Guiding theme: Biological Transformation

The “biological transformation” has long since begun. Like the “digital transformation”, which has become an indispensable part of people’s everyday lives due to the Internet and the use of smart phones, it has also changed production processes with new biological active substances in medicine and with the systems approach of bioeconomy, which we will consider separately because of its great importance for the Institute’s research strategy. In particular, the interaction between digital technologies and artificial intelligence on the one hand and the interconnection of life, materials and production sciences on the other will make far-reaching innovations possible in the future. As an example, self-learning systems are conceivable whose learning processes are controlled by simulating processes of real cells in combination with digital algorithms and are used in the manufacture of completely new products.

According to the definition given by Fraunhofer-Gesellschaft, biological transformation makes use of the principles, materials and structures of living nature. These are not necessarily synonymous with the use of biological systems (cells, tissues) – as the highest level of integration. Rather, the production systems of the future will also be able to imitate and adapt the principles of biology or its materials and structures. This means that the production process of the future has learned from nature and its principles and processes and applies them to biotechnologically produced pharmaceuticals and “biologized medicine” or – in the case of other sectors – in the sense of natural material cycles.

For more than 40 years, IGB has focused its work on the development of biotechnological processes and biobased products, which are used in the medical, pharmaceutical and diagnostic, food processing, chemical and renewable energy sectors, among others, based on the added social value of new and sustainable products while maintaining functionality and quality. At IGB, industrial value creation and environmental aspects were linked at an early stage as a solution for sustainable economic activity.

With its commitment to the innovation process of biological transformation, the Institute is actively addressing the challenges of biologized medical care for people and bringing together individual value chains – “from raw material to product”, “nature’s own chemical plant”, “Nexus water, nutrition and energy” – to create holistic value creation cycles for the production systems of the future. The abundance to which the Institute draws on in this respect is illustrated by the examples selected below for the various biological “system levels”.

Biological systems consist of individual or a large number of cells that multiply through metabolisms and processes organized in control loops and interact in complex structured networks. The understanding of these intracellular (metabolism) as well as extracellular (cell differentiation in the organism) control and regulation mechanisms is an essential tool for the development of effective microorganisms, not only for the production of enzymes or biopolymers, but also for the development of drugs that balance disturbed cellular control and regulation mechanisms. Examples of this are the administration of insulin for diabetes or highly individualized therapies such as CAR-T cell therapy for tumor diseases.

From recognition at molecular level...

Among other things, IGB contributes to the decoding of these networks and control mechanisms by developing and applying innovative methods in the field of high-throughput sequencing (Next-generation sequencing). IGB is therefore laying the foundation for the identification of biomarkers for the personalized diagnosis of various diseases, for the molecular analysis of infection processes or for the characterization of microorganisms for industrial biotechnology. Furthermore, the Institute uses this technology to capture complex microbial metagenomes and transcriptomes for diagnostics as well as for environmental biotechnology. Based on these findings, new production organisms for biobased chemicals or pollutant-degrading microorganisms are identified and subsequently optimized using molecular biological methods.

...to material conversion with bioprocess engineering

As a further core element of biological transformation, bioprocess engineering deals with the development, modelling, operation and scaling of biotechnological processes in order to implement them in industrial practice. On the one hand, the optimal cultivation conditions for the targeted build-up of products or degradation of pollutants by the organisms must be set. In addition to material conversion, IGB also integrates the appropriate digestion, extraction or purification procedures into the process. In this context, our aim is to achieve maximum material and energy efficiency as well as product quality throughout the entire process chain.

We therefore also develop specific reactor systems for the various tasks, for example membrane reactors for immobilizing enzymes or bioreactor systems, with which the hydraulic residence time can be decoupled from the biomass residence time and thus the space-time yield can be increased.

The complex control mechanisms inside and outside the cells also require comprehensive measurement and control technology for the entire system. The integration of artificial intelligence into these systems will enable both process intensification and accelerated adaptation to rapidly changing conditions.

