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ISIS Report 24/05/10

Synthetic Life? Not By a Long Shot

Dr. Mae-Wan Ho exposes the hype that scientists have created life but is cautiously optimistic provided no patents are granted on life, synthetic or otherwise

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Living Rainbow H2O. By Dr. Mae-Wan Ho The hype

Scientists have created life in the test-tube? The popular media appeared to have gone into overdrive on the latest episode in the long-running saga of ‘synthetic biology’. The same happened when the human genome sequence was announced ten years ago as the “book of life”, though it told us absolutely nothing on how to make life, let alone a human being.

The media are only slightly exaggerating what the scientists themselves are claiming. The title of the article published online 20 May 2010 in Science Express is [1] “Creation [emphasis added] of a bacterial cell controlled by a chemically synthesized genome.” It had 24 co-authors including team leader J. Craig Venter from the J. Craig Venter Institute based in Rockville, Maryland, and San Diego, California, in the United States. Venter is the maverick who famously came up from behind to an ‘equal finish’ with the public consortium in the race to sequence the entire human genome. And he is grabbing the headlines again with the latest stunt.

The hopes and fears

So is this the genesis of the brave new world of synthetic life-forms owned and controlled by unaccountable corporations hungry for power and profit that would make our worst nightmares come true? Or is it the greatest boon to mankind that will solve all the problems that human folly has created, beginning with cleaning up the gigantic and still growing oil spill in the Gulf of Mexico, and going on to the energy crisis and climate change?

Mark Bedau, a philosopher at Reed College in Portland, Oregon, and editor of the journal Artificial Life, calls it “a defining moment in the history of biology and biotechnology”, while yeast biologist Jef Boeke at John Hopkins University School of Medicine in Baltimore, Maryland, says it is “an important technical milestone in the new field of synthetic genomics” [2].

Professor Julian Savulescu from the Oxford Uehiro Centre for Practical Ethics at Oxford University tells the BBC [3] that the potential of this science is “in the far future, but real and significant”, though “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.”

Paul Rabinow, an anthropologist at the University of California Berkeley, says the experiment will “reconfigure the ethical imagination” [2]. Kenneth Oye, a social scientist at the Massachusett s institute of Technology in Cambridge sums up: “we are shooting in the dark as to what the long-term benefits and long-term risks will be.”

The science

The tiny genome of the bacteriophage fX174 (5 386 bases) was sequenced in 1977. It took another 18 years before Venter and colleagues sequenced the first genome of a self-replicating bacterium, Haemophilus influenzae (1 830 137 bp). Since then, the speed of sequencing genomes has increased exponentially, as has the ability to digitize genomic information [1].

Venter and his team got the idea of building a minimal cell that contains only essential genes in 1995, when they sequenced the 580 kbp genome from Mycoplasma genitalium, a bacterium with the smallest number of genes of any known self-replicating organism.

Through a long series of experiments that involved knocking out the genes one by one, they found that 100 of the 485 protein-coding genes are surplus to requirement.

Next, they developed a strategy for assembling genomes of viruses that are large DNA molecules, though much smaller than those of bacteria, as a stepping stone to making the synthetic genome of M. genitalium. That was accomplished in four stages, first by joining up DNA pieces averaging about 6 kb in size, then proceeding on to larger sizes, both in the test tube and in cells of the yeast Saccharomyces cerevisiae. The entire synthetic genome was stably replicated as a special yeast extrachromosomal plasmid.

A major bottleneck to progress was the slow growth rate of M. genitalium. So the team switched to two faster growing species M. mycoides subspecies capri as genome donor and M. cacpriocolum subspecies capricolum as recipient.

The team also had to develop a method for cloning entire bacterial chromosomes in yeast as plasmids with centromeres. A centromere is a special part of the chromosome responsible for getting each of the replicated chromosome to a daughter cell during cell division, so the chromosome could be stably propagated..

