Will a Test for Brain Trauma Protect NFL Players—or End the NFL?
In November, Kevin Hrusovsky paid a visit to the NFL’s headquarters on Park Avenue in New York. Hrusovsky (pronounced ruh-sov-skee) is chairman and chief executive officer of Quanterix, a life sciences startup that makes machines for measuring proteins and other biomarkers in the blood. He had the NFL’s attention because researchers have been using his company’s machines to hunt for markers of concussions and neurodegenerative disease. In an open letter NFL Commissioner Roger Goodell published in September about the league’s commitment to player safety, he wrote that Quanterix was developing “a blood test to reveal a concussion diagnosis.” It would be, Goodell said, “a major breakthrough.” The league, through a partnership with General Electric, has awarded Quanterix $800,000 in grants in the past three years. Hrusovsky was hoping to persuade the NFL to invest directly.
A few minutes after his sitdown with the league, Hrusovsky preaches to me over coffee at a hotel restaurant in Midtown. “My goal is transforming health care,” he says. At 55, with a broad mouth, smiling eyes, and graying hair, he resembles first-term George W. Bush. His homespun, slightly jumbled way of talking adds to the impression. Hrusovksy’s pitch to me is roughly the same as the one he just gave Jeff Miller, the NFL’s senior vice president for health and safety—skittering from drones, to driverless cars, to Tesla, to heart attacks and diabetes. “I’m still addicted to pastries at night,” Hrusovsky says before circling back to his thesis: Quanterix’s machines are on the brink of delivering a revolution in medicine, as scientists use them to detect diseases earlier, target them more precisely, and create breakthrough treatments for cancer, heart disease, diabetes, and Alzheimer’s, to name a few.
Researchers have also begun using Quanterix tests to search for signs of chronic traumatic encephalopathy, or CTE, the neurodegenerative disease that’s been found in the brains of at least 90 dead former NFL players. Among them are Dave Duerson, the former Chicago Bears defensive back who fatally shot himself in the chest (preserving his brain) in 2011, and Junior Seau, who did the same in 2012, three years after finishing a 20-year career as a linebacker.
The disease has changed the conversation about head trauma in football. While concussions are often visible—the hit, the woozy trip off the field, and, usually, the return—CTE is insidious—the slow, inevitable collapse of the brain from within. There’s currently no way to test for CTE in the living. By the time there are noticeable symptoms—which include mood swings, depression, impulsiveness, and memory loss—the disease is far along. As a result, early detection of CTE has become a grail for scientists in the field. A diagnostic test would make it possible to distinguish the disease from Alzheimer’s, to know how widespread it is, to begin to figure out why some people get it and others don’t, and, potentially, to develop treatments or a cure. Quanterix is one of several life sciences companies in the race. Its approach, a simple blood test, is the most elegant and the most challenging.
While the NFL is backing Quanterix, a test for the living could present an existential crisis for the league. Discovering, for instance, that half its linemen show signs of CTE could starve the league of talent or force changes that make it unrecognizable to fans. And football isn’t alone: CTE presents similarly dire questions for hockey, soccer, and ultimate fighting, among other contact sports.
“The NFL may not realize they have awakened an animal here,” Hrusovsky says. “If they want it, they should invest like crazy in it. If they don’t really want it, holy moly, what have they created? Because I am not going to go away.”
A few weeks later, Hrusovsky and I meet again, at Quanterix’s offices in Lexington, Mass., a suburb northwest of Boston where college professors live in well-kept colonials next to tech startups in single-story office parks. Hrusovsky keeps a bowl of buckeye nuts in his office to pass out as mementos; the buckeye is the state tree of his native Ohio and the mascot of his alma mater, Ohio State University. “The Indians named it a buckeye because it looks like a deer’s eye,” he says. “It’s great for good luck.”
After donning white coats and protective goggles, we enter the lab and watch technicians load a Quanterix Simoa HD-1 Analyzer. The machine, about the size of two refrigerators, is home to a microscopic technology called single-molecule array. Simoa uses millions of tiny beads, each about one-thirtieth the width of a human hair, trapped inside millions of tiny wells, to detect proteins in the blood.
