimer’s patients and their families. But another development was that the ADRDA chapter made a grant of $3000 for my research on MSF at U.T. El Paso. Their generosity was a badly needed shot in the arm and their gift provided enough to buy four monkeys for some new MSF tests.
The afternoon my new monkeys arrived, I was ecstatic. They had smooth chestnut-colored hair and shiny brown eyes. They were tired from their trip from New York and cowered in the backs of their cages, glancing around the room. The veterinarian in charge of our animal colony and I took them out of the cramped travel cages and put them in a quarantine room where they would stay for a couple of weeks.
I waited with them long after they’d been settled into their new homes that evening, talking to them, being sure they had plenty of fresh water, and offering them slices of oranges. They were the most beautiful animals I’d ever seen.
* * *
To convince my critics that MSF wasn’t too toxic, I’d have to give my monkeys high doses that went well beyond the minimum required to treat dementia and see if they got sick. If I could do that, get to doses that produced more than fifty percent AChE inhibition in the brain without harming my animals, I’d have strong evidence that MSF was safe and that it could more effective than anything else available.
The problem I faced was that I couldn’t measure AChE inhibition directly in the brain without taking biopsies. I didn’t want to subject my monkeys to the stress and pain of repeated surgeries. To get around that problem, I chose to measure AChE activity in red blood cells as a surrogate measure of what was happening in the brain. It should have been an easy experiment.
The first hitch was that I had to learn a simple way to get a drop of blood from a monkey. This was a learning experience for both the monkeys and me. It required pulling the back wall of their cage forward until the monkey got squeezed against the front bars. With it immobilized, I could reach a foot, clean it, prick it, and squeeze out a drop of blood without having any of my fingers bitten.
After I got that procedure mastered, I tried giving MSF in a capsule buried in an orange slice. They ate the fruit but the blood tests didn’t show any change. Either they weren’t absorbing the drug or they were hiding the pill in their cheek pouch until they could spit it out. I gave up on oral dosing and started giving them intramuscular shots. With injections, I was sure they received the drug.
These first weeks brought us to a routine working relationship. I certainly was not one of their favorite visitors because every time I showed up I gave them an injection or poked the bottom of their feet. They learned to put up with me with quiet resignation.
At the beginning of the experiment, I randomly selected two monkeys to get shots of only peanut oil and two others to get peanut oil laced with MSF. I started at very low doses and gave them three shots per week. Now I could see their red cell AChE values going down. That’s what I expected. The experiment was working.
As each week went by, I gave the MSF monkeys a higher dose. Their blood AChE dropped more. And then I gave them an even higher dose. Blood values went lower still. I increased to higher and higher doses – more AChE inhibition. Every day I checked each animal and their cage, looking for diarrhea, vomit, or any change in behavior. I weighed them – no change in weight. They ate their food. Nothing amiss.
After two months, I was up to a heroic dose of MSF. The monkeys’ red cell AChE was so low I had trouble measuring it. I wondered why the monkeys weren’t showing any ill effects. My initial conclusion was that MSF might not be getting out of the blood. Maybe it was being destroyed before it could get to the muscles or the brain.
As a last resort, I doubled the dose. And then I doubled it again. At that dose, I was far above what I estimated would be needed for patients. After giving them that amount three times per week for four more weeks, in desperation I doubled it again. The day after that huge dose, I thought that I could see that one of the MSF monkeys was a little lethargic. I still didn’t see any vomiting or diarrhea, signs that would have also been reported in a most spirited manner by the caretaker who cleaned the cages. In addition, the MSF monkeys were still eating their normal rations and hadn’t lost weight, suggesting that they weren’t even nauseous.
At that level, about ten times the amount I would need to treat patients, I lost my nerve. I couldn’t go higher without knowing what was going on. My monkeys were too important to me and I’d come to really like the little buggers.
The only way to answer the question about what was happening in the brain was to take a biopsy, see if MSF was doing what I hoped. The day of the surgery, two and one-half days after the last and highest dose I dared to give, I loaded all four monkeys into portable cages and took them over to a local animal hospital where they were anesthetized and samples of cerebral cortex, each about the size of a BB, were taken for my AChE analysis.
As the veterinarian operated on each monkey I felt a new flood of anxiety like I was watching surgery on a child. I hated that I had to put them through the ordeal and I suffered with them as they stumbled around, confused as they began to come out of the anesthesia. I wanted to stay with them longer but I had to get back to the lab to analyze the samples while they were fresh.
Working over the spectrophotometer back at my lab, I found that AChE activity in the samples from the two monkeys getting MSF was 80% inhibited compared to the two controls. Doing a quick calculation in my notebook to account for new AChE the brain had made during the two and one-half days between the last dose and the time the samples were taken, the last dose had pushed AChE inhibition to more than 90%.
I stared at the results. Considering that the accepted standard for treating dementia was to get over 50%, and conventional drugs made people sick at that level, MSF could rocket over what was needed clinically. No other drug could come close to matching MSF. My concerns evaporated. I now had real answers for questions about toxicity and efficacy.
This was the strongest evidence yet that I was right about MSF. A feeling of elation flooded over me, all the work over the previous years was paying off, even without the patent. These data proved that MSF could be an unparalleled treatment for dementia.
And I hadn’t lost a monkey.