Illustration: Leigh Nelson

Scientists try to untangle the mystery behind a rare neurodegenerative disease. Natalie

Jacewicz follows their twisting path. Illustrated by Leigh Nelson.

 

Tom Looney was speaking to top government security officials in 2007 when he began to feel

dizzy. Looney, the industry director of homeland security and public safety for Microsoft,

carefully descended the steps from the stage in Redmond, Washington. He stumbled back to

the green room and passed out.

Assuming Looney had suffered a heart attack, his coworkers called an ambulance. But

doctors at the hospital were puzzled. “You didn’t have a heart attack,” Looney recalls them

saying, “but something’s not right.”

That was the last time Looney went to work, and the first of many days spent in hospital

waiting rooms. He was 48.

Looney had developed a rare brain disease—an ailment that increasingly encroached on his

day-to-day routine. As he wrestled with the disease in ensuing years, the ailment began to

transfix the scientific community as well. Partly by accident, researchers in San Francisco

      

think they discovered the cause underlying Looney’s condition: tangled meshes of protein.

What’s more, they now believe similar tangles underlie Alzheimer disease, Parkinson disease,

and other debilitating illnesses that wage war on the mind.

Scratching sheep

The recent research into Looney’s condition and others like it began in the 1980s with

Stanley Prusiner, a neurologist at UC San Francisco. He was studying neurodegenerative

diseases—ailments that attack the nervous system.

He focused on scrapie, a disease that causes sheep to stagger around pastures and scrape

themselves against fences, as though scratching an insatiable itch. The same illness causes

mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. The disease is

contagious; humans can become infected by eating contaminated beef. Prusiner wanted to

understand how this contagion worked.

After subjecting scrapie-infected brain tissue to a battery of chemical tests,

Prusiner discovered a baffling commonplace cause of contagion: proteins.

Consisting of long chains of amino acids and found throughout the body,

proteins fold into three-dimensional shapes determined by how the

charged amino acids attract and repel one another. The complex folds hide

parts of the protein and leave other sites exposed, dictating how each

specifically shaped protein interacts with other molecules.

The proteins Prusiner identified seemed to co-opt this system. Through unknown means,

these proteins refolded into unnatural contortions and then proselytized others, converting

one protein after another into jumbles that mobbed the brain. Cells, unable to digest these

disordered masses, lost function and died.

Prusiner proposed the word “prion” to describe the infectious proteins. He chose “PrP,” for

“prion protein,” to name the proteins vulnerable to misfolding. Prions, he claimed, caused

scrapie. But he didn’t stop there. Protein clusters in patients’ brains also typified other

neurodegenerative diseases, like Parkinson and Alzheimer. Prusiner suggested prions might

also set off those diseases.

Much of the scientific community, however, balked at the suggestion that a rebel protein

could replicate itself without the help of DNA or RNA, the genetic molecules of life. “Prions

have extraordinary biological characteristics, not the least of which is their possible non-

existence,” says neuropathologist Laura Manuelidis of Yale University, one of Prusiner’s

steadiest critics.

Prusiner stopped talking with reporters after several critical stories, but he continued to

argue for prions, knowing many scientific breakthroughs initially seem heretical. “The

incredulity of my colleagues only strengthened my conviction,” he wrote in his book Madness

and Memory.

Other experiments gradually strengthened Prusiner’s claim, and most scientists grew

convinced of the connection between prions and a small collection of diseases like

Creutzfeldt-Jakob. But others thought prions might be a symptom of an infectious virus, not

a cause themselves. Despite continuing controversy, Prusiner won the 1997 Nobel Prize in

Physiology or Medicine. The committee usually honors teams working in broadly accepted

disciplines. That year, Prusiner received the prize alone.

Labeling the disease

Ten years after Prusiner’s prize, Looney’s doctor visits began. A married father of two sons,

Looney credits college basketball for enduing him with determination—which he later

applied to his career at Apple and Microsoft. Now, he turned that determination toward

discovering his disease.

When doctors asked him about his symptoms, Looney

catalogued a sundry list of seemingly unrelated bodily

rebellions. He could no longer crisply cap his words with

consonants, and his slurred speech morphed into difficulty

swallowing. His bladder felt constantly full, and when he

stood up to his full height of 6 feet 5 inches, Looney sometimes fainted.

