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PhD Defense Minliang Chen
Minliang Chen successfully defended his PhD thesis. Congratulations!

Present research at IBB is done mainly along two lines:

  1. Methodology und fundamental studies in systems and synthetic biology to understand and design biomolecular and cellular processes;
  2. Enabling technologies and tools such as automated global screening and optimization of biomolecules and cells, new bioreactors for electrofermentation and CO2 bioconversion.

They are integrated for developing new bioproducts or more efficient bioprocesses and biosystems in industrial and medical biotechnologies.

 

Modelling and Design

Modeling is used as a fundamental tool for understanding and designing biomolecules and cell factories. In particular, a multicsale modeling approach from molecular dynamcis to kinetics of reactions is implemented for the design and evolution of biomolecular sensors, regulatory proteins, enzyme reaction cascades and metabolic pathways. Cells are designed as smart robots for biocomputing and in vivo high-throughput screening.

Experimental: Build and Test

As a key step of the Design-Build-Test cycle, experimental studies range from evaluating designed biomolecules, pathways and microorganisms at molecular level to bioprocess optimization at different scales of bioreactors (up to 300 L) and miniplant for integrated biosynthesis and product purification. Both microbial and mammalian cells and cultivation systems are studied in the context of systems and synthetic biology and process development.

Applications

We develop new bioproduction systems with high yield and productivity for (1) chemicals and fuels such as 1,3-propanediol, caproic acid, n-butanol and biogas; (2) fine chemicals and pharmaceuticals such as amino acids, microbial lipids and recombinant proteins.  Waste materials and C1 (e.g. CO2) carbons are more and more in focus as substrates. We collaborate with industrial partners in different ways, such as contract research and development, consulting and feasibility study.

 

 

List of projects

This page lists all our current projects with links to individual descriptive reports and/or results summaries (PDF).

Please also refer to the general project overview site.

Attention: all information presented here is protected by copyright.

 

Electrobiotechnology

 

DFG SPP 2170 Project (2020 -)

CaproMix – Development of new and defined mixed cultures for bioproduction of caproic acid from carbon dioxide

In collaboration with Dr. Frank R. Bengelsdorf, Ulm University

 

This project brings together well complementary expertise of two academic groups from microbiology and molecular biology (Dr. FR Bengelsdorf) and bioprocess engineering/systems biology (Prof. AP Zeng). The objective is to gain quantitative and fundamental knowledge of synthetic co-culture(s) producing caproic acid (CA) via lactic acid (LA) from CO2 and H2. CA is an appealing C6-compound with a wide range of important applications. In the anaerobic co-culture to be studied an acetobacterium such as A. woodiimutant should produce LA autotrophically and a selected strain and its mutants should convert LA into CA. The compatibility of different combinations (co-cultures) of these microbes will be first examined in terms of growth physiology (optimal pH, T, nutrient requirement and growth inhibition or enhancement). Metabolic interactions of the selected co-culture will then be studied more quantitatively and in more detail, e.g. regarding kinetics of cell growth, substrate consumption and product formation. For the quantification of cell population a metabolic engineering approach will be applied to generate A. woodii mutants expressing a special fluorogenic protein tag that causes a distinct fluorescence pattern to distinguish cells of different species, along with use of fluorescence-based flow cytometry to quantify the other microbe in the co-culture. A special two-chamber bioreactor system will be used to better study metabolic exchanges and interactions of the two microbes, among others for metabolic flux analysis. Similarly as with the characterization of the co-culture integrated biomolecular and bioprocess engineering approaches will be collaboratively applied to improve the performance of the co-culture for bioprocess development. In addition to extensive genetic and metabolic engineering work planned to improve LA production in A. woodii an adaptive laboratory evolution approach will be implemented to generate a hyper LA producer by suppressing cells that do not produce LA via the use of a LA induced selection pressure. A novel cultivation strategy using a bioelectrochemical system will be applied that allows tuning the in situ electrolytic H2 generation and consequently the metabolism of A. woodii according to the requirement of the LA-consuming and CA-producing strain in the co-culture. Accumulation of toxic LA concentration can be prevented via online measurement of LA which serves as a feedback control parameter for the in situ electrolysis. In summary, this project deals with a number of key scientific questions for developing efficient co-culture technology for the production of value-added products such as lactic and caproic acids from CO2 and regenerative electricity. It bears several methodological and technological innovations which not only help to realize the special goal of this project, but could be also applied to related products.

