How big is Venter's synthetic breakthrough?

By Peter Griffin 21/05/2010

Whenever geneticist Dr Craig Venter outlines new research he is involved in the whole world listens.

Source: Science
Source: Science

That’s because Venter was involved in one of the biggest scientific breakthroughs of the last 20 years – the sequencing of the human genome. The implications of that advance for the field of genetics has been huge and helped pave the way for the $1000 genome which scientists claim they are close to cracking.

Since working on the Human Genome Project, Venter’s real driving interest has been in the area of synethetic biology. Why? Well, Venter sees synthetically generated cells as the key to engineering our way out of some of the big problems facing the world – such as climate change and our existing reliance on fossil fuels. As Venter told New Scientist in 2007:

Over the next 20 years, synthetic genomics is going to become the standard for making anything. The chemical industry will depend on it. Hopefully, a large part of the energy industry will depend on it. We really need to find an alternative to taking carbon out of the ground, burning it, and putting it into the atmosphere. That is the single biggest contribution I could make.

Not surprising then that the big science story of the week is that Venter and colleagues have published a paper in Science detailing how they synthesized an entire bacterial genome and used it to take over a cell. The paper itself is barely readable for the layperson, given its complexity and even the images that accompanied the paper don’t add much for the average reader. But media coverage from the likes of the New York Times add useful context:

Dr. Venter’s aim is to achieve total control over a bacterium’s genome, first by synthesizing its DNA in a laboratory and then by designing a new genome stripped of many natural functions and equipped with new genes that govern production of useful chemicals.He took a first step toward this goal three years ago in showing that the natural DNA from one bacterium could be inserted into another and would take over the host cell’s operation. Last year his team synthesized a piece of DNA with 1,080,000 bases, the chemical units of which DNA is composed. In a final step, a team led by Daniel G. Gibson, Hamilton O. Smith and J. Craig Venter report in Thursday’s Science that the synthetic DNA takes over a bacterial cell just as the natural DNA did, making the cell generate the proteins specified by the new DNA’s genetic information in preference to those of its own genome.

So just how significant is this? Many scientists consider the latest development a landmark moment in science (see comments from scientists below). But as BBC Newsnight’s science editor Susan Watts points out, such is the hype that often surrounds Venter’s work, it is hard to know just how close to true synthetic life we actually are.

Dr Venter has been promising this for years, and now that he has succeeded we’ll be hearing a lot about how he has “created life in the lab”. It’s not quite that – not yet – but it’s close. Dr Venter and his team built “Synthia”, as they’ve named their new life form, from snippets of DNA called “cassettes”. But he is still relying on a naturally-occurring microbe to act as a host – with its own DNA stripped out. Don’t misunderstand me. What Dr Venter has done is incredible science. I’ve already heard it described as Nobel prize-winning, “landmark”, work. But there is always an element of razzmatazz surrounding Dr Venter’s research that makes it harder to sift fact from hype.

On the other hand you don’t have to go far to read reports of the dissenting voices who are worried that Venter is taking us down a dark and rocky path – one which will deliver us to an ethical dilemma as we gain the power to engineer life itself.

Meanwhile, here’s how scientists in the UK greeted the news. Quotes courtesy of the Science Media Centre in London:

Professor Dek Woolfson, University of Bristol and Principal Investigator, BBSRC Synthetic Components Network, says:

’Craig Venter’s step forward is to show that genomes — the stuff that programmes natural cells and organisms — can be made chemically in the lab and then transplanted and ‘booted up’ in another cellular host. This could eventually allow the genes for the synthesis of drugs or biofuels to be smuggled into bacterial or yeast cells, which could then be made to produce these useful products. This is one end of synthetic biology that might be termed ‘genome engineering’.

’Other groups, including those in the UK, are working at understanding how we might design and engineer biological systems at the more-basic molecular level; e.g., can we make miniature motors out of proteins and other molecules from first principles? This is a very exciting time for the emerging field of Synthetic Biology, and the UK has a key role to play in it.

’The aim of Synthetic Biology is to design and engineer new biological building blocks that allow the reliable and predictable construction of biological or biologically inspired systems. In turn, these systems could be used to produce new biomaterials, biofuels, or drugs more cheaply, efficiently and in environmentally friendly ways.’

Professor David Delpy, Chief Executive of the Engineering and Physical Sciences Research Council (EPSRC), said:

’This latest announcement demonstrates the crucial role that engineering, chemistry, physics and maths play in driving forward developments in synthetic biology and that the range of UK research activities that we are supporting in this area will contribute to the advancement of this new technology.

