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Dr. Guest


 
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Research Update Video

 


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"Faculty Spotlight
Dr. James Guest"

 

 


Contact Information


 

The Miami Project
to Cure Paralysis

 

1095 NW 14th Terrace

 

Locator Code R-48

 

Miami, Florida 33136

 

Tel:  (305) 243-7059
Fax: (305) 243-3255

 

jguest@med.miami.edu

 

 

 

Home Our Research Faculty >  James D. Guest, M.D., Ph.D.

 

JAMES D. GUEST, M.D., PH.D., F.A.C.S., F.R.C.S.(C)

Clinical Professor, Department of Neurological Surgery

 

Augmented Recovery after SCI; Application of Therapeutic Combinations in Preclinical Studies, and Early Phase Clinical Trials

  

Research Interests

 

The current focus of the Guest lab is on the transplantation of autologous glial cells to repair spinal cord injuries. We utilize several types of animal models with an emphasis on solving translational questions related to human clinical application. We also emphasize minimally-invasive surgical lesion-making and transplantation techniques. Sophisticated outcome assessment techniques are used to evaluate transplant effects in both the acute and chronic state of injury. These include kinematic assessment of hand function and gait, electrophysiologic study of conduction across lesion sites, and sensory testing. Other areas of research include studies of human post-mortem spinal cord tissue, intraoperative human spinal cord conduction studies, and research design for human clinical trials.

 

Interview with Marc A. Buoniconti, President, The Miami Project to Cure Paralysis

 

MARC: Today we are spending a few minutes with Dr. James Guest, one of our principal investigators. Over the past year or so, I’ve been interviewing people about their life, not only their research life, but trying to understand how you got to this point, some of the inspirational things that you’ve gone through, and the choices that you’ve made that led you to spinal cord injury research and neurosurgery. Let’s start at the beginning. Tell me a little bit about your family, where you were born, get me at least through high school, give me a brief overview of high school and then when you went to high school , where you went to college and what was that decision process.

 

Dr. Guest: I was born in Ontario Canada, in a small town called Newmarket. I grew up in Markham, another town just north of Toronto. My father is a mechanic and from a farming background, so I was raised in a blue collar environment. For example, I never knew any doctors until I was in medical school. I went to public schools and had an interest in science from an early age. I participated in the science club and had my first microscope in grade six.

 

MARC: Do you recall what it was about science that interested you? Was it from your father being a hands on kind of person, or just your interest in learning about things? Was it someone you knew or a teacher or was it a friend or was it anything like that?

 

Dr. Guest: Well, from my father I gained the confidence to repair things and work with my hands. It was unusual for a practical problem to arise that we couldn’t solve ourselves. One of my school friends influenced me. He was very smart and we worked on science fair projects together and I was impressed that he read far ahead of our school curriculum. At that time he was very interested in simple life forms such as fungi and invertebrate animals. I looked him up awhile back and interestingly he became a soil scientist. My first science fair involved a behavioral conditioning experiment (I was about age 10). I used gerbils and made a specialized cage in which I placed an electrified mat under the bedding in one half of the cage. I randomly turned on the power to the grid and the idea was that when the gerbils would go over on the mesh area that was covered by bedding they would experience some minor shock-like sensations. Perhaps they would learn to avoid that area and the question was how many repetitions would it take before the they chose to avoid the area entirely. This was based on some reading about Pavlov’s experiments and it did work. So, I think peers and opportunities like Science Fairs help promote a science interest.

 

MARC: So your interest continued through high school?

 

DR. GUEST: Not really. During high school, one of my friend’s sisters was studying law and she influenced us in the direction of history, political science, and languages. I continued to be very interested in repairing things and this extended to cars, wood craft and electronics. I built several radios and modified cars. But the whole idea about going to medical school and being involved in science didn’t start until I was out of high school. Also, we moved from the Toronto area to a small town near Edmonton just prior to my senior year, and I played a lot of sports that last year in high school.

 

MARC: Talk about your choice for undergraduate education.

