Summer 2010

Progress in Research

very dark prognosis – how could there be any progress at all if there wasn’t even any- one really working on the problem? The Reeve Foundation helped to change all that. Today we have a sophisticated re- search program that incorporates multiple initiatives and institutions and approaches, a very full research continuum. We helped build the Foundation out to the point now where it will take basic research and move it down a translational pipeline. We put the infrastructure in place for developing our North American Clinical Trials Net- work, for example, and the NeuroRecov- ery Network. We have built what I consider to be a world-class organization.

Q. So the Foundation is more broadly based than in the days when cure was the focus? A. Yes, that is right. Now, our efforts are based much more on our interaction with the community. We released our paralysis survey last year and found out there are many more people living with Continued on page 4

Photo by Peter Billard Inside Jack Hughes, Foundation Board Chairman: A Family’s Commitment to the Reeve Mission Mendell Lab: ohn (Jack) Hughes is the Reeve Foundation, enabling the organization to Collaboration Foundation’s fifth Chairman of the significantly expand its research program. by Design Board since its inception in 1982 as Michael Hughes died in 2007. Greg Jthe American Paralysis Association remains active, chairing the Foundation’s (APA). He follows Hank Stifel, Christo- Connecticut Chapter. Jack Hughes, CEO Animal Core Lab: pher Reeve, Dana Reeve and Peter Kier- of Topcoder, the world’s largest competi- Building Capacity nan. Hughes has been a member of the tive software development community in Board since 2000; his family has been as- Glastonbury, CT, spoke with Reeve Foun- sociated with the Reeve Foundation for dation staff member Sam Maddox. Mary Bunge: A Long over 25 years. After Jack’s brother Greg was spinal cord injured, Michael Hughes, Q. In the early days when your family was Career In Progress their father, became involved with the thrown into the world of , Foundation and was for many years a what was the sense of scientific progress? Research News board member. In 1999, the Hughes fam- A. Almost 30 years ago, when my brother ily made the largest-ever gift to the Reeve Greg was injured, spinal cord injury had a MARY BARTLETT BUNGE: A LIFE IN SCIENCE, IN PROGRESS Mary Bartlett Bunge, a distinguished has studied over most of her career. Laboratories at Bar Harbor “changed the scientist at the Miami Project, thought This article, then, is not a retirement course of my life. One day we put rabbit about retiring after 57 years at the bench. notice. It is a tribute to Dr. Bunge and a heart muscle into tissue culture and I saw Last year, she decided not to participate in thankful appreciation for her many years it beating. I didn’t want to be a technician. the three-year renewal proposal for the of work with the Consortium. I wanted to get into research.” Reeve Foundation International Consor- Mary Bartlett was interested in science Dr. Bunge went to graduate school at tium on Spinal Cord Injury; she had solid- at an early age. “I used to row a small leaky the University of Wisconsin, at the invita- ified her plans to retire by the end of 2010. rowboat along a stream in front of our tion of Dr. Robert Schilling. They worked Her Consortium colleagues threw her house and look at all the wildlife, particu- on projects and published papers related what they thought was a retirement party. larly the tadpoles and the very tiny frogs. to intrinsic factor and gastric juice. “I saw “Can I just say I’m not retiring?” says That inspired me to wonder how the de- him recently. He’s now 90 years old, still Dr. Bunge. “There is a graceful time to re- velopment occurred from tadpole to frog.” working. He said that our papers pub- tire and I don’t think it’s quite as close as I She might have been a fashion de- lished in 1956 and 1957 are still highly re- thought it was. I’m just working, hopefully signer. “I used to design and make my own garded. But I wasn’t really interested in gastric juice.” She received her masters in Medical Physiology. “In the meantime I had taken this course in cell biology with Dr. Hans Ris and had looked at images in the electron microscope. That was another inspira- tional, defining moment. We were using one of the first electron microscopes in the United States; we had to hammer the lenses into place. But still the images were just captivating.” As a graduate student Dr. Bunge took courses with medical students. This is where she met Richard Bunge. “There was this lanky looking guy. I used to sit in the front row and he sat in the front row at the other end. Then, for a summer Richard worked in Dr. Schilling’s lab, on blood samples in the cold room. I didn’t see him during the day. Then at 5 he would vanish into the hospital cafeteria where he washed dishes to help support himself while in medical school. I thought, this guy needs fresh air. I invited him to go sailing and that’s how we got to know each other. When the wind died down in the middle of Lake Mendota we had wonderful long conversations. Dick was going to medical school so he could be a missionary; his hero was Albert Schweitzer.” Back on campus, Dr. Bunge began what University of Miami Miller School Medicine – Photo by John Zillioux was to be a lifelong collaboration with a little bit less.” She says she’s cut back to clothes before I went to college so fashion Richard, who had changed his mind about 75 percent. “I have a new postdoc in my design was a possibility. I was also inter- being a missionary in favor of research. Be- lab. I’m continuing some studies because ested in child psychiatry but biology won tween getting her masters and her Ph.D., there are things that I still want to do and out. I was thinking that’s something I can- Mary and Richard were married. “He really I still am energetic and have a passion to not do on my own. I could make clothes introduced me to . From grad try and do something more.” on my own. But I could not get into bio- school on, we worked together.” They One of the loose ends Dr. Bunge wants logical studies on my own so I decided I demonstrated that myelin could be re- to tie up is a pending clinical trial for spinal needed training for that.” formed in the mature mammalian spinal cord injury using a combination of treat- After high school Dr. Bunge took col- cord. “When I put a section of kitten spinal ments including Schwann cells, a type of lege courses to become a laboratory