How tainted drugs “froze” young people—but kickstarted Parkinson’s research
Published 26 May 2016
In 1982, a tainted drug caused a handful of young Californians to become mysteriously frozen, unable to move. Their doctor’s ensuing investigation helped catalyze the start of modern Parkinson’s disease research, which is on the verge of its first clinical stem cell trials.
“There was this big argument that broke out on the ward,” remembers William Langston, chief scientific officer and founder of the Parkinson’s Institute, a clinic and research center in Sunnyvale, California.
The argument he’s recalling took place in 1982 at the Santa Clara Valley Medical Center in San Jose, California. It was over a newly admitted patient named George Carillo who, curiously, couldn’t move or speak—he appeared completely frozen. “The psychiatrists thought it was neurologic and the neurologists thought it was psychiatric,” says Langston. The center soon asked Langston to weigh in on what it thought might be catatonic schizophrenia.
Searching for clues
“I walked in and did one simple test and knew it was not catatonia,” Langston told Ars. Patients with catatonia do appear the way George did, totally stiff and rigid. When you move their limbs for them, the muscles tighten and put up resistance. When Langston moved George’s hand, however, it did not put up a smooth resistance. Instead, his hand displayed what is known as cogwheel rigidity, moving in small jerking motions. “It went, click, click, click when I tried to move his wrist back and forth,” says Langston, “a classic sign of Parkinson’s disease.”
Today, Parkinson’s disease affects more than one million people in the United States. It’s typically diagnosed after age 60 with the symptoms progressively worsening over the course of years. But George was only 42 then and had gone from healthy to frozen in just three days. It didn’t make sense.
The mystery deepened when doctors became aware of George’s girlfriend, Juanita. She was also frozen and only 30 years old. Afraid that she might be arrested for drug use, Juanita’s family had been taking care of her on their own for nearly two weeks.
It was puzzling. “Scientists and doctors, we go into this because we want to help people, but we also have a tremendous amount of intellectual curiosity. When you get a mystery like that, you just can’t let go of it,” says Langston. “I remember thinking if the head of the hospital knew how much time I was spending on the case, I would’ve been in trouble.”
The first clue as to what was going on came from George himself. Noticing George’s fingers moving ever so slightly, a medical student wrapped George’s hand around a pen, held a notepad to it, and started asking questions. It took George nearly half an hour, but eventually he was able to write: “I’m not sure what is happening to me. I only know I can’t function normally. I can’t move right.”
But the key moment came when George was asked if he was on any medications. He wrote one word: “heroin.”
A second clue came from a conversation between two neurologists. Phil Ballard, one of the physicians working with Langston, was catching up with a friend he’d made during his neurology residency. “And as neurologists will do, they started talking about unusual cases,” says Langston. To Ballard’s shock, his friend started to describe two young brothers, Bill and David. Just like George and Juanita, these siblings were completely frozen and seemingly in the advanced stages of Parkinson’s disease. The only thing the four had in common was heroin.
In time, two more frozen patients, Connie and Toby, found their way into Langston’s clinic. Both were heroin users (Toby a dealer), and both were very young—Connie was only 21 years old. Langston suddenly found himself with six frozen patients and a growing suspicion that some bad heroin was circulating in northern California.
New drugs, old disease
In 1982, the drug world was in the middle of a cat-and-mouse game with the law. Chemists were making synthetic drugs that weren’t officially illegal but could get you high just as well—or even better—as heroin. When the law eventually caught up and banned a drug, the chemists would tweak its molecular structure just slightly, making it a new, not-yet-illegal drug with the same old high.
The frozen six were victims of this arms race. As it turns out, they had not taken heroin at all, they had taken a synthetic opioid.
But the opioid itself couldn’t explain the Parkinson’s-like state. Langston set out on what became an incredible investigation into the bizarre condition. He was able to track down samples of the drugs some of the patients had used and send them to a lab for analysis. The lab used a mass spectrometer in an attempt to identify the drug.
At the time, there was no Internet to speak of, and the only comprehensive database of mass spectra was located in Washington, DC. So, after the drug samples had been analyzed, someone had to take their spectra to Washington to manually compare them against those of 40,000 identified substances. “It was quite a lot of work,” says Langston.
Unfortunately, there were no matches. However, a toxicologist working with the police was able to determine that the drug was molecularly similar to Demerol, an opioid painkiller. But Demerol is widely used and doesn’t trigger these side effects; this still didn’t explain the freezing. Fortunately, nobody was immune to the intrigue of the case—the toxicologist continued to ponder its details until she remembered reading about an equally peculiar case from the 1970s.
As Langston began to look into that, he found more and more similarities. A college student named Barry Kidston, after reading up on synthetic opioids, started making his own with a chemistry set his parents had given him. He managed to do this successfully for a while, but he got sloppy with one batch. Within days of injecting it, he appeared severely Parkinsonian, just like Langston’s patients.
