Decades later, trials of stem cell treatments are about to
begin.
by Mallory Locklear - May 18, 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.”
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Some of George's
handwriting, the first clues as to what had happened to him and the other patients.
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.
MASS SPECTROSCOPY
A mass spectrometer adds charges to molecules and then separates
them according to their mass using a magnetic field, creating a spectrum from a
complicated chemical mixture. Each molecule ends up at a specific location on
the mass spectrum, and the spectra of unknown substances can sometimes be
identified by comparing them to those of known substances.
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 intended drug (left) and the toxic product of a side-reaction (right).
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.”
Years of progress
Nearly 35 years after
George first showed up in Langston’s clinic, we now know a lot about
Parkinson’s disease, and researchers are tackling it from all angles:
prevention, treatment, and cure.
As far as treatment
goes, levodopa remains the most popular and effective treatment. Levodopa can now be
paired with drugs that make it last longer by inhibiting the enzymes
in the brain that break down dopamine. But levodopa comes with rather severe side effects.
It can lead to dyskinesias, or involuntary muscle movements, as well as vivid
hallucinations. As the disease progresses, patients typically need higher
doses, but with higher doses come more side effects. Usually patients end up
having to go off of levodopa for a while until their tolerance lessens and they
can start the drug again at a lower dose.
There are, however, a slew
of drugs at various stages of clinical trials aimed at treating either the side
effects of levodopa or the symptoms of Parkinson’s disease—everything from
dyskinesias to problems with swallowing to cognitive decline. Recently, the FDA
approved the first drug to
treat the delusions and hallucinations that come with Parkinson’s-induced
psychosis.
Drug treatments
ultimately face a hard limit, though. Helping neurons produce dopamine or
treating symptoms of the disease are only relevant options when there are still
living cells to help. Once all of the substantia nigra cells die, drugs aren’t
going to help. Even deep brain
stimulation, a treatment that places electrodes in the brain to
reverse some of the symptoms, doesn’t stop or even slow the progression of the
disease. So, it’s imperative that cures and preventative treatments continue to
be pursued, too.
/ Operation with
stereotactic placement of electrodes in the brain of a patient with Parkinson's
by Professor Philippe Cornu (at the hospital Pitie-Salpetriere).
Fanthomme Hubert for
Getty Images
Testing stem cells
At the forefront of a
search for a cure is Russell Kern,
executive vice president and chief scientific officer of International Stem Cell Corporation
(ISCO). Beginning in May, Kern and ISCO are scheduled to begin the first stem
cell clinical trial for the treatment of Parkinson’s disease. Doctors at the Royal Melbourne Hospital in Melbourne,
Australia, will transplant stem cells into the brains of 12 participants, all
of whom are suffering from moderate to severe Parkinson’s disease. Kern expects
the transplants to be completed within six months, and each participant will be
observed for six years.
The surgery is similar
to the one received by George, Juanita, and Connie, but instead of cells
extracted from a fetus, ISCO’s trial will be using a type of neural precursor
cell called human
parthenogenetic stem cells (hPSC). The hPSCs being used by ISCO are
derived from unfertilized eggs rather than human embryos, so they circumvent
the controversy surrounding embryonic stem cells. They also circumvent the
problem of embryonic stem cells being patented.
Another advantage is
that patients shouldn’t have to take immuno-suppressing drugs to keep the body
from rejecting the stem cell transplant. “Our stem cells can immuno match
millions of people,” Kern told Ars. “That’s very important for transplantation
reasons; otherwise, you have to use immunosuppressants.”
This is possible
because of the nature of hPSCs.
These cells are derived from an unfertilized egg, so they have two sets of
maternal chromosomes, not a combination of maternal and paternal chromosomes
that cells from a fertilized egg would carry. That means they have two
identical copies of the genes of the human leukocyte antigen (HLA) system.
When the HLA genes of
donated tissue are significantly different from that of the recipient, the
likelihood of rejection is higher and immunosuppressing drugs are required.
Because the hPSCs have two of the same (maternal) set of HLA, it’s easier to
obtain hPSCs that match the HLA systems of a larger number of recipients.
Meaning just a few versions of the hPSCs could very well immuno-match a
significant portion of potential patients.
The trial is a phase
I/IIa trial, meaning the treatment will be tested for side effects, appropriate
dosage, and safety. ISCO is currently in discussions with the FDA to begin a
US-based phase IIb trial, which will depend on the results of the Australia
one. “To begin the phase IIb trial, we’ll have to show that phase I was
successful and safe,” says Kern. He also hopes to extend this stem cell
treatment to stroke and spinal cord injury.
Some are apprehensive
about the trial. Langston, for one, isn’t sure the issues surrounding previous
transplants, which were not reliably successful, have been fully worked out. Others
have expressed concern that ISCO hasn’t made the results of preclinical tests
of the treatment available. But Kern is confident. He says the most likely side
effects of the transplants would be dyskinesias. “However, when we were doing
preclinical studies, we used primates, which wasn’t done with earlier clinical
trials,” says Kern. “We observed the side effects and didn’t find any
dyskinesias in those studies.”
