BioSysteM Cluster of Excellence: rethinking biology

Enlarge

Life is factory work on the nanoscale: In every cell, tiny molecular machines are busy making proteins, transporting loads, relaying signals, and building structures. Connected via complex networks, these machines are precisely controlled and yet flexible enough to adapt to changing requirements. For a long time, this machinery of life was thought too complex to fully understand – never mind reconstruct.

But now a new era could be dawning: Our knowledge of the mechanisms of biological systems has made huge advances. New tools such as innovative sequencing techniques, DNA nanotechnology, and CRISPR/Cas allow researchers to investigate and modify these systems in targeted ways – and at all levels, from the individual molecule to the cell and to organisms. Moreover, protein design is on the rise thanks to new AI approaches. “All this brings us to a point where a biorevolution is a genuine possibility,” says Ralf Jungmann, Chair Professor for Molecular Physics of Life at LMU and leader of the Molecular Imaging and Bionanotechnology research group at the Max Planck Institute of Biochemistry in Martinsried.

Introducing “Engineering Biology”

Advancing this revolution is the goal of the new BioSysteM Cluster of Excellence. The research network is seeking to develop a new research direction called “Engineering Biology,” which not only imitates biological systems, but actually designs them – with a logic that is based on nature but surpasses its repertoire. “From individual molecules to cells through to macroscopic structures like organoids, our approach is to design biological systems at all scales from the ground up,” explains Jungmann, who is a spokesperson for the cluster along with Professor Petra Schwille from the Max Planck Institute of Biochemistry and Professor Friedrich Simmel from the Technical University of Munich. Not only will this afford a whole new look at the principles of life, but it is also meant to pave the way for new applications in domains such as medicine and materials science.

BioSysteM is a joint initiative between LMU and the Technical University of Munich (TUM), while the Max Planck Institute of Biochemistry and Helmholtz Munich are involved as partner institutes. “The cluster is rooted in a very long tradition in the Munich scientific milieu. Its core consists of molecular biophysics, where the partners have always been very strong,” says Jungmann. Some 50 research groups from the spheres of physics, chemistry, biology, bioinformatics, and medicine create an interdisciplinary research environment in the cluster, which is divided into four closely networked research areas.

Molecular building blocks and artificial systems

Enlarge

Within BioSysteM, the size and complexity of the biological systems continuously increases from area to area. Area A starts at the place where everything begins: the molecular building blocks of life. The work here centers on DNA nanotechnology and protein design for creating modular platforms that work in a robust manner. The vision is customized nanofactories in which individual parts, such as DNA origami structures or proteins, are assembled into molecular machines or motors in a molecular ‘assembly line.’ To ensure reproducibility, the cluster also plans to set standards in documentation: “For each molecular component and each molecular design, we will publish datasheets and protocols, so that they can be used by all researchers inside and outside the cluster,” says Jungmann. “In this way, we create genuine Engineering Biology.”

The work in Area B is about assembling such molecular building blocks featuring simple cell components like cytoskeleton proteins and lipid membranes into miniature artificial systems that imitate the initial characteristics of living cells. Such minimal models help scientists understand the fundamental biological processes: How do patterns and shapes arise? How can biomolecular processes be programmed such that complex structures form? In the long term, the researchers are striving to build a synthetic protocell – capable of growth and division.

Cellular communication and organoids

If molecular components are still viewed in isolation in Areas A and B, the cell and in particular communication within and between cells are the focus in Area C. A key goal here is to integrate the molecular building blocks and tools developed in Areas A and B into cells and to program them in such a way that they can take on new tasks – as sensors, for example, or for targeted drug delivery, for executing biological functions, or for controlled communication with their environment.

And finally at the upper end of the size scale, we have the researchers in Area D. They work with organoids – that is to say, organlike structures created in the laboratory. Using molecular tools, such as those employed in Areas A and B, the researchers will seek to control the formation and functioning of the organoids in targeted ways. At the same time, the organoids will serve as a test system for these tools and for possible applications. “With the organoids, we investigate really complex structures that can open up new approaches in diagnostics and therapy,” says Jungmann.

To keep an eye on the big picture, there are also four focus groups (research themes) devoted to fundamental questions running like a golden thread through all levels of the cluster. For example, how signals are relayed and how forces are transmitted play a role in all biological systems. The focus groups are conceived as a discussion forum which, among other things, organizes workshops and seminars for networking across the research areas. “It was very important to us that we do not practice research in silos,” explains Jungmann. After all, if you really want to understand how life works, you need to know how everything works together.

From research to application: mission-driven projects

Enlarge

BioSysteM is first and foremost a basic research project – but one with an eye on applications. For transfer into practice, there are the so-called “mission-driven projects,” or M-projects for short: thematically focused undertakings with a clear translational perspective, which also work on a cross-cluster basis and for which almost a fifth of the budget has been allocated. “The M-projects are a completely novel concept,” emphasizes Jungmann. “We want to define flagship challenges that subsequently lead to spin-outs and genuine applications in spheres such as medicine and the material sciences.” The M-projects will be supported by cooperation partners from the world of private enterprise and entrepreneurship centers, which will help identify highly promising ideas and implement them in practice.

The first project to be launched is concerned with the development of targeted immunotherapeutics to fight cancer. To this end, the researchers are analyzing the surface of cells with high-resolution microscopy in order to recognize characteristic receptor patterns – a sort of molecular fingerprint. Next, they plan to develop tiny nano-agents that specifically bind to cancel cells and prompt the immune system to attack them. Such highly specific drugs could not only be more effective, the scientists hope, but could also have fewer side effects than current treatments.

Social and ethical implications: dialog with society

Beyond engineering, however, the cluster also has an eye on the social and ethical implications of future developments. A post-doc from the social sciences will be incorporated into the M-projects and analyze the social and ethical challenges that arise when basic research transfers to application. Moreover, the general public is invited to discuss the future of biosystems research with the scientists. The Biomolecular Design Studios will serve as bridges to the public: maker spaces and experimentation rooms in which students, classes of schoolchildren, and curious citizens gain insights into the research. Here they can experience how proteins are designed or DNA structures are simulated while also doing hands-on experiments themselves. In this way, they can become, to a certain extent, architects of nanofactories of the future.

“With our project, we’re bringing the vision of a molecular factory that can be adapted to various requirements a good step closer,” summarizes Jungmann. “A cluster is always additionally a lighthouse initiative that defines a new field. BioSysteM wants to raise the concept of synthetic biology to a whole new level and open up brand new possibilities.”