Spinal Cord Injuries: Solving the Enigma
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Profiles provide insights into the lives, backgrounds, career paths, and futures of scientists who serve as Experts on ACS Chemical Biology’s online Ask the Expert feature. Readers are encouraged to submit questions to the Experts at www.acschemicalbiology.org. The editors will post the most interesting exchanges on the website.
Published online August 22, 2006 10.1021/cb600332x CCC: $33.50 © 2006 by American Chemical Society
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bout 400,000 Americans are living with spinal-cord injuries, according to the Christopher Reeve Foundation. Modern medicine has thus far offered no reliable treatments to regrow neurons or halt the auxiliary nerve damage and death that typically accompanies the initial injury. However, spinal-cord injuries offer an intriguing challenge to researchers interested in combining the disciplines of biology and chemistry. One such investigator is Molly Shoichet of the University of Toronto (U of T). For the past decade, Shoichet and her colleagues have worked to develop novel materials that could protect surviving neurons or spur regrowth after a neurological injury. Though she and other researchers have far to go before individuals can overcome their sometimes devastating disabilities, her approach offers a promising new way to combat this type of injury. Combining Interests Shoichet was born in Toronto in 1965 to parents who worked in business: her mother managed a picture-frame-manufacturing business, and her father ran an executive charter company. “My parents were always wonderfully supportive of the different things I’ve wanted to do,” says Shoichet. “They didn’t necessarily agree with all of them, but they supported my own choices.” That encouraging attitude led her to pursue scientific research, an interest she began cultivating in high school. A particularly energetic teacher “made chemistry fun,” Shoichet says. Rather than use memorization to tackle the subject, the instructor led Shoichet and her classmates through numerous hands-on experiments. “What makes science fun now is discovery, and there was plenty of discovery in the
way he taught class,” she says. Shoichet notes that this approach also probably played a hand in one of her two brothers’ career choices. Brian Shoichet, who studied under the same high school chemistry teacher, is now a professor of pharmaceutical chemistry at the University of California, San Francisco. By the time she graduated from high school, Molly Shoichet had decided to follow in Brian’s footsteps by attending Massachusetts Institute of Technology (MIT) in Cambridge. Early on, she chose to major in chemistry. Shoichet notes that chemistry offered a hidden advantage over other majors—the program required few classes, so she could fill her time pursuing other interests, such as biology. Taking classes in the life sciences sparked a curiosity for medicine, she says. However, many of her other chemistry classes—especially those in polymer chemistry—ignited her interest in basic research. In a few settings, she was able to combine those two interests. For example, during her senior year, she worked with MIT materials scientist Ionnis Yannis on a new project he started to create polymers for nerve repair. However, by the time she graduated from college in 1987, Shoichet was unsure whether she wanted to ultimately pursue research or practice medicine. Unable to decide, she applied to both medical school and graduate school. That fall, she enrolled in a graduate program in polymer science at the University of Massachusetts, Amherst (UMass). “I thought I knew what a doctor did, but not what a scientist did,” Shoichet says. “Part of my rationale with pursuing a graduate degree was to try to understand that.” For the next 2 years, she deferred her acceptance to medical school, in the end deciding that basic research was her preferred path. w w w. a c s c h e m i ca l biology.org
After arriving at UMass, Shoichet was intent on pursuing basic polymer research. She found a valuable mentor in Tom McCarthy. Under McCarthy’s guidance, Shoichet investigated different ways to modify polymer surfaces without affecting the bulk structure. She focused on fluoro polymers because they are inherently chemically inert, allowing the surface to be chemically modified with limited affect on the morphology or topology of the surface. Shoichet introduced carboxylic acids to fluoropolymer films (1 ) and then used these charged surfaces to control the adsorption of oppositely charged poly(l‑lysine) (2 ). An important offshoot of this work was determining how changes in surface properties affected the behavior of cells cultured on polymer films—work that would guide her future career. She and McCarthy published several papers based on this research (3–7 ), and she completed her doctoral degree in 1992. Industry and Innovation As her time at UMass wound down, Shoichet was determined to find a job that combined medicine and chemistry. She pursued several strategies to track down the best opportunity. Contacting everyone on a list of speakers from a recent Gordon Conference eventually led her to CytoTherapeutics, based in Providence, RI. The company’s main focus was encapsulated cell therapy: using cells, which were encased in polymer capsules to protect them from immune rejection, to deliver biologics to treat injuries and diseases. CytoTherapeutics, which is now a part of the Palo Alto-based Stem Cells, Inc., focused on treating neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease). “In conventional drug delivery, we’re limited to how much drug we can give at one time, and drugs lose their bioactivity www.acschemicalbiolog y.o rg