Finally, he visited a doctor who recognized the bizarre symptoms. Looney probably had

multiple system atrophy, or MSA—a fatal disease causing nerve cells to lose function and die.

When delivering the diagnosis, the doctor began to cry. So did Looney’s wife. Looney did not.

“I told myself, ‘You’re an athlete. You endured six years working for Steve Jobs,’” says

Looney. “To me, it was a relief because now we could put a label on this thing.”

Natalie Jacewicz talks with Tom Looney, a longterm survivor with the rare neurodegenerative diseaseMSA, about his daily strategies to maintain his health. Click on image to play.

While Parkinson disease strikes about 1.6 percent of the elderly population, MSA afflicts just

3 in every 100,000 people over age 50. But MSA kills patients twice as quickly. On average,

they live no longer than 10 years past diagnosis. There is a variable mix of symptoms,

SciCom Slugs Surviving with Multiple System Atrophy Share

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including slurred speech, flailing limbs, and choking. No definitive test proves someone has

MSA, so these symptoms offer the best clues to flummoxed doctors.

“This is a really challenging disorder,” says neurologist Kathleen Poston of Stanford

University. “I’d say 90 percent of my patients are misdiagnosed the first time they’re seen by

physicians. It can take years of seeing doctors before patients are diagnosed with MSA.”

Even with that verdict, doctors can do little to help.

No known treatment cures MSA or slows its

progression. Several clinical trials are under way to

ease the disease’s symptoms. “Unfortunately,” Poston

says, “most [trials] in the past have failed.”

But when Looney did his own research, he learned

one person with the disease had lived 17 years past

diagnosis. He wanted to see his two sons, ages 12 and

15 in 2007, graduate from high school. So he decided

to learn everything he could to live longer with MSA.

“I dove into this,” he recalls. Soon, he discovered:

“Wow, this is an amazing world.”

Spinning mice

As Looney began his research, Prusiner’s group began learning more about MSA as well.

The Prusiner lab at UC San Francisco’s Institute for Neurodegenerative Diseases consists of

long, interconnected galleries with rows of lab benches overlooking the city’s downtown.

Visitors don disposable blue jackets and plastic gloves in a receiving chamber. The team

shares no equipment with other labs to prevent contamination.

A postdoctoral researcher named Amanda Woerman joined the lab in 2013 to study proteins

associated with Alzheimer and Parkinson. In both diseases, different types of protein were

refolding and accumulating to form tangles in the brain. A few years earlier, scientists had

found evidence that these prion-like tangles could spread to uninfected brain tissue

transplants received by Parkinson patients.

Photo: Natalie Jacewicz

Researcher Amanda Woerman outside her lab at UCSF.

The lab’s researchers had set out to prove that Parkinson tissue was contagious, but they

quickly ran into a problem. After injecting mice with liquefied Parkinson brain tissue—what

Woerman calls a “brain milkshake”— the scientists could not identify a single sick mouse.

The experiment had failed.

But they found something even stranger. While the Parkinson mice seemed healthy, two

other groups of mice did not. They staggered with an uncoordinated gait and spent most of

their time whirling in pirouettes. When researchers scanned the brains of the mice, they

discovered images alight with green blobs: masses of protein.

These two groups had received a different brain cocktail. The scientists had chosen tissue

from a brain with MSA, a disease never shown to be infectious. Now, the team had stumbled

on a discovery: Perhaps Parkinson wasn’t contagious, but MSA brain tissue was.

Testing an accident

Prusiner and his researchers knew their accidental discovery could have major ramifications.

In the time since they had shown PrP proteins could morph into prions, scientists had linked

no new prions with neurodegenerative disease. But the MSA mice showed clusters of a

different protein called “alpha-synuclein.” Healthy brains contain this protein, but its

function remains unknown.

Kurt Giles, one of the scientists involved in the first Parkinson study, began leading a team to

replicate the results.

Photo: Natalie Jacewicz

UCSF researcher Kurt Giles in his office.

Soft-spoken with a British accent, Giles maintains a neat office near the lab. An old map of

Oxford University, his alma mater, hangs in the corner. If asked to draw a picture of a

misfolded prion, he says he can’t. Scientists are still trying to figure out what the individual

structures of prions look like. Just as the same sheet of paper can crumple into multiple

shapes, prions from the same type of protein might twist into different forms and cause

different diseases.