The beads and wells were conceived in the lab of David Walt, a chemistry professor at Tufts University. Two decades ago, Walt and his team came up with a novel way to map the billions of DNA base pairs that make up a human genome. They took an existing process, which involved setting off chemical reactions that lit the pairs up in coded colors, and ran it on tiny silica beads sitting atop tiny wells, like scoops of ice cream nested on cones. The method dramatically sped up the work of gene researchers. Walt co-founded Illumina in 1998 to bring the technology to market; the company went public two years after. It later won a worldwide race to sequence a human genome for less than $1,000, and now has annual sales of $2.4 billion.
In 2005, Walt and his lab began tinkering with another application for the beads and wells. Instead of using them as a kind of Lite-Brite for DNA, they tried putting lids across the wells, trapping tiny amounts of fluid in which they could hunt for molecules. The idea was to build a better test for blood and other bodily fluids.
For decades, the gold standard for blood tests has been the Elisa, or enzyme-linked immunosorbent assay. The process relies on antibodies that attach themselves, like puzzle pieces, to specific molecules. Enzyme reactions then make these matched pairs light up in fluorescent colors. It’s an analog system: The final step is reading the intensity of color in a few drops of blood. For the signal to be bright enough to measure, you need at least 30 million target molecules per drop.
Walt’s micro-wells made it possible to break the standard Elisa test into hundreds of thousands of mini tests. He co-founded Quanterix with then-CEO Nick Naclerio in 2007 to develop the method, which works like this: Beads are coated in hundreds of thousands of antibodies, like microscopic fur, and submerged in fluid samples, where the antibodies grab hold of any target molecule that comes into contact with them. The captured molecules, now attached to beads, are then tagged with an enzyme, as in a traditional Elisa, and the beads are rolled across a plate of wells, where they drop inside, one per well, and are sealed along with a trigger fluid. If the enzyme is present, the well lights up. If not, it doesn’t. “You are basically breaking up the sample into 500,000 little samples,” Hrusovsky says as we watch the machine work. “And you’re checking each one of them to see if they have got a protein.”
Sample vials of blood and other fluids go in a tray on the left, where the machine mixes in the antibody beads and the enzymes. On the right, it traps the beads in micro-wells sandwiched inside a compact disc, the same size as those that play music. The wells are arranged into 24 plots, each about the size of a baby’s fingernail, that are arrayed around the perimeter of the disc. Each plot holds 212,000 wells, meaning a single disc can yield more than 5 million results. The machine racks the loaded discs and turns them slowly, like an underpowered jukebox, to photograph the plots.
The method is a thousand times more sensitive than the Elisa, capable of detecting molecules in concentrations as low as 30,000 per drop—the equivalent, Hrusovsky says, of finding a grain of sand in 2,000 swimming pools. Simoa also offers digital results, with each well sending out a “yes” or “no” signal in microscopic plots of light and dark, which can then be charted to come up with molecule counts.
In 2013, Quanterix began selling its Simoa analyzer to drug companies for about $165,000 each. It sold some 65 in 2016, to customers including Eli Lilly, Merck, Novartis, and Pfizer. Quanterix also sells antibody kits, and it charges smaller researchers to run experiments in its lab—sales were almost $20 million last year. In March the company raised $46 million from investors, who pegged its value at about $150 million. Hrusovsky is using the money to expand the menu of antibody kits and build a cheaper, tabletop version of the company’s machines. He hopes to begin selling them—and to take the company public—before the end of the year.
