“The challenge is to bring these masked mini-proteins to real-world clinical applications"

Marta Gargallo Garasa, a PhD student at the IQS Bioengineering Department, has obtained a grant from the Ramón Areces Foundation to carry out her doctoral thesis in the field of biotherapies – Life and Material Sciences – Biomedicine. The Ramón Areces Foundation collaborates in the training of people starting their careers as scientific researchers through highly competitive calls, funding contracts to carry out doctoral theses in doctoral programs at Spanish universities.

Marta’s thesis, directed by Dr. Benjamí Oller Salvia within the ChemSynBio research group at IQS, focuses on the development of conditionally-active therapeutic miniprotein binders for the treatment of glioblastoma. This thesis falls within the group’s protein research line, aimed at designing therapeutic tools capable of acting selectively on tumor cells. The ChemSynBio group combines biological and synthetic chemistry tools to develop precision biotherapies based on proteins and peptides.

We spoke with Marta Gargallo about her incorporation into the IQS group, her research, and what obtaining this prestigious grant has meant

Marta, what has been your career path leading up to IQS?

I am from Girona and I studied Biotechnology at the University of Girona, a discipline that particularly attracted me due to its multidisciplinary nature: it allows working in the entire drug development process, from the most basic research to industrial scaling and its final application.

When I finished my degree, I went to the Netherlands to do a master’s in Molecular Medicine at the University of Rotterdam. There, I participated in various research projects focused on understanding the molecular mechanisms of certain diseases. The goal was not to apply the knowledge directly, but to decipher what happens at the cellular and molecular level to generate new foundations that could serve as a starting point for future applications.

When I finished my master’s, I started working in the pharmaceutical industry, and the experience was very positive. However, I realized that I wanted to go beyond executing experiments, and also participate in the design and conceptualization of new projects. This led me to decide to do a PhD, in which I could not only deepen my scientific knowledge but also develop key skills such as critical thinking, problem-solving, and project management.

So I started looking for research groups in the biotechnological field, especially in Barcelona, due to its strong activity and projection in scientific research. That’s how I met Dr. Benjamí Oller, who explained the projects they develop in the ChemSynBio group at IQS. His research interested me a lot and ended up encouraging me to apply for a grant to do my PhD in his group. And here we are!

Which research line of the ChemSynBio group have you joined?

The research of this group is oriented towards the development of new strategies to treat glioblastoma, one of the most aggressive brain tumors, and can be divided into two main areas: on the one hand, there is a line focused on overcoming the blood-brain barrier, which includes the OBGate project, based on the design of orthogonal receptors to access the brain specifically and controllably. On the other hand, a protein engineering line that seeks to design highly selective therapeutic tools to treat the tumor once this barrier is overcome. This second line is the one I have joined.

My thesis project focuses on the development of proteins that are administered in an inactive form and are only activated in the tumor. Recently, the group has developed a method to “mask” proteins through computational design, in collaboration with Dr. David Baker (2024 Nobel Prize in Chemistry) from the University of Washington. In this research, recently published in the Journal of American Chemical Society, masks have been designed to inactivate miniproteins reversibly, managing to block the interaction with their target. The mask is connected to the miniprotein through a linker that can be cleaved by proteases present only in the tumor microenvironment, where the mask is removed and the protein’s activity is recovered. This allows controlling where and when the therapy acts and reducing side effects.

So far, the base tool has been developed – masking the proteins – and the challenge now is to take the concept to different therapeutic protein formats.

“Now we want to take the already developed masking tool to different therapeutic protein formats.”

What is the novelty you propose in your thesis?

My project seeks to take the idea of masked miniproteins towards therapeutic formats with high efficacy and the potential to reach the clinic. On the one hand, we want to generate conjugates in which the miniprotein is linked to a cytotoxic drug, since by itself it often does not have enough activity to eliminate the tumor. In addition, we incorporate transporter peptides that facilitate passage through the blood-brain barrier and allow reaching the brain. On the other hand, we also explore alternative formats that bind to various targets, allowing, for example, activating immune system cells to recognize tumor cells or degrade target proteins.

Overall, the goal is to develop new conditionally active therapeutic tools for glioblastoma, capable of reaching the brain and acting selectively on the most resistant tumor cells. The goal is to develop conditionally active therapeutic tools for glioblastoma and act selectively on the most resistant tumor cells.

“The objective is to develop conditionally active therapeutic tools for glioblastoma and selectively target the most resistant tumor cells.”

To carry out your thesis, you have obtained a grant from the Ramón Areces Foundation. What has it meant for you to get it?

I am very happy, having obtained one of these grants is a great opportunity for growth, both personally and as a researcher. It allows me to develop my research in good conditions and dedicate myself fully, with the time and resources necessary to learn and generate knowledge. I am very grateful to the Ramón Areces Foundation for having trusted me and the project.

“I am very grateful to the Ramón Areces Foundation for having trusted me and the project.”

You are at IQS since January of this year. What is your assessment so far?

I am doing very well, learning a lot every day and enjoying the environment! Although I just started, it is a pleasure to work with the whole team: it is a multidisciplinary and international group, with people who provide very diverse points of view and who are helping me grow both personally and scientifically. Furthermore, the ChemSynBio group, and IQS in general, is an environment with many resources that make it especially stimulating for research.

“IQS is an environment with many resources that make it especially stimulating for research”

What about the director’s opinion, Dr. Benjamí Oller? What does Marta’s incorporation mean for your group?

Marta’s incorporation has been very positive for the group. In these first months, she has proven to be an exceptional researcher, with great motivation, an excellent learning capacity, team spirit, and a high degree of autonomy. She also stands out for humility unusual in people with her talent; she is a great person who has integrated perfectly into the group.

“It is a pleasure to direct this thesis and I foresee that this is just the beginning of a very fruitful collaboration”

It is a pleasure to direct her thesis, and I foresee that this is just the beginning of a very fruitful collaboration, in which we hope to achieve important advances, both in the methodological field of activatable protein engineering, and in the contribution to the therapy of brain tumors.