An interview with Molly S Shoichet. Developing biomaterials and mobilizing resources for assaults on some of the most devastating medical problems

Abstract

Disorders of nervous tissues, in particular those of the central nervous system (CNS)—spinal cord, brain, and retina—are of the most challenging to treat, requiring a combination of complex tools and a collaborative team of materials scientists and engineers, molecular and cell biologists, and clinical scientists. It would be a notable undertaking for a scientist/engineer to assume the leadership role in developing the necessary tools and in assembling the team required to attack any one of the CNS problems. So it is all the more remarkable that Professor Molly Shoichet has been able to make substantial contributions to the experimental treatments for disorders in all three of the CNS organs. A major part of the challenge of treating these CNS defects is their small size and containment within otherwise healthy tissues. These features necessitated a new way of thinking about the required properties of the biomaterial as a delivery vehicle for therapeutic agents and cells, in addition to its role as a matrix/scaffold. It would have to be injectable through an exceedingly small bore (34 gauge) needle and in amounts as small as 1 µl (for sub-retinal injection). One of the biomaterials that Professor Shoichet synthesized, a hyaluronic acid-methyl cellulose hydrogel, can do just that!Professor Shoichet's studies have not only laid the groundwork for promising approaches to some of the most difficult of clinical problems, but have also inspired the work of many other investigators, some of whom were students and fellows that she supervised and mentored, and others, like me, who are ardent readers of her journal articles. For a productive and insightful leader like Professor Shoichet, there are many questions. This is the second of a series of interviews with leaders in the field [1, 2].Molly Shoichet was born in Toronto, Canada and attended the Toronto French School. She received her SB degree in Chemistry at the Massachusetts Institute of Technology (1987), followed by a PhD from the University of Massachusetts, Amherst in Polymer Science and Engineering (1992). From 1992–95 she worked at the company CytoTherapeutics Incorporated, Providence, RI, on encapsulated cell therapy, and held an adjunct faculty position at Brown University, also in Providence, in the Department of Molecular Pharmacology and Biotechnology. In 1995 she joined the faculties of the Department of Chemical Engineering and Applied Chemistry and Department of Chemistry at the University of Toronto, where she is currently Professor of Chemical Engineering and Applied Chemistry, Chemistry and Biomaterials and Biomedical Engineering. In 2002, she founded the matREGEN Corporation, in Toronto.Professor Shoichet is the author of numerous journal articles and the recipient of many awards. She holds the Tier 1 Canada Research Chair in Tissue Engineering, a prestigious University research professorship, and is the only person to be a Fellow of Canada's three National Academies: the Canadian Academy of Sciences of the Royal Society of Canada, the Canadian Academy of Engineering, and the Canadian Academy of Health Sciences. In 2011, Professor Shoichet was appointed to the Order of Ontario, Ontario's highest honor, and recognized as a Fellow of the American Association for the Advancement of Science. In 2013, Professor Shoichet's contributions to Canada's innovation agenda and the advancement of knowledge were recognized with the QEII Diamond Jubilee Award.Professor Shoichet's biosketch, list of publications and ongoing research can be found online [3]. An interview with Professor Shoichet published online in 2010 by the Canada chapter of the Controlled Release Society describes some of the technical details in her development of a hydrogel formulation for injection into the injured spinal cord [4]. Other features of Professor Shoichet's background can be found in an article published in Lifestyles Magazine in 2009 [5].A connection between the first interviewee in this series, Professor I V Yannas, and the second, Professor M S Shoichet, which recently came to light, is that Professor Shoichet was a researcher in Professor Yannas's lab when she was an undergraduate at MIT—a generational connectedness between two leaders of the field.Myron Spector (MySp): I read in one of the articles about you that in high school you had an interest in becoming a doctor. At what point in your education did you decide not to pursue a medical degree?Molly Shoichet (MoSh): I was ‘pre-med’ at MIT, but through a series of research opportunities (through MIT's Undergraduate Research Opportunities Program, UROP), I became increasingly interested in a research career. In my advanced organic chemistry lab, I synthesized poly(vinyl alcohol) which sparked my interest in polymers. This led to my internship with Professor Yannas and my pursuit of a graduate degree in polymer science and engineering. I have to admit that when I started graduate school, I had deferred my acceptance to medical school. After two years of deferring medical school and passing the qualifying exams for graduate school, I had to make a decision. I really liked the idea of inventing the future versus applying the past, and thus decided to