Eric Lau (email@example.com)
Graduate Program: Molecular Pathology
Lab PI: Wei Jiang, Ph.D.
Undergraduate Education: University of California, San Diego
Clinical training area of Med-into-Grad: Hematology Oncology
Main clinical mentors:
Thomas J. Kipps (firstname.lastname@example.org) &
Januario E. Castro (email@example.com)
Quote: “I felt that one of the most important things to come out of this experience for me was a renewed sense of purpose for my research. I was reminded that although my research sometimes seems far from the clinic, it is nonetheless, one piece of a complicated puzzle of developing highly cancer-specific therapeutics. I was able to observe first hand, how, although current standards of anti-cancer therapeutics can suppress disease progression or even achieve remission in some patient cancers, many times it comes with a heavy price. In CLL, many of these patients achieve slowed/arrested disease progression, but have low to no immune function during treatment, and experience serious complications from indirect causes, such as infection. Current chemotherapeutics must be improved, and their specificities to target cancers must be improved. We in the laboratories are the answer.”
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:
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 focuses on DNA replication. Specifically, I have investigated the post-G1 functional role of pre-replication complex (pre-RC) protein, Cdc6, and have demonstrated a critical S-phase role for Cdc6 in the regulation of origin firing dynamics and temporal DNA replication boundaries. I currently investigate the basis for a potentially exploitable disparity between normal and cancer cells: normal cells exhibit non-lethal cell cycle blockade during pre-RC deficit, while cancer cells partially block, but exhibit increased cell death. I was interested in participating in the Med-into-Grad training program because I have an interest and passion for clinical impact. I felt that my graduate research, was too far removed from the clinic, and I felt a need to put my research back into perspective. I wanted to experience the workings of the clinic and to learn about how issues and needs of the clinic can be improved by basic science research.
Medical training and identification of medically-relevant research issues:
My area of interest in the Med-into-Grad training program was leukemia. I participated in various activities and training at the Hematology-Oncology Department, in the clinic of Drs. Thomas J. Kipps, M.D., Ph.D. and Januario E. Castro, M.D.. On a weekly basis, I attended the morning Grand Rounds, where patient cases and specific hematology oncology issues and questions would be addressed in a round-table fashion. I also attended a weekly international Chronic Lymphocytic Leukemia (CLL) Research Consortium (CRC) teleconference, where clinical trial management and issues were discussed and debated. I attended patient procedures, such as bone marrow aspirations, and also attended bone marrow conferences, where patient bone marrow samples were examined and discussed. I toured and saw the workings of the CRC tissue bank, and learned much about clinical trial management and design from the clinical trials office. I further attended weekly Clinical Rounds, where I accompanied either Drs. Kipps or Castro to see patients, where I participated in discussion about diagnosis and treatment with patients.
I felt that one of the most important things to come out of this experience for me, was a renewed sense of purpose for my research, as well as the insight that medical treatment is not just a black and white one-shot cure or answer. As CLL is a chronic disease that is not necessarily “cureable”, the notion of “do no harm” was often raised in the clinic. “Doing no harm” is not always simple, in the context of heterogenous disease progression/insufficiently specific therapies. I was reminded that although my research sometimes seems far from the clinic, it is nonetheless, one piece of a complicated puzzle of developing highly cancer-specific therapeutics. I was able to observe first hand, how, although current standards of anti-cancer therapeutics can suppress disease progression or even achieve remission in some patient cancers, many times it comes with a heavy price. In CLL, many of these patients achieve slowed/arrested disease progression, but have low to no immune function during treatment, and experience serious complications from indirect causes, such as infection. Current chemotherapeutics must be improved, and their specificities to target cancers must be improved. We in the laboratories are the answer.
The idea of research collaboration did arise during scientific discussions with Dr. Castro, but due to scheduling and timing issues with finishing my graduate degree, did not materialize. The idea was to investigate abnormalities in DNA damage response in CLL cells, in the context of my research on pre-replication complex (pre-RC) proteins. In my graduate research, I had found that untransformed cells non-lethally arrest cell cycle progression during deficit of pre-RC proteins, while cancer cells, in contrast, exhibit partial cell cycle arrest and elevated cell death. The discrepancy lies in a response mechanism governed by ATR/ATM signaling in normal cells, which does not seem to be active in cancer cells. CLL cells have known mutations in these DNA checkpoint signaling pathways, and exploitations of the defects in these pathways might be able to provide targets for more cancer-specific therapy.
