Antonio Bertoletti from Alpine to viral peaks | MEDICUS 2024 Issue 4

Antonio Bertoletti: From Alpine to viral peaks
By Dr Chua Li Min

Prof Antonio Bertoletti in his office // Credit: Norfaezah Binte Abdullah, Duke-NUS

“So what do you want to know?” quipped Antonio Bertoletti, in his unmistakable Italian accent somewhat seriously before letting out a laugh, instantly lightening the mood for our interview.

With Bertoletti, what you see is what you get. And it in pretty direct terms. But it is his spontaneity and quick wit that most around him find endearing.

Also refreshing is the change of perspective he often provides, shared Ooi Eng Eong, Bertoletti’s long-time colleague and fellow professor at Duke-NUS: “Having Antonio, who speaks his mind constructively, as a colleague, makes our programme thrive. I, for one, value the partnership and friendship that we have,” said Ooi, who like Bertoletti is with the Emerging Infectious Diseases Programme at the School.

Another long-time collaborator and friend, Mala Maini, now a professor at University College London, put it like this in her recent editorial on Bertoletti’s Recognition Award by the European Association for the Study of the Liver: “He always prioritises time for his colleagues and is always ready to stir up good humoured discussions with his provocative ideas.”

Even as Bertoletti explains how parts of the body’s immune system come together to mount a response against an invading pathogen, he has a knack for drawing people in.

“I think I’m just really lucky to do a job that I like. I don’t want to end work, because again—I still like it.”
Antonio Bertoletti

“I’ve always been interested in infectious diseases…how viruses or bacteria interact with humans to cause diseases, and how they have evolved to persist somehow,” said Bertoletti.

His face lights up as he expands on the details, with each point sending his hands into action, adding layers to his enthusiasm.

“Too much?” he paused to ask suddenly.

With a tale as exciting as the one playing out between the body’s immune cells and pathogens, you simply cannot fault Bertoletti.

And his favourite part of the story?

How the immune system leverages cells such as T lymphocytes or T cells, to suppress viral infections, in particular Hepatitis B—an area of research that the three-time Singapore Translational Research (STaR) Investigator Award winner has pursued passionately for more than 35 years across continents, starting from the town of Cremona in the north of Italy.

Scaling peaks of mountains and knowledge

For Bertoletti, growing up in Northern Italy meant having an exclusive pass to the mountainous ranges of the Alps: their lush green coniferous forests during summer for hikes and exciting ski trips down their snowy white slopes during winter.

“So a lot of my time when I was young, I spent on the mountains,” he chuckled.

Bertoletti (centre) shares a wefie with his friends on a ski trip // Credit: Antonio Bertoletti

On those trips, he would return with prized biological specimens he collected from his walks. “I’ve always been interested in biology…animals, flowers. I always had a little bit of interest on the biology of living things,” added Bertoletti.

Influenced by his love of biology, Bertoletti decided to read medicine at the University of Parma: “It is also pretty much similar (to biology), but more applicable to real life.”

But whenever the weekends rolled around, he would venture up the slopes of the Alps again, exploring the many routes up the mountains.

“There is always the curiosity to see what you can see when you are at the top, which is something that I like and it’s also very similar to what we are trying to do in the lab now,” said Bertoletti, with a sparkle in his eyes. “It’s something that I still miss.”

“You need to like it, it’s like cooking.”

As a young medical doctor working on the infectious diseases ward, Bertoletti was drawn to understanding the fundamental mechanisms of diseases and how they translate into patients’ symptoms.

His curiosity led him to Carlo Ferrari’s lab, where he studied the role of T cells in suppressing a Hepatitis B infection.

Part of Bertoletti’s project involved trying to grow the very cells that help eliminate pathogens like viruses and bacteria by killing infected cells.

“I’ve always been interested in infectious diseases…how viruses or bacteria interact with humans to cause diseases, and how they have evolved to persist somehow.”
Antonio Bertoletti

With very few of these cytotoxic T cells present in samples from infected patients, “it was considered nearly impossible at the time” to grow them in the lab, he recalled. But when Bertoletti explored using samples from patients who had cleared an infection, he succeeded, generating clusters of these cells in wells.

“You need to like it (growing the cells), it’s like cooking. If you like it, then you’ll put your heart into it,” replied Bertoletti, when asked about his secret to success.

Spurred to further his research, Bertoletti pursued it full-time as a postdoctoral fellow in La Jolla, California, on a joint grant Ferrari shared with renowned viral immunologist Frank Chisari at The Scripps Research Institute.

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While he couldn’t speak a word of English when he touched down in the United States, it wasn’t something that fazed him. “You learn to manage,” he quipped.

What mattered more was having the opportunity to hone in on the exact way in which T cells are able to recognise the Hepatitis B viral protein, and how it affects disease progression—a groundbreaking discovery that Bertoletti and Ferrari made over countless faxed exchanges.

“I would find my office full of fax paper strips sent by Antonio that were accumulated during the night because of the time difference between La Jolla and Parma,” recalled Ferrari, who was a professor of infectious diseases at the University of Parma.

Added Ferrari: “Thanks to his (Bertoletti’s) real ‘hunger’ for science and novel knowledge, and unique capacity to make very sophisticated and well-designed experiments to test new working hypotheses, he gave a fundamental and original contribution to almost all studies published in Parma by our group.”