 

Dr. GUEST: When I was a senior I was thinking about becoming a lawyer so I went into Business Administration program at the University of Alberta. But after 2 years I decided I wasn’t cut out for accounting and marketing so then I took some time off. I worked for a year at a Dow chemical plant as a power engineer to make some travel money and then I worked in Southeast Asia for 3 years as a volunteer with UNICEF, the Red Cross and other organizations. Those travels had a large impact on my future. For example I spent one year working on the border of Thailand and Cambodia where I was trained to perform veterinary procedures on water buffalo. Later on I started doing wound care for children who had lost limbs from mines or had limb abscesses. That was my initial exposure to using my hands for medical purposes and I found it gratifying. After those experiences I made the decision to go into medical school with a view to working in less developed countries as a surgeon or infectious disease specialist. At that point I went back to The University of Alberta, re-enrolled and completed a B.A. in East Asian studies, and then entered premed.

 

MARC: How long did that take?

 

Dr. GUEST: Three years until I entered medical school but I started doing research during premed. At that time Alberta had a very generous summer studentship program supported by the Alberta Heritage Fund and I received a scholarship 3 years in succession. The project I started in premed continued as an honors thesis in medical school. The research was my first training in laboratory techniques and designing experiments. My supervisor was Dr. Wanda Wenman, a pediatric infectious diseases expert and I was also strongly influenced by Dr. Lorne Tyrell, a virologist and physician. Dr. Tyrell had incredible energy and enthusiasm for the physician scientist life. He went on to be Dean of the Medical School and a strong promoter of clinician scientists. So, from early on I had clinician scientist mentors. My project was to make monoclonal antibodies to a protein that coats the elementary bodies of the type of infectious agent that causes Trachoma, an eye disease very prevalent in underdeveloped countries. That project culminated after the second medical school year when I combined this project with a surgical rotation in India. There, I did a small clinical study by taking eyelid specimens from patients with suspected Trachoma and smearing them on nitrocellulose paper. Back in Edmonton I reacted the specimens to the monoclonal antibody that I had made. It turned out the antibody labeled the clinical specimens well.

 

MARC: So you were quite busy at that time in your life?

 

Dr. GUEST: Yes. For many years! My first exposure to spinal cord injury occurred first year medicine when my girlfriend (we later married) was a physical therapist rotating at the Aberhart, which was the hospital that provided spinal cord injury care at that time in Edmonton. She started telling me about the spinal cord injury (SCI) patients and so I went and spoke to the director (Dr. Nikas) about why he chose to work in SCI. He had been an orthopedic surgeon but retrained as a physiatrist due to the large needs he saw in the SCI field. He encouraged me to learn more about SCI research. I was the editor of our Medical School Journal and so I went around and visited several scientists’ at the University of Alberta such as Dick Stein, Keir Pearson, Arthur Prochaska, and Tessa Gordon. I talked to them about how their research related to aspects of SCI and recovery and then I wrote a review article.

 

MARC: So what did you do after graduating from Med School?

 

Dr. GUEST: I did a 1 year rotating internship in Vancouver

 

MARC: So you graduated and did your internship in Vancouver. Tell me about that experience.

 

Dr. GUEST: It was a rotating internship including several surgical rotations but also medicine, psychiatry, and pediatrics. I liked all of the rotations and really wasn’t sure what area to specialize in but I was considering surgery, still with a view to work in less developed countries. I had a neurosurgery rotation early in the internship, and then after the rotation the surgeons often called me to help them out at night so I ended up doing a fair bit of basic neurosurgery that year and I enjoyed it. I also met the neurosurgery program director, Dr. David Fairholm who had extensive experience in developing countries. He made a strong impression on me and became an important mentor.

 

MARC: So your internship runs out and then what?

 

Dr. GUEST: What actually happened was pretty funny. Although I matched in general surgery, I hadn’t applied to neurosurgery. However, Dr. Fairholm called me and said that a resident had dropped out of Neurosurgery and asked if I would I like to take his position. It seemed like a great opportunity. So I started Neurosurgery. In the third year I had a lengthy spinal cord rotation at the SCI unit which was then in Shaughnessy Hospital in Vancouver and my preceptor was Dr. Peter Wing, an orthopedic spine surgeon. I was so moved by that rotation, seeing patients with acute SCI, and recognizing that treatments were limited that I decided to seek involvement in SCI research and started making inquiries.

