Life's Greatest Secret (42 page)

A recent experimental study showed that horizontal gene transfer could help ordinary bacteria to become plant symbionts by simultaneously transferring genes involved in symbiosis and genes that led temporarily to an increased mutation rate in the bacteria. As a result, the bacteria responded rapidly to selection pressure, accelerating their transformation into symbionts.
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Horizontal transfer effects may not be limited to genes – the parasitic plant dodder exchanges not genes but mRNA with its plant host. In some circumstances even gene products can jump the species barrier.
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Even more spectacularly, horizontal gene transfer was at the heart of the evolution of the eukaryotic lineage, which includes all multicellular organisms, along with some single-celled organisms such as yeast. As well as containing the DNA of the ancestor of the mitochondrion, our genome also plays host to many genes from prokaryotic organisms, which were transferred into our ancestors by horizontal gene transfer. We are all the product of gene transfer between species. Faced with the evidence that gene transfer between species is so widespread, no one can argue against GM technology on the basis that it is unnatural.

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Some applications of genetic engineering relate to areas of technology that are neither controversial nor bizarre. By manipulating the genetic sequence, it is possible to use DNA to store information generated by humans, perhaps providing an efficient, compact and future-proofed storage system. DNA, unlike cassettes, floppy discs or VHS tapes, will not go out of date. In 2013, Ewan Birney’s group in Cambridge announced that they had written 739 kilobytes of computer data into DNA, using a code made out of groups of nucleotides.
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They synthesised DNA containing this encoded information, sequenced it and reconstructed the original files – these included a text file containing all of Shakespeare’s sonnets, a PDF version of Watson and Crick’s description of the double helix, an MP3 extract of Martin Luther King’s ‘I have a dream’ speech, and a JPEG image of the team’s laboratory. There was not a single error, and all the files were functional.

The idea behind this proof of principle was to find a method that could guarantee future data storage in systems where huge amounts of data are being produced, such as at CERN, where the amount of data from the Large Hadron Collider and other experiments currently stands at more than 80 petabytes (1 petabyte (PB) = 1,000,000,000,000,000 bytes, or 10
¹⁵
bytes) and is growing by at least 15 PB per year. At the moment, these data are stored on magnetic tape; DNA storage would be ideal for archiving data that rarely need to be accessed, in particular with the inevitable future decline in costs for reading and encoding DNA. Information storage in DNA is far more space-efficient than in other materials: a single 1-gram drop of DNA could store as much information as hard drives weighing around 150 kilograms. In November 2014, New York rock band OK Go announced that their new record,
Hungry Ghosts,
would be released on DNA as well as in the usual formats.
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Although this was clearly a stunt, it may point the way to the future: DNA-based data cannot be read as quickly as a magnetic tape, but it can be safely stored for thousands of years if kept in the right conditions. One joker has facetiously suggested that the double helix would be particularly useful for storing the wave of genetic sequence data that is being generated at an exponential rate in laboratories all over the planet.*

Perhaps the most exciting recent development in DNA information storage has been the announcement by Fahim Farzadfard and Timothy Lu of MIT that they were able to engineer a population of bacterial cells to record real-time data as the cells were treated with a particular chemical inducer – or, as Farzadfard and Lu put it, they created ‘genomic “tape recorders” for the analog and distributed recording of long-term event histories’.
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This information was stored in a special form of DNA that only has one strand; it could be written and rewritten, and could be recovered after several days. This breakthrough brings the development of organic sensors, for both environmental and medical uses, much closer.

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Although we generally describe the structure of DNA as a double helix, it is in fact a bit more complicated than this. Unlike a screw thread, which has a constant pitch or interval between each turn, the double helix has two different intervals, which alternate as the molecule spirals round. These are known as the major and minor grooves – the major groove, which is larger, tends to be the point at which DNA-binding proteins affect gene activity, as the sequence of bases is physically more accessible there. Above all, the DNA double helix spirals in only one direction – anticlockwise as seen from the top, or right-handed, like a normal screw. It is easy to get confused about which way the double helix should spiral, and in many representations of DNA the molecule spirals the wrong way. In 1996 Tom Schneider began posting images of leftward spiralling double helices on his web site, but he was soon overwhelmed by the number of examples.
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I will not cast the first stone over mistaken representations of DNA – I once managed to put a wrong double helix on the side of a building: it was not even left-handed, it was geometrically impossible.

