Launched in 2016 with the sprawling ambition to build large genomes, the synthetic biology initiative known as Genome Project–write (GP-write) is now, slowly, getting down to specifics. Ahead of a meeting today in Boston, GP-write’s leadership announced a plan to organize its international group of collaborators around a “community-wide project”: engineering cells to resist viral infection.
GP-write’s original proposal to design and assemble an entire human genome from scratch seems to have receded from view since the project’s rocky launch, when a private meeting of its founders sparked accusations of secrecy and speculations about labmade humans. A proposal published weeks later in Science described GP-write as a decadelong effort to reduce by more than 1000-fold the cost of engineering and testing large genomes consisting of hundreds of millions of DNA letters.
The narrower project announced today—redesigning the genomes of cells from humans and other species to make them “ultrasafe”—represents “a theme that could run through all of GP-write,” says geneticist Jef Boeke of New York University Langone Medical Center in New York City, who leads the project along with Harvard University geneticist George Church, lawyer Nancy Kelley of Nancy J Kelley + Associates in New York City, and biotechnology catalyst Andrew Hessel of the San Francisco, California–based software company Autodesk Research.
For now, GP-write and the nonprofit Center of Excellence for Engineering Biology set up to manage it aren’t offering researchers any funding to make the new project happen. (“We’re organizing ourselves to be able to tell a story for a foundation or philanthropic investor or governmental funder,” Kelley says.) But if the goal of ultrasafe cells leads to a more formal collaboration among synthetic biology labs worldwide—like the nearly completed synthetic yeast genome project that Boeke leads—it could have practical payoffs. Drug companies are sometimes forced to halt production when the cells they use to crank out therapeutic proteins get contaminated with a virus. Resistant cell lines would be safer and more efficient medicine factories that might require less monitoring.
More broadly, the project might help researchers move beyond editing tools such as CRISPR, which typically tweak DNA at a few specific locations, and toward more widespread redesign of genomes, says Farren Isaacs, a bioengineer at Yale University and a member of the GP-write scientific executive board that selected the project. He envisions future efforts to “rewrite genomes … to impart entirely new function into [an] organism,” such as the ability to thrive only in the tightly controlled environment of a biocontainment lab. Beyond virus resistance, the GP-write organizers are also considering other ultrasafe cell features, such as resistance to cancerous mutations, radiation, and freezing.
Virus-proofing the genetic code
Making cells impervious to viruses will require “recoding”—changing the three-letter DNA sequences, known as codons, that encode the amino acid building blocks of proteins. Because multiple codons can represent the same amino acid, researchers can swap out redundant codons and still preserve a cell’s vital functions. And by eliminating certain codons altogether, researchers can safely get rid of some of the cellular machinery used to translate those codons into proteins—machinery that viruses also depend on to decode their own genes when they hijack the cell and try to replicate. The recoded cell can’t play host to viruses because “it basically speaks another language,” says Torsten Waldminghaus, a chromosome biologist at Philipps University of Marburg in Germany who is not involved in GP-write.
Making human cells virus-resistant will involve at least 400,000 changes to the genome, according to GP-write’s announcement today. Depending on how that new genome is designed, Isaacs says, the project might still rely heavily on editing—tweaking the existing DNA sequence by a few letters here and there. But to swap out codons that are densely packed into a certain part of the genome—or, further in the future, to insert entirely new sets of genes—researchers will have to design and ferry in larger stretches of lab-synthesized DNA.
The project will likely require technology born in the labs of GP-write’s founders and leaders. Isaacs began experiments to recode the genome of the bacterium Escherichia coli in 2005 as a postdoctoral researcher in Church’s lab. In a 2013 paper, Isaacs, Church, and their collaborators swapped out all 321 instances of a single codon in E. coli, rendering it resistant to certain viruses. And both labs are now working on removing additional E. coli codons.
“It worked in E. coli, and I would expect it to work in human cells also,” Waldminghaus says of the recoding idea. “It’s not amazingly new scientific insight … but I still think it’s worthwhile.”
Practical questions remain
It’s not yet clear how this community-wide project would be executed. Boeke, who would like to prioritize the human and mouse genomes for recoding, expects to gather feedback and gauge the interest of potential collaborators at today’s meeting. If the new project is modeled on the ongoing yeast genome project, known as Sc2.0, groups that opt in would come up with funding for their share and divide up the work by chromosomes. (“I think there may be a lot of competition for the smaller chromosomes,” Boeke says.)
Boeke anticipates other challenges that Sc2.0 didn’t face. The yeast project has involved “a relatively small team that worked really well together,” he says. “I don’t necessarily anticipate it’s going to be as straightforward with this much larger, more diverse group.” GP-write counts nearly 200 scientists among its participants, some of whom have self-organized into nine “working groups” to tackle topics from technology and infrastructure development to the ethical, legal, and social implications of the project. Since GP-write’s meeting last year, the groups have been developing “charters” and “road maps” for future work, which they’ll present today.
Intellectual property considerations might also complicate the project. “There’s just generally a lot of IP [intellectual property] around synthetic biology and synthetic genomics,” Boeke says, “and the payoff in humans might be much higher than in yeast.” Isaacs notes that Harvard, Yale, and the Massachusetts Institute of Technology in Cambridge all hold patents related to recoding. But among GP-write’s working groups is an intellectual property team to explore how the technology used in GP-write—and any future breakthroughs it might inspire—will be shared.