In July 2015, 100 geneticists met at the New York Genome Center to discuss yeast. At 12 million base pairs long, it's the largest genome scientists have tried to produce synthetically.
Andrew Hessel, a researcher with the Bio/Nano research group at software company Autodesk, was invited to speak at the event. The audience asked him which organism should be synthesised next. "I said, 'Look around the room. You've got hardly anyone here and you're doing the most sophisticated genetic engineering in the world," Hessel recalls. "Why don't you take a page out of history and set the bar high? Do the human genome."
This triggered a panel discussion that stuck in Hessel's mind for weeks. Soon afterwards, he contacted George Church, a prominent geneticist at Harvard University, to gauge his interest in launching what would effectively be the Human Genome Project 2.0. "To me it was obvious," Hessel recalls. "If we could read and analyse a human genome, we should also write one."
A year later, his provocation had become reality. In May 2016, scientists, lawyers and government representatives converged at Harvard to discuss the Human Genome Project-Write (HGP-Write), a plan to build whole genomes out of chemically synthesised DNA. It will build on the $3 billion (£2.3bn) Human Genome Project, which mapped each letter in the human genome.
Leading the Harvard event was Church, whose lab is synthesising the 4.5-million-base-pair E. coli genome, and Jef Boeke 1, the NYU School of Medicine geneticist behind the yeast synthesis project. "I think we realised the two of us were getting good enough at those two genomes that we should be discussing larger ones," says Church.
A Science paper published after the meeting formally laid out the group's proposal: to dramatically advance DNA-synthesis technologies so that the artificial production of genomes becomes easier, faster, and cheaper. Currently, we can synthesise short strands of DNA, up to about 200 base pairs long, but the average gene has several thousand base pairs. Even this limited process is inefficient, costly and slow. But it's vital: in biological sciences, synthesised DNA is the foundation of experiments that drive everything from cancer research to vaccine development. For scientists, it's like working with a blunt yet necessary instrument.
The immense three-billion-base-pair human genome is seen as the project's ultimate goal, dangling like a carrot to drive innovation. Scientists intend to have fully synthesised it in a living cell - which would make the material functional - within ten years, at a projected cost of $1 billion. The fruits of HGP-Write could have wide-ranging, real-world impacts. But in its current form, say the scientists, it's primarily a call for technological advancement in synthetic biology. The May announcement received a frosty reception from some, however. A handful of scientists invited to the event declined to attend, due to organisers' decision not to include the press. Church says they were excluded because of an embargo on the forthcoming paper.
There are bigger concerns: artificial production of genomes raises the ethically unsettling question of gene patenting. Other worries, echoing those that first surrounded the gene-editing technology CRISPR, are of designer humans and parentless babies. "Moving beyond reading DNA to writing DNA is a natural next step," concedes Francis Collins, director of the US National Institutes of Health. He warns, however, that any project with real-world implications would require "extensive discussion from different perspectives, most especially including the general public".
Applications beyond the lab are a distant reality: synthesising a human genome may even prove unworkable. In any case, none of the project's deliverables will be "as exciting or as evocative as a baby", Hessel says. "Some of the things that were said [after the meeting] were so ludicrous that it allowed us to get through that bubble of misinformation and misinterpretation quickly."
HGP-Write's central goal is to improve synthesis technologies so it's easier to write longer strands of genetic material. DNA is made using software that designs the layout of a strand, followed by machines in a laboratory that use this template to synthesise and assemble it. It's a clunky process that limits production to short stretches of DNA. But Hessel sees the potential for enhanced software allowing more precise genome design and printing tools that, for instance, harness enzymes to build DNA the way it happens in our cells. "If we can achieve this, it should be possible to write large genomes in hours," he says.
Smaller plant and animal genomes could also be synthesised along the way. One major scientific benefit could be the creation of living cell lines for pharmaceutical testing. Whole-genome synthesis would also bring down the cost of gene editing. CRISPR allows individual edits to DNA, but producing a full genome would allow thousands of edits in one go. Church sees the potential of genomes being edited to have multiple-virus resistance, for example.
But these are the "byproducts" of HGP-Write, in Hessel's view: the project's true purpose is to create the impetus for technological advances that will lead to these long-term benefits. "Since all these [synthesis] technologies are exponentially improving, we should keep pushing that improvement rather than just turning the crank blindly and expensively," Church says. In 20 years, this could cut the cost of synthesising a human genome to $100,000, compared to the $12 billion estimated a decade ago.
In coming months, scientists will try to take HGP-Write from proposal to project. That depends on funding. Autodesk has pledged $250,000, but organisers want to secure $10 million by the end of 2017. In the meantime, they'll be expanding the HGP-Write conversation. "I want it to be as open and transparent as possible," says Hessel, "and to keep up as much interest in this powerful universal technology, which will enable us to bring our intention into the machinery we call life. And boy, do we need to get good at it."
- Boeke, JD, et al (2016) The Genome Project-Write, Science, 10:1126/science.aaf6850.
This article was originally published by WIRED UK