For a while now, Hrusovsky has been rhapsodizing about the future of medicine to anyone who will listen. In September he organized a conference called the Powering Precision Health Summit at the Marriott in Cambridge, Mass., drawing a crowd of about 300 cardiologists, neurologists, oncologists, and pharmaceutical executives. He delivered his opening remarks wearing a black turtleneck and blue jeans—a not-so-subtle homage. “It was 19 years ago when Steve Jobs took the stage at Macworld right here in Boston,” he told the audience. Jobs, he reminded them, had just come back to Apple from Pixar, and he used the stage that day to prod his company to try new things. Hrusovsky ticked through the list of products that followed in the next 15 years: the iPod, iPhone, iPad, and more. It was, he said, probably “the most unprecedented level of innovation that you can ever imagine.”
Quanterix, he suggested, was at the center of something similarly grand: a burgeoning $30 billion market for blood screens that would upend notions of health and sickness. “It’s a huge opportunity to do a big transformation,” he said, “almost an Apple level of transformation, right here in health care.”
Hrusovsky was aware of what everyone was thinking: He wasn’t the first executive to don Jobs’s mantle and promise a revolution in health care through high-tech blood tests. On screen, he displayed the cover of a year-old issue of Inc. magazine with Elizabeth Holmes, the CEO of Theranos, in a black turtleneck under the headline “The Next Steve Jobs.” Theranos, once valued at $9 billion, had crashed to earth in the months after the Inc. cover, following a series of articles in the Wall Street Journal showing that its technology didn’t work as promised and that it was relying on other companies’ machines. In July federal regulators banned Holmes from operating a medical lab for two years (pending an appeal by the company). “You may be wondering why I am wearing black, given what’s going on in the industry right now,” Hrusovsky said. Then, to assure the crowd that he was no Holmes, he pulled on a white lab coat. He seemed not to know that Holmes had done likewise for many photos—including for Inc.
Hrusovsky’s backstory contrasts with Holmes’s too-perfect tale of dropping out of college and finding a calling to disrupt medicine. He got a degree in mechanical engineering and an MBA, and spent 30 years at a handful of unsexy companies: DuPont, FMC, Zymark, Caliper, PerkinElmer. He worked in plastics, agricultural chemicals, pharmaceuticals, and lab robotics. He’d planned to spend his late career advising life sciences companies from the boardroom, but in 2014 a few Quanterix investors persuaded him to come aboard. The company had churned through four CEOs since its founding, and its backers were growing impatient. The vision of marketing diagnostic tools for a variety of diseases required not only the creation of “bleed-to-read” tests but also getting them approved by the Food and Drug Administration and persuading health insurers to help pay for the tests. “It was taking a long time and a lot of money, and it was getting frustrating,” Hrusovsky says.
As CEO, he shifted the focus to selling analyzers to drug companies, who would use them for research that might one day lead to diagnostic tests. Unlike at Theranos, Quanterix’s technology isn’t a trade secret: Dozens of scientists have detailed their work using the company’s machines in more than 80 peer-reviewed papers. They’ve used it to detect markers of cancer, Parkinson’s, Alzheimer’s, heart disease—and head trauma.
In 2013, Henrik Zetterberg, a professor at the University of Gothenburg’s Institute of Neuroscience and Physiology in Sweden, published a study in the journal Brain Injury, based on Quanterix tests, that showed increased levels of a protein called tau in the plasma of Olympic boxers after their bouts.
As proteins go, tau is famous. It helps hold together the intricate railway that carries signals between tens of billions of brain cells. When a brain slams against the inside of the skull, some tau dislodges and crosses the blood-brain barrier—the wall that prevents infection but also makes it hard for doctors to know what’s happening inside the organ. If a brain is jostled too often, even with subconcussive blows, tau proteins can begin to deteriorate, becoming “misfolded” and falling off the railway. This deformed tau, known as P-Tau, is the primary marker of CTE. In stained slices of autopsied brains, P-Tau shows up as brown splotches.
The first known case of CTE in a former NFL player was found in the brain of Mike Webster, a Hall of Fame center for the Pittsburgh Steelers who died in 2002 after a long decline into mental illness. Bennet Omalu, the doctor who autopsied Webster, concluded that football had, in essence, caused his brain to collapse from within. (Omalu is the protagonist of the film Concussion, starring Will Smith.) Since then, the brains of 90 deceased former NFL players have been diagnosed with the disease.