 

                        

DFG SPP 2240 project (2021 - )

HP-eBio - Systems metabolic engineering of Hydrogenophaga pseudoflava for aerobic biosynthesis of fatty acids using CO2 and electron carriers in a novel bioelectrochemical system

In collaboration with Prof. Dr. Bastian Blombach, Technical University of Munich (TUM) 

 

Electrobiotechnology is a promising technology at the interface of electrochemistry and biotechnology to use CO2 and electricity for the microbial biosynthesis of chemicals and fuels in bioelectrochemical systems (BES). An appealing approach in this regard is the conversion of CO2 to CO and the formation of syngas (H2, CO, CO2) electrochemically; the latter is then biologically converted into chemicals or liquid fuels. Although the decoupled bioconversion of syngas has made impressive progresses recently, this technology still has several inherent obstacles such as limited mass transfer of gases into culture medium, low uptake or inefficient transfer of electrons or electron carriers to the microbial host, and safety issues regarding toxicity and explosiveness of the substrates. Furthermore, acetogens as the mostly used microbial hosts for syngas bioconversion have a limited spectrum of products since the production of more complex molecules is outside the metabolic capacity. In this project, the great potential of Hydrogenophaga pseudoflava in theaerobic utilization of syngas and the capacity of engineered H. pseudoflava for the production of fatty acids will be explored in a novel direct electromicrobial production system with in situ and on demand production of H2 and O2 (from water) and CO (from CO2). To develop a systemic and quantitative understanding of the electron transfer and its impact on redox and energy metabolism of this carboxydotrophic bacterium, we will apply metabolomics, flux analysis and quantify kinetic parameters of the wild type and engineered mutants defective in electron transfer, energy and redox metabolism under given gas compositions provided by an optimized BES. The BES will address current limitations of bio-electrochemical systems and gas fermentations as already mentioned above. The gained knowledge will be utilized to set up a first metabolic and electron transfer model of the autotrophic metabolism of H. pseudoflava, especially regarding uptake of the different electron carriers, energy and redox balances. Furthermore, we will engineer H. pseudoflavafor the production of fatty acids which represent an ATP and NADPH intensive product class and therefore its overproduction will challenge the metabolism of H. pseudoflava especially under autotrophic conditions. A quantitative analysis of the developed strains will be used to evaluate and refine the metabolic and electron transfer model. This project will open up new possibilities to engineer efficient electromicrobial production strains and to develop improved electro-fermentation.

 

 

DFG SPP 2240 project (2021 - )

AiO-eChemsBio - Chemoenzymatic reaction cascade in an All-in-One electrochemical system with in situ supply of H2O2 for biosynthesis in aqueous and organic media

In collaboration with Prof. Bodo Fiedler and Prof. Andreas Liese, TU Hamburg

 

