2321. Should We Synthesise a Human Genome?

By Drew Endy and Laurie Zoloth, Cosmos, May 12, 2016

At Harvard today, an invitation-only group of about 150 scientists, lawyers, and entrepreneurs, met to discuss if and how to construct from scratch an entire human genome – the heritable genetic material that in nature is transferred from parents to children.

The meeting was originally organised to focus on “deliverables and industry involvement” with the primary goal of the project being “to synthesise a complete human genome in a cell line within a period of 10 years”.

Such a synthetic genome could then be tested in a laboratory by replacing the existing genome within a human cell. All this would still be far removed from making a synthetic human.

However, the possibility of making a human cell, whose genome is realised from only digital information and raw materials, should trigger broader considerations.  

For context, total synthesis of a human genome is becoming plausible at an accelerating rate. Thanks to new production techniques developed since 2003 the cost of assembling the genetic material encoding genes, the “building blocks” of life, has decreased from $4.00 to just three cents per individual letter, or “base pair” of deoxyribonucleic acid (DNA). 

As a result, the estimated initial cost of printing the DNA fragments encoding a three billion base pair human genome has dropped from $12 billion to $90 million. 

If cost reductions continue in the way they have been, then this price would approach $100,000 within 20 years. However, such dramatic additional cost reductions might never be realised without an overwhelming demand.

Advocates of synthesising a human genome, therefore argue that some open, collaborative “grand challenge” is needed to drive development of such technologies. 

While we strongly agree that sustained improvements in DNA construction tools are essential for advancing basic biological science and improving public health we are sceptical that synthesising a human genome is an appropriate demand driver.

We recall how controversies associated with many of the earliest genome synthesis projects delivered unintended consequences. 

For example, a project that made polio virus from scratch in 2002 generated such fear that public funding for improving DNA synthesis tools was cancelled, unwittingly harming research across diverse and unrelated fields while policy makers struggled to imagine how such tools could ever be controlled.

We argue that the synthesis of less controversial and more immediately useful genomes along with greatly improved sub-genomic synthesis capacities (for example, the real-time printing of plasmids  the casettes that transfer genes between cells) should be pursued instead.

These are alternatives that would deliver broad and diverse public benefits.

Other topics on today’s agenda included changing the human genome itself.  For example, could scientists synthesise a modified human genome that is resistant to all natural viruses? 

They likely could, for purely beneficial purposes, but what if others then sought to synthesise modified viruses that overcame such resistance? Might doing so start a genome-engineering arms race? 

And, what of even greater changes that can be imagined?

In a world where human reproduction has already become a competitive marketplace, with eggs, sperm and embryos carrying a price, it is easy to make up far stranger uses of human genome synthesis capacities. 

Would it be OK, for example, to sequence and then synthesise Einstein’s genome?  If so how many Einstein genomes should be made and installed in cells, and who would get to make them? 

Taking a step back, just because something becomes possible, how should we approach determining if it is ethical to pursue?

Given that human genome synthesis is a technology that can completely redefine the core of what now joins all of humanity together as a species, we argue that discussions of making such capacities real, like today’s Harvard conference, should not take place without open and advance consideration of whether it is morally right to proceed.

When the first people at the table mostly have significant and direct material interests in proceeding, everyone, not just those in the room, risk out-of-control competition between public and private interests, ethical conflicts of interest, and temptations to manipulate human subject consent.

Pluralistic, public, and deliberative discussions are instead the best appropriate way to frame paths forward.

We note that the narrative of creation of the human is the central narrative for many religious communities.

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 perspectives of others including self-identified theologians, philosophers, and ethicists from a variety of traditions should be sought out from the very beginning.

Critical voices representing civil society, who have long been sceptical 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 industrialised or fully commodified. It remains an act of faith, joy, and hope. 

Discussions to synthesise, for the first time, a human genome should not occur in closed rooms.   

Drew Endy is Associate Professor of Bioengineering at Stanford University.

Laurie Zoloth is a professor of medical ethics and humanities at Northwestern University, Chicago.

Related post: Synthatic Biology: Making Humans from Chemical?

2320. Synthetic Biology: Making Humans from Chemical?

By Andrew Pollack, The New York Times, May 14, 2016

Sixty trays can contain the entire human genome as 23,040 different fragments of cloned DNA. Photo: James King-Holmes/Science Source

Scientists are now contemplating the fabrication of a human genome, meaning they would use chemicals to manufacture all the DNA contained in human chromosomes.

The prospect is spurring both intrigue and concern in the life sciences community because it might be possible, such as through cloning, to use a synthetic genome to create human beings without biological parents.

While the project is still in the idea phase, and also involves efforts to improve DNA synthesis in general, it was discussed at a closed-door meeting on Tuesday at Harvard Medical School in Boston. The nearly 150 attendees were told not to contact the news media or to post on Twitter during the meeting.