Long term impact: The Med-into-Grad training program left me with new clinical perspective that has indeed affect my long term goals. As a senior graduate student, I was at an interesting crossroads, in that it was time for me to look for a postdoctoral research position as I approached the end of my thesis research. I felt the desire to steer my research in a more transitional direction. While I am still passionate and interested in investigating molecular signaling pathways, I wanted to make sure that whatever kind of research I ended up doing, that it had clinical significants and flavor. After considering a few options in the San Diego area, I settled on the laboratory of Dr. Ze’ev Ronai, Ph.D., where I will actively investigate the mechanism underlying altered translocation of ATF2 in melanoma and skin carcinoma development. Whereas ATF2 is enriched in the nucleus in malignant melanoma, ATF2 is predominantly cytosolic in squamous and basal cell carcinomas and benign papillomas. Determination of how this differential enrichment occurs will explain much about melanoma vs. skin carcinoma development, as well as identify specific anti-cancer targets. I will be working with patient tissue sections, patient-derived melanoma cell lines, tumor tissue microarrays, as well as more conventional cell-based assays. Ultimately, I hope to attain a faculty position at an academic biomedical institution, where I will continue to address clinically relevant biomedical issues using cutting edge basic science research.
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: Unfortunately, the diagnosis for CLL is most often the indirect result of blood screening for other pre-existing problems. Sometimes people live for years with CLL without previous knowledge, as the disease can be smoldering and asymptomatic, or if slowly progressing, might be overlooked, as symptoms might conform to patterns of other, clinically less significant diseases. However, current standards of chemotherapy for CLL, still too often take the form of conventional DNA damage agents. These, at times, brutal agents can cause the patient to feel sicker than they previously were before treatment. More recently, monoclonal antibody therapy has yielded quite effective results, although many of these antibodies simultaneously target both leukemic cells and immune cells. Thus, while patients may experience disease suppression, they also suffer from immune suppression. Particularly since CLL patients often tend to be older, immune deficiency is not a problem to be taken lightly. Finally, bone marrow transplants offer another form of treatment that requires a stable state of patient health, and a matching donor.
Unfortunately, screening for CLL is not a common regiment of general practitioners. In most cases, CLL is diagnosed after disease progression becomes apparent. One would never know to be screened for CLL, unless they had prior family history of the disease. Therefore, to improve diagnosis, diagnostics need to incorporate early event markers in CLL development. DNA replication protein up-regulation, for instance, has been shown to be an early even in the onset of CLL. Screens incorporating such markers would indicate disease progression much earlier than what is now observed in the clinic. Treatment design now needs to be honed specifically for cancer cells. This will come with time, as CLL cell-surface-specific antigens or deregulated signal transduction pathways are elucidated.
Diagnostic & therapeutic collaborations: My ideas for improved therapeutics would be to target pre-RC proteins (as mentioned above). If CLL cells respond to pre-RC functional deficit like other cancer types, then treatment with a pre-RC-specific compound will partially arrest CLL populations in G1 of the cell cycle and induce partial CLL cell death in S-phase cells. Removal of the compound would allow for the remaining arrested CLL cells to restart cell cycle progression, whereupon additional drug treatment would kill cells that progressed into S-phase. In contrast, untransformed immune cells with intact ATR/ATM function would simply arrest in the cell cycle, still alive, and able to carry out normal immune function. This sort of treatment would allow gradual reduction and clearance of CLL cells, while sparing untransformed immune cells, and thus immune function during treatment.
Student-specific experiences: The Med-into-Grad training program was truly a unique experience for each one of us. Too often, graduate students will question the meaning or significance of their research, and this is a prime opportunity to recharge the passion that drove you to choose your area of research in the first place. Furthermore, this training experience gives clinical insight to questions or problems in the clinic that can only be answered by what we are capable of in the laboratory. Well worth the time commitment, although one piece of advice is to be extremely organized and motivated.
Advice for new trainees--autumn preparatory quarter:
Talk to your mentors early to determine the proper contacts for all possible activities in/around the clinic. Clinicians are often much harder to get a hold of than laboratory scientists. Outline a weekly schedule with your mentors and participate in as many things as possible! Some of us completely stopped experiments during the training program in the clinic. If you can organize your schedule well enough, some productivity in your laboratory during the clinical training is not out of the question.
Advice for new trainees—winter clinical training quarter:
Don’t be shy. Sometimes you may be thrown right into an examination room with a patient you’ve never seen. You might be asked to help write-up a report. Ask questions. Talk to the patients. You might be surprised to find out that your patient has an extensive knowledge of their disease! Support each other (trainees), especially if you are in the same clinic or group.
Take home perspective on Med-into-Grad at UCSD: I would definitely recommend this training program, particularly to more junior students, as that increases later options for collaborations. This program is very custom-fit to your own interests. Some people used it as a springboard to switch from basic science to medicine altogether. For me, it reinforced the notion that I made the right decision to do a Ph.D., rather than medical school. It reinforced the importance of my current and future work, and knowing that my work could directly impact a suffering person has given me renewed motivation. I didn’t really know what to expect out of the experience going into it, but I certainly have a newfound appreciation for the relationship between the clinic and basic science research coming out of it.