A different group is
working toward a US-based stem cell trial. Jeanne Loring is professor
of developmental neurobiology and the director of the Center for Regenerative Medicine at the Scripps Research Institute, and she is a
researcher with the non-profit group Summit for Stem
Cell. The organization raises money to fund the research Loring and
others are doing as they work toward a clinical trial, which they hope to begin
by 2018.
Like ISCO, Loring’s
group wants to transplant stem cells into the brains of Parkinson’s patients,
but will be using a different type of cell. Rather than using stem cells
derived from human eggs, Loring intends to use patient-specific
stem cells, generating them from cells obtained from the patients’
own skin. This is a different approach but one that will hopefully circumvent
the same issues Kern is trying to avoid: stem cell controversy and the need for
immunosuppressants. “If you ask anybody in this field, I don’t think there
would be a lot of people who would say it would be better to immunosuppress
people than to use autologous cells,” says Loring, referring to the cells that
would be harvested from one patient and later transplanted into that same
patient. “I think the reason other people aren’t doing it is because of the
expense and the longer time frame it’s going to take for us to prove our cell
lines are effective.”
Loring’s approach also
differs from Kern’s in that her group is coming from an academic setting rather
than a biotech one. “The project is completely funded by a private
philanthropy. It’s really driven by the caretakers and the patients
themselves,” says Loring, “They’re just amazing people.” Loring emphasizes how
beneficial the patients’ role is with her research. “There’s sort of a placebo
effect in becoming involved in the development of the therapy of your own
disease.”
She also highlights
some of the intrinsic differences between academia- and biotech-driven
research. “Pharma companies are so secretive, but we’re completely
transparent,” she says. “The patients know our results on practically a daily
basis.”
Loring hopes that stem
cell treatment takes the place of deep brain stimulation in the future. “If
you’re going to drill a hole in someone’s head, do you want to put in
electrodes that don’t actually prevent the death of more cells?” she says. “Or,
would you rather fill up the bucket with living cells?”
Prevention
Though both Kern and
Loring are confident in the promise of this treatment, Kern also notes the need
for prevention. “Of course it would be nice if we could diagnose the disease at
the early stages,” says Kern. “If we could prevent Parkinson’s disease, that
would be even better.”
Samantha Orenstein and
Dr. Esperanza Arias, department of developmental and molecular biology, Albert
Einstein College of Medicine, Bronx, New York.
In the last few years,
researchers have discovered a few aspects of the disease that may eventually
lend themselves to preventative interventions. It turns out Parkinson’s disease
doesn’t begin and end in the subtantia nigra; it has been proposed that the
disease actually starts lower in the brainstem and spreads. Problems work their
way up toward the substantia nigra and elsewhere, with tangles of proteins
called Lewy bodies forming in the damaged areas. Scientists, including
Langston, have begun extensive research into this disease path and the Lewy
bodies. “I think we’re in the best place we’ve been in,” says Langston. “I’m
the most excited about the current work going on than I ever have been.”
As far as cures go,
Stony Brook’s Evinger doesn’t expect one any time soon, but he does think the
disease will be treatable in the near future. “I can see that we aren’t
dramatically far away from turning Parkinson’s disease into something that’s
more like diabetes, something that you can treat and is manageable,” says Avenger.
Even if stem cell
transplants become a viable treatment in the near future, there
is evidence
that whatever causes Parkinson’s disease can affect the new cells. Follow-up
studies of patients who received fetal cell grafts showed the formation of Lewy
bodies some years later, though many of the grafted cells remained unaffected,
and the patients’ symptoms were limited or absent.
It could be that
because Parkinson’s symptoms take so long to appear naturally, the disease’s
effect on new cells would take similar lengths of time to produce symptoms, which
would often be outside of a patient’s lifetime. In other words, they’d be dead
before problems returned.
For most of the frozen
six that helped scientists develop this entire field of research, all the
progress came too late. Langston’s epic tale is told in detail in his 1995 book
written with Jon Palfreman, The Case of the
Frozen Addicts. As reported in the book’s epilogue, Bill
passed away in 1994 due to an illness. Since the book was published, according
to Langston, Bill’s brother David returned to a life of crime as did George.
David hasn’t been heard from in many years and is presumed dead, while George
was murdered. Connie regained enough motor control to return home and see her
child grow up, but she was largely housebound until her death. Juanita’s
surgery was quite successful, and she moved back to her reservation and
thrived. She passed away a couple of years ago.
Toby is still alive
and, according to Langston, has experienced a new development in his condition
just in the last few weeks. Langston isn’t ready to talk about it just yet, but
after 35 years, the fact that one of the frozen six is still surprising him
speaks both to the sheer amount we have learned and achieved and to the
remarkable aspects of the disease and the brain that we have yet to explain.
Mallory Locklear is
a freelance science writer with a PhD in neuroscience. She lives and works in
New York.
http://arstechnica.com/science/2016/05/medical-mystery-how-tainted-drugs-froze-young-people-but-kickstarted-parkinsons-research/
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