CHAPTER 4: The Spinal Cord Research Center in the 21st Century

By John Houle, PhD
Professor in the Department of Neurobiology & Anatomy at Drexel University College of Medicine, and director of the Spinal Cord Research Center

Working my way to Philadelphia

It was a long journey, but in 2005 I finally made it to the place I had been dreaming of being since my graduate student days in the late 1970s when I first starting reading papers by Goldberger and Murray (or Murray and Goldberger) about plasticity in the injured spinal cord. For a short scientific perspective, at the time I was a PhD student in the lab of Dr. Gopal Das at Purdue University, who was the first to demonstrate that transplants of fetal neural tissue into the brains of adult rats would survive, differentiate into specific types of neurons and form synaptic contacts with host neurons. It also was a time when Sam David and Albert Aguayo in Montreal demonstrated for the first time that adult mammalian axons would regenerate if provided a supportive environment, such as a graft of peripheral nerve.

At my 1978 SfN poster presentation, I met Barbara Bregman, who was Michael Goldberger’s PhD student, and quickly we became close friends. Barbara introduced me to Michael and Marion and the Medical College of Pennsylvania (MCP) culture, and immediately I knew that it was a place I had to try to go to. I interviewed for a postdoctoral position with Michael and Marion in February 1981 and discussed the possibility of doing fetal transplants to promote recovery after spinal cord injury. At that time no one had managed to do this in an adult animal, and it was an exciting possibility to do this with the MCP group. On that visit I met Theresa Connors, Hazel Murphy, Tim Cunningham and Alan Tessler (who would later become a good friend and collaborator). The only hang-up was finding funding for my position, and unfortunately having two young children meant that I could not wait long before having to make the decision to accept an offer elsewhere. The timing was just bad, but I felt certain that at some point there would be another opportunity to be part of the MCP experience.

Working hard at a spinal cord injury (SCI) conference in Las Vegas in the late 1990s
People from L to R: Simon Giszter, John Houle, Marion Murray, Justin Snow, Alan Tessler (kneeling), Yi Liu (MD/PhD) and Kenny Simansky

After spending several years in Canada working on astrocyte lineages and the glial reaction to injury, Barbara informed me that her former postdoc advisor, Dr. Paul Reier, was establishing a spinal cord research group at the University of Florida and was looking for someone to run his new laboratory. Barbara and Paul had been transplanting fetal spinal cord tissue into neonatal spinal cord injured rats and Paul was now ready to move this into adults. I jumped at the chance to get back into the transplant field and went to join Paul in 1984. During my time there (1984-’87) I began my own studies on the potential for chronically injured neurons to regenerate and performed experiments with intraspinal peripheral nerve grafts. I also started collaborating with Alan Tessler, who had come to UF to learn the art of intraspinal transplantation to promote dorsal root regeneration. That was also when I first became acquainted with Dr. Tim Himes, then a graduate student with Alan. Together we did some groundbreaking work involving the demonstration of synaptic evoked potentials from regenerating dorsal root axons and their extension beyond the transplant back into the host spinal cord. Alan and I also published a top-five cited review (“Repair of Chronic Spinal Cord Injury”) in Experimental Neurology for five years in a row.

When it was time to start my own laboratory I found a department chair (Dr. Shirley Gilmore) at the University of Arkansas for Medical Sciences who reminded me very much of Marion Murray. Shirley was a leader in her field of spinal cord development, she was the first woman to serve as department chair at the medical school and was a no-nonsense leader who stood up for her faculty when appropriate and admonished us when necessary. Shirley was the mentor I needed as a new assistant professor, and she gave me the support and encouragement to withstand the disappointment of some less than favorable early reviews. I have tried to impart these features in my mentoring of students and faculty throughout my academic career. Interestingly, I find many of the qualities that I admired in Dr. Gilmore in Dr. Fischer, and they make him such a pleasure to work with both professionally and personally.

Highlights of my time in Arkansas as they relate to Drexel

I was fortunate to establish collaboration with two groups in Arkansas that helped my work move forward: locomotion physiologists and muscle biologists. Together we started to explore electrophysiological parameters of regenerated axons and their ability to promote some measure of functional recovery, and to develop rehabilitation approaches to train reestablished neuromuscular circuits after SCI. This included the building of motorized exercise bikes for spinalized rats that we later shared with colleagues at Drexel, University of Florida, University of Louisville and University of British Columbia.

As my research program on regeneration began to gain some notoriety I received an inquiry about postdoctoral research possibilities from a talented PhD candidate at the University of Hong Kong. In 1998 I welcomed Dr. Ying Jin to my lab to begin a productive two years of training. Ying worked tirelessly (as she still does) examining the neuronal response to injury and the beneficial effects of neurotrophic factors in reducing axonal dieback. Ying was instrumental in performing the experiments of a new collaboration with Dr. Itzhak Fischer, who had genetically modified fibroblasts to release the neurotrophic factor BDNF. Soon after completing this study, Ying left for a position at the University of Kentucky, but little did we know that we would be working together again in Philadelphia about eight years later. It is interesting to see how many of our paths cross at different times in different places.

