Anokhi J. Kapasi (akapasi@ucsd.edu)

Graduate Program:  Molecular Pathology
Lab PI: Deborah H. Spector
Undergraduate Education:  Harvey Mudd College
Med-into-Grad: Infectious Diseases
Main clinical mentor: Douglas Richman (drichman@ucsd.edu)

Quote:  “This was the type of exposure I was hoping to get in my first year of classes in graduate school.  It would have been really helpful to know the realities and challenges of translating work from the research bench to treating a patient.  Every biomedical researcher should comprehend the multiple diagnostic and therapeutic challenges involved with their disease of interest”.

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:
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:  My thesis research attempts to determine how the host’s cellular transcription machinery is hijacked during the human cytomegalovirus (HCMV) infection and is altered to preferentially engage in synthesis of viral transcripts.  I have documented that the upregulation in expression and activity of the cellular components of transcription start during the immediate early phase of the HCMV infection, and that this is accompanied by their relocalization within the host cell nucleus.  In fact, within the first hours of infection, several cellular components of transcription (i.e. RNA polymerase II, Cdk7, Cdk9, Cyclin T1, etc.) are recruited and accumulate to concentrated levels at the sites where the HCMV genome is deposited within the host nucleus, forming the viral transcriptosomes (see figure below). These sites function in synthesis of the viral immediate early transcripts.  These alterations in the HCMV-infected host cell are key events that allow the infection progress into a productive one.  By understanding these processes, one may then be able to prevent the infection at this step, such as with my work with cyclin-dependent kinase inhibitor drugs.

Left: Infectious plaque consisting of human fibroblast cells infected with human cytomegalovirus, which is visible on a monolayer of growing cells (picture by R.Sanders) 
Right: Immunofluorescence analysis showing that a cellular regulator of transcription, Cdk9, co-localizes with the input HCMV genome within a few hours post infection in the nucleus of an HCMV-infected cell.

I believe that regardless of the level at which you are studying a disease, it is important to keep in mind the therapeutic value of your research.  The Med-into-Grad program excited me because it offers knowledge at the clinical level.  I wanted to learn about how patients present symptomatically during various viral infections, what is being done clinically to treat these patients, and what are the existing challenges that clinicians and patients face in recovery from these viral infections.  By gaining this knowledge, as a researcher, I would be able to ask the right questions during my experimental endeavors.

Medical training and identification of medically-relevant research issues: From the very start, I began to attend some of the grand rounds where a certain infectious disease (ID) would be spotlighted. I found these sessions informative because, not only did they expose me to the “clinical world”, but the history of the disease as well as current research and existing issues would be detailed.
            The ID case rounds were very integral to my understanding the problems and issues in treating infectious diseases patients. I was exposed to how the medical faculty and clinicians of all different levels of experience interact with each other and work together in understanding the microbe being discussed and effective treatment plans.  Often times the patient case being presented was still in medical care and the presenter would be asking for advice on the next step of treatment, and at other times the patient’s medical treatment was completed and the presenter wanted feedback on the successes and flaws of the treatment that was provided.  I learned about classic symptoms of various infections, treatment strategies, infectious diseases terminology, and factors involved in diagnosis.
            The medical microbiology sessions were the most informative to me because it was a very visual learning experience of the various microbes, and complemented the patient rounds and photos from the case studies during which we were exposed to how the infections finally manifest in the patients.  This educational portion consisted of group analysis of laboratory results from samples obtained from patient body fluids or infected wounds.  The type of microbes that were grown were analyzed and discussed.  These discussions encompassed background of the organism, diagnostic tests that confirm the presence of this organism in the patient, therapeutic drugs to be administered (and often the mode of action of these drugs).  Usually, there were also discussions of the advantages and disadvantages of the current diagnostic tools and the present therapies available. 
            For the last 2 weeks of the Med-into-Grad program, I followed the medical and pharmacy residents and attendings during ID consults at the VA Hospital.  This was instrumental in helping me recognize that these patients are presenting symptoms from multiple diseases, and that infectious diseases are complexly intertwined with many other systemic diseases.  A few times I joined the ID consult group at the Spinal Cord Injury Unit, where often the trauma the injury to the patient’s body would expose them to several infectious diseases as well.

