In his quest to bring a revolutionary treatment to market, Boston entrepreneur Frank Reynolds aims to get the better of traumatic spinal cord injury. Again.
In his quest to bring a revolutionary treatment to market, Boston entrepreneur Frank Reynolds aims to get the better of traumatic spinal cord injury. Again.
Frank Reynolds was about to give up hope. He had been living in almost constant pain, his body bound in a knee-to-neck body cast, flat on his back in a small Philadelphia condominium. Before the car accident, nearly anything had seemed possible. He was planning his wedding and studying for a career as a hospital administrator. Then, on the morning of December 14, 1992, while he was driving to his job as a psychotherapist at the Philadelphia Psychiatric Center, another motorist slammed into the rear of his Oldsmobile Cutlass coupe. When he came to that night in the University of Pennsylvania hospital, Reynolds couldn't move. Trauma-room surgeons had operated to stabilize a dislocated vertebra in the middle of his back, he learned. But the wayward bone had also pinched his spinal cord -- an untreatable wound that left him unable to walk.
His world withered. Days consisted of long hours staring at the ceiling, punctuated by excruciating sessions of physical therapy. After three years, Reynolds could walk just 80 feet, and afterward he would be in agony. He was 30 years old, and some of the nation's top spine doctors warned him that further improvement was unlikely, if not impossible.
Then, one day in 1995, Reynolds's wife brought home a VHS cassette of the movie Lorenzo's Oil. The film is about a couple that defy the medical establishment to discover a cure for their son's rare illness, and for Reynolds, it sparked an epiphany. "I thought, Jesus, I could do that," he says. And so began what Reynolds calls a "crusade" to regain the ability to walk. He set about learning everything he could about spinal cord injury, or SCI. Using a glacial early Internet connection, from his bed he tapped into the databases of university libraries; through supporters at St. Joseph's University in Philadelphia, where he had been studying for a master's degree before his accident, he secured interlibrary loans of hard-to-find medical publications.
Somewhere in those pages, Reynolds came across a theory -- a notion that has since gained credibility among many experts -- that by intensifying his physical rehab routine, he could reactivate dormant neural connections and make his spine come alive again. Instead of 45-minute sessions with a therapist three times a week, he began daily workouts that combined hours of aquatic therapy in a YMCA pool with as much time as he could handle on a treadmill. Supporting himself with his upper body, he grimaced through the pain and simply forced his legs to move. After three months, he could walk a quarter of a mile a day; after a year, he could manage five. He was now able to drive himself, using both feet. He removed his body cast and got ready to go back to work.
"It's kind of surreal: I spent years in bed dreaming about walking in the woods and walking on the beach and putting a golf ball, never believing it would happen," Reynolds, now 45, says. "I spent five years staring at the ceiling saying, 'God, give me another chance.' "
Somehow, that opportunity materialized. But once it did, he found that a second chance just for himself was not enough. That's when Frank Reynolds's second crusade got under way. Some 12,000 Americans a year suffer traumatic spinal cord injuries. Two-thirds of those who are injured endure chronic, and often severe, pain, and only about a third are able to eventually hold a job. Reynolds wants them to have their second chance, too. And as co-founder and CEO of the Cambridge, Massachusetts–based biomedical start-up InVivo Therapeutics, he won't stop moving until they get it.
The scar on Reynolds's back starts between his buttocks and runs in a ragged line 14 inches to the middle of his back. It's a constant reminder of what he is trying to accomplish. So is the pain. The stainless-steel screws that hold his spine together sit just beneath his skin; when they get cold, he says, "it feels like a little bomb in there." In the area in which surgeons cut away bone to relieve pressure on his swelling spinal cord, he says, "The only thing between me and my spinal cord is muscle, fat, and skin. If you had a stick, you could actually paralyze me." It could be a distraction -- the hole in your back, the pain, the awareness that your own damaged spinal tissue is gradually degenerating. It's what keeps Reynolds focused.
His goal is wildly ambitious -- in large part because of how little is really understood about the central nervous system, which consists of the brain and spinal cord, and its healing mechanisms. "We're just scratching the surface of what's going on," says Steve Williams, a specialist in spinal cord injury and rehabilitation at Boston Medical Center. "It's like studying deep space -- like a big black hole. How does it really work?"