A few years after Ying moved to Kentucky she was joined there by a bright young postdoctoral fellow from China, Dr. Shaoping Hou. Shaoping had contacted me in 2004 about a possible postdoctoral position in my lab, but I was being recruited for the position at Drexel at the time and was unsure of whether I could provide for additional personnel right away. I suggested that he contact a close friend and colleague, Dr. Sasha Rabchevsky, at the University of Kentucky about a position. I had great confidence in Sasha as a possible mentor for Shaoping because of my connection with Sasha during his graduate work with Paul Reier in Florida. I think what this starts to illustrate is how the influx of new investigators helps new spinal cord centers become established, allowing the field to expand in scope; yet we remain strongly bonded and interconnected by a common goal of improving the quality of life of individuals with a spinal cord injury.

My pre-Drexel period ended in 2004 with two very happy events. Early in the year Dr. Veronica Tom joined the lab after finishing her PhD work with Dr. Jerry Silver at Case Western University. Her in vitro work with extracellular matrix molecules and chondroitinase to promote axonal growth had led the way for some in vivo experiments that I was working on with Jerry’s assistance. I was fortunate to entice Veronica to come to Arkansas for postdoctoral training, and together we finished a study demonstrating recovery of forelimb use due to regeneration of axons through an intraspinal peripheral nerve graft. Right away I felt comfortable with our scientific relationship and knew that she had great potential for stardom. I just needed to stay out of her way! Around this time Itzhak contacted me about coming to Drexel to give a seminar and to talk about the position of director of the Spinal Cord Research Center. Certainly I was interested, because it was the place I always wanted to be; the people at Drexel were some of my closest friends and colleagues, and professionally it was the right time to consider a move.

The major consideration not to move was that my wife Katherine had lived most of her life in Little Rock, and all of her family lived there, including our three grandchildren. Nevertheless, she agreed to visit Philadelphia for a long weekend with me. I believe destiny finally caught up with me because Katherine had a great time on the trip, meeting Itzhak and Gloria Fischer, Alan and Dee Tessler, Marion Murray and Justin Snow, and touring parts of Philadelphia. Katherine was so supportive of my making this move that we even found a house in Chestnut Hill that we wanted to buy before I had accepted an official offer. The last step was to convince Veronica to make a second major move within a year’s time, but I feel she was pretty easily swayed once she visited Drexel and appreciated the possibilities for scientific growth and collaboration at Queen Lane. I couldn’t have picked a better new boss than Itzhak. Everything we discussed about the position came to fruition, he was honest and up-front with his expectations and I believe we have shared an unrivaled 15-year period of productivity and growth because of our mutual interest in the development of young investigators.

Spinal Cord Research Center, 2005-2020

Itzhak Fischer with John Houle in a meeting (mid 90s)

The research strengths of the Spinal Cord Research Center in 2005 were transplantation to promote regeneration (Drs. Itzhak Fischer, Alan Tessler, Tim Himes, Marion Murray), robotic and treadmill training to promote functional recovery (Drs. Simon Giszter and Michel Lemay) and restoration of neuromuscular circuitry (Drs. Young Jin Son and Tony Burns). A core facility led by Dr. Jed Shumsky was developing behavioral assessments to detect sensorymotor recovery, and one of the important outcomes of this work was publication of a rat forelimb locomotor scale (FLS) to evaluate recovery of arm and forepaw use, which was analogous to the famous BBB scale used to evaluate hindlimb use after SCI. Assisting Jed on this project was Harra Sandrow, who later became the first PhD graduate student to join my lab. Theresa Connors was (and remains) the mainstay of the day-to-day operation of the center. The MCP/Hahnemann/Allegheny/Drexel spinal cord research group had long been known for their collaborative work and NIH support in the form of a program project grant, and it was a major goal of mine to continue this tradition.

With everyone’s input we designed a proposal around three PIs (Fischer, Houle, Lemay) and four core facilities (behavior, surgery, microscopy/histology and tissue culture) with directors from the group. Marion served as senior advisor for the project. Our first attempt received encouraging reviews but, not unexpectedly, it needed some revisions. With another great team effort, we were successful with the resubmission and funding of the P01 entitled “Spinal Cord Injury, Plasticity and Transplant Mediated Repair” began in April 2008. At that time, we were the only NIH funded program project for spinal cord injury research, and that remained the case for the full five years of the grant. There were larger and perhaps more prestigious institutions in the U.S. involved in SCI research, but to be the only P01 meant that we were held in high esteem by our peers. I felt our group worked hard every day to maintain their professional respect.

Starting a P01 with new colleagues was a really exciting time for me because it opened up many research possibilities and facilitated recruitment of high-quality graduate students and postdoctoral fellows, which had been difficult during my tenure at the University of Arkansas for Medical Sciences. Getting settled in the lab with Veronica, adding Harra to my group and working daily with Alan and Itzhak was like a dream come true. I learned so much from everyone over the first couple of years and had such great, stimulating conversations that it was like being at SfN every day. The center members always worked as a team. We expanded the range of techniques and training available within each of the core facilities, had some wonderful summer trainees and visiting PIs, and managed to have some fun along the way. There were many occasions for celebration: invited international talks, new grants, promotions, additions of new personnel. Here are a few highlights during the first five years of the P01: Ying Jin joined the Fischer lab, Veronica was promoted to assistant professor, Dr. Marie Côté joined my lab as a postdoctoral fellow (we got Julien as a bonus signee in that deal), Dr. Megan Detloff joined my lab as a postdoctoral fellow (interestingly her PhD advisor, Dr. Michelle Basso, was a postdoctoral fellow with Michael Goldberger at MCP), and Shaoping Hou joined Veronica’s lab as a research associate.

