Jumping into the unknown

Published on 22/08/2022

As we walk along the narrow, dark blue corridors of the Friedrich Miescher Institute and move deeper into the basement of the old research building in the venerable industrial Rosental quarter in Basel’s north-east, our sense of disorientation and mystery rises with every single step.

Buried under the pavement level, where all daylight has vanished, we enter a darkroom with high-tech gear that is destined to change the course of medicine and biology. In the seemingly makeshift shack with a few tables, we are presented with one of the world’s most unique laser microscopes that can shed light on how cells form into living systems.

As unassuming as the imaging technology looks to a layman, it creates a spectacle as beautiful and informative as one can imagine. Liberali and her team are not only able to generate high-resolution images of single cells with the help of the tool. They can also produce films that show how cell formations arise from a single unit – showing us nature’s biological dance.

It took years to build the system, which consists of the unique imaging gear and a biological system that uses genetics and top-notch biotechnology. But above all, it was Liberali’s unique drive and stubborn sense of purpose that drove her to set up the infrastructure and put together one of the largest research groups at the FMI.

“Actually, I started out as a chemist, but became increasingly interested in molecular cell structures, on which I focused during my Ph.D. years,” says Liberali, who spent her formative academic years at Sapienza University of Rome and later in Switzerland. “After that, I started to focus on how cells self-organize and behave in a collective way.”

A deep burning question that has intrigued her throughout her career, which also saw her work at the Swiss Federal Institute of Technology and the University of Zurich, was summed up in her 2018 TED Talk, when she said: “I always found fascinating what Aristotle said: ‘The whole is more than the sum of its parts,’ and I wondered what is this ‘more’?”

Once she took up her group leader position at the FMI in 2015, she went on to look for an answer to this question. Part of the quest required her to work with stem cell technology. Using this tool, scientists take normal skin or blood cells and revert them back into stem cells.

These cells are then reprogrammed into any kind of other cells and even organoids – cellular clusters that behave like quasi-organs. The Nobel Prize-winning technique, for example, allows researchers to study organs in a non-invasive way, for example the brain or, as in Liberali’s case, intestines.

But to really understand and see how these cells develop and form into systems and how they interact with each other, Liberali had to travel far and wide. “I wanted to work on these organoids and to do it in the first months when I arrived at the FMI. But this seemed very difficult. I like to take risks and to jump into the unknown. I was trying different kinds of microscopes and even joined the Janelia Research Campus in Washington to work with Nobel Prize winner Eric Betzig to use his state-of-the-art imaging technology. But it didn’t yield the right results. So, we built the microscope we needed at the FMI.”

To engineer the microscope, Liberali broadened her team’s range of skills, adding optical engineers to her roster of specialists. “I found these guys who were as crazy as me,” Liberali remembers. “And I took my starting financial package and said, ‘Let’s build this microscope.’ I barely slept for weeks because I was thinking: ‘What the hell am I doing? If this one doesn’t work, it’s over.’”

But the team succeeded in creating what is now known as a high-content image-based screening platform or, in lay terms, a microscope that looks nothing like a microscope but is able to capture the formation of cell systems in real time.

Liberali is still thrilled when she thinks about the time she first saw the film, which shows a flickering of red-and-green dots before they evolve into a ring of clustered intestinal cells, like in a ballet of colored soap bubbles. “It was just incredible to see how it all formed into a whole system, contracting a three-week process into a few seconds.”

Aside from being beautiful, the imaging technique is unlocking important information as to how cells form into bigger clusters and how they interact and communicate with each other as they grow. This, Liberali says, is also important to understand the genesis of diseases such as cancer, which are not always triggered by genes but by other factors, including the immune system or age.

“We now have, for example, 100 organoid lines from patients, where we have the tumor from a colon cancer and healthy tissue. So, we can compare tumor cells and healthy cells from the same patient. This allows us to start really digging into human-to-human variability, understanding where the sources of the disease come from, really at the fundamental point,” Liberali says.

The breakthrough also helped Liberali and her team, which has grown to more than a dozen specialists from different fields in biology, physics and chemistry, to receive coveted European Research Council (ERC) grants, which are disbursed as part of the European Union’s Horizon research program.

“Usually, when I write the application for an ERC grant, many people always tell me that my ideas are too ambitious, too crazy. But then, when I get invited for an interview after applying for an ERC grant, I can be quite convincing as I have this ‘just do it’ attitude.”

The video they created also helped when she applied for a grant a few years back. “If I had just told the jury that I have built a microscope, the only one that can chronicle organ growth, they would probably have shrugged this off. But when I showed them the video, I saw how the faces of the people changed and how this helped us get the grant.”

Liberali says the fact that this was all possible in a relatively short timeframe is mostly down to having the right people in the lab and building trust with her colleagues. “You can tell them to go to the moon and back. But you also have to feel the responsibility that you are putting their career at risk if you fail. So, it’s important to create the right environment for them to thrive as well.”

Crazy ideas

The FMI, Liberali says, offers this environment, in both an aspirational and an operational sense. Created in 1970 by Novartis predecessor companies Ciba and Geigy to bridge the gap between academic research and the pharmaceutical industry, the institute has been a beacon of basic research for more than five decades, drawing some of Europe’s best scientists to Basel.

“I can take risks here and do something I never did before,” Liberali says. “The FMI is thus the perfect place where you can focus on pure innovation and see the applicability of what you do immediately, as well as having the interaction and the collaboration with an industry leader such as Novartis.”

Today, the FMI has 20 research groups and employs around 340 researchers from 44 different countries. The FMI achieved early breakthroughs in cancer research, which have also benefited the drug development programs of Novartis. The institute is currently focused on the research areas neurobiology, genome regulation and multicellular systems. It is one of Europe’s leading research institutes when it comes to receiving ERC grants.

But this is now at stake as Switzerland has partly dropped out of the European Union’s research program Horizon Europe. “This is really bad, in terms of both competition and funding,” Liberali says. “The key reasons I came to Switzerland are that science is well respected and that the system in which we operate is meritocratic, but also because Switzerland could participate in the Horizon program.”

By dropping out of the European system, says Liberali, echoing other academic scientists, basic researchers are not just losing access to funds: “What we are losing is access to the best reviewers and committees that can really assess our work and give the funds according to the best science. Hence, we’re losing the ability to compete with the best, and this is certainly a disadvantage,” Liberali says.

Liberali is not exaggerating when she talks of the FMI’s scientific excellence. Many of the FMI’s researchers regularly receive some of the world’s most prestigious science awards. For example, this year, Silvia Arber received the Brain Prize and Nicola Thomä was awarded the Otto Naegeli Prize. In 2021 Piero Caroni received the Science Prize of the City of Basel. Liberali herself has just been awarded the EMBO Gold Medal 2022, which recognizes outstanding life scientists in the early stage of their careers. She is also a recipient of the Friedrich Miescher Award.

“This really reflects the high-level science that is conducted here at the FMI, which is also a consequence of the fact that we are competing with other institutes in Europe. So, the challenge of not being able to continue in this race may have negative consequences in the short and long term, if we start failing to attract young and motivated scientists.”

Nevertheless, while Switzerland is trying to renegotiate full access to Horizon Europe, Liberali will continue her work on organoids research and try to produce the best science possible. But she reiterates: “In order to achieve the best science, you need the best people. Just imagine if I had not been able to work with my microscope specialists and all the other scientists who have joined the team … my crazy ideas would just be that.”