Chemoenzymatic reaction cascades have a great potential for biosynthesis and sustainability, especially when coupled with the latest advances in electrochemical systems and material sciences. This envisaged project connects the expertise of three truly interdisciplinary groups in biocatalysis, bioprocess engineering, bioelectrochemical systems (BES) and nano-materials in a unique way to address fundamental challenges in developing a novel and individually optimizable platform for hydrogen peroxide-dependent enzymatic cascade reactions. H2O2 plays an important role as a green and powerful co-substrate or co-factor in the biosynthesis of a vast variety of value-added products and can be electrochemically efficiently generated from H2O and O2 as demonstrated in conventional BES with three-electrodes. One of the first objectives of this project is to develop a fully controllable BES for in situ and on-demand synthesis of H2O2 based on a novel All-in-One (AiO) electrode developed recently by one of the project partners. To realize a controlled H2O2generation in the AiO electrode with high energy efficiency, highly porous carbon foams coated with carbon nanotubes (CNTs) will be designed and tailored by a sophisticated novel CVD process, yielding low density and high conductive hierarchical porous structure. H2O2 generated in such a controlled way is instantly used by enzymatic oxyfunctionalization in multistep chemoenzymatic reaction cascades. The selected reactions will be investigated using both free and immobilized enzymes on functionalized CNTs. This integrated approach is unique and promising in tackling one of the major issues in H2O2 -dependent enzymatic oxyfunctionalization, namely the lowered half-life time of enzyme activity in the presence of H2O2. By integrating the AiO-electrode in an organic reaction medium in situ H2O2 addition will be realized without the addition of water, omitting side reactions. With a fine-tunable system in hand, the rates of electrochemical H2O2 synthesis and enzymatic H2O2 consumption can be tightly coupled, enabling a constantly low concentration of H2O2 during the whole cascade reaction. This will open up new possibilities to develop chemoenzymatic reaction cascades with improved enzyme stability and activity and a more stable entire process.

 

 

C4F (2020 -)

Power to Lipids - Electrochemically supported CO2-neutral bioproduction of lipids

The aim of this project is to create a sound technological basis for the development of a novel electrochemically supported and CO2-neutral bioproduction process of high-quality lipids. The innovation of this project lies on the one hand in the use of electrobiotechnology (EBT) for the use of regeneratively generated electricity for resource-saving, CO2-neutral bioproduction. EBT is an emerging interdisciplinary research area at the interface between natural and engineering sciences. It combines electrochemical and biotechnological advantages in order to make production processes more economical and ecological. It has great potential for developing new processes and for answering technological and social questions, for example by converting CO2 into valuable chemicals and materials using regenerative electricity. In this way, it can ideally help to drive the necessary change towards a sustainable and climate-neutral economic system (bioeconomy). On the other hand, the innovation, interdisciplinarity and creative potential lie in the unique integration of new technology and process components for a specific process: the microbial production of high-quality lipids, which are widely used in the cosmetics and food industries.

 

 

Power to Lipids - Elektrochemisch unterstützte CO2-neutrale Bioproduktion von Lipiden

Ziel dieses Projektes ist es, eine fundierte technologische Basis für die Entwicklung eines neuartigen elektrochemisch unterstützen und CO2-neutralen Bioproduktionsprozesses von hochwertigen Lipiden zu schaffen. Die Innovation dieses Projektes liegt zum einen im Einsatz der Elektrobiotechnologie (EBT) für die Nutzung von regenativ erzeugtem Strom zur ressourcenschonenden, CO2–neutralen Bioproduktion. EBT ist ein aufstrebendes interdisziplinäres Forschungsgebiet an der Schnittstelle zwischen Natur- und Ingenieurswissenschaften. Sie kombiniert elektrochemische und biotechnologischen Vorzüge, um Produktionsverfahren wirtschaftlicher und ökologischer zu gestalten. Dabei besitzt sie hohes Potential zur Entwicklung neuartiger Prozesse und bei der Beantwortung technologischer und gesellschaftlicher Fragen, etwa durch die Umwandlung von CO2 mit regenativem Strom in wertvolle Chemikalien und Materialien. Hiermit kann sie idealerweise helfen, den notwendigen Wandel hin zu einem nachhaltigen und klimaneutralen Wirtschaftssystem (Bioökonomie) voranzutreiben.

Zum anderen liegen die Innovation,  die Interdisziplinarität und das kreatives Potential  in der einzigartigen Integration von neuen Technologie- und Prozesskomponenten für einen konkreten Prozess (Abb.1): die mikrobielle Herstellung von hochwertigen Lipiden, die in der Kosmetik- und Nahrungsmittelindustrie breite Anwendungen finden.

