Dustin Wakeman (dwakeman@burnham.org)
Graduate Program: Biomedical Sciences
Lab PI: Evan Y Snyder
Undergraduate Education: University of Illinois at Urbana-Champaign
Med-into-Grad clinical training area: Neurodegenerative Disorders
Main clinical mentors:
Dr. David D Song MD PhD; dsong@ucsd.edu
Dr. Stephanie Lessig MD; slessig@ucsd.edu
Quote: “One of the most important moments in my MIG experience occurred in the basement of the VA Hospital with Drs. Mark Tuszynski MD and Harry Powell MD, discussing the relative distances a dopaminergic neural precursor would have to correctly extend projections from the midbrain substantia nigra to the striatum in order to correctly reconstruct and reinnervate the mesostriatal system with regulated dopaminergic tone in a typical Parkinson’s disease patient. It immediately became clear why the plethora of positive data obtained in rodent and non-human primate models for fetal DAergic transplants failed to predict gross adverse effects in human PD patients; The unequivocal differences in anatomical organization and cortical mass that humans exhibit are easily overshadowing when modeling complex human disease in simpler organisms. MIG provided the necessary exposure to fine tailor my current work to ensure accurate pre-clinical testing as stem cell therapy becomes a clinical reality in the future.”
Rationale for Med-into-Grad training:
Medical training and identification of medically-relevant research issues:
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
Diagnostic, therapeutic, and research collaborations:
Student-specific experiences:
Long term impact.:
Advice for new trainees--autumn preparatory quarter:
Advice for new trainees--winter clinical training quarter:
Take home perspective on Med-into-Grad at UCSD:
Rational for Med-into-Grad training: As a doctoral student in Biomedical Sciences (UCSD), I have been fortunate to work with clinical experts in developmental neurobiology (Dr. Joseph Gleeson (UCSD); Dr. Tony Wynshaw-Boris (UCSD) and stem cell development (Dr. Evan Snyder (TBI); Dr. Leanne Jones (SALK). As mentors, they ensured that I developed and matured as an efficient independent scientist capable of tackling complex problems from multiple vantage points. These rotations provided initial background in neurodevelopment and stem cell biology utilizing several animal models including Drosophila, rodent, and non-human primate as the building blocks for my current thesis research studying the neuroprotective mechanisms of embryonic derived and fetal human neural stem cells, in vitro and in vivo, in the MPTP lesioned, non-human primate model for idiopathic Parkinson’s Disease.
As part of an ongoing multi-center collaboration, we are developing novel neural stem cell based therapies in the most clinically relevant model for idiopathic PD, exploring the interactions between stem cells and the dysregulated cytoarchitecture and microenvironment of the MPTP-lesioned nigral-striatal pathway. In collaboration with Dr. Eugene Redmond MD at Yale, we have found a large degree of cross talk between the degenerating microenvironment and the stem cell; the stem cell appears to exert homeostatic forces on the host cytoarchitectural milieu. An important goal of this work will be to determine the interplay between endogenous and/or donor stem cells and their micro-environment as well as the mechanisms involved in functional recovery of MPTP-lesioned primates after successful human neural stem cell engraftment.
In order to ensure greatest patient benefit, it is imperative for the researcher to understand the symptoms and clinical pathology of the specific neurological deficit as well as the various molecular mechanisms underlying the individual patient’s specific combination of symptoms. Understanding which symptoms are most important to alleviating patient comfort should be considered when determining treatment strategies. In much the same manner, the researcher should tailor his efforts towards that which most benefits the patient, so that our models accurately portray true mechanisms of the neurodegenerative disease. I believe the Neurodegenerative Diseases Med Into Grad (MIG) Initiative offers the perfect translational bridge from bench to bedside as I progress in my career. Our current work implicating that human neural stem cells can promote functional recovery in PD-like non-human primates, offers great future clinical promise. The MIG program offers a unique experience to understand how new therapeutic strategies become clinical realities, gaining prospective into patient symptoms to better model the pathology of idiopathic PD.
Medical training and identification of medically-relevant research issues: In order to immerse myself into the clinical setting, I first (wk1-2) decided to sample two general neurology clinics, located at two very different hospitals, the VA (UCSD) as well as Hillcrest (UCSD). Under the guidance of Drs. Stephanie Lessig, Douglas Galasko, and David Song, I learned the basics of the classic neurological examination (motor and mental), standard imaging techniques, as well as the overall theory and practice of a quality patient interview, essential to an accurate and meaningful diagnosis. The importance of non-leading, yet descriptive nomenclature was key to gaining a full comprehension of each patient’s individual natural/case history as it pertained to his/her illness. Only with an accurate landscape can we begin to diagnose and consider the available treatments and possible alternatives for future patient care.
