Nathan Lewis (natelewis.3@gmail.com)

Lab PI: Bernhard Ø. Palsson, Ph.D.
Graduate Program:  Molecular Pathology
Undergraduate Institution: Brigham Young University
Med-into-Grad clinical training area: Neurodegenerative Diseases
Main clinical mentors:
Dr. Richard Haas (rhaas@ucsd.edu)
Dr. Alan Gruber (abgruber@ucsd.edu)
Dr. Michael Rafii (mrafii@ucsd.edu)

Quote:  “In my PhD research, about half of my work has been on basic science involving the analysis of large metabolic and gene-regulatory networks in microbes. My clinical experiences, however, has encouraged me to pursue more clinically-relevant research questions. In about a year I will begin searching for postdoc positions, and I now plan on searching for positions that will allow me leverage my network biology skills on human systems or mammalian models of disease.”

Rational for Med-into-Grad training: As a bioengineering student, I have been deeply interested in the computational analysis and modeling of biological systems. My central project as a graduate student has been the reconstruction and analysis of metabolic pathways active in various cell types in the human brain. The models I constructed represent more than 1100-1200 chemical/transport reactions of metabolites in the astrocytes and different types of neurons. After building this network, I have been able to run simulations of metabolism in normal and diseased tissues, and study the active processes in brain mitochondria. Since several neurodegenerative diseases have prominent metabolic components, I have used to model to look at Alzheimer’s disease. The Med-into-Grad program offered me a view that I could not get from the literature of this and other neurometabolic disorders. The program has provided insight and ideas on the relative importance of metabolism and mitochondrial function to these disorders, and provided additional knowledge on how these diseases are currently treated.

Medical training and identification of medically-relevant research issues:  As a med-into-grad student, my focus was on neurodegenerative diseases and neurometabolic disorders. In the fall quarter I attended several of the brain cutting conferences and looked at patient tissues with the physicians in the pathology lab at the VA. These were very interesting and gave me a view of what various disorders look like on an autopsy brain, including the effects of heavy drinking, ischemia, and tumors. The majority of the samples we saw in the pathology department demonstrated various levels of severity of cancerous growth in the brain. It was interesting to see how it interferes with the normal distribution of cells in various brain regions.
During the winter quarter, I participated in various clinics for Alzheimer’s disease, pediatric and adult metabolic disorders, and migraines (since there is a clear mitochondrial inheritance in some cases). In these clinics I had the chance to interact with a number of physicians, who each had their own approach to these disorders and insights into the pathologies. For me, this was a real eye-opener. Over the past few years I have been reading much on various areas of research, and rarely does one actually read a paper that accurately sheds light on the current mode of treatment for a given disease. I was actually surprised to see the disparity between the proposed treatments in the literature and what is actually done in the hospital. Moreover, being in a research lab, the idea of sequencing one’s mitochondrial DNA is nothing more than just using a few reagents and loading it onto a next-generation sequencer. However, in the clinical practice, there are great financial constraints on many of such tests. Therefore, in the metabolic clinics, only occasionally did they set up to get assays on mitochondrial function or search for mDNA mutations. Usually they just relied on trying a few vitamin supplements to try to keep the disorders under control. Lastly, it really impacted me how many of the disorders I saw were essentially lifelong diseases for which it was not exactly clear what exactly they were. Essentially all of them were genetically based, so cures at this point were not an option. The whole goal was to improve the condition of the patient and keep it from deteriorating again.

Potential Research collaborations:  To date, mitochondrialdisorders have been difficult to diagnose and even more difficult to treat. In the neurometabolic clinics, I saw some of the leading physicians use primarily metabolic tests and occasionally genetic tests to narrow down on the metabolic diseases. In this clinic, Dr. Richard Haas told me of an idea he had for a treatment. It just so happens that the treatment could be modeled using the models I have built for brain metabolism. Therefore, I was able to run some initial tests on the efficacy of that treatment. The calculations, however, were very rough estimates. Therefore, additional work and another type of model would potentially answer the question as to the efficacy of the treatment prior to the implementation of the clinical trial.

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: During my time in the clinic, I had the opportunity to see a wide range of mitochondrial and neurodegenerative diseases. In the Alzheimer’s clinic, there was not a wide variety of diagnostics or treatments. Each patient would undergo a small quiz in which a wide range of cognitive functions were tested. Depending on the results, the doctor would either just advise them on how to improve their cognitive function if there was only minor forgetfulness, or begin prescribing medications if it was more severe. However, in the clinic where I was at, almost every patient with even mild cognitive deficits were sent for a volumetric MRI to measure the volume of their hippocampus. Over the weeks in which I was there, we did get a few more interesting cases which were clearly not Alzheimer’s disease, rather other neurological disorders that affected the memory. However, I only saw the diagnosis of these and not the treatment.
The metabolic clinics, however, was very heterogeneous. I never saw the same disorder twice, except when two siblings came in with the same cytochrome c oxidase mutation. In general, each patient would have a blood chemistry screen to measure the concentration of a number of metabolites. These were used to verify that the disorder might be mitochondrial. If it was, they would often just supplement with coenzyme Q. Given the disorder, occasionally they would take muscle biopsies to test the mitochondrial physiology and genetics. Some known disorders were treated with special diets.