 

MARC: And you saw the actual patients as opposed to hearing about them?

 

Dr. GUEST: Every day I admitted the new acute injuries and it was difficult emotionally. I remember one patient in particular. He was a young man my age that became a C5 quad after a sky diving accident. He was very stoic, but I felt very sad and still think of him. To find out the best places to receive research training I obtained advice from Dr. Charles Tater in Toronto who has remained a mentor throughout my career. One of my co-residents from Vancouver attended the Research Update in Neuroscience for Neurosurgeons where he met Dr. Allan Levi (Miami Project faculty member) and he said Allan Levi was doing a Ph.D. at a place called The Miami Project at the University of Miami, so I contacted Allan, who was very enthusiastic. I came to Miami in late 1992 for an interview and I met Dr. Richard Bunge. He accepted me to spend a year working on the pathology of human spinal cord injury using the spinal cord collection. I started in Summer 1993 and within two months I was so thrilled with the research that I decided one year wasn’t going to be enough so I applied to the Ph.D. program in Neuroscience and was accepted, starting in August.

 

MARC: You were doing Neurosurgery at the time?

 

Dr. GUEST: Technically, I was still a resident but my neurosurgery program in Vancouver had a designated research year. Subsequently, I was fortunate to receive an American Association of Neurological Surgeons Research fellowship for the second two years. Thus, during my Ph.D., I didn’t have patient care responsibilities although there was a lot of clinical teaching, and I met Dr. Green. After three years I defended my Ph.D., went back to Vancouver, and finished my residency which was another two years. While I was there I continued some research with ICORD (International Collaboration on Research Discoveries) having been befriended by Dr. Wolfram Tetzlaff and Dr. John Steeves, who also became long-term friends. I then went to Phoenix for a clinical spinal surgery fellowship and also obtained my first experience in large animal experiments with Dr. Allan Gibson. After that I returned to The Miami Project and the University of Miami as a faculty member in 1999.

 

MARC: You said you came here and fell in love with it. I know you can fall in love with the Bunges pretty easy, would you say that that’s what put you over the top pretty much or was it the idea of The Miami Project in general?

 

Dr. GUEST: Yes, it was so exciting to come from the ward care of patients with SCI into a multidisciplinary research environment. Here, we had biweekly conferences in which the radiology and histology of an autopsy injured spinal cord was presented for discussion, often with novel observations. These were very enriching and although I was a neophyte I felt welcomed. My first project was to detect demyelination in the injured human spinal cord. I used chronically injured autopsy cords that had been donated to the spinal cord bank and I enjoyed the histology and neuropathology. I was lucky because I had good results within the first month that I was here. Those results eventually led to the paper where we described the existence of significant demyelination after human spinal cord injuries. After that, I was offered a chance to work on transplantation of human Schwann cells into the spinal cord and that became my thesis project. In a way, I’m still doing my thesis extending it- increment by increment.

 

MARC: Let’s fast forward now; you’ve done a lot of different projects. I guess at some point along with Damien, Mark and Mary we’ve come together with what we think is the best scenario for recovery based on what we have to date. What, I guess the question is, looking at, I guess stepping back and looking at science, what do you think of the protocol, what do you actually think of it, what do you think the chances are of it being successful and from there, what do you think? Or how do you think maybe the state of SCI research and how the trial fits in there?

 

Dr. GUEST: An important question is whether studies that we do in the animals predict what’s going to happen in people, and to the degree that that’s true then the animal studies give us cause for optimism. It’s going to be exciting when we start to transplant people because we may then learn new things that we may not be able to anticipate from animal studies. Most of my experience has been in cell and tissue transplantation in several animal models. We know that transplanted cells can promote many beneficial effects in the damaged spinal cord including neuroprotection and new axon growth. One of the things that is difficult in the translation to humans is knowing the optimal timing of when an intervention is likely to be most beneficial and when will the intervention will not have an effect. Because you don’t have an infinite number of chances you have to make really good guesses based on our animal work and clinical knowledge. So to answer the initial question, I think that our trial is supported by a large amount of good data from both animal experiments and human autopsy cases.