tech- cord into the electron microscope, there in support cell in the nervous system that she nician. A summer course at Jackson the first area of the first section I looked at, 2 was an image like the old fashioned ice The Bunge lab had begun some tongs with the oligodendrocyte cell body Schwann cell transplantation projects in a at the top and two cytoplasmic arms com- spinal cord injury model when Richard got ing off the cell body and it was forming an invitation in 1988 to be scientific direc- myelin at the end of each arm. And that’s tor at the Miami Project. how I discovered that the oligodendrocyte “We realized that moving to Miami was the cell that made the myelin sheath for would be a better opportunity for us to the central nervous system. That was one continue our work in the spinal cord and of my big moments in research.” Martin Schwab, Mary Bunge, Lisa Schnell, on to pursue our interest in repairing the cen- Dr. Bunge says her husband became in- the occasion of Maryʼs ʻretirementʼ party. tral nervous system. We needed to build a terested in nerve tissue culture and wanted myelin repair. Says Dr. Bunge, “Rather bigger team to do this.” to go to New York to study with Dr. Mar- than take a piece of tissue and try to see The Bunge lab at the University of garet Murray at Columbia. “She helped de- how much differentiation we could Miami became one of the preeminent SCI velop the techniques for nerve tissue achieve, the Margaret Murray approach, labs in the world. In 1993 Richard Bunge culture and was able to achieve myelina- we wanted to separate the cells in the pe- was invited to join the Reeve International tion in culture.” Fortunately, there was an ripheral nervous system. With Dr. Patrick Consortium on Spinal Cord Injury. Soon electron microscopy lab at Columbia Wood, we could grow neurons by them- thereafter, however, he became ill with headed by Dr. George Pappas. Very little selves, the Schwann cells by themselves or esophageal cancer (he died in 1996). Mary work had been done to look at the detail in the fibroblasts from peripheral nerve by Bunge took his place in the Consortium. these tissue cultures. “Again we were look- themselves. Then we could prepare differ- “It has been a remarkable and beneficial ing at myelination; actually Dick and I were ent combinations and observe a number of and exciting opportunity for me for which the first to describe synapse formation in tis- important interactions that occur between I am extremely grateful.” Dr. Bunge says sue culture.” these cells, not possible in an animal.” the collaborative approach of the Consor- In New York the Bunges had two sons, Much of the work in St. Louis was tium is essential. “Because we’re dealing Jonathan and Peter. Mary Bunge continued directed toward multiple sclerosis, which is with such a complex problem, we have to part time in the lab. The family left Colum- characterized by myelin loss. “Even though think of combination strategies. I don’t bia in 1970 for Washington University Dick and I were really basic scientists, we think any one of us is adept at all the tech- School of Medicine in St. Louis. Dr. Bunge always were interested in how we could niques that need to be used to solve this continued to balance lab work and family translate — that word wasn’t used at that very complex problem. I have a number of life and also began to teach; she became a time — how we could extend our basic sci- papers with other members of the Consor- full professor in 1978. ence results to help repair a deficiency or de- tium. It’s been wonderful.” The Bunge lab continued in the area of generation in the central nervous system.” – Sam Maddox MARY BARTLETT BUNGE’S SCIENCE STORY: GREAT EXPECTATIONS Q: People in this country, including many with spinal injuries, have very sheathing glia or with an elevation of cyclic AMP. In most cases high expectations for progress in research. What is your message as when we added one of these interventions to the Schwann cells, far as this goes? the results were better. There were more nerve fibers in the Dr. Bunge: This is a very hopeful time but spinal cord injury is Schwann cell bridge and there were fibers recruited from the brain- very complicated and there are many pieces of the puzzle to be stem onto the bridge. In animal models we found there was some solved. This is a very young field; modern day spinal cord injury re- improvement in locomotion. pair research didn’t really start until 1980. We are making good The combination strategy, much of it in collaboration the Reeve headway but there is still much work to be done. Foundation Consortium, is more effective than Schwann cells alone. Q: You developed a novel bridging approach using Schwann cells. Can Q: A clinical trial has been proposed to the FDA? you give us a brief description of what that is? Dr. Bunge: That’s correct. We have had an initial dialog with Dr. Bunge: We wanted to address axonal regeneration. To rule the FDA and they have requested additional preclinical studies — out sparing of axons and the possibility of sprouting from those such as do Schwann cells form tumors? Do they migrate around axons we created a complete gap of several millimeters in the the body? Are they toxic? How long do they survive? Despite spinal cord; we placed a thread of purified Schwann cells into that our many years of work with Schwann cells, there are still ques- gap, ensuring that the thread was in contact with each cut end of tions to be answered. For example, we know that the Schwann the spinal cord. This was held in place by a polymer channel, sort cells stay put when they are placed into the spinal cord but we of like a drinking straw, and we inserted each end of the cut spinal have followed the animals generally for three or four months. The cord into this channel. FDA wants us to follow them for six months. Also we have not We saw regrowth of axons into this Schwann cell bridge. It looked at other organs to see whether Schwann cells have gone to was very striking. But then we discovered that we were promot- places outside the spinal cord. We don’t believe that to be the case ing axonal regrowth from sensory roots or from neurons that but we have to prove that for the FDA. We are doing these pre- were in the spinal cord. Nothing from above the spinal cord. So clinical studies now. we turned to developing a combination strategy. We have com- Q: Do you have a timeline for meeting the FDA’s needs? bined Schwann cells with growth factors or with olfactory en- Dr. Bunge: A summer meeting with the FDA has been scheduled.