The amount of tau that gets into the bloodstream following a concussion is minuscule, not enough to detect with any established test. Doctors and trainers rely instead on checklists of symptoms and patient reports. When a football player gets knocked down and doesn’t know what day it is, the diagnosis is clear enough. But not every blow is spectacular, and players, eager to stay in the game, don’t always report symptoms. It’s especially hard to know when a player has recovered. “We desperately need a blood test,” says Robert Cantu, an investigator at Boston University’s CTE Center and a consultant to the NFL’s head, neck, and spine committee.
A year after Zetterberg’s boxing study, he and his team looked at players in the Swedish Hockey League, again using Quanterix tests, and found that tau levels spiked in the first hour after a head injury, then dipped over the next 12 hours before rising again over the following two days. For a study published in January 2017 in Neurology, Jessica Gill, a head trauma researcher at the National Institute of Nursing Research in Bethesda, Md., tested the blood of 46 concussed college athletes from the University of Rochester and found that those with the highest levels of tau six hours after the injury were the least likely to be able to play again within 10 days.
Hrusovsky sees this research as prelude to a concussion blood test. “A finger prick could tell you the answer within 20 minutes,” he said in an appearance on Good Morning America in December 2015. At the time, Quanterix said it might have a test ready within a year. By September, at his conference in Boston, Hrusovsky was speaking of the company’s “ability to see concussions in blood.”
It’s a long way, however, from a handful of studies showing correlations to a reliable biomarker test. To get there, Quanterix will need to establish tau baselines across populations and locate thresholds for injury, then test its method against results from clinicians trained to spot concussions. “When he talks in front of audiences, he kind of often comes off like it’s done,” Cantu says, “but it’s not done.” During my visit in November, Hrusovsky said a test was four to five years away.
A blood test for CTE is further off. Quanterix hasn’t yet identified an antibody that latches on only to the P-Tau proteins that mark the disease. And even if its researchers find one, there might not be much P-Tau to detect. With concussions, the impact sends tau proteins across the blood-brain barrier; with CTE, they may stay contained. “I don’t think there is liberation in the bloodstream constantly of any proteins,” says Julian Bailes, chairman of the department of neurosurgery at NorthShore Neurological Institute in Illinois. “I think there are damaged areas that are fixed.”
Bailes was one of the first doctors to recognize the significance of Omalu’s early findings. He believes positron emission tomography, or PET, scans, which rely on dyes with radioactive tracers, offer a better chance than blood tests of diagnosing CTE in the living. Jorge Barrio and Gary Small, scientists at the UCLA Brain Research Institute, have been scanning retired NFL players in search of the disease. Barrio and Small use a tracer called FDDNP that binds to tau and other proteins associated with neurodegenerative disease. For a study in the journal PNAS in 2015, they injected 14 former players with the experimental drug and found protein deposit patterns consistent with those identified in autopsies of players diagnosed with CTE.
A company called TauMark holds the license for FDDNP and is working to be able to market brain scans to athletes, military veterans, and others who’ve suffered head trauma. Small and Barrio own TauMark, along with Omalu, longtime NFL agent James “Bus” Cook, and Bob Fitzsimmons, the West Virginia plaintiffs’ attorney who represented Webster in his disability case against the NFL. Fitzsimmons says the company is looking for funding for a long-term study, which could lead to an FDA-approved test. For the study, TauMark plans to scan dozens of terminally ill patients suspected of suffering from CTE, then compare the results with autopsies after they die. Omalu has done this with former Minnesota Vikings linebacker Fred McNeill, who died of Lou Gehrig’s disease in 2015 after suffering years of dementia; McNeill’s family told CNN that the PET scan and autopsy showed matching patterns indicating CTE.
Aethlon Medical, a San Diego immunotherapy company, is coming at CTE from yet another angle, using exosomes, bits of cells that break off and show up in all types of bodily fluids, as biomarkers. Last year researchers found elevated levels of a tau-related exosome in former NFL players, compared with a control group. In January, Aethlon announced that it was looking to begin a study of 200 former NFL players.
