Julianne McCall (julianne.mccall@gmail.com)

Graduate Program:  Biomedical Sciences
Lab PI:  Dr. Armin Blesch
Undergraduate Institution:  Denison University
Med-into-Grad Clinical training area: Neurology and Neurosurgery
Clinical mentors:  Joseph Ciacci (jciacci@ucsd.edu),
Thomas Hemmen (themmen@ad.ucsd.edu)
Erik Viirre (eviirre@ucsd.edu)
Patrick Delaney (pdelaney@ucsd.edu)
and the VA Spinal Cord Injury Center physicians and therapists
Contact: Susan MacWilliams: susan.macwilliams@va.gov
Inigo Garcia-Zozaya, MD and Amy Magnusson, MD.

Quote: “Med-into-Grad renewed my drive to eagerly pursue medical research and gave me an entirely new perspective on the problem at hand--powerfully from the experience of the patient.”

Rational for Med-into-Grad training:
            My research addresses the genetic and molecular mechanisms that trigger a regenerative growth state in adult neurons of the peripheral and central nervous systems.  By comparing the neuronal response to injuries in the rat PNS and the CNS, my group is identifying transcription factors, and their signaling pathways, that are up-regulated and essential to the successful PNS repair process and that are also unchanged in the CNS.  We then apply a viral vector delivery system to express the genes of interest within the CNS to promote axonal growth following a spinal cord injury (SCI).
            At this time, there is very little that medicine can offer victims of SCI and brain trauma beyond vital stabilization and pain management.  I initially pursued medical research because I was frustrated by the limitations of clinical practice in neurology and neurosurgery in facilitating prognoses that met the hopes of patients.  Where modern medicine was unable to provide answers, I wanted to devote my career to contributing to the design and development of novel therapies.  But while the field of adult nerve regeneration research has offered numerous strategies, regenerative success is rarely achieved beyond particular rodent models.  I realized that a broader perspective of the problem was paramount to better direct my future research in SCI.  The MIG training program granted me the opportunity to explore the clinical condition as a scientist, rather than as a patient advocate or young student.  I was able to speak with patients about their experiences with neurological injuries and diseases, discuss diagnostic and treatment plans with physicians, and discover the impressive collection of technological devices and techniques used in diagnostics and therapeutics.  The training provided a foundation from which I could assess my research in terms of clinical priority and resourceful efficiency.