Their initial attempts to extract the M. mycoides genome from yeast and transplant it into M capriocolum failed. The native M. mycoides genome had extra signals to protect it from being broken down by DNA-cutting enzymes (restriction enzymes); and the same enzymes are present in the donor and acceptor species. The signals consist of specific DNA bases that are methylated (methyl group added), so restriction enzymes cannot recognize the cutting sites. The chromosomes grown in yeast cells are unfortunately non-methylated. To solve that problem, the team methylated the donor DNA with purified methylases, enzymes that do the job, or simply with crude extracts of M. mycoides or M. capricolum containing the methylases.

The team started building the synthetic chromosome by “going DNA shopping” [2]. They bought more than a thousand 1 080-base sequences that covered the entire M. mycoides genome to make it easier to assemble the pieces in correct order, as the ends of each sequence had 80 bases that overlapped with its neighbours. In order to mark it as a synthetic genome, four of the pieces contained sequences that in code spelt out an e-mail address, the names of many of the people involved in the project, and a few famous quotations besides.

They used yeast to assemble the pieces in stages, first splicing 10 starting pieces together to make 10 000-base sequences, then 100 000-base sequences, and finally the complete 1 080 000-base genome [1].

But when they tried to put the synthetic genome into M. capricolum, nothing happened. It took them three months to track down a single-base error responsible for the glitch. A single bp deletion had frame-shifted the entire polypeptide chain of an enzyme essential for DNA replication. They corrected the error, and some months later, the breakthrough arrived.

A tiny blue colony was growing on the agar plate, the blue colour an indicator that a cell had taken up the synthetic genome and was multiplying successfully with it. To confirm, they sequenced the DNA in the colony, and found it was indeed the synthetic genome complete with the “water mark” of extra sequences inserted. The microbes were making proteins characteristic of the donor M. mycoides rather than M. capricolum, as checked by two-dimensional gel electrophoresis. They have genetically modified the bacterium entirely by giving it the genome of another species.

No life was created

Clearly the scientists have not created life or the bacterial cell. There is a yawning chasm in the physics and chemistry of the living state [4] (The Rainbow and the Worm, The Physics of Organisms, ISIS publication) that the team hasn’t even begun to address, let alone bridge. They did not create the genome that was used to transform the bacteria cell, only copied it from another species of the genus, adding a “water mark” for identification, and no doubt, for staking their claim to the synthetic genome. This synthetic genome was not even made from scratch, but cobbled together from pieces found in a catalogue, and then ‘transplanted’ into cells of the recipient bacterium species (a close relative of the donor) using an antibiotic to select for cells that have accepted the artificial chromosome and allow them to grow. The procedure is similar to the nuclear transplant experiment that made Dolly the cloned sheep in the 1990s and other animals since.

Anthony Forster, a molecular biologist at Vanderbilt University in Nashville, Tennessee, lauds the “pretty amazing accomplishment”, but is among those stressing that the work did not really create life because the genome was put into an existing cell [2].

In many ways, synthetic biology is a linear progression from genetic engineering, only much more extensive and sophisticated, thanks to quantum leaps in DNA sequencing and synthesis techniques, and exponential growth in information technology within the past decade.

No patents on life, artificial or otherwise

No one should underestimate the potential risks of synthetic biology. Already, the disastrous health and environmental impacts of genetically modified organisms are coming to light all over the world (see my Foreword to GM Food Angel or Devil [5] for a succinct summary). Nevertheless, there are also potential benefits to synthetic biology.

The approach can open the door to much more precise design of ‘synthetic’ organisms, which, if successful, are just greatly improved genetically modified microorganisms that could help clean up oil spills and make hydrogen from water, for example.

The techniques could also contribute to basic scientific understanding of how the fluid genome works (see [6] Living with the Fluid Genome, ISIS publication) and solve the age-old conundrum of nuclear-cytoplasmic interactions in heredity and development (see [7-9] Beyond neo-Darwinism: an Epigenetic Approach to Evolution, Environment and Heredity in Development and Evolution, and Development and Evolution Revisited ISIS Scientific publications).

