The research portfolio of KAUST’s Computational Bioscience Research Center (CBRC) encompasses computational biology and bioinformatics with applications in life sciences.
The latest technological developments in experimental biology, the depth of scientific questions raised and the demands of genomic sciences clearly demonstrate that bioinformatics and computational biology are necessary key components of the process leading to fundamental discoveries and technological developments. Computational bioscience is particularly important in the disciplines of metabolic engineering and synthetic biology, which both can be considered as control engineering of biological systems. The capability to efficiently alter the behavior of a living cell, usually a microorganism, or to introduce by design a new functionality, is scientifically challenging and exciting. At the same time, development of such a capability for microbes opens many routes to useful biotechnology applications that may lead to scalable carbon capture combined with production of industrially important chemicals or biomass-derived products. This new, engineered phenotype is achieved by insertion of designed molecular constructs into the cell genome. The road to efficient design of such ‘new functionality’ molecular blocks, requires sophisticated computational methodologies and systems that still have to be developed. The necessary scientific insights for many important functional aspects of cellular behavior necessary for informed (rational) molecular designs for synthetic biology relies on information that can only be obtained from high-throughput assays, omics including next generation sequencing (NGS) experiments. In recent years biology has witnessed a dramatic increase in the volume of data generated through such experiments, which demands novel computational solutions that can fully exploit the modern computational architectures to enable efficient analyses of these data. With all these factors in mind, we define the mission of the Computational Bioscience Research Center (CBRC) as follows:
Design of novel high performance computational biology/bioinformatics methods, tools, resources and models that will lead to and speed up development of applications in synthetic biology and biotechnology and validating these applications in engineered cells.
CBRC Research Focus
Through its mission, CBRC is uniquely and justifiably positioned to address some of the above-mentioned problems right away. With this objective in mind, CBRC aims to develop computationally driven methodologies, tools and resources to enable, enhance and speed up development and design of “efficient microbial cell factories” (MCFs) (microorganisms engineered and optimized to produce biomass or specific chemicals for industrial use) and to validate the same in well-designed experiments.
CBRC aims to develop:
- An infrastructure for bioinformatics and computational/mathematical modeling of microbial systems to generate deeper insights into functioning of microorganisms.
- An infrastructure for rational design of synthetic biology constructs (parts and their compositions) to enable informed engineering of microorganisms for industrial applications feasible and relevant within the Saudi Arabian context.
- Engineered microorganisms capable of carbon capture and conversion to targeted industrially important chemicals, enzymes and biomass.
Road to achieving our goals
The focus of our research is modeling the key processes in the living cell so as to be able to explore the way cell reacts to different challenges, for example, being able to explore and accurately simulate the effects of chemicals on different cellular processes, as well as model of synthetic biology constructs, optimize metabolic pathways, and reduce the search space for suitable pathways. The solutions in this domain are generic and could find applications in single cell, as well as complex multicellular organisms.
From a perspective of computational science, development of computational methods and their application in biology are key areas for generating high impact results and discoveries. This is primarily driven by the recent developments in systems approaches to biological research using a variety of high throughput techniques (genomics, transcriptomics, proteomics and metabolomics) that provide insights into whole-genome responses and large quantity of data, but do not provide direct answers to important biological questions. The output of these activities has several distinctive characteristics such as:
- Size: the resulting experimental data is often enormous in size of the order of gigabytes to terabytes.
- Complexity: available data points to networks of extremely complex interactions between entities encapsulated within data.
- Dependency: available information is typically strongly context-dependent, further frustrating analysis of biologically relevant relationships.
Direct application of traditional computational methodologies is not able to adequately address the three challenges mentioned above due to their computational intractability. For that reason, a considerable part of the CBRC`s activity is related to addressing these problems. These remedies are largely contaimed in two complementary approaches:
- Development and application of methods resulting in new algorithms that can address computational intractability by providing acceptable solutions.
