Jason E. Chan (jechan@ucsd.edu)

Graduate Program:  Bioinformatics
Lab PI: Richard D. Kolodner, Co-advisor: Trey Ideker
Undergraduate Education: University of California, Berkeley
Clinical training area of Med-into-Grad:  Infectious Diseases
Main clinical mentors:
Joseph Vinetz (jvinetz@ucsd.edu)

          

Quote:  “I think Med-into-Grad really opened my eyes in terms of the benefit of researching better diagnostics methods. Prior to entering my clinical rotation, I’m afraid I was a bit naïve.  It simply never occurred to me that with all our current medical technology, we would still have such problems as diagnosing disease.  I think my clinical experience convinced me of a need to balance research aimed at searching for a cure and researched aimed at finding a diagnosis.  I realize now that diagnostics and treatments go hand in hand, as one cannot adequately treat something unidentified, and that the need for better diagnostics is equally as great as that of the search for better treatments.  In retrospect, the role of diagnostics tests makes perfect sense, but it was not until I entered the wards and watched a disease progress to a fatal conclusion did I realize just how important a role they play.”

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:

Rationale for Med-into-Grad training:  I applied to the Med-into-Grad program because I am interested in attending medical school and in understanding how comparative genomics might play a role in clinical medicine.  The Med-into-Grad program allowed me to take a quick peek into the world of clinical medicine while still in graduate school.  In searching for access to clinical education during graduate school, I found that there exists a large amount of support for medical students to pursue a doctoral program (MD->MD/Ph.D), while there is little to no support for the reverse (PhD->MD/Ph.D).  Usually the impetus for clinical education into a graduate curriculum comes from individual students, and the Med-into-Grad training is the only program I’ve found that fills the void in terms of structural support for graduate students interested in a clinical education.
            My main research actually explores two questions: 1) What role do retrotransposon elements play in DNA stability? and 2) Can we use high throughput genetic data to identify components of genome instability?  Needless to say, these two questions focus more on cancer than infectious disease.  However, because my research involves both wet lab and dry lab components, I joined two labs, one of which studies elements related to cancer biology and one of which utilizes functional and comparative systems biology approaches to understand biology and, in particular, microbes.
In the past, I’ve compared protein-protein interaction data from the pathogen Campylobacter jejuni with protein interaction data from other organisms (Helicobacter pylori, Saccharomyces cerevisiae, and Escherichia coli) (Parrish, Yu et al. 2007).  Besides identifying conserved complexes across species, we noted potential gene homologs and more importantly, their potential nonhomologous interactions.  We hypothesized that such unique interactions might provide suitable targets for drug therapy, as the effect between species might be minimized due to the differences in the interaction of their proteins.  What might be a detrimental interruption of an interaction in one species might go unnoticed in another.  My interest in infectious disease stems from the wish to use such comparative genomics and proteomics approaches to study different pathogens.

Medical training and identification of medically-relevant research issues:  As part of my clinical rotation, I rotated at all 3 UCSD affiliated hospitals: Thornton in La Jolla, the VA in La Jolla, and at the UCSD Hillcrest hospital.  Over the course of 3 months, I: participated in the physical examination and interview of different patients, both with the fellow and with the attending on duty; attended microbiology rounds; read patients’ charts; viewed and consciously analyzed patients’ radiology images; attended various infectious disease clinics, weekly infectious disease case conferences, fellows conferences, and weekly general medicine grand rounds; presented 3 basic science presentations at the infectious disease case conferences; and presented basic science research centered around patient conditions to the attending and the fellow during rounds.  In addition to my normal duties, I also: contacted a doctor in Peru about an experimental treatment based on in vitro sensitivity studies of a patient with Balamuthia mandrillaris CNS infection; contacted an author of a study performed at the California Encephalitis Project describing the use of a drug in vitro against Balamuthia mandrillaris; called the CDC about compassionate use drug treatment options; contacted the J. Craig Venter Institute’s Infectious Disease group about possible sequencing of Balamuthia mandrillaris; watched part of an autopsy; and listened in on a telemedicine conference at the Owens AIDS clinic with UCSD fellows in South Africa.  Needless to say, it was a great and diverse experience.
            I think Med-into-Grad really opened my eyes in terms of the benefit of researching better diagnostics methods. Prior to entering my clinical rotation, I’m afraid I was a bit naïve.  It simply never occurred to me that with all our current medical technology, we would still have such problems as diagnosing disease.  I think my clinical experience convinced me of a need to balance research aimed at searching for a cure and researched aimed at finding a diagnosis.  I realize now that diagnostics and treatments go hand in hand, as one cannot adequately treat something unidentified, and that the need for better diagnostics is equally as great as that of the search for better treatments.  In retrospect, the role of diagnostics tests makes perfect sense, but it was not until I entered the wards and watched a disease progress to a fatal conclusion did I realize just how important a role they play.

Research collaborations:  I did not develop any research collaborations during my rotation.  However, I did contact the J. Craig Venter Institute’s Infectious Disease group to spark interest in Balamuthia mandrillaris whole genome sequencing, and I also developed a great set of contacts at UCSD across a broad array of topics in infectious disease.
 