The DNA double helix comes in several shapes. The two forms studied by Wilkins and Franklin – A-DNA and B-DNA – both have right-handed helices; B-DNA is the iconic version that exists in your cells, and A-DNA occurs under conditions of low humidity and can be found in organisms although its biological function (if any) is unclear. In 1961, a group including Wilkins observed a third right-handed form of DNA, known as C-DNA, which appears in the presence of particular salts and has a slightly different structure again.
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Left-handed DNA, known as Z-DNA, can be found in our cells. In one of the ironies of history, the first structure of a DNA molecule to be determined precisely was of the Z form, in 1979.
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For complex chemical reasons, the Z form lacks the minor groove, and it turns in a looser helix than the B form – it has twelve base pairs per twist, whereas the B form has ten base pairs.
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It is not simply an elegant left-handed version of the B form, but a kind of twisted Bizarro-DNA, with bases turned upside down relative to the B form, so the phosphate backbone of the molecule forms a zigzag rather than a smooth spiral.
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The function of Z-DNA is still being explored – early hopes that it would turn out to be of importance in gene regulation or a useful tool in biotechnology have yet to be fulfilled.
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DNA can also form other structures, including the four-stranded G-quadruplex and a cruciform shape; although it is assumed that these non-helical structures have some functional role, probably in regulating transcription, the evidence is still unclear.
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DNA is not the only molecule that can form a double helix. In 1961, Watson and Crick, together with Alexander Rich and David Davies, suggested that in certain circumstances, RNA, which is normally single-stranded, could double up.
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Over half a century later, researchers were able to crystallise double stranded RNA and to describe its structure. It, too, has a right-handed spiral.
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There is no evidence that the RNA double helix has any biological function in normal cells, but it may be possible that biotechnology will be able to employ this novel molecular structure. Although RNA is generally presented on diagrams as a single strand, in fact RNA molecules often bend around on themselves, forming complex double-stranded stems with a single-stranded loop at the top, like a hairpin. Such secondary structures may be important in the various functions of RNA – they give tRNA its distinctive shape, for example.

Both DNA and RNA are made of a common ribose-phosphate backbone, onto which are linked the bases (A, T, C and G) that carry the genetic information. In 2012 a collaborative project led by Philipp Holliger at Cambridge described the creation of six new kinds of informational molecule that did not use ribose, dramatically called xeno-nucleic acids or XNA. In place of ribose, these weird molecules each have different forms of sugar in their backbones onto which the usual bases can be attached. As well as creating these six forms of XNA, the group also engineered the enzymes necessary to enable DNA to be copied into XNA, and for XNA to be copied into DNA – this was a truly remarkable feat.
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In a series of experiments the group demonstrated that genetic information (that is, the sequence of bases) could be successfully copied from DNA into XNA and back again. They were even able to subject one of the XNAs to selection and to show that its sequence evolved as a result. In principle, DNA and RNA are not the only potential informational molecules. Alien life-forms – if there are any – may well use non-DNA or non-RNA information.

The biotechnological potential for XNA is immense. As Holliger’s group concluded:

‘synthetic genetics’ – that is, the exploration of the informational, structural, and catalytic potential of synthetic genetic polymers – should advance our understanding of the parameters of chemical information encoding and provide a source of ligands, catalysts, and nanostructures with tailormade chemistries for applications in biotechnology and medicine.