Medical training and identification of medically-relevant research issues:
            I decided that an overview of various neurological diseases and injuries would best contribute to my knowledge of the nervous system, repair mechanisms, and clinical therapeutic strategies.  The first part of my clinical experience was conducted at the VA SCI Center, shadowing rehabilitation physicians while they met with patients and managed staff meetings and rounds, speaking with orthopedic surgeons about various reconstructive procedures, and learning from occupational and physical therapists about which devices and exercises were effective in maximizing spared function.  I was intrigued by the sophistication and sheer amount of prosthetic machines that help to compensate for loss of motor ability or fine control.  For example, one neuroprosthetic splint wrapped around the foot, ankle, and shin and evoked an electric signal every time it sensed that the foot was not lifting high enough for a balanced step.  The stimulation would activate the tendons which would lift the end of the foot to avoid falling.  Another neuroprosthetic helped to relieve tension in muscles that opposed and prevented desired movements (for example, the bicep versus the tricep) through excessive stimulation to the point of muscle fatigue.  With the further development of technology and biofeedback mechanisms, research in prosthetics has much to offer in collaboration with the more slowly progressing biological research.
            Time spent in Outpatient Neurology offered much time looking at stroke, migraine, and tumor cases.  I spent several days with physicians who were using state-of-the-art Transcranial Doppler equipment, which allowed for non-invasive diagnoses of vascular issues, such as ischemic stroke.  I learned and conducted the basic neurological exam to test for functional reflexes, intact cranial nerves, and appropriate sensory capacities.  Some other procedures observed were electromyography for peripheral neuropathies, electroencephalography for seizures, lumbar puncture to sample CSF, and CT, MRI, and fMRI scans.  At the time, the physicians were involved in a study to correlate the parameters of the carotid artery with risk and background of stroke with and without certain prescription blood thinning drugs for unrelated reasons.
            The Inpatient Neurology Department gave great insight into the complexities involved with dealing with diseases and fellow humans.  Many patients were unconscious from trauma or stroke.  Some patients were emotionally unstable and unable to answer questions appropriately or comply with testing.  More often, patients were diagnosed with more than one disorder, which added further complications with treatment paradigms.  Specialists of other departments were often called for consults, demonstrating the necessity for collaboration and comprehensive patient care.
            The last part of my clinical experience was spent with the Neurosurgery Department.  Most of the cases dealt with reconstructing the spine for support and movement using rods, screws, and clamps, while others involved tumor removal.  Unlike the clinical approach to spinal cord injury, researchers rarely expend energy maintaining the integrity of the spinal column, so that arose as a potential research study to test how the structural stability of the spine might affect the cellular therapies that are currently being tested in the lab.  The lack of any clinical therapy to address the damaged nerve tissue was as expected, and unfortunate.  Treatments used were generally geared toward suppressing the inflammatory response from exacerbating secondary damage.
            In the research lab, I had been skeptical about the benefits such modest results would yield, for example, inducing axonal growth 2cm beyond a spinal cord lesion cavity, versus the target distance of 3cm.  Clinically, I was astonished at how dramatically the quality of life improves from such a slight biological difference.  In terms of SCI, a distance of relatively similar length, between, for example, a C5 and C6 lesion, would determine whether a patient would be able to use his or her hands.  I have renewed hope that even a marginal effect size in the laboratory can be translated to clinical treatments of great significance for certain patients.

Potential Research collaborations:
            With regards to SCI specifically, I was very interested to learn that there are few means by which to measure plasticity in the human spinal cord.  By that, I am referring to correlating the precise location of the lesion with the initial functional consequences, and later with the amount of rehabilitation that is achieved upon years of therapy.  Even in rodent models, it is largely unknown how much of the observed regeneration is due to sprouting of spared cells and how much is due to growth from damaged cells.  A better understanding of how rehabilitation therapy changes a patient’s motor and sensory abilities would influentially direct neural repair research on many levels.
            The VA Spinal Cord Injury Center has offered to provide my laboratory group, The Center for Neural Repair, with post-mortem spinal cords from patients with spinal cord injuries.  Detailed analysis, using light and electron microscopy with three-dimensional rendering of the lesion cavity for parameters of the glial scar, spared tissue, neuronal architecture, synaptogenesis, and membrane integrity would help to clarify the state of the spinal cord following acute and chronic injury as well as rehabilitation paradigms.  Meticulous clinical records regarding functional capacity could be linked with the above-mentioned data, collected by immunohistochemistry for each signal.  This would require a bank of spinal cord tissue, to best allow for controlled injury conditions and rehabilitative programs.  But a study of this magnitude and specificity could have the potential to provide some answers to a very significant mystery: the degree to which restored function is a result of spared tissue sprouting.

Training in diagnostics & therapeutics, and identification of unmet diagnostics & therapeutics:
            Traditional diagnostics utilizing the neurological exam in combination with modern scanning technology have cultivated relatively sharp accuracy for most disorders and trauma cases.  However, the therapies available to patients are severely lacking.  Most therapeutic strategies, for stroke and tinnitus, for example, depend upon the patient’s long-term commitment to behavioral and lifestyle changes.  Personal choices and financial limitations were two of the most common excuses I witnessed to explain why patients were incapable of successfully following their treatment plans.  A comprehensive cellular, pharmacological, or genetic based regime would be much more effective, if developed.  Also, physicians cannot guarantee that any single drug (and dosage) will be effective for any given patient, due to genetic, physiological, and behavioral variables.  Numerous visits are often required for a patient to find the proper balance to fulfill their need.  With the enormous rise in genomic research, neurology may benefit from individually targeted regimes based on genetic background.

