A public crowd-funding campaign has been launched by a starter Biotech company Genome Compiler, to create bioengineered glow-in-the-dark plants that will be given away to donors. This will be the first organism created by synthetic biology techniques to ever be released into the wild and most astonishingly, it will bypass any regulatory approval procedures in the process. LINK

Institute of Science in Society

Synthetic Biology is genetic engineering with greater knowledge and precision, but much bigger, faster, and with unnatural molecules thrown in, yes we should be afraid.   

Dr. Mae-Wan Ho

Labs create bird flu virus that may spread from human to human

Researchers at the University of Wisconsin-Madison in the United States created a hybrid strain of bird flu that could potentially spread between humans by merging a mutant strain of bird flu virus with the swine flu virus. The hybrid strain spread readily between ferrets. The work was completed in 2011 and submitted to the journal Nature, but was delayed after the US government’s biosecurity advisers said the details could be exploited by terrorists. The advisers raised similar concerns over a second paper submitted to the journal Science, involving a mutant strain of bird flu virus that also spread in ferrets, created by researchers at Erasmus Medical Centre in Rotterdam. This led to months of debate among scientists, government officials and journal editors over the risks of publishing the papers [1].

The scientists argued that they were addressing a major unknown about bird flu, whether it could evolve in the wild into a strain that spread easily among humans. Until now, the virus had only spread from birds to humans. After meeting twice and hearing presentations from US security officials, the National Science Advisory Board for Biosecurity (NSABB) finally approved the publication of both papers.

Studies of the virus revealed that infection was controlled by just four mutations in the haemagglutinin protein of the virus which determines the binding of the virus to specific host cells [2]. Lead researcher Yoshihiro Kawaoka told the Guardian newspaper that one of the mutations identified is already circulating in viruses in the Middle East and Asia, so there is a worry that these viruses could acquire more mutations and become transmissible in mammals. If surveillance teams know which mutations are important, they would be alert to the emergence of viruses with pandemic potential and inform authorities to take appropriate precautions.

Malik Peiris, a bird flu expert at the University of Hong Kong, not involved in the research, said it was “absolutely necessary” to publish [1].

This research highlights both the dangers and the potential benefits of synthetic biology that has taken over from genetic engineering.

Furore over redesigning life

Synthetic biology appears to touch a raw nerve right from the start, and no wonder. Steven Benner, a chemist now at University of Florida in Gainesville, USA, wanted to call his 1988 conference to explore the possibilities for making artificial chemical systems with essential features of living things “Redesigning Life” [3]. But that created such furore among potential participants that he had to change it to “Redesigning the Molecules of Life”. He explained to consultant editor for the journal Nature Philip Ball that individuals as distinguished as Nobel laureates were convinced the title would incite anti-recombinant-DNA riots in Switzerland. Ball’s own 2004 article was no less provocative in its headline – “Genetic engineering is old hat. Biologists are now synthesizing genomes, altering the genetic code and contemplating new life forms” – even though everything it said was true, as he went on to describe work done under the banner of synthetic biology.

Virologist Eckard Wimmer and his team at the State University of New York at Stony Brook had built live polio virus in 2002 using mail order segments of DNA and a viral genome map freely available on the internet. More microbial genomes have been built since, and many times faster. Back in 1989, Peter Schultz, a chemist now at Scripps Research Institute La Jolla, California, engineered bacteria that incorporated an unnatural amino acid into protein, producing enzymes with subtly different activities. Schultz has added more than 80 unnatural amino acids to proteins. In the same year, Benner coaxed cells to insert a new base pair into their DNA. In 2000, biological physicists Michael Elowitz and Stanislas Leibler at Princeton University, New Jersey, designed a genetic circuit that produced a fluorescent protein so the population of bacteria glowed periodically. Other genetic circuits have been built that could be controlled by external signals or chemicals.

A report entitled Extreme Genetic Engineering released in 2007 echoes Ball’s headline [4]:“Genetic engineering is passé” it began. “Today, scientists aren’t just mapping genomes and manipulating genes, they’re building life from scratch – and they’re doing it in the absence of societal debate and regulatory oversight.” That, however, is not true. Synthetic biologists have done a great deal, but have singularly failed to create life “from scratch”, and for good reasons.

