At the third meeting of GP-write, researchers decide to create virus-resistant human cells
by Ryan Cross
May 14, 2018 | A version of this story appeared in Volume 96, Issue 20 c&en
A year ago, a group of scientists convened in New York City to discuss an audacious plan: construct an entire human genome from scratch. The proposal was billed as a sequel to the Human Genome Project, the nearly $3 billion effort to sequence, or read, a human genome from start to finish for the first time. Now proficient in reading genomes, the scientists wanted to begin writing them.
That New York gathering was the second meeting of what has come to be known as Genome Project-write, or GP-write. This month, GP-write participants assembled for a third time, at Harvard Medical School. The motley crew—100-plus educators, engineers, entrepreneurs, ethicists, lawyers, programmers, and scientists—laid out the challenges they face while also presenting the beginnings of a strategy to move the project forward.
“We have lofty goals and don’t know how to accomplish most of them,” said Jeffrey A. 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, he added.
To spur technology developments needed to synthesize the first human genome, the scientists have chosen a simpler pilot project: the creation of a human cell that is resistant to viral infection. Engineering such a cell 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.
The new project is comparatively tame, but researchers estimate it could still take 10 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. In addition to recoding cells for viral resistance, the group 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,”
said Andrew Hessel, one of GP-write’s four cofounders and CEO of Humane Genomics, a biotech start-up developing cancer therapies for dogs.
The ultrasafe cell line will require recoding the human genome, a task that is already under way with bacterial cells in the lab of Harvard University geneticist George Church, another of GP-write’s cofounders.
We have lofty goals and don’t know how to accomplish most of them.
Jeffrey A. Schloss, a former director, National Human Genome Research Institute
Recoding a genome is a complex process. Three letters of DNA compose a codon, which a cell’s machinery can translate into a single amino acid, the building block of proteins. Each of nature’s 20 amino acids can be translated by multiple different codons: For instance, GGT, GGC, GGA, and GGG are all codons for the amino acid glycine. If scientists replace every GGG in a genome with GGA, the cell will still translate that codon into glycine, and thus make the same protein. But that tiny change could prevent a virus that relies on the GGG codon from hijacking the cell’s protein machinery to replicate.
In 2013, Church’s lab published an experiment replacing all 321 instances of a particular codon in the Escherichia coli genome. Since joining Church’s lab as a postdoctoral researcher in 2014, Nili Ostrov has been leading an effort to replace six more codons from the bacteria’s genome, which will require 62,000 edits in all. The project will be completed and published “very soon,” she said at the meeting.
In addition to viral resistance, Ostrov explained, 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 is to remove every copy of a particular codon. Researchers then reintroduce the code at select spots in a gene. Additional engineering allows that codon to be paired with the new amino acid, integrating it into the protein.
The method, which allows drug designers to tweak the chemical properties of therapeutic proteins, is already the basis of the biotech start-up Gro Biosciences, cofounded by Church and some of his former students.
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,” Ostrov said. That’s 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.”
That vision is beginning to attract interest from the drug industry. The French cell therapy company Cellectis announced during the meeting that it would give Church’s lab access to its TALEN gene-editing platform. Compared with the popular CRISPR gene-editing technique, TALENs are older and more difficult to design, but they actually “seem to be a little more specific” in their editing, Church said.
Cellectis CEO André 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 said. “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.”
Technological leaps are not cheap, however, and a major hurdle for the GP-write team is figuring out how to pay for the project.
In the 15 years since the Human Genome Project was declared finished in 2003, the cost of reading a whole human genome has plummeted to about $1,000. Scientists estimate that writing a full human genome with today’s DNA synthesis technology could cost upward of $100 million. That number was the group’s declared fundraising goal in 2016, but it still doesn’t have centralized funding dedicated to the task. This year, some GP-write participants suggested that patenting the ultrasafe 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 recognize the importance of intellectual property protection to incentivize private investment,” she observed. During the meeting, Neuman encouraged the group to consider patents for cells and technology developed by the group while still making the ultrasafe cell line available to researchers doing basic science.
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 added 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 said. 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.”
At the end of the GP-write meeting, the group’s goals seemed at once more focused and much broader. Church said the group is not backing down from synthesizing a full human genome and that the ultrasafe cell line gives the consortium an immediate task with a clear payoff. But in the end, the GP-write story may be less about completing a project and more about uniting a multidisciplinary cohort of scientists behind something big.
“Our goals aren’t fixed in stone yet,” Church said. “Hopefully they won’t be fixed in stone even at the finish line.”.