After two weeks of apprenticeship in general neurology, (spent mainly silently observing, with follow-up discussions outside patient quarters) I decided to sample many of the San Diego specialty neurology clinics, including: general neurodegenerative disorders, movement disorders, Parkinson’s disease/ Lewy Body/ Multiple Systems Atrophy, Alzheimer’s disease, Huntington’s Disease, Multiple Sclerosis, and migraine headache. It was in these two weeks (wk3-4) that I learned the complex nature of human disease that plagues every practicing physician; Each patient’s individual cache of symptoms produces a plethora of plausible causes and effects, which manifest themselves in a temporally variable manner. It is up to the physician to educate themselves enough to be confident in their empirical decisions while being flexible enough to alter status quo treatments for specialized care. Although the first four weeks of clinic were a rather crude and somewhat intimidating introduction to clinical medicine, once I became more familiar with the initial examination/interview process, I gained poise with my patients, to the point where I was confident in my ability to provide accurate professional care and could sense that they were also comfortable with me relaying critical information to their primary care physician. Overall, there was an extremely quick learning curve, thanks mainly in part to efficient training by both Drs. David Song and Stephanie Lessig.
To further my understanding of neuroanatomy and the brain’s intricate cytoarchitectural composition, I arranged to participate in the VA/Hillcrest’s weekly brain cutting Pathology Seminar, where selected human brain specimens of a variety of developmental stages are fully autopsied under the direction of Drs. Harry C Powell MD and/or Lawrence A Hansen MD and prepared for classic histopathological analysis. These weekly “hands-on” meetings provided both a macroscopic analysis of post-mortem whole brain as well as specimen preparation for further microscopic analysis to decipher cause-of-death and any specific brain anomalies or perturbations that may exist within the patient or contribute to the overall pathology of the brain.
One of the most important moments in my MIG experience occurred in the basement of the VA Hospital with Drs. Mark Tuszynski MD and Harry Powell MD, discussing the relative distances a dopaminergic neural precursor would have to correctly extend projections from the midbrain substantia nigra to the striatum in order to correctly reconstruct and reinnervate the mesostriatal system with regulated dopaminergic tone in a typical Parkinson’s disease patient. It immediately became clear why the plethora of positive data obtained in rodent and non-human primate models for fetal DAergic transplants failed to predict gross adverse effects in human PD patients; The unequivocal differences in anatomical organization and cortical mass that humans exhibit are easily overshadowing when modeling complex human disease in simpler organisms. As a result, I have re-iterated the essential use for extensive non-human primate research in both my own work (Redmond Jr., DE PNAS 2007 Jul 17;104(29):12175-80) as well as all stem cell transplantation biology (Wakeman DR Regen Med. 2006 Jul;1(4):405-13), to fully assess the fate and efficacy of future clinical therapies.
While becoming more familiar with the post-mortem brain and the overall complexity of human neural organization, I decided to concentrate specifically on learning the dynamics of Parkinson’s disease by transitioning from a more general clinical setting to a few specific neurological clinics that specialize in symptoms most commonly associated with classic idiopathic PD, Multiple Systems Atrophy, and Lewy Body Disease (wk 5-12). Specifically, the Perlman PD and dystonia clinics (La Jolla) provided a diverse array of patient experiences that helped me further understand and discriminate between cognitive and motor deficit when accurately diagnosing patients. In addition to their major neurodegenerative disorders, these patients often displayed a variety of other off-target ailments that may be directly or indirectly caused by their primary complaint. Furthermore, I gained a greater understanding of the complexity of progressive disorders like idiopathic PD as I learned about not only the voluntary motor deficits involved but also the progressive deterioration of the the autonomic nervous system (ANS) and its variable effectors including: heart rate, digestion, salivation, diameter of the pupils, micturition, and sexual arousal. I found it astounding that many PD patients eventually meet their demise due to swallowing problems that lead to choking or hospital laden infections from bed sores, not from pathology directly related to brain atrophy.
Rather unexpectedly, I gained a greater understanding of conditions atributed to neurological deficit, such as the motor condition dystonia. I was not previously aware of the complexity of this disorder or that Botox was routinely administered at high doses to pharacologically block and alleviate these severe muscle spasms. In addition, I previously had an extremely negative view of Deep Brain Stimulation (DBS) of the LG for treatment of severe dyskinesia in PD patients; however, when properly administered and accurately tuned on a regular basis, I personally witnessed real-time beneficial results in highly dyskinetic patients that were previously experiencing extreme pain, muscle cramping, and severe spasm. This is a testament to the need for extremely well qualified and highly trained physicians to properly diagnose complex disease and research scientsts to accurately model these diseases and provide safe eficacious new therapies for physicians to implement.
