MDC Alumna Henriette Uhlenhaut: “Getting things moving in health research”
In the future, the insights Uhlenhaut has gained could help in preventing the severe side effects of anti-inflammatory medications such as cortisone. For this work, she has now been awarded the Schering Foundation’s 2015 Friedmund Neumann Prize, which will be conferred in Berlin on September 28.
Uhlenhaut now leads an independent Emmy Noether Group in the field of Molecular Endocrinology at Helmholtz Zentrum München’s Institute of Diabetes and Obesity. But she obtained many of her important results during her three-year stint as a post-doc at the Max Delbrück Center for Molecular Medicine. Having trained as a biologist, Uhlenhaut had moved to Berlin in 2010 to work at the MDC. A fellowship from the European Molecular Biology Organization (EMBO) had enabled her to return to Europe after working at the Salk Institute in La Jolla, California. The reasons for the move were both personal (her husband had a position in Berlin) and professional – the MDC’s genome center, with its cutting-edge technology, offered Uhlenhaut everything she needed to carry out ambitious research in molecular biology.
Uhlenhaut found ideal conditions in a working group headed by Norbert Hübner at the MDC and devoted to the Experimental Genetics of Cardiovascular Disease. “I wanted to connect my genome-wide research with disease-relevant processes,” says Uhlenhaut. At the Salk Institute, she had already started focusing on the molecular biology of hormone receptors, particularly the mechanisms that govern the effects of anti-inflammatory agents such as cortisone. These steroid hormones have to bind to receptor proteins in cells before they can take effect. They are administered for a wide range of conditions, from allergies, asthma and rheumatism to multiple sclerosis and some types of cancer. The significance of cortisone, and the group of medications to which it belongs, Uhlenhaut explains, starts with their very wide use: “About one percent of the Western population is taking a steroid hormone from the glucocorticoid group.”
However, these hormones can have drastic side effects including weight gain, bone and muscle loss, and sometimes even diabetes. Uhlenhaut hopes that revealing the mechanisms that underlie the effects of these molecules will help reduce or prevent such side effects in the future. Her insights into glucocorticoid receptors have already helped Uhlenhaut take a decisive step in that direction. These receptors are found in nearly all human cells and play important roles in regulating crucial metabolic processes. For example, they bind to cortisone – a derivative of cortisol, a hormone that the body naturally produces – and thereby inhibit genes involved in inflammatory processes.
Uhlenhaut was the first to show that the glucocorticoid receptor latches directly onto DNA after binding to cortisone, and that it always latches onto the same sequence. This DNA sequence is found in the vicinity of genes involved in inflammations and a number of metabolic processes that are related to the side effects of cortisone. Paradoxically, when the glucocorticoid receptor binds, it has both deactivating and activating effects; it switches off genes for inflammation even as it switches on genes related to diseases.
“That, of course, is bad for the development of medications,” says Uhlenhaut. But this is not a woman who gives up quickly. Uhlenhaut and her colleagues assume that additional regulatory proteins or DNA sequences, so far unknown, play a role in the way hormone receptors regulates. Uhlenhaut now wants to look for those proteins and sequences using next-generation sequencing technologies to examine the entire genome of the mouse, an important model organism in the lab, and that of human cells.
Uhlenhaut continues to work on these topics in collaboration with Norbert Hübner’s group at the MDC. She has just received €1.5 million from the European Research Council to support her research, and she hopes that her findings on the glucocorticoid receptor will help produce new therapeutic approaches to diabetes and other diseases. As well as being involved in the inhibition of inflammation, the hormone receptor regulates important metabolic procsses involving sugar and fat.
Now 38, Uhlenhaut has a fascination for genetics that has marked her entire career in research. She began her biotechnology studies in the 1990s at the Technical University in her home town of Braunschweig. As a young student, she was already a keen globetrotter. Her degree program was very new and only offered in a few places. One was Georgia Tech in Atlanta, which had an exchange program with Braunschweig that Uhlenhaut had the opportunity to participate in. As an ambitious young biotechnologist, she completed her Master of Science “on the side” during her year in Atlanta, and shortly thereafter moved to the Salk Institute in La Jolla to work on her thesis. It was a big leap both academically and geographically, taking Uhlenhaut from an "average university" to one of the world’s leading research institutes.
At the time, efforts to sequence the complete genomes of living organisms were still in their infancy. The DNA of the mouse had not yet been decoded, which limited what could be done with this model organism. So Uhlenhaut, fascinated by the potential offered by whole-genome analysis, first turned her focus to the molecular biology of plants, since the genomes of several plant species had been completed.
After completing her thesis, Uhlenhaut returned Germany and to research devoted to mammals. The focus of her doctoral dissertation, completed at the European Molecular Biology Laboratory (EMBL) in Heidelberg, was FOXL2, a gene that was to become the foundation for her later research. Under the mentorship of doctoral advisor Mathias Treier, who has since moved from the EMBL to the MDC, Uhlenhaut discovered that in female mice, this gene constantly suppresses male genes to prevent the formation of male characteristics. This inhibition, which also has important functions in humans, occurs when the gene-regulating FOXL2 protein binds to another hormone receptor: the estrogen receptor. In this research, Uhlenhaut was especially fascinated by the question of just how hormone receptors switch off genes.
This prompted her to return to the Salk Institute in 2008 to work with Ronald Evans, an international expert on hormone receptors, before then moving to Berlin. “Research really is cutting-edge in the United States,” she says. Many scientists have experience of moving around a lot, especially to the U.S. “It’s something that's just expected of you – and it does offer lots of new opportunities,” says Uhlenhaut. However, she says, the institutes of the Helmholtz Association, which include her workplaces in both Berlin and Munich, rank right up there with U.S. institutions. She emphasizes that excellent, internationally competitive research is being conducted here in Germany too.
There’s one more thing that the molecular biologist is passionate about. Uhlenhaut wants to make decisive contributions to health research, of course, but she also hopes to be a role model for women who want to go into science. Does pursuing a scientific career mean giving up family life? Uhlenhaut is living proof that it doesn't: after giving birth to twins in 2012, she became head of her own research group in 2013. She loves to spend her free time with her children at a playground or in the great outdoors. For family reasons, Uhlenhaut would like to remain in Germany for a while. As far as her science is concerned, however, she plans to keep things moving.
The MDC press release on the occasion of the Friedmund Neumann Prize 2015. (German only)
Featured Image: Nina Henriette Uhlenhaut really got around in her career. This is a picture from her Berlin years – it wasn't because the lakes around Berlin couldn't compete that she moved from Berlin to Munich. Picture: Private