Miriam Erlacher: apoptosis research – balancing clinical work and research
Programmed cell death plays an important role in embryonic development and has also been identified as the cause of a range of diseases. It also plays a key role in the development and survival of higher organisms. Its regulation is based on a sophisticated system of interacting antagonistic signals in a network that is still largely unknown. Disturbances in this delicate balance promote the development of diseases such as cancer. Dr. Miriam Erlacher from the Department of Paediatrics and Adolescent Medicine at the Freiburg University Medical Centre is specifically focussed on apoptotic mechanisms that are thought to cause blood disorders such as myelodysplastic syndrome and leukaemia. Miriam Erlacher was recently awarded a 5-year ERC Starting Grant of 1.5 million euros from the EU.
Miriam Erlacher pours her heart and soul into her work as researcher and doctor. She was born in the Italian city of Bozen in South Tyrol in 1978, which is where she grew up. As a young high-school student, she had so many academic interests that she initially found it rather difficult to make up her mind what to study. At 19, she decided to follow her strong interest in science and study medicine in Innsbruck, Austria, a move that she has never regretted. When she was working on her doctoral thesis in medicine, Miriam discovered her passion for scientific work. “I suddenly realised that I wanted to stay in the laboratory and decided to do a three-year scientific PhD course,” says Miriam Erlacher, who is now a paediatrician in the Department of Paediatrics and Adolescent Medicine in the Division of Paediatric Haematology and Oncology at the Freiburg University Medical Centre.
In 2006, Miriam Erlacher was awarded a dissertation prize by the Austrian Society for Allergology and Immunology (ÖGAI) for her PhD thesis on the role of certain Bcl-2 proteins in an apoptosis signalling pathway. She has since continued to concentrate on the role of apoptotic signalling in the development of tumours and immune responses. Miriam Erlacher points out that her career path is the result of many accidental events, but that at some stage she was certain that she wanted to specialise in paediatric oncology, a decision that brought her to Freiburg. The training at the Children’s Hospital took longer than originally planned as she decided to divide her time between clinical work and research.
Grants helped her move towards her current profession
Supported by third-party funds and grants, Erlacher developed an increasing fascination for apoptosis during early haematopoiesis. In 2009, she received a grant from the Margaret von Wrangell habilitation programme, which provides qualified female academics with financial support during the habilitation process. The four-year grant enabled her to remain in the clinic while completing her research work.
“This programme is excellent for doctors who also want to focus on research; young doctors like me do not want to spend three years just working in the laboratory, we prefer to spend an extended period of time on our education by dividing our time equally between the laboratory and the clinic.” In 2013, Miriam Erlacher was awarded a publication prize from the German Study Group for Bone Marrow and Stem Cell Transplantation (DAG-KBT), and in 2014 a grant from FRIAS (Freiburg Institute for Advanced Studies), which enabled her to continue her research.
In early 2015, Miriam Erlacher was awarded an ERC Starting Grant, one of the most prestigious European Union prizes for young investigators at the early career stage. The grant provides her with funds totalling 1.5 million euros for five years and enables her to hire four doctoral students, a technical assistant and three or four new staff members as well as move her ApoptoMDS project forward.
The many faces of bone marrow failure
Miriam Erlacher’s research topic, which involves a combination of laboratory and clinical work, deals with apoptosis in blood-related medical conditions such as congenital bone marrow failure, myelodysplastic syndrome (MDS) and leukaemia. Erlacher and her team hope to discover mechanisms that explain how elevated apoptosis rates affect the development of such disorders. Congenital bone marrow failure and MDS are characterised by the ineffective production of blood cells and can lead to the development of severe anaemia in patients.
Congenital bone marrow failure (i.e. Fanconi anaemia) is a fairly rare genetic defect in a cluster of proteins that is responsible for DNA repair. As a result, Fanconi anaemia patients have congenital defects such as abnormalities of a number of body organs (e.g. skins, arms, ears) and many patients also develop bone marrow failure. The patients have very low numbers of erythrocytes, leukocytes and thrombocytes; affected children suffer from frequent nosebleeds, a high susceptibility to infections and an early risk of developing other types of cancer.
