Now Accepting Submissions for Three Special Issues

"Plant BioDesign Hub" -- "Designing Proteins With New Folds and Function" -- "Engineering Microbiomes for Biodesign Applications" -- Submit to a special issue today!

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Journal profile

The open access journal BioDesign Research, published in association with NAU, publishes novel research in the interdisciplinary field of biosystems design.

Editorial board

The editorial board, led by Xiaohan Yang (Oak Ridge National Laboratory) and Alfonso Jaramillo (University of Warwick), is comprised of experts who have made significant and well recognized contributions to the field of biodesign research.

Special issues

Accepting submissions for three special issues:

Plant BioDesign Hub (deadlines: Aug 31, 2021; Mar 31, 2022; Mar 31, 2023)

• Designing Proteins With New Folds and Function (deadline: Dec 31, 2021)

• Engineering Microbiomes for Biodesign Applications (deadline: Mar 31, 2022)

Latest Articles

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Research Article

In-Depth Computational Analysis of Natural and Artificial Carbon Fixation Pathways

In the recent years, engineering new-to-nature CO2- and C1-fixing metabolic pathways made a leap forward. New, artificial pathways promise higher yields and activity than natural ones like the Calvin-Benson-Bassham (CBB) cycle. The question remains how to best predict their in vivo performance and what actually makes one pathway “better” than another. In this context, we explore aerobic carbon fixation pathways by a computational approach and compare them based on their specific activity and yield on methanol, formate, and CO2/H2 considering the kinetics and thermodynamics of the reactions. Besides pathways found in nature or implemented in the laboratory, this included two completely new cycles with favorable features: the reductive citramalyl-CoA cycle and the 2-hydroxyglutarate-reverse tricarboxylic acid cycle. A comprehensive kinetic data set was collected for all enzymes of all pathways, and missing kinetic data were sampled with the Parameter Balancing algorithm. Kinetic and thermodynamic data were fed to the Enzyme Cost Minimization algorithm to check for respective inconsistencies and calculate pathway-specific activities. The specific activities of the reductive glycine pathway, the CETCH cycle, and the new reductive citramalyl-CoA cycle were predicted to match the best natural cycles with superior product-substrate yield. However, the CBB cycle performed better in terms of activity compared to the alternative pathways than previously thought. We make an argument that stoichiometric yield is likely not the most important design criterion of the CBB cycle. Still, alternative carbon fixation pathways were paretooptimal for specific activity and product-substrate yield in simulations with C1 substrates and CO2/H2 and therefore hold great potential for future applications in Industrial Biotechnology and Synthetic Biology.

Research Article

Durable CRISPR-Based Epigenetic Silencing

Development of CRISPR-based epigenome editing tools is important for the study and engineering of biological behavior. Here, we describe the design of a reporter system for quantifying the ability of CRISPR epigenome editors to produce a stable gene repression. We characterize the dynamics of durable gene silencing and reactivation, as well as the induced epigenetic changes of this system. We report the creation of single-protein CRISPR constructs bearing combinations of three epigenetic editing domains, termed KAL, that can stably repress the gene expression. This system should allow for the development of novel epigenome editing tools which will be useful in a wide array of biological research and engineering applications.

Research Article

Phagocytosed Polyhedrin-Cytokine Cocrystal Nanoparticles Provide Sustained Secretion of Bioactive Cytokines from Macrophages

Many cells possess the ability to engulf and incorporate particles by phagocytosis. This active process is characteristic of microorganisms as well as higher order species. In mammals, monocytes, macrophages, and microglia are among the so-called professional phagocytes. In addition, cells such as fibroblast and chondrocytes are classified as nonprofessional phagocytes. Professional phagocytes play important roles in both the innate and adaptive immune responses, wound healing, and tissue homeostasis. Consequently, these cells are increasingly studied as targets and vectors of therapeutic intervention to treat a range of diseases. Professional phagocytes are notoriously difficult to transfect limiting their study and manipulation. Consequently, efforts have shifted towards the development of nanoparticles to deliver a cargo to phagocytic cells via phagocytosis. However, this approach carries significant technical challenges, particularly for protein cargos. We have focused on the development of nanoscale cocrystalline protein depots, known as PODS®, that contain protein cargos, including cytokines. Here, we show that PODS are readily phagocytosed by nonprofessional as well as professional phagocytic cells and have attributes, such as highly sustained release of cargo, that suggest potential utility for the study and exploitation of phagocytic cells for drug delivery. Monocytes and macrophages that ingest PODS retain normal characteristics including a robust chemotactic response. Moreover, the PODS-cytokine cargo is secreted by the loaded cell at a level sufficient to modulate the behavior of surrounding nonphagocytic cells. The results presented here demonstrate the potential of PODS nanoparticles as a novel molecular tool for the study and manipulation of phagocytic cells and for the development of Trojan horse immunotherapy strategies to treat cancer and other diseases.