Organizers said the project could have a big scientific payoff and would be a follow-up to the original Human Genome Project, which was aimed at reading the sequence of the three billion chemical letters in the DNA blueprint of human life. The new project, by contrast, would involve not reading, but rather writing the human genome — synthesizing all three billion units from chemicals.

But such an attempt would raise numerous ethical issues. Could scientists create humans with certain kinds of traits, perhaps people born and bred to be soldiers? Or might it be possible to make copies of specific people?

“Would it be O.K., for example, to sequence and then synthesize Einstein’s genome?” Drew Endy, a bioengineer at Stanford, and Laurie Zoloth, a bioethicist at Northwestern University, wrote in an essay criticizing the proposed project. “If so how many Einstein genomes should be made and installed in cells, and who would get to make them?”

Dr. Endy, though invited, said he deliberately did not attend the meeting at Harvard because it was not being opened to enough people and was not giving enough thought to the ethical implications of the work.

George Church, a professor of genetics at Harvard Medical School and an organizer of the proposed project, said there had been a misunderstanding. The project was not aimed at creating people, just cells, and would not be restricted to human genomes, he said. Rather it would aim to improve the ability to synthesize DNA in general, which could be applied to various animals, plants and microbes.

“They’re painting a picture which I don’t think represents the project,” Dr. Church said in an interview.

He said the meeting was closed to the news media, and people were asked not to tweet because the project organizers, in an attempt to be transparent, had submitted a paper to a scientific journal. They were therefore not supposed to discuss the idea publicly before publication. He and other organizers said ethical aspects have been amply discussed since the beginning.

The project was initially called HGP2: The Human Genome Synthesis Project, with HGP referring to the Human Genome Project. An invitation to the meeting at Harvard said that the primary goal “would be to synthesize a complete human genome in a cell line within a period of 10 years.”

But by the time the meeting was held, the name had been changed to “HGP-Write: Testing Large Synthetic Genomes in Cells.”

The project does not yet have funding, Dr. Church said, though various companies and foundations would be invited to contribute, and some have indicated interest. The federal government will also be asked. A spokeswoman for the National Institutes of Health declined to comment, saying the project was in too early a stage.

Besides Dr. Church, the organizers include Jef Boeke, director of the institute for systems genetics at NYU Langone Medical Center, and Andrew Hessel, a self-described futurist who works at the Bay Area software company Autodesk and who first proposed such a project in 2012.

Scientists and companies can now change the DNA in cells, for example, by adding foreign genes or changing the letters in the existing genes. This technique is routinely used to make drugs, such as insulin for diabetes, inside genetically modified cells, as well as to make genetically modified crops. And scientists are now debating the ethics of new technology that might allow genetic changes to be made in embryos.

But synthesizing a gene, or an entire genome, would provide the opportunity to make even more extensive changes in DNA.

For instance, companies are now using organisms like yeast to make complex chemicals, like flavorings and fragrances. That requires adding not just one gene to the yeast, like to make insulin, but numerous genes in order to create an entire chemical production process within the cell. With that much tinkering needed, it can be easier to synthesize the DNA from scratch.

Right now, synthesizing DNA is difficult and error-prone. Existing techniques can reliably make strands that are only about 200 base pairs long, with the base pairs being the chemical units in DNA. A single gene can be hundreds or thousands of base pairs long. To synthesize one of those, multiple 200-unit segments have to be spliced together.

But the cost and capabilities are rapidly improving. Dr. Endy of Stanford, who is a co-founder of a DNA synthesis company called Gen9, said the cost of synthesizing genes has plummeted from $4 per base pair in 2003 to 3 cents now. But even at that rate, the cost for three billion letters would be $90 million. He said if costs continued to decline at the same pace, that figure could reach $100,000 in 20 years.

J. Craig Venter, the genetic scientist, synthesized a bacterial genome consisting of about a million base pairs. The synthetic genome was inserted into a cell and took control of that cell. While his first synthetic genome was mainly a copy of an existing genome, Dr. Venter and colleagues this year synthesized a more original bacterial genome, about 500,000 base pairs long.

Dr. Boeke is leading an international consortium that is synthesizing the genome of yeast, which consists of about 12 million base pairs. The scientists are making changes, such as deleting stretches of DNA that do not have any function, in an attempt to make a more streamlined and stable genome.

But the human genome is more than 200 times as large as that of yeast and it is not clear if such a synthesis would be feasible.

Jeremy Minshull, chief executive of DNA2.0, a DNA synthesis company, questioned if the effort would be worth it.

“Our ability to understand what to build is so far behind what we can build,” said Dr. Minshull, who was invited to the meeting at Harvard but did not attend. “I just don’t think that being able to make more and more and more and cheaper and cheaper and cheaper is going to get us the understanding we need.”

Related post:
Should we synthesise a human genome?