In the first experiment, the scientists had used mice with a tiny genetic mutation sometimes

found in Parkinson patients. By using mice predisposed to Parkinson, the researchers had

hoped they’d be more likely to succeed in transmitting the disease from infectious tissue.

Instead, they apparently uncovered a genetic vulnerability to MSA.

In the replication experiment led by Giles, 12 groups of mice with the same single mutation

received MSA brain tissue. But the team also put MSA tissue in mice with two copies of the

mutation, as well as in some mice with no mutation at all.

The mice with no mutations developed no symptoms. But after four months, mice with one

copy of the gene mutation began showing signs of neurodegeneration. Masses of alpha-

synuclein prions cluttered their brains. The mice with two copies of the genetic mutation

showed symptoms in even less time: three months.

The team had confirmed the initial experiment’s results. A genetic error seemed to

predispose alpha-synuclein proteins to misfolding, and other prions could trigger the

process. Giles and his team had discovered a new prion.

The finding excited scientists who suspect that prions cause several diseases. “I’m not

surprised at all,” says Glenn Millhauser, a biochemist researching prions at UC Santa Cruz.

“It speaks to Prusiner’s vision.”

Graphic: Natalie Jacewicz

Click on image to view larger version.

Growing a disease

Still, the experiment wasn’t perfect. “Everyone accepts that these models are far from ideal,”

Giles says of the mice.

For one thing, MSA is a disease that occurs naturally in humans, not mice. Scientists can re-

create the symptoms in mice, but they can't study how mice develop the disease without

human intervention. What’s more, many neurodegenerative diseases take years, even

decades, to unfurl in humans—well beyond a mouse’s life span. Mice might die naturally

before symptoms even appear. Finally, mice brains lack entire regions found in human

brains.

That’s where Amanda Woerman came in. To study the prions effectively, scientists needed to

isolate them from the muck of compounds that swamp brain tissue and test them in human

cells. Woerman worked on transmitting isolated prions to human embryonic kidney cells,

which grow faster than neurons. Prusiner’s lab had perfected a technique for isolating a

different type of protein and injecting it into cell samples. Using a giant automated

microscope, Woerman had run tests on those samples to spot clumping proteins chemically

treated to glow green.

Now Woerman applied the same technique to alpha-synuclein prions in fast-

growing human cells. She transmitted the prions to 18 samples from an

immortalized line of human kidney cells. After four days, all of them were

infected by prions. Glowing blobs lit up the cells where the misfolded proteins

had spread.

Linking prions to MSA bolstered Prusiner’s claims about their role in Parkinson

and Alzheimer as well. Though Parkinson doesn’t exhibit clusters of PrP, it does

involve clusters of alpha-synuclein. If these proteins operate as prions in MSA, they might do

the same in Parkinson.

Woerman’s work also challenged prion critics who argue that infectious viruses, rather than

prions, cause these diseases. Woerman had treated the proteins with chemicals that break

down DNA and RNA before transmitting them to cells, so the protein blobs that formed

could not have arisen from a DNA-bearing virus.

“In science, nothing ever works the first time,” Woerman says. “But the synuclein assay was

just beautiful.”

The persistence of memory

Still, some scientists doubt the claims. Jeffrey Kordower, a neurosurgeon who studies prions

at Rush University in Chicago, estimates that only one-quarter of doctors and neuroscientists

believe prions underlie most neurodegenerative illnesses. Just using the term “prion-like”

can raise eyebrows among colleagues when submitting papers for publication, he notes.

Critics raise several issues with attributing MSA to prions. For example, researchers thus far

have failed to infect normal, nonmutant mice with MSA. Not all humans who contract MSA

have gene mutations, so theoretically, if they truly trigger disease, prions also should infect

nonmutant mice. One recent experiment at the University of Florida suggested that prions

might not cause protein clusters at all. Scientists injected mice with healthy prion-free brain

tissue. The mice developed masses of protein all the same.

But even scientists with reservations about the MSA study admit they find the work

interesting. The conversation has progressed since Prusiner first proposed that prions exist,

says Millhauser of UC Santa Cruz. Just a few researchers still believe neurodegenerative

diseases are caused by viruses, even if they have other reservations, Millhauser comments:

“There are people out there who will push back on anything Prusiner says.”

