Complement system

Dogma-breaking research

Focusing on patients

People

Following a blood line

Fascinated by science and medicine since his childhood days, Antonio Risitano was pulled towards working as a physician-scientist early on in his professional career. While the double role at bench and bedside was not without its challenges, the trained hematologist feels no regrets about choosing this thorny path, as his efforts have helped pave the way for a new treatment for a rare blood disorder.

Text by Goran Mijuk, photos by Adriano A. Biondo

Antonio Risitano with his colleagues in the clinical lab.

Table of contents

Complement system

Dogma-breaking research

Focusing on patients

Published on 23/10/2023

Shaken many times throughout its history by wartime destruction, political revolutions and the toxic spews from nearby Vesuvius, the City of Avellino, an hour’s ride from Naples, has risen many times from its ashes to reemerge as a more beautiful version of itself.

Last time calamity struck its 60 000 inhabitants was in 1980, when an earthquake destroyed a large part of Avellino, only to unleash a building frenzy and power an economic boom that has continued to this day.

Like a symbol of this cycle of destruction and rebirth shines the San Giuseppe Moscati hospital, built triumphantly on a hilltop that frees the view to the undulating landscape of Southern Italy’s Campagna region with its majestic chestnut- and hazelnut-covered mountain ranges.

The large hospital – named after the first scientist-saint who was born in the region and known for his deep care for patients – is where we finally meet Antonio Risitano, whom we had been chasing for the last few months.

As one of the few physician-scientists in Italy, Risitano is not only busy as a clinician at the San Giuseppe Moscati, where he runs a lab at the hospital’s hematology department. Despite his natural restraint and shyness, he is a sought-after speaker with a busy international travel schedule.

Early inspiration

So, when we finally shake hands, we are not only glad to talk to him in person but spend the morning to tour his lab and clinic ward, where he also takes us through a time tunnel that stretches back nearly half a century, along the long and winding road of his scientific and medical journey.

“It was my father who really inspired me for science and medicine,” Risitano reveals, when we enter his clinic office with its paper-plastered table and walls full of science posters and photos of the people who shaped him. “He was also a hematologist like I am today.”

“So, at the age of just six or seven, I was already starting to use the microscope and studied cells, in a very playful manner, of course. It triggered my love for the sciences: biology, chemistry, mathematics,” Risitano recalls as he shows us his father’s portrait.

Next to this, another image hangs prominently on the wall, showing the face of Bruno Rotoli, his teacher and colleague when he was already well advanced in his scientific and medical career. “Bruno was my mentor when I was working in Naples and deepened my interest in the area of blood disorders.”

It was also Rotoli who nurtured Risitano’s dual fascination for the lab and the clinic. “I was very lucky because, early on in my career, Bruno suggested that I spend time at the National Institutes of Health in Bethesda, where I spent three years doing basic science and continued working in the clinic as a doctor,” Risitano says.

The years at Bethesda were game-changing for Risitano as he concluded that this is what he aspired to do during the rest of his career. “At the NIH, I realized that working like this was my goal in life. I wanted to be a physician-scientist, spending time both in research and in the clinic.”

However, his wish ran into resistance in Italy. “Physician-scientist is a role that is more common in the United States, but not in Europe, and even less so in Italy. But when I came back to Italy, I stayed on this path, even though it was not always easy.”

While physician-scientists may be more common in the United States, their number is still relatively low. It is estimated that only around 2 percent of all doctors in the United States are also doing research in the lab. In Europe, the number is much lower, which also means that work aspects such as organization and funding are more challenging.

Complement system

One of the key research areas Risitano was focusing on as a hematologist was the complement system, a part of the immune system which is sometimes described as a first line of defense.

The complexity of this system is mind-numbing: It consists of several proteins that circulate in the blood and, when activated by microbes or damaged cells, trigger a cascade of reactions that leads to the cleavage of other proteins and the formation of protein complexes.

In healthy people, the cascade results in the destruction of microbes and the recruitment and activation of phagocytes – immune cells that engulf and destroy foreign and damaged material. For people in whom the cascade is dysregulated, it can lead to diseases that can affect the kidneys or blood cells, for example.

When Risitano started research in this field around the turn of the millennium, medical treatments available for patients suffering from complement-related disorders were limited. But he and his mentor Bruno Rotoli embarked on their own research.

“It was difficult from the start. But, hey, you always have a dream. So we said, ‘Okay, let's do it. Maybe we will have a chance of developing new agents,’” Risitano says, recalling the time he embarked on the collaboration with Rotoli.

Chance meeting

While Risitano and Rotoli continued their work around the millennium, Novartis and other pharmaceutical companies were also trying to tackle the complement system by interfering in the complex cleavage cascade.