The spinal cord may be best understood as a thick data cable that processes and transmits the constant stream of electrical impulses that flow between your brain and the rest of your body, enabling motion and sensation. Motor signals move downstream, from the brain, and sensory signals move from the rest of the body up. The center of the cord is gray matter -- essentially an extension of the brain, like a tail -- that is sheathed in fibrous white matter, with long, thin nerve fibers called axons shooting out at intervals to wire every part of the body.
Normally, the sensitive cord tissue is protected by the flexible stack of 33 bones that make up the spinal column. But when these bones are knocked out of line -- auto accidents are the most common cause -- the cord inside may be bruised, stretched, cut, or even severed. The result: The flow of signals up and down is impeded or blocked completely at the level of the injury, leaving most victims of SCI with some degree of paralysis. Upon discharge from the hospital, more than 25 percent of SCI patients have complete paraplegia, meaning they are unable to feel or move their legs; more than 20 percent suffer from complete tetraplegia, or paralysis in all four limbs and the torso.
Physical therapy aimed at rebuilding neural pathways can often improve a patient's level of functioning in the months and years after a spinal cord injury. But Reynolds believes that his company's technology can give SCI victims a better shot at recovery by taking advantage of the window of opportunity that exists in the immediate aftermath of the injury. At that point, there is often still enough surviving spinal cord tissue to allow for a sort of neural workaround, a rerouting of signals to maintain the flow of sensory and motor signals below the wound. But in the following hours and days, the body's self-defense mechanisms backfire: White blood cells come in to clean up dead tissue, which causes massive inflammation, which in turn triggers healthy cells in the surrounding tissue to self-destruct in a process called apoptosis. This secondary injury amplifies the original wound and the corresponding loss of function, creating a true dead area in the spinal cord that defies rehabilitation.
Reynolds and his team have developed a device -- a fingertip-size implant that is inserted at the site of the wound -- to help contain the secondary injury. Made of a polymer that has already been approved by the FDA for applications such as biodegradable sutures, InVivo's implant seems to undermine the biological ripple effect that leads to apoptosis, essentially by leading the body to believe that the damage is not that bad, which tones down the immune response and helps the healthier neural tissue survive and heal.
Few companies have focused on treating acute SCI. For the most part, emergency treatment today looks very much as it did at the time of Reynolds's accident. Surgeons clean up and stabilize the backbone with screws and pins, and close the patient up, leaving the spinal cord itself virtually untouched. To reduce spinal cord inflammation, they may also administer a powerful steroid called methylprednisolone -- also used to treat arthritis pain -- although side effects, including an increased risk of infection, make it inappropriate for many SCI patients. Geron, a company in Menlo Park, California, recently received FDA clearance for the first human clinical trials of a human embryonic stem cell–based therapy for acute SCI that scientists believe could generate fresh nerve cells in the spine. "Stem cells have great potential," says Williams. "But we'll need other innovative therapies, too." A device like InVivo's, he says, rather than competing with stem cell treatments would more likely work in synergy with them.
For Reynolds, who has spent five years and some $4.5 million, including most of his own savings, on his quest to change lives, do-or-die time is fast approaching. Primate studies of InVivo's technology have been under way since 2008. Once the final results of those studies are analyzed this spring -- and the early evidence has been encouraging -- the challenge will be to get FDA approval for human trials and then bring the treatment to market. Doing that, Reynolds estimates, will require an additional $15 million. And so far, despite InVivo's A-list team of scientific advisers, including MIT professor and renowned inventor Robert Langer, no major investor has been willing to sign on. But if Reynolds is discouraged, he is not letting it show. For a guy with just 10 full-time employees and a science team made up largely of grad students and consultants paid in company stock, Reynolds exudes a surprising amount of swagger. "Frank is totally committed," says Langer. "If he had to run through a wall, he'd do it. He's got very good people. But anyone can put together a great team -- Frank's strength is this relentless commitment to wanting this to work."
Reynolds's day begins around 6 a.m., when he checks his e-mail from home. It usually ends after midnight -- though predawn e-mails to colleagues suggest that Reynolds seldom truly rests. He pilots a white Lincoln Navigator with "INVIVO" plates from his home in the Boston suburbs to InVivo's headquarters, which occupy three office bays with desks for 14 in the Cambridge Innovation Center, a shared business-incubator space a block away from the main MIT campus. At 9 on a November morning, the building's other tenants are just trickling in as Reynolds begins a meeting in a small conference room overlooking the Charles River. Along with his executive assistant, Lauren Mitarotondo, 24, and his IT manager, George Calapai, also 24, Reynolds is reviewing the data being collected from a primate study that the company is conducting at a research center on the Caribbean island nation of St. Kitts.
