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In vivo Directed Evolution As a Service for the development of novel microorganisms leveraging the full potential of White Biotechnology.

Periodic Reporting for period 2 - IDEAS (In vivo Directed Evolution As a Service for the development of novel microorganisms leveraging the full potential of White Biotechnology.)

Reporting period: 2022-01-01 to 2022-12-31

The objective of IDEAS project is to develop an advanced platform for Adaptive Laboratory Evolution (ALE) as an enabling technology for the Industrial Biotechnology (IB).

IB has the potential to replace fossil-based processes by sustainable processes capable to convert recycled or renewable materials into matters daily used by Humans with applications in food, feed, agriculture, materials, fuels, chemicals, materials or cosmetics. The sector already has a significant economic impact in Europe and a large potential to grow. Outlook to 2030 shows that employment in the industrial biotech value chain may increase to well above one million jobs, contributing up to €99,5 billion to the EU economy.

The microorganism’s performance is a main driver in the economics of fermentation processes. Yet, the knowledge about living organisms remains limited and we cannot predict which mutations are required to bring the microorganism to a level of performance compatible with its profitable exploitation at industrial scale. Besides, genome editing tools cannot be used in applications where Genetically Modified Organisms (GMOs) are banned by either regulation or end consumers. For these reasons, the potential of Industrial Biotechnology still must be achieved.

In this context, ALE is a powerful approach that delivers not only microbial strains adapted to industrial requirement but also valuable and strategic information. ALE harnesses natural selection to enhance microorganisms through the accumulation of beneficial mutations in its genome without a priori knowledge on the underlying mechanisms that would confer the microorganism with the optimized performance. The fast development of affordable techniques to characterize living cells, such as genomics, transcriptomics and other omics creates a strategic opportunity for ALE as the latter generates beneficial mutations that can be characterized and interpreted with the former techniques.

IDEAS project ambitions to bring ALE solutions to industrial companies and support their Research & Development in the field of Industrial Biotechnology, through the achievement of i) an industrialized hardware design capable to automate long-term ALE experiments in continuous culture on one hand (Work Package 1), and ii) digital solutions that support the automated selection of enhanced microorganisms, the operation by laboratory technicians, the supervision by project managers and the continuous improvement of the technology’s efficiency through data analysis (Work Package 2).
The 1st Work Package aims at developing the industrial version of the Genemat system (GM4). During this 1st year, we evaluated and selected the best partner through a call for tender. The initial steps of the workplan were performed: (i) refining the specifications and identifying the key functions, (ii) building a set of breadboards for testing technologies for each of the key functions and downselecting the best, (iii) designing and building a prototype for testing all the elements integrated together. A subset of these key functions includes the integration of new sensing capabilities, the extension of existing sensing ranges and the addition of new monitoring features. The breadboards were developed to provide representative experimental conditions and capabilities for long-term testing up to 3 months.
Simultaneously, we performed experimental and modelling studies to improve our knowledge about key parameters controlling the hardware operation.

The 2nd Work Package covers 1) the Altar’s digital transition toward internal users or external customers and 2) the improvement of the evolution protocols performed in the hardware setup.
Regarding the 1st goal, a product manager was hired with a focus on defining the product vision and orientation of the main software we want to deploy. We started doing a round of interviews with former and current customers, as well as internal interviews and field observations. We decided to focus first on improving our operational efficiency and free the Project Managers from low added-value tasks so that they can focus on higher value work.
We are building a project management dashboard that will include three main building blocks: project monitoring, reporting, data storage and visualization. As of the end of 2021, an initial software architecture using these blocks was established and the user interface/experience was completed. We performed initial developments to evaluate some software solutions for building a database collecting all the data generated by the hardware and for visualizing the evolution experiments. In parallel, after an evaluation period, we bought an Electronic Lab Notebook software and initiated the transition towards digital tools for our lab operations.
To achieve the 2nd goal of improving the evolution protocols, we firstly investigated some characterization capabilities for monitoring microorganisms’ phenotypes along the evolution experiment. Classical approaches using standard or improved micro-well plate readers were compared to more advanced technologies developed by startup companies and leveraging recent advances in microfluidics. The study allowed us to collect our requirements (such as cost of instrument/consumables/operation, reliability, support, automated data processing), evaluate all these approaches.
We initiated a program to leverage the data continuously generated by our devices, aiming at identifying statistical correlations between observed evolution trajectories and parameters set for the evolutionary experiments, and at developing analytical models. We also investigated new methods for data processing supporting real-time decision-making.
Progress beyond the state of the art
• Integrating sensors inside a cultivation chamber frequently cleaned with harsh chemicals
• New evolution protocol decreasing the required duration to achieve a target
• Data science to improve understanding and monitoring of adaptive laboratory evolution
• Unique visualization tool to present an interactive evolutionary map
• Online dashboard specifically designed for presenting data from ALE experiments and performing actions to control them

Expected results until the end
We still expect to achieve the ambitious goals that were set at the beginning of the project:
• A new hardware designed for industrial production with the associated safety certification allowing its fabrication in countries outside EU. New generation ALE protocols will be released, supported by innovative architecture and novel capabilities for real-time monitoring.
• A dematerialized platform serving the internal users and external customers, presenting dashboards for each specific user (internal project manager, external project manager, lab technician) with actionable links
• Improved understanding and control of our evolution protocols by including further microbial strain characterization along the evolution and data processing

Potential impacts
• Positioning Altar as the ALE leader company with unique technology and know how
• Bringing more customers to Altar by democratizing ALE through digital approach with a customer-centric interface
• Filing patents and publishing the results from this project
• Fulfill ALE potential as an enabling technology that fosters competitiveness of Industrial Biotechnology
Altar's team
Production laboratory with Evolution platforms
Data visualization