3 “We thought about starting our own foundation ... from page 1 ground was in finance and he helped insti- ganizations funding research, we decided injury and paralysis than previously tutionalize financial procedures and sys- to support the Reeve Foundation. The thought – the problem is much larger than tems that were non-existent in those early Foundation was already very substantial; any of us knew. Five times bigger than days. APA was growing and building a they already had the infrastructure in place what was commonly stated. Our approach solid base and over time we stayed involved to vigorously pursue spinal cord injury re- to the community is very straightforward, in various aspects of the organization. search. They already had assembled a ros- very honest, very true to what we’re trying Then Christopher Reeve was injured. He ter of the very best scientists to assure the to accomplish in terms of integrity of the research tomorrow’s cures and program. They already had today’s care. We have an a fundraising structure. It awful lot to offer. We made sense to support the have the Paralysis Re- Reeve effort rather than source Center, which is a create something new. In major information asset. terms of the choices my We have a robust quality family made to invest both of life program that pro- our time and money, I vides grants to commu- couldn’t be happier with nity organizations. We where we ended up. have research programs that span from basic dis- Q. You joined the board covery science to our clin- then, were you coming on as ical initiatives. I’m a big a finance guy too? optimist in terms of A. No, I had a particular in- where the Foundation is terest in the research side. I going. But there’s a lot of joined what was then called work left to do and we the RPC, the Research need the help of every- Planning Committee. I’m body who is touched by not a scientist, I’m a lay- spinal cord injury and man, but the board decided paralysis or knows others that they wanted someone who are — and that’s vir- outside the research com- tually everyone. munity who had some knowledge of the particu- Q. Your family has been lars but wasn’t necessarily a involved with the Founda- scientist — so that there tion since almost the would be some oversight. beginning? The committee did quite a A. Yes, that’s right. Greg bit of work in structuring was injured around the how research is done, along same time Henry Stifel with Susan Howley, who was, in 1982. His father, had attracted a really strong Hank Stifel, began the roster of scientific institu- Stifel Paralysis Research tions and individual scien- Foundation the following tists to this area of research. year to support spinal cord research and it soon Q: You must on occasion get became aligned with the a phone call, maybe from a larger American Paralysis person who has a family

Association (APA). After Photo by Peter Billard member with a new injury. Greg's injury, we had What’s your message? started to look around for resources, to see started his own foundation and then de- A: What I tell them is that the spinal cord who was doing research. But there was very cided to merge with APA. At about that field now versus five or ten years ago is little going on anywhere. Shortly after the time, my family wanted to make a substan- alive with exciting research and promise Stifel/APA affiliation in 1986, my dad de- tial gift to support SCI research. We and that there is legitimate progress being cided to commit to that organization. He thought about starting our own founda- made. It’s a completely different story volunteered quite a bit of time; his back- tion. After considering that, and other or- going forward. 4 ... but the Reeve Foundation was already substantial.”

Q. What are some of the ideas you have as a start to have therapies that have an effect and how much looms large – it’s uncharted board chair that can encourage the public to on the physiology, you’re still going to have territory at the moment. see the Reeve Foundation as a place to invest a whole host of other things that you have their charitable contributions? to deal with — bone density, bladder, Q: Over the time Christopher Reeve was in- A: We very much view ourselves as part of strengthening muscles. How do you reha- jured you met him many times. Do you have the large community of people affected by bilitate people? How do you do all of any insights about what drove him? spinal cord injury paralysis, including those things? There are huge areas of re- A: Chris was just a very special individual. friends, relatives, caregivers, doctors and search that have yet to be undertaken. So He was determined not to quit and he scientists. That community needs to be in- it’s not as simple as stem cells curing every- never did. He wasn’t going to let paralysis volved in helping to move both research body. And I think people are starting to re- define his life; it didn’t. He wanted to con- and quality of life initiatives forward to im- alize that. The spinal cord is just tribute and to be productive and he was — prove the lives of people living with paral- enormously complex, and traumatic injury extremely so. What made him tick? He was ysis. And obviously that takes money, so we is not a static process. Patients eventually just a very determined individual. The want to be able to open up the avenues for will be given a carefully orchestrated series Reeve Foundation today is a big reflection participation as wide as possible. We want of treatments and drug cocktails pegged to of that determination. I think that’s what to attract donors from all segments of the their type of injury, its location, time since he left us, the idea that even when faced community. We’re adding chapters and trauma, their age, general health and so on. with great obstacles you keep going, you Team Reeve is expanding around the coun- Then the question of what kind of rehab just do what you can to change it. try. We have a formal affiliation with Life Rolls On. We have a very active presence on the Internet to encourage giving. THE MICHAEL A. HUGHES SOCIETY is a community of planned giving donors – people who have generously included the Reeve Foun- Q: Is there a strategy to build relationships dation in their estate plans. Planned gifts include bequests through donors’ wills, among other organizations to spur progress? charitable trusts, and other life-income vehicles, and gifts such as retirement plans A: Very much so. We have begun partner- and life insurance policies. The Society is named for Mike Hugues, who came to the ships with organizations that raise funds Reeve Foundation more than 20 years ago when his son Greg was paralyzed in an for SCI research, including the Sam Schmidt Paralysis Foundation and the accident. Mike went on to become one of the Foundation’s most enthusiastic and Quad Foundation. Also, we have an initia- hands-on supporters, providing wise counsel, encouragement, and, ultimately, an tive on aging with paralysis that includes extraordinary gift. Two of his children are following in his footsteps, holding Reeve participation from the Kessler Foundation, Foundation volunteer leadership positions. For more information about including the Miami Project to Cure Paralysis and the Reeve Foundation in your estate plans or making an outright gift, please the Craig H. Neilsen Foundation. Aging contact the Development office at (973) 379-2690 ext. 7131. with a disability is emerging as an enor- mous issue for the field and for society at large. So it makes all the sense in the world that we work together on it. We all bring our particular strengths to different aspects of the problem, so to be able to collaborate with folks and bring a broader set of strengths to bear is good for everybody.

