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Publishing in the journal Science a group of researchers in the field of synthetic biology have proposed a project to help the understanding and development of tools and methods for large-scale synthesis and editing of genomes – an organism’s DNA blueprint.
Prof. Richard Kitney, Professor of Biomedical Systems Engineering, Co-Director and Co-Founder of the Centre for Synthetic Biology and Innovation, Imperial College London, said:
“Most of the key points have been eloquently made by my colleagues Prof Paul Freemont and Dr Tom Ellis; however, I have made a few additional points below.”
Why would scientists want to create a synthetic human genome?
“In modern medicine it is now clearly understood that, wherever possible, the treatment of disease should be seen in the context of what is now known as the biological continuum – the hierarchy comprising whole-body, systems, viscera, tissue, cells, proteins, and genes. Whilst medicine has treated disease at the upper levels of the continuum for many years, it is only comparatively recently that it has begun to become possible to treat disease at the molecular level – hence the terms, the new medicine and molecular-based medicine. The original project associated with sequencing the human genome, which has still not been fully completed, was all about reading DNA. This resulted in the development of more and more effective methods for reading DNA, which have subsequently also developed into the ability to chemically write DNA. The importance of the proposed project to create a human genome is because it will address the actual function of all parts of the genome and to quote Richard Feynman “what I cannot create, I do not understand”. Hence, there is a direct link between building a human genome and obtaining a much better understanding of the genetic basis of disease.”
How far are we from being able to do this technically? And what kind of financial cost are we talking about?
“Colleagues involved in the yeast synthetic genome project estimate that it could take 15 to 20 years of intensive to complete a synthetic human genome. With regard to cost, estimates of between $500m and $2bn have been floated. However, this needs to be seen in the context of expenditure on health, which in the UK, for the NHS, was £127.5bn ($168bn) in 2013 – and that is only over one year (Source – Nuffield Trust).”
Anything else to add?
“I did not attend the meeting in Boston. However, it is my overall impression that this was the start of a long discussion between the scientific community, the media and the more general public. As with most scientific projects in this general area, there is now the protocol of responsible research innovation, which normally considers the ethical, societal and environmental implications of any scientific project. Work on a synthetic human genome will therefore be transparent and subject to scrutiny by, the public, media and the registry authorities.
“As pointed out in the paper, there are likely to be a number of key underlying developments in relation to tools and methodology in relation to the HGP-Write Project. First, the project will make it possible to get a far better understanding of biological systems operation – potentially at various levels of the biological continuum – and to place this information in the context of the systems biology approach, enabling the ability to undertake far more detailed modelling leading to an even greater understanding of the biological processes.
“As with the case of the HGP-Read Project, new areas of technology were developed which made it possible to read DNA rapidly, accurately and now, inexpensively. It is, therefore, likely that the HGP-Write Project will result in similar, but different, underlying technological developments. One potential example of this is the ability to undertake a much more systematic approach to gene therapy, with the ability to undertake the systematic design of replacement genes and gene circuits. This systematic approach will take molecular based medicine (particularly therapy) to a new level.
“An important aspect of the paper is the undertaking that the benefits of the project will be applied to “the pressing needs in different global regions”. There is a strong emphasis in both the paper and the more general field towards applying any technology which is developed to problems in the developing world as well as the developed world, in the context of responsible research innovation.”
Prof. John Ward, Professor of Synthetic Biology for Bioprocessing, The Advanced Centre for Biochemical Engineering, UCL, said:
“Twenty-five leading scientists in the field of synthetic biology have published a perspective paper (sort of like a Government white paper) in the journal Science calling for the establishing of the next logical phase of the human genome project. The paper is titled ‘The Genome Project–Write’ and where the decoding of the human genome was The Genome Project-Read, this new call to arms is to develop ways of building larger and larger segments of DNA up to chromosome and genome sized DNA molecules. The ultimate goal would be to synthesise the complete human genome from scratch.
“This is as bold an aim as the original human genome project (HGP) and the authors of this Science paper acknowledge that their new aim will be met with similar controversy as the original HGP had to contend with. But its now well accepted that the original HGP opened up the possibility and increasingly, the reality, for new medical treatments in human genetic diseases and cancer and we will be reaping the benefits of this for decades to come.
“The subtitle of this Science Perspective is ‘We need technology and an ethical framework for genome-scale engineering’ and the first part of this title belies the scale of the enterprise. The size of even the smallest human chromosome is 48 million base pairs which is 22 times the size of the largest yeast chromosome at 2.2 million base pairs. There is currently an international project to build a synthetic yeast genome but the genome of yeast is tiny and is composed of 16 chromosomes and totals 12 million base pairs whereas the human genome is 3.2 billion base pairs spread over 23 chromosomes.
“Having a goal such as this Genome Project-Write will help to push the methods of chromosome sized DNA construction and undoubtedly new methods will be developed just as we now sequence (read) DNA by dramatically different technologies than were used to sequence the human genome. The speed of DNA sequencing is now about 300,000 times faster and 1 million times cheaper and those advances have been made in just the last 15 years. This new project needs to build DNA at 1,000 times smaller cost and 1,000 times faster than current methods.