Robert Stern, director of clinical research at BU’s CTE Center, oversees the university’s seven-year, $16 million effort to find a diagnosis for living patients. Over the years, he’s used blood tests, PET scans, exosomes, and more to test former NFL players. Speaking at the Boston conference about his results with Quanterix, he said, “We found a pretty robust relationship between the cumulative head impact exposure and total tau through this simple blood test.” Still, he doesn’t believe a standalone blood test for CTE is coming. Instead, he says, blood work will likely serve as a screen to find patients who need PET scans and other tests. “It will always require these extra steps. It won’t be the kind of thing that will be immediately able to be done in, let’s say, a Simoa.” (Stern declined to comment for this story.)
“I would say that the jury is still out on how far we’re going to be able to get,” Hrusovsky says of a standalone blood test.
During this year’s playoffs, the NFL has been airing TV commercials with the tag line “The Future of Football.” One of them shows a white-coated technician loading blood samples into a Quanterix machine. “We’re trying to develop the best tools, ones that will allow us to diagnose concussions in real time,” says the narrator, Teena Shetty, a neurologist who consults with the New York Giants. Quanterix’s concussion research fits into the NFL’s vision of a future in which head trauma is neatly contained. A pinprick sideline test would make everyone rest easy when a player who just took a head shot returns to the field.
The CTE research is less comfortable for the league. For several years after Webster died, the NFL downplayed the problem of head trauma. In 2009, after being called to testify before Congress, Goodell ducked questions about the link between football and neurological disease. “Medical experts would know better than I do,” he said.
Nobody knows how common CTE is among current and former NFL players. “Some people have said up to 90 percent,” Bailes says. “I think it’s much less than that.” Not everybody who suffers repetitive head trauma winds up with the disease. And nobody knows why some get it and others don’t. It could have to do with the intervals between hits, with genetics, with nutrition. A test for the living would make it possible to begin sorting this out, to devise prevention programs, and maybe even find drugs that can reverse the damage. This is the hope, both for CTE sufferers and for the NFL.
For now, the league has the problem contained, at least from a legal standpoint. In 2013 it settled a lawsuit brought by more than 5,000 retired players who claimed the league had failed to share what it knew about the long-term effects of head trauma. The NFL promised to pay at least $675 million to former players whose symptoms make them eligible and to set aside $90 million for medical monitoring and research. In March of last year, Miller, the NFL health and safety executive, openly acknowledged the link between football and CTE. And in September, in his open letter, Goodell committed an additional $100 million to fund further research in helmet engineering and neuroscience. All of this was on top of a 2012 grant of $30 million to the National Institutes of Health for research on brain injuries.
With CTE on many fans’ minds, the NFL has little choice but to present itself as eager to learn more about it, though not everyone is convinced the league is prepared to acknowledge the full scope of the problem. “The NFL, in my opinion, still has weasel words,” says Fitzsimmons, the West Virginia attorney who represented Webster. The league, he says, has yet to “fully embrace the notion that hitting the head against another head is not good for people and that the brain is not designed to take those forces without damaging it.”
“We understand that there are many, many unanswered questions,” says Joe Lockhart, a spokesman for the NFL. “Our ultimate goal is to do our part to contribute to finding the answers. We are prepared to follow the science to wherever it leads.” That didn’t include buying a stake in Quanterix. The league sticks to grants, Lockhart says, so that there’s no question its goal is to advance the science rather than to direct it or profit from it.
Hrusovsky left the November meeting feeling less than loved—a league representative, he says, chided him for failing to mention its funding during his appearance on Good Morning America—but the NFL has gone out of its way since then to show its support. The commercial featuring the Quanterix machine was one example. “I think they’re just trying to get their hands around what all this can mean,” he says.
His message to the NFL was not to fear what’s coming. “The objective test might wind up being your best friend,” he says. “Maybe it’s a big risk, or maybe it’s salvation.”