Meghan Miller (m4miller@ucsd.edu)

Graduate Program:  Biomedical Sciences
Lab PI: Palmer Taylor
Undergraduate Institution: Colgate University
Med-into-Grad clinical training area: Pediatric neurology and genetics
Main clinical mentors: 
Marilyn Jones (mjones@rchsd.org)
Doris Trauner (dtrauner@ucsd.edu)
 

 Quote:  “The MIG program has been an inspiring experience.  Through close interactions with physicians and patients I have gained a broader perspective of the clinical pathology of children with neurological and/or dysmorphology disorders.  In the context of my current research, the experience has emphasized the need for better classification techniques and diagnostic criteria in disease categories where the clinical symptoms cover a broad spectrum.  Without this initial foundation it is difficult if not impossible to understand the biological basis of these complex diseases, and therefore, difficult to develop therapeutic treatments.  Overall the program has emphasized the importance of an integrative approach for developing biomedical techniques that address patient needs.”

Rational for Med-into-Grad training:  My research over the years, as a post-baccalaureate fellow at the NIH and graduate student at UCSD, has ranged from diagnostic radiology, to molecular genomics and bioinformatics, to structural biology and pharmacology.   Over the years I have learned various ways in which we study the pathological basis of disease, however, my exposure to the clinical aspects of research and therapeutic development has been limited.  The HHMI med-into-grad program was a compelling opportunity for me to step outside the realm of bench science and get some first hand exposure to biomedical applications at the doctor-patient level.  The program has a strong focus on translational research, an area that I would like to pursue in my future career.  My current research is focused on the structural neurobiology of synaptic complexes that are essential for excitatory/inhibitory neurotransmission.  These networks of protein-protein interactions have been linked to human neurodevelopmental disease, most notably the autistic spectrum disorders (ASD).  ASD is a complex disease that follows a multifactorial inheritance pattern, where there are clearly both genetic and environmental contributors.  There is a great need to understand the pathological basis of this spectrum of diseases in order to improve diagnosis and therapeutic treatment, and potentially learn ways in which we can reduce risk. My thesis research will contribute to our understanding of the neurobiology of excitatory/inhibitory pathways, and will shed light on the importance of specific protein-protein interactions in maintaining the appropriate balance between these two pathways, which may be applicable to drug development.    I was interested in the med-into-grad program because of the clinical perspective it offers, providing insight into the symptomatic phenotypes that present themselves in this and other neurodevelopmental diseases.  Furthermore, the med-into-grad program is a great opportunity to establish collaborations with clinicians, thereby bridging the gap between basic science research and clinical medicine. 

Medical training and identification of medically-relevant research issues: Over the course of 6 months I did two clinical rotations in pediatric medicine.  My first rotation, with Dr. Doris Trauner, was in pediatric neurology at Rady Children’s Hospital in San Diego. Here I observed many patients with  neurodevelopmental disorders, most often some form of autism and/or epilepsy, but also some unique cases where there was often no clear diagnosis.  For the most part these patients had already been given a primary diagnosis to the best of the physicians’ capabilities, and were being followed for treatment purposes.  The first thing that became very evident to me was the importance of routine re-evaluations of the patients’ symptoms and developmental progress. The treatment of neurodevelopment disorders can be difficult and somewhat subjective.  It may require a combination of drugs and behavioral or developmental therapy, and is often specific to each patient. Over the months/years, these treatment plans need to be changed to reflect the progression of the disease. Furthermore, I learned about the imaging and functional tools that are used to interpret and monitor neurodevelopment of brain structure and function. Neurological disorders are unique from other types of disease in that it is nearly impossible to use invasive techniques for diagnosis purposes.  To that end there is a great need for the development of more advanced, higher resolution imaging techniques that allow doctors to visualize brain activity and development.  Another important area of research that would lead to improved diagnostic and therapeutic measures is the identification of molecular markers, such as genetic or proteomic profiling. 
My second rotation was with Dr. Marilyn Jones in genetics and dysmorphology at Children’s Hospital.  Here I observed patients primarily with dsysmorphology syndromes, with and without a known genetic basis.  Interestingly, there was a clear correlation between the symptoms of patients diagnosed with genetic disorders as those with neurodevelopment disorders.  Many of these patients exhibited mild to severe neurological symptoms that are found in many of the neurodevelopemental diseases.  As a medical geneticist, Dr. Jones sees many patients with classical genetic disorders such as Down’s syndrome, Turner syndrome and DiGeorge syndrome.  In these cases morphological features are the initial clues that lead to a putative diagnosis.  From here there are specific genetic screens that can give a definitive diagnosis.  However, genetic testing is still relatively expensive, and therefore usually requires that the doctor have a good idea of what he/she is looking for.  Dr. Jones is an expert on identifying genetic abnormalities, but even then it is sometimes hard to identify these by eye.  In these cases it would greatly benefit the patient to have access to affordable and genetic screening.  At the present time there is no comprehensive genetic screening technique. In some cases Dr. Jones might order microarray studies, which is essentially a “genetic fishing” expedition.  However, these studies can often be misleading and inconclusive, and therefore must be used with this precaution in mind.  The development of more robust microarray technologies is an area of research that would greatly improve diagnostic capabilities. 

