Ellen O’Dea (eodea@ucsd.edu)
Graduate Program: Chemistry and Biochemistry
Lab PI: Alexander Hoffmann
Undergraduate Education: Cal Poly- San Luis Obispo
Med-into-Grad clinical training area: Rheumatology/Inflammation
Clinical mentor: Gary Firestein, gfirestein@ucsd.edu
Quotes: “I discovered a much needed area of research involves predicting which patients will (positively) respond to current available therapeutics. For example, anti-TNF treatment in rheumatoid arthritis works well (induces complete remission, with some flares) in about 70% of the patients. Disease symptoms in some of these patients are only partially reduced, and the remaining patients do not respond at all to treatment. The field must gain more insight into what makes TNF-inhibitors work in responding patients”.
“I now have a first hand realization of the importance of applying basic science findings to real physiological situations. I was previously less interested in the design of drugs that treat symptoms of disease, but this experience has opened my eyes and mind to a personal view of the seriousness of the need for symptomatic treatment.
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: My lab uses a combined computational/experimental approach to studying signal transduction of pathways related to NF-kB signaling. NF-kB is a critical regulator of the inflammatory response and play a key role in control of immune function and cellular behavior involving survival, development, and proliferation. My research has investigated the mechanisms of stress-induced NF-kB, particularly on ultraviolet irradiation (UV)-induced NF-kB. In investigating the mechanism of UV-induced NF-kB, I found that the responsiveness of NF-kB to UV critically depends on two different constitutive pathways of the degradation of the inhibitor of NF-kB, IkB. The studies have led to further examination of extra- and intra- cellular signals that induce metabolic stress and how these signals may amplify NF-kB signaling in the context of low levels of inflammatory signals. My future research will focus on cross-talk between inflammatory signals and interferon signaling in the context of NF-kB activation and function.
I was interested in Med-into-Grad because my training is focused on studying the basic signaling pathways involved in inflammation and its misregulation (disease), but I am lacking a true understanding of the inflammatory signals themselves. We often state in our research that the pathways we study are important for diseases such as rheumatoid arthritis and other chronic inflammatory conditions, but I did not feel that I really understood how the misregulation of the pathways we study would be manifested in a human disease. I was also interested in understanding the current modes of treatment for inflammatory diseases and to gain insight into the needed areas of research for inflammatory diseases and the complexities involved. I felt that seeing and learning about the diseases in real human patients is the best way to truly see the complexities involved in treating these diseases.
Studying cellular signaling networks and pathways is fascinating, but I feel that it could be substantiated by a real understanding of the diseases that are associated with certain signaling molecules and their misregulation. Further, I was very interested to see how the pathways that I study in tissue culture models manifest themselves as diseases in various organs of the body, interacting with all the body tissues.
Medical training and identification of medically-relevant research issues: I rotated with the Rheumatology group: I went to 2-3 outpatient clinics a week, one at the VA hospital and one-two at the Hillcrest hospital. For the in-patient consults service I rounded with the on-call fellow, residents, and med students as the consults were called in, and occasionally we would all sit down with the attending doctor to discuss a certain disease or patient that they were treating. For the outpatient clinics I would essentially shadow the resident/fellow/student as they examined the patient, then watch, and maybe participate as the resident/fellow/student presented to the attending. I would then follow back to the patient with the attending for the further examination. Following this, I usually discussed some aspects of the patient’s condition with the attending and how one may go about treating them in different situations, or why they were treated as they were. I also attending the rheumatology rounds which included case presentations, journal clubs, and seminars. I also attended the Rheumatology rounds every week, which included journal clubs, case presentations, and seminars by experts in related fields.
The most common diseases that were presented in the clinic were rheumatoid arthritis (RA), psoriatic arthritis (PA), osteoarthritis (OA), gout and pseudogout, SLE lupus, reactive arthritis, scleroderma, and ankylosing spondylitis (AS).
