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Simone Fulda - Cell death for the benefit of patients

Simone Fulda, 40, is an extremely inquisitive person who has managed to turn her passion into a profession. In 2007, the petite woman from Cologne was appointed professor of paediatric research at the University of Ulm (University Children's Hospital), where she is working on the relationship between apoptosis and cancer and the development of new methods for cancer treatment.

Prof. Dr. Simone Fulda (Photo: University Hospital Ulm)
When she was a student, Dr. Fulda spent a lot of time studying abroad and she became involved in cancer research very early on. Her interest in apoptosis (programmed cell death) first became apparent when she attended summer academies and during her studies at the Harvard Medical School at the beginning of the 1990s, at a time when many scientists around the world started to focus on the cellular suicide programme.

Programmed cell death was soon connected with the development of diseases and has become one of the most dynamic fields in medical research. Approximately 50 papers are published on apoptosis every day (Cell death and Differentiation 15, 1087-1088 (doi:10.1038/cdd.2008.35). Simone Fulda became one of the international researchers to work on apoptosis, an area which she found more exciting and challenging than other scientific areas where a lot of research had already been done.

What happens when too few cells die?

Programmed suicide of a cell (Photo: Fulda, University Hospital Ulm)
It soon became clear that programmed cell death was the key to cancer research. Simone Fulda explained that cancer not only develops through the uncontrolled proliferation of cells, but also because not enough cells die. The young researcher was fascinated by the inability of cells to undergo apoptosis. She is still very glad that she chose this thrilling topic for her research.

In Greek, apoptosis refers to the “dropping off “ of petals or leaves from plants in autumn. It is a form of programmed cell death in multicellular organisms and is highly conserved in evolutionary terms. Apoptosis happens on its own and does not require an external stimulus, explains the researcher. It involves a series of signalling pathways that is fairly similar in all multicellular organisms, from those as simple as threadworms to complex organisms like humans.

Disturbed imbalance between growth and death

In an average person’s body, apoptosis leads to the death of between 50 and 70 billion cells per day. An imbalance between cell growth and cell death leads to tumours, neurodegenerative diseases, diabetes mellitus or HIV. The development and severity of an increasing number of diseases can be explained by defects occurring in the cellular suicide programme.

Which molecules induce the biochemical events involved in apoptosis?

Simone Fulda explains that apoptosis is a very complex signalling machinery involving a large number of different molecules. However, the number of molecules involved in apoptosis is still unknown. Programmed cell death involves a series of biochemical events and Fulda and her colleagues hope to identify the key players in this process.

Detailed understanding is important for medicine

“Detailed knowledge of the molecules and events leading to apoptosis would give the field of medicine enormous potential for new diagnostic and therapeutic applications,” said Fulda outlining the key importance of apoptosis research. This knowledge would provide researchers with information on why cancer cells stop dying and it would open up possibilities for repairing the defects with apoptosis inhibitors or activators and driving defective cells into programmed death. This would not only be useful for cancer research. Since apoptosis is a basic process in multicellular organisms, further understanding of the underlying mechanisms would have a huge effect on many areas of medicine, said the Ulm researcher highlighting the importance of apoptosis research.

Restarting a blocked programme

Simone Fulda’s “Apoptosis and Tumour Therapy” research group is hoping to understand defects occurring in the apoptosis programme of cancer cells and the mechanisms that make cancer cells resistant to apoptosis signals. Fulda is hoping to develop ways of restoring programmed cell death, either directly or by making cancer cells more sensitive to conventional treatments. She is working on altering conventional chemotherapy or radiotherapy so that it reactivates apoptosis in cancer cells.

This research is based on the assumption that cancer cells have many defects that lead to the blocking of the cellular protection programme. Therefore, the researchers are envisaging the possibility of activating the apoptosis programmes by intervening with the events leading to cell death on different levels. Simone Fulda is convinced that insights into these mechanisms will increase the probability of being able to reverse the cells’ resistance to cell death.

Fulda’s finding opens up the development of new drugs

An intact cancer cell (left) and a cancer cell in which apoptosis has been initiated and which displays the typical morphological changes that fragment the nucleus. (Photo: University Hospital Ulm)
Intact cell (left) and cell in which the apoptosis programme has led to the dissolution of the cell. (Photos: Fulda, University Hospital Ulm)
Simone Fulda has received many awards, including the renowned Johann Georg Zimmermann Research Prize 2007/2008 for “a decisive contribution to apoptosis research in cancer cells”. Six years ago, she succeeded in proving on an animal model that SMAC (second mitochondria-derived activator of caspases) agonists can be used to sensitise tumour cells to apoptosis. The Nature Medicine (doi:10.1038/nm735) paper proved that SMAC could be used in experimental tumour therapy and Simone Fulda has substantiated this finding with other findings and substances. Fulda’s findings gave a number of pharmaceutical companies the basis for developing SMAC agonists. The first clinical phase I trial was started in 2007.

Natural substance for the therapy of malignant brain tumours

Fulda and her colleagues are hoping to use betulinic acid derivatives for the treatment of malignant brain tumours. (Photo: Fulda, University Hospital Ulm)
In her search for new anti-cancer drugs, Simone Fulda discovered betulinic acid as a novel mitochondritoxic anti-brain cancer drug. Betulinic acid, which is found in the bark of birch trees, triggers apoptosis in neuroectodermal and other tumour cells. Fulda was the first researcher to describe how this mechanism is triggered in such cells. Working in collaboration with Guido Kroemer‘s team from the Gustave Roussy Cancer Research Institute in Villejuif close to Paris, Fulda’s research group succeeded in developing derivatives with a greater anti-tumour effect. The German Federal Ministry of Education and Research is funding this cooperative project, which is coordinated by Simone Fulda and which aims at pharmacodynamically optimising the betulinic acid-derivative BA10 and evaluating the substance in a phase I clinical trial for its effect on malignant brain tumours.

The pharmaceutical industry is working with Simone Fulda

Fulda’s research group is part of several regional, national and international research networks. In the EU-funded ApopTrain Marie Curie Research Training Network, fifteen partners from nine European countries are working together, offering a programme for structured training, knowledge transfer and professional promotion in apoptosis research. The network aims at the investigation of the molecular mechanisms of cell death and the development of more effective cancer therapies. Fulda is extremely pleased that public funding institutions also promote the involvement of industry in projects such as ApopTrain, in particular considering the limited amount of public funds available for university research. Simone Fulda is convinced that the translation of the findings into clinical application is only possible with the financial support of the pharmaceutical industry.

Research with no time limit

Fulda tells us that her research is not restricted to regular working hours. “I am only able to work so hard because I really enjoy what I am doing,” said the researcher who habilitated in 2001 with a thesis on “apoptosis mechanisms and cytotoxic therapy”. Fulda is also happy with the translational aspect of her work that stands at the interface between basic research and clinical application. “We have reached a tremendously interesting point. We are now able to translate the research findings of the last few years into clinical application.”

Many more details have to be investigated before the researchers are able to find out whether the findings can be transferred from animals to humans. But Fulda finds it very exciting that the findings can now be transferred more quickly from the laboratory bench to bedside applications. Simone Fulda is looking for global cooperation partners to help her in her search for the answers to “truly big questions”.

Walter Pytlik - 18th June 2008
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