What is synthetic biology?

‘Synthetic biology’ is the new buzzword for what used to be called genetic engineering – chopping, changing and splicing DNA (or RNA) – but also includes much more. Synthetic biologists come in two kinds, according to Benner and Michael Sismour [5]: those using unnatural molecules to reproduce natural living behaviour, with the goal of creating artificial life; and others looking for interchangeable parts from natural biology to assemble into systems that function unnaturally. The act of synthesis, they said, forces scientists to encounter and solve problems that they otherwise would never come across, and encourages new paradigms to emerge. (Let’s hope.)

At bottom, synthetic biology combines molecular biology with engineering design. At its best, this can increase the speed as well as precision, reliability, efficacy and efficiency to previously haphazard, unpredictable and uncontrollable processes.  At its most ambitious – which is where the greatest public antipathy and anxiety is aroused – synthetic biology aims to design and create organisms (including human beings) with new, or improved functions, and even to create life itself.

Synthetic biologists have not created life

Synthetic biology has certainly not succeeded in creating life from scratch, as neither the molecular biologists nor the engineers or chemists involved know what life is. Their idea of life as molecular nuts and bolts assembled like Lego pieces is simply misguided (see below). Life is more than just a combination of the right molecules (see [6] The Rainbow and the Worm, The Physics of Organisms and its sequel [7] ‘Living Rainbow H2O’, ISIS publications) for a radically different and much more realistic view of cells and organisms). To begin with, molecules in living organisms are dynamically organized by a very special quantum state of water [8] (Living H2O the Dancing Rainbow Within, SiS 55); and synthetic biologists, like most biologists, are totally oblivious to the key importance of water for life.

Consequently, I can confidently predict that synthetic biologists will never create life from scratch if they remain on their present trajectory.

One main approach to synthetic biology is constructing ‘biobricks’ – prefabricated genetic circuits or standardized parts – that can be assembled into any desired system. The online open access Registry of Standard Biological Parts has more than ten thousand entries (it has more than double that in 2012 [9]). But the vast majority have not been characterized, and do not work as designed. Participants at a synthetic biology meeting in July 2010 concluded that of the 13 413 items then listed, 11 084 did not work. One presenter remarked [10]: “Lots of parts are junk.”

I am much less confident however, that synthetic biologists will not cause harm in attempting to create artificial life or recreate life, in addition to the hazards predicted for genetic engineering that have been documented both in the field and in the laboratory (see numerous reports on ISIS website since 1999, among the latest [11] GM Feed Toxic, New Meta-Analysis Confirms, SiS 52).

James Collins, a pioneer synthetic biologist at Boston University Massachusetts, presents a fairly representative view of how practitioners see the field. “Scientists are combining biology and engineering to change the world,” said the heroic headline of his article “Bits and pieces come to life” [12],  “With a box of Lego, you can create a whole range of different structures…a growing group of scientists [synthetic biologist] is thinking about parts of cells in much the same way.”

Collins himself sees synthetic biology potentially solving major global problems like “famine, disease, and energy shortages.”

And on his what-if-we-can list, Collins suggests “humans with sonar, like that used by bats, to help us navigate in the dark”, or with “genes to get energy from sunlight, like plants.”

Nevertheless, Collins admits that “the complexity and messiness of biology means we are a long way from having a manual for how a cell works. Many areas are still in need of clarification and elaboration.”

Successes of synthetic biology so far

What has synthetic biology to show beyond proof of principle genetic toggle switches, oscillators, and even a network that plays tic-tac-toe against any human opponent and never loses, provided it makes the first move [12]?

One of the early successes was a yeast strain engineered with a group of genes to produce the compound artemisinin [13], the most effective antimalarial available from the plant Artemisia annua. Yeast artemisinin was to go into production in 2012, but how much cheaper than getting it from the plant is still unclear. A major worry is that yeast artemisinin will displace farmers growing the plant crop in Asia, Africa and Brazil [14]. The global supply of natural artemisinin goes through boom and bust cycles, and the drug is still priced beyond the reach of poor people. It is clear that the socioeconomic impacts of synthetic need to be part and parcel of risk assessment, as they are in genetic modification. But one should also consider the possibility that the farmers may be better off if they were compensated for losing their crop and switching to growing their own food instead.

