Yeast grow on an agar plate in the form of the microbe’s chromosomes, with colors representing whether a chromosome exists in a synthetic form (yellow) or just wild-type (orange).

Drew Gurian

Money still missing as the plan to synthesize a human genome takes another step forward

Tuesday morning, more than 200 biologists, businesspeople, and ethicists will converge on the New York Genome Center in New York City to jump-start what they hope will be biology’s next blockbuster: Genome Project-write (GP-write), a still-unfunded sequel to the Human Genome Project where instead of reading a human genome, scientists create one from scratch and incorporate it into cells for various research and medical purposes. For example, proponents suggest that they could design a synthetic genome to make human cells resistant to viral infections, radiation, and cancer. Those cells could be used immediately for industrial drug production. With additional genome tinkering to avoid rejection by the immune system, they could be used clinically as a universal stem cell therapy.

The project got off to a bumpy start last year and despite the central rallying cry of a synthetic human genome, many of those attending the conference will bring in different expectations and ambitions. Some resent the unwanted attention and criticism that the project’s public objective has brought, saying it distracts from the goal of improving DNA synthesis technologies, because cheaper and faster methods to write DNA have many applications in applied and basic research. Others say that a made-to-order human genome is inevitable anyway, hoping to seize the publicity and controversy it creates as an opportunity to educate the public about synthetic biology.

“If you put humans as the target, even though you are not going to make a human baby, it will be provocative, it will be misinterpreted, but people will engage,” says Andrew Hessel, a self-described futurist and biotechnology catalyst at Autodesk in San Francisco, California, a successful software company that specializes in 3D design programs for architecture and other fields that has been exploring synthetic biology applications in recent years. Hessel is one of the four founders of GP-write, along with lawyer Nancy Kelley and geneticists Jef Boeke of New York University Langone Medical Center in New York City and George Church of Harvard University.

GP-write debuted prematurely in May 2016, when an invitation-only meeting at Harvard became public and sparked a media firestorm about the lack of transparency for an initiative that to some people sounded like a plan to create genetically enhanced humans—the leaders say it isn’t, although Church wasn’t shy when musing about designer humans in a 2012 book he authored. The intent of the closed-door meeting was to allow scientists to speak freely, Hessel and the other leaders say, and to prepare a peer-reviewed paper describing the project that was later published in Science in June. The month gap between the meeting and the Science paper created further confusion because the paper’s embargo forbade scientists from discussing the project.

GP-write’s founders hope that this week’s open meeting will reinforce the seriousness of the initiative. Ethicists and lawyers are now sprinkled throughout the group’s many nooks, and several young biotech startups and software developers have expressed interest in GP-write. Scientists are also encouraged to propose their own pilot projects to serve as stepping stones, although many participants are careful to note that these projects are valuable regardless of whether the group decides to reach for the ultimate goal of synthesizing a human genome.

“There is definitely an internal tension” among GP-write’s supporters, Hessel says. “Scientists are a conservative community. 

Controversial by design

Hessel first proposed a vision to synthesize a human genome in a Huffington Post article back in 2012. Several years later, during an international conference about synthesizing the yeast genome in 2015, Hessel reiterated the goal in a panel discussion, saying it should be biology’s next big science effort. “Frankly, I was surprised that the scientific community hadn’t organized to suggest something like this,” Hessel says. “It just seemed kind of obvious and I think it stunned the crowd.”

A week later, Hessel called Church and asked whether he would be open to leading the initiative. Church agreed, provided Boeke, the leader of the international synthetic yeast project Sc2.0, came aboard as a co-leader. Boeke took a bit more convincing. “My immediate reaction was, ‘Oh my gosh, you have got to be kidding me,’” Boeke says. “I am definitely the conservative of the group.”

But then he was persuaded that some of the pilot goals of the project were worthwhile. “I got most excited about it when George brought his idea of virus-resistant mammalian cells on the table, and the idea of an ultrasafe cell line, which could be a relatively short-term win,” Boeke says. Engineering an ultrasafe cell line would be a boon to biotechnology companies that use large vats of cells to crank out biologic drugs or industrial molecules. They now must constantly monitor for signs of a viral infection that could wipe out tanks of cells across an entire manufacturing facility.