- Development of new and modification of the existing algorithms in a way that makes it possible for efficient execution on HPC systems. This involves, among other, code optimization and parallelization that allows for properly harnessing the unique advantages offered by KAUST`s leading edge HPC and other computational resources within an academic environment.
The ability to analyze large and complex data sets facilitates the Center`s research in a broad scope of biological problems. These include, for example, modeling of biological networks; construction of in silico genetic and metabolic cellular models; modeling and metabolic engineering of heterotrophic and photosynthetic MCFs for carbon capture and conversion into renewable chemicals or biomass.
Knowledge-based development of engineered microorganisms for targeted production is a complex multidisciplinary program with huge potential for multiple significant downstream impacts. Achieving the desired outcomes is impossible through the isolated efforts of any single discipline. It requires tight integration of computer science, mathematics, biology, chemistry, physics and engineering to cover different domain-specific expertise needed in this development process. These disciplines are synergistically intertwined in CBRC and in our research program. Development of engineered microorganisms requires validated synthetic biology constructs, reusable ‘molecular modules’, as building blocks for altered or new functionality of the microorganisms. These cannot be efficiently developed without advanced high-quality modeling of the relevant molecular processes. This modeling, in addition to the ‘first-principles’, data-based and graph-type descriptions of interactions, requires experimental data for model verification and tuning. Due to specifics of different microorganisms, modeling crucially requires high-quality NGS and omics analyses, such as genome assembly and functional annotation, inference of signaling pathways, gene regulation, protein interaction networks and metabolic pathways, as well as interplay between genomic and metabolic layers of control. These cannot be obtained without comprehensive bioinformatics and computational biology analyses of high throughput assays, genomic, transcriptomic, proteomic and metabolomic experimental data that capture the microorganisms’ behavior. Such analyses also require more efficient algorithms and tools to provide the needed quality and speed in obtaining the results. Moreover, to enable efficient designs, good knowledgebase infrastructure that not only integrates information from disparate sources, but also enables automated analyses of important segments in the design process and easy exploration of the relevant information is necessary. This meaningful integration of various disciplines within the CBRC is the key for their synergistic effects to our research program and its success.
Impact of Center`s work within the Kingdom of Saudi Arabia
CBRC works to develop novel and efficient technology platforms focused on design and engineering of MCFs and delivery of selected MCF systems. The applications of these platforms, while focused on MCF design, are not restricted to the few selected microorganisms, pathways or enzymes, but are generic in their capacity to search for potential solutions for missing or optimized functionality of microorganisms. These analysis and design platforms are themselves of high IP value. The platforms will be validated through the actual design and construction of MCFs based on selected, optimized and engineered microorganisms targeting specific metabolites and enzymes, which are expected to generate further biotechnology-oriented IP. In this program we focus on microalgae- and cyanobacteria-based multiproduct MCFs (e.g. Ulvophyte microalgae spp., Chroococales spp. and Oscillatores spp. e.g. Geitlerinema cyanobacteria spp. and Halobacteria spp.) for carbon capture and conversion processes in KSA, production of selected osmoprotectants (e.g. high value sugars, sugar alcohols, and their phosphate derivatives) that accumulate to high levels in cells (e.g. for use as animal/fish food resource), production of selected enzymes including those involved in the synthesis of the above, as well as protein industrial catalysts, and finally selected metabolites (e.g. sulfonium compounds for chemical feedstocks, petrochemicals and fertilizers) as well as lipids for biofuels which can offset internal KSA oil consumption. This plays to the competitive strengths of computational bioscience (being able to rapidly predict cellular behavior from large biological data) as well as those of the KSA, which is the preeminent site for large-scale photosynthetic microbial culture. Thus, the downstream impact on KSA is expected to be of the game-changing nature.
Review of the Center's Activities
The main activities in the Center can be summarized as follows:
- Research and publications
- Education and training
- Technology, software, prototype, and patent development
- In-KAUST collaboration and research support/guidance/consulting
- Academic collaboration, both within and outside of the Kingdom
- Industrial collaboration, both within and outside of the Kingdom