Potential Research collaborations: The med-into-grad experience has highlighted the need for clinicians and researchers to collaborate in order to integrate their knowledge of both the molecular mechanisms and pathological symptoms of a disease to improve diagnostic and therapeutic tools. One area of research where this would be particularly applicable is genetic linkage studies of complex diseases, such as autism, where there is a multifactorial inheritance pattern, suggesting multiple genetic contributors.  Genetic linkage studies require the grouping of a population into affected and non-affected subjects, however, more complex diseases often benefit from linkage studies done by sub-grouping the affected subjects based on distinct phenotypic traits.  Such a study for the autistic spectrum disorders has the potential to be highly beneficial.  A collaborative effort between pediatric neurologists, such as Dr. Doris Trauner, who understand the subtle variations in symptoms, and medical and research geneticists, such as Dr. Jones and Dr. Dan Geshwind at the UCLA Center for Autism Research and Treatment, who can perform large genome studies and data interpretation, would be a great example of a collaboration between doctors and researchers. 

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: I found my clinical experience to be particularly interesting because I got to experience two different clinical practices that clearly had some distinct overlap in terms of patient symptoms, diagnosis and treatment.  It was clear in both clinics how a comprehensive patient history and physical exam was essential to the deductive reasoning process.  While behavioral profiling, brain imaging and electrical brain activity (EEG) were the most prevalent diagnostic tools used in neurology, analysis of anatomical morphology and genetic screening were predominant in the genetics clinic. However, these tools could be, and often were, used across both clinics.  I would say there is an overarching need to develop and improve molecular diagnostic tools, such as genetic profiling.  These tools are highly beneficial because they can be definitive if used correctly, and are less invasive to the patient.  

Long term impact:  The MIG program has been an inspiring experience.  Through close interactions with physicians and patients I have gained a broader perspective of the clinical pathology of children with neurological and/or dysmorphology disorders.  In the context of my current research, the experience has emphasized the need for better classification techniques and diagnostic criteria in disease categories where the clinical symptoms cover a broad spectrum.  Without this initial foundation it is difficult if not impossible to understand the biological basis of these complex diseases, and therefore, difficult to develop therapeutic treatments.  Overall the program has emphasized the importance of an integrative approach for developing biomedical techniques that address patient needs.

Student-specific experiences:  I had the unique opportunity to go to Tijuana with Dr. Marilyn Jones and a couple other physicians who volunteer their time at a small hospital just across the boarder.  I enjoyed this experience a lot because it emphasized to me how we can also work towards improving healthcare in countries other than our own.  Furthermore, it offers an opportunity to identify health issues that may be more specific to a certain race or culture, which in turn may contribute to our understanding of some diseases.  It was also very interesting to me to see how health care systems can work effectively in developing countries.  I think it is an important responsibility of ours to share our knowledge and medical expertise beyond our boarders, particularly in developing countries where healthcare is limited and difficult to afford.  

Advice for new trainees--Autumn preparatory quarter:  There are a lot of good introductory activities in the fall.  Take this time to ask lots of questions.  The course, “at the crossroads,” will give you a good idea of the types of questions that medical doctors ask their patients, and the deductive reasoning process that is used to make a diagnosis.  Very often the problem is not obvious, therefore asking the right questions is very important in the clinic.  The self-study histology section is both interesting and useful.  If you have not already done so in the course of your thesis research, take this time to learn a little bit more about an aspect of your current research that might help you to understand the pathological basis of the disease you are studying. 

Advice for new trainees—Winter clinical training quarter:  While you must realize that you are not a doctor and therefore will have limited ability to interact with the patients, don’t just stand in the corner.  You will be able to participate at some level, and this should be established early on between you and your clinical mentor.  Be proactive about developing a mentor-student relationship with the clinician(s) that you are working with, and again, make sure to ask lots of questions.   Discuss your research and ideas with the doctors.  They will often have useful insight or good question that you may not have considered.  Most of all, challenge yourself!  This will likely be a new environment for you, and may not be the most comfortable, but the more you immerse yourself into it, the more you will get out of this experience.

Take home perspective on Med-into-Grad at UCSD:  Overall, the Med-into-Grad program offers a valuable opportunity for graduate students to learn more about the clinical impact of their research.  It is a great way to train young scientists to translate their knowledge of basic science towards developing new ideas for therapeutic and diagnostic tools. I highly recommend participating in the Med-into-grad program as a way to train yourself to think about medical problems from a more patient oriented perspective.