Research collaborations: Through the self-taught short course in Pathology, the Brain Cutting Seminar, and the individual lecture on PD, I was able to show personal data to an expert on alpha-synuclein, Dr. Eliezer Masliah MD, as well as obtain precious human PD patient tissue for histopathology related to my thesis research. This valuable tissue can be used as positive controls for a variety of immunohistochemcal assays or even probed for newly discovered proteins involved in the progression of PD.
Long term impact: I gained a much greater understanding for the complexity of human disease and the relatively simplistic ways we as researchers have chosen to model these ailments. As a result, I recently made a trip to our African green monkey colony to examine and study the Parkinsonian behaviors of our MPTP lesioned non-human primate PD model. I was reaffirmed that not only does our model faithfully depict the motor ailments of advanced idiopathic PD, but we have successfully created a model that also recapitulates autonomic dysfunction. While not perfect, I am confident we are using the most accurate representation of classic idiopathic PD available and recently completed a study utilizing both human fetal neural stem cell transplantation and viral gene therapy with GDNF to explore the possibilities of combined treatments for restoration of the damaged DAergic system.
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: When analyzed by a highly trained and well experienced neurologist, cognitive and motor diagnostics can be extremely effective for proper patient diagnosis. Coupled with advanced imaging technologies such as SPECT, MRI and PET, the cognitive Mental examination (variable length and complexity) and classic extensive motor exam usually can detect greater than 95% of PD cases I personally witnessed. In addition, there are a variety of Parkinsonian specific exams for scoring gradation in disease onset such as the Hoehn and Yahr, UPDRS, and a newer version being currently tested by Drs. Lessig and Song that is more comprehensive and tailored to deciphering specific “phenotypes” of PD. Therapeutics, unfortunately, have not progressed much since PD was first characterized, as combination therapy of oral Carbadopa/Levadopa or a dopamine agonist is still the first and best line of treatment. Furthermore, long term pharmaceutical treatment has a distinct ability to “wear off” after several years of therapy, create off-target neurological deficits, as well as significantly induce the recurrence of severe dyskinesias. As a result, DBS has been successfully implemented to help “wean” long-term patients off of high dose medication regimens.
The most urgently needed diagnostics for PD are earlier detection methods to start treatment before striatal DAergic tone has been extensively lost, which probably could be developed as new methods/techniques and state of the art equipment in non-invasive neural imaging and plasma biomarker analysis progresses. For example, Drs. Lessig and Song are currently investigating the loss of certain odorant receptors as a first alert symptom for PD patients. When coupled with advanced imaging techniques, we may be able to develop a characteristic set of early warning signs to better predict PD for more aggressive therapy at the onset of disease before the degeneration is too extensive to treat. Ultimately, treatments for PD would probably benefit most from more accurate basic science modeling and better diagnostic readouts of DAergic deficit/gain of function post treatment. Even if we manage to develop a great new therapy, functional readout is still limited. Coupling SPECT analysis with other diagnostic imaging techniques could provide necessary keys to solving these issues.
Diagnostic & therapeutic collaborations: In general, pharmaceutical treatment is still the most widely accepted form of treatment, although I firmly believe, under the highly skilled neurologist’s guidance, DBS could make a huge impact in the PD field. In addition, most neurologists I have spoken with do not have high expectations for cellular replacement or gene therapy. Although favorable results have been seen in many animal models, these results have failed to translate into human clinical trials, leaving the experienced neurologist extremely skeptical of proposing a complicated stereotactic injection deep within the brain. In fact, it is very hard to find a well read neurosurgeon that would even consider the proposition without much more extensive experimental data. However, these often harsh criticisms should be thought of as a necessary check to keep the modern research scientist in balance with present day medical ethics. In this spirit, we have surged ahead and recently married the fields of stem cell biology and viral gene therapy, combining AAV5-GDNF, (a neural chemoattractant) and human neural stem cells in hopes of creating functional hNSC derived A9 (Girk2+) DAergic cell bodies in the SN with appropriately guided striatal innervations. Our preliminary data utilizing fetal ventral mesencephalon explants with AAV5-GDNF in a similar manner were extremely positive and provide the initial framework for the future progress of this work. We look forward to pushing the limits of both fields as we strive to provide novel therapeutics to a growing population of PD patients.
