Building to Understand: The Constructionist Approach to Studying Gene Regulation

Organisers: Jef Boeke, Stefan Mundlos and Sudarshan Pinglay

Date: 15–18 July 2024

Location: Buxted Park, East Sussex, UK

The genomics revolution has resulted in the generation of a large catalogue of non-coding regulatory elements in the human and other genomes that are implicated in the control of gene expression. However, we still lack an understanding of:

1) the grammar within regulatory elements that specifies how they exert their influence

2) how these elements work together across large genomic windows to specify gene expression

3) how to ultimately predict gene expression from primary sequence. Answering these questions will reveal our developmental blueprint, clarify disease mechanisms, and unlock the potential of personalized medicine and gene therapy.

Inspired by Richard Feynman’s famous aphorism: “What I cannot create, I do not understand”, advances in genome editing, sequencing, synthetic biology, and computational models have converged to enable a ‘constructionist’ approach to understanding gene regulation in complex genomes. Analogous to in vitro reconstitution in biochemistry, such a bottom-up approach has great potential to uncover the intricacies of gene regulation as it allows for exquisite control over all components in the system.

Despite the promise of this approach to set a new paradigm in studies of gene regulation, there has not yet been a venue to bring together the various groups beginning to pursue this ‘constructionist’ strategy. At this Workshop, we aim to organise this burgeoning field into a collaborative community, discuss the philosophical foundations and identify the biggest technology development opportunities to drive the field forward. We will also ponder the implications of what it would take to fully satisfy Feynman’s directive: designing entire genomes from the ground up?

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