Q: People sometimes say, Reeve, you’re the stem cell people. Do you hear that as well? A: We’re aware of it but people are getting a sense that the Foundation is about a whole lot more than stem cells. That does- n’t mean stem cells don’t have a role. The message that we would like to convey is that we are all about building this commu- nity and moving this field forward and not about one particular approach. I learned a long time ago that trying to tie yourself to one particular approach isn’t going to work, there’s no magic bullet for repairing Members of the Hughes Family (from left to right): Robert, Mike, Helen, Greg, Mary the injured spinal cord. Even when you Abel, Laurie Paternoster, and Jack.

5 MENDELL LAB: COLLABORATION IS HOW WORK GETS DONE Lorne M. Mendell, Ph.D., heads a lab- ter understand the effect of growth factors or progress, also underscore the joint effort oratory at the State University of New and of activity (or training) on neurons in between labs to enhance neural function. York in Stony Brook. The Mendell lab, the spinal cord. “In this study,” says Dr. Mendell, holding a one of six in the Reeve Foundation Inter- “The fact is,” says Dr. Mendell, “the manuscript, “we combined our interest in national Research Consortium on Spinal spinal cord below the level of an injury is NT-3 with our long-standing focus on Cord Injury, is focused mainly on plastic- alive; it works. It’s just disconnected from NMDA receptors [key molecules for con- ity of the mammalian spinal cord – that is, the brain. We can show you videos of adult trolling plasticity of nerve synapses and the ability of nerve cells to adapt after rats with fully transected spinal cords – the memory]. We then became interested in trauma or disease. The specialty in this lab animals step or hop on a moving treadmill combining them with anti-Nogo, which is is electrophysiology, a field of research that after treatment with . Of studied in the Schwab laboratory [Consor- measures the electrical tium lab of Martin E. activity of nerve cells. Schwab, Ph.D., at the This is valuable for University of Zurich, understanding the Switzerland] or with process of recovery chondroitinase, which is and the effects of vari- studied in the Fawcett ous treatments on laboratory [Consortium nerve cells, especially lab of James W. Fawcett, when the effects are Ph.D., University of not obvious in the be- Cambridge, Cambridge, havior of the animal. UK].” Both of these stud- The Consortium, ies were carried out with by design, encourages Dr. Victor Arvanian, a re- collaboration between search scientist formerly labs. Indeed, that is in Dr. Mendell’s lab and how Dr. Mendell’s now at the VA Medical current work has Center in Northport, emerged. The Con- Long Island. The aim has sortium labs of Reggie been to encourage the for- Edgerton, Ph.D., at mation of conducting de- UCLA and Rusty tours around a partial Gage, Ph.D., at The injury of the spinal cord. Salk Institute have Initial results are encourag- been integral to ing and we hope to be able Mendell’s most recent to use these results, perhaps efforts. Edgerton’s re- in combination with oth- search underpins the ers, to improve function of idea that activity and the partially damaged rehabilitative training spinal cord. enhance recovery; this Dr. Mendell explains is why, for example, locomotor or treadmill course the hind limbs are not coordinated his specialty: “One of the things you learn training can improve outcomes for people with the forelimbs, and the rats require when you do electrophysiology is that even with spinal cord injury. Coincidental to re- support in order to achieve balance. Our though neurons might look perfectly nor- covery of function, however, Edgerton’s electrophysiological recordings from these mal in the microscope, they might not be team noted that production of certain neu- same animals provide suggestions of possi- functioning normally. That could mean rotrophins or growth factors – NT-3 and ble mechanisms initiated by treatment you didn’t know what you were looking for BDNF – was increased after locomotor ac- with the neurotrophins that could account when you did the anatomical studies; you tivity. Dr. Mendell’s lab had been studying for the stepping. The question is, how do didn’t have the right stain or you weren’t the physiology of neurotrophins in the you activate these circuits reliably to sup- looking at the right parameter. Sometimes context of and synaptic plasticity. port useful behavior? This is not a trivial electrophysiology will bring that out for Meanwhile, Gage’s lab has developed ge- problem and may require combination you, particularly if it involves the behavior netic techniques to enhance levels of these with other approaches. This is the value of of neurons under dynamic conditions.” growth factors in the spinal cord in vivo. the Consortium since we have a broad array As an example, Dr. Mendell describes Working with his postdoctoral fellow, Dr. of approaches with which to combine neu- an experiment where electrophysiological Vanessa Boyce, Dr. Mendell combined rotrophin treatment; plans are underway to recordings helped to open up a new under- those strategies and used his behavioral exploit this translational possibility.” standing of the damage produced by spinal and electrophysiological techniques to bet- Several recent journal papers, in print cord injury. “We had done hemisections of 6 can try to devise ways to strengthen the DISCOVERING SCIENCE change so it will affect Lorne Mendell set off to McGill the behavioral out- University to be a physician. “My come, which is after brother’s a lawyer, and by tradition I all, what we’re really would have been a doctor. But one interested in.” night, I was in the library. I had been Collaboration is working on and off all day on a differen- more than a good tial equation that I couldn’t solve. And idea; it’s really the then suddenly the solution occurred to only way most neuro- me. I remember the moment like it was science studies get yesterday. And at the time I thought done now. Says Dr. that I would have many more of these Mendell, “The field is wonderful moments of discovery if I so big and the spinal went to graduate school and became a cord is so complex that no one person or scientist. It was a great decision.” lab alone can expect Dr. Mendell rose quickly in the sci- to solve the big prob- ence profession. He got his Ph.D. in Neurophysiology from M.I.T. in 1965.