 

MARC: What about the research community, outside the Project? How do you think we’re being received?

 

Dr. GUEST: How do I think the Schwann Cell Phase 1 study will be received? If we put together an excellent clinical protocol based on strong preclinical studies and obtain FDA approval, and conduct the study well, we’ll get respect from the research community. People know that this is coming and it’s an option that makes good sense based on several lines of evidence. I think that many eyes will be on us to see how well we can do this. We’ve been fortunate to have excellent large animal models to extend the rodent studies. These have allowed us to actually test the human methodology for the transplants and have been very helpful to the extent that we have learned things that we would have otherwise and unfortunately learned on people. So these models have truly increased the safety of Phase 1 study for autologous Schwann cell transplantation.

 

MARC: I guess it’s like preparing for anything, you try to do as much as you can, with comparable research models, to gain as much experience as you can ahead of time, but I think eventually you have to take that leap of faith. Regarding the Schwann cell trial, as a scientist what do you think is going to happen? If anything, do you think success is going to be measured by different things like cells surviving, or the fact that there are no complications or do we feel that there needs to be some kind of improvement?

 

Dr. GUEST: At the moment our working scenario is that we’re going to select patients who are neurologically complete right up until the time of transplantation. So they’ll be admitted acutely, their peripheral sural nerve will be harvested, cells will be grown and then at 3 weeks, they’re going to have another consent process and be re-examined to make sure that they are still neurologically complete. At that time point, with a complete injury in the thoracic spinal cord, the expected spontaneous motor recovery would be in the single digits. So, I think with this patient selection the emphasis will be on safety, such as not causing ascent of the neurological level. Another concern we’ll test is whether the Schwann cell transplant causes additional neuropathic pain. In these first patients it would be remarkable to see major neurological recovery. The initial patients will help us to determine that there are no obvious adverse effects of the transplant. Subsequently we can enroll patients with severe incomplete injuries who may have a better chance to show clear benefits from the transplantation. It’s important to be careful initially because after the initial studies are completed we have several ways to potentially enhance Schwann cell transplantation through use of other drugs and molecules. By building up clinical experience showing safety we enhance our ability to test therapeutic combinations. But if we are too aggressive in our early patient selection and were to cause a loss of function in an incomplete patient, it might be difficult to obtain approval to undertake the combination treatment studies.

 

MARC: We can’t forget about chronic injuries.

 

Dr. GUEST: Right, although we have less animal data from chronic injuries, what we have is quite encouraging. Of course there is even more variability amongst those with chronic SCI than acute SCI. However, if people have reached their maximum recovery with optimal rehabilitation they can serve as a their own “control” to see if cell transplantation elicits additional recovery.

 

MARC: What do you think are the differences in recovery potential for people with chronic cervical and thoracic injuries?

 

Dr. GUEST: Well there are two important sources of data. Firstly, longitudinal studies from people with SCI showing the time course and extent of their recoveries. Secondly, what we know from animal models of complete versus incomplete chronic injuries. For people with complete SCI, most of their recovery occurs within one year. Those with incomplete injury who undergo specialized rehabilitation suitable for them may show increasing recovery for a longer period of time. It is very challenging to use animal models of complete cervical injury, so most are incomplete. In animal models, those with incomplete injuries may show a benefit from a transplant during the chronic injury phase.

 

MARC: I guess I’m talking about the large animal study that you did with the chronic cervical injury and then had a Schwann cell transplant?

 

Dr. GUEST: We made an injury in the lowest part of the brain stem, specifically in the cortical spinal pathway and the animal was hemiplegic for over 2 years and underwent intensive rehabilitation. We then injected the Schwann cells into the lesion site and continued to do aggressive training on a treadmill and with hand activities. The animal’s ability to walk on the treadmill improved to an unexpected degree as did use the affected arm, although the hand function did not recover. I really didn’t expect the results that we obtained.

