Frederic and Joost remember exactly when and where their radical idea first emerged. It’s 2006, and the two young group leaders are discussing strategy in their shared office. It’s still early days in setting up their joint research lab at VIB, and TANGO—a computer algorithm they had been working on during their postdoc at EMBL—had only just been released to the world.  

“TANGO basically predicts which regions in protein sequences are likely to aggregate when unfolded,” explains Schymkowitz. “It came at a time when the whole field was fixated on the questions of specificity—why does one protein aggregate in disease x and another in disease y? —and toxicity— are the aggregates themselves the problem, or is it the loss of this one particular protein that is now all crumpled up?” 

TANGO provided a broad window on everything with the potential to aggregate. “The premise was quite simple: if all proteins could aggregate—given the right conditions—we could solve these burning questions,” says Rousseau. “We could take a protein with known function, cause it to aggregate and see what it would lead to.” 

“I remember Fré saying, ‘If we combine the right parts, we should be able to pull down any protein into an aggregate’,” says Schymkowitz—providing the seed for what would become Pept-in, the trade-mark technology platform exploited by VIB spin-off Aelin Therapeutics. 

A quick biochemistry 1.0.1 recap: proteins catalyze virtually all biological processes in our cells. They fold into a 3D structure during and after synthesis, but some unfavorable conditions or disruptions such as mutations can interfere with the folding process. Unfolded or misfolded proteins can aggregate, rendering them inactive and causing a debris problem in the cell, eventually leading to its demise.  

Aggregation-prone regions have been identified in almost all proteins, even those without a natural tendency to aggregate. Schymkowitz and Rousseau’s idea was to trigger protein aggregation by seeding the process with a synthetic peptide containing an aggregation-prone region matching one found on the target—any target—protein. In this way, they wanted to turn something problematic—protein aggregation—into a weapon against proteins and cells that we in fact want to destroy. 

Rousseau: “We’ve been trained to think like engineers: what we try to do is to build a (biological) machine from scratch. If it does what it’s supposed to do, this means you’ve understood its workings.” 

Dekeyser: “Joost and Fré’s proposal immediately captured our attention. The tech transfer team sees many inventions every year, but only about one or two are truly transformational, and this was clearly one of them. We were almost on the spot convinced that their breakthrough invention could be the start of a broad and deep technology platform with multiple applications. At least conceptually. Feasibility was another question, but if you are exposed to a new idea that has never been explored before, you cannot use feasibility as an exclusion criterion for brainstorming discussions and discovery research at the frontier of science. We wanted to see whether we could inspire the two bright young scientists.” 

Schymkowitz and Rousseau were a bit skeptical of these big leaps, to say the least. It seemed too easy to make bold claims about an idea that, at that point, still lacked any proof of principle. 

Rousseau: “Their ideas were really miles away from our comfort zone. We had never even conceived, let alone done any in vivo work! We were probably the last two people who really believed this could work.” 

But the duo was pleased the idea of targeted aggregation triggered excitement and were eager to give it a go—even if their own ambitions remained modest for the time being.  

“We were still rookies at the time,” remembers Schymkowitz. The two had started their co-led lab only three years earlier and were still very much in the stage of making a name for themselves. “With our major postdoc papers just published, we still had to scratch to find good students willing to take a bet on us for their PhD training.” 

All of a sudden Rousseau and Schymkowitz found themselves on a rollercoaster doing ultra-multidisciplinary research. “Rudy and Jan convinced us that if we really wanted to know if our idea of targeted protein aggregation is broadly applicable, we needed to try it in every system to our disposal.” 

Thanks to the interdisciplinary nature of VIB, partnerships were swiftly set up with people working in plants, in fungi, in bacteria, in zebrafish, in mammalian systems… “We were used to working with just peptides, and all of a sudden we were forced to work with high-level model systems—and a lot of them at once.”  

Rousseau: “In retrospect, our tech transfer adventure probably started too early in our professional development as scientists, and also too early in terms of the research results. The whole endeavor was at times hugely overwhelming and massively distracting.” 

"Take the massive opportunity that is VIB,” adds Schymkowitz. “Our institute brings so many fantastic people together, but at the early stage of your career, this can be a mixed blessing, as you are still shaping your own ideas. It can feel like a playroom with too many toys.” 

Pretty quickly, they started finding phenotypes in different model systems. The duo wondered, “Could this idea actually work?” 

Now the real work could start: would Schymkowitz and Rousseau be able to convince first of all themselves that the effects were specific and that targeted protein aggregation could indeed work as a kill-switch? 

Proving specificity in vitro is hard, but it’s even harder in vivo. After the encouraging first results, the tedious work of checking and re-checking was underway. Some model systems were quicker to deliver promising results than others. Doubts about the technology came and went as small successes and temporary setbacks rolled in. 

“Lots of people don’t realize that it easily takes six to seven years before you actually have solid proof of your concept working in vivo.” 

Beirnaert: “I was immediately triggered by how radically new this idea of targeted protein aggregation was. In the years prior, I had been closely involved in the development of the Ablynx nanobody platform and had only ever thought of protein aggregation as a nuisance. Something to avoid at all costs when you are trying to produce a batch of biologicals. Now here was a completely new platform, opening up an entirely novel target space for therapeutics as it could essentially disable any protein, irrespective of function, structural class, or sub-cellular localization and, contrary to small molecule drugs or biologicals, completely independent of the presence of an active site or epitope. If it worked, it would be a real game changer in so many disease fields.”

Schymkowitz: “Having someone in our corner who had gone through the steps of getting a new technology from the lab to phase II clinical studies before, who understands how much time things can take, and who could help keep perspective and focus, provided much-needed peace of mind for the two of us. Even if the climb ahead was still long and arduous, it definitely helped to have experienced people on board who were in it for the long haul.” 

Beirnaert: “We were able to support each other because there was mutual trust from the get-go: Joost and Fré were fully in charge of running the experiments, and they trusted me in my role as investor matchmaker and fundraiser.” 

“We did a lot of things the unconventional way, simply because we were total newbies,” says Rousseau. “Probably that has been our luck.” At the same time, taking a broad approach also meant the team had burned a lot of cash in the process. 

Schymkowitz: “Risk perception of venture capital is very different here compared to the US. If we had been working across the Atlantic, we probably wouldn’t have had to go quite all this way, but in Europe, investors require much more derisking.” 

Slowly but surely, the data and publications began to add up: “Our first publication found a home in the Journal of Molecular Biology. Next, our story on specific protein aggregation in plants came out. We talked for years with investors; everyone showed interest but held off in anticipation of (a lot) more data.” 

The key moment was the team’s 2016 Science paper De novo design of a biologically active amyloid. This was really an important turning point and a massive relief, according to both scientists.  

“The fact that this was such an incredibly collaborative paper was important, as was proof of principle in a hot field such as oncology,” says Beirnaert. “Things really started to crystallize from that moment on. Investors were already talking to each other, and after the publication in Science, everything came together.”  

Schymkowitz and Rousseau stress it is important for younger colleagues to realize that tech transfer and academic publications are more aligned than most think. “When you are building up IP, you may need to accept some publication delays. But in the end, an impactful publication that’s received well in the research community is also important in the world of investors. It gives credibility to your idea—however fantastic on its own.”  

Aelin’s dream came to a halt in June 2023. Despite having shown impressive scientific results in the past years, due to an increasingly difficult investor climate, the company failed to secure additional funding through a second round of capital raising. Consequently, it was forced to initiate the process of an orderly winddown.

“Aelin Therapeutics had made significant progress in identifying candidate treatments for bacterial infections and cancer. The company was even on the cusp of determining its first preclinical candidate drug,” explains now ex-CEO Els Beirnaert. “However, the limited funds posed a challenge to the continuation of our research and potential future (pre)clinical development. Investors became somewhat cautious due to the combination of innovative yet complex technology and the early stage of the company's development."

While the company faced liquidation, efforts are being made to explore the possibility of the further development and valorization of the Pept-in^TM technology, perhaps in other fields of application. The future remains uncertain, but the dedication and passion that drove the team are evident. Despite the challenges faced, Aelin Therapeutics remains a symbol of determination and innovation, with its visionary founding team and researchers exploring new horizons and promising to embark on new technology transfer adventures when given the opportunity.