BIH Excellence Award Previous Winners Update

Prof. Dr. Ralph Knöll (AstraZeneca/Karolinska Institut Stockholm, Sweden ) and Prof. Dr. Jeanette Erdmann (Universität Lübeck/DZHK) are the recipients of this year’s BIH Excellence Award for Sex and Gender Aspects in Health Research. 

Prof. Dr. Ralph Knöll 

Professor of Myocardial Genetics, AstraZeneca / Karolinska Institute

Award Project: Sex-dependent impact of constitutive myosin light chain phosphorylation on cardiac function 
Project Partner: Prof. Dr. Sophie van Linthout (BIH) and Prof. Dr. Carsten Tschöpe (BIH)  

Cardiac insufficiency, often referred to simply as heart failure, is characterized by the inability of the heart muscle to function properly. The muscle cells have structural defects and are interspersed with connective tissue. Cardiologists distinguish here between the condition where the heart chambers become massively enlarged and the condition where there is an uncontrolled increase in wall thickness of the left atrium and a reduced volume of the left ventricle. In women the latter form of heart failure is much more common, but research does not know why. So far there are no specific treatment options for women or men. To remedy this, Ralph Knöll, Sophie Van Linthout, and Carsten Tschöpe have teamed up to study gender-specific differences in mice in which a genetic modification causes a particular muscle protein (myosin) to be constantly active, contributing to the loss of function in heart muscle cells and to the development of fibrosis and severe enlargement of the left atrium. 

Short biography 

Ralph Knöll is Chief Scientist at the British-Swedish pharmaceutical company AstraZeneca and a Principal Investigator at the Karolinska Institutet in Stockholm. He was recruited from Imperial College London where he was Professor and Chair of Myocardial Genetics from 2009 to 2014. He was formerly head of a research group studying cardiovascular molecular genetics at the University of Göttingen from 2004 to 2009. Knöll has a strong interest in genetics, physiology and pharmacology of the cardiovascular system. His translational research aims to unravel the epigenetic mechanisms underlying the biology of human cardiac disease and to use these findings as a basis for developing new therapies for heart failure. 

Prof. Dr. Jeanette Erdman

 DZHK Professor for Cardiovascular Genetics, Universität zu Lübeck

Award Project: Bridging the sex-gap in coronary artery disease 
Project Partner: Dr. Teresa Gerhardt (BIH/ Charité) Dr. Elisabeth Strässler (Charité)  

The research project focuses on coronary heart disease. Although overall the death rate from heart attacks and strokes has dropped by 60 percent in the last 20 years, we have seen that young women are the least likely to benefit from this improvement. Prof. Erdmann an her collaborators have found a gene called MYOZ2 that is linked to cardiovascular risk in women, but not in men. The researchers want to insert the pathologically mutated gene into human induced pluripotent stem cells (hiPSCs) – specifically into female and male hiPSCs. They then plan to let the genetically modified stem cells mature into vascular cells in the laboratory to study what effects the altered gene produces. 

Short biography 
Jeanette Erdmann studied biology in Cologne and did her doctoral work at the Institute of Human Genetics in Bonn. After receiving her doctorate, she served as a research group leader in Berlin and Regensburg. She qualified as a professor at Universität Regensburg. Since 2003 she has been working at the Universität zu Lübeck. In 2012 she was appointed to a tenured DZHK Professorship by the German Centre for Cardiovascular Research Diseases. Since 2013 she has successfully led the newly founded Institute for Cardiogenetics, which aims to better understand the genetic factors that lead to cardiovascular diseases, e.g., atherosclerosis and heart attacks. She is a member of the German National Academy of Sciences Leopoldina. 

Antoinette Maassen van den Brink from Erasmus University Medical Center in Rotterdam is the recipient of BIH Excellence Award for Sex and Gender Aspects in Health Research 2019. Together with her project partner at Charité – Universitätsmedizin Berlin, Professor Tobias Kurth, the director of the Institute of Public Health, Maassen van den Brink is investigating to what extent reproductive factors in women affect the course of migraine as well as researching the link between migraine and cardiovascular events. With the award, which comes with a prize of €40,000, the BIH supports medical research projects that take into account gender differences. The award ceremony was held in Berlin on September 24. 

Prof. Dr. Antoinette Maassen van den Brink 

Erasmus Medical Center, Rotterdam, Netherlands
Award Project: Migraine and vascular risk; a headache for women 
Project Partner: Prof. Dr. Tobias Kurth (Charité) 
 
Research focus 
Antoinette Maassen van den Brink investigates the neurovascular aspects of migraine, with a special emphasis on the role of female sex hormones in disease development. Previous studies by Antoinette and Tobias Kurth of Charité-Universitätsmedizin Berlin showed that the link between migraine, vascular health, and cardiovascular events is complex. Since many patients experience migraine only during certain periods of their lives, the course of migraine also plays an important role. The scientists suspect that other factors also influence migraine and the vascular system. They now want to investigate this in further research, which in Rotterdam will include functional studies in the lab and at the Charité a reanalysis of epidemiological data from the Women’s Health Study, which since 1993 has examined the health of women employed in the healthcare sector. Her research has a translational focus and involves in vivo experimental animal studies, human tissue models, and clinical trials. 
 
