Now That We Can Read Genomes, Can We Write Them?

NEW YORK CITY—Since the Human Genome Project (HGP) was completed in 2003, scientists have sequenced the full genomes of hundreds, perhaps thousands, of species. Octopuses. Barley. Mosquitoes. Birch trees. Reading genomes is now commonplace, but that’s not enough for the group of scientists who gathered at the New York Genome Center on Tuesday. They want to write entire genomes with the same ease, synthesizing them from scratch and implanting them into hollow cells.

One team already did this for a tiny bacterium in 2010, creating a synthetic cell called Synthia. But the New York group has set its sights on building the considerably larger genomes of plants, animals, and yes—after a lot of future discussion—humans.

For now, that’s technically implausible. You’d have to make millions of short stretches of DNA, assemble them into larger structures, get them into an empty cell, and wrap and fold them correctly. In the process, you’d go bankrupt. Although we can sequence a human genome for less than $1,000, writing all 3 billion letters would still cost around $30 million. Still, even that exorbitant price has fallen from $12 billion in 2003, and should reach $100,000 within the next 20 years. And the group assembled in New York wants to double that pace.

They’re pushing for an international project called Genome Project-write—GP-write—that aims to reduce the costs of building large genomes by 1,000 times within 10 years. “It’s an aggressive goal, but based on what we saw with the HGP—the reading project, if you will—we think we can do this,” said Jef Boeke from New York University School of Medicine. And just as the HGP helped to drive down the cost of DNA-sequencing, the GP-write team hopes that the demand created by their initiative will push down the cost of DNA-writing tech. “I want to see a time in the not-too-distant future when, in elementary schools, it’ll be routine to think: I want to do some DNA synthesis as a project,” said Pamela Silver from Harvard Medical School.

But GP-Write is still more of an idea than an actual thing. The group hopes to raise $100 million, but in the year since the project was first proposed, little of that sum has materialized. That cast a strange air upon the first day of the New York meeting, as if speakers were pitching ideas to a collaboration that has yet to successfully pitch itself.

Better news arrived on Wednesday, when the team announced that Boeke and Harris Wang from Columbia University have secured $500,000 for a GP-write pilot project, from the Defense Advanced Research Projects Agency (DARPA). They’ll use that money to engineer human cells into self-sufficient nutrient factories. Early on in our evolution, animals lost the ability to manufacture certain vitamins and amino acids, forcing us to get these essential nutrients from our diet. But plants, fungi, and bacteria can still produce these nutrients, and by exploiting their genes, we could restore that lost manufacturing ability to our own cells. That would make it much easier and cheaper to grow such cells in laboratory cultures.

DARPA’s involvement inevitably invites visions of self-sustaining soldiers who don’t need to eat, but the GP-Write team has explicitly said that they’re not trying to make synthetic people. They’re only ever planning to create synthetic cells, or blobs of tissue (organoids) made from those cells—not eggs or embryos.

For example, another possible pilot project involves creating lineages of “ultrasafe” human cells. Such cells could have their cancer genes deactivated so they could be more safely injected during stem cell treatments. They could be tweaked to avoid triggering an immune reaction, and so be used to grow organs for transplants. They could be made resistant to viruses, so that biotechnology companies could use them to pump out medicines and vaccines without fear of costly contamination. (In 2008, Genzyme lost millions of dollars after a virus hit its cell lines and forced it to close a manufacturing plant for months.)

Scientists can already do some of that with gene-editing techniques like CRISPR, which allow them to make precise changes to an organism’s DNA. But powerful though CRISPR is, it has limits. And as Nili Ostrov from Harvard University reminded me, editing requires synthesis—to use CRISPR, you need to make genetic material to guide editing enzymes to the right spot. And if you want to make a lot of edits, it might be more efficient to just build everything from scratch.

For example, the human genome is full of repetitive chunks called “retroelements.” These are the result of ancient viruses that wheedled their way into our DNA, stayed there, and copied themselves again and again. Yasunori Aizawa from the Tokyo Institute of Technology wants to know whether these sequences are important, but because they’re all very similar, he can’t use CRISPR to target any particular one of them. But with better DNA-writing tech, he could create cells with any number of retroelements, and test if they’re affected.

