Samuel Stupp didn't trust his eyes.
The mice in the video flickering on his colleague's computer screen were moving their legs. Their back feet trailed behind them from time to time, but the fact that they were walking at all was astounding. Only a few weeks earlier, they'd been paralyzed from the waist down. Then Stupp's team at Northwestern University injected them with made-to-order molecules. Now the mice were trying to run around their cage. "I wasn't satisfied with the video, so I went to the lab to see it myself," remembers Stupp. "I was totally stunned."
Those mice were the first living glimpse of the future that Stupp is hoping to accelerate in his role as the director of the Institute for BioNanotechnology in Medicine at Northwestern. It's a future in which molecular self-assembly — where researchers direct molecules to spontaneously combine into ordered structures — will help the body heal itself. The prospect is straight out of The Six Million Dollar Man, but one better, since damaged parts will be replaced with actual human tissue instead of metal.
The intrepid Stupp, 61, first made his name as a materials scientist in the highly technical field of self-assembly, which has traditionally involved developing products for industrial use — a computer chip, for example, or a protective coating. But back in the late '90s, when "regenerative medicine" still sounded like something from a sci-fi novel, he began to wonder if he might be able to apply the principles of molecular self-assembly to biology. "I have an interdisciplinary brain," Stupp says in a lilting in-between accent (born in Costa Rica, he speaks four languages fluently). "We had this idea that you could have a single platform that would cover an extremely broad range of conditions.
"It's always easier when you specialize in something, and there is a place for that," he continues. "But if you're trying to solve these kinds of problems, you cannot do it without interdisciplinary research." So he has built a lab in his own image, boasting biologists, physicists, chemists, and nanotechnologists, as well as materials scientists; he has also forged partnerships with neuroscientists and surgeons.
With his shiny bald pate and unflinching gaze, Stupp reminds me of actor-producer Bruce Willis, and when he says he'd want to make movies if he weren't a scientist, it makes sense. It's the directorial thrill of fitting the right puzzle pieces together, the synergy of assembling a diverse team and watching the sparks fly, that appeals to him. "You can motivate and inspire people to a higher level of creativity. I guide the process, give the 35,000-foot view."
The potential of that process is breathtaking. One day, the specialized molecules — the "noodle gels" and macroscopic scaffolds — that Stupp and his team are creating could repair injured spinal cords and treat brain disorders. Success would mean better lives for countless patients and enormous profits for Nanotope, the startup Stupp founded to commercialize the lab's discoveries. And even failed ideas can serendipitously turn into better ones. "When you see something interesting, you have an idea what might happen," Stupp says, "but you might discover something completely orthogonal that you didn't predict."
The Institute for Bionanotechnology in Medicine (IBNAM) takes up the 11th floor of the towering Robert Lurie Medical Center at Northwestern's downtown Chicago campus, just steps from the shore of Lake Michigan. When I arrive, Stupp is running late, so Dorota Rozkiewicz, one of his junior colleagues, gives me a whirlwind lab tour, complete with superlatives about her boss. "He does great science, but many people are innovative," she tells me conspiratorially, between spiels about the state-of-the-art mass spectrometer and the clean room. "He also has this vision of where the work is going — which subjects will be a great success in the future."
Rozkiewicz and I are still chatting in a conference room overlooking the lakeshore neighborhood when Stupp enters, so soundlessly that I don't realize he's there. He typically works on dozens of projects at any one time, but he doesn't seem stressed, or rushed. Instead, he fetches me a bottle of water and insists I tell him how I got into writing. It's only when he starts talking about what motivates him that I get a real sense of the magnitude, the ambition, of his self-imposed mission. "I don't like the idea of applied research — develop a product and that's your focus," he says, looking straight at me without hesitation. "I want to leave behind a scientific legacy that can be used by other people in other fields."
Stupp didn't always have such a strong sense of his scientific calling. He grew up in Costa Rica, where his Eastern European parents had fled after Hitler rose to power, went north to attend UCLA, and then pursued a materials-science PhD at Northwestern. It seemed a practical choice, since he was hoping to go back to Costa Rica someday and he knew the country's economic situation was shaky.
Materials scientists were early to the evolving universe of nanotechnology, which involves manipulating materials on an atomic scale to produce molecular structures that can't be achieved with traditional manufacturing techniques. Nanotechnology, in turn, gave rise to molecular self-assembly, where researchers create molecules programmed with instructions that allow them to join together into complex structures. By the time Stupp secured a job in the materials-science department at the University of Illinois at Urbana-Champaign, he was already fascinated by self-assembly. "I saw the potential," he says, "in designing a molecule that would assemble into a nanostructure that would have a specific shape."
