Heisenberg Professur für Kardiale Zelluläre Elektrophysiologie
Medizin und Gesundheit
Rund 96 % aller neu getesteten Arzneimittel scheitern in klinischen Versuchen. Der Hauptgrund dafür ist, dass sie meist nur an Tieren oder an humanen induzierten pluripotenten Stammzellen (hiPSC) getestet wurden.
Die Forschung von Prof'in Dr'in Molina basiert auf humanen Geweben, die bei Operationen von Patient*innen anfallen und normalerweise entsorgt werden. Mit diesen Geweben und den daraus isolierten Zellen erforscht sie neue pharmakologische Ziele und Arzneimittel, wobei sie viele klassische Techniken einsetzt.
Diese Forschung war bislang jedoch limitiert, da viele hochmoderne Techniken, die für die Prüfung von Arzneimitteln oder neuer Gentherapien zum Einsatz kommen, nicht mit humanen Herzzellen funktionieren, da diese wenige Stunden nach der Isolierung absterben. Dies machte den Einsatz dieser Methoden in der kardiovaskulären Forschung bislang unmöglich mit humanen Herzzellen.
Prof'in Dr'in Molina hat daher eine Methode zur Isolierung humaner Herzmuskelzellen entwickelt, die es ihr ermöglicht, diese Zellen über mehrere Tage hinweg am Leben zu erhalten - genug Zeit, um alle erforderlichen Tests durchzuführen. Diese Methode könnte es ihr zukünftig sogar ermöglichen, neue Gentherapien an echten humanen Herzzellen zu testen, was bisher unmöglich war. Auf der Grundlage all dieser Methoden hat sie kürzlich ein neues therapeutisches Ziel für Vorhofflimmern, die häufigste Herzrhythmusstörung, namens PDE8B gefunden.
Heisenberg Professur für Kardiale Zelluläre Elektrophysiologie
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“A healthy future demands an excellent science that focuses on humans” Why did we choose to start a scientific career? Why did we specialize in the research field we are in? The driving force in my career was to improve the life and well-being of humans. That was the reason for me to choose the cardiovascular field, the leading cause of death, and atrial fibrillation (AF) specifically, which is the most common cardiac arrhythmia and which highly affects the well-being of patients limiting their health-related quality of life. I have the vision that we can not only improve the health of humans with cardiovascular research, but that we can at the same time significantly reduce the impact of our research e.g. in animal testing. Therefore, I integrated the 3R (Refinement, Reduction, Replacement) approach, or as I would say the 4R (the above mentioned plus Responsibility) approach, into my research. 4R because we as leading scientists are responsible for educating and leading into a future that includes all aspects of a sustainable and responsible research into account. Having worked in Hamburg and seen first-hand the huge demonstrations against animal testing here has sharpened my vision that we also have to take into account, what the public expects from us and that we can always show that we proactively improve the current status. We have furthermore to breed a younger generation of scientists that are willing and capable of improving what we achieved.
Let me give you an insight on what path this thinking has led me so far: I am a 20 years experienced cardiac cellular electrophysiologist. During all these years, I not only built up my expertise in various areas, i.e. electrophysiology or Ca2+-handling and nanodomains, but also used my knowledge to develop my own methods creating an international visibility of my research. A prove of this visibility is my re-election as a nucleus member of the Working Group in Cellular Cardiac Electrophysiology in the European Society of Cardiology. I use patch-clamp, confocal Ca2+ imaging, fluorescence resonance energy transfer (FRET), immunostaining and molecular techniques to study the role of receptor-mediated modulation of ion currents, intracellular Ca2+-handling and second messengers in AF. During the last years, I was specially interested in cyclic nucleotides signaling and how phosphodiesterases (PDEs) can differentially affect cellular nanodomains in human atrial tissue and myocytes (HAMs). Many of these classical and state-of-the-art techniques require the isolation and culture of myocytes. But human myocytes die only few hours after isolation. This has been a problem over the past several decades for all the experts working in cardiac research and one of the main reasons to work with animal models. Animal experimentation in these cases was required. However, current alternative strategies for cardiac research and safety evaluation of drugs in the heart, such as hiPS-CMs or even animal models, have shown significant limitations, resulting in a low percentage of successful therapies when translated to patients. Thereby, during my career I worked with different strategies to develop more predictive, human-relevant preclinical approaches to solve this problem.
I achieved my PhD in Cell Biology with a summa cum laude in 2009 working at Sant Pau Hospital in Barcelona (supervisor: Dr. Leif Hove-Madsen), using patch-clamp techniques and confocal Ca2+ imaging in HAMs from patients with AF. I gained expertise in nanodomains during my first postdoc in France, at the laboratory of Dr. Rodolphe Fischmeister. There I developed my own isolation method which allowed me to transduce and culture, for the first time, HAMs and to monitor cAMP changes in these cells using FRET. I then provided evidence for PDE4 contribution to cytosolic cAMP dynamics in HAMs from sinus rhythm patients (Molina et al., JACC 2012). Afterwards, I obtained an IEF Marie Curie grant. I moved to Germany to deepen my knowledge in the field of AF with Prof. Dr. Dobromir Dobrev and Prof. Dr. Niels Voigt. Since 2018, when I got my group leader position at UKE in Hamburg, I improved the isolation/culture method for human myocytes in order to use it with any kind of cardiac human tissue, from cm to mm sized tissues, atrial or ventricular, from healthy or from diseased patients. Actually, many worldwide recognized experts collaborate with me for translating their research into a human model thanks to this technique (M. Zaccolo, Oxford University; J. Gorelik, Imperial College London; S. Sossalla, UKGM Giessen; VO Nikolaev, UKE).
My plans as a Professor at UKE with my own research team include using this isolation method 1) to transduce HAMs with FRET sensors in order to visualize cAMP, cGMP and CaMKII, 2) to genetically manipulate human myocytes in order to study genes of interest in cardiac diseases and validate gene therapies as a proof-of-concept, and 3) to establish a HAM computational model which includes PDE nanodomains and that will have the potential to predict drug-induced pro-arrhythmia risk.
Prof’in Dr’in Cristina E. Molina