Another success is the branched DNA assay invented in 1997 [15], which has greatly speeded up the detection of viral and bacterial sequences in diagnostic tests, with much improved sensitivity and specificity (see Box 1).

Both examples are extensions of conventional genetic engineering.

Box 1Branched DNA assayA branched DNA (bDNA) assay detects minute amounts of DNA sequence by amplifying the signal, rather than amplifying the target DNA sequence as in the conventional polymerase chain reaction (PCR), which is time-consuming and prone to error and contamination.The bDNA assay begins with short single-stranded DNA molecules – capture probe – tethered to a solid support and sticking up into the air. They are hybridized to the extender, single strand sequence with two domains, one complementary to the capture probe and hybridizes to it, and the second complementary to the target DNA sequence to be detected. When capture probe and extender molecules are in place, the sample is added, and the target DNA molecules in the sample will bind to the extender molecules. Next comes the amplification step during which is added a label extender, DNA molecules with two domains, one complementary to the target, and hybridizes to it, and the other to the preamplifier, DNA molecules again with two domains, the first hybridizes to the label extender and the second to the amplifier, DNA molecules with a second domain linked to enzymes giving a colour or fluorescent reaction. Branch DNA assay is much faster than conventional PCR, and offers greatly improved sensitivity and specificity for detecting viral and bacterial sequences in diagnostic and screening tests.

According to Collins [16], many of the initial applications in synthetic biology were in converting biomass or sunlight into biofuels, but so far these have not scaled up well. “It can cost US$4 to make $1-worth of fuel.” (But see recent success in making ethylene from CO2 [17] Photosynthetic Bacterium Converts CO2 into Petrochemical and O2, SiS 56).

What we should be afraid of

Collins is upbeat about medical applications of synthetic biology, moving from synthetic biology of microorganisms into mammalian system, and engineering microbial communities that colonize the digestive system for therapeutics. These are exactly some of the applications that give me reasons to be afraid. Although microbial systems can be modified quite precisely, all attempts to target genetic modifications in eukaryotic cells have so far failed (which is why genetic modification of plants and animals is inherently uncontrollable and unpredictable), and methods to monitor the precision of gene targeting in mammalian cells are just now being developed [18]. Engineering microbial communities in the digestive system that we hardly know about is sheer recklessness, as these microbial communities are intimately intertwined with the physiology and immunity of the human host (see [19] Genetically Modified Probiotics Should Be Banned, ISIS scientific publication).

Profit before safety

In June 2011, the US Defense Advanced Research Projects Agency (DARPA) announced a $30-million, three-year programme called Living Foundries to support academic and corporate researchers bringing products to the market. “It’s too early to predict the commercial importance of such a young field,” Collins remarked [16], “whether it will turn out to be the next semiconductor industry is hard to say.”

Not to be outdone, Britain issued A Synthetic Biology Roadmap for the UK in July 2012 [20] – commissioned by the Department for Business and Skills and published on their behalf by the Technology Strategy Board – citing an estimate that the global synthetic biology market will grow from $1.6 bn in 2011 to $10.8 bn by 2016, and calling for substantial public investments into establishing multidisciplinary centres, synthetic biology networks, and a “leadership council” with appointed subgroups to direct, coordinate, and oversee it all, and to ensure smooth passage from research to commercialization. It sounds like a potential bureaucratic nightmare of managed science by those who have little or no understanding of science, let alone safety, which is why I am thankful to have left academia.

Although the words “responsible” and “ethical” appear often enough, no civil society organisations were involved in drafting the document, only representatives from industry and research councils plus a few academic synthetic biologists and social scientists. There was no mention of public consultation at all. Being “responsible” seemed nothing more than adhering to “existing regulatory guidelines”, i.e., those applying to genetic modification for contained use and deliberate release, which may well be relaxed in future, in order not to unduly hinder commercialization. And the word “safety” does not appear anywhere.