Research Article

CFPU: A Cell-Free Processing Unit for High-Throughput, Automated In Vitro Circuit Characterization in Steady-State Conditions

Forward engineering synthetic circuits are at the core of synthetic biology. Automated solutions will be required to facilitate circuit design and implementation. Circuit design is increasingly being automated with design software, but innovations in experimental automation are lagging behind. Microfluidic technologies made it possible to perform in vitro transcription-translation (tx-tl) reactions with increasing throughput and sophistication, enabling screening and characterization of individual circuit elements and complete circuit designs. Here, we developed an automated microfluidic cell-free processing unit (CFPU) that extends high-throughput screening capabilities to a steady-state reaction environment, which is essential for the implementation and analysis of more complex and dynamic circuits. The CFPU contains 280 chemostats that can be individually programmed with DNA circuits. Each chemostat is periodically supplied with tx-tl reagents, giving rise to sustained, long-term steady-state conditions. Using microfluidic pulse width modulation (PWM), the device is able to generate tx-tl reagent compositions in real time. The device has higher throughput, lower reagent consumption, and overall higher functionality than current chemostat devices. We applied this technology to map transcription factor-based repression under equilibrium conditions and implemented dynamic gene circuits switchable by small molecules. We expect the CFPU to help bridge the gap between circuit design and experimental automation for in vitro development of synthetic gene circuits.


Plant Biosystems Design Research Roadmap 1.0

Human life intimately depends on plants for food, biomaterials, health, energy, and a sustainable environment. Various plants have been genetically improved mostly through breeding, along with limited modification via genetic engineering, yet they are still not able to meet the ever-increasing needs, in terms of both quantity and quality, resulting from the rapid increase in world population and expected standards of living. A step change that may address these challenges would be to expand the potential of plants using biosystems design approaches. This represents a shift in plant science research from relatively simple trial-and-error approaches to innovative strategies based on predictive models of biological systems. Plant biosystems design seeks to accelerate plant genetic improvement using genome editing and genetic circuit engineering or create novel plant systems through de novo synthesis of plant genomes. From this perspective, we present a comprehensive roadmap of plant biosystems design covering theories, principles, and technical methods, along with potential applications in basic and applied plant biology research. We highlight current challenges, future opportunities, and research priorities, along with a framework for international collaboration, towards rapid advancement of this emerging interdisciplinary area of research. Finally, we discuss the importance of social responsibility in utilizing plant biosystems design and suggest strategies for improving public perception, trust, and acceptance.

Review Article

Biosystems Design to Accelerate C3-to-CAM Progression

Global demand for food and bioenergy production has increased rapidly, while the area of arable land has been declining for decades due to damage caused by erosion, pollution, sea level rise, urban development, soil salinization, and water scarcity driven by global climate change. In order to overcome this conflict, there is an urgent need to adapt conventional agriculture to water-limited and hotter conditions with plant crop systems that display higher water-use efficiency (WUE). Crassulacean acid metabolism (CAM) species have substantially higher WUE than species performing C3 or C4 photosynthesis. CAM plants are derived from C3 photosynthesis ancestors. However, it is extremely unlikely that the C3 or C4 crop plants would evolve rapidly into CAM photosynthesis without human intervention. Currently, there is growing interest in improving WUE through transferring CAM into C3 crops. However, engineering a major metabolic plant pathway, like CAM, is challenging and requires a comprehensive deep understanding of the enzymatic reactions and regulatory networks in both C3 and CAM photosynthesis, as well as overcoming physiometabolic limitations such as diurnal stomatal regulation. Recent advances in CAM evolutionary genomics research, genome editing, and synthetic biology have increased the likelihood of successful acceleration of C3-to-CAM progression. Here, we first summarize the systems biology-level understanding of the molecular processes in the CAM pathway. Then, we review the principles of CAM engineering in an evolutionary context. Lastly, we discuss the technical approaches to accelerate the C3-to-CAM transition in plants using synthetic biology toolboxes.