 

 

FNR - Förderprogramm Nachwachsende Rohstoffe

Biber - Bioelektrochemisches System zur flexiblen Biogas-Erzeugung (2020 - )

In Zusammenarbeit mit Prof. J. Gescher (KIT), Prof. S. Kerzenmacher (Uni. Bremen) und Industriepartnern

 

Ziel des Gesamtprojektes ist die Etablierung einer Regeltechnik für den Biogasprozess. Diese Regeltechnik beruht auf der steuerbaren Elimination von organischen Säuren im Biogasreaktor über ein bioelektrochemisches System. Ziel des Teilvorhabens ist zunächst die Modellierung des integrierten bioeletrochemischen Systems zur flexiblen Erzeugung von Biogas und zur Nutzung der darin enthaltenen Gaskomponenten (Wasserstoff und Kohlendioxid) für anschließende Biosynthese. Auf Basis der Modellierung sollen Regelungsstrategien für die Steuerung der Reaktionsschritte entwickelt werden.

 

 

Biber - Bioelectrochemical system for flexible biogas production (2020 - )

The aim of the overall project is to establish a control technology for the biogas process. This control technology is based on the controllable elimination of organic acids in the biogas reactor via a bioelectrochemical system. The aim of the sub-project is initially the modeling of the integrated bioeletrochemical system for the flexible generation of biogas and for the use of the gas components (hydrogen and carbon dioxide) contained therein for subsequent biosynthesis. Control strategies for controlling the reaction steps are to be developed on the basis of the modeling.

 

 

Biomolecular Engineering & Synthetic Biology

 

DFG SPP 1934 project (2019 - )

EnzymAgglo – Multiscale model-based investigation of functional enzyme and protein agglomerates for biotechnological applications – Phase 2: From structure to function

In collaboration with Prof. S. Heinrich and Prof. M. Dosta, TU Hamburg

 

The model based understanding of the structure defining processes of multi-enzymatic systems and protein agglomeration, as well as their relation to function (e.g., activity) has received increasing interest in recent years. With new multi-scaled modeling approaches and increased computational capabilities in recent years (especially GPUs), the detailed investigation and prediction of such macromolecular phenomena comes into reach. To achieve this, we developed a generally applicable multi-scale model framework, termed “Molecular discrete element method (MDEM)”, during the first project phase.

Specifically, it focuses on the structural development of such systems depending on process conditions. It applies on the macro-molecular scale (ms and µm) and will be finalized in the remaining time of the first period of the project. The MDEM framework allows investigations of biologically and technically interesting structural phenomena due to its speedup of 5 to 7 orders of magnitude with respect to simulation time and/or scale in comparison to traditional MD. At the same time, it retains the necessary detail on the meso-scale through anisotropic consideration of properties. While, during the first project phase, the framework was established using the multi-enzymatic pyruvate dehydrogenase complex (PDC) as a model system, it has received very positive feedback from other SPP project partners for applications to numerous other processes and phenomena (e.g., protein absorption at the oil-water interface). Initial collaborations have been initiated and are planned to be intensified. 

The focus of the second project phase will lie on expansion of the MDEM approach with respect to the determination of function from structure; increased size and time scales; and application of developed framework to new processes in collaboration with SPP project partners. To achieve these goals, the MDEM framework will be coupled to population balance modeling (e.g., for experimental validation and parameter studies). Further, protein-protein and protein-interface interaction will be refined and extended to cover density effects (molecular crowding; diffusion limitation), and competitive interaction of multiple partners. 

 

Literature

[1] Depta P.N., Jandt U., Dosta M., Zeng A.-P., Heinrich S. (2018). J. Chem. Inf. Model., DOI: 10.1021/acs.jcim.8b00613 

[2] Jandt U., Depta P.N., Ilhan S., Müller C., Dosta M., Zeng A.-P. (2018). In: Himmelfahrtstagung 2018 (Poster).

[3] Depta P.N., Jandt U., Ilhan S., Müller C., Dosta M., Zeng A.-P., Heinrich S. (2018). CIT, DOI: 10.1002/cite.201855443

[4] Hezaveh S., Zeng A.P., Jandt U. (2017). ACS Omega, 2(3), 1134-1145.

