Leading stress expert Ron de Kloet on hormone's dual nature: From protection to harm

LEIDEN, Netherlands, 10 December 2024 – In a wide-ranging Genomic Press Interview, eminent neuroscientist Dr. Edo Ronald (Ron) de Kloet reveals crucial insights into how stress hormones can shift from protecting to potentially damaging the brain, a discovery that has transformed our understanding of stress-related mental disorders and opened new therapeutic pathways.

Dr. de Kloet, Professor Emeritus at Leiden University Medical Centre and an Academy Professor of the Royal Netherlands Academy of Arts and Sciences, has dedicated his career to understanding the fundamental mechanism of the stress response in the brain. His groundbreaking discovery of how cortisol acts through mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) has revolutionized our understanding of stress-related mental health conditions and their treatment.

The extensive interview, published in Genomic Psychiatry, offers remarkable insights into both the scientific journey and the personal story behind these crucial discoveries. "Endocrinology is a concept, an approach, or even a method," Professor de Kloet explains, reflecting on the inspiring words of his role model, Professor Marius Tausk. "Whatever the specific endocrine subdiscipline, topic, or subject, the binding element is the objective: understanding how signals coordinate the processes in cells, tissues, and organs."

His research team's pivotal finding – that a single hormone, cortisol, could both protect and damage the brain through different receptor systems – came after years of meticulous investigation. This discovery led to the formulation of the MR:GR balance hypothesis, which suggests that the proper functioning of stress responses depends on the delicate balance between these two receptor systems.

"Upon imbalance of the MR and GR-mediated actions, the stress response's initiation and management becomes compromised," Professor de Kloet elaborates. "At a certain threshold, this may lead to a condition of neuroendocrine dysregulation and impaired behavioural adaptation, which potentially can aggravate stress-related deterioration and promote vulnerability.”

The impact of this work extends far beyond theoretical understanding. In collaboration with Corcept Therapeutics, the research by Professors Ron de Kloet and Onno Meijer, his successor, has led to the development of novel Selective Glucocorticoid/Mineralocorticoid Receptor Modulators (SGRM/SMRM). These compounds, now in phases 2 and 3 clinical trials, show remarkable promise in treating various stress-related conditions while potentially offering fewer side effects than traditional treatments.

His current research collaborations include a groundbreaking program with Dr. Megan Galbally in Melbourne, Australia, examining how early-life stress influences childhood anxiety disorders through cortisol action in the amygdala. This work is providing crucial insights into the developmental origins of stress-related disorders and suggesting new approaches for early intervention.

Throughout his career, Professor de Kloet's contributions have earned him numerous prestigious honors, including the Geoffrey Harris Award (2005), the ECNP Award (2007), and the Golden Emil Kraepelin Medal (2014). He was knighted in the Order of the Dutch Lion in 2010, and recently, alongside his long-time collaborator Professor Marian Joëls, received the 2024 Global Stress & Resilience Network Pioneer Award.

The Genomic Press Interview also reveals Professor de Kloet's philosophy on scientific leadership and collaboration. His approach to mentorship has helped shape generations of neuroscientists, with over 57 PhD students completing their theses under his guidance. "Focus, collaboration, and mutual respect are the ingredients for an exciting scientific journey," he shares, emphasizing the importance of multidisciplinary approaches in modern neuroscience.

Professor Ron de Kloet's Genomic Press interview is part of a larger series that highlights the people behind today’s most influential scientific ideas. Each interview in the series offers a blend of cutting-edge research and personal reflections, providing readers with a comprehensive view of the scientists shaping the future. By combining a focus on professional achievements with personal insights, this interview style invites a richer narrative that both engages and educates readers. This format provides an ideal starting point for profiles that delve into the scientist’s impact on the field, while also touching on broader human themes. More information on the research leaders and research rising stars featured by Genomic Press can be found in our publication website: https://genomicpress.kglmeridian.com/.

The full Genomic Press Interview, titled "Edo Ronald de Kloet: How does the action of glucocorticoids change from protective to harmful? What is the cause? And what are the consequences?,” is available on 03 December 2024 in Genomic Psychiatry, offering readers an unparalleled opportunity to explore the thoughts and experiences of one of the most influential minds in neuroscience and neurobiology of brain disorders. The article is freely available online at https://doi.org/10.61373/gp024k.0088.

About Genomic Psychiatry – Genomic Psychiatry: Advancing Science from Genes to Society (ISSN: 2997-2388) represents a paradigm shift in genetics journals by interweaving advances in genomics and genetics with progress in all other areas of contemporary psychiatry. Genomic Psychiatry publishes peer-reviewed papers of the highest quality from any area within the continuum that goes from genes and molecules to neuroscience, clinical psychiatry, and public health.