Logo of the first Human Genome Project. Image courtesy of the U.S. Department of Energy Genomic Science program.

Professor Paul Freemont, Co-Director SynbiCITE

On June 3^rd an opinion paper was published in Science entitled ‘The Genome Project – Write’. The publication followed a supposed “secret meeting” of 150 scientists, policy makers, ethicists, social scientists and DIY biologists held at Harvard University Medical School in Boston US. The main subject discussed was a proposal to chemically synthesise the human genome and develop human cell lines which contained synthetically designed chromosomes. As one can imagine this caused a huge controversy, extensive global media coverage and open debates and arguments on social media. I attended the meeting but was not an author on the paper and I wanted to write this short blog to try to demystify the meeting and publication and put a perspective on what is proposed in the context of recent advances in research and technologies for large-scale genetic engineering.

Let’s start at the beginning with the discovery and publication in 1953 by Jim Watson and Francis Crick of the structure of DNA which is the common genetic material that all living systems use for instructing the mechanisms of life. It is thought by many that this discovery and subsequent discoveries in the 1960s on the nature of the genetic code (formed of four building blocks G, C, A, T, arranged in pairs) and the biochemical mechanisms that translate the code into living functions mediated by proteins, are among the most significant of all human discoveries.

For the first time in human history we had insights into the basic principles that lie at the core of life where the DNA genetic material acts as a rich and dense information store that can be rapidly replicated, inherited, repaired and decoded into biochemical functions. Further rapid advances in the 1970’s and 80’s allowed us to sequence or read the genetic code and then chemically synthesise the code. These discoveries now underpin all modern molecular and cellular biology research culminating in 2001 with what is surely another major landmark in human discovery – in my opinion comparable to the discoveries of gravity, magnetism or electricity - the reading or sequencing of the human genome which has nearly 3 billion G, C, A, T building blocks.

Although finished in 2001, this extraordinary global research project was first discussed back in the 1980’s as some sort of pipe dream. It began to gather serious momentum in the 1990’s when the justification around human health and medicine were accepted by funders and governments, particularly in the USA. The fruits of this project are only now being felt, with huge technological advances in reading DNA that now make this inexpensive (~$1-5K per genome), rapid and even portable. The medical implications are also being keenly explored in precision medicine around cancer treatments and diseases like neurodegeneration as well as providing insights into the genetic variations between human populations. One unexpected aspect of the human genome sequence was that only ~2% of the genetic sequence actually codes for genes/proteins leaving nearly 98% of the genome sequence apparently unaccounted for and like ‘dark matter’.

Why are we now discussing a second human genome project, namely Write? Well the reasons are several fold. Firstly, we are now at a point to consider such a project thanks to rapid advances in DNA synthesis and assembly as exemplified by the Sc2.0 project. In this international collaboration, researchers around the world, including here at SynbiCITE, are synthesising all 16 chromosomes for the commonly use Bakers yeast or Saccharomyces cerevisiae, which constitutes ~12 million building block pairs, a fraction of the human genome and due to complete in 2018. The largest human chromosome is made up of 249 million base pairs and would need an enormous and highly expensive amount of DNA for its creation.

At present, estimates suggest it would cost around $100 million worth to create a human genome. And that is just the cost of making DNA. The technology to handle these long and fragile lengths of DNA and place them into mammalian cells where they can be grown and studied does not exist at present. However, these are just the sorts of technologies that HGP-Write would develop.

Secondly, synthesising the human genome would actually be a natural extension of the sequencing project as it would allow researchers to explore the nature of the ‘dark matter’ contained within it. We would learn about the complexities of epigenetics, gene regulation, chromosome organisation and replication, the biochemical consequences of genetic variability to name but a few. It would provide molecular and cell biology researchers the tools to truly extend their research directions and would inevitably lead to technology development in DNA synthesis and synthetic chromosome assembly as well as our ability to move large pieces of DNA between cells. In terms of applications one could imagine new forms of gene/chromosome replacement therapy. It could also lead to a greater understanding of many human diseases, leading to new therapeutic areas being uncovered.

So what are the ethical issues that everyone is so concerned about? Would HGP-Write leads to designer humans? Medical researchers already replace sections of human DNA in cell lines that are grown in laboratories to investigate how specific human genes work and to establish what happens when they go wrong. There are very tight regulations concerning such research. It should also be noted that the HGP-Write project is explicit about only developing cell lines and not altering ova or embryos. So, personally I don't see this as some sort of secret route to creating or cloning humans or designing future super-humans, however it is absolutely essential that the project has direct public involvement. We should therefore establish common goals for both the public and researchers as part of an open and transparent debate to establish the best way forward in an era where technology is advancing so rapidly. It is possible that we need a different mechanism for discussing major ethical research projects, and - publishing the aims of HGP-Write is really the only start of this process.

References
(1)Human Genome Project HGP-read https://en.wikipedia.org/wiki/Human_Genome_Project
(2)Human Genome Project HGP-write - Boeke JD et al The Genome Project – Write, Science (2016) DOI: 10.1126/science.aaf6850
(3)Synthetic Yeast project http://syntheticyeast.org/sc2-0/