Another momentous occasion was the official retirement of Marion in 2013. Fortunately for us she continued reviewing our manuscripts and grant proposals, but her research career was complete with the thesis defense of Dr. Laura Krisa (now associate professor, Department of Physical Therapy, Thomas Jefferson University). Sadly, there were two valuable members of my lab who lost their battle with cancer within a few years of each other. Dr. Gang Liu was instrumental in moving my research into more molecular-based approaches, concentrating on changes in micro-RNAs associated with the PTEN-mTOR pathway after SCI. Dr. Vicki Zhukareva was an extraordinary protein biochemist whose protocols for tissue preparation and Western blot analysis are used routinely in many labs in the department. They were dedicated scientists and truly wonderful people and have been missed every day.

For the P01 competing renewal, one of the innovations we proposed was to embark on a five-year expansion program of the Spinal Cord Research Center whereby we would actively seek the best and brightest young SCI investigators to bolster our existing expertise and expand into new research areas. Already we had kept one of the best and brightest in Dr. Tom and realized we should do that again with Dr. Côté based on her work on post-SCI spasticity and importance of potassium-chloride co-transporters. We then went outside the department and pursued two extremely talented individuals. We were fortunate to secure the services of Dr. Michael Lane, knowing that he would be an ideal candidate to lead studies of secondary complications after injury, concentrating on respiratory dysfunction. Michael’s connection with my former mentor, Paul Reier at UF, only positively influenced my judgement. When looking to expand our research portfolio in the area of interneurons and motor control, the input from Dr. Rybak was critical in leading us to the recruitment of Dr. Kim Dougherty from her postdoctoral position in Sweden. For the final two positions we chose two individuals who had demonstrated great success in securing research funding in areas that were highly significant for our center program and had strong potential to run an independent program: Dr. Shaoping Hou for his interest in autonomic control of bladder and cardiac function after SCI, and Dr. Megan Detloff for her work on neuropathic pain, inflammation and exercise. While this major expansion was supported in small part by the renewal of the program project, the success of this five-year growth plan was due primarily to Dr. Fischer’s negotiating skills with Dean Schidlow and his willingness to use departmental funds to back people who we had complete faith in as new investigators.

Growth within the center was not yet finished, though. Over the last few years Dr. Rybak has attracted some outstanding postdoctoral fellows to his computational neuroscience research program. First with the addition of Dr. Simon Danner and then Dr. Jessica Ausborn, there now was a critical mass of young investigators in Ilya’s group. These talented individuals followed a familiar formula of publishing outstanding papers, submitting grant proposals and securing NIH funding for their independent research. Given our proven success with ‘in-house’ promotions, Dr. Fischer worked his charm again with the new dean and secured tenure-track positions for both Simon and Jessica to begin in 2020. Not everything about this year of the pandemic has been awful!

While quite accomplished in their own areas of SCI research, each of these seven new faculty appointees had to have one thing in common – the understanding and desire to be part of a special culture where research ideas are shared freely in a collegial atmosphere. This has been part of the core principle of the SCI group since it was established by Michael and Marion at MCP over 40 years ago, and it is an important part of our identity. It has been so rewarding to see how each of them has matured professionally and grown their individual research programs while developing collaborations within the center that could lead to future programmatic funding. In September 2018, Marion Murray, one of the founders of the spinal cord research group at MCP, died. This was a deeply felt loss of a friend and colleague for everyone in the department, if you had been here for 40 years or for 40 days. In a memorial ceremony at Queen Lane held a few months later, there was an outpouring of appreciation for what Marion had contributed to each individual in the room. During the opening remarks I was grateful to be able to announce Drexel’s official naming of the Marion Murray Spinal Cord Research Center. Every day that I pass the lettering at the end of the corridor proclaiming it her center I think back on what it was like at the beginning when few people believed in the plasticity and regeneration work that she started, and how I so much wanted to be part of it. I then realize how lucky I am to have been a part of the group for the last 15 years.

As I was finishing this perspective there was an announcement of the 2020 Daniel V. Schidlow, MD, Transformational Leadership Award, and I wanted to recognize Dr. Fischer as the first recipient of this award, because it reflects what his contribution has been to the Marion Murray Spinal Cord Research Center for over 25 years. “This award is presented to a faculty member who exhibits substantial leadership to transform and make change through example and articulates an energizing vision. This faculty member encourages, inspires, mentors and sponsors a diverse, inclusive and equitable next generation of clinicians, scientists, educators and staff. This transformational faculty leader motivates members of the institution to innovate and create change that will help grow and shape the future success of the institution.”

 
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