Fides Zenk's pioneering work from animal models to brain organoids

What do an acorn, the brain of a fly embryo and a lab-grown organoid all have in common? Off-hand, you would think the answer is simply that they’re all made up of cells – but it’s actually much more complicated. To find out, we need to delve into the exciting research being carried out by Fides Zenk at EPFL’s School of Life Sciences, which she joined two years ago.

Zenk is originally from Lower Saxony in northern Germany. She became interested in nature as a child, as she enjoyed watching how plants grow and develop in her native countryside. “I’ve always loved observing biological processes – seeing how nature evolves over the years, how flowers and fruit are formed, and then disappear, and then grow again,” she says. “I initially thought I’d become an ecologist, collecting and documenting different types of plants and seeds. As a university student I learned all about the underlying science and molecular mechanisms.”

For her master’s in biology, Zenk studied gene sequencing methods and became interested in gene regulation, or the critical process behind cell differentiation. This took her from examining plant seeds to analyzing animal embryos. “The gene regulation patterns in animals are very interesting,” she says. “In the early phase of embryogenesis, cell genes aren’t yet transcribed – the embryo depends entirely on its mother’s RNA and proteins; the genome is completely silent. This is when the genome’s 3D structure develops and the various gene regulation patterns form. Only then do the embryo’s genes begin to transcribe. It’s really fascinating.”

Award-winning research

Today, it’s hard to conduct research on molecular genetics without venturing into the field of epigenetics (see box). Amazing progress has been made in this field over the past 20 years, and Zenk finds that it’s opening up a wealth of possibilities. During her PhD at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany, she examined how embryos form and develop in living organisms, through the lens of epigenetics. “I studied the embryogenesis of fruit flies and tried to understand what controls those first few moments of life,” she says.

I didn’t want to keep performing research on animal models because it’s never clear how much our findings can be translated to human health

Zenk’s thesis investigated the fledgling theory of how epigenetic instructions are passed down from one generation to the next. Specifically, she found that in fruit flies, epigenetic modifications could be transmitted from the mother to the embryo and help regulate gene expression. That was a considerable breakthrough, and it was proven again in mice by another research group, suggesting a mechanism that is conserved between species. Embryos inherit not only genetic information from their parents, but also information about gene expression, which is transmitted by the mother through the epigenetic machinery.

Making use of organoids

“After completing my thesis research, I suspected that some of the mechanisms that control gene expression in the very early phases of embryo development also play an important role in the differentiation process for somatic cells,” says Zenk. “But I didn’t want to keep performing research on animal models because it’s never clear how much our findings can be translated to human health.” That’s when she began using another kind of research model – organoids, or 3D tissue samples that are grown in vitro from human stem cells. Organoids have major potential for applications in biology and human medicine.

Zenk completed her postdoc at the ETH Zurich Department of Biosystems Science and Engineering in Basel, developing “technology for studying the epigenome at the level of a single brain cell,” she says. “That let us develop a map of human neural organoid development in order to examine how epigenetic modifications become established and control decisions on cell differentiation.”

Focusing on human embryonic brain development

Now based on the shores of Lake Geneva, Zenk is continuing her research on embryonic development and the design of new technology, partly at EPFL’s Campus Biotech in Geneva. “We are moving towards more human-relevant questions, to try to understand early developmental disorders and, in particular, neurodevelopmental disorders that are probably established very early in embryonic development.” The hope is that this work will eventually lead to new therapies. This summer, Zenk’s pioneering efforts earned her the 2024 3Rs Award from the Swiss 3R Competence Centre (3RCC). This award recognizes major contributions to the three Rs – replacement, reduction and refinement – of animal testing. “Traditionally, studies of early brain formation have relied heavily on animal models, especially mice, which often fall short in mimicking human-specific biology. Fides Zenk's work challenges that norm,” says the 3RCC press release.

In addition to Campus Biotech, Zenk also conducts research at EPFL’s Lausanne campus, where she gives bachelor’s classes. She’s taking advantage of EPFL’s fertile ecosystem of biologists and engineers to develop a reliable system that can help the neuroscientific community find answers to the many questions still surrounding the development of the human brain. Zenk also plans to learn French so that she can communicate more easily with her students and transmit her epigenetic knowledge.