Synthetic biology and immunology

Program aims to advance the synthetic biology with focus on the regulation of mammalian cells and design of modular proteins by the construction of new types of biological systems that will endow them new interesting properties. Additionally we will continue researching the molecular mechanisms of immune response with emphasis on signaling and plan to integrate those discoveries with the developed tools of synthetic biology towards therapeutic applications, predominantly cancer immunotherapy and gene therapy. In the next funding period the program will focus on three main themes: 1. Development of tools of synthetic biology for mammalian cells, 2. Molecular immunology with therapeutic translation and 3. Design and application of new modular protein assemblies, primarily based on the designed coiled-coil modules. The program combines concepts and tools across all three themes, in the areas where we have a proven track record such as in innate immunity (Hafner-Bratkovič, Nat.Commun. 2019; Manček-Keber et al., Blood 2019; Ha et al., PNAS 2019), designed modular proteins (Ljubetič et al., Nat.Biotechnol. 2017; Lapenta et al., Nat.Commun. 2021; Aupič et al., Nat. Commun. 2021) and design of information processing in mammalian cells (Fink et al., Nat.Chem.Biol. 2020; Lebar et al., Nat.Chem.Biol. 2019, 2020). Specifically our goals are to design a new type of allosteric regulation of protein function that could be applicable to a wide range of proteins, design new type of regulators based on human proteins that can be regulated by the approved drugs and endogenous compounds and therefore better suited to therapeutic applications, introduce improvements of the CRISPR-based genome editing tools for gene therapy, further elucidate the molecular mechanisms of innate immune signaling via MyD88 and NLRP3 and their role in disease, design reversible regulation of cancer immunotherapy via chimeric antigen receptors, explore additional potentials of modular protein design beyond the current ERC Advanced grant run by the leader of the program, such as the ability to internalize into mammalian cells, design of artificial protein assemblies based on domain swapping and design of proteins with defined shapes aimed to be used as labels for the cryoelectron microscopy. This ambitious plan will be performed by a group of dedicated researchers using a wide range of techniques and instrumentation available in house, from structural biology using cryoelectron microscopy to therapeutic cells tested in the animal models and in collaboration with researchers and clinicians from Slovenia and abroad. We expect that the proposed innovative concepts will enrich our understanding of biological and biomimetic systems, and expand the methodology applicable to research as well as for translation into therapy.

The proposed research program will respond to important issues in the field of life sciences, with focus on medically important processes, designed biological and biomimetic systems. In addition, we aim to prepare new synthetic biology tools for bionanomaterials and cell engineering. This type of tools will be very useful to a wide range of researchers in the field of synthetic biology, as well as to the broader biotechnology and life sciences in general. Our results on modular protein folds, design of cellular logic in mammalian cells using modular DNA-binding proteins as well as in innate immunity have attracted significant attention in the last years with publications in prestigious journals and invitations to international conferences, which contribute to high impact. We expect that the results will be important for the advancement of science and for translation into primarily therapeutic and biotechnological applications. The proposed directions of research will contribute to shaping the cutting edge of synthetic biology as one of the propulsive directions in life sciences. Understanding of the activation mechanism of innate immunity receptors is one of the fundamental problems of immunology. The implementation of this knowledge in therapeutic applications is very important. Due to the wide-spread role of TLRs in sterile inflammatory processes the relevance of these studies ranges from the fields of autoimmunity, cancer, and neuropathic pain to many other diseases. Increased focus on translation and collaboration with clinicians in the proposed program is aimed to develop therapeutic improvements. The innovative combination of synthetic biology and immunology has in our opinion a great potential to become a showcase of the relevance of synthetic biology for health.

Based on the high international recognition of the scientific achievements and by providing training to highly qualified personnel, the research program Synthetic biology and immunology holds a substantial potential impact for the society. Synthetic biology is one of the technologies where the beneficial principles of biological systems, such as precise structuring at nanoscale, evolution, self-repair, self-assembly, self-replication, high energy efficiency and efficiency of recycling. Our program is an important player in human resource development. Pharmaceutical and biotech industry have been continuously expressing a strong interest for employing our researchers, with more than 15 researchers recruited just to one pharmaceutical company, and several employed by the high tech companies abroad. Tens of students that obtained their training through iGEM project continue their research career in other program groups as well as at top universities abroad. These students represent a bridge between the Slovenian and foreign science and can translate their experience to Slovenia after completion of their training abroad. Members of our program group contributed significantly to the promotion of science to the wider audience through their engagement in science communication. Through those activities we will continue to inspire young people to study science and technology and try to increase the public support for the investments in science. Program is expected to generate intellectual property rights that will be protected by patent applications and could be used to commercially exploit these results, either through licensing or through the formation of a spinout company.