Mathis was passionately in love with his work, so much so that as he warmed to his topic, he tended to speak very rapidly. His sense of humor was wry, and he had permanent crow’s-feet that deepened when he laughed. It was an honest laugh, the kind you had to earn.
His office at the University of Pittsburgh Medical Center’s sprawling Presbyterian hospital was buried deep on what he called the ninth-and-a-half floor, in a suite where the laboratory was lined with lead and copper to keep radiation in check. His office wall had been knocked down to allow cranes to hoist in a new cyclotron, and his office window looked out across the street to the yellow brick façade of the Western Psychiatric Institute and Clinic, where Bill Klunk, one of his collaborators, worked.
Mathis had begun his career spending much of the early eighties helping to make fluorodeoxyglucose. FDG is a radioactive chemical used in imaging to diagnose, among other things, lung cancer, breast cancer, and melanoma. In those early years, scientists were also starting to try it out as a diagnostic tool for Alzheimer’s patients.
Eventually, at a neurologist’s request, Mathis began to radiolabel a dye called Congo Red that was tested in dead patients. By adding radioactive atoms to its chemical composition, scientists can track a dye as it works through the body. It can then, theoretically, be manipulated further by altering its chemical makeup so it will stick to certain proteins—for example, amyloid beta or tau.
In the early part of his career and for many years after, Mathis continued working with Congo Red. As its name suggests, it’s a bright red, toxic sodium salt first created in 1883 by a German scientist who was trying to create a textile dye. The company didn’t like its gory color, so the scientist sold it to the AGFA company of Berlin, which christened the dye “Congo Red” in honor of the 1884 Berlin West Africa Conference, a key event in the colonization of Africa.
One hundred or so years later, Congo Red found a new purpose as a dye used in radiology for imaging. Scientists discovered that its chemical properties allowed it to stick to amyloids in much the same way it once bound to textiles.
The problem for Mathis, though, was that it refused to cross the blood-brain barrier, making it pretty much worthless for a study of amyloid in the brain. Finally, he gave up on the dye, but the failure grated on him for years.
One day, however, a young psychiatry professor named Bill Klunk walked into Mathis’s office at Pitt, saying, “I’ve got a new compound. It’s much better than Congo Red.”
• • •
Klunk’s journey had begun in 1987. A shy, soft-spoken native of Hanover, Pennsylvania, he was fresh out of Washington University in St. Louis, having been recruited by David Kupfer, who was then the chairman of the University of Pittsburgh’s Department of Psychiatry.
While he was still at Washington University, Klunk had become interested in the biochemistry of the brain and how it changes in people with dementia. Like Mathis, he started with the erratic Congo Red, which researchers thought might keep beta-amyloid protein molecules from sticking together and forming plaques. It didn’t.
But he kept monkeying with the chemistry of the compound, hoping that one of its derivatives would at least help him take better pictures of the brains of Alzheimer’s patients.
“I had small grants here and there, and I kept this interest active at a low level until we got to the point of writing a paper about what we had done,” recalled Klunk.
That was in 1994, and Klunk was thinking about patenting some of the technologies used in his research to date. As he talked to Pitt officials about his idea, they referred him to Mathis. It was that series of Congo Red derivatives that he pitched when they met.
Mathis agreed to work with him, and they started with a few grants from the Alzheimer’s Association. Eventually, a drug company became interested and provided more funding. But they weren’t exactly working at a breakneck pace.
“We had years of just sort of crawling towards our goal, from ’94 to ’99, in this Congo Red series of compounds,” said Klunk, who found that he wasn’t having any greater success with the dye than Mathis had. “There were a lot of lean years here. We made hundreds of compounds that failed.”
Those failures—more than three hundred, in fact—didn’t just bring frustration; they also carried a certain amount of risk to Klunk’s career. In academia, when a scientist is up for tenure and promotion, the university typically asks people in related fields to provide feedback based on the candidate’s track record of publications and grants; hence the maxim “publish or perish.”
For most of the century, science had been unable to view Alzheimer’s inside the brain, matching the internal progression of plaques and tangles with the deterioration of a person’s memory and function. The field was desperate for a closer look at the disease it was fighting, hoping to gain a more precise measurement of how effective different therapies were. Unfortunately, too many of them were afraid that the quest would kill their careers in the process.
But what if the scientist, instead of worrying about establishing an elaborate track record, decided to pursue the holy grail? What if he decided that he was not going to make a superficial stab at it; he was going to devote all his time to a single huge feat, trying and failing over and over again? And what if his efforts, though noble, didn’t yield many papers or grants?
In some academic settings, the university would have pulled the plug. But Klunk was lucky: Kupfer had the faith to stand by him, and a handful of colleagues in the field quietly pleaded with the university, in their independent evaluations, to allow him to keep going, knowing how important his work might be to the rest of them.
• • •
The decision to finally abandon Congo Red altogether came either from frustration or altruism, depending on whom you ask. The drug company that had funded Klunk and Mathis’s research started losing interest. It was time to try another tack.
When Klunk had started in 1987, he ordered the three basic compounds that are known to work with amyloids: Congo Red, Thioflavin T, and Thioflavin S. As he turned to his remaining two options, he asked Mathis a question: What properties do you need for imaging?
