Human Practices

On the 27th of August we met online with Riccardo Zanolli, one of Sammy Basso’s closest friends. Riccardo had known Sammy since they were very young: they went to high school together and built a deep friendship inside and outside the classroom. After graduation, they took a life-changing trip along Route 66, and later shared the experience of running several marathons and races side by side, overcoming physical differences and difficulties.
During our conversation, we had the opportunity to ask Riccardo all the questions we had about Hutchinson Gilford Progeria Syndrome. First we talked about Sammy as a person. He was an intellectual, a scientist, and deeply spiritual. Riccardo told us that one of the words that best described him was “aware” - aware of his condition, of his strengths and of his ability to change the world through science, faith and outreach.
Within the science community, Sammy embodied a unique dual role: both researcher and patient of his disease. His expertise was recognized by some of the most renowned scientists worldwide. Through Riccardo's words, we gained a better understanding of what it truly means to live with Progeria, and how research, and the hope of a cure, can profoundly impact the lives of those affected. Sammy himself was an active researcher, he often said he knew that his efforts would benefit future patients, even if not himself.

Riccardo showed us the strength and joy of a profound friendship, built on mutual respect and admiration. Through his eyes, we discovered an extraordinary person in all his facets - someone who faced and accepted his illness with remarkable courage and resilience.

Focusing on the goals of our project, we gathered precious information about Lornafarnib, the farnesyltransferase inhibitor used to currently extend the lifespan of patients affected by the disease. For example, Riccardo told us about the side effects Sammy experienced while undergoing the treatment, such as deep insomnia. In spite of this, he often managed to rest a few hours each night, spending much of the remaining time studying, creating, writing and expressing himself.

On the 1st of September 2025 we had the opportunity to meet in person the Associazione Italiana Progeria Sammy Basso APS (AIProSaB). AIProSaB was founded in 2005 with the aim of helping Progeria research, both from the scientific aspect and the human side. In particular, they raise charity funds to sustain research and free communication between researchers. Also, they support families with Progeria in order to give them the ability to handle the disease in the best way possible. The association agreed to have a meeting with us and answer our questions about Sammy, the disease and our project.

We met Amerigo and Laura, Sammy’s parents and heads of the association, and several members of AIProSaB management. We got to know each other, sharing experiences and projects between the iGEM group and the association.
We realized that AIProSaB had a lot to teach us, in particular about the approach we should keep in our project. They taught us to always keep in mind that our work is beneficial to actual patients. Additionally, they shared with us the way they operate to benefit those in need, which is useful to us as future researchers.

Some of the most significant aspects that we took home, and then to the Jamboree, are the Sammy and the association modus operandi. They work, they fight to benefit those who will come after Sammy, after them. Sammy’s parents shared with us that he knew his fight would not help himself, but he did it to help future people with Progeria. In this concept, Sammy embodied the role of a scientist: in iGEM most of our projects do not benefit their author directly, but are a base to build together a better future.

Also, the association works every day to improve communication between researchers in order to cooperate and find a cure. The association founded the Network Italiano Laminopatie (“Italian laminopathy network”), a space for scientists to share their projects, collaborate and communicate. In the same way, iGEM is a place to share ideas and create collaborations between teams.
Finally they gave us hints to identify the best way to communicate the disease during the Jamboree and our presentations. At the Jamboree we will meet hundreds of future scientists and we want to be able to communicate the disease properly. We asked AIProSaB how to express the difficulties that the disease brings. They gave us precious suggestions, such as avoiding sensationalistic expressions and being direct.

In early September 2025, we had the opportunity to meet Niccolò Gherardi, a young man from Milan born in 2004, who lives with the same condition we are studying — Progeria. We got in touch with him through the AIProSaB association, which also allowed us to have Mrs. Laura Basso, Sammy’s mother, join the call. With Niccolò, we had time to introduce ourselves, share our stories, and then ask him some questions about Progeria in general, before going deeper into our project.

He told us that, for him, living with Progeria was never something to be “discovered”: he was simply born with it, just like someone born with a visible characteristic, and gradually learned to understand the less evident aspects of the condition. Growing up different from others gave him a strong drive for motivation and self-determination, without preventing him from enjoying life. According to him, one of the hardest aspects of the disease is being perceived by strangers as “different,” when in reality the difference is merely aesthetic. However, once people truly get to know him, they realize that his diversity is only external. He always tries to show his true self, with maturity and authenticity, believing that the best way to overcome prejudice is simply to be oneself.

