OUR SCIENCE
From sequence
to understanding.
We use genome writing as an experimental approach to explore how DNA shapes biological function.
GENE WRITING
An introduction to gene writing
The principle of gene writing: Gene Writing draws inspiration from mobile genetic elements (MGEs), some of evolution’s greatest genome architects. Since Barbara McClintock discovered the first mobile genetic element in maize in the 1950s, these elements have been recognized as important participants in biology.
Mobile genetic elements are DNA sequences that can move within a genome, including transposons and bacteriophage elements. Transposons are a major focus of research. Transposition involves a DNA sequence being copied or excised from its original position, circularized and inserted at another site, where it may influence downstream gene regulation. Such sequences are called transposons or jumping genes. Approximately 6,000 retrotransposons for RNA-based gene writing and 2,000 potentially useful transposons for DNA-based gene writing have been identified.
Imagine the human genome as a train and its DNA segments as individual carriages. Most carriages keep their positions and order, whereas a transposon can change position—for example, moving from carriage 2 to carriage 8. In cut-and-paste or copy-and-paste movement, an existing carriage can be transferred to a new position, or a copy can be inserted while the original remains in place. Special DNA sequences define the two ends of a transposon. The protein-coding region between them can be removed to make room for a new gene segment.
Gene writing adapts the ability of transposons to carry a gene of interest and insert it into a genome, with the aim of enabling the insertion of long DNA sequences.
By drawing on the biology of mobile genetic elements, gene writing offers four potential ways to address challenges in genetic medicine:
- Unlike nuclease-based gene editing, gene writing relies little on the host’s DNA repair pathways, potentially enabling the efficient addition of long or short genetic sequences to somatic-cell genomes.
- Unlike gene therapy based on adeno-associated virus (AAV) vectors, newly added DNA could remain permanently in dividing cells.
- New DNA sequences could be inserted into a genome through RNA delivery.
- Patients could receive multiple doses for repeat treatment, potentially addressing limitations of current gene therapies.
How can we write mammalian genomes at scale?
What do complex genomic regions do?
How do genomic changes cause disease?
GENOME WRITING & ENGINEERING
Build the tools.
Expand the questions.
What becomes experimentally accessible when we can rewrite larger stretches of a genome?
We develop technologies for mammalian genome writing and editing, opening up ways to construct and compare designed genomic sequences.
Write designed sequences to test how the genome works.
COMPLEX GENOMIC REGIONS
Understand the
genome in context.
How does a regulatory element’s surrounding sequence influence its function?
We investigate large regulatory elements and complex genomic regions, where studying an isolated sequence may miss the contribution of its genomic context.
DISEASE MODELS & MECHANISMS
From association
toward causality.
Which genomic alterations drive disease, and how?
We construct cellular and animal models to examine the biological consequences of genomic changes and investigate mechanisms that may inform future interventions.