George Church

George Church giving the first lecture in the Department of Biology’s four-part IAP seminar series, Biology at Transformative Frontiers. (Photo: Raleigh McElvery)

Genome Project-write (GP-write) was born a year ago when a group of scientists convened in New York City to discuss the plan of constructing an entire human genome from scratch. 

Now, nearly a year on GP-write participants assembled for a third time at Harvard Medical School, to lay out the challenges they face while also presenting the beginnings of a strategy to move the project forward, writes c&en

“We have lofty goals and don’t know how to accomplish most of them,” said Jeffrey Schloss, a former director at the National Human Genome Research Institute. “I actually think this project is way more difficult” than sequencing the first human genome. In a bid to encourage developments needed to synthesise the first human genome, the scientists have chosen a simpler pilot plot, and that’s the creation of a human cell that is resistant to viral infection. 

Engineering a cell in this way will require scientists to make at least 400,000 changes to the human genome and would serve as a stepping-stone to eventually writing the full 3 billion base pairs that make up the entirety of our genetic code. 

Even though the new project is considered tame, researchers estimate that it could still take ten years to complete. The so-called ultrasafe human cell line might find applications in research labs and at pharmaceutical companies, where viral contamination in vats of cells has halted the production of protein-based drugs. As well as recoding cells for viral resistance, the group also plans to add genes that could allow them to survive radiation and freezing, and potentially even prevent cancer. 

“It is important to have an achievable short-term project that is not ambiguous and scary,” explained Andrew Hessel, one of GP-write’s four cofounders and CEO of Humane Genomics, a biotech start-up developing cancer therapies for dogs. 

In order to be successful in this project, the ultrasafe cell line will require recoding the human genome, a task that is already underway with bacterial cells in the lab of Harvard University geneticist George Church, another of GP-write’s cofounders. 

There is a strong belief from researchers that aside from viral resistance, another reason to recode genomes is to give proteins new powers. Researchers have already figured out how to incorporate amino acids that don’t exist in nature into proteins. The first step involves removing every copy of a particular codon. Researchers then reintroduce the code that selects spots in a gene. Additional engineering allows that codon to be paired with the new amino acid, integrating it into the protein. This method is already the basis of biotech start-up Gro Biosciences and allows drug designers to tweak the chemical properties of therapeutic proteins. 

But, of course recoding a human genome, which is about 600 times as big as the E.coli genome, will be more difficult. “Theoretically, you can use current methods to do the recoding one by one, but that is not the smartest way to do it,” said Nili Ostrov, a postdoctoral researcher, who joined Church’s lab in 2014. This is exactly why she is leading a GP-write working group for technology and infrastructure development. “The overall goal of GP-write is not just to make a single cell line but to make the technology for making many cell lines faster, easier, and cheaper.”

This vision is just beginning to gain momentum from the drug industry. This is With French cell therapy company Cellectis announcing during the meeting that is would give Church’s lab access to its TALEN gene-editing technique, TALENs are older and more difficult to design, but they actually “seem to be a little more specific” in their editing, said Church. 

Cellectis CEO Andre Choulika said he can’t imagine using recoded or fully synthetic genomes in cell therapy anytime soon. “But projects like this are what makes science move forward,” he added. “I think GP-write is probably a milestone in the history of humans. People have no idea how this is going to change our lives in the 21st century and beyond.”

However, one large hurdle for the team right now is working out how to pay for the project, as technological leaps are not cheap. Some GP-write participants have suggested that patenting the ulstrasafe cell line or technologies developed along the way could encourage financial support from investors. 

“It may be essential,” said Kristin Neuman, executive director for biotechnology licensing at the patent firm MPEG LA. “Some of the scientists want to see everything open access. Others recognise the importance of intellectual property protection to incentivise private investment,” she explained. During the meeting, Neuman encouraged the group to consider patents for cells and technology developed by the group while still making the ulstrasafe cell line available to researchers doing basic science. 

With this in mind, GP-write cofounder Nancy Kelley said a systematic fundraising effort will begin soon. “A couple years ago we had a rocky beginning, and we really needed to do some work on straightening out the message,” she said. “I now believe we have something serious to talk about.”

Church went on to explain that more than 100 research groups involved in GP-write have their own significant funding. “I don’t think we are underfunded at this point; I think we just need to execute,” he explained. Teams can now begin signing up for a chromosome, or part of a chromosome, to recode or help with technology development. “There are plenty of things for people to do today.”

When the meeting came to an end, the group’s goals seemed more focused and much broader. Church explained that the group is not backing down from synthesising a full human genome and that the ultrasafe cell line gives the consortium an immediate task with a clear payoff. But in the end, it may well just be less about completing a project and more about uniting a multidisciplinary cohort of scientists behind something big. 

“Our goals aren’t finished yet,” Church said. “Hopefully they won’t be fixed in stone even at the finish line.”