Mathis’s number one priority: It had to get into the living brain.
Most dyes like Congo Red carry an electron charge, which is what makes them bind to things like textile fibers, the purpose for which they were originally invented. To get them past the barrier, scientists must experiment with attaching them to molecules that can cross over, such as glucose or amino acids. But these efforts are only intermittently successful. The difference between success and failure sometimes rests on a single atom.
Mathis’s ideal dye couldn’t just leak into the brain in trace amounts; enough had to get through to give a full and accurate image in a brain scan. And it had to be nimble, too, showing up in the brain within two to three minutes of being injected into the patient’s arm, then quickly exiting the body without damaging anything in the process.
As they moved back to the drawing board in 1999, Klunk and Mathis started with Thioflavin T, which was a simpler molecule and easier to make since it only had one electron charge.
Finally, after years of crawling, they broke through with that one change: In fact, they were on their feet and sprinting. Five months after switching to Thioflavin T, they found entry into the brain.
“Whether it was blind luck or the fruits of persistence, no one can say,” Mathis and Klunk wrote in a paper about the discovery. It didn’t matter. Within a year, they had a hundred different derivatives, including one that would come to be known as Pittsburgh Compound B, or PiB.
When they injected the new compound into mice, it worked at a rate ten times better than any of their previous efforts. They already knew, through trial and error, that it would stick to the beta-amyloid proteins—although they still aren’t sure why. They don’t care, either, because when it gets into the Alzheimer’s brain, it illuminates plaques on a scan in glowing red, a brilliantly displayed road map of the disease.
After testing the compound’s ability to highlight amyloid on human cadavers, they were ready for clinical trials in living patients. Klunk and Mathis contacted Bengt Långström, the director of the Uppsala University PET Center in Sweden, who was leading the field of positron emission technology (PET) imaging with microdoses, or less than ten milligrams, of a radiotracer—the equivalent of about one-ten-thousandth the amount of drug found in a low-dose aspirin.
The study was scheduled for Valentine’s Day 2002. Klunk and Mathis would never know the name of the first person dosed with PiB; she was only identified as “AD2.” They knew simply that she was relatively young and that her memory problems had forced her to give up her career as a health care professional. Her cognitive testing scores were just below normal. And she knowingly agreed to be their guinea pig.
Throughout that day, Klunk and Mathis waited on tenterhooks in Pittsburgh for any word from Sweden, which was six hours ahead. And then Långström phoned.
“I think we have something to celebrate,” he said.
Through the Swedish research team, Klunk and Mathis wrote a letter to that first, anonymous volunteer:
It is only through selfless individuals such as you that medical scientists can push ahead the frontiers of research, they wrote. You should take pride in knowing that you played an important role in allowing these changes to begin. Thank you very much.
The patient known only as AD2 died five years later, in late 2007, from Alzheimer’s disease.
• • •
The compound worked just as well in the brains of other Alzheimer’s patients. Klunk watched, breathless, as PiB left the bloodstream, crossed into the brain, found plaques, and then worked its way into the center of the plaque. The entire process took about ten seconds.
The only thing that could hold them back now was if a company became interested in their work and argued over intellectual property rights to the new family of compounds. That hadn’t happened yet, but now that they were finally having some success, Mathis didn’t want to risk it. He had finally conquered the problem that had been dogging him for most of his professional life, and now, just when his research was starting to accelerate, a relatively minor scuffle over intellectual property could throw down spike strips.
He told Klunk he wanted to publish their results and make them part of the public domain, effectively voiding any company’s interest in patenting the compound. End of problem.
But Klunk was more pragmatic. “Yeah, we could do that,” he told Mathis. “But the ultimate goal is to help people, and if we did that, no company would pick it up.”
Mathis hadn’t thought about it, but it was true. Once their research was publicly disclosed, for all intents and purposes, it would have no commercial value. The reality of drug research in the United States is that without corporate funding to develop it, PiB would never find its way to the millions of Alzheimer’s patients waiting for a diagnosis. And nothing that followed—the potential for trying out preventive drugs—would happen, either.
“It shows you: He was thinking about that,” Mathis said of his partner, with pride in his voice.
Since they were university employees, Pitt had the right of first refusal for their work. Under the terms of the agreement, Mathis and Klunk were supposed to be paid one dollar. (They never got it.) Pitt then sold it to a British company called Amersham that was acquired by General Electric in 2004.
Klunk resisted praise for the decision. Of course he was thinking about the patients, he pointed out: He was a psychiatrist. Mathis was a radiochemist, so he was thinking about the science. And that, he said, was the key to their partnership.
Meanwhile, the research field exploded. The discovery of PiB “represented a major breakthrough,” recalled Kupfer, the department chair who had stood by Klunk through a decade of failure. “It offered a new sense of hope—not only to patients and families, but to the whole investigation field.”
Moreover, the breakthrough justified Kupfer’s faith in the two men, proving that risky projects could still carry a huge payoff.