Short biography  
Dr. Antoinette Maassen van den Brink is Associate Professor of Pharmacology in the Department of Internal Medicine at Erasmus University Medical Center in Rotterdam, the Netherlands. She is a board member of the Dutch Headache Society and the Dutch Pharmacology Society, as well as a founding member of the Dutch Society for Gender and Health. In addition, she sits on the board of directors of the European Headache Federation and of the Federation of European Pharmacology Societies. She has received numerous awards/grants for her work, including from the American Headache Society, the International Headache Society, the Netherlandse Organisation for Scientific Reseearch, and the Dutch Heart Foundation. She is co-editor of the book Gender and Migraine, published by Springer.  

Studying sex and gender in medical research should not be considered as something special, but it should be part of everyday scientific life. Sex and/or gender are important determinant in research of all levels, i.e., biological/preclinical, clinical, and population-level research.  In biological/preclinical research, biological sex may be a more important determinant than gender, which is influenced by behavioural and societal aspects.  Even in experiments on isolated cell cultures, results obtained in cells isolated from a male individual may differ substantially from results obtained in female cells.

Further, it is obviously important to consider the sex of experimental animals. In this respect, many researchers have in the past preferred to use male animals only, expecting the variability of the results to be smaller in male animals than in female animals with an estrous cycle.

However, as was recently demonstrated , variability between male animals is not smaller than that between female animals, in view of differences between dominant and subordinate males. In clinical research, it is important to have a clear picture of how sex and gender may affect results obtained in a study, which aspects would be relevant for one of the genders only, and which conclusions may be drawn from such a study. In both preclinical and clinical research, it should not be a dogmatic rule to have the same group sizes for male and female individuals, as this may lead to unethically and financially not feasible large research populations.  Rather, research questions and data analysis plans should be defined while clearly considering the influence of sex and gender. Population-level research can teach us a lot about sex and gender differences in health and disease.  In this context, it remains a challenge to properly disentangle the components of sex and gender, respectively, which may obviously also interact with each other. 

In our migraine-related research, facilitated by the BIH grant 2019, we have recently reviewed existing knowledge on this topic. In addition, we identified knowledge gaps and set priorities for further interdisciplinary and translational research on sex and gender differences, as well as gender-specific therapies, in migraine.

2017 ging der BIH Excellence Award an Louise Pilote, die in Zusammenarbeit mit mir, Vera Regitz-Zagrosek, und dem Institut für Geschlechterforschung an der Charité neue Konzepte zur Einführung des soziokulturellem Geschlechtes, Gender, in klinische Studien entwickeln wollte. Der Preis war eine Initialzündung. Wir entwickelten Ideen, wie die Konzepte aus Kanada auf Europa übertragen werden konnten, und von der ursprünglichen kardiovaskulären Kohorte auf andere medizinische Bereiche. Es resultierte das BMBF geförderte Projekt Gendage, das sich mit Geschlechterunterschieden im Alter auseinandersetzte, GeSeMS, ein Projekt zu Geschlechterunterschieden bei multipler Sklerose , gemeinsam mit Professor Stefan Gold in der Neurologie der Charité, und ein Projekt zu Geschlechterunterschieden bei Frailty und Tumoren, das vom DZHK unterstützt wurde. Und natürlich wurden die Gedanken zu Sex und Gender in die Forschung bei COVID eingebracht, vor allem In Zusammenarbeit mit den Kolleginnen an meiner neuen zweiten Wirkstätte an der Universität Zürich in ein Projekt des Schweizer National Nationalfonds  – Sex, Gender und COVID – und ein Projekt der Stiftung „The Loop“. Da alle gestarteten Projekte Langzeitprojekte waren, wird es noch dauern, bis die Ergebnisse publiziert sind.

    Erste Veröffentlichung finden Sie hier:

    Catherine Gebhard et al. (2020)

    Nauman et al. (2021)

The study of sex differences in disease reveals important clues into naturally occurring disease modifying factors.Understanding these sex differences and what causes them can lead to new treatment targets for novel therapies for each disease.

In multiple sclerosis for example, women are affected about three times more often than men. My lab recently identified X chromosome effects that can lead to increased susceptibility to autoimmunity in women as compared to men. One paper (JCI) shows an effect of an X chromosome gene Kdm6a and the other paper (PNAS) shows a role of imprinting of X genes due to parental-of-origin effects, each on autoimmunity. These papers will be discussed in the context of each other and other sex chromosome effects during first symposium of this year’s annual meeting of the Organization for the Study of Sex Differences (OSSD Virtual 2021). 

Also in multiple sclerosis, while women are more susceptible to developing disease, when men get MS, they demonstrate worse disability and worse brain atrophy.

A study was recently published as a collaboration between Charite (Friedemann Paul, Stefan Gold, Claudia Chien) and UCLA (Rhonda Voskuhl, Allan MacKenzie-Graham, Kevin Patel) which shows more atrophy of regional gray matter in MS men compared to healthy men versus that observed in MS women compared to healthy women. 

A key aspect off this work was that since there are known sex differences in brain regions in healthy people. Previous studies compared brain region volumes in MS females versus MS males, so were confounded by known sex differences in volumes of brain regions during health. Instead our group removed this confound by comparing MS versus healthy within each sex to reveal the effect of disease on atrophy within each sex. This study was made possible by imaging data from Charite from both MS and healthy individuals.

This approach can now also be applied to other neurodegenerative diseases with a sex difference including Alzheimer’s disease and Parkinson’s disease.