’In synthetic biology we have a whole set of new possibilities to move from hypothesis to reality in areas as diverse as disease diagnosis, vaccines, fuel production or neutralising contaminants such as oil spills.

’EPSRC, together with BBSRC, have been mindful of the concerns that the public may have over what is a relatively new area of research, and from the outset have encouraged our researchers in the synthetic biology networks to actively consider the ethics of their work and discuss it with the public.’

Professor Julian Savulescu, Uehiro Chair in Practical Ethics and Uehiro Centre Director, University of Oxford, said:

’Venter is creaking open the most profound door in humanity’s history, potentially peeking into its destiny. He is not merely copying life artificially as Wilmut did or modifying it radically by genetic engineering. He is going towards the role of a god: creating artificial life that could never have existed naturally. Creating life from the ground up using basic building blocks. At the moment it is basic bacteria just capable of replicating. This is a step towards something much more controversial: creation of living beings with capacities and natures that could never have naturally evolved. The potential is in the far future, but real and significant: dealing with pollution, new energy sources, new forms of communication. But the risks are also unparalleled. We need new standards of safety evaluation for this kind of radical research and protections from military or terrorist misuse and abuse. These could be used in the future to make the most powerful bioweapons imaginable. The challenge is to eat the fruit without the worm.’

Dr. Gos Micklem, Department of Genetics at the University of Cambridge, said:

“This is undoubtedly a landmark paper. The group has been building towards this step and, from their earlier published work, are leaders at synthesising and re-assembling large segments of DNA. There is already a wealth of simple, cheap, powerful and mature techniques for genetically engineering a range of organisms. Therefore, for the time being, this approach is unlikely to supplant existing methods for genetic engineering. DNA synthesis is rapidly becoming cheaper and so this could change, but not soon.

“The technique could potentially come into its own if one wanted to introduce a large number of changes into an existing genome. However making a system that works predictably after introducing a large number of changes is one of the design challenges of the young field of synthetic biology: in the general case it is a challenge that is unlikely to be solved soon.”

Professor Paul Freemont, Co-Director of the EPSRC Centre for Synthetic Biology at Imperial College London, said:

’The paper published in Science today by Craig Venter and colleagues is a landmark study that represents a major advance in synthetic biology. Venter and colleagues have for the first time demonstrated that a single genome of around 1 million base pairs can be chemically synthesised and assembled correctly and transplanted into a recipient cell. The step change advance, which has alluded them in previous publications, is that they have now demonstrated that the transplanted synthetic DNA can be ‘booted up’ to operate the functions of the new recipient cell in terms of replication and growth. Although the recipient cell is not man-made but is another natural cell, what Venter’s team have shown is that after transplantation and multiple cell divisions the recipient cell take son the characteristics or phenotype of the newly transplanted genome. (This is like taking a Mac computer operating systems and installing it onto a PC and the PC becoming a Mac computer.)

’This is a remarkable advance as it now provides a ‘proof of concept’ that we can chemically synthesise and assemble full genomes and transplant them into recipient cells, which after selection contain only the synthetic genome, and after rounds of cell division become a new and one might argue synthetic cell. The applications of this enabling technology are enormous and one might argue this is a key step in the industrialisation of synthetic biology leading to a new era of biotechnology.

’Of course one also needs to be cautious, as it is not clear if this approach will work for larger and more complex genomes or for transplantation in different bacterial cells. However, this is a landmark step in our abilities to manufacture man-made cells for man-made purposes.’

Additional information from Professor Freemont:

In detail the paper describes the chemical synthesis and assembly of the 1.08Mbp genome of Mycoplasmamycoides. This organism is a small bacteria and lives as a parasite in cattle and goats. Mycoplasma lack cell walls, have no discernable shape and are the smallest (0.1 µM) known free-living life forms and are most likely to have evolved from Gram-positive bacteria. They are present in both animal and plant kingdoms and act as colonisers. The choice of Mycoplasma by the Venter group for genome synthesis and transplantation is based on the small size of the genome and for the mycoides species has a reasonably fast growth rate. The difficulties they report in terms of getting the synthetic genome booted up were due to a single base pair mutation in an essential gene (dnaA) which they noted after several attempts. Correcting this mutation allowed the synthetic genome to work properly, although its not clear how the mutation occurred — whether in the synthesis or assembly step. The transplantation process involves using an antibiotic selection process where the newly transplanted genomes infer resistance to the transplanted cell to live in the presence of a lethal antibiotic.

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