 

MARC: I’ve always thought that the human body and human spirit is something above and beyond animals so that even if we were to have a small improvement that we will be able to maximize that to a large improvement because we have a will and a lot of animals don’t. You’re not discounting that fact that there could be some recovery? And you wouldn’t be totally surprised if you saw a little bit of recovery?

 

Dr. GUEST: I think that the human will is powerful and that you are right, it may push the recovery further. Regarding whether we’ll see recovery in the Phase 1 study with neurologically complete patients? We might see unexpected recovery, but that would be exceptional. I don’t want to create false expectations.

 

MARC: I’m talking about myself more than anything. There can be an ability for recovery and the fact that the human spirit is what it is could even maximize that beyond so there is a possibility. Personally, what I would see as successful is if there are no complications to the surgery, that there are no tumors or toxicity or any hemorrhaging or anything out of the ordinary, that the cells survive and we can show that type of recovery, that we show regeneration and that there may be some improved function or sensation or lack of neuropathic pain, you know those are the main concerns, I think that would be great, that would be wonderful. That would be recovery. I always felt that it either works or it doesn’t work.

 

Dr. GUEST: I agree that the study will be a success if it shows that autologous Schwann cell transplants can be made within the first month of injury without causing adverse effects. This will be the cornerstone for subsequent studies. Beyond that if we could prove that new connections form, even if those connections weren’t causing major functional gains, it would be another crucial step that would show that the transplant increases new connectivity. Subsequently by transplanting in those with early incomplete severe injuries we may observe functional gains on currently accepted measures.

 

MARC: But that doesn’t help all of us.

 

Dr. GUEST: I know, if we talk about your situation, we need to consider that the effects of cervical injuries are due to both white matter (tract) injuries and loss of key gray matter neurons that supply muscles associated with that injury level. It may be necessary to repair tracts, and in addition, supply new neurons to repair the gray matter.

 

MARC: Anyone ever tried to transplant gray matter?

 

Dr. GUEST: Yes, several researchers such as Paul Reier and Barbara Bregman tested fetal tissues with some positive results. Subsequently there was a clinical trial at Gainesville and other sites where fetal tissue was implanted into the cavities of patients with chronic SCI. One of the important lessons from the human trial was that the quantity of tissue available was much less than needed to fill the gaps in the injured spinal tissue. Over the past decade interest has shifted to the use of cultured stem cells that may become glia or neurons after transplantation and there are many fewer experiments with whole tissues, partly due to complexity of regulating the safety of such transplants that may need to combine tissue from more than one donor.

 

MARC: Enrollment for some current research studies are slower than expected, do you see us experiencing something similar when we get going?

 

Dr. GUEST: I think this depends on several factors. It will help if we are referred patients to our trial who meet the eligibility criteria. The other issue is that FDA may mandate a wait time between each patient. Our enrollment time frame is an advantage because we have a few days after injury to obtain the nerve.

 

MARC: In the acute setting the hard thing is we don’t even know who the patient is until they’re paralyzed. If the study is in chronic injuries like mine it’s something different but if we’re waiting to for someone to get paralyzed, people who are going to be in the study are still walking around right now and that’s the craziest thing.

 

Dr. GUEST: I agree that’s an awful thought. Regarding chronic transplantation, if we show safety in this subacute injury cohort, we can consider chronic patients and acquire additional preclinical data to support transplantation in chronic patients. It will also be important to pre-train such patients to ensure they are at their best baseline before transplantation. But it’s quite likely we will test the transplantation in those with chronic injuries as well.

 

MARC: I hope you know that I’ve enjoyed my friendship with you and our camaraderie, especially you taking time to explain things to me and helping me along the way. And I hope you enjoy being here because we enjoy having you here. It’s going to be interesting to see what happens in the next couple of years based on this trial.

 

Dr. GUEST: Marc, you inspire me a lot and seeing your commitment inspires many people. I feel I’ve been very lucky. I’ve had my career transformed by coming here, doing a PhD with the Bunges, and being able to start my career as a surgeon scientist in a very supportive environment. For that I’m grateful.

 
 
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