“The second part of that subtitle is the ethical framework. The project is not as controversial as some observers might be saying. First we already replace segments of human genes in cells growing in culture dishes. This is well regulated and is the very core of the new advances in medical genetics. Making large and larger pieces of human chromosomes and putting them into host cells in culture dishes will enable more deeper understanding of what all the genes and the non-coding DNA actually does. On the route to the final goal of this new initiative will be a myriad of new therapies for treating medical conditions from genetic diseases to viral infections. There is no call to make an entire human being just as there is no push for doing that with current studies using human embryos.
“The 25 scientists propose that this project would be carried out with public involvement using the framework of Responsible Innovation where common goals of both the public and the science are identified and worked on from the beginning. The debate by scientists at a recent meeting gave rise to this white paper and it’s fascinating to see the speed of progress from that debate only 23 days ago to this carefully formulated proposal.”
Prof. Paul Freemont, Co-Director of the Centre for Synthetic Biology and Innovation at Imperial College London, said:
What regulations are in place in the UK?
“There are no formal government regulations for the synthesis of DNA but companies that supply synthetic DNA have formed an International Gene Synthesis Consortium. The IGSC was initially an industrial organisation operating as a trade association promoting best practices for gene synthesis biosecurity under its operating policies embodied in the “Harmonized Protocol.” In April, 2015, the IGSC became a not-for-profit US company with a Board of Directors and procedures pertaining to best practices in biosecurity, with formal membership processes/vetting for new members including academic foundries. From the initial membership of 5 companies, the organization has grown and industrial members include all the major global synthetic DNA suppliers including Origene (Blue Heron), DNA2.0, Gen9, Genscript, ThermoFisher (Geneart/Life Technologies), IDT, Twist Bioscience and Synthetic Genomics (SGI-DNA).”
Why would scientists want to create a synthetic human genome?
“The sequencing of the human genome was a major landmark in human discovery as it allowed humanity to decipher the genetic code that provides the basis of all human life. This huge project led to major technology developments that have also accelerated biomedical research. The human genome sequence and further genome sequences are now providing insights into many human diseases not just hereditary but also disease like cancer and neurodegeneration and also 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’.
“The human genome synthesis project is a natural extension of this project in that by synthesising the human genome we will be able to uncover what the ‘dark matter’ in the human genome does and why we have it. We will also be able to elucidate details of how genes are regulated and also why we have such variation between humans and human populations. It will also provide technologies for advanced gene therapy and lead to a much greater understanding of how the genome is organised and how in disease cells this becomes altered. Ultimately we will be able to uncover new mechanisms of human biology and disease that will provide a firm basis for new therapies and disease interventions.
“It’s important to note that the human genome synthesis project, if started, will be implemented in a non-reproducing laboratory cell line.”
How far are we from being able to do this technically? And what kind of financial cost are we talking about?
“We will be able to initiate a genome synthesis project today as we are already synthesising genomes from other organisms like bacteria and yeast. Although the scale of the human genome (3 billion letters) is enormous the technologies exist, although improved technologies will be required. The costs are difficult to estimate at this stage but could be as much a $3bn today although the costs will become significantly reduced as new technology developments emerge. This will be due to new technology developments similar to what happened in the human genome sequencing project such that it can now cost a few thousand dollars compared to the >$2.7bn costs of the original human genome sequencing project.”
There must be lots of legal, and IP-related issues as well – are these issues already being discussed?
“This commentary and associated meeting is merely the start of an open and transparent debate on the human genome synthesis project.”
Are there more imminent projects on the horizon in the UK?
“The main genome synthesis project in the UK is as part of the synthetic yeast Sc2.0 project where all 16 chromosomes from baker’s yeast are being synthesised which constitutes >12 million letters which is a fraction of the human genome. Imperial College and the University of Edinburgh are involved in synthesising specific chromosomes and it is estimated that this project will be completed by 2018 where a yeast cell will comprise a completely synthetic genome.”
Could a lone scientist/group of scientists do this in a lab somewhere in the world, or will it take huge amounts of infrastructure/people/computing power etc and be more along the lines of a biological version of CERN where loads of scientists would have to weigh in?
“The scale and magnitude of the human genome requires a huge investment in researchers and infrastructure and would involve many hundreds of researchers (even thousands).”
Dr Tom Ellis, Senior Lecturer and Group Leader, Centre for Synthetic Biology and Department of Bioengineering, Imperial College London, said:
Why would scientists want to create a synthetic human genome?