Stranger dangers than conventional GMOs

While increased precision and reliability can improve the safety of genetic modification, the greatly expanded possibilities for engineering novel constructs and organisms also multiplies the dangers of intentional or accidental releases.

It is now possible to construct whole genomes of viruses and bacteria out of sequence information freely available on the web. Apart from the poliovirus synthesized from its published sequence in 2002 (see above), the virus responsible for the 1918-19 flu pandemic was similarly reconstructed in 2005 [21]. In 2008, Craig Venter Institute synthesized the first bacterial genome of M. genitalium; and in 2010, the team assembled the genome of M. mycoides and transplanted it into a M. capricolum cell to create new M. mycoides cells [22] (see also [23] Synthetic Life? Not By a Long Shot, SiS 47)

Many of the genetic constructs and organisms involved are novel in kind, such as the new bases for DNA, and new amino acids to be incorporated into proteins (see above), the safety of which is entire unknown. At the same time, ethical issues surrounding genetically modified animals and even human beings are brought into much sharper relief (see [24] Unspinning the Web of Spider-Goat, SiS 54).

In the present series, I highlight two flourishing areas that are on the point of exploding. One is the expanding use of nucleic acid aptamers, short sequences of RNA or DNA that bind to proteins or small molecules ( [25] Aptamers for Biosensing, Diagnosis, Druge Delivery and Therapy, SiS 56). The second is the rapid modification of entire genomes for practically any required use ([26] Mass Genome Engineering, SiS 56). These are developing so fast that safety is in real danger of being left behind.

As Ball remarked in 2004 [3]: “The expanding toolbox of ways to re-engineer microbes — and even construct new ones — has opened up extraordinary possibilities for biomedical discovery and environmental engineering. But it also carries potential dangers that could eclipse the concerns already raised about genetic engineering and nanotechnology.”

In July 2011, the Synthetic Biology Project at the Woodrow Wilson International Center for Scholars in Washington DC assembled a group of synthetic biologists and ecologists to explore the possible risks of introducing novel organisms into the environment, and how to assess those risks. These scientists are developing an eco-risk research agenda to help move the field forward in a productive fashion, while aiming to avoid serious ecological impacts.

They propose four areas of risk research:

  • Differences in physiology of natural and synthetic organisms, in the production of toxic substances or other harmful metabolites
  • How escaped microorganisms might alter habitats, food webs or biodiversity;
  • The rate at which the synthetic organism and its genetic material evolves,
  • Horizontal gene transfer.

They suggested a (very) minimum investment of $20 to $30 million over 10 years on risk research.

What the group of scientists have failed to propose is a moratorium on all environmental releases until the synthetic molecules and organisms are proven safe.

The issue is pressing, as pointed out in a report submitted to the Subsidiary Body on Scientific, Technical & Technological Advice of the Convention on Biological Diversity by an International Civil Society Working Group on Synthetic Biology [8]. There is at present no legal instrument that covers the regulation of the new constructs in synthetic biology, and no risk assessment protocol. There is a general assumption in the field that physical containment of synthetic organisms is not practical, especially within large scale commercial production systems. Natural disasters such as floods, earthquakes could readily lead to unintentional releases, as in the foot and mouth outbreak in the UK traced to broken waste-water pipes from Pirbright Laboratory. The behaviour of the novel constructs and organisms are simply unpredictable. It is now recognized that horizontal gene transfer is much more extensive than previously thought. A report published in 2010 documented horizontal gene transfer frequencies in the ocean thousands to hundreds of million times higher than previous estimates [27]. There should be no doubt that genetically modified DNA can spread readily by horizontal gene transfer with unpredictable and potentially uncontrollable consequences (see [28] Scientists Discover New Route for GM-gene ‘Escape’, SiS 50).

We should indeed be afraid of the lack of public consultation and regulation of an endeavour that may yield many beneficial and useful results, short of creating life; but could also unleash exotic deaths and destruction on people and planet.

A fully referenced version of this article is posted on ISIS members website and is otherwise available for download here.


Print Friendly
Email this to someoneShare on FacebookTweet about this on TwitterPin on PinterestShare on RedditShare on StumbleUponShare on Google+Digg thisShare on LinkedInPrint this page

Tags: , , , , , ,

Comments are closed.