Whatever your qualms about animal research, it's hard not to share Reynolds's awe and excitement when you watch the video from InVivo's tests. The pièce de résistance of a presentation Reynolds has been polishing up for meetings with potential investors, the video compares two African green monkeys whose spinal cords have been partially severed to paralyze one of their hind legs. Two days postinjury, both animals drag their feet behind them. But after two weeks, one of the monkeys -- the one with the InVivo implant -- not only walks but runs, curling its tail and pivoting effortlessly on the once-paralyzed leg. Reynolds believes the device will yield equally miraculous results in humans.
The company's first primate trials, in 2008, involved just four animals and achieved similar results. A second trial, with more monkeys, however, got off to a bad start and was halted. Exactly what went wrong remains a matter of dispute, but Reynolds sued the test facility and negotiated a settlement he says he is "very happy" with. Still, that false start threw InVivo off schedule. The company had hoped to begin human trials in early 2010, but they will now be delayed at least until the third quarter.
So InVivo headed back to St. Kitts, where it is testing 16 animals -- enough to yield results that can be presented to the FDA as conclusive. In addition to the video, InVivo has been collecting motion-analysis data and using electromyography, or EMG, implants to directly monitor activity in the animals' muscles. It's a wealth of data, and Reynolds is grilling Calapai to make sure that every piece of it is properly documented and secured. When he submits the company's application to move ahead with human trials, Reynolds wants it to be bulletproof. And he thinks it will be. "This will blow them away," he says. "Nobody's shown up and said, 'Look at this animal running and look at the electrical activity going on.' They've never seen this. We're really excited."
Reynolds has always been something of an optimist. The son of Irish immigrants, Reynolds grew up in the Bronx, New York, with three siblings. He shined shoes on weekends to help out financially. After the family moved to a New Jersey suburb, Reynolds worked two newspaper routes, caddied at a local golf club, and worked in restaurants. He attended Catholic schools and lettered in football, basketball, and golf in high school. When he was 17, his father was debilitated by Parkinson's disease; by the age of 18, Reynolds was managing the family businesses, which included restaurants, bars, and real estate interests, while attending college full time. "When I was becoming a man, my father kind of disappeared from the scene and didn't even know who I was a lot," he says. "It was 25 years of agony and pain on my family."
At the time of his accident, Reynolds was on the verge of starting a new career. But those long years of convalescence had taken a toll on his finances. So when Reynolds returned to the work force, he abandoned hospital administration and looked for higher-paying sales jobs. He felt certain that landing a position would be easy; employers, he believed, would be impressed by his astonishing recovery. Instead, they all seemed to focus on the long gap in his resumé. "It was shocking to have them say that I hadn't been working for six years," Reynolds says. "I was working."
So Reynolds, who had experienced the power of the Internet in the quest for his miracle cure, started his own business -- an IT consulting firm called Expand the Knowledge, which helped medical researchers coordinate their work online. "I worked 100 hours a week, went to school, and slept three or four hours a night," he says. "I wanted to make the most of my second chance." After selling his business and earning additional degrees in technology and engineering management, Reynolds went to work at Siemens USA, a division of the German electronics and electrical engineering giant, where he was identified as an emerging leader and put into a special mentoring program. Soon, he was director of global business development. In 2005, Siemens offered him the chance to attend the Sloan Fellows Program at MIT, a prestigious one-year M.B.A. program for midcareer executives whose graduates include Kofi Annan and Carly Fiorina.
It was at MIT that Reynolds heard Langer give a talk on a novel treatment for SCI. Langer, an MIT Institute Professor with some 750 patents issued or pending worldwide, was one of the first people to apply chemical engineering methods to medical applications, pioneering the use of specially designed polymers for targeted drug delivery and tissue regeneration. The 100 or so researchers in his lab develop ideas on those basic themes. The technologies they spin out have been licensed or sublicensed to more than 220 pharmaceutical, chemical, biotech, and medical device companies.
In the mid-1990s, Langer was working with colleagues at Harvard Medical School to study the idea of using biomaterials in combination with cells or drugs to improve functioning in people with spinal cord injuries; he published the results of rodent studies in 2002. After Reynolds introduced himself and shared the story of his recovery, Langer asked him to become the unofficial "business person" on his team working on SCI treatment. Reynolds helped with grant applications, identified opportunities in the SCI treatment market, analyzed research data, and devised a product development strategy. This work turned into his M.B.A. thesis, "InVivo Therapeutics" -- and the business plan for a company of the same name, which would move Langer's technology out of the lab and up the ladder from rats to primates and ultimately to humans. In November 2005, Reynolds filed incorporation papers, began securing the relevant patents from MIT's technology transfer office, and gave notice at Siemens, a company he loved.