Diagnostic & Therapeutic collaborations:
            Many animal research projects, unfortunately, seem to reach the point of developing a beneficial process without further optimizing the results because of the limitations on resources and laboratory expertise.  Combinatorial therapy plans will likely be the frontrunner in clinical trials for spinal cord injury and stroke because of the enormous potential for neural plasticity and the fact that little is known about what may trigger the boost in neuronal growth and reorganization.  Passive movements of affected limbs of SCI patients help to prevent spasticity and avoid painful positions.  Some animal research seems to neglect what clinical practice already does regularly.  While studying signaling pathways and cellular therapies in animal models in vivo, a combinatorial regime of various therapies should be applied to best optimize the opportunity for beneficial effects.  For example, while testing the efficacy of over-expression of a gene within the injured rodent cord, that animal could also be subjected to behavioral activity, such as passive limb movement on a treadmill.
            It is imperative for my area of study that research continues to finesse the practice of gene delivery into humans.  Once that practice is developed, I will be eager to direct therapeutic targets toward activity-driven plasticity, relieving the inhibitory components of the CNS environment through enzymatic (Condroitinase ABC) or antibody (Nogo-R) application, grafting a permissive substrate across the lesion site (such as bone marrow stromal cells), and stimulating the intrinsic growth program via gene delivery to up-regulate the transcription factors that are naturally involved in PNS repair.

Long term impact:
            Upon meeting the patients and discussing the clinical problems with the physicians and surgeons, I am more inclined to set a research project goal that has clear, clinical relevance.  I will begin working directly with physicians and other research groups to develop each step in the process toward fostering a multi-faceted, combinatorial therapy for SCI.

Student-specific experiences:
            As interested as I was about the process of clinical and surgical healthcare, the physicians and surgeons were also eager to learn about the current state of research.  There are enough clinical journals to easily fill any trace of spare time as a physician; also attempting to stay up-to-date with the research literature would nearly justify hiring a full-time intern.  I found myself reviewing literature beyond my own research field for progress and breadth in methodology, in order to accurately portray the more general scope to the physicians.  This became an excellent exercise that I will try to maintain throughout my graduate studies. Also, with grandparents reaching the ages of almost inevitable neurological decline, I have been surprised at how often I have discussed with family members and friends my experiences with patients of similar ailments, my knowledge of and ability to perform neurological tests, and the life-changing conversations about values, education, and wellness that I have had the honor of sharing with some of the patients between appointments when they simply wanted to talk.

Advice for new trainees--Autumn preparatory quarter:
            In addition to several, very helpful on-campus medical courses recommended by Mark, I was able to attend a one-time orientation for new residents at Hillcrest hospital.  While much of the content dealt with paperwork unrelated to a MIG student, there was also much information about the system and schedules of rounds, inpatient and outpatient handling, and other issues, such as hospital transfer patients and resident research projects.  In addition, prior to beginning the clinical experience, it may also be useful to attend the weekly Neurology Educational Conference, which is attended by 3rd-year medical students actively involved in their Neurology rotation.  The intensive and case-driven discussion and review of techniques may help to prime you for on-the-spot analysis in the clinic.

Advice for new trainees—Winter clinical training quarter:
            Never stop asking questions!  While a level of tact is certainly recommended, because not all physicians, residents, and patients will be open to constant discussion, many respond very well to initiation and interest.  Also, prior practice in conducting the neurological exam will save you the embarrassment in front of the patient and physician.

Take home perspective on Med-into-Grad at UCSD:
            The MIG program has been an unbelievable experience, to say the least.  It has renewed my drive to eagerly pursue medical research and given me an entirely new perspective on the problem at hand, powerfully from the experience of the patient.  The method by which I approach research aims and formulate rationales will necessarily adopt clinical relevance and significance.  I would whole-heartedly recommend this program to every student in the field of biomedical research.  It has been an honor to be a part of the program and I look forward to applying my experience to my research in more depth, now and throughout my career in research.