It wasn't until 1995 that one of his nanotechnology experiments steered him onto an entirely new scientific course. He was trying to make molecules called rodcoils line up side by side to create a large polymer sheet with one side shiny and the other sticky, properties that might make the sheet useful for industrial applications. But something unexpected happened. Instead of forming a single thin membrane, the rodcoils coalesced into trillions of tiny individual structures that looked like mushrooms.
Stupp initially wrote off the result as a failure, but he quickly realized that the mushroom-shaped nanoparticles might have a host of advantages. "It was not our target, but it was extremely interesting," he says. The structures had optical and electrical properties, and could produce an electric current. And their formation showed Stupp and his team the principles of how to build nanofibers. "I said, 'We could actually make a nanostructure that could do something within the body.' "
Stupp's mind started to race. What if he could inject the nanomolecules into the bloodstream so they could serve as microscopic vehicles to deliver therapeutic compounds? Even better, what if he could modify the nanomolecules so that they would attract the body's own healing compounds to an injured area, kick-starting the repair process without introducing any foreign cells at all? The "mushroom" paper Stupp published in 1997 attracted lots of attention, and Northwestern lured the rising star to its materials-science program in 1999. The very next year, Stupp founded IBNAM, the lab he hoped would bring his interdisciplinary ideas to fruition.
At first, Stupp struggled to find his stride in the nascent world of regenerative medicine. Since he wasn't a biologist or a clinician, he didn't know how to design studies to evaluate the real-life usefulness of a given medical approach. He started tinkering with potential therapies without a clear idea of how to get them to patients. "We published a paper in November 2001 about a molecule that could be used to help tissue regenerate," he recalls, "but there was no real biology in that paper." Shortly afterward, when he started seriously considering trying to treat spinal-cord injuries with molecular self-assembly, he decided to recruit his friend and colleague Jack Kessler, a Northwestern neuroscientist. "Clinician-scientists like Kessler understand very clearly what the problems are to be solved," Stupp says. "We may know generally that it would be great to have a therapy for spinal-cord injury, but that's different from knowing how you would go about testing it in an animal model." He also had a hunch that Kessler would be intrigued by the project, since his own daughter had become paralyzed after a bad skiing accident.
Stupp proposed to Kessler that they use a nanofiber structure containing portions of a protein called laminin. In in-vitro experiments, these laminin components had helped develop neural stem cells into more-specialized neurons — a reaction that had the potential to encourage healing in the brain and spinal-cord tissue over time. The particles Stupp had designed would assemble spontaneously into cylindrical nanofibers. Inside the body, he hoped, these nanofibers would supply a framework for the neural cells to grow onto. "The beauty of this approach," Stupp says, "is that it just involves injecting something that looks like water."
Kessler supplied the biological expertise, including the knowledge of how to conduct experiments with live animals, and designed a study to assess the effectiveness of the treatment by injecting the nanofibers into partially paralyzed mice. The cross-disciplinary collaboration hit pay dirt. Six weeks after Stupp and his colleagues injected the fibers into the mice in the spring of 2005, the mice began to move their legs again — and headlines followed.
Characteristically, by the time people got excited about his spinal-cord work, Stupp was onto something new: cartilage. "I get dozens of emails saying, 'I have problems with my knee, I need more cartilage,' " he says, gesturing forcefully to convey the sheer scale of the need. "It's a huge deal." (Osteoarthritis, he notes, is a $65 billion industry.) To regrow damaged cartilage, which does not usually come back on its own, Stupp devised self-assembling polymer nanofibers. Once inserted into the body, these nanofibers would form microscopic scaffolds that bind to a growth-factor compound that circulates naturally in the body. When the scaffolds had harvested enough of this compound, Stupp predicted, its high concentrations would direct existing cartilage cells to start multiplying and growing into the scaffolds.
To vet his approach, Stupp enlisted materials scientist Ramille Shah, a member of his IBNAM team. She'd been turned on to Stupp's bionanotech vision as an undergrad — "He sort of opened my eyes to the field," she says — and then worked with cartilage during a tissue-engineering PhD stint at MIT. Shah did a series of in-vitro studies in the lab to establish that new cartilage cells would actually thrive in the matrix of the self-assembling molecules Stupp had devised. Then her husband, Nirav Shah, an orthopedic surgeon, stepped in to help test the technique on rabbits, drilling a series of tiny holes into the bone just beneath the damaged regions and seeding the holes with a gel containing Stupp's molecules. The intervention worked — a result that Ramille attributes in part to Stupp's shrewd management skills. "He really has a knack for knowing the potential of people and what teams will work best together."