Great interest, little money so far

The synthetic biology effort was originally called Human Genome Project 2, but the founders changed the name to Human Genome Project-write by the time of the closed-door meeting last May. Since then, they dropped “human” in an attempt to diffuse public controversies. “The human part of it really got a lot of people overly excited, and that kind of overshadowed the intent to make it be about writing genomic sequences in general,” Boeke says. “Both George Church and I from the very beginning always envisioned this as not being limited to humans.” That expanded vision is particularly apparent in this week’s meeting, which will include talks from scientists working with genomes from species as varied as bacteria, yeast, octopuses, and plants. 

But despite the carefully crafted allusion to the Human Genome Project, which garnered about $3 billion in financial support from government and industry, GP-write, for now, doesn’t have any money to offer researchers. “We hope the [National Institutes of Health] will be involved in GP-write but thus far they haven’t been as enthusiastic as we are,” Boeke says.

GP-write’s current funding is a far cry from the $100 million they hoped to raise in 2016. Last year, Autodesk contributed $250,000 to GP-write to kick-start planning and organization. The next round of funding may come from Labcyte, a firm specializing in machines that manipulate miniscule amounts of liquid through ultrasound. According to a meeting organizer, Labcyte will be GP-write’s first corporate partner. The company confirms it has made a 3-year financial commitment, but has not disclosed the terms yet.

So far, scientists hoping to be part of GP-write are pursuing synthetic biology pilot projects with funding they’ve gotten independently. Harris Wang of Columbia University told ScienceInsider that he will receive $500,000 from the Defense Advanced Research Projects Agency (DARPA) to engineer about 40 nonhuman metabolic genes into human cells, enabling them to produce the nine essential amino acids that we now must get from our diet. A small tech company called Chromologic received $200,000 from DARPA to study methods for shuttling large strands of synthetic DNA into cells, although this project was not explicitly related to GP-write. And early stage startup Neochromosome, which includes Boeke, intends to raise money to design synthetic chromosomes for medicine that could be used in an off-the-shelf universal cell line in cell therapies and transplants with minimal risk of rejection from the immune system.

Technical feasibility aside, an undertaking right now to synthesize a complete human genome would be extraordinarily expensive—easily upward of $100 million with current pricing. The human genome is 3 billion nucleotides long. “That’s a million times bigger than the longest piece [of DNA] we make today,” says Emily Leproust, CEO of Twist Bioscience in San Francisco. Her company has developed a faster, higher-throughput method to assemble DNA for about $0.09 per base compared with a previous average of $0.25, she says. And although companies like Twist could stand to benefit from large orders of DNA from GP-write, she notes that “to do the kind of science that the GP-write is talking about, there needs to be a massive technology improvement.”

One young startup, Molecular Assemblies in San Diego, California, has rejected the decades-old organic chemistry method of linking DNA bases. Instead, they are refining a new method that utilizes a little-studied DNA-making enzyme found in some cells. The company anticipates going commercial within 2 to 3 years with a process using a template independent polymerase—an unusual enzyme that, unlike most polymerases, synthesizes DNA without having a strand whose sequence can be copied. “Our nascent company motto is that we think DNA will be the industrial polymer of the 21st century,” chief scientific officer Bill Efcavitch says. Beyond the numerous synthetic biology applications, Efcavitch envisions that cheaper and more rapid DNA synthesis will push innovation in nanotechnology applications, such as using DNA for biosensors and data storage.

“There is lots of good science going on, but it is initiated and funded outside GP-write, because there is no funding yet,” says Seattle, Washington–based biotech investor Robert Carlson, an author of the GP-write paper published in Science. “You can conceive of this meeting as some people gathering around a beer or a whiteboard and saying, 'Let’s lay out some experiments to test some ideas about how genomes are put together and why they are organized the way they are.'”

Whether the project develops financial legs to carry out its goals remains to be seen, but at the very least, it is recruiting a passionate, if not fully unified, group. “At the end of the day, it is really about putting the foundation in place to write much larger genomes than we are presently able to, and to recognize that these technologies are coming very quickly whether we are ready for them or not,” Hessel says. “I think this is just going to be a kickass meeting. The room is going to be full of interesting folks. And I am sure there will be dissenters too.”

Correction, 6:25 P.M. This story has been changed to clarify that no specific announcement regarding Labcyte's funding is planned for the New York meeting.