Commenting on the creation of XNA, the veteran biochemist Gerald Joyce recognised that it opened the road to what he called an alternative biology, but he also sounded a warning.
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Use of DNA-based and RNA-based synthetic molecules carries a fail-safe mechanism in that they are susceptible to degradation by enzymes that have evolved over billions of years – indeed, this is one of the obstacles that restricts their widespread use. Furthermore, all DNA-based life-forms are susceptible to attack by other organisms and the enzymes they contain. This would not necessarily apply to XNAs. As Joyce put it:

XNAs are unnatural and would pass through the biosphere unscathed. The benefits of their unusual chemical properties must be weighed against their greater cost, both literally and with regard to operating in the uncharted waters of XNA biochemistry. … Synthetic biologists are beginning to frolic on the worlds of alternative genetics but must not tread into areas that have the potential to harm our biology.

For the moment, no one has been able to create an informational molecule that does not contain phosphate. In December 2010 a twelve-person team including the NASA astrobiologist Felisa Wolfe-Simon published an article online in
Science,
suggesting that bacteria found in Mono Lake in California, which has high levels of arsenic, naturally replace the phosphorus in their DNA by arsenic.
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This claim, which was announced at a high-profile NASA news briefing to the excitement of the world’s press, was immediately contested on social media, such as Dr Rosie Redfield’s blog RRResearch. What became known on Twitter as #arseniclife took on the proportions of a major scientific row and also showed the power of social media to act as a form of peer review. In 2011, when the original paper was finally published in
Science,
it was accompanied by an unprecedented seven short articles that were critical of the paper’s claims. Redfield and others eventually published papers in
Science
that showed that, in this case, there was no integration of arsenic into DNA.
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The original Wolfe-Simon paper has not been retracted, and it remains possible that, perhaps on another world or eventually in an Earth laboratory, other forms of informational molecule without phosphate may exist.

The #arseniclife debacle was partly driven by an idea put forward in 2005 by Carol Cleland and Shelley Copley of the University of Colorado, who published a speculative paper exploring the possibility that our planet hosts microorganisms that do not use DNA or RNA or our set of amino acids, and which are therefore undetectable by traditional methods such as the polymerase chain reaction.
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This hypothesis, which has been given the dramatic names ‘the shadow biosphere’ or ‘weird life’, has attracted some interest from those prone to theoretical speculation, but has not been treated with any degree of seriousness by the scientific community. As Cleland and Copley put it, ‘the fact that we have not discovered any alternative life forms cannot be taken as evidence that they do not exist’. That is logically correct, but it is hardly an enticing starting point for a research programme and would not be taken seriously by any funding agency.

Physicists have realised that 95 per cent of the Universe is made of stuff we cannot directly detect – dark matter and dark energy – because calculations of the amount of matter in the Universe based on gravitational effects revealed a substantial discrepancy between observed and expected values. For the shadow biosphere to be more than day-dreaming, a similarly overwhelming signature of its existence would be necessary. Those intrigued by the remote possibility of weird life have come up with some potential indicators of its existence, such as the supposedly anomalous varnish that is found on desert rocks.
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However, something as impressive as the indirect evidence of the existence of dark matter and dark energy would be required for this hypothesis to be taken seriously.

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The potential for synthetic biology is enormous. Scientists are already able to integrate unnatural amino acids into proteins, for example by manipulating enzymatic machinery associated with an ‘amber’ stop codon (UAG) that has been introduced into bacteria, yeast, the nematode worm
Caenorhabditis elegans
and even mammalian cells.
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A synthetic form of transfer RNA is used to allow the UAG codon to code for an unnatural amino acid, thereby producing a novel protein. Some of these engineered proteins produce pulses of light when they are subjected to particular forms of biochemical activity in the cell, acting as an exquisitely sensitive marker. Some produce modifications in the three-dimensional structure of the protein, allowing greater understanding of the precise organisation of the molecule; others enable light to be used to activate molecules in the cell, giving an insight into the roles of key components of the cellular machinery. For the moment, many of these novel proteins are aimed at increasing our understanding of basic processes. But it is only a matter of time before they will be used to develop new forms of biotechnology with potentially massive implications for our future.