"Frank had a great opportunity at Siemens to return to," says George Nolen, the recently retired CEO of Siemens USA, who mentored Reynolds in his early years at the company. "But this was a passion and a personal dream for him. You always hate to lose people who are talented, but I told him, 'You may only get one chance to chase a personal dream. God bless you and the people you want to help."
Angling through a parking lot on a trajectory that gets him from his office to the Langer Lab at MIT in about three minutes, Reynolds strides along like some kind of baby-faced Irish gangster, in a tailored pinstripe suit, metallic tie, designer eyeglasses, a Rolex, and the chunky MIT ring that marks his membership in what he jokingly refers to as "a secret society." As always, Mitarotondo is at his side. The two are on their way to meet with Chris Pritchard, a 24-year-old Ph.D. candidate and Langer protégé, with master's degrees from Oxford and MIT, who heads InVivo's research and development efforts.
Reynolds is unabashed about preferring young employees. "We'll need tenured people with great experience as the company evolves," he says, "but in these early, innovative days, we need sharp people who really don't have any preconceived notions." Plus, he adds, Pritchard knows as much about the science as anyone. At biotech start-ups based on cutting-edge technologies, it is often the case that graduate students are among the most knowledgeable people available. And the price is right. InVivo paid for a year of Pritchard's graduate fellowship and funds his research in Langer's lab; in exchange, Pritchard brings to InVivo insights gleaned from some of the smartest scientists working in biomaterials anywhere.
Aside from Pritchard and InVivo's medical director, a prominent Boston neurosurgeon named Eric Woodard, In-Vivo's virtual R&D team consists of consultants and a handful of big-name advisers -- including Richard Roberts, winner of the 1993 Nobel Prize for Medicine -- who work in exchange for InVivo stock options. (Langer and Woodard receive advising fees, in addition to options.) Roberts, a research scientist at New England Biolabs, has a personal reason for wanting InVivo to succeed: His oldest son has been quadriplegic since being injured in a car accident.
In a cramped, cluttered conference room adjacent to Langer's office, Reynolds and Pritchard start their meeting by discussing the timeline for publishing the results of InVivo's primate studies. The goal, Reynolds says, is to create "a cascading series of events" leading to the human trials later this year. For now, however, they settle on a plan to submit a paper to a neuroscience journal, in which they describe the novel techniques InVivo has used to evaluate SCI and recovery in primates. A more comprehensive paper, which Pritchard and Langer aim to publish in the influential science journal Nature, will be written once all the data from the final primate trial have been analyzed. Assuming, of course, that the results are good.
While they await those results, Reynolds and his team stay busy by laying the foundations for InVivo's next generation of products, part of what Reynolds envisions as a suite of spine-related therapies. His ultimate dream is for InVivo to become as big and influential as other biotech firms in the neighborhood. "I look forward to being Biogen," Reynolds says. Given that Biogen is a $4 billion giant best known for its cutting-edge cancer treatments, the comment seems outlandish, even slightly delusional. On the other hand, Biogen has its roots in a Cambridge start-up founded in 1978 by MIT and Harvard scientists working in small, separate labs on then-radical theories, pursuing research dead ends and racking up debt until blockbuster drugs for treating leukemia, MS, and non-Hodgkin's lymphoma brought major commercial success.
To be sure, the market for SCI treatment is smaller than that for cancer drugs. But if doctors, patients -- and maybe most important, insurers -- decide that InVivo's device is worth the proposed price of $100,000, annual sales could hit the billion-dollar mark. And treatments for chronic conditions could yield a much greater return. One day, Reynolds says, a version of InVivo's implant, packed with stem cells or hormones, might help the six million Americans who are chronically paralyzed from SCI and other central nervous system disorders improve their level of functioning. An injectable version of InVivo's biomaterial may prove valuable in treating acute spinal cord contusion injuries, common in accidents when the spinal column is compressed, as well as other degenerative conditions.