• • •
GE Healthcare licensed PiB with plans to bring it to commercial market. Meanwhile, dozens of other research institutions around the world used it, and in 2012, the FDA approved Amyvid, a PiB cousin with a longer half-life that belongs to the pharmaceutical giant Lilly.
Mathis and Klunk continued to work on other compounds, including one funded by actor Michael J. Fox to take images of Parkinson’s disease. They were also trying to image tau, the protein that makes up tangles, since PiB focuses only on plaques.
In 2008, for their discovery of PiB, Klunk and Mathis were awarded the American Academy of Neurology’s Potamkin Prize, which is nicknamed “the Nobel Prize of neurology” and recognizes achievements in research for Pick’s, Alzheimer’s, and related diseases.
“Bill always says we got really lucky,” said Mathis. “I say, ‘No, Bill, we didn’t get lucky. We were due success.’ ”
Pondering that thought, Klunk finally agreed. To a scientist, serial disappointment is the price of admission for a moment of great discovery.
In other words, to triumph, “you’ve got to fail,” said Klunk.
Ten
DÉJÀ VU
IN NOVEMBER 2003, Karla watched a PBS documentary called The Forgetting: A Portrait of Alzheimer’s. At the small college where she worked as an administrative assistant, a psychology professor gave her the film, knowing her father had died from Alzheimer’s. The Forgetting featured Bill Klunk, who talked about his discovery of Pittsburgh Compound B and what it could mean for early diagnosis and prevention.
The Forgetting also introduced a family from Massachusetts, the Noonans. They were ten siblings who were roughly of an age with the DeMoe kids. Their mother had developed strange symptoms starting when she was thirty-nine; doctors thought it might be a nervous breakdown or some acute form of depression. Like Wanda DeMoe, she was given shock treatments. Ultimately, she died of pneumonia.
One of her daughters, Julie Noonan Lawson, was interviewed in the documentary. Like Karla, she wore her blond hair in a short bob. After their mother died, the children thought they had closed that tragic chapter of their lives, Julie explained—until decades later, when her older sisters, Fran and Maureen, also started showing symptoms.
“That’s when we realized: We’re not done. That’s when I realized the magnitude of this disease,” Julie told the camera. “This is gonna hit us again.”
The parallels were astonishing. Karla was riveted; she watched The Forgetting over and over and showed it to her mother. The documentary explained that the Noonans’ affliction was caused by a rare genetic mutation. Was her family like the Noonans? Was this what the doctor meant when he told her mother that half of the children might get it? Had some of them inherited this disease that had taken their father?
• • •
In February 2004, Gail received a disturbingly familiar phone call from a coworker of Brian and Doug.
“Gail, I think there’s something wrong with your boys,” he confessed. “They aren’t able to do their jobs like they were.”
The news didn’t come as a complete surprise; for a few months, the family had been making the same observation. Since his late twenties, Doug—who, ironically, shared a birthday with his uncle Jerry—had been repeating himself. And while everybody in town noticed it, nobody wanted to believe the disease was coming back for another round. But fear was beginning to simmer in their collective subconscious.
Gail and Brian visited Karla in Fargo for Christmas just two months before the phone call. As they had done eight years earlier, when they saw Jerry at the family reunion, the women discussed some of the changes they’d observed in Doug. Despite her earlier efforts at denial, and perhaps motivated by what she’d seen in The Forgetting, Karla thought it would be a good idea to get a doctor’s opinion.
Brian, who was sitting with them, didn’t say anything. “When I think about it now, he was the
re, but he wasn’t really in the conversation,” Karla said. “We knew Brian wasn’t like he should be, but he had smoked pot for so many years. So we thought the pot did it . . . I never, ever in my mind would have thought Brian had the disease.”
For fifteen years, ever since Moe’s death, Karla had been living in a state of denial. Even after Jerry’s diagnosis, she refused to think about her generation dealing with Alzheimer’s. She banished the thought any time it tried to enter her brain, as though she could will the possibility into submission. It wasn’t fair, after what they’d already endured. Their happy childhood had been cut short; hadn’t they at least earned the right to a happy ending?
But that February phone call changed everything.
Gail and Karla enlisted Dean to design an elaborate ruse that would get the boys to submit to testing. Karla found a neurologist’s office in Fargo and described her situation to the staff; miraculously, they offered an appointment in just a few weeks. Brian and Doug would come in for three days of interviews, neurological testing, and scans at a hospital, believing—with the doctors’ cooperation—that the entire family would undergo the same tests because of their history. Dean, who was now living on Karla’s side of the state, near Grand Forks, reinforced the cover story by taking time off from work to attend. In reality, he was only there for moral support.
Ever since Dean’s move, he and Karla had grown closer, just as he had visited Lori often when he was living in Colorado. Both Dean and Karla were deeply involved parents, and their kids were near enough in age to relate to one another. If bad news emerged from the testing, they vowed to team up and become their brothers’ caretakers. As Gail grew older, it only made sense for someone from their generation to assume the burdens she had once shouldered for their father, and neither Brian nor Doug had wives who might look after them. Lori and Steve were still moving according to the whims of his railroad job, but Karla and Dean were now firmly planted in North Dakota and raising their kids there.
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