[5] Hezaveh S., Zeng A.P., Jandt U. (2018). J. Chem. Inf. Model., DOI: 10.1021/acs.jcim.7b00557

[6] Hezaveh S., Zeng A.P., Jandt U. (2016). J. Phys. Chem. B, 120(19), 4399-4409.

[7] Ilhan S., Müller C., Jandt U. (2018). CIT, 90: 1280-1280, DOI:10.1002/cite.201855325

[8] Guo, J., Hezaveh, S., Tatur, J., Zeng, A-P., Jandt, U. (2017). Biochem J, 474(5), 865-875.

[9] Wurm, M., Ilhan, S., Jandt, U., Zeng, A.-P. (2018). Analyt. Biochem. 10.1016/j.ab.2019.01.006

 

 

I3 – Lab project (2020 - )

I³ - Novel Products from Maritime Resources

 

In collaboration with Profs. G. Antranikian, A. Liese, M. Kaltschmitt, TUHH and industrial partners

Macroalgae are a natural waste and an abundant resource at the same time at the German seashores. They contain diverse valuable components, such as rare sugars, structural polysaccharides, proteins and unique polymers. To make these intermediates available for the two aimed at products of protein-based polymers and alginate derivatives, an efficient macroalgae biotransformation process will be developed. This necessitates further collaboration within the TUHH in respect of material modification and application.

 

 

BMBF 

protP.S.I. Teilprojekt C5 - Einsatz von Carboanhydrasen und Hochdruck für die Fällung spezieller Calciumcarbonate

In cooperation with industrial partner(s)

 

Zu den Zielen des Projektes gehören (1) die technische Anwendung der Carboanhydrase zur  Modifikation der Morphologie und (2) Realisierung einer wirtschaftlichen Fällung bei bisher nicht etablierten milderen Betriebsbedingungen. Außerdem soll unter dem Einsatz von erhöhtem Druck eine für z.B. Biopolymere dienliche Kristallstruktur erreicht werden. Eine Synergie (5) zwischen hochaktiver Carboanhydrase, der durch den Druck erhöhten Gaslöslichkeit und weiterer thermodynamischer Effekte wird untersucht.

 

 

 

Systems Biology and Metabolic Engineering

 

Microbial Systems and Biorefinery 

 

BMBF ELBE –NH (2019 - ):

Effektivitätssteigerung von Lignin- Bioraffinerien durch Ergänzende Nutzung von Hydrolysaten

In Zusammenarbeit mit Prof. I. Smirnova, Prof. M. Kaltschmitt und Industriepartnern

 

Das Hauptziel dieses Projektantrags ist die Verwertung der Hydrolysate (hier ein Nebenstrom) einer bisher auf die Ligninproduktion ausgerichteten Lignocellulose-Bioraffinerie, die von mehreren Antragstellern in der vorherigen Zusammenarbeit entwickelt wurde („BIORAFFINERIE 2021“ Förderkennzeichen BMBF 031B0091). Der Antrag ELBE-NH adressiert hauptsächlich Fragestellungen aus Modul 2 (Sekundärraffinerie) der aktuellen Förderbekanntmachung.

Die Wirtschaftlichkeit der im Vorprojekt ausgearbeiteten Bioraffinerie ist durch die Isolierung und Verwertung des Hydrolysats in einer Sekundärraffinerie zu erhöhen, die hierbei nichtverwerteten Reste in einer Biogasanlage zu vergären. Als Zielprodukte werden primär Milchsäure(LA) und Propionsäure (MA) (mikrobiologische Umsetzung der Hydrolysate) sowie Fructane (C6-Oligomere) und Pentosane (C5-Oligomere) (Abtrennung aus Hydrolysaten durch chromatographische Verfahren) ausgewählt.