With visible excitement, Pritchard shows Reynolds some rat-tissue slides he has just received from V. Reggie Edgerton, an expert on SCI at UCLA and another member of InVivo's R&D team. Edgerton's slides offer a remarkably detailed picture of what happens to the spinal cord in the aftermath of a contusion injury. The images dramatically show the progression of the secondary injury and the chaotic molecular environment that makes conventional drug delivery to the affected area so challenging. That's where Reynolds and others see the potential for biomaterials to play an increasingly important role.
By the end of the meeting, Reynolds is shifting in a small, uncomfortable chair. He is red in the face and wincing. Pain is a constant in his life. "When I was in my late 30s, a doctor told me I had the spine of a 70-year-old," he says. Now and then, his legs go numb, and he gets up to walk around and assure himself that all is well. Recently, he has relied on spinal injections to help control the pain. "I need my technology to come to market to keep my spine healthy," he says. "That helps drive me at 11 p.m."
Perhaps the only thing more daunting than the science behind InVivo's technology is figuring out how to fund it. If you simply wanted to get rich, you would pick something other than SCI to focus on. The federal government is the biggest source of funding, and even that doesn't amount to much. In 2008, the National Institutes of Health spent $80 million on SCI research -- about the same amount that went to inflammatory bowel disease -- compared with $5.6 billion for cancer and $3.6 billion for infectious diseases.
InVivo received a boost last year, when the Massachusetts Life Sciences Center, a quasipublic agency that helps promote science-based businesses in the state, awarded the company a $500,000 unsecured loan to support its research. "Our reviewers found the technology to be unique and extremely innovative," says Susan Windham-Bannister, a veteran life-sciences consultant who serves as the center's CEO.
Nonetheless, Reynolds hasn't managed to excite the venture capitalists who sometimes seem to lurk behind every test tube in Cambridge. This doesn't surprise Patrick Fortune, a partner in Boston Millennia Partners, a VC firm focused on life-sciences and health care investments. Because of the relatively small market and the long, unpredictable path to getting a product made and approved, SCI therapies tend not to be the kinds of investments VCs flock toward. "It's a complex field to navigate," Fortune says. "There's still a fair amount of misunderstood or nonunderstood science. Without a great deal of validated animal data or preliminary human data, this is a tough one to raise money for."
Apart from the Massachusetts Life Sciences grant, InVivo's funds have come from a few dozen friends-and-family debt investors -- and from Reynolds's own pocket. (Reynolds did well in his years at Siemens.) But if the constant scrambling for funds has been a limitation, it has also helped keep InVivo lean and fast. The company has moved from research on rats to the cusp of human trials in less than five years at a cost of less than $5 million, a process that can often take twice that long and cost many times more. But even if a big round of funding comes through -- and Reynolds remains confident that it will -- the path ahead still hides IEDs of all sorts. "I've seen trip-ups at almost every stage of the way," says Langer. "Things go wrong. You just need to be prepared for it."
On a late-afternoon call with a life-sciences analyst at a major investment firm, Reynolds walks a fine line between caution and conviction. "We're pumped up!" he tells the analyst. He is eager to share the details of the animal study -- the fact that all the treated monkeys are now walking. But until InVivo has all the data, Reynolds tries to keep his natural enthusiasm in check and be careful what he divulges. The call is brief, concluding with a vague invitation for Reynolds to come and give his presentation.
By this point, Reynolds has been going nonstop for nearly 12 hours. For a moment or two, his energy seems to flag. Then there's an e-mail on his iPhone. It's the analyst he was just speaking to, and he has some news: A major medical device maker would like to arrange a meeting. Will this meeting result in anything substantive? Probably not. But Reynolds believes the constant stream of meetings and presentations will help lay the groundwork for an acquisition or partnership. "I have to create the options," he says. "If we don't have options, I've failed."
Outside, the sun is setting over the Charles River, and before I leave, Reynolds takes me to his office. Small and windowless, it's one of the cheapest in the building. Indeed, his young employees share a much bigger space, with a view, across the hall. But that doesn't bother Reynolds. If he needs something to look at, there's a painting of his hero, Christopher Reeve, and a color-copied image of what looks like a photo taken by accident -- all you can see is a ceiling, partially in shadow. "That's the view from I had from my bed from when I was recovering from being paralyzed," Reynolds says. "I would imagine myself in the dark part, moving toward the light. That picture's hung in every office I've ever had since then." It hangs in the offices of his employees, too, all of whom receive a copy of Lorenzo's Oil when they join the company.
Adam Bluestein, a Burlington, Vermont–based writer, also wrote this month's Case Study about eMusic.