“There were moments when I was almost ready to give up”

Renato Paro meets us in his office on the eighth floor of the Department of Biosystems Science and Engineering (D-BSSE) on Basel¡¯s Rosental campus. The windows of his tidy, spacious office look out over the whole town. Roche and Novartis, two global pharmaceutical giants, have their offices just a few hundred metres away; the University¡¯s Biozentrum and the University Hospital are also within easy reach on the far side of the Rhine.

It has been 13 years since Paro returned to the town he grew up in to establish a unique research centre that has now inspired imitations around the world. ¡°I¡¯m proud of what we¡¯ve managed to build up here over the past years,¡± Paro says just a few weeks before he is due to become Professor Emeritus of Biosystems. Not least because when it started out, the project seemed doomed to fail. ¡°Back then in 2006, the year we founded the centre, there were moments when I was almost ready to give up,¡± he remembers. ¡°I knew how to manage a research group and head an institute, but not how to set up a research centre from scratch and build it up in the face of resistance from some of my colleagues.¡±

Biozentrum rather than architectural studies

Paro was born in Italy. He lived with his grandparents in Treviso, near Venice, until he was three years old. His parents had emigrated to Birsfelden, in the greater Basel area, in search of work. In 1957 they brought their son to Switzerland. After attending primary school and high school near Basel, he wanted to study architecture in Zurich. But this was not to be, as his parents simply couldn¡¯t afford the travel and accommodation costs associated with a course of study at ETH.

But there was a Plan B: Paro¡¯s biology teacher sparked his enthusiasm for a field that was in the throes of a revolution at the start of the 1970s, with scientists at Stanford University having recently created recombinant DNA molecules for the first time using genetic engineering. Biotechnology that made use of such recombinant DNA held out the hope of completely new medicines and revolutionised pharmaceutical production. The University of Basel responded by setting up an interdisciplinary department known as the Biozentrum. Paro was among the new department¡¯s first students, and he benefited from a unique curriculum that was strongly focused on the then booming field of molecular biology.

Renouncing the DNA-centric view

After completing his doctoral thesis in Basel, Paro and his wife first moved to Edinburgh for a year to work as postdocs before spending three years in California, where he did research at Stanford University¡¯s Department of Biochemistry, the birthplace of recombinant DNA. ¡°It was a dream destination in many ways¡±, Paro says. Living and working on the famous campus was exciting and the intellectual stimulation was unique. ¡°Looking back, this was arguably the high point of my career, with a great deal of research freedom and not too much responsibility for other people yet.¡±

It was during this period that he moved into the discipline that would define his research from then on: epigenetics. Unlike genetics, this field focuses on processes which do not depend on DNA sequence that nonetheless have a major impact on cell development. ¡°This was terra incognita,¡± Paro now says. ¡°Back then, biology was completely centred on the DNA sequence.¡± The idea that people may inherit, say, a predisposition to cancer or diabetes not through DNA alone but equally via proteins outside it was at that time still considered unlikely. Although the theoretical basis for epigenetics had been developed back in the 1960s, it wasn¡¯t until the turn of the millennium that the field began to boom.

After returning to Europe, Paro built up his first research group at the newly established Centre of Molecular Biology at the University of Heidelberg, turning his attention to cellular memory. He was driven by the question of how cells with identical DNA could differentiate into liver and heart cells and pass this knowledge on to the subsequent generation of cells. ¡°We found out that the difference lies in how the DNA is ¡®read¡¯ epigenetically,¡± Paro explains. ¡°This is done by certain proteins called histones. They activate or suppress certain characteristics of a cell and pass these markers on to subsequent generations of cells. The result is a heredity mechanism that is not based on the DNA sequence.¡±

One product of Paro¡¯s research in Heidelberg was chromatin immunoprecipitation (ChIP), an experimental technique used to investigate the interactions between proteins and DNA in living cells. This enables epigeneticists to determine the locations of the interaction between DNA and the histones that play a key role in cellular memory. Thousands of biology labs around the world use the ChIP method today. Did his invention make Paro rich? ¡°No,¡± he says, ¡°we decided against applying for a patent at the time. My priority as a young group head was to get the work published.¡± He admits now that this was a missed opportunity.

Obstacles at the start

In December 2005, Paro received a call from the then ETH President Ernst Hafen with an offer to build up a new centre for systems biology in Basel. Paro accepted. ¡°I was 51 and I still had the appetite for change,¡± he recalls. ¡°I felt that this offer was a chance for me to give something back to Basel, the city to which I owe so much.¡±

But what Paro didn¡¯t know at the time was that the establishment of this new centre was a highly politicised issue. Swiss federalism demanded another federal research institute outside Zurich. According to Paro, however, most ETH professors in Zurich were very sceptical about this project, fearing that the establishment of a new ETH offshoot would draw money away from their own research. Even worse, shortly after Paro returned, Ernst Hafen resigned as ETH President ¨C meaning Paro lost an important backer for the project. ¡°That was an incredibly stressful time with lots of sleepless nights,¡± he remembers. ¡°Only once Ralph Eichler, Hafen¡¯s successor, had managed to convince a number of professors in Zurich to help me set up the new department did things really get going.¡± Finally, the Swiss government earmarked 100 million Swiss francs for the newly established department, securing its future into the medium term.

Today, D-BSSE is spread across four buildings on the Rosental campus. It comprises 19 research groups with over 350 personnel. ¡°The key to our success is that we¡¯ve been set up in a multidisciplinary way from the outset,¡± Paro says. Research breakthroughs and new technologies around the turn of the millennium made it possible to systematically analyse thousands of proteins and base pairs simultaneously. The necessary infrastructure and analysis of the huge amounts of data call not just for biologists but also for mathematicians, bioinformaticians and engineers.

In 2014 the decision was taken to relocate the department to a new building that cost 220 million Swiss francs on the Sch?llem?tteli campus across the Rhine. Paro is particularly excited about this move, not only because it means the future of D-BSSE is secured beyond his becoming professor emeritus, but also because it lays the foundation for the department¡¯s move from fundamental research into clinically applied research. For one thing, the new building lies between the University Hospital and the Biozentrum; for another, it will be equipped with special labs for certifying medications for clinical testing. Paro hopes that systems biology will deliver important breakthroughs in cancer and diabetes research as well as in regenerative medicine using cell-based therapies. ¡°The next phase of medicine and pharmaceuticals will be defined not by the development of new molecules but by the reprogramming of cells,¡± he says with conviction.

By the time ¡°his¡± department relocates to Sch?llem?tteli in 2022, if things go to plan, Paro will already be a professor emeritus. But he will retain his current office in D-BSSE for at least two more years. Paro is planning to dedicate his newly freed-up time to founding a spin-off from his current research group. ¡°We¡¯ve managed to identify an RNA molecule that is very effective against cancer cells,¡± he says, without wanting to give too much away.