 

 

ELBE –NH (2019 - ): Increase in the effectiveness of lignin biorefineries by integrated use of hydrolyzates

In cooperation with Prof. I. Smirnova, Prof. M. Kaltschmitt and industrial partners

 

The main objective of this project is the utilization of the hydrolysates (here a side stream) of a lignocellulose biorefinery process, which was previously focused on lignin production and which was developed by several project partners in the previous cooperation ("BIORAFFINERIE 2021" funding code BMBF 031B0091). The ELBE-NH project mainly addresses issues from module 2 (secondary refinery) of the current funding announcement.

The profitability of the biorefinery worked out in the preliminary project will be increased by isolating and utilizing the hydrolyzate in a secondary refinery, and fermenting the unused residues in a biogas plant. Lactic acid (LA) and propionic acid (MA) (microbiological conversion of hydrolysates) as well as fructans (C6 oligomers) and pentosans (C5 oligomers) (separation from hydrolysates by chromatographic processes) are primarily selected as target products.

 

 

EU ERA-Bio Project (2018 - )

Biochem - Novel BIOrefinery platform methodology for a driven production of CHEMicals from low-grade biomass

Project partners: 

Prof. Marta Carballa Arcos, Universidade de Santiago de Compostela

Dr. Johanna Maukonen, VTT Technical Research Centre of Finland Ltd.

Prof. An-Ping Zeng, Technical University Hamburg

 

The technical evolution that would make waste treatment technologies evolve and become processes for the production of chemicals lies at the core of the circular economy paradigm. Nevertheless, the attempts to produce resources from waste have been limited to the production of energy (e.g. by combustion or by the production of biogas) or low-added value chemicals (e.g. methane, water, fuels). Transformation of waste by mixed culture fermentation has been recognised as a relatively inexpensive means to produce higher added-value chemicals in the previous years. However, the development of a new bioprocess based on mixed-culture fermentation is an extremely challenging task. Targeting the desired product requires finding a certain region in a very large operational space. In the case of an anaerobic fermentation the operational space is composed by the variables such as pH, temperature, retention time and substrate nature. The main objective of BIOCHEM is to provide an integral method for model-aided design of a novel bioprocess using mixed-culture fermentation. In particular, BIOCHEM focuses on two essential aspects when designing a novel bioprocess: to reach a high selectivity of the desired product(s) and to achieve high productivity so that the process is economically feasible. 

The BIOCHEM project aims at:

1). Development of bioenergetics-based and kinetic models for prediction of mixed-culture population preferred metabolic routes

2). Assisting the experiments by targeting the range of operating conditions with the use of bioenergetics-based models and process engineering tools

3). Engineering the optimal microbial communities for desired product spectrum and product yield, by manipulation of the operating conditions.

4). Increasing the productivity and overcoming product inhibition by using in-situ product removal techniques

5). Developing a virtual plant to optimise the design of the novel bioprocess and adjust it to the production of any of the possible products from a variety of substrates.

 

 

  • EU:  Novel BIOrefinery platform methodology for a driven production of CHEMicals from low-grade biomass (BIOCHEM)

 

Cell Culture Technology

 

 

Accomplished projects

Following is a list of previously accomplished projects with links to individual descriptive reports and/or results summaries (PDF).

  • TUHH: Growth of Clostridium pasteurianum in bio-electrochemical H-cell reactor
  • TUHH: Development of New Methods in Fast Sampling and in Sample Processing for Microbial Metabolomics
  • EU (EFRE): Bio-Profi - Modellgestützte Bioprozessentwicklung zur Herstellung von natürlichen Milcholigosacchariden für medizinische Anwendnungen
  • BMBF: e:biofilm: Fighting biofilms of Streptococci by a novel biofilm inhibitor: from bench to dental products
  • DFG/SPE: Multiskalige modellgestützte Untersuchungen der Formation von katalytisch aktiven Clustern und Agglomeraten großer Multienzymkomplexe
  • TUHH: Rational design of riboswitch-based biosensors with expanded response range
  • TUHH: Reengineering substrate specificity of E. coli glutamate dehydrogenase using a position-based prediction method
  • TUHH: Creation of novel allosteric regulation of proteins for synthetic biology based on a new concept of thermodynamic model