Warning: this episode contains references to drug use.
Last year, I posted up a response to a redditor who messaged me asking if there’s a way to reduce his chances of developing Parkinsons. The question sent me on a research trip of epic proportions, and sadly, I didn't end up finding anything out there that might help. However, I was hopeful, because it was not inevitable that they would develop it, and the current pace of medical technology (and human technology in general) is such that there is very much hope that even if it did strike, we might in our lifetime discover a way to overcome it.
It turns out, we may not have much longer to wait.
Part detective story, part morality tale, the search for the Holy Grail of brain medicine is full of complexities - both technical and political - but carries with it the power to end the scourge of neurodegenerative diseases.
Disclaimer: I Am Not A Doctor of any kind, and this is NOT medical advice. If that is what you seek, please speak to a qualified medical professional.
Synthetic Nightmares
It was the Summertime of 1982 in the Northern Hemisphere, and a bad batch of dope was making its way through the various drug supply networks of California in the USA. This was no "ordinary" case of tainted Heroin, not that anything to do with Heroin should ever be considered "ordinary".
In those early July days, the emergency wards all across the state began receiving patients that had developed paralysis seemingly out of nowhere. They initially put it down to a kind of "Catatonic Schizophrenia". These individuals - mostly young and otherwise healthy - had fallen into a stiff daze, a kind of stupor, and were unable to respond to even the most potent of stimuli.
One such patient - George Carillo, a Hispanic man of 42 - had the soles of his feet scraped with the claw-end of a hammer, blunt force applied to the tips of his fingers, and intense ammonia smelling-salts held to his nostrils in an effort to snap him out of it, to no effect. He was sent to the psych ward as a "mental case", and the doctors moved on with other patients.
Another by the name of Connie Sainz was taken to Stanford Hospital - thought to have some of the very best doctors in the world - but it was quickly decided she must be experiencing some kind of "hysterical emotionally-driven sympathetic paralysis", since they were told her symptoms started after her boyfriend - who was also her dealer - had become paralysed himself. She, too, was dumped on the psych ward, doctors having decided there was nothing "really" wrong with her.
While there, she was injected with "truth serum" (Pentobarbital) by the psychiatrists to force her to talk about her "deeply rooted psychological problems", to no avail. After two weeks of this nonsense, the psychiatrists simply gave up and sent her home, still in her frozen state, telling her mother she'd get better on her own.
She and George were both utterly locked-in to their bodies while fully aware, with no way to communicate with anyone, no way to move, no escape, and in constant agony. They experienced everything that was said and done to them during their paralysis, and the experience became burned in their memories.
Two brothers, David and Bill Silvey, were found paralysed in their apartment by their Mother who had come looking for them. They had been stuck there for days, unable to answer the phone, unable to drink or eat, but fully aware and terrified. Taken by ambulance to the nearest hospital, there too the doctors just shrugged and handed them off to the Psychiatrists, saying the problem was "all in their minds".
I have enormous respect for medical professionals of all kinds, especially those on the emergency wards; every single day they are faced with decisions of life and death, seeing people from all walks of life at their very worst moments, all while working inhumane hours. They do the very best they possibly can with any and all situations, and sometimes that means making difficult choices on very limited information. Despite ER doctors that have seen just about everything, no one had ever seen anything like this before in the early 1980s. There was no textbook saying what to do when patients with sudden onset paralysis of this kind turned up out of nowhere.
Regardless, it's hard to look at a story like this and not feel angry about the way these individuals were treated. What's more remarkable is despite going to several different hospitals, many were treated essentially the same way: the doctors would look at them, sometimes attempt to snap them out of their paralysis, but would often decide that since no immediate physiological cause could be identified, there must not be any.
Luckily, one patient was not given up on: George Carillo.
