"In times when young scientists are given an expiry date of 12 years", the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Scientists was "all the more important", said its first laureate Ana Martin-Villalba in 2006 in Frankfurt's Paulskirche. The prize "set a ball rolling" for her, she says today. The professor heads the Department of Molecular Neurobiology at the German Cancer Research Centre (DKFZ) and enjoys “highest reputation in neuronal stem cell research", as the German Research Foundation recently certified.

A just award
"No other experience in my scientific career has been more groundbreaking for me than this prize," says Martin-Villalba. This is also due to the fact that it is "a very fair prize", which does not primarily depend on the intercession of a "patron", but rather on the decision of a committee before which one presents and defends one's own research in a selection symposium. "I had to work hard for this prize and show that I have potential."

What convinced the jury at the time was the young doctor's findings on signal transmission via the CD95 receptor in the nervous system. This receptor had been discovered in 1989 at the DKFZ as a checkpoint of apoptosis, the programmed suicide of a cell. Extracellularly, apoptosis is mainly mediated via CD95L, a messenger substance that binds to CD95. After spinal cord injuries, however, the CD95 receptor does not primarily activate an inflammation-free apoptosis, as Martin-Villalba postulated, but rather provokes an inflammatory response that leads to the destruction of nerve tissue. By pharmacologically switching off CD95L messengers circulating in the blood, Martin-Villalba was able to reduce damage to the spinal cord in experimental animals and stimulate regeneration of their nervous system. In this way, she succeeded in restoring motor functions in previously paraplegic mice.

Against the prevailing opinion
She extended her hypothesis that it was important to inhibit the CD95 signalling system to the treatment of tumours, thus turning against the prevailing doctrine at the time that the "death receptor" CD95 had to be activated in order to drive cancer cells into apoptosis. In fact, CD95L often doubly promotes tumour growth. If it binds to the CD95 receptors of cancer cells, it usually stimulates both the proliferation of solid tumours and their migration into healthy tissue. Consequently, Martin-Villalba showed, a CD95L inhibitor can not only regenerate nerve tissue but also curb the growth of brain tumours. As APG101, this active substance is being developed by the biotech company Apogenix, a spin-off of the DKFZ.

Beyond apoptosis
Over the years, the professor and her team gathered more and more evidence that the CD95 signalling pathway physiologically fulfils a wealth of functions that go far beyond apoptosis. Molecule by molecule, for example, she traced the CD95-mediated chain of command that induces peripheral immune cells to invade damaged nerve tissue and trigger inflammation that amplifies the damage. She found that these signals within the cell all converge on tyrosine kinases. "Our group has pioneered research into the non-apoptotic role of CD95," says Martin-Villalba.

A new field was then opened up to their research by the observation that in the adult brain, neural stem cells - once thought not to exist - express CD95, but mature neurons do not. "We found that stem cells are activated via this receptor." Since then, Martin-Villalba has focused her work on specifically exploiting the developmental potential of neural stem cells in the brain to replace dead neurons when needed. For this, she was awarded a grant of two million euros by the European Research Council in 2018. In the same year, she took over the chairmanship of the DKFZ Scientific Council, which advises the Board of Trustees and the Foundation's Executive Board on all significant scientific matters.

A tightrope walk with perspectives
The activation of neural stem cells must, however, be done so carefully that it does not promote the development of brain tumours. In a Nature publication in 2019, Martin-Villalba's group proved how real this danger is, focusing on the tyrosine kinase mTOR, a central switch in cell proliferation. When neural stem cells begin to differentiate into neurons, they dampen down the growth-promoting TOR signal without switching it off completely. For a certain time, they thus retain the ability to turn back into stem cells by flipping the switch up. If they do this too often, it can cause cancer because mTOR sends growth signals.

Controlling mTOR activity is just one of the many challenges to making stem cell stimulation in the central nervous system as safe as possible, given the immense complexity of intracellular signal transduction. Martin-Villalba's team keeps an eye on many communication channels of the cell with sophisticated technologies in order to control neuronal regeneration as precisely as possible on the one hand and to fight tumour cells as effectively as possible on the other. "Only a few of us are still working on CD95 directly, we have now discovered much finer pathways and points of attack."

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