Life's Greatest Secret (44 page)

A glimpse of the radical implications of CRISPR is given by the suggestion from a group of Harvard researchers that CRISPR could be used to potentially ‘prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species’.
⁵⁰
None of the researchers were ecologists, but they sounded the alarm about potential side-effects, and simultaneously published a call for discussion about how to regulate the new technology, coming up with criteria that should be adhered to before the implementation of any such programme, and also identifying regulatory gaps that need to be filled by legislators around the globe.
⁵¹

In January 2015, the same group of Harvard researchers came up with an ingenious technofix for ensuring that GMOs with potentially problematic modifications do not cause havoc in the environment – a group from Yale simultaneously published a similar report. Both groups used a ‘genetically recoded organism’ – a special strain of
E. coli
in which certain codons had been manipulated to code for synthetic amino acids that are not available in the environment. These synthetic amino acids are essential to the functioning of key proteins in these organisms, which are therefore effectively restricted to living in artificial conditions. Were the bacteria to escape, they would die. Furthermore, the authors claim that the alternative genetic code used by these organisms effectively prevents horizontal gene flow. This would seem to open the road to creating potentially hazardous GMOs in the knowledge that they would be contained by their engineered physiological requirements. However, a great deal of further work will be needed before this approach can be applied in the real world, and I suspect few scientists – or readers – would want to rely solely on this technique to ensure biosecurity.
⁵²

These responsible approaches to the potential impact of a new technique of unprecedented power are a direct descendant of the Asilomar conference on recombinant DNA that so successfully guided science as it was catapulted into the new world of genetic manipulation. In 2008, Paul Berg reflected on the impact of the Asilomar conference:

In the 33 years since Asilomar, researchers around the world have carried out countless experiments with recombinant DNA without reported incident. Many of these experiments were inconceivable in 1975, yet as far as we know, none has been a hazard to public health. Moreover, the fear among scientists that artificially moving DNA among species would have profound effects on natural processes has substantially disappeared with the discovery that such exchanges occur in nature. … That said, there is a lesson in Asilomar for all of science: the best way to respond to concerns created by emerging knowledge or early-stage technologies is for scientists from publicly-funded institutions to find common cause with the wider public about the best way to regulate – as early as possible. Once scientists from corporations begin to dominate the research enterprise, it will simply be too late.

Faced with a future potentially populated by CRISPR-modulated DNA-based organisms and full of bizarre synthetic life-forms that use XNA and unnatural base pairs and can record what is happening to them in their genetic material, Berg’s view, from a man who has looked at the question from both sides, is a salutary reminder for us all. His approach was to recognise the potential dangers and to find ways of countering them in conjunction with the public and regulators. The implication is that science is too important to be left to the corporations – or to the scientists.

* I’m afraid it was me.

–     FIFTEEN     –

In May 1953, a week before Watson and Crick’s second
Nature
paper introduced the world to the concept of genetic information, an article appeared in
Science,
signed by a 23-year-old PhD student, Stanley Miller.
¹
Together with his supervisor, Harold Urey, Miller had attempted to discover how life might have begun on Earth. Using two connected flasks, they replicated the conditions of about 3.5 billion years ago: one flask represented the primitive ocean (sea water), the other represented Earth’s early atmosphere, and contained hydrogen, ammonia and methane (oxygen appeared in large quantities much later, and reached modern levels only about 600 million years ago). Pulses of electricity were periodically sent through the apparatus to mimic the effect of lightning. To Miller’s surprise, within a few days he could detect amino acids, in particular glycine. A simple chemical process, with no direct human guidance, had produced the components of a protein. Glycine has since been detected on a comet, showing that amino acids exist elsewhere in the Universe and could have been brought to Earth by comets shortly after the formation of the planet.
²

Although the Miller–Urey experiment shows that amino acids can be formed relatively simply, it does not shed light on how life arose – we are more than just bags of amino acids. There are several scenarios for the origin of life – we do not know which is correct, and it is possible that we will never know. Here I will describe one hypothesis that is being explored by Nick Lane at University College London and Bill Martin at the Heinrich-Heine-Universität in Düsseldorf.
³
According to this view, the first replicating molecules appeared perhaps 4 billion years ago in the microscopic pores of rock around a deep-ocean hydrothermal vent.* Experimental evidence shows that such pores can act as a cell, containing and constraining molecular interactions, including the accumulation of nucleotides, and also allowing compounds to be exchanged with the outside world.
⁴

Today every cell on the planet uses electrochemical gradients to move energy around and power its activities – known as proton gradients, they are also found around hydrothermal vents, where alkaline water bubbling up from under the sea bed meets acidic sea water. According to Lane and Martin, early life, which would just have consisted of a small number of types of replicating molecule, could have used these proton gradients to gain energy. Deep in the sea, and encased in rock, these molecules would also have been protected from the destructive effects of the powerful ultraviolet radiation that bombarded the surface of the planet at that time.
⁵

Other scenarios are available. In his 1981 book
Life Itself,
Francis Crick put forward a theory he developed with Leslie Orgel, in which he argued that life was the result of what they called directed panspermia. Their surprising suggestion was that life on Earth originated with microorganisms that ‘travelled in the head of an unmanned spaceship sent to earth by a higher civilisation which had developed elsewhere some billions of years ago.’
⁶
Aside from the distinct lack of proof, this does not explain the origin of life at all – it simply puts the problem back a long time ago in a galaxy far, far away.
⁷
It is possible that life originated elsewhere in the Universe and came to Earth on a meteorite or a comet. However, that hypothesis does not seem to be necessary – we seem to be within touching distance of understanding the chemical dynamics that created life spontaneously.

Proteins and DNA, which are so important to life today, have not always been present. The RNA machinery that exists in every cell of every organism on the planet, and the ability of RNA molecules to act as enzymes, catalysing biochemical reactions without the involvement of proteins, all indicate that another form of life existed before DNA-based life-forms: the RNA world.
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Exactly what the first replicating molecules were, and how they made the transition from merely replicating to also interacting with the world and therefore truly becoming alive, we do not know – they may have been RNA molecules, or simpler compounds, such as peptides.
⁹
One essential feature of those early replicating systems would have been that they