While George was in the psych ward, he was visited by Dr Phil Ballard of the Behavioural Neurology Department at Santa Clara Valley Medical Center. He and his boss, Dr Bill Langston, did some tests, and realised George was in the grip of something Neurological, not Psychiatric. Whatever was going on, it was coming from damage to the very brain itself. They decided to try putting a pen in George's hand along with a paper notepad. Very, very slowly, the hand moved, and writing began to form on the page over several minutes. This is what George wrote:
"I'm not sure what is happening to me. I only know I can't function normally. I can't move right. I know what I want to do. It just won't come out right."
When he was asked what medications he was on, George wrote only one word:
"Heroin."
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Kids on Chemicals
These patients came from diverse backgrounds and personal situations, but they all had 2 things in common. First, they had spontaneously developed paralysis from head-to-toe. Second, they had all used Heroin shortly before their symptoms began. Several of them were regular Heroin users and had never experienced anything like this before from previous use. This was something new.
It occurred to Langston and his colleagues that George’s condition seemed oddly similar to a case report they had seen some years previously. The journal was dug up from the archives.
In 1976, a kid named Barry Kidston, in Maryland, USA was a 23-year-old chemistry graduate student with a keen interest in finding ways to synthesise novel narcotics which were not addressed by any law. His goal was to produce something like Pethidine, a Schedule II opiate-like drug. In the USA, Schedule II is a classification given to drugs which are considered to be only barely therapeutic, or have an extremely high addiction potential. Heroin, LSD, Ecstasy, etc are all under Schedule I, meaning "verboten."
So one day, our friend Barry the undergraduate chemist comes across a paper published in 1947. The authors described a method for synthesising a compound called Desmethylprodeine - or MPPP - and had tested it on Rats. The Rats seemed to tolerate it very well, and the effects reported seemed similar to morphine. No laws referencing MPPP seemed to exist, and so Barry decided that was good enough for him. He'd give it a go and see what it was like.
He started producing batches of the stuff and injecting it into himself. The first few batches apparently worked quite well, and produced the effect he was hoping for. However, he became careless. He rushed the production of a new batch, and injected it into his arm. Suddenly, he realised all to clearly that this was a catastrophic mistake; there was a severe burning sensation on his skin, spreading out from the injection site, and within moments Barry found himself physically slowing down. Then, like the "Frozen Addicts" patients that would come after him, he lost control of his own body entirely, and became trapped inside. Treatment with first-line Parkinsons drugs like L-Dopa helped at first, but only so much, and lost effectiveness over time. His case puzzled his doctors. This sort of thing just doesn't happen to young people. Parkinsons takes decades to develop, it doesn't just spring up spontaneously.
So they continued treating him as best they could, though his mental state was deteriorating just as much as his physical state; one day 18 months later, he was found dead under a tree from a cocaine overdose, possibly the result of extreme depression, a common comorbidity with Parkinsons.
Combing through his lab, they discovered the manufactured batches of MPPP, some of which contained a distinct impurity that occurs when the temperature of the reaction is not properly controlled and escalates too high. This impurity is called MPTP. When injected into Rats, the investigators found no sign of Parkinsonism, and so they couldn't be certain whether this impurity had any connection with what happened to Barry. An autopsy on Barry's brain found all the same hallmarks of Parkinsons, such as Lewy Bodies and deep damage to the Substantia Nigra, one of the Brain's main sources of Dopamine manufacture. What's more, it seemed the damage was remarkably localised to just those neurons. Their results remained buried in a journal for years.
Synthetic drugs have been circulating ever since chemists have existed. The "war on drugs" has simply forced more people to try their hand at chemistry, searching for ways to get the same effect while making it easier to get past sniffer dogs and drug tests. It's essentially grass-roots drug research, but with no safeguards, no checks and balances, no oversight, done by people with no qualifications or prior study, made using a cooking pot in a trailer or a basement, and then tried on various human guinea pigs and addicts; or, sometimes, even the producers themselves. Sometimes it works out fine. A lot of the time, it ends up a disaster; occasionally, it’s even fatal.