Student-specific experiences: The MIG program was an amazing bridge between basic and clinical science. It allowed me to fully assess the quality of life and current state of healthcare that patients suffering from neurodegenerative disorders experience everyday. I gained a much greater understanding of the complexity of human disease and the various struggles managing care physicians must deal with on a daily basis. In addition, there is a certain level of gratitude and appreciation that you receive from patients that is often overshadowed in basic scientific research. You can truly impact the health of individuals on a daily basis as an MD, whereas, we as bench scientists often lose sight of the true goal at hand, making people better. I will definitely never forget the first time I had a follow-up visit with a specific DBS patient after he/she had their settings re-adjusted. He/She was a completely different person, fully functional in all motor tests and mentally positive for the first time in months. This was remarkable progress, within 3 weeks period of time, a true testament to the powers of modern medicine and the years of diligent research tested in large animal models despite negative publicity.
Advice for new trainees--autumn preparatory quarter: The autumn preparatory quarter was extremely useful because the staff was so well prepared and developed an extremely well balanced curriculum composed of a panel of expert physician/scientists and patient interviews. Dr. Jess Mandel MD organized and executed a very well developed overview of human disease that allowed each MIG concentration to not only interact with an expert in their field, but also exposed us to disease areas of related interest. The most influential portion of this course was the observation of Dr. Mandel’s patient interview. Learning the art of a proper and efficient patient interview determines the entire outcome of their diagnosis and treatment. I believe I witnessed no finer interviews in my time in all clinics I have ever been in than the public interviews Dr. Mandel arranged for the class. This professional display set the tone for the start of my clinical experience and helped immensely when I began interviewing patients on my own.
The histology short course and the Brain Cutting Seminar gave me a much greater understanding of the anatomy and complexity of the human brain. I would highly recommend any chance you have to see master neuropathologist Dr. Harry Powell in action. His historically accurate recounts and attention to detail are unparalled. I plan to continue these weekly meeting after the MIG program has completed.
Advice for new trainees—winter clinical training quarter: Appropriate behavior in the clinic is key to gaining the respect and TRUST of your mentor physician. There is a strict pecking order in the medical field that should not be tested. Your place as an MIG student is dead last in the order, which is clearly delineated by that silly short white coat you and every physician before and after you are required to wear. In order to “get off on the right foot,” be sure to read up on your target areas including some basic pharmacology and proper medical terminology; Knowing the lingo and talking the talk are the first steps to walking the walk. When you first arrive at clinic (on time), look GREAT, I mean SHARP, take a look in the mirror and ask yourself, Would I want my doctor to look like me?” if the answer is Yes, you may proceed through the door to your mentor, who will probably be knee deep in paper work and late patients by then. Introduce yourself and get ready to get down to business immediately. The most important thing to remember at the beginning is PAY ATTENTION, TAKE NOTES, and OBSERVE, which does not include interjecting and asking patients any questions. You will know when the time is right to ask questions. Before then, listen to the way the interview is conducted and how the questions are worded. These are the key to a great interview. The more comfortable your mentor becomes with you, the more likely they are to ask you to conduct your own patient interview and report back to them with your findings. If your mentor leaves out a question you feel is pertinent, ask them outside patient quarters. There is often a rationale for the order and pertinence of these questions that will not seem apparent till later. As you gain the TRUST of your mentor, you will become much more confident and find the experience to be much less intimidating and extremely enjoyable. Finally, you will make mistakes, forget important patient information, etc., and when you do, expect your mentor to come down hard on you, possibly in the form of an all out verbal assault, often referred to as “pimping” in the clinic. Just remember their job as a physician is to provide the highest quality patient care available, which includes training the most skilled doctors, and during your MIG experience, that medical student is you. Ultimately, respect the time and dedication your mentor has provided for you at zero benefit to them and they in turn will provide an excellent crash course in clinical medicine.
Take home perspective on Med-into-Grad at UCSD: This program provided the necessary exposure to fine tailor my current work to ensure accurate pre-clinical testing as stem cell therapy becomes a clinical reality in the future. Exposure to IRBs, raw patient data, and expert physicians provided knowledge of the entire clinical process for developing and implementing new therapies in patients. The Med Into Grad program is the perfect addition to complete the transition from grantsmanship to experimental design and finally clinical output. I believe this opportunity will provide the catalyst for my graduate career and ensure a complete and well-rounded graduate training regime, increasing my potential as a scientist and production to the Parkinson’s disease community. I would highly recommend the MIG program to any research scientist attempting to better understand and model human disease.