pursue a PhD. Perhaps this was an over-simplistic view of research versus medicine, but I am very happy with my decision and enjoy working closely with both medical doctors and basic scientists.MySp: Why did you choose to pursue a doctoral degree in polymer science and engineering?MoSh: It all goes back to that advanced organic chemistry lab that I took as an undergraduate at MIT. I remember one of the other chemistry students telling me to stir the reaction with my eyes closed—all of a sudden, I couldn't stir the solution any more as I had formed a crosslinked polymer. I had finally synthesized something that I could see, which seemed very exciting. I took a series of courses in chemical engineering and materials science and engineering, which furthered my interest in polymers. Working in Yannas' lab allowed me to see the potential of polymers in medicine. In retrospect, it's funny to think that I worked on a nerve regeneration project in Yannas' lab—funny because, who would have thought I would build my career in engineering strategies for application in the nervous system. At the time (and perhaps still), the University of Massachusetts in Amherst had the best polymer program in the US and Canada, and once I was accepted, it was an easy decision to go.MySp: When you entered the doctoral program did you have in mind a career in academe?MoSh: Not really. Polymer Science is one of those fields that emerged from industry and most of the UMass Polymer Science and Engineering graduates pursued careers in industry. The same was true for me. My first job was in industry, at a small biotechnology company in Providence, RI. I was able to take advantage of my experience in polymer science at CytoTherapeutics where polymeric capsules were processed to encapsulate cells for transplantation. CytoTherapeutics was primarily focused on the CNS (Parkinson's disease, chronic pain) and it was my experience there that opened my eyes to the challenges required to overcome diseases of the CNS and the opportunities available to polymer chemists, like myself. After three years in industry, and my husband (Kevin Bartus) finishing his MBA at Harvard, we looked for opportunities in Toronto where I'm from. I was most excited about the research going on in Chemical Engineering at the University of Toronto, and that's really how I ended up in academia. 1995 was actually an awful time in Canada to go into academia, but I was fortunate to win a national fellowship from the Natural Sciences and Engineering Research Council (NSERC) which provided me with partial salary support and a small grant to get my research started.MySp: At what point did you pick up your biomedical knowledge, which is substantially broader and deeper than one would expect of an undergraduate chemistry student and a doctorate in polymers science and engineering?MoSh: Working at CytoTherapeutics was like a well-paid post-doctoral fellowship—I was able to work on cutting edge projects, with brilliant neuroscientists and engineers, and I was allowed to publish. While I dabbled in cell-material interactions during my PhD (my PhD advisor, Tom McCarthy, gave me a lot of freedom during my studies), it really was my experience at CytoTherapeutics that opened my eyes to the challenges and opportunities to make a difference in the CNS. When I wrote my first research proposal at the University of Toronto, I wanted to propose a set of studies that would take advantage of my experiences in polymer science and the CNS. Spinal cord injury seemed like a logical choice, as I could envision implanting tubular structures in the transected spinal cord through which axonal (nerve fiber) regeneration could be guided. Soon after I joined the University of Toronto, Christopher Reeve had his tragic accident. He brought significant attention to this devastating and traumatic injury of the spinal cord, resulting in more funding for the type of research I was already pursuing. Since I had been interested in medicine previously, working at the interface of chemistry, biology, engineering and medicine was somewhat of a sweet spot for me—building on my interests and experiences. I have been very fortunate to collaborate with internationally-renowned leaders in neuroscience and stem cell biology. It is from my collaborators, students and post-doctoral fellows that I have learned my biomedical knowledge—but there is a lot more for me to learn, which is what makes my job so exciting.MySp: You discovered that blending hyaluronic acid (HA) and methyl cellulose (MC) in certain percentages results in properties, including its gelation rate and thixotropic behavior, which are favorable for an injectable gel for an array of applications [6]. Was this an unexpected finding—i.e., did you expect the result based on the chemistry and physical properties of the two polymers?MoSh: We knew that MC is an inverse thermal gelling polymer—that is it gels when it is heated; however, it takes too long to gel. We also knew that salts can be added to MC to promote gelation—but we had no idea that adding HA to MC would provide the material properties that we observed. We now think that HA acts like a salt to promote MC gelation, but we didn't know that this would happen. We believe that it is the shear-thinning properties of HA that makes HAMC injectable through very fine needles and the effects of HA on MC