Fascinatingly, the wikipedia article on Schedule II classification currently includes the following line:
These drugs vary in potency: for example fentanyl [a Schedule II drug] is about 80 times as potent as morphine (heroin [a Schedule I drug] is roughly two times as potent). More significantly, they vary in nature. Pharmacology and CSA scheduling have a weak relationship.
(Emphasis added.)
That means Fentanyl is 40 times more powerful than Heroin.
The drug classification system in the USA - and much of the western world - makes no sense.
Impure Dreams
MPTP on its own isn't particularly dangerous. The problem begins when it crosses the blood-brain barrier. Once in the brain, reactions begin taking place which convert MPTP into something called MPP+, the result of the Monoamine Oxidase enzyme attempting to metabolise it. Like a Trojan horse having made it through the gates, its violence is swift and total, and with a stunning rapidity it wipes out the Substantia Nigra, destroying the brains ability to produce the Dopamine necessary for motor control. A process that normally takes decades in cases of Parkinsons disease is completed in mere hours.
The Substantia Nigra, in a fully-grown adult, is roughly the size of a marble. Sitting within the Basal Ganglia, it interconnects with many of the systems that deal with motor movement and planning. Its destruction results in many of the prototypical Parkinsons symptoms of gait, stiffness, and shaking.
While much of our bodies can re-grow and heal themselves, neurons do not. The brain does not grow back. No one is quite sure why that is. Unfortunately, neurogenesis ends during embryonic development, and that's all you get. Neurons can sprout compensating fibres when necessary - making new connections, patching up ones that are severed for whatever reason - but they don't divide like skin or blood cells, and even if the adult brain has a store of Neuroblasts (stem cells for neurons), it doesn't use them to patch up the damage. In all likelihood, every neuron powering your brain on the last day of your life will have been there since your birth. Any neurons you lose are gone forever.
So, right now, the only real treatment for Parkinsons involves supplementing the lost Dopamine with L-Dopa, a precursor chemical that is transformed into Dopamine after crossing the blood-brain barrier. This is not nearly as straight-forward as it sounds, and is riddled with challenges, because Dopamine isn't just used in the control of our movements, nor is it only produced by the Substantia Nigra.
For example, I recently learned the Retina uses and produces its own Dopamine. If all Retinal Dopamine was lost, visual clarity would be significantly degraded; some foreground objects would seem to merge with background ones, and we'd be unable to properly adapt our vision to varying light conditions.
Although Parkinsons causes varying amounts of damage to 3 of the 4 major Dopaminergic pathways - in addition to nearly obliterating the Substantia Nigra - we can't target only the damaged and destroyed neurons with the supplimented Dopamine. When we add more of it to the bloodstream, we essentially saturate the whole brain, and the rest of the body.
Everything else that uses Dopamine for some purpose will now have an excess of it, and the resulting side-effects can range from the uncomfortable, to the bizarre. The Vagus nerve can be triggered when the concentration in the blood gets "too high", leading to an upset stomach. Schizophrenic hallucinations can occur, and so can mood swings resembling hypomania or bipolar disorder. It can even trigger psychosis in some cases, or sudden bouts of extreme daytime sleepiness in others.
Connie Sainz was one such example of the extreme side-effects that can occur with L-Dopa treatment: she would sometimes get up late at night and stalk around her house with a knife, lunging at invisible demons to strike them down. George Carillo was often seen trying to walk through doorways that simply were not there, becoming frustrated on discovering only a solid wall.
Then there's the fact that the treatment loses effectiveness over time.
So, clearly, if we can’t efficiently replace lost Dopamine, and we can't stop the brain’s destruction, there’s only one alternative:
To grow a new one.
This was Part 1 of The Brain Factory, a history of Neurogenesis. Part 2 will be out on Tuesday, 27th August. Thank you so much for reading! This series has taken me an age to write, and every single time someone reads a post of mine it’s a huge boost to my motivation. If you liked this, please share with friends too!