Dozens of people crowd into a conference room set up like a mini-auditorium, with multiple tiers of seats, for the biweekly lab meeting in late August. The first speaker is Mark McClendon, a grad student in chemical and biological engineering, who proposes piggybacking on Stupp's noodle-gel idea to create a tube that could serve as an artificial blood vessel. Throughout the presentation, Stupp keeps up a volley of questions about how the vessel will be manufactured. Could the vessel be constructed with a multilayer structure — an outer layer of smooth muscle cells and an inner layer of epithelial cells? He doesn't hesitate to interrupt, to interject an even-toned "I doubt that," during these talks. Between bites of cold-cut sandwiches, lab members from every specialty follow his lead, jumping in with ideas. One biology expert says that McClendon needs to find a way to measure how effectively the cells in the gel vessels are combining into tissues, while a chemist recommends an ion that will help the vessel solution gel more quickly.
Bombarding up-and-coming talents with questions, criticisms, and alternative possibilities is, Stupp says, the ideal way to train scientists to think beyond the boundaries of traditional disciplines. But he also understands the importance of encouraging his collaborators to trust their own instincts. Researchers who've worked under him report that he is hands-on in helping them choose their topics of study, and more hands-off thereafter. In a sense, then, Stupp's approach to science is as self-assembling as the molecules he creates: He sets the bar, articulates the genetic code of an idea, and watches as the crack team he's selected pitches in to pull things together.
He steered Rozkiewicz, who was trained as a materials scientist in the Netherlands, toward trying to create cells from scratch, using molecules created in the lab. She admits the research has forced her outside of her scientific comfort zone; dealing with cells instead of chemicals, she says, "you have to work with biologists and they use a different language, different terms." But she can't resist the challenge of such a revolutionary project.
"You have to understand what makes them tick," Stupp says of his way of delegating work to his colleagues. "How is it that they think?" He can do that, physicist Monica Olvera de la Cruz points out, because he listens. "Stupp takes the time to drink good coffee, to look at people," she says. "He pays attention to human beings in a way I've never seen from someone at his level."
"I want to show you," Stupp says urgently. He clicks on a movie file on his laptop. On the projector screen at the front of the room, the tip of a pipette deposits a thin line of a substance that looks a little like Vaseline. A microscopic close-up shows the nanofibers that make up the gel bundle right next to one another, like a line of soldiers standing at attention. The spaghetti-shaped noodle gel, Stupp explains, serves as a conduit — it's ideal for delivering proteins, stem cells, and other healing agents exactly where they're needed.
"I can put live neurons [nerve cells] in the liquid, and when I draw the noodle, what I really have made is a cell wire," Stupp says, trailing his hand off to one side as if to conjure the wire from thin air. "A surgeon could just draw it right in tissue."
Like Stupp's career in regenerative medicine, the noodle gels originated by accident. Materials scientists in the lab "were doing something else and this showed up from left field," he says. The peptide molecules Stupp was working with arranged themselves into a flat sheet when they were heated, but when they were cooled, they shattered into bundles of fibers that lined up neatly as they were squeezed from a pipette. To understand why, Stupp turned to Olvera de la Cruz, a specialist outside his own wheelhouse, who figured out that the sheets were breaking into bundles for much the same reason as streams of water from a faucet combine into droplets: to minimize their surface area. She dubbed the phenomenon "two-dimensional Rayleigh instability."
Now that the noodle gels have made the July 2010 cover of Nature Materials, Stupp is off and running, musing on the thousand and one variations that might transform this single good idea into an entire field of study. Why couldn't he put the noodles in damaged hearts to restore them? The noodle would act like a live wire, conveying an electrical signal from one part of the heart to another. And for people with degenerative neurological disorders like Parkinson's disease, the noodles could spirit new neurons to the parts of the brain that need them the most. "If you could make a noodle starting where migration of stem cells in the brain starts and draw it to where there's been a brain injury," he says, "the noodle will be an artificial highway for the cells." He recently formed a high-profile partnership with neuroscientist Georg Kuhn of Sweden's Gothenburg University to test this concept in the lab, with the eventual goal of trying it on humans down the line.
In fact, Stupp hopes to shepherd several of his lab's innovations into clinical trials within the next couple of years — particularly the treatments for spinal-cord injuries and cartilage damage, as well as a heart-repair technique based on molecular self-assembly. He knows human testing will be a protracted and complex undertaking; in the best case, it will be more than five years before any of his therapies make it to the clinic. But this fall, Stupp's startup, Nanotope (in which Northwestern is a stockholder), formed a multimillion-dollar partnership with London-based orthopedic and medical-device company Smith & Nephew to develop a cartilage-regeneration product based on Stupp's animal studies. The agreement stipulates that Smith & Nephew will cover all human-clinical-trial costs. "Some things may not work, but then some things will," Stupp says. "That is very encouraging, the breadth." More than a decade of out-of-the-box science has taught him that frustration and revision are the constant companions of meaningful innovation. "You have to be in a learning mode, always on your toes. It's like you're moving all the time. You have to keep learning new languages in order to survive."
Elizabeth Svoboda is a Fast Company contributing writer. Her last article for the magazine was "Creative Cures" (November 2010).