On of the most important research areas that I found to be important in improving human health was in how inflammation in general differs between diseases and the effects it has on different organs and areas of the body. For example, while both ankylosing spondylitis and rheumatoid arthritis are inflammatory joint conditions, inflammation in rheumatoid arthritis can rapidly induce bone destruction and joint remodeling, whereas inflammation in ankylosing spondylitis slowly induces bone fusion and joint remodeling of a different nature. Thus, anti-TNF treatment in RA can prevent bone destruction, anti-TNF treatment in AS will not help to prevent the bone fusion and joint remodeling. Also, I found very interesting other inflammatory diseases such as scleroderma that seem to be regulated by different pathways leading to terrible fibrosis affecting the connective tissue. Although these diseases are also inflammatory conditions, they cannot be treated by the anti-inflammatory drugs used in RA or OA.
Further, I discovered an important area of research involves predicting which patients will (positively) respond to current available therapeutics. For example, anti-TNF treatment in rheumatoid arthritis works well (induces complete remission, with some flares) in about 70% of the patients. Disease symptoms in some of these patients are only partially reduced, and the remaining patients do not respond at all to treatment. Because a patient must go several months on one or more of the TNF-inhibitors before moving on to other modes of treatment, they must endure the disease and the accompanying damaging effects of the disease during this process, it would be wonderful if we could understand why some people respond and some do not. I believe that much of this will be related to gaining more insight into how the TNF-inhibitors are actually working in the responding patients.
Another very important research area that I discovered that is critical for improving human health is in understanding the triggers and mechanisms behind autoimmune disease (autoantibody production) in general. This research encompasses everything from epidemiological studies to genetic screening to study of basic immune regulatory pathways.
Long term impact: I have certainly been impacted in terms of my future research and the paradigm through which I view my current research. I now have a first hand realization of the importance of applying basic science findings to real physiological situations. I was previously less interested in the design of drugs that treat symptoms of disease, but this experience has opened my eyes and mind to a personal view of the seriousness of the need for symptomatic treatment. While prevention or complete elimination of the disease would be ideal, I now understand the complexity of that, especially since disease will vary so greatly between individual patients. Thus, while I am still very interested in researching the basic pathology and initiation of rheumatic diseases, I see the need for development of therapeutics for disease symptoms. This experience has motivated me as a researcher because I have seen and talked to so many patients experiencing not only the pain of these rheumatic diseases, but also the frustration of the life-altering medicines that they must take. I will in the future pursue a more translational research position where I can see a fusion of basic science with medicine, aimed at development of therapeutics and understanding of the initiation of autoimmune diseases.
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: I really do feel that I acquired a very solid understanding of the therapeutics and diagnostics used in the rheumatology field. Whereas the use of therapeutics is quite extensive, the diagnostics are a bit more scattered and really seem to vary between practitioners.
For most inflammatory diseases, a patient may initially be given a dose of steroids with the aim of not having to use them again, except in the instances of a disease flare. There is heavily increasing use of biologic agents e.g. antibodies designed to target some of the signaling molecules that traduce inflammatory pathways or target lymphocytes to decrease the immune response. This therapy can be very effective at putting a patient into remission from a disease (especially with RA and PA). Rheumatology has a whole class of drugs referred to as disease modifying anti-rheumatic drugs (DMARD) that are used to control most of the inflammatory conditions seen in a patient. For SLE lupus, most patients have to be on immunosuppressive therapy and must treat flares with steroids. These drugs clearly have negative side effects that can be as bad as the disease itself. Also what I learned that was very interesting was how patients are treated with different drugs depending on whether they are experiencing chronic or acute inflammation- the drugs target the different cell types associated with either acute or chronic inflammation.
Diagnosis of many of the disease I saw was almost purely based on clinical presentation, but could be substantiated by lab results. Because many of the diseases I saw vary so greatly between individual patients, diagnosis was very difficult, though lab tests could be used to eliminate certain diseases/infections from contention. There are some lab tests that are specific for diseases such as rheumatoid arthritis, such as detection of CCP (citric citrullinated peptide) or RF (rheumatoid factor). However, there are some patients that clearly have all the clinical finding of a patient with RA yet are negative for RF or CCP. These common discrepancies between lab results and clinical presentation make diagnosis of rheumatic diseases very tricky, but with an incline to rely on clinical presentation and patient response to therapeutics.