The first compounds to be developed showed efficacy and were hailed as a big breakthrough. But Risitano and Rotoli saw the potential for the development of more potent medicines by interfering earlier in the cleavage cascade.

“We understood the complement system well and hypothesized that, by interfering earlier in the cascade, we could create better outcomes for patients,” Risitano says.

While their strategic route seemed to make sense, managing their lab work with their clinical duties was not always easy. “From an organizational point of view, as well as regarding the structural support, our task was challenging. But we persisted and were able to make progress,” Risitano remembers.

But before they could showcase the first results from their research, Rotoli died from cancer in 2009. “In the last few months of Bruno’s life, I was sharing the preliminary research data with him,” Risitano says. “I was very grateful for that, also because it was one of the elements that kept him looking ahead despite his disease.”

Risitano continued to work on the project after his mentor’s death, experiencing the ups and downs of his unique position as a physician-scientist, which made him sometimes feel isolated. “We made further progress over these years even as we had many challenges to overcome,” he says.

However, the tide turned during a hematology meeting in 2015, when Risitano ran into Anna Schubart, a scientist from the Novartis Institutes for BioMedical Research (NIBR), who was working on a series of complement inhibitors. The two connected immediately since both found what they had been looking for. It was a match made in heaven.

Schubart had been designing a series of assays to prove the efficacy of a complement inhibitor Novartis had been working on. While she had made progress in her efforts, what she lacked were patient cells. This was exactly what Risitano had to offer. For his part, he was on the lookout for a complement inhibitor that interfered early in the complex cascade. This was Schubart’s contribution.

The importance of mentors.

Dogma-breaking research

“The reigning dogma at the time was that, if you interfere with the complement system, you could create toxic reactions,” Risitano explains. “Hence the idea that, if you interfere at all, it would be better to do this late in the cascade. We were convinced otherwise.”

Risitano’s years-long in vitro studies at the University of Naples had shown him that an early interference in the complement cascade was possible. After meeting Schubart, he had the chance to prove his point in clinical trials – an opportunity he readily accepted, since it gave him the chance to put his hypothesis to the test.

For Risitano, the early results and the ensuing clinical studies were a major vindication, and not only regarding his dogma-breaking research. It was also a sort of absolution for his personal decision to pursue the career of a physician-scientist, who juggles the complexities between bench and bedside.

Looking back, Risitano also says that, despite the challenges he faced during this career, he would most likely do the same thing again, following a blood line that was started by his father. “I have this kind of passion, which is something that you can’t teach. Maybe sometimes you can translate from person to person. And I have to say, my father and my mentor are the key people who motivated me to do this job, even if it meant a lot of hardship at times.”

The patient ward in Avellino.

Focusing on patients

Another key driver to continue his research was his innate care for patients. “I still remember a patient we treated with one of the first complement-inhibiting compounds. She only benefitted from a minimal effect and was crying, asking why the therapy didn’t work with her.”

The encounter, which happened many years ago, was an extra motivation for Risitano. “Of course, it took us many years to get where we are now. But finally, we have another treatment that may be useful not just for this woman, but for any other patient suffering from this condition,” he says.

While Risitano is mostly focused on his clinical work these days, he says that “the only way to better understand diseases in patients is keeping up with biology and basic science. Otherwise, as doctors, we would just use drugs, tablets, compounds with different colors.”

Besides a keen interest in science, Risitano argues that collaboration with industry players such as Novartis is also crucial when it comes to pushing the limits in helping patients. “Of course, collaboration is complex, bringing together the interests of industry, academia, regulators and patients. It can be exhausting at times, but it’s worthwhile, because it is always done in the interest of patients.”

As we walk through the clinic ward and see the patients waiting in long hallways before they get their appointment, Risitano’s words hammer home the message with powerful effect.

Many of the waiting patients had traveled from remote villages in the Campagna region to get their appointment and have a chance to talk to him or his colleagues. It is almost as busy as in a train station.

Later, Risitano also escorts us to a special ward, where some of the sicker patients lie stretched on their beds. Given their poor health and risk of infection, they are shielded off like in a prison cell. Their only contact with the outside world is through a glass pane and a telephone line. Their hope lies in the work of people like Risitano, who is untiring in his efforts to help them.

Every now and then, we also see a statue of the Virgin Mary, adorned with flowers, beads and postcards placed there by patients and their relatives, seeking otherworldly assistance. In Avellino, such heavenly presence may be felt in the passion of doctors such as Antonio Risitano.

It might be a similar desire that also inspired the man that lent his name to the hospital, Giuseppe Moscati, who, as the doctor of the poor, never gave up on his patients, much like Antonio Risitano.

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