“The most important applications of protein sequencing will be the ones we have no idea about today”

Giovanni Maglia’s pioneering work in nanopore-based sequencing led him to overcome ‘impossible’ scientific problems and found Portal Biotech. As one of the keynote speakers at the 6th edition of ‘Revolutionizing Next-Gen Sequencing’, he sat down with Sarah Geurs, Technology Expert at the VIB Tech Watch Core, to share his journey through academia, research, and entrepreneurship.

Maglia originally started his academic journey in Bologna, Italy, where he studied pharmaceutical chemistry. As part of his master’s degree, he spent time at the University of Pennsylvania, an experience that would open up a new world of possibilities.

Maglia: “Not only did I immerse myself in an English-speaking research environment for the first time, but I also saw how science was done at a top-tier institution. So after graduating, I went looking for a research-intensive environment and moved to the UK for my PhD at the University of Birmingham, where I focused on enzymology and biophysics.”

He spent some time in a biophysics group in Leuven, Belgium, before heading back to the UK for a postdoc at Oxford. “That was where I first worked with nanopores, combining my passions for proteins, enzymes, and single-molecule research. Working with Hagen Bayley, a pioneer in the field, was a defining experience for me.”

“When I first started working on nanopores, sequencing DNA this way was considered impossible. People would ask, ‘What’s your project?’ and when I told them, they’d laugh and say, ‘You know that’s impossible, right?’ Honestly, I thought so too. But I started because I thought that’s what academic research should be about: to do something which can have a big impact, but is very hard to do, and to find out if it's possible or not.”

After four and a half years at Oxford, Maglia was ready for the next step. “I secured an ERC grant to start my own group and returned to Leuven, now with two children and, luckily, still the same wife!”

Four years later, he moved to the University of Groningen in the Netherlands. Fast-forward a few years (during which he is appointed a full professor, obtains another ERC grant, and obtains plenty of other competitive funds), and we land in 2021, when Maglia founded Portal Biotech to commercialize his group’s proprietary nanopore technology, securing $10 million in seed investment later that year.

Pursuing the impossible

Maglia’s success story is one of pursuing high-risk, high-gain projects. Back in the day, he shares, plenty of colleagues thought he was wasting his time with nanopore sequencing.

“When I first started working on nanopores, sequencing DNA this way was considered impossible. People would ask, ‘What’s your project?’ and when I told them, they’d laugh and say, ‘You know that’s impossible, right?’ Honestly, I thought so too. But I started because I thought that’s what academic research should be about: to do something which can have a big impact, but is very hard to do, and to find out if it's possible or not.”

As it turned out, nanopore-based DNA sequencing was possible, and it led to the rise of Oxford Nanopore Technologies. The experience taught Maglia not just about the underlying science but also about intellectual property and research valorization. He saw firsthand how fundamental research could evolve into real-world applications. This would become a common theme throughout his career.

Protein sensing

“When I moved to Leuven, I wanted to do blue sky research through my ERC-funded project, more specifically, combining nanopores with enzymes to study enzyme behavior at single-molecule level. As the work progressed and the project began to succeed, we made an unexpected discovery: enzymes could also be used to identify other molecules, such as their substrates. This led us to realize that we effectively had a transducer: something that could convert the concentration of a molecule into an electrical signal. That’s exactly what nanopores do: they transduce biological information into electrical information, which is crucial if you want to build real-world sensing devices.”

In the back of your mind, you are a bit scared to figure it out. What if it doesn’t work?

Maglia filed a patent through KU Leuven and licensed it to Oxford Nanopore Technologies. “At the time, I thought this was a great move, as it secured funding for my research. But just six months later, when investors approached me about starting a company, I learned a hard lesson: once your IP is licensed out, launching your own startup becomes much harder.”

An alternative solution for pore-based proteomics

Meanwhile, the field, including Maglia, had also started dreaming of protein sequencing with nanopores. Could it be done?

“For a long time, I thought it was simply not possible because of fundamental physical limits. But gradually, together with my students and postdocs, our research over the years suggested that there were ways around those limitations.”

One of the main issues with nanopore protein sequencing is threading a polypeptide through the pore. You can’t use an electric field like you would with DNA sequencing because, unlike DNA, proteins are not uniformly charged. 

Maglia and his team, however, started exploring a different approach: instead of using direct electrical forces, they worked with electroosmotic flow. This force had been known for a long time, but was considered too weak to be useful. 

“At that time, we were writing grants about protein sequencing and the real question was: is this electroosmotic force strong enough to transfer proteins? In the back of your mind, you are a bit scared to figure it out. What if it doesn’t work? My career might take a different turn.”