Photos by Sam Maddox lems such as restoring The following year he published a land- Dr. Mendell and his postdoc Vanessa Boyce function after spinal cord injury. You can mark paper that has been continuously the spinal cord which involve damaging certainly see this in the way papers are cited since. He defined for the first only one side of the cord. We originally ex- written. As a Ph.D. student, my thesis time a phenomenon called wind-up, pected that there would be no difference paper was authored with me as sole author. wherein certain nerves, when stimu- in conduction of nerve signals on the other As a postdoc, the only authors on the pa- lated, result in progressively increasing side of the spinal cord immediately across pers were my postdoctoral advisor and me. response in the spinal cord. from the damaged side. But we were very The more usual thing today is a published Dr. Mendell was on the faculty of surprised to find that there was a rather paper with many more authors from two Medical Center from substantial change in conduction begin- or more labs.” 1968 to 1980, and joined Stony Brook ning after several weeks. Once you see that Knowledge is more and more special- University in 1980. He served as chair something has happened,” says Mendell, ized and this dictates the need for collabo- of the Department of Neurobiology “then one can look for the cause. In this ration. “Although present knowledge and Behavior from 1986 to 2006 and is case, it may be that leads to encourages us to believe that we can im- currently Distinguished Professor of changes on the uninjured side, perhaps by prove the lives of spinal injured people, we Neurobiology and Behavior. From 1996 increased levels of molecules known as are still missing many important pieces of to 1997 he was Treasurer of the Soci- proteoglycans.” Taking the concept a step the puzzle. We need a steady stream of ety for Neuroscience and from 1997 to further, Dr. Mendell speculates that any new ideas from basic science, as well as 1998 served as its President. He is treatment that could depress the level of novel ways of translating them to achieve presently Chair of the Spinal Cord proteoglycans might lead to recovery of practical benefits for people with spinal Injury Research Board of the State of conduction in the spinal cord. He is now cord injuries.” New York as well as a Director of the recording electrical activity in the brain to Dr. Mendell sees science as an interac- Craig H. Neilsen Foundation. identify any effects of chronic spinal le- tive dynamic process, an activity under- Dr. Mendell has trained more than sions on sensory input to the brain. taken by a community of investigators. 30 Ph.D. students and postdoctoral fel- Only recently have scientists begun to “The important pioneering findings gen- lows and has influenced an entire gen- understand that spinal cord trauma affects erally will stimulate the experiments of eration of neuroscientists. Last year a the entire nervous system. others, and this is what brings them into science symposium organized at Wright “Measuring behavior can be fraught the scientific mainstream. They will be dis- State University by former students with challenges,” says Dr. Mendell, “and cussed by the community and their repro- honored him and his life’s work. The sometimes it can be very difficult to really ducibility will be determined on the way symposium, Mechanisms of Plasticity in understand what changed. There might to building on them to obtain subsequent Neuronal Connections, attracted over 50 not be a big enough or coherent enough results. So science today is not what I orig- leading scientists from seven countries. change to observe something in the behav- inally thought it was when I began as a Dr. Mendell’s wife is a Professor of ior. Or the behavioral change may be too young student: that it was sort of a solitary Applied Math and Statistics at Stony complex to determine where the change endeavor, the concept of the ivory tower. Brook; they have two children. When has occurred. So that’s where electrophys- It’s not that at all. It’s very social. It’s a lot he is not in the lab, Dr. Mendell relaxes iology can be helpful – we can know with different from what it was like when I at the piano playing chamber music certainty that a particular pathway has began in science.” with other musicians. changed. And if that is the case, then we – Sam Maddox 7 ANIMAL CORE LAB: BUILDING RESEARCH CAPACITY The International Research Consor- that had expertise. “As the Consortium pro- anything. They may supply us their com- tium on Spinal Cord Injury is a Reeve gressed, the demand on the labs that did pound, their cells or whatever it is and Foundation initiative to build collabora- have spinal cord injury expertise grew sig- we’ll run the experiments. They can come tion between a group of distinct laborato- nificantly. The idea came about to increase in and get training, very much like a Con- ries. The idea is to focus the brainpower of opportunity for collaboration and decrease sortium member would, or they can come top scientists to more quickly exploit the the load on individual labs by making a core here and work with us to run a full project.” capacity of the adult nervous system to re- facility – a separate lab that first and fore- The idea is to give people who may not pair and remodel itself and to switch on most provides support to the main Consor- be SCI experts a chance to get some pilot nerve regeneration after injury. tium labs.” The Animal Core opened in data. “They may be immunologists or tis- Aside from the basic research of the 2001, under Anderson’s leadership. sue engineers who have a compound or a group’s principal scientists, the Consor- The Core lab facilitates collaboration drug or a scaffold or cell that has a poten- tium also features a common lab that per- by offering specialized skills, and also by tial application in the spinal cord injury; and by working with us, they can gather enough data to know whether they take that next step and apply for actual funding through the Reeve Foundation, the NIH or other resources. We’ve worked with a lot of different investigators who have been successful turning their Core pilot data into research grants.” The Core also services the biomedical research industry. “The Reeve Foundation is interested in expanding opportunity and ideas toward its mission to develop treat- ments for SCI. As an example, maybe a biotech company has a compound for multiple sclerosis and wants to know the potential application for spinal cord injury. To organize a rigorous experiment for test- ing the compound in a spinal cord injury model is an enormous hurdle for most