over time. The idea [at CytoTherapeutics] was that if we deliver cells, they’re con stantly producing new therapeutic mole cules. With that approach, we should have a ready supply of therapeutic molecules for a long time,” she explains. Shoichet found her new job “a wonderful opportunity,” she says. Though CytoTherapeutics used polymer chemistry to create the capsules that surrounded cells, few polymer scientists worked at the company when she arrived. That gave her ample openings to carve a niche at the company: she worked with neuroscientists to evaluate the materials that would pro mote long-term survival and functioning of cells encapsulated within the hollow fiber membranes (8–10 ). After nearly 3 years, Shoichet left Cyto Therapeutics for personal reasons—her husband, Kevin Bartus, had finished his master’s degree in business administration at Harvard University and secured a job with a consulting company in Toronto. This gave Shoichet and her husband an opportunity to move back near her family in Toronto. She took away a valuable lesson from her time at CytoTherapeutics. “I noticed that biologists would just take materials off the shelf and make them work,” she says. “What became clear to me is that if I could understand the design criteria that they needed materials for, I could make materials specifically for biological and medical applications instead of just taking something off the shelf.” Seeking new opportunities once she and her husband relocated, Shoichet initially looked for industry jobs similar to the one she left. However, a prospect that intrigued her more was working at the U of T. Shoichet learned about an annual grant program awarded by the Natural Sciences and Engineering Research Council of Canada geared toward women interested in pursuing research in the physical sciences and engineering. Over the next
few months, she prepared a proposal that combined her interest in medicine with her growing expertise in polymer science. “I realized that spinal-cord injury was an area in which I could apply my knowledge,” she says. “It’s a big problem that’s unanswered, and I thought that people in universities should work on these big problems.” Shoichet proposed using polymers to create nerve guidance channels for protecting and regrowing damaged neurons. She won the grant and was immediately offered a position at the U of T. She quickly became aware of the intricacies involved in treating spinal-cord injuries. “Every year, I understand a bit more how complicated it will be to come up with a solution,” she says. “I know now why it’s such a niche area.” The nervous system has a variety of mechanisms that seem to actively fight repair after injury, Shoichet explains. A cascade of cellular events releases biomolecules that cause damaged axons to degenerate further. Later, a glial scar walls off damaged tissue at the injury site. These complications make treating spinal-cord injuries difficult even immediately after the trauma occurs, and more difficult as time goes on. Polymer Cure? However, since she arrived at the U of T in 1995, she has focused her work on several approaches that offer renewed hope for treating spinal-cord injuries. For example, Shoichet and graduate students in her lab have collaborated closely with U of T neurosurgeon Charles Tator; they have developed an injectable hydrogel that could deliver neuron-saving drugs directly to the site of an injury. For the past several years, Shoichet and her colleagues have tested prototype polymer gels on rat models of compression injuries, in which the spinal cord is VOL.1 NO.7 • 414—416 • 2 0 0 6
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“What became clear is that if I could understand the design criteria needed, I could make materials specifically for biological and medical applications instead of just taking something off the shelf.”
crushed. The biggest initial concern when testing their new method was safety, says Shoichet. Hydrogels have never been used to treat spinal-cord injuries in this way. It was unknown whether this approach could have detrimental effects, such as lingering in the spinal column and blocking fluid flow, which can lead to increased pressure in the brain. In 2003, she and her colleagues published the first paper showing the safety and feasibility of this method to localize drug delivery (11, 12 ). This year, Shoichet’s lab provided evidence that a new hydrogel formulation provides some protection to neurons on its own, without additional drugs. “While we were really looking for safety, we saw that the new gel had its own benefits,” she says (13 ). She and her colleagues are currently investigating which drugs and biomolecules might further encourage cell survival and limit degeneration after compression injuries. She and her colleagues are also pur suing methods to regrow severed axons by creating nerve guidance channels, or polymer tubes, that encourage axon regeneration by providing a permissive environment. Here, Shoichet and her team are testing their prototypes on a more severe injury model, fully transected rat spinal cords. Working again with Tator and also with U of T neural-stem-cell biologist Cindi Morshead, Shoichet and her lab are currently investigating strategies to add various factors to the channels to encourage axon regrowth. For example, the researchers are embedding signaling molecules that stimulate axon growth during development into polymer nerve guidance channels. In ongoing studies, Shoichet’s lab is investigating biomimetic approaches for axonal guidance. These strategies include creating scaffolds that guide axons with immobilized concentration gradients of neurotrophic factors (14, 15 ) and scaffolds that guide axons with cell adhesive peptides, within a 3D, photochemically patterned hydrogel (16, 17 ). 416
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Recently, Shoichet’s lab has turned its focus to solving another biomedical challenge—crafting materials for cancer-drug delivery. “It’s a new area for us. We’d developed some really interesting polymers” in the course of developing the hydrogels and nerve guidance channels, says Shoichet. “We thought that the ideas we had in developing those polymers and some of their properties would be interesting for targeted cancer-drug delivery.” Much of the lab’s work in this area, adds Shoichet, has centered on copolymers that they created with a random distribution of hydrophilic and hydrophobic components that are also charged. She and her colleagues found that these components can self-aggregate to a diameter of
