Investigator Spotlight: December 2014
Charmaine Simeonovic, PhD &
Christopher Parish, PhD
Dr. Simeonovic & Dr. Parish joined nPOD in 2010.
- Tell us about your education and background – where are you from, where did you go to school?
Charmaine Simeonovic: I was born Charmaine Joy Tranter (my maiden name) in Lismore, a North Coast country town in the state of New South Wales (NSW), Australia. At that time, the Lismore area was known particularly for its dairy farms and farm produce. I attended South Lismore Primary School, until I was 12 years old and then Lismore High School until I was 18 years old. Growing up, I learned dancing (ballet, tap, highland) from my mother (who was a dancing teacher) until I was about 12 years old and studied music (piano) until I was 17. My tertiary education, a Bachelor of Science degree with Honours (BSc (Hons)) was done at the Australian National University (ANU) in Canberra, ACT, about 1,000 miles from my home town. I also obtained my PhD at ANU in 1983.
Chris Parish: I was born and educated in Melbourne, Victoria, Australia, completing my secondary education at Wesley College. My father was a chartered accountant, with a strong farming background, and my mother was a journalist. My parent’s diversity in professions meant that during my childhood I was exposed to a wide range of family friends, such as businessmen, farming folk and newspaper workers. My childhood was further enriched when my father purchased a sheep farm on the outskirts of Melbourne when I was 4 years old. As a result I experienced rural and city life throughout my childhood, weekends being spent on the farm and weekdays in suburban Melbourne. Enthused by the farming life, my first degree was a Bachelor of Agricultural Science at the University of Melbourne. But during my agriculture degree I became particularly interested in biochemistry and agriculture had no PhD projects in this area that interested me. Fortunately, across the road from the Agriculture School was the Walter and Eliza Hall Institute, a world-renowned research institute in immunology. I heard the Institute was recruiting PhD students, paid them a visit and was immediately fascinated by their immunological research. I decided within minutes to undertake a PhD in immunology, a decision I have never regretted.
- Where do you currently work and what is your position? What does a “day in the life” look like for you?
Charmaine Simeonovic: I am the Team Leader of the Diabetes/Transplantation Immunobiology Laboratory, at the John Curtin School of Medical Research, ANU, Canberra and have held this position essentially for over 25 years. My daily routine involves supervising my Honours (graduate) and PhD (post-graduate) students, postdoctoral fellow and my three expert technical officers in our type 1 diabetes (T1D) and type 2 diabetes (T2D) studies, analysing data and planning experiments with my colleague and collaborator professor, Chris Parish. In addition, much time is devoted to preparing grant applications to obtain external funding to allow us to continue our diabetes research. My time is also spent preparing our research data for publication or for presentation at national and international diabetes conferences, and as a reviewer of grant applications and manuscripts for funding agencies and international journals for diabetes-related research, respectively.
Chris Parish: I am currently the Leader of the Cancer and Vascular Biology at the JCSMR. A “day in my life” is very much divided between running a large medical research institute and supervising the research staff and students in my research group. I have a number of research projects in my group, but one of the most important and productive is the collaboration with Dr Charmaine Simeonovic on T1D and T2D. My laboratory office is close to Charmaine’s and we interact on a daily basis.
- Why diabetes? How did you get involved in diabetes and/or what made you want to work in diabetes research?
Charmaine Simeonovic: My introduction to diabetes-related research was during my PhD studies under Professor Kevin Lafferty, studying the transplantation of pancreatic islet tissue as a treatment for established T1D, focusing on understanding how the tissue was rejected and approaches to preventing transplant rejection. In fact I continued to focus on this work, particularly inter-species islet transplants (pig islet xenografts) until 2007. Around this time, my interests turned to understanding how T1D develops (the pathogenesis of T1D disease). Early in my career it became very clear to me that there existed a critical need for a better understanding of how the disease develops and for improved treatment. Only by understanding the disease process, can we develop novel drugs for preventing disease development. On a personal level, I have two cousins (siblings) who were each recently awarded a Kellion Medal for living with T1D for 50 years. Their life history is a testament to how it is possible to live long lives with T1D. However, over the years my cousins’ health issues (e.g. toe amputations) have also highlighted to me, the need for us to develop safe drugs for halting T1D progression so that T1D complications can be prevented.