The drug Barry had been making looked an awful lot like the drug Langston was trying to identify, but it wasn’t clear what chemical was at fault. Both drug samples had contained smaller amounts of other substances in addition to the drug. The researchers investigating Barry’s case had injected some of his home-made drug into rodents but didn’t see any permanent effects. They had also tested some of the additional substances found in the drug, but again to no avail.
There was, however, one chemical in the mixture, likely a side product of the drug synthesis that they had not tested on its own. According to the mass spectrum Langston had, his drug contained the same substance.
The culprit
The drug Barry and the frozen six had been injecting was called MPPP, and it was five times more potent than the Demerol it was mimicking. When MPPP is being synthesized, the chemistry has to be just right. If not, you run the risk of creating a side product called MPTP.
MPTP on its own is not technically a problem, but chemically, it looks a lot like the neurotransmitter dopamine. Neurons release dopamine as a signal to nearby peers, telling them to fire (or not fire; responses depend on the type of neuron and where it is in the brain). To make sure that signal doesn’t last too long, enzymes in the brain (examples include MAO or COMT) quickly break down the dopamine, chopping it into inactive pieces. The brain likes to recycle as much as it can, so those pieces get taken back into the neuron where they are reassembled into dopamine for future use.
Because MPTP looks like dopamine, some of those enzymes break it down, too, creating a chemical called MPP+. Neurons import MPP+ along with the broken up bits of dopamine. The problem is MPP+ is a toxin that immediately begins killing the neuron. The cells most seriously affected by MPP+ are the dopamine-releasing neurons in a brain area called the substantia nigra, an area that’s necessary for controlling movement. This brain area might be the primary target of MPP+ because it has high levels of the enzyme MAO-B, which is responsible for breaking down MPTP. Areas that rely on other dopamine-targeting enzymes wouldn’t turn MPTP to MPP+, thus dodging the lethal results.
The details of how MPTP works would be discovered a bit later, but Langston concluded that the Parkinson’s-like symptoms of the frozen six essentially were Parkinson’s disease. According to Langston, “If it looks like a duck, walks like a duck, it’s a duck.” He treated the patients with what was and still is the most effective drug therapy, levodopa.
Levadopa allows surviving neurons in the substantia nigra to produce more dopamine, compensating for the loss of brain cells. Essentially, it allows the remaining neurons to pick up the slack left behind by the dead neurons. Langston gave the patients levodopa and the effects were remarkable. “George couldn’t move, and 30 minutes later he was sitting on the bed, legs crossed, smoking a cigarette,” recalls Langston. “I don’t even know where he got that cigarette.”
Eventually, three of the six patients, George, Juanita, and Connie, underwent an experimental surgery in an attempt to more permanently correct the damaging effects of MPTP. The trial, happening in Sweden, involved isolating subtantia nigra cells from aborted fetuses and transplanting them into the area damaged by MPTP.
Working with the research group in Sweden, Langston got George and his girlfriend Juanita recruited into their trial, but he had to beg them to accept Connie, the drug dealer’s girlfriend. Connie’s response to levodopa was limited, suggesting that her illness may have been too advanced to benefit from the procedure. But her story had particularly touched Langston, so even though she wasn’t an ideal candidate for the trial, he kept pushing.
Connie and Langston ultimately flew to Sweden so that she could be more fully examined. There, she received a dose of the drug. “I was praying,” says Langston. Connie walked about 10 feet before having to sit down, but it was enough. She, along with George and Juanita, had the experimental implant; it helped all three regain their motor function, though it helped George and Juanita far more than it did Connie.
A new model
The nightmare that the frozen six endured had a substantial silver lining. “It spurred an epidemiological renaissance,” Langston told Ars. Until then, there were no animal models for Parkinson’s disease, meaning research into its causes, mechanisms, and potential treatments was severely limited. Without an animal model, researchers and physicians largely had to rely on what they observed in humans, which didn’t tell us much since Parkinson’s diagnoses typically aren’t made until well into the disease. By that time, significant cell loss has already occurred.
MPTP changed all of that. Stan Burns, a neurologist who had been following the frozen six case, injected MPTP into primates after it was clear the drug wasn’t affecting rodents. Within hours, the primate began to appear Parkinsonian; follow-up tests showed that the drug was specifically targeting substantia nigra cells.
With that, an animal model was born. “It completely opened up primate research for the study of Parkinson’s disease, which is what really made a big difference,” says Craig Evinger, professor of neurobiology at Stony Brook University in New York and co-director of the Thomas Hartman Center for Parkinson’s Research. “With the MPTP primate model, what’s striking is how identical it is to a person. What we’re studying today really came from looking at primates. It was a huge advancement in the understanding of the pathophysiology of Parkinson’s disease.”
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