“There are a variety of different reasons, but the primary reason to synthesise any genome is to aid in the understanding of what the DNA sequence of the genome does. By building a synthetic genome from the information currently available, we can assess how much our knowledge of the roles of genomic DNA is true. If we can delete or drastically change regions of the genome without having any effect on the behaviour of the cell, then that lets us know that the DNA within that region is not really important for basic functions. Conversely, every time we incorporate changes in the synthetic genome that affect the way the cell behaves, then we learn that the DNA sequence in that region has a specific function. Scientific research has typically worked this way for decades, but now with the ability to synthesise huge regions of DNA and even genomes, we can do this at a much larger scale and assess many different questions at the same time. We call this ‘learning by building’ – it’s a key part of synthetic biology and one of the major drivers for the work that myself and some of the authors of this paper have been doing in the Sc2.0 project, where we write a synthetic version of the yeast genome.”
How far are we from being able to do this technically? And what kind of financial cost are we talking about?
“I think we are 15 years away from this being achieved if it gets significant backing and 20+ years if it just remains the project of a few labs. There’s no chance of this being done in the next 5 years given our lack of technologies for quickly incorporating very large DNA into mammalian cells. We also don’t really know enough about the human genome to make a lot of definite decisions about how to re-design the sequence in a synthetic genome. We actually still don’t have a complete human genome sequence yet as some parts are so hard to sequence! The amount of DNA that would need to be made is also considerable – at least 3 billion bases for doing a complete haploid human genome if that is the goal. That would cost over $100 million in DNA costs alone right now, although everyone expects the costs of synthesising DNA to fall considerably in the future. The real cost, which isn’t really being addressed in the paper is the amount of people time this would take. Over 15 years, in many labs around the world it would put the cost of this work past the half a billion territory.”
There must be lots of legal, and IP-related issues as well – are these issues already being discussed?
“Yes, very much so. At the Boston meeting nearly half of the schedule was related to the legal and ethical issues. There were some very insightful discussions. Whose genome to base the sequence on? Who is allowed to work on the project and use the synthetic genome in the future and for what uses? Do the institutes that make the various synthetic genome regions retain any control or IP on what they have made? This last point is especially interesting as Jef Boeke, who already leads the synthetic yeast genome project, has got all institutes involved in that project to agree not to retain any IP, making the synthetic yeast genome available to anyone who wants to use it who has an appropriate lab. So companies can use it without any restrictions.”
Are there more imminent projects on the horizon in the UK?
“Aside from the UK’s ongoing work on the synthetic yeast genome (at Imperial in my lab, and in Edinburgh in Yizhi Cai’s lab), there are no other synthetic genome projects in the UK as far as I’m aware. Large-scale synthetic biology projects in mammalian cells like human cells are being started at Edinburgh by Susan Rosser and others and are also planned at Imperial.”
Could a lone scientist/group of scientists do this in a lab somewhere in the world, or will it take huge amounts of infrastructure/people/computing power etc and be more along the lines of a biological version of CERN where loads of scientists would have to weigh in?
“Definitely the latter. This is a very large project that would require at least 50 dedicated people for 15 years plus and a very large budget. If you call Craig Venter a lone scientist, then I guess he counts… but in reality he has a whole institute doing the work for him.”
Anything else to add?
“The discussions about a coordinated effort to synthesise a human genome is where things began for the group who’ve produced this paper. However, in the months since the project has morphed into something a little less ambitious and a bit more amorphous. My take from the Boston meeting was that getting going on writing a synthetic human genome is still 5 years away or maybe more and what the group are trying to do is begin discussions as early as possible. I think this is a good and responsible move. Start the conversations early, before the technology makes it doable. And in the meantime, plan and begin a variety of different projects at a smaller scale (say 1 million base pairs+) in mammalian cell systems to test and push the technology while making scientific discoveries or developing useful applications. While I’m still unsold on the idea of a complete synthetic human genome, I do like the ideas behind many of the possible smaller-scale pilot projects and I think synthetic biology can make much more progress in general if people around the world are tackling projects like this in coordination and adhering to set standards – both technical and IP/ethical. I’m sure the UK will be involved and I’d like to be involved at this level myself. It’s a great opportunity for global researchers to pool resources and work together.”
‘The Genome Project–Write’ by Boeke et al. published via First Release, a Science platform on Thursday 2nd June.
Declared interests
Prof. Ward: “I am employed full time by University College London. I receive grant funding currently from the BBSRC, EPSRC, Almac, Biocatalysts, Synthace and Novartis. In the past I have also received funding from MRC, Wellcome Trust, Royal Society, Cobra Therapeutics, Lonza, Pfizer and GSK. I am a member of the Society for Microbiology, the Society for Applied Microbiology and The Biochemical Society. I was involved with the first UK Synthetic Biology Roadmap and the Roadmap Refresh. I am part of Synbicite and on the UK Synthetic Biology Leadership Council subgroup. I run an MSes in Synthetic Biology here at UCL. I have share options in Synthace.”
Prof Freemont: “I attended the meeting in Boston in early May.”
Dr Ellis: “I’m a collaborator on the Sc2.0 project with three of the authors Jef Boeke, Leslie Mitchell and Yizhi Cai. I also attended the meeting in Boston in early May.”