Diagnostic & Therapeutic collaborations:  The disorders I saw in the clinic are very complex, and the underlying pathophysiology is either very poorly understood or the complexity of the disorders have challenged treatment beyond vitamin supplementation. However, assuming my model can make valid predictions, perturbation simulations can be run until one is found to bring the model phenotype closer to the normal metabolic state. I have discussed this, complete with predictions with Dr. Gruber, and run some simulations for Dr. Haas. In the case of Dr. Haas’ predictions, he is already putting together a clinical trial for it. However, additional computational simulations are needed for more detailed predictions.

Long term impact:  In my PhD research, about half of my work has been on basic science involving the analysis of large metabolic and gene-regulatory networks in microbes. My clinical experiences, however, has encouraged me to pursue more clinically-relevant research questions. In about a year I will begin searching for postdoc positions, and I now plan on searching for positions that will allow me leverage my network biology skills on human systems or mammalian models of disease.

Student-specific experiences:  Beyond motivating my research, it impacted me as a person. As a young undergraduate, I’d occasionally go to nursing homes with friends just to talk to the people there. However, it’s been a long time since I’ve done anything like that. The clinics I attended here affected me more deeply for a number of reasons. First, I have a deeper biological understanding of the diseases, and so it shed a new light on how I viewed the patients. Second, I have a wife and children, and so the neurometabolic clinic at the children’s hospital and the Alzheimer’s clinic I attended can make one look at their own life to evaluate how they’re spending their time. It’s made me appreciate the health of my family and had made me more motivated to improve the quality time I spend with them.

Advice for new trainees--Autumn preparatory quarter:  During the autumn preparatory quarter, I did the self-study histology program. This was not very demanding, but to get the most out of it, I did extra things beyond just reading in the texts. To supplement my study I made sure to look at slides on the microscope and I went through most of medpics online to get a good idea of what to look for on the different slides. However, I found that the most interesting and helpful part of the autumn preparatory time were the brain-cutting clinics at the VA morgue. While the pathologists helped me with my neuroanatomy, I asked to be able to join them while they were looking at histological sections from autopsies and from live patients undergoing brain surgery. Through this they were able to show various types of pathological features of the tissues.
As more of a logistical issue, be sure to immediately get your ID badges for the hospitals, when the paperwork is ready. I had trouble getting mine in December due to UCSD furloughs.

Advice for new trainees—Winter clinical training quarter:  If possible, try to meet with the clinicians before you start, so that you can get their expectations and share your research. I had the opportunity to do this with one of my mentors, and it served as a really nice introduction. He also gave me a list of papers and a book to read so as to enrich my clinical experience.
Be sure to have some slides ready to detail your research and the methods underlying it. While many clinicians will not necessarily have time for a long discussion, each one of them asked about my research and asked many detailed questions. The one time I’d brought my laptop and slides, the clinician took a good 15-20 minutes to discuss the clinical implications of my research. This opened up the door for regular discussions with this physician at the end of each day to discuss research ideas.
In some clinics, you may (or may not) have break periods between patients. Get permission from the physician to look at the patients charts beforehand and discuss the case with the physician. Look up papers on it online and read about the possible disorders in Wikipedia to get a better view of the potential common symptoms, the pathophysiology, and current treatments.

Take home perspective on Med-into-Grad at UCSD:  The Med-into-Grad program was more than worth the time. The program gave me increased insight into the how metabolic and neurodegenerative diseases are treated. Surprisingly, these facts are not addressed at length in the literature, so it gave a whole new insight into the treatment. It also helped motivate me to actually see the patients and talk to them about their challenges and experiences. It also opened up several opportunities for collaboration.
However, in my opinion, the coursework was very short, though, this is probably better for students, like myself, who are trying to balance research at the same time. The clinical work was brief, and I would have preferred more structured training on how to do a physical examination and neurological examination prior to the clinical experience. Even more so, I would have liked to better understand for what each procedure was testing.
I would strongly recommend the Med-into-Grad program to any student who has interest in biomedical sciences. Moreover, even students that are inclined to prefer basic science research may gain much from these experiences. While my research has involved much study and analysis of brain metabolism, I have also spent much time doing basic research in microbial metabolic and transcriptional regulatory networks. Thus, my research by in large has been highly theoretical. However, my experiences in the clinic and in the Med-into-Grad courses have provided me with more ideas on how I can move my research more towards disease-related studies, and potentially towards predicting clinical outcomes of various treatments.
Therefore, I would recommend this program to any student that wants to get a broader view of the clinical endpoint of their research, and is willing to sacrifice a few months of research time for this increased understanding. It can really help redirect research efforts and priorities to more clinically relevant and more meaningful directions.