Long term impact:  The knowledge that I gained from the infectious diseases MSP has not impacted my thesis project at a molecular level, but has put into perspective the degree of clinical significance and relevance of my research. It has trained me to always attempt to address and impact all levels of a biomedical investigation, the molecular and cellular up to the clinical.

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: The medical microbiology lab sessions and to some extent, the case study sessions, introduced me to the common diagnostic tests used in hospitals.  The common procedure, as I understand it, is to first collect the patient sample of the suspect region (sputum, blood, stool, urine, open wound, etc.).  First, the sample is examined microscopically (wet mounts, gram stains) for the presence of inflammatory response cells and foreign microorganisms.  The patient samples are also cultivated.  Blood cultures allow measuring the microorganismal titers in the patient as well as a source for subculturing.  Agar plates with selective media help determine the type of organism and further tests with direct sensitivity assays indicate possible antimicrobial doses.  Metabolic-deficient or -supplemented media reveal the biochemical activity of the microorganism, which also contributes to the identification of the organism.  In addition, serology tests for the presence of antibodies against specific microorganisms are also commonly used, especially for virus identification and titers (agglutination, neutralization, immunofluorescence).  Sometimes, PCR is also used.
Direct sensitivity assays allow you to determine the susceptibility of the microorganism for a particular antimicrobial agent.  From this possible drugs and doses are determined. It seems that usually they try to use the minimal dose necessary for treating the infection.  Often multiple drugs are used to treat the patient because some drugs work synergistically and also this may prevent resistant strains from appearing.  If the patient forms an allergic reaction or experiences uncomfortable side-effects, then sometimes a suboptimal treatment plan is followed.
One of the biggest diagnostic problems is false-positives due to contaminants and false-negatives for slow-growing microorganisms during blood cultures.  Another problem is skin contamination during sample collection (microorganisms from the skin surface get into the sample during blood collection) and central lines creating an environment that fosters microbial growth.  Some of these things cannot be changed because technical expertise of the specimen collector will always vary, but by being very descriptive about location/time/method of sample collection can help avoid unnecessary misdiagnosis.  Another thing to consider is that the environment in a blood culture is very different (agitation, aerated, pH changes) than at the site of infection in a patient.  Also, we were told that you could not base a diagnosis or completely rule out several microorganisms during diagnosis with just one biochemical test.  Another challenge is the time it takes for diagnosis.  The general practice is to store the patient sample or let a culture that is negative keep going just in case they need to be looked at further, but this policy is different between hospitals.
Therapeutically, I would say a big challenge is treating highly resistant strains of microorganisms and preventing resistant strains from appearing.  Many clinicians look towards combination therapy for this matter and low dosage.  Also, making sure the drug will reach the site of infection and avoiding toxicity of the drug.  Another complication is when a patient has several medical issues other than an infection, because this may limit treatment options due to drug tolerance or cross-reactivity with current medication.   The issue of toxicity and cross-reactivity is generally addressed by using the lowest required dose of a drug to treat an infection. 

Student-specific experiences:  Several aspects of this MSP confirmed my desire to study infectious diseases at the international public health level.  Through the medical microbiology and case study discussions, I have become aware of the epidemiology of problematic infectious diseases, differences in the public knowledge, the disparity in accessibility of available treatment.

Advice for new trainees--Autumn preparatory quarter:  I thought basic knowledge in anatomy and physiology would have been useful, especially with comprehending the ID case studies.  I suggest finding someone who can teach you basics of how to read and orient yourself for reading X-ray and CT-scans. Since some of the first indications of infection are determined by abnormal levels of various blood cells, some background knowledge in what is considered normal/abnormal would be helpful.  Finally, consider acquiring a list of basic medical terminology within the field.

Advice for new trainees—Winter clinical training quarter:  I highly recommend integrating the medical microbiology sessions with occasional opportunities to go on clinical rounds with the ID consult team.  That way, you may even see some of the patients that are being discussed during the lab sessions. In addition, if you could find a resident or fellow who is willing to be your medical mentor, it would be useful to have them as a source of information and maybe informal tutor.

Take home perspective on Med-into-Grad at UCSD:  This was the type of exposure I was hoping to get in my first year of classes in graduate school.  It would have been really helpful to know the realities and challenges of translating work from the research bench to treating a patient.  Every biomedical researcher should comprehend the multiple diagnostic and therapeutic challenges involved with their disease of interest.