Human cells are like tiny, multi-purpose factories. In his research, ETH biologist Gabriele Alessandro Fontana investigates how cells repair damaged DNA. The mechanisms he has identified will help us to gain a better understanding of diseases and to develop new drugs.
Expose your skin to the sun for too long without protection, and you’ll get a sunburn. In other words, the sun’s UV radiation will cause an inflammatory response in the exposed skin cells. Get burned too many times and you’re likely to experience premature skin ageing, wrinkles and a higher risk of skin cancer. But what actually happens inside your skin cells when they are damaged by the sun’s rays?
Microscope images of baker’s yeast cells (dotted white lines). In case of DNA breakage, the broken DNA moves to the nucleus’ edges (red), where Rif1 binds them, forming green “spots” in close proximity to the nuclear membrane and starting the repair process. Image credit: G.A. Fontana et al., Nat. Commun. 2019
That’s the question Gabriele Fontana – a postdoc at the Laboratory of Toxicology run by ETH professor Shana Sturla – sought to answer in his most recent research project. Fontana, who grew up near Cremona in Italy, has been conducting research at ETH Zurich since 2019, but his fascination with the molecular world of cells began much earlier.
A flair for molecular biology
Fontana developed an interest in chemistry and biology while he was still at school. He has an extraordinary enthusiasm for scientific experimentation, yet it is not traditional biology, with its focus on botany and zoology, that quickens his pulse. Fontana’s real interest lies in the relatively young research field of molecular biology, which deals with the regulation and function of our genes and examines how genes interact with proteins. It’s here inside our cells where Fontana believes we will find the key to improving our understanding of diseases and our ability to develop effective drugs.
When he began his degree in biology in Milan in 2001, DNA analysis and sequencing were still laborious and expensive. Yet as his degree programme progressed, Fontana saw the process becoming quicker and easier, even for the sequencing of entire genomes. Excited by the potential opportunities of new genetic techniques, he was determined to experiment with them himself.
He stayed on at the University of Milano-Bicocca for his doctoral studies, in which he examined the molecular causes of amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. After completing his doctorate, he decided to take up a postdoctoral position at the Friedrich Miescher Institute for Biomedical Research in Basel.
A sticking plaster for DNA damage
By the time he was 30, Fontana was in Basel investigating how cells repair their damaged DNA. These mechanisms are crucial, since more severe damage can lead to malignant mutations that may ultimately cause cancer. “In the course of my work with colleagues at the Friedrich Miescher Institute, we discovered the key role of a protein called Rif1,” Fontana says. This protein acts as a kind of molecular “sticking plaster” for damaged DNA.
Fontana realised that this process takes place at very specific locations within the cell. “When a DNA strand is broken,” he says, “the damaged DNA is shunted to the edge of the nucleus, where the protein Rif1 is located, waiting to receive the broken DNA extremities and start the repair process.” When the ETH researcher observed this process under the microscope for the first time, he could hardly believe his eyes. It showed there was indeed a specific place in the cell – a kind of workshop with its own delivery service – where certain types of DNA damage are repaired. No one had ever demonstrated this quite so clearly.
Skin cells under the microscope
Nothing about the inconspicuous grey box in the Laboratory of Toxicology at ETH Zurich indicates that it is the Ferrari of UV irradiation devices. Sandwiched between a centrifuge and a glass case full of lab equipment, the square stainless-steel box is easy to miss, at least to a layman’s eyes. For Fontana, however, it’s an essential tool for studying the harmful effects of UV radiation on human skin.
After five exciting years in Basel, he moved to Zurich in 2019 to take up a post at ETH, where he continued his work on DNA damage and its pathological consequences. But unlike his research project in Basel, where he primarily worked with yeast cells, he was now studying human skin cells. How these cells respond to DNA damage is particularly relevant, as they are constantly exposed to environmental influences that destabilize their genome.
Fontana took human skin cells that were cultured in the lab and systematically exposed them to UV radiation. He then used a microscope and various biochemical and genetic methods to examine what happens inside the cells as a result of this exposure. In doing so, he came across a mechanism that scientists have long struggled to fully comprehend.
The basis for new sunscreens
“Increased UV radiation causes damage and mutations in specific locations in the nuclear and mitochondrial DNA – and we can use these changes in skin cells as a new indicator of skin disease and ageing,” says Fontana, summing up the results of a study he will publish in collaboration with his supervisor, Hailey Gahlon. In future, it should be possible to use those specific mutations as biomarkers to improve and accelerate the detection of pathological skin cells.
But the biologist not only discovers a molecular connection between UV radiation and DNA mutations in skin cells. In collaboration with the Mibelle Group, a Swiss company, Fontana also studies the molecular basis of how the UV-induced DNA damage could be mitigated by special active ingredients that could be easily added to cosmetic products in the future. “These findings could form the basis for a new generation of sunscreens with more efficient UV filters,” he says, with understandable pride.
Collaboration as the key to success
In 2021, Fontana received the James Mitchell Award for his research work at ETH Zurich. This award honours early-career researchers who foster collaborative, interdisciplinary research projects. “Without active collaboration with other disciplines, molecular biology would come to a standstill,” Fontana says emphatically. His research group alone includes chemists, physicists, molecular biologists, toxicologists and bioinformaticians, all working on common points of interest.
They share a goal: to improve our understanding of the molecular mechanisms of diseases in order to lay the foundations for new treatment methods. This dismantling of the silo mentality is one of the things that Gabriele Fontana finds particularly fascinating about molecular biology.
Source: ETH Zurich