GoKawiilTen years ago, when I was a first-year graduate student, my PhD adviser smuggled me into a private meeting at Harvard Medical School in Boston, Massachusetts. I listened in thrall as participants from academia, industry and government debated the ethics, promise and pitfalls of an ambitious project: building a copy of the human genome from scratch using synthetic DNA.
A synthetic genome is built by replacing, piece by piece, a cell’s natural genome with DNA made in the laboratory. The artificial sequences can be copies of their natural counterparts or designed to give the cell properties that aren’t found in nature.
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When the synthetic human genome project was made public in June 2016, it had two main goals. First, to slash the cost of engineering large genomes by 1,000-fold within a decade. And, second, to produce a cell line with an ‘ultrasafe’ synthetic genome that was engineered to, for instance, make the cells less prone to viral infection.
But efforts never really got off the ground. At the time, the technological landscape was not ready to support the project’s ambitions and, failing to gather enough funding, the project remained a series of pilot research proposals and meetings rather than the centralized programme it set out to be. That no longer needs to be the case.
DNA synthesis and assembly methods have improved enough to reliably produce long genomic sequences. Scientists can insert synthetic DNA into cells — although this remains a bottleneck in research. Artificial-intelligence models can help scientists to predict how changes to DNA will affect cell biology. And there are signs that funders are starting to take the idea of a synthetic human genome seriously. For example, UK researchers are aiming to build the first fully synthetic human chromosome through a £10-million (US$13-million) project launched in 2025.
As such work begins, it’s time for synthetic biologists, ethicists and others to revisit a genome-scale project. However, such a project should follow a different path from the original plan.
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The goal to produce an ultrasafe modified cell line, although worthwhile, was arguably of limited scientific value. Broad, genome-wide resistance to viruses would require rewriting the genetic code across thousands of sites in an organism’s DNA. Such work would mainly use existing knowledge of genetic-code redundancy rather than uncover new biology. In many cases, targeted strategies — such as blocking viral entry or modifying a smaller set of genes — can provide adequate resistance without the need for whole genome recoding.
A more ambitious and potentially transformative goal would be to define the minimal human genome — stripping it down to the smallest set of genetic elements required for a cell to function. The focus would switch from large-scale editing to gaining a deeper understanding of which elements are essential.
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