Meanwhile, June Medford from Colorado State University wants to eventually engineer the genomes of plants so they could filter water or detect chemicals—she showed a slide of an airport gate encircled by explosive-detecting shrubbery. These are complicated traits involving large networks of genes, and many plant genomes are already disproportionately big. “I don’t think you could do it just by modification,” she told me.

Building genomes also allows you to effectively test genomes. You could make cells with every possible mutation in critical genes to see which ones are likely to cause disease. You could reconstruct genomes from earlier points of a species’ evolutionary history. It’s an engineer’s mentality: repeated cycles of designing, building, and testing. “I want to know the rules that make a genome tick,” says Boeke. “[Physicist Richard] Feynman said, ‘What I cannot create, I cannot understand.’ That has become a manifesto for our field.”

The first genomes to be completely synthesized were that of tiny viruses, like poliovirus back in 2002. It took another 8 years to do the same for a bacterium, with a million DNA letters in its genome. Boeke’s team of international colleagues is on the verge of repeating that feat for baker’s yeast—a simple fungus with a 12-million-letter genome. The pace of their progress is impressive, but the human genome is almost 300 times bigger still.

It is also far more controversial. When GP-write was first announced last year, it had an H (for ‘human’) at its head and bad publicity already at its heels. Boeke, Church, and their colleagues had invited 135 scientists and other interested parties to discuss the project at a meeting at Cambridge, Massachussetts. But because they had submitted a paper about HGP-write to the journal Science, whose embargo process forbids any prior announcements or interactions with the press, the meeting took place behind closed doors.

The lack of transparency drew sharp rebuke from Drew Endy, a synthetic biologist at Stanford University who had been invited (and who founded a DNA synthesis company), and Laurie Zoloth, a professor of bioethics and medical humanities at Northwestern University. They published an opinion piece lambasting the group for holding a closed meeting and failing to engage with the ethical consequences of their goals. After all, the HGP-write project may not be looking to make designer humans but as journalist Antonio Regalado has pointed out, one of its leaders—George Church—clearly discussed that option as the climax of such research, in his 2012 book Regenesis.

To which Endy and Zoloth wrote: “To create a human genome from scratch would be an enormous moral gesture whose consequences should not be framed initially on the advice of lawyers and regulators alone,” the duo wrote. “Critical voices representing civil society, who have long been skeptical of synthetic biology’s claims, should also be included. The creation of new human life is one of the last human-associated processes that has not yet been industrialized or fully commodified. It remains an act of faith, joy, and hope.”

The GP-write group have listened. The New York meeting was more open than the Cambridge one. And they dropped the H to emphasize that they’re working toward techniques that will be broadly applicable all kinds of organisms. HGP-write will still exist within that umbrella, but as a slower-moving project that will leave time for public discussion. These are all good steps, says Zoloth. What matters now is how the community wrestles with important questions. “In whose interest is the work being done?” she asks. “For what purpose?  Over whose oversight?  In a world where we cannot assure that everyone can get a clean glass of water, how is just to imagine a powerful technology being fairly developed and fairly distributed?”

The answers were not yet forthcoming at the New York meeting. Speakers included several ethicists who rightly noted the need for transparency, responsible communication, and open dialogue. But the discussions felt thin and all-too-familiar. When I asked if GP-write had unique ethical dimensions that differed from those that have already been endlessly discussed for CRISPR, stem cells, cloning, and other biotech, no one offered a clear answer. One attendee noted that the discussion largely echoed that from the Asilomar conference in 1975, when delegates debated the ethics of nascent genetic-engineering technology. Another noted that if GP-write finally takes off next year, it would coincide with the 200th anniversary of Mary Shelley’s Frankenstein.

Still, the GP-write group has committed to detailed ethical discussions over the next several years, and will dedicate a certain portion of any future funds towards that. “The notion that we could write a human genome is simultaneously thrilling to some and not so thrilling to others,” says Boeke. “We recognize that this will take a lot of discussion.”

Indeed, that’s partly why the project needs to exist, says Virginia Cornish from Columbia University. “Any new field needs to be out front, thinking about ethical and safety implications—and that’s not something I as a single scientist can do,” she says. “We need to be well-organized to have a real presence with government, industry, and the public.”