that promotes fast gelation. We originally designed HAMC for local delivery of biomolecules to the injured spinal cord, thereby circumventing the blood-spinal cord barrier, by delivering biomolecules directly to the tissue. More recently, we found that HAMC can also be used for cell delivery—this was another surprise because we actually showed that HAMC is non-adhesive to cells (one of our original design criteria), so it was surprising that it was useful for cell delivery. Interestingly, MC promotes greater solubility of hydrophobic drugs, providing yet another unexpected benefit of the gel.MySp: I recall at the end of a presentation that you made at a 2006 Radcliffe Institute (of Harvard University) Symposium on Tissue Engineering that you showed a slide of your graduate students participating as a team in an annual fundraiser for victims of spinal cord injury. I can imagine that the opportunity for students/fellows to interact with individuals with spinal cord injury would have a positive impact in bringing the students/fellows closer to the importance of their work. Is that what you have seen?MoSh: For years (until it was discontinued), we participated in the Rick Hansen Wheels in Motion event that raised public awareness and funds for individuals with spinal cord injury. It was a great team building event—and we always won for either enthusiasm or speed—and it did make what we were doing in the lab everyday more real for the students and me. Having a greater appreciation of the big picture is very important, especially when so many experiments don't work. It's great to know that you're working towards a solution for a very big problem, for which currently there is no solution. Even if it is just a baby-step that you are taking in finding a solution, it is really important to have some interaction with the patient community to make the research more real.MySp: Your recent work [7] demonstrating that a hydrogel injected onto the surface of the brain (in a mouse stroke model) is as effective (or perhaps even more so) in delivering therapeutic proteins to the brain as intracerebroventricular infusion, without the attendant damage to the brain related to the implantation of the cannula, is compelling. What is the next step toward advancing this technology to the clinic?MoSh: We are actively pursuing this strategy with a larger animal model. Step 1 is moving from a mouse to a rat, where the brain is four times larger and the behavioral studies better defined. This is an ongoing collaboration with Cindi Morshead and Dale Corbett, who bring their expertise in neuroscience/stem cell biology and environment enrichment/rehabilitation to the team. There are many steps required to get this to the clinic, but the rat studies are a key first step.MySp: What hope do you hold for biomaterial-based approaches finding their way into the clinic to the treatment for the treatment of spinal cord injury, stroke and retinal disease?MoSh: Biomolecule and cell delivery to the CNS is complicated by the blood-brain barrier (BBB). Biomaterials (such as ours) offer the opportunity to achieve local delivery, directly to the tissue, thereby obviating the need to overcome the BBB. There is a clear advantage with biomaterial-based delivery—but there are also key design criteria for that biomaterial, such as matching the modulus of the CNS tissue, degrading/resorbing, being biocompatible/cytocompatible, among others. The hope is that these clearly advantageous systems will provide the means to develop successful products that will ultimately enhance the quality of life for patients with these diseases.MySp: You have been teaching biomaterials-related courses at the University of Toronto for 20 years. How has the course content and method for teaching the material changed in that time?MoSh: The courses I've taught at the University of Toronto have changed since 1995, when I joined the faculty at the University of Toronto. I currently teach Organic Chemistry to 3rd year engineering science students and Chemical Properties of Polymers to graduate students. I enjoy both courses, but the latter changes every year because we spend a significant amount of time reading the current literature and critiquing it. This allows students to gain knowledge on cutting edge research, hone their critical thinking skills and develop their communication skills. A big change for me in biomaterials is going from investigating cell-material interactions in 2D (i.e., flat surfaces) to 3D (i.e., in hydrogels). We are very excited about developing 3D chemical patterning of hydrogels using photochemistry and multi-photon laser processing [8]. The materials science is fascinating and using these hydrogels to guide cell growth and ultimately tissue growth will allow us to ask questions not possible in 2D.MySp: Finally, can you tell us what you think about the future of biomaterials-based therapeutic approaches to the treatment of injury and disease.MoSh: This is definitely the future. The key challenges to stem cell delivery are cell survival and tissue integration. Biomaterials can be designed to provide an environment that promotes cell survival and integration. I think that biomaterials are key to success in injury and disease. This is clear from our own research and that of many others.MySp: Many thanks, Molly, for allowing us this conversation.