Chris Parish: As an immunologist I have been interested in the autoimmune aspects of T1D for many years. My direct involvement in diabetes research, however, was inspired by research seminars by Professor Kevin Lafferty some 15-20 years ago. Kevin frequently referred to the paradoxical observation that in T1D prone NOD mice, leukocytes accumulate around the insulin producing islets, causing no harm, but then suddenly gain the ability to enter the islet and destroy the insulin-producing beta cells. Based on my earlier cancer metastasis studies, where metastasizing tumor cells need to traverse basement membranes lining blood vessels by deploying a range of degrading enzymes, I suggested that islets may be surrounded by a basement membrane that can only be breached when the auto-reactive leukocytes express the correct degrading enzymes. I also hypothesized that the enzyme heparanase, an enzyme that degrades the polysaccharide, heparan sulfate, and is critical for tumor metastasis, may be involved. I approached Charmaine with this idea about 10 years ago and a very productive collaboration developed which demonstrated that heparanase and heparan sulfate play a much more profound role in diabetes development than I had originally envisaged (look below for more detail).
Tell us about your research.
Our research has pioneered a new understanding of islet beta cell health and disease, based on the level of the complex sugar, heparan sulfate (HS), in insulin-producing islet beta cells. Our breakthrough discovery was that HS inside beta cells is critical for their survival and is normally present at high levels (a strikingly unique property). We think that the function of this HS is to protect the insulin-producing cells from harmful reactive chemicals (oxidants) that are produced by the beta cells themselves as a result of their high metabolic activity. During T1D in both mice and humans (demonstrated in new-onset T1D nPOD human pancreas specimens), we have found that the beta cells progressively lose their HS during disease development. Our experimental studies of autoimmune T1D in mice have revealed that this loss of islet HS is due to the production of a HS-degrading enzyme, heparanase, by autoimmune white blood cells (leukocytes) and that a new class of drug that acts as both a heparanase inhibitor and HS mimetic (a drug that is chemically similar to HS) prevents HS loss and T1D development. We have also found that T2D is associated with loss of beta cell HS but is due to a different mechanism than for T1D. Based on our discoveries, a new start-up biotechnology company, Beta Therapeutics, has been established to develop our new drug for clinical trial in new-onset T1D patients.
- What are your thoughts on the progress being made in T1D research as a whole?
The failure of recent clinical trials of immunotherapies in new-onset T1D patients has been very disappointing and emphasizes the need for new approaches for preventing disease progression. Our novel dual activity heparanase inhibitor/HS mimetic drugs offer the bonus of not only inhibiting the disease process but also potentially fortifying the islet beta cells by HS replacement, a process which would maintain the beta cells in a healthy state and thus able to continue to produce insulin in response to elevated blood sugar levels.
Why is diabetes research so important?
While insulin therapy keeps people with T1D reasonably healthy and prevents ketoacidosis, it is difficult to achieve precise blood glucose control. In the long-term, serious T1D-associated vascular complications can develop, ultimately leading to kidney disease, heart disease, nerve damage and blindness. T1D research is critical for elucidating how beta cells are destroyed in T1D and this in turn allows us to develop safe, new therapeutics for preventing the progression of the disease and its complications.
Do you have anything extra you would like to share? Is there anyone to thank or acknowledge?
JDRF-nPOD has played a critical role in allowing us to establish the clinical relevance of our experimental findings for HS loss and T1D. JDRF and JDRF/nPOD, the National Health and Medical Research Council of Australia (NHMRC) and JDRF/Roche Organ Transplantation Foundation have played vital roles in providing funding that has helped us to understand the role of HS in beta cells, its intracellular function and vulnerability during immune attack and to identify novel therapeutic drugs for preventing T1D progression. Continuation of such funding is absolutely essential in order to further validate our research findings for human beta cells with and without T1D, and to support the development of our novel drugs for testing in clinical trials with new-onset T1D individuals.
- When you’re not working, what do you like to do for fun?
Charmaine Simeonovic: Indoor and outdoor gardening.
Chris Parish: Bushwalking, enjoying good food and searching for the perfect cup of coffee.