Over time, Fanconi anaemia can develop into MDS, which can also be caused by chemotherapy-induced damage or simply be due to age. With increasing age, the formation of blood cells becomes more difficult and mutations that lead to defective blood cells have had more time to accumulate. “Most Fanconi anaemia and MDS patients develop acute myelogenous leukaemia (AML),” says Erlacher who is specifically focussed on studying the different disease stages from Fanconi anaemia to the development of AML.
Does massive cell death also lead to cancer?
Erlacher is specifically interested in finding out how apoptosis is associated with the early loss of bone marrow function. Some time ago in Innsbruck (Austria), Prof. Dr. Andreas Villunger, Dr. Verena Labi and Miriam Erlacher made an interesting discovery. The prevailing belief is that damaged cells die, thus preventing the development of cancer. “However, we found that the death of a rather large number of cells requires cells in their vicinity to divide more in order to compensate for the loss of the dead ones,” says the oncologist. “If these cells are damaged, this might help a potentially aggressive cell to proliferate.”
It seems that apoptosis rate and the composition of neighbouring cells influence the fate of the tissue where these particular cells are located. “It's likely that nothing will happen if all neighbouring cells are healthy. However, premalignant tissue with some kind of tumour precursor cell is particularly prone to developing into cancerous tissue,” says Erlacher. She assumes that excessive cell death promotes the development of cancer because malignant cells divide more and are therefore more likely to prevail. In other words, the higher the apoptosis rate, the quicker tumours might develop. “We are studying whether too much apoptosis promotes the development of leukaemia, how and why the cells die and what happens if we manage to prevent them from dying,” says Erlacher who finds it particularly fascinating that her findings contradict an old concept according to which too low an apoptosis rate is associated with an elevated cancer risk.
Miriam Erlacher now wants to investigate what happens when apoptosis is inhibited in the early stages of disease. Does it reduce the risk of bone marrow failure, improve the formation of blood cells and is it maybe even associated with a lower risk of developing leukaemia? “If fewer cells die, then individual, potentially slightly abnormal cells have less chance of turning into a truly malignant cell,” says Erlacher. In this case, a larger number of stem cells would be available for normal blood cell formation.
Pro- and anti-apoptotic proteins of the Bcl-2 family
The Bcl-2 family of proteins is key in the cell-intrinsic apoptosis pathway. The family’s representatives are well known for their ability to promote or prevent cell death. Erlacher is specifically studying the pro-apoptotic molecules PUMA and NOXA, which are activated in the presence of damaged DNA, thus triggering the cell death programme. However, the Bcl-2 family also includes anti-apoptotic proteins (like Bcl-2 itself) which protect cells against apoptosis.
It is known that many cells undergo apoptosis in the early stages of bone marrow failure and MDS. However, it is also known that apoptosis-resistant cells are selected when these conditions have developed into leukaemia. Erlacher is hoping to gain a detailed understanding of the mechanisms that lead to the cells’ susceptibility to apoptosis during early disease stages, with the aim of, at some stage in the future, being able to block apoptosis pathways, improve the formation of blood cells and delay the development of leukaemia.
Miriam Erlacher and other up-and-coming scientists have founded a network to facilitate the exchange of information. SciNet (Junior Scientists and Academics Network Freiburg) pools technical and scientific resources with the aim of fostering innovative and collaborative action and increasing the visibility of the young researchers at the University of Freiburg. In addition, she hopes to be able to continue working at the interface between clinical and laboratory work as she finds that the two areas benefit greatly from one another. When she is not working, she likes to go hiking in the Dolomites, read books and go out with friends. “An excellent way for me to relax,” concludes Miriam Erlacher.
Dr. Miriam Erlacher
Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine
Freiburg University Medical Centre.
Phone: +49 (0)761/270 43010