These and other potential benefits of synthetic biology can only be realised if it is kept in the public domain, and no patents are granted for putative “synthetic organisms” that should remain strictly contained and confined in the laboratory unless and until proven safe for health and the environment.

Venter says his institute has already applied for several patents on the work [2]. The technology watchdog ETC based in Ottawa has argued these could result in a monopoly on synthetic biology. The monopoly on genes and genetic modification has already proven disastrous for scientific research and the public good [10] (Corporate Monopoly of Science, SiS 42). The controversial breast cancer gene patents have been challenged by a large coalition of learned societies, scientists, not-for-profit organisations and individual patients, and declared invalid by a judge in a New York City district court at the end of March 2010 [11].

What are the ethical dimensions? I don’t see any ethical dimensions different from those of cloned or genetically modified organisms (see [12] Human Farm Incorporated and other articles in the series, SiS 13/14, and [13] Transgenic Animals for Food Not Proven Safe, SiS 41). Synthetic organisms have the same potential of abuse and misuse, and need to be thoroughly scrutinised and openly discussed without the restrictions of patents that grant ownership to life, synthetic or otherwise.

References

1. Gibson DG, Glass JI, Lartigue C, et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Sciencexpress.org/20 May 2010/science.1190719

2.  “Synthetic genome brings new life to bacterium” Elizabeth Pennisi, News Science 2010, 328, 958-9.

3. “Artificial life’ breakthrough announced by scientists”, Victoria Gill, BBC news, 21 May 2010, http://news.bbc.co.uk/2/hi/science_and_environment/10132762.stm

4. Ho MW. The Rainbow and the Worm, The Physics of Organisms, 3rd edition, World Scientific, Singapore and London, 2008, http://www.i-sis.org.uk/rnbwwrm.php

5. Ho MW. Foreword to GM Food Angel or Devil, by Yimin, Renmin University Press, 2010,  http://www.i-sis.org.uk/GM_Food_Angel_or_Devil.php

6. Ho MW. Living with the Fluid Genome, ISIS/TWN, London/Penang, 2003, http://www.i-sis.org.uk/fluidGenome.php

7. Ho MW and Saunder PT. Beyond neo-Darwinism: an epigenetic approach to evolution. J. theor Biol 1979, 78, 573-91. http://www.i-sis.org.uk/onlinestore/papers.php#section1

8. Ho MW. Environment and heredity in development and evolution. In Beyond neo-Darwinism: An Introduction to the New Evolutionary Paradigm, Academic Press, 1984, pp. 267-87. http://www.i-sis.org.uk/onlinestore/papers.php#section1

9. Ho MW. Development and evolution revisited. In Handbook of Developmental Science, Behavior and Genetics (K. Hood, C. Halpern, G. Greenberg, and R. Lerner, eds.), Blackwell Publishing, New York, 2010. http://www.i-sis.org.uk/developmentAndEvolutionRevisited.php

10. Saunders PT. Corporate Monopoly of Science, Science in Society 42, 12-13, 2009.

11. “U.S. judge rejects breast cancer gene patents”, ScienceInsider, 30 March 2010, http://news.sciencemag.org/scienceinsider/2010/03/us-judge-rejects-breast-cancer-g.html

12. Ho MW. Human farm incorporated. i-sis news13/14, 4-5, 2002.

13. Cummins J and Ho MW. Transgenic animals for food not proven safe. Science in Society 41, 43-45, 2009.

There are 2 comments on this article so far. Add your comment
Rory Short Comment left 25th May 2010 15:03:18
I agree the only way to progress in this matter is 'without the restrictions of patents that grant ownership to life, synthetic or otherwise'. Granting patents on the essentials of life is illogical. It is 'the whole' authorising parts of itself, the patent holders,to have exclusive ownership of parts of itself. This simply does not make sense. It is an attempt to deny the very fact that life, of which we each are an individual expression, belongs to all of us not to any particular subset of us.
tony villar Comment left 25th May 2010 15:03:07
dr.Ho. pls keep up the good work.

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