Long term impact:  These last few months of clinical rotations cemented my belief in the need for individuals with experience in both clinical and basic science realms.  These fields are highly diverse, and in my experience, both have strengths and weaknesses.  I believe developing a well balanced individual comfortable in both the clinic and the bench is crucial to the success of translational research and I am a big believer in the idea that diversity can bring out the best views and best combination of ideas.  I believe that providing support for graduate students to enter into medical school will lead to better medical technologies.  Unfortunately, while there is a push for clinically inclined students to obtain basic science experience (via MSTP and other MD/PhD programs once in medical school), there is generally a lack of coordinated support for PhD’s to obtain a clinical education (ie. entrance to medical school from Ph.D programs).  I think the Med-into-Grad program is great because it fills the void left by the current infrastructure. 
While in my clinical rotation, I realized just how dependent current research technology is on sequencing.  Again, while this may seem obvious, I think I took for granted the existence of such data and only now realize the dearth of sequence information in what would seem like an obvious realm to target – human pathogens.  As a result, I feel that there is much work to be done in the field of comparative genomics to exploit differences in pathogens for diagnostic and therapeutic purposes. 

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: Most of what I learned regarding diagnostic techniques came from my experience with microbiology rounds.  Doctors and technicians currently identify organisms in a gross manner through the use of stains and microscopy.  In conjunction with biochemical tests to help identify classification and drug resistance, these techniques form the bulk of what has been classically available to identify infectious diseases.  In recent years, PCR identification, microarrays, and other genomics tools have entered the field.  However, one major obstacle to their universal adoption is cost, both in utilizing the tools and in validating them, especially with the newer technologies such as microarrays.  Major costs are associated with running the trials necessary to identify rates of false negatives and positives to pass an IRB review.   Other costs include the use of expensive reagents and the labor intensive techniques to perform the tests on a daily basis.  As a result, certain steps commonly taken in research laboratories are skipped and this can lead to a decrease in the sensitivity, specificity, and versatility of a normal lab test.  For instance, I was quite surprised to find out that unlike research labs, DNA for PCR reactions is not necessarily purified and separated from the sample from which they are obtained.  This is due to practical considerations, including cost, labor, and, to some extent, sample availability.

Diagnostic & therapeutic collaborations:  I believe a great amount of versatility can be garnered from genomic sequencing of the many of clinical isolates gathered from patients in the hospital.  This in turn can feed into diagnostic tests by way of hybridization probes, the ultimate form of which might be the microarray.  Assuming microarray technology comes down in cost, the utilization of >= ~44,000 hybridization probes per patient could allow for simultaneous testing of hundreds, if not thousands, of viruses, bacteria, and fungi.  Development of this diagnostic tool would require the use of comparative genomics to identify regions or combinations of regions of genomic DNA that can act as a signature for each organism.  Then, it should simply be a matter of performing array comparative genomic hybridization to analyze the result.  Besides the need for large amounts of genomic sequencing, another obstacle to this microarray hybridization probe is the lack of concentrated DNA in clinical samples.  This could be alleviated by purification of DNA and amplification of the purified product via PCR, albeit each of these steps makes the process more costly and labor intensive.
Other ideas I entertained include associating proteins with their drug sensitivities, and then using a comparative genomics approach to identify other organisms with potential sensitivities containing homologous proteins, and possibly identifying potential infection control issues through the use of graph theory.

Student-specific experiences:  I found the Med-into-Grad program gave me a different perspective as to how medicine is practiced from the doctor’s point of view.  Additionally, as I followed the team around and talked about the patients on the ID service, they really became, in my mind at least, “our patients”.  With my limited clinical knowledge I found myself thinking through the effects of drugs on the patients’ conditions as well as the effects of actions taken by both the infectious disease and other services on my patients’ well-being.  One really does develop an affinity to the people in your care, and it’s rather hard to accept when patients fail treatment.  If Med-into-Grad highlighted any glaring flaw about me, it’s that I lack the knowledge to help others in a clinical sense, which was, at times, highly frustrating.  While I had a basic handle of physiology and rudimentary anatomy, it was frustrating that I could not match what I saw with a disease or condition, simply because I did not even know that such diseases and conditions existed.  I think that Med-into-Grad provides graduate students an opportunity to be exposed to a set of diseases which they normally would know nothing about and lets them become passionate about exploring them.

Advice for new trainees--autumn preparatory quarter:  I highly recommend new students familiarize themselves with histology and the use of a microscope, especially since the microscope is often used as the general method of diagnostics in the hospital.  Additionally, a healthy understanding of human anatomy and human physiology is also helpful when reading doctors’ notes.  I also suggest practice reading example patient charts (if such a thing exists), as deciphering foreign abbreviations and medical jargon while trying to read a doctors’ handwriting can be quite challenging at times.

Advice for new trainees—winter clinical training quarter:  I advise future Med-to-Grad students to seize the early weeks as an opportunity to ask as many questions about clinical science as they can, as that is the reason why this program exists.  I would also suggest, however, that to form a good basis from which to ask intelligent questions, future trainees might want to consult The New England Journal of Medicine, Lancet, or Up-to-Date about patient conditions, perhaps while the fellows gather patient statistics in the morning.  I found it helpful to focus my search on medical literature pertaining to my patients’ conditions, as nothing focuses you more than seeing what harm disease can cause. 

Take home perspective on Med-into-Grad at UCSD:  I would definitely recommend the Med-to-Grad experience to others.  Unlike before, I now understand the practical subtleties between use of a technique in a research setting and use of the same technique in a diagnostic setting.  The Med-into-Grad experience also gave me an unprecedented view of how medicine is practiced from the bench to the bedside and illustrated how research affects patient care.