Organisms are highly complex systems and are endowed with the highest degree of organization, or in other words thermodynamic order. They consist of cells, organelles and functional molecules, which themselves are also structured in a complex way and are linked to each other by various interactions. In biological systems, each new hierarchical level is characterized by properties that were not previously present and the newly emerging structural level is always more than the sum of the individual components.

Wherever materials come into contact with biological systems, the properties of the materials and their interaction with the physiological environment play a decisive role. In the case of medical devices, our focus is on the interaction at the interface between the technical and the biological system. Depending on the objective, we modify the surface of the material used in such a way that the function of the biological component is not only not impaired (biocompatible), but in many cases even supported (bioactive). Depending on whether the interfaces are to adhere to each other (implants) or be moved against each other (joints), adequate mechanical properties are required in addition to the chemical properties to stabilize the bond.

To optimize the mechanical properties, the third dimension comes into play. The two-dimensional boundary surface becomes a three-dimensional boundary phase. For this case nature has developed and combined special materials with unusual mechanical properties. One example is joints. With its special viscoelastic properties, joint cartilage, together with synovial fluid or its defined viscosity, ensures that joints can fulfill their function even under greater mechanical and intermittent stress. The implementation of such systems in technology still requires a great deal of fundamental research. Cartilage, for example, is anisotropic in its mechanical properties. We tackle this challenge with special printing techniques using “bioinks” developed at IGB.

In future, new materials from the matrix of tissues, bioinspired structures and biofunctional or biologized surfaces will ensure that medical devices, prostheses and implants are better tolerated. Materials that replicate the biochemical and mechanical properties of natural tissues can minimize irritation in the organism and prolong the shelf life of medical devices: In the future, materials will be available that can be fully integrated by the body, making them both patient-friendly and cost-effective.

The catalysts of biological cells are enzymes, proteins that bring about all chemical reactions in the metabolism. Enzymes have conquered numerous areas of everyday human life, from detergents to shampoo and toothpaste. As sensors, they reliably measure pollutants and help determine the blood sugar content of diabetics. Biocatalysts are highly specific to the substrate being converted and can also be used to produce compounds that are chemically difficult to access. Due to this specificity, the biocatalytically prepared products are of high purity – no by-products are formed.

IGB uses enzyme reactions for its own developments, but also produces new enzymes on behalf of customers. Development begins with the screening of suitable enzymes, e.g. in soil samples or in sequence databases. Once candidates have been found, bacteria or yeasts are used for the efficient production of the enzymes and the cultivation is optimized from laboratory to pilot scale.

While the decoding of the human genome in the Human Genome Project still took more than 10 years, today entire organisms are sequenced within days or hours thanks to new and considerably faster sequencing methods for DNA, the so-called high-throughput or next-generation sequencing methods. This rapid development makes a lot of data accessible that allows the analysis of complex biological systems in unprecedented ways. This ranges from the understanding of cellular communication in complex organisms to the analysis of biological networks in microbial communities, so-called microbiomes. In the future, platforms of machine learning (artificial intelligence) and artificial neural networks can be used for the analysis and evaluation of these complex data sets in order to further accelerate the understanding of complex biochemical processes in cells and organisms and the identification of biomarkers for diagnostics and therapy.

Metagenome-wide data analysis has also created completely new possibilities in the diagnosis of diseases. IGB uses these possibilities to develop new methods for NGS-based diagnostics. Procedures for the preparation of patient samples and new bioinformatic methods have been developed in order to determine, for example, genetic identification traits from the sequence data of a blood sample, with which microorganisms can be unambiguously diagnosed as pathogens of infectious diseases. Since resistances are also determined by genes, high-throughput sequencing even makes it possible to identify not only the biological type of the pathogen in the same analysis, but also its resistance genes – and thus a further starting point for the respective optimal therapy. Patient benefit and cost reduction go hand in hand here.