And then there was light

When he returned to Italy, Bertoletti was offered tenure at the hospital where he first started, the University of Parma Hospital. But with most of his time devoted to caring for patients, a yearning for a return to the lab began to bloom.

“Leaving a tenure position then was probably almost unheard of,” said Bertoletti. “But I knew I could not be a classical clinician,” he added, a fact that his then-girlfriend, now wife, understood and supported as well.

So he accepted a full-time research position with the Medical Research Council Unit in London but with a twist—he would be working in Africa, based in Banjul, the capital of Gambia, to set up a T-cell analysis facility for HIV research.

The time spent in Africa proved fruitful for Bertoletti, who met many fellow researchers, including Andrew McMichael from the University of Oxford, whose team had just developed a type of molecule called HLA class I tetramers that could bind to specific T cells in the blood.

Immediately, Bertoletti saw the opportunity to harness this innovation for Hepatitis B research.

His visionary approach won him the support of McMicheal’s team at Oxford which offered him a project to produce new reagents to quantify Hepatitis B virus (HBV) specific cytotoxic T cells.

By coupling McMichael’s newly developed molecule with short sequences specific to T cells that could then be detected with fluorescence, Bertoletti and his collaborators, including Maini, succeeded in using this new tool to count the exact number of T cells in samples.

To this day, that moment is still etched in his mind.

“We were putting the reagents to see whether it was lighting up, and I still remember, that it was perfect. It was one of the best days of my life,” beamed Bertoletti.

Bertoletti explaining the science behind one of his memorable moments in research // Credit: Norfaezah Binte Abdullah, Duke-NUS

“Before we were doing only indirect experiments to look at whether there were T cells. With the tetramers, we could understand immediately how many there are and what they’re doing. It was really a big jump,” he remarked.

From there, he would go on to make other discoveries that cemented the important role which cytotoxic T cells play in suppressing HBV infections.

Going to where it matters most

When the opportunity to move to Singapore arose, Bertoletti’s interest was stirred. “My passion has always been on Hepatitis B, which is much more present in Asia,” he said. “So that’s why I decided to come.”

The prospect of enjoying sunlight all year round also appealed. “So I asked my wife, Elisa: ‘Shall we go? Shall we try?’” he recalled.

After a resounding “yes”, the couple and their son, Matteo, relocated to Singapore in 2006, where Bertoletti set up his lab first at the Singapore Institute for Clinical Sciences at A*STAR.

In 2007, the family welcomed their second son, Luca before Bertoletti moved to Duke-NUS in 2013 after winning his first STaR award.

With just three people in the lab at the beginning, including Bertoletti’s then-honours student, Anthony Tan, Bertoletti remained actively involved in experiments. “He would try and spread the workload, and also teach me at times,” recalled Tan, now an assistant professor with the Emerging Infectious Diseases Programme at Duke-NUS and still a steadfast member of the Bertoletti lab.

The lab has since flourished into a bigger team of more than 10 researchers. Many of its members, including Tan and Nina Le Bert have also launched independent research careers.

The Bertoletti lab poses for a group photo at the iconic Duke-NUS wall // Credit: Courtesy of Antonio Bertoletti

But it wasn’t just the team’s strength in numbers that grew but also the impact of their research.

Together, the team has made several breakthroughs in the realm of T-cell research in viral infections, while exploring these cells’ therapeutic applications. One of their promising innovations involves using a patient’s T cells and modifying them in the lab to recognise and treat chronic HBV infections and recurring liver cancer caused by the virus.

The therapy is now in the second phase of clinical trials, an undertaking that is spearheaded by Lion TCR, a startup founded by Bertoletti.

“What we are doing is really to reconstitute the immune system to fight cancer,” explained Bertoletti.

His translational approach to research continues to inspire Tan: “I think that has been the mantra of the laboratory from the beginning.”

Just like when the COVID pandemic broke in 2020 and the lab rapidly pivoted from studying T cells in HBV infections to study the role of T cells in fighting SARS-CoV-2. “We got this Nature paper that remains one of the most cited papers in the world—that was very memorable,” said Bertoletti.

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While Bertoletti appears to be a quintessential researcher, his medical training still subtly influences his work.

Observed Ooi: “Antonio agonised over the safety aspects of T-cell therapy and has chosen a more conservative approach. Preliminary results from patients who have received the therapy Antonio’s lab has developed have been promising and exciting, enabling treatment with minimised risk.”

With many accomplishments under his belt, Bertoletti is far from done as he readies himself to scale the next peak to expand the therapeutic potential of T cells to fight cancer and other viral diseases.

“I think I’m just really lucky to do a job that I like. I don’t want to end work, because again—I still like it.

“To me, it’s still clinical work, but only in a different light because what we are doing now is mainly to understand how we can improve the treatment. So to be honest, I still feel like I’m very much in medicine.”

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Before we ended the conversation, Bertoletti gave another fascinating explanation about how the Hepatitis B virus had evolved to remain in the human population:

“Some similar viruses have also been found in primitive birds when dinosaurs were still alive…so it really has evolved even before the human species.”

Intrigued, I just had to google and of course, he was spot on! (For interested readers, click here to read more.)