Giles argues many scientists agree with the Prusiner lab’s fundamental claims that these

proteins exist and self-replicate. But they may have narrower definitions of “prion,” such as

applying it only to proteins contagious in day-to-day circumstances. “It’s a knee-jerk reaction

to the term,” Giles says of prion critics.

Some researchers simply resist ascribing disease to prions more broadly. Giles points out

that people have studied prions in yeast for years, and “no one’s ever complained.” Other

researchers, with little controversy, have claimed prion-like refolding may have an upside:

Photo courtesy of Tom Looney

Tom Looney at his home.

helping the brain retain memories. But Giles says whenever scientists blame prions for

disease, “everyone throws their hands up.”

According to Giles, prions could give researchers and doctors more tools to treat patients,

rather than constraining them. “What this is really leading to,” he says, “is a new way of

looking at these diseases. If new therapeutics come from this, that’s definitely the goal of

basic research.”

Eight years and counting

Tom Looney saw the group’s study when it came out in 2015 in Proceedings of the National

Academy of Sciences. He now serves as the first patient to sit on the Board of Directors for

The MSA Coalition, a national charity funding MSA research.

Looney does not seem like

someone who has lived with

MSA for eight years. One doctor

refused to believe Looney had

MSA until running advanced

tests of his autonomic nervous

system, which the disease

degrades. Looney is

characteristically sunny as he

describes being X-rayed when

he swallowed liquid barium:

"One of the coolest tests! You

can literally see your insides."

Over time, Looney says, he has

learned to “manually” execute body functions that work automatically in healthy people.

Thanks to speech therapy, his slur is no worse than the average lazy English speaker’s.

Rather than cut back on exercise, Looney increased walking and learned to maintain his

balance by sucking in his stomach when he stood up. His diet is healthier, and he no longer

drinks alcohol.

In January 2016, Looney’s wife called 911 after he passed out twice while seated in their

North Carolina home. Looney didn’t want to call for help, but he knew it would make his wife

feel better. He saw his sons finish high school. In May, his eldest son earned his college

degree; his youngest will graduate in two years.

“I think it’s going to be really cool when all of this gets figured out,” he says. “I want to stick

around.” After a pause, he adds, “I’m giving it my best shot.”

© 2016 Natalie Jacewicz / UC Santa Cruz Science Communication Program

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Biographies

Natalie JacewiczB.A. (biology) Harvard College

Internship: National Public Radio

The day I turned 11, my father roused seven friends and

me at 6 a.m. to come see “a natural phenomenon” in the

back yard. We tripped out of our sleeping bags and raced

outdoors, expecting a solar eclipse or incoming meteor.

Instead, we found two dung beetles rolling a clump of

golden retriever scat. We went back to sleep.

Communication drives whether we celebrate a scientific discovery or wipe it off our shoes.

Soon enough, nature’s rich stories drew me in. The evolutionary tale of Anolis lizards

seduced me into a biology degree. My policy interests led me to management consulting in

Washington D.C., where I learned how drug companies prioritize research and how NGOs

select projects.

Science and policy profoundly shape each other. I want to awaken readers to the intricacies

of both.

Natalie Jacewicz’s website

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Leigh NelsonB.A. (English, concentration in Gender and Women’s

Studies)

B.M. (vocal performance) Oberlin College

Certificate (premedical studies) Mills College, Oakland

Certificate (botanical illustration) Cornell University

I graduated from Oberlin and began a master’s of music

with the intent of singing opera professionally. When that

didn't look so promising, I made a giant academic U-turn into a two-year pre-med program.

Mills strived to devour my soul because the skills I brought to the table (writing, creativity,

art) were completely useless in a pre-med environment. During my second year, to save

myself from utter despair while I toiled through two semesters of physics and organic

chemistry, I took an advanced drawing class.

Later, as I reflected on my experience at Mills, I realized that my favorite part was that

drawing class. My second favorite class was biology lab, because I got to draw things. This

did not bode well for a career in medicine, but it did point the way toward medical and

natural science illustration, where my interest in science could productively co-exist with my

predilection for visual presentation. I have continued to perform with professional opera

companies on the side.

Leigh Nelson’s website

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