Maglia decided, like he did before when working on DNA sequencing, there is only one way to know for sure. His team went all in and, through careful engineering, succeeded in optimizing their approach until they had a force strong enough to pull proteins through a nanopore.

“That was our eureka moment. Suddenly, what was once ‘impossible’ became ‘likely’.”

Right now, this breakthrough enables nanopores to be used to identify known proteins and their characteristics. “Think of it like language,” says Maglia. “There are 150,000 words in English. You don’t need to be able to spell every word to be able to speak the language. Similarly, you don’t need to sequence the protein when you can recognize proteins based on characteristic patterns. Following the language analogy, we are now learning to speak and later how to write.”

“I see protein sequencing at the end of a journey—eventually, that’s where you want to finish. But there are many steps along the way that are interesting in their own right because they open doors to a variety of applications that rely on protein identification and detection of ​ post-translational modifications and mutations.”

“There are going to be many different applications, but the most important will be the ones we don’t know yet.”

De novo protein sequencing

To enable true de novo sequencing—determining an unknown protein’s exact amino acid sequence—the field still has some way to go. “Our discovery got us really excited about the possibility of protein sequencing, but there are many aspects that will need to be worked out,” Maglia says. 

The signal generated by a protein passing through a nanopore is influenced by multiple amino acids at once. To decode this, we need advanced machine learning models and continued engineering of the nanopore system.

How long will it take for us to get there? Nobody knows, but according to Maglia, it will be sooner than people think. “Progress isn’t linear. A few years ago, protein sequencing was considered ‘impossible’. A year ago, it became ‘likely’. Now, it’s very likely. We’re moving fast.”

While the scientific and pharmaceutical implications of protein sequencing are already significant, Maglia believes the true impact may lie in the discoveries we haven’t yet imagined. “There are going to be many different applications,” he says, “but the most important will be the ones we don’t know yet.”

Much like DNA sequencing revolutionized biology and medicine, uncovering layers of information we’re still working to fully understand; next-gen proteomics is poised to do the same. “We're going to open a window into a system we had no idea about,” Maglia explains. “When you create a new technology, you don’t just find answers to existing problems, but you open the door to entirely new questions.”

The winding road to valorization

While Maglia initially wanted to develop wearable biosensors, that’s not the focus of Portal Biotech today. “My original idea was a device that could track your health in real-time, detecting early signs of disease before symptoms appear. If you get this right, it could be a transformative technology, but securing funding for that idea proved to be very hard. Investors were hesitant because human diagnostics require massive financial investments and regulatory approvals.”

At the same time, one of Maglia’s colleagues in Delft was working on a startup focused on protein sequencing. “Since I had filed patents related to nanopore-based protein analysis, he invited me to join. That got me thinking more seriously about sequencing.”

Still, Maglia didn’t abandon his plan for a health-based biosensor. He reconnected with Andrew Heron, a former colleague from Oxford (and now CEO of Portal Biotech) who shared his vision for nanopores applications in healthcare. The two started seeking funding together. Interestingly, talks with investors eventually convinced them both to shift their focus. 

Surround yourself with the right people. Alone, you're not going to do anything

“They told us, ‘Forget wearable biosensors, it’s too slow and expensive. Focus on protein sequencing instead. The research market is much easier to enter than human diagnostics, and it requires far less investment to bring a product to market.’ We were in doubt, however. Scientifically speaking, molecular sensors were a much more advanced concept. How we would make a product for protein sequencing was still quite fuzzy to us. But we were convinced that we should at least give it a try.”

Portal Biotech pivoted toward protein sequencing, raised pre-seed funding, and is now finishing its seed round. “Of course, building a company is exponentially harder than I expected, but we are making it happen!”

Solid science as foundation

For Maglia, science is the foundation of everything. Together with his team, he continues pushing the research forward—because, of course, turning protein sequencing into a practical reality still requires ongoing work in both academia and industry.

A deep biophysical understanding of the system is essential, and it’s what makes the team of founders uniquely positioned to succeed. “There aren’t many people who truly understand this technology at the level my co-founder and I do,” Maglia explains. “That knowledge allows us to protect every aspect of it: from the nanopores themselves to the complex, interdependent components that make the whole system function.”

When asked if this advice also applies to aspiring entrepreneurs, Maglia is clear: “You need to start with solid science. Understand your field deeply and be confident in your unique expertise. Then, find your vision—something compelling enough to inspire others.”

“Finally,” he says, “surround yourself with the right people. Alone, you're not going to do anything. Find mentors, collaborators, and business partners who complement your skills. 

“In the end, there are many paths, and every journey is different. But I am convinced that if you really want something, you’ll find a way to get it.” The real challenge comes afterwards, he says. “Once you’ve started, you need to make it work.”

Interested in becoming a part of the impactful work happening at VIB? Check out the available positions here.