Photo by Sam Maddox companies, but we, basically, can grant them access into the Core.” Companies forms specialized work for member labs, teaching those skills. Says Anderson, “If pay for chemicals, reagents and basic costs. for investigators in the SCI field outside of any of the Consortium labs wants to run a But they don’t have to pay anything for the Consortium, and even for the biomed- spinal cord injury experiment, we can assist personnel or expertise. ical industry. Aileen Anderson, Ph.D., is with the experimental design and indeed “We can run a full project for them to scientific director of the Consortium’s An- run the full project for them right here. give them preliminary data back – sort of imal Core Laboratory at the University of Typically, our role involves the animal a thumbs up/thumbs down to give valida- California, Irvine. She explains what the model and surgical components, but it can tion to their idea, to see whether it shows Core lab does. involve everything through histology and promise and should be pursued. The “At the time the Consortium was returning data at the end of a full study.” Reeve Foundation hopes, therefore, to formed, only a handful of the labs had di- The Core is often used as a training fa- stimulate industry and perhaps bring new rect expertise in spinal cord injury. The cility. “If Consortium lab postdocs need treatments bench-to-bedside a little bit rest of the players were SCI novices – well training in any sort of technique, say in be- quicker. Access to our Core might broaden respected within their individual fields, havioral assessment, or anesthesia, or in the horizon for an existing drug that very prominent labs, but from other re- any number of technical things their home biotech otherwise wouldn’t have consid- search areas.” The array of Consortium labs labs are not well versed in, they can come ered for SCI. They might find an had specialization in Alzheimer’s studies, here to the Core for training.” There are approach here they otherwise would not stem cells, electrophysiology, developmen- no fees or costs to the Consortium labs. have discovered.” tal biology and gene transfer. “The goal,” The role of the Core has expanded There are no contract labs in the US says Anderson, “was to get the various labs over time to include contract lab work and that can run spinal cord injury experi- to direct their particular expertise to the training for scientists who are not in the ments. “Biotech companies rely a lot on problem of spinal cord injury.” Consortium. Says Anderson, “Basically an contract labs. If you want to do stroke Forming a focused collaborative net- individual investigator, once approved by work, you can send compounds out to work meant that the labs had to either our Consortium Advisory Panel, is Charles River for testing. If you want to quickly develop expertise, or rely on the labs granted access to the Core. They don’t pay study diabetes, you can send compounds 8 ANDERSON LAB: THE CONSORTIUM INVESTS IN TALENT Aileen Anderson is Associate Professor of unanticipated training component. Pulling Physical Medicine & Rehabilitation and new talent into the field has made a big im- Anatomy & Neurobiology at the University pact on the field of spinal cord injury. of California, Irvine. She got her Ph.D. there Many of those original Associates, includ- under the tutelage of Carl Cotman, whose ing me, have now gone on to develop their lab was one of the original Consortium own laboratories and are training their own members. Anderson was the Cotman lab’s postdocs and graduate students in the field of Consortium Associate, his liaison to the spinal cord injury; we have diverse areas of other labs in the network. She hadn’t planned research that are bringing stem cells and a career in spinal cord injury but was drawn genetics and microarray analysis and lots of to it by this early career work. different tools and technologies to the prob- “A unique thing about the Consortium,” lem. For the Reeve Foundation, that has been says Anderson, “has been an indirect, perhaps a really far-reaching investment.”