A very important aspect that will complicate therapeutic development that I learned by seeing so many patients with inflammatory diseases, is that you need to understand from a standpoint that the a certain disease is rarely a one-dimensional problem. Patients will often have complicating factors such as: allergy to medication, susceptibility to infection (including exposure to TB), pregnancy, an infectious disease (e.g. HIV- complication with other drugs the patient requires or hepatitis, complication with drug effects on the liver), alcoholism, non-response, non-compliance.
A common problem I saw with the inflammatory diseases and available therapeutics was that the majority of the therapies are systemic drugs. Many of the diseases I saw affect only one area of the body, such as the skin or joints, yet patients have to be on systemic drugs that affect the whole immune system rather than just the skin or joints. It would be ideal to be able to develop drugs that can be targeted to just the synovial joint cells and prevent the inflammatory attack occurring there, rather than repressing it throughout the whole body.
Diagnostic & therapeutic collaborations: It is known that in scleroderma, the disease will often reverse itself over time. I think that it would be interesting to take advantage of this process and to study how the body is able to initiate and progress this reversal of the skin thickening. If we can discover how this occurs then we may be able to develop drugs that will imitate this process to either slow down or prevent actively progressing scleroderma. I think that the best was to study this would first have to be in animal models of scleroderma and determination of the upregulated and downregulated genes at these different stages of the disease.
Another area that I think would be interesting to study would be in how inflammation in various inflammatory diseases affects bone homeostasis. I think that the joint fluid from patients with different diseases (AS, OA, RA) needs to be examined for the various proteins that may be affecting osteoclast levels and osteoblast levels. The difference in these profiles may lead to insights and drug targets for control bone destruction/ proliferation. I have not discussed in any detail these ideas with the physicians, though I have discussed with them the many areas of ongoing research for these diseases.
Student-specific experiences: This program has not only given me a higher degree of motivation to do disease based research, but also has given me a personal view into how effective therapies can really change the course of a disease and have a powerful effect on so many people’s lives.
Advice for new trainees--autumn preparatory quarter: For Rheumatology I would recommend reading about general immunology and mechanisms of self-versus non-self to understand molecular aspects of autoimmune disease. Learning the cellular and molecular basis behind inflammation would also be useful in understanding in the clinic how and why they treat different diseases as they do. The histology focus was helpful, but focus on inflammatory conditions. . .you won’t see too much histology in the clinic. Understand the difference between gout and pseudogout crystals, because these are often used as diagnosis (accompanied by uric acid levels and clinical presentation). Read as much as you can about the rheumatic diseases and the mechanisms behind them- then in clinic you will see how to identify them and treat them (if there is treatment).
Advice for new trainees—winter clinical training quarter: Be proactive, do not be shy. You will be told at times that you can’t follow along. . .its not personal. But do have common sense- give the doctors their space as they are writing their notes. Ask lots of questions. Don’t be shy with the patients- ask them questions. For the in-patient consults you may want to contact the on call fellow on a regular basis to find out about rounds (they will forget about you). And do identify yourself immediately as a med-into-grad trainee. You will often be confused (at the beginning) for a medical student and the attendings will try to have you see patients (or wonder why you are not seeing patients). Remind them that you are just there to learn and follow them- that you want to gain this clinical training side such that you can better apply you research and future research goals towards this field.
Take home perspective on Med-into-Grad at UCSD: This is a great program to open your mind up to thinking about research in a different way and to provide strong motivation to do research. I would absolutely recommend it to those who have any interest in understanding how the biological processes and pathways they study are regulated or misregulated in human disease. I understand now that you really cannot have a full understanding of a disease or how a disease is manifested without seeing the effects it has in person, on a frequent basis, with several different patients.