Collaborative Effort Accelerates Progress

In 1985, Barth Green, M.D., his patients and families touched by traumatic spinal cord injury, and the University of Miami School of Medicine came together to establish a unified effort to find new treatments and ultimately a cure for paralysis. Ten years later, The Miami Project to Cure Paralysis spans disciplines in neuroscience, rehabilitation and clinical sciences.

In more than a dozen laboratories, seventy faculty members, students, fellows and technical staff work together studying the mechanisms that cause spinal cord damage, the physiological changes that occur after injury in spinal pathways and the nerves and muscles that control nerves and muscles that control movement, cellular transplantation aimed at replacing lost nerve cells and stimulating regeneration, and the use of electrical stimulation and other therapies available today to maintain health and overcome limitations on individuals who have sustained SCI.

The concept of bringing together scientists from different disciplines, with varied but complementary expertise and interests, has resulted in a highly motivated and collaborative scientific effort. This effort is invigorated by the interactions Miami Project scientists have with colleagues in their own disciplines at universities and biotechnology companies across the globe. With grant support from other agencies that seek to support the best in SCI research, new projects are initiated that accelerate the progress in many of the most promising areas of research.

Visitors Mark Sliwkowski, Ph.D., Cynthia Rask, Ph.D., Jennie Mather, Ph.D., and Glenn Hammonds, Ph.D., from Genentech pause for lunch and a photo during a day-long symposium hosted by the Miami Project. Symposium participants included (Back row, from left) Cristina Fernandez-Valle, Ph.D., Pat Wood, Ph.D., Richard P. Bunge, M.D., Mather, Hammonds, James Guest, M.D., and (Front row) Sliwkowksi, Rask, and Gizelda Casella, M.D.

Case Studies in Collaboration

Miami Project scientists often reach out to scientific colleagues who have expertise in technical areas outside the realm of SCI research, or who have had seminal influences on SCI-related fields. Two examples are Scott Whittemore, Ph.D., and Christine Thomas, Ph.D. Although their research interests differ greatly, they share a similar view on the importance of collaboration.

"Good science is so technically demanding it requires many different areas of expertise to address cutting edge questions," stated Whittemore. "You really need to collaborate with experts in other areas to pursue science in depth."

Whittemore's efforts to genetically engineer cells to develop cell lines useful in repairing the damaged spinal cord are technically demanding, indeed. From optimizing methods to introduce new genes into human cells, to discovering how nerve cells differentiate, Whittemore's studies have benefited from interactions with other scientists.

Among his collaborations with the UMSM Department of Neurology, Whittemore counts work with Micheline McCarthy, M.D., Ph.D., showing how viral infections used to introduce genes into cells affect developing human nerve cells. How nerve cells develop their specific chemical communication systems is being addressed with colleagues Mordecai Globus, M.D., and Julie Staley, Ph.D.

In collaboration with Robert Keane, Ph.D., in the Department of Physiology and Biophysics, Whittemore and his colleagues studied the immunological properties of nerve cell lines. They established that the neuronal cell lines developed in the laboratory were free of proteins that cause graft rejection.

"Collaborators have been very important for my work because we can bounce ideas off each other and mutually benefit. They have generously given me critical equipment and electrodes that aren't available commercially", explained Thomas.

Two such collaborators are Roland Johansson, Ph.D., who taught Thomas micro-neurography, and Goran Westling, Ph.D., who visited Miami from the University of Umea to study the properties of sensory nerves in chronic SCI. Johansson generously supplied Thomas and Westling with hand-made electrodes and a constant current stimulator, without which their experiments could not have been carried out. Their studies provided information critical to those who design stimulation strategies appropriate for paralyzed muscles. Other visiting collaborators to Thomas' laboratory include Tessa Gordon, Ph.D., former Knight Visiting Lecturer, who helped Thomas develop her animal model of partial muscle paralysis, and Bruce Ross, Ph.D., from the University of Otago in New Zealand. Ross and Thomas are comparing the nature of spasms after SCI with muscle cramps in non-injured individual.

Cultivating New Ideas

Another commonality between Whittemore and Thomas is that both have received "seed money", 1-2 year grants, from the American Paralysis Association. Whittemore received APA support to develop human and rat oligodendrocyte cell lines. Based in part on research supported by this grant,Whittemore successfully competed for NIH funding for further research aimed at developing cell lines from nervous system tissues.

More recently, Thomas received an APA grant to study sprouting patterns of paralyzed and functional motor axons. This work led to NIH support for research aimed at understanding how innervation to paralyzed muscles might be restored and whether new nerve growth at the muscle could result in strengthening a partially paralyzed muscle group.

This year, Mary Eaton, Ph.D., received funding from the Paralyzed Veterans of America's Spinal Cord Research Foundation. She will explore treatments for alleviation of the chronic pain suffered by many people with SCI. Specifically, Eaton will insert a gene for the growth factor "brain derived neurotrophic factor" (BDNF) into a cell line developed in Whittemore's laboratory. Upon exposure to BDNF, this cell line expresses serotonin, a chemical known to be important in spinal cord pain pathways. Eaton will test whether transplanting the engineered cells into the rat spinal cord will reduce oversensitivity after SCI.

PVA President, Richard Grant (right) and Director of Research and Education, Laurance Johnston, Ph.D (left) toured the Miami Project in October and presented Miami Project President Barth Green, M.D., Instructor Mary Eaton, Ph.D., and Marc Buoniconti with a check representing grant support for Dr. Eaton's studies from the PVA's Spinal Cord Research Foundation.

A Corporate Commitment

The rapid progress being made in studies of neurotrophins and other growth factors underway in Miami Project laboratories is made possible by the generosity of biotechnology companies, exemplified by Regeneron and Genentech.

In 1992, Ron Lindsay, Ph.D., Vice President of Regeneron Pharmaceuticals, Inc. visited the Miami Project as a Knight Lecturer. During that visit, new collaborations were formed and Regeneron has generously provided neurotrophic factors to several investigators. One study utilized BDNF and neurotrophin-3 added to Schwann cell filled guidance channels to bridge a gap in the rat spinal cord. This stimulated regeneration by brainstem nerve cells, a finding recently published in Experimental Neurology by Mary Bartlett Bunge, Ph.D., and her colleagues.

John Rudge, Ph.D., of Regeneron, joined Whittemore in studies on the involvement of another factor, ciliary neuronotrophic factor, in mediating the choice of chemical transmitters made as a nerve cell develops.

Collaborations with scientists at Genentech, Inc. have dramatically advanced the study of human Schwann cell biology by Richard Bunge, M.D., and his colleagues. Work utilizing these cells for transplantation into the rat spinal cord is ongoing thanks to a growth factor supplied by Genentech that stimulates the proliferation of human Schwann cells.

In October, a group of four scientists from Genentech visited the Miami Project to exchange information about new techniques and recent findings. In a series of nine presentations and a discussion that continued over dinner, researchers from both groups caught up on the state-of-the-art and forged new ties.

Work with human nerve tissues would not have been possible without the generosity and dedication of members of the University of Miami Organ Transplant Team, J.D. Walters, Les Olson and their colleagues. Waters' tenacity in making tissues available for research has been unparalleled and his dedication to these studies has been inspirational.

In other cases, research programs have evolved, in large part, thanks to ongoing corporate support. General Reinsurance Corp. has underwritten research in Whittemore's laboratory for many years.

"General Re supported our work from the beginning", said Whittemore, "and allowed the lab to expand. We developed new projects to the point where they could compete successfully for funding, then put the General Re dollars into new areas of research."

Another Miami Project researcher, Blair Calancie, Ph.D., credits the loan of equipment from companies with enabling him to perform his experiments on subjects with SCI. Cadwell Laboratories made a long-term loan of a magnetic stimulator that has been the basis of Calancie's work studying ongoing return of function in some individuals following SCI. Thomas has used the stimulator in her studies of arm movement, as well.

Calancie credits a new multipulse transcranial electrical stimulator contributed by Digitimer, Ltd. with energizing his studies of intraoperative monitoring, a project whose earlier results are protecting many patients undergoing spinal surgery today.

Expanding Horizons

As the Miami Project moves ahead, its scientific influence and interactions will only increase. Richard Bunge has joined a new APA research consortium linking laboratories of eight premier neuroscientists in the search for new treatments for SCI. Similar to the Miami Project approach, the consortium represents a wide array of experience, research strategies and analytical models.

We will continue to work together with organizations throughout the world seeking to find a cure for SCI. The International Spinal Research Trust, based in England, has earmarked support Miami Project transplantation research. Through collaboration, we continue to affirm our dedication to accelerating the search for new treatments to overcome paralysis.