Microorganisms are particularly well suited for the production of biobased chemicals or for food production, as they can multiply very quickly using biogenic nutrients and are therefore highly productive in the long term. In particular, higher microorganisms such as fungi or algae have a large number of metabolic networks that generate metabolic products that can be used by us. Penicillin is one of the most important products derived from fungi, but basic molecules for polymers (succinic acid, malic acid, itaconic acid) or biosurfactants for use as detergents, emulsifiers or as active ingredients in cosmetics and crop protection can also be obtained as biobased chemicals from fungi and other microorganisms, as we demonstrated at IGB.

It is often possible to achieve increased production by microorganisms of the desired substance through selection procedures without genetic modification. However, the metabolic networks often have to be modified in such a way that molecules that are normally used differently by the organism are converted into the desired substance (metabolic engineering).
 
In many cases, completely new metabolic pathways are implanted into the organism. This is the case, for example, in the production of enzymes, but also for pharmaceutical proteins in mammalian cell lines. Although mammalian cell lines are much more sensitive than microorganisms, due to their similarity to human cells, they form, in contrast to microorganisms, most of the desired proteins with comparable modifications to humans. This dramatically increases their effectiveness. With our molecular biological expertise in the modification of microorganisms and the recombinant production of proteins in mammalian cells, we contribute to the biotechnological production of biobased chemicals as well as to the production of therapeutic proteins through the recognition and modification of metabolic networks.

Tissues and organs consist of different differentiated cells which in each case take over specific functions for a common task via cellular communication and regulatory mechanisms. In order to understand these mechanisms and be able to reproduce them in a manageable system, we reproduce models of human tissues and organs in the laboratory, with which human physiology and its diseases can be reproduced much better than in animal models.

Complex models made up of human cells also contain components of the immune system and we use them as test systems for the development and evaluation of new pharmaceuticals. 3D tissue models can also be used to set up test systems with disturbed control and regulation mechanisms (e.g. from patient biopsies or via specifically modified human cells), on which active substances that compensate for this disturbance can be validated.

The cultivation of the smallest functional unit of an organ into artificial microfluidic systems, so-called organ-on-a-chip systems, is another new technology for providing meaningful test systems for drug development. IGB constructs such organ-on-chips from human induced pluripotent stem cells. These hiPS cells can be specifically differentiated so that tissue can also be obtained that cannot be isolated from primary biopsies. Since the cells of the organ-on-chip in the micro-physiological system react to drug candidates in the same way as would be the case in the human organism, they are used to investigate active substances that cannot be evaluated in animal experiments – and animal experiments can be increasingly replaced.

Waste does not arise in living nature. In the biological cycle, plants and microalgae from carbon dioxide and inorganic nutrients such as nitrogen, phosphorus and sulphur form organic matter by means of photosynthesis, which is used by other organisms via the food chains to build up their biomass. Through respiration and microbial degradation of dead organic matter, CO₂ and nutrients are finally available again for new biosynthesis cycles.

IGB research at the “environment” system level is oriented towards natural material cycles that are not influenced or disturbed by humans. The aim of our concepts for the treatment of wastewater, for example, is to recover ingredients in a recyclable form. In our system approach “semi-decentralized integrated water management” we use anaerobic microorganisms to convert the organic matter present in the wastewater into biogas. The remaining nutrients can be precipitated in a plant-available form or, with the purified water, used for fertilizing irrigation.

In addition to the wastewater treatment plants common in Western civilization today, in which nutrients are disposed of in non-recyclable form instead of being processed for return to the biological cycle, it is above all industrial agriculture that withdraws nutrients from the natural cycles. When the plants are harvested, the nutrients are removed from the agroecosystem and hardly any return takes place. This makes the supply of synthetic fertilizers necessary. With our newly patented technologies, we focus on the recovery of nutrients from wastewater and liquid manure, fermentation residues and residual materials from the food industry and on agriculture that is oriented towards natural material cycles.