doing good laboratory practice at a biotech calls from Newsweek and Science and cer- company for FDA submission.” tainly from patients. The number of patient Anderson says staff have to be versatile, inquiries that emerge after every stem cell and broadly trained. “They might spend paper that has to do with spinal cord injury Photo by Sam Maddox one week doing nothing but surgeries. is staggering. And all of us who do SCI re- Rebecca Nishi and Aileen Anderson That can be a four-to-six-person job for search hear this question: ‘My brother was out to a number of contract labs and get a seven days straight. The next week, they just injured this morning in a car accident preliminary test. If you want to test your might do nothing but sectioning and im- and they’re telling me he’s C3 and he’s materials for spinal cord injury, our Core munostaining. To get a technician fully never going to walk again. Can we fly him lab makes it possible.” trained and up-to-speed takes at least six to China to get a stem cell transplant? The Core staff varies between four and months, actually closer to a year – we need “The big message I try to convey is sim- six technicians. It is managed by Rebecca them to perform at a very high level.” ple: There are studies that have looked at Nishi. “Rebecca is phenomenal; she inter- Anderson also has her own workload at people who went overseas for stem cell faces with some of the Consortium or in- UCI. “I direct the Core but I also have a lab transplantation. Those studies have shown dividual investigators directly and, with 20 people in it working on two differ- no beneficial effects but they have shown mercifully, does most of the nitty-gritty ent aspects of spinal cord injury: the role of adverse events in certain cases. And so de- tasking, record keeping and problem solv- inflammation in SCI and the effect of spite what you might find on somebody’s ing.” There is endless detail to track. “Every transplanting human neural stem cells and blog on the web, the clinical data don’t project, every surgery sheet for every ani- human embryonic stem cells that might be support the idea that this transplant is mal, every behavioral assessment sheet, used to effect repair and recovery. going to be a good thing for you. I tell peo- every data analysis file for every animal in- Because Anderson’s lab at UCI works ple there are published reports of those jury, every immunostaining record sheet, with stem cells and spinal cord injury, she kinds of transplantations resulting in tu- all of that gets tracked and coordinated attracted attention for research showing mors and making people worse. and put together very much as if we were therapeutic effect in animal models. “I get “I emphasize that there are cell thera- pies that are going to clinical trial now that might be beneficial and that a transplant in China now will make a person ineligible for any future therapies shown to be safe and effective. Sadly, a lot of people don’t want to hear that. “The other thing I feel quite strongly about is the locomotor treadmill training data. Stem cells aren’t there yet but loco- motor training is. I’ll direct them to the Reeve Foundation’s NeuroRecovery Net- work. I encourage them to consider doing very intensive step training rehab – it’s what I would personally do if I were in- jured or if it were my daughter, family member or friend. I stress that I would not go to China – or any other off-shore clinic

Photo by Brian Cummings offering cell transplants.” Core lab staff: Hongli Liu, Chelsea Pagan, Rebecca Nishi, Aileen Anderson – Sam Maddox

9 NEW INDIVIDUAL RESEARCH GRANTS Concomitant Function: Investigation of the use of invasive 2003. Dr. Furlan’s recent work has shown mechanisms of transcranial direct current brain stimulation that while the mortality rates in the elderly stimulation of motor cortex for treatment of – with electrode with SCI are dramatically higher than in in spinal cord injury placement using the younger population, elderly survivors Felipe Fregni, MD, PhD, Spaulding Reha- neurosurgical do indeed have the potential for good bilitation Hospital, Boston, MA techniques. This functional recovery. method is costly This raises important questions: (a) Chronic pain is a serious consequence of and associated what pathobiological factors in the elderly spinal cord injury (SCI) and has a signifi- with surgical contribute to increased mortality after cant impact on quality of life. No satisfac- risks, but Dr. SCI?; (b) are there mechanisms that can tory treatments are available. Dr. Fregni, a Fregni’s team has be modified to improve outcomes in the neurologist also affiliated with Harvard shown that a new elderly with SCI? Medical School, believes that chronic pain non-invasive, rel- Furlan’s team hypothesizes that an al- results from poor sensory processing in the atively simple tered inflammatory response in the elderly brain after the loss of input from periph- method of brain with SCI contributes to adverse outcome eral sensory systems due to spinal cord in- Felipe Fregni stimulation – He plans to investigate this hypothesis by jury. Because drugs have a diffuse effect transcranial direct studying immunochemical, neuroanatom- they offer limited benefits for pain control. current stimulation (tDCS) – reduces ical and molecular investigations in spinal He suggests a more focal attack. pain in spinal cord injury. In an earlier cord specimens donated for research pur- Until recently the only method to study, there was “remarkable” pain reduc- poses. The project will compare the num- modulate pain-processing centers was with tion in patients with untreatable chronic ber of inflammatory cells and neural spinal cord injury pain. He now proposes survival within spinal cord sections from to assess the mechanisms of action of both elderly and younger individuals and tDCS in alleviating pain using the state- examine programmed cell death (apopto- of-art methods such as magnetic reso- sis) of oligodendrocytes in the spinal cords nance spectroscopy, single and paired of injured and uninjured individuals from

PETER T. WILDEROTTER pulse transcranial magnetic stimulation older and younger patients. Furlan hopes President and Chief Executive Officer (to assess cortical excitability) and elec- the research project will lead to therapies troencephalogram. It is hoped the results to limit inflammation and protect nerves, JOSEPH A. CANOSE of this study will speed the development and to cell-based treatments individual- Vice President, Quality of Life of this novel therapeutic approach and will ized according to the age group to opti-

BILL CAWLEY also shed light on the causes of chronic mize outcome after SCI. Director of Chapter Development pain in spinal cord injury. Concomitant Function: Effects of Respi- STEPHEN COLEMAN ratory Muscle Training and Functional Vice President, Military Programs Electrical Stimulation on Task Specific MAGGIE F. GOLDBERG Respiratory Muscle Activity in Individuals Senior Vice President, after Spinal Cord Injury Marketing and Communications Alexander V. Ovechkin, MD, PhD, Uni- versity of Louisville, Louisville, KY, SUSAN P. HOWLEY Executive Vice President, Research People with upper thoracic and cervical in- AIMEE HUNNEWELL juries often have pulmonary complications Vice President, Development associated with respiratory muscle weak-

EDWARD T. JOBST, CPA ness, paralysis and spasticity. Lack of mus- Controller Julio Cesar Furlan cle strength and poor respiratory muscle control lead to breathing insufficiency and MICHELE LOIACONO Neuroprotection: The impact of age on ineffective coughing; this can lead to air- Vice President, inflammation, neural apoptosis and axonal way obstruction and the development of Human Resources and Special Initiatives survival after spinal cord injury pneumonia. Inspiratory muscle training  Julio Cesar Furlan, MD PhD, The Toronto with resistive loading is known to increase Western Hospital Research Institute, inspiratory muscle strength and en- PROGRESS IN RESEARCH ©2010 Christopher & Dana Reeve Foundation Toronto, ON durance, leading to improved pulmonary 636 Morris Turnpike, Suite 3A, Short Hills, NJ 07078 function. However, little is known about Toll-free 800-225-0292 Aging of the North American population the effectiveness of expiratory muscle www.christopherreeve.org has considerably increased the proportion training in SCI patients. Dr. Ovechkin Written and produced by Sam Maddox/Reeve Foundation of those over 65 with spinal cord injury and his team suggest that resistive cycle in- from 5 percent in 1973 to 18 percent in spiratory and expiratory muscle training 10 Reeve Foundation Board of Directors

OFFICERS

John M. Hughes Deborah Flynn Chairman Manager, Luscombe Engineering

Arnold H. Snider Janet Hanson Vice Chairman Founder, 85Broads, President and CEO Milestone Capital Management Henry G. Stifel, III Kelly Anne Heneghan, Esq. Alexander V. Ovechkin Vice Chairman NextSteps Chicago (RMT) in combination with functional Joel M. Faden electrical stimulation (FES) for expira- Chairman, Executive Committee Daniel Heumann tory muscles will improve pulmonary Founder, Heumannly Capable function by facilitating spinal neural net- Robert L. Guyett works for breathing and by restoring res- Treasurer Peter D. Kiernan, III piratory muscle activity. They predict Kiernan Ventures that RMT synchronized with FES will Michael W. Blair, Esq. significantly increase respiratory muscle Secretary Francine LeFrak strength and endurance, thus improving President, LeFrak Productions the breathing function of individuals with chronic cervical SCI with intact Peter T. Wilderotter John McConnell phrenic innervation. President and Chief Executive Officer Founder, McConnell Media, LLC This study will recruit 24 people with cervical SCI with intact phrenic nerve DIRECTORS and 10 neurologically intact individuals Jon O'Connor Proprietor, NextSteps Chicago (to evaluate normal baseline variables). Josh Billauer Ovechkin will assess respiratory muscle Life Rolls On control, pulmonary function and respi- John Osborn ratory functional outcomes using surface President and CEO, BBDO New York electromyography (sEMG), spirometry, David Blair CEO and Director, respiratory muscle strength (RMS), res- Patricia Quick piratory muscle endurance (RME), and Catalyst Health Solutions, Inc.. 2 peak oxygen consumption (VO peak) Alexandra Reeve Givens tests. Testing will be performed before Carl Bolch, III and after the RMT or FES and after a Chairman & CEO, Bolch, LLC Matthew Reeve three-month follow-up period.

Jacqueline C. Bresnahan, Ph.D. (ex officio) Krishen Sud University of California, San Francisco Founding Partner, Special Thanks Sivik Global Healthcare Alan T. Brown PROGRESS IN RESEARCH is Co-Founder, Alan T Brown Foundation to Marci Surfas made possible through a Cure Paralysis President, PrimeTime generous gift from Carl Vogel Director and Senior Advisor, DISH Network Hank and Charlotte Stifel. Paul Daversa CEO, Daversa Partners James O. Welch, Jr. The Reeve Foundation is deeply Former Chairman, Nabisco, Inc. appreciative of their support. Stephen Evans-Freke Managing General Partner Robert W. Yant, Jr. Celtic Pharma Management LP Newport Beach, CA

11 Science Advisory Council William Snider, M.D. SAC provides advice and funding recommendations to the University of North Carolina, Chapel Hill, NC Foundation’s Board with respect to the Individual Grants Program. Oswald Steward, Ph.D. Jacqueline C. Bresnahan, Ph.D., Chair Rick Lieber, Ph.D. Reeve-Irvine Research Center University of California, San Francisco University of California, San Diego University of California, Irvine

Barbara S. Bregman, Ph.D. J. Regino Perez-Polo, Ph.D. Wolfram Tetzlaff, M.D., Ph.D. Georgetown University School of Medicine University of Texas Medical Branch, Galveston University of British Columbia, ICORD Washington, D.C. Vancouver, BC

Moses V. Chao, Ph.D. Consortium Advisory Panel CAP provides counsel to the Foundation’s Board with New York University Medical Center, NY respect to the International Research Consortium on Spinal Cord Injury. Carl W. Cotman, Ph.D. Institute in Brain Aging Albert J. Aguayo, M.D. University of California, Irvine Director, Center for Research in Neuroscience Montreal General Hospital, Montreal Jean de Vellis, Ph.D. University of California, Los Angeles Robert G. Grossman, M.D. Chairman, Department of Neurosurgery V. Reggie Edgerton, Ph.D. The Methodist Hospital, Houston TX University of California, Los Angeles Samuel L. Pfaff, Ph.D. Louis F. Reichardt, Ph.D. Michael G. Fehlings, M.D., Ph.D. The Salk Institute, La Jolla, CA Professor, Physiology/Biochemistry/Biophysics Toronto Western Research Institute University of California, San Francisco University of Toronto Mahendra Rao, Ph.D. Invitrogen Corporation, Frederick, MD Charles H. Tator, M.D., Ph.D. Alex Kolodkin, Ph.D. Professor of Neurosurgery Johns Hopkins University School of Medicine Jerry Silver, Ph.D. University of Toronto Baltimore, MD Case Western Reserve University, Cleveland, OH Toronto Hospital, Western Division