From a more scientific perspective, Niccolò explained that, unlike Sammy, he did not experience major side effects from taking the drug Lonafarnib. Regarding an aspect particularly relevant to our project, we asked him which feature of Progeria he would most like to see improved by a potential therapy. He replied that the most important aspect would undoubtedly be the heart, since it is vital and indispensable. At the same time, he admitted that, on a more personal level, he would also like to alleviate bone-related problems, even if one can live with pain or hip dislocations, but not without a healthy heart. This insight is especially meaningful for us, as it informs the future DBTL cycle dedicated to the viral delivery phase. Based on his perspective, it will be worth focusing our therapeutic delivery strategies primarily on cardiac and skeletal tissues.

At the end of September, we had the opportunity to visit Niccolò in Milan. We had the chance to meet in person a 20-year-old like us — someone with different passions, such as illustration, but ultimately a past not so different from ours. We also took the opportunity to film some minutes of the 15-minutes long video, as we wanted him to speak in first person during the presentation of our project, giving him the space to share whatever message he wished with the young scientific community of iGEM. We discovered a very relaxed and genuinely kind person, full of stories and insights to share.

After finding several scientific papers on Progeria and related molecular mechanisms authored by Dr. Giovanna Lattanzi, we decided to contact her directly to discuss our project. Dr. Lattanzi is a senior researcher at the CNR Institute of Molecular Genetics (Bologna, Italy), a leading expert in laminopathies, and the head of the Laminopathies and Muscle Biobank. Her extensive experience in the study of nuclear envelope diseases and in the molecular mechanisms underlying Hutchinson–Gilford Progeria Syndrome (HGPS) made her an invaluable advisor for our work.

During the meeting, we presented the rationale and design of our project, addressing several questions about its experimental feasibility and about specific molecular aspects of progerin biology.
Dr. Lattanzi pointed out that using a progerin–mEGFP fusion protein could lead to mislocalization of progerin, as the mEGFP tag may interfere with its proper nuclear anchoring. Based on her suggestion, we decided to maintain the mEGFP–progerin construct only for fluorescence-based expression validation, while relying on progerin–SpyTag and mEGFP–SpyCatcher constructs for localization assays.

This exchange was crucial in refining our experimental approach and ensuring that our cellular models more faithfully represent the molecular behavior of progerin in patient cells.

The human perspective shaped our motivation; the scientific guidance shaped our method.
To strengthen the technical side of our project, we met with professors and researchers whose expertise helped us refine our computational pipeline and validate our experimental design.

When analyzing the AlphaFold predictions, we evaluated the Predicted Alignment Error (PAE) plots, which indicate confidence levels across amino acids. The majority of the protein showed well-defined structures with strong cross-correlation, reflecting high prediction accuracy. In sharp contrast, the C-terminal region exhibited very low confidence, suggesting that it is intrinsically disordered. AlphaFold was therefore unable to assign a stable structure to this region.

At this stage, Professor Roberto Steiner provided us with invaluable advice and clear guidance on how to proceed. He not only helped us interpret the PAE output but also put us in contact with a researcher from DeepMind. Based on their suggestions, we focused specifically on the C-terminal part of the protein and ran isolated predictions of this fragment, testing different lengths. This approach enabled AlphaFold3 to better focus on the region and generate multiple plausible conformations of the C-terminus. Interestingly, when predicted in isolation, the confidence values increased—though remaining moderate—yielding more coherent conformations. However, since AlphaFold is context-dependent, the predictions are strongly influenced by the surrounding environment. For this reason, the isolated fragments should be regarded as snapshots of possible C-terminal foldings, best interpreted as a library of likely structures.

This insight allowed us to refine and strengthen our computational pipeline, ultimately broadening the pool of possible interactors to be designed against progerin.

During the development of our bioinformatic pipeline and throughout the data analysis phase, we had the pleasure of collaborating with Professor Alexander Miguel Monzon. His contribution was invaluable in conceptualizing the initial stages of structural modeling, which proved particularly challenging due to the presence of an intrinsically disordered region (IDR). Together, we confirmed the absence of favored secondary structures and evaluated the possibility of modeling quaternary assemblies in the form of progerin–progerin dimers, an approach that was later discarded.

Moreover, Professor Miguel guided us in the final stage of interaction analysis by recommending the use of RING (Residue Interaction Network Generation), which provided a residue-level interaction map as output.

Finally, he drew our attention to two recent publications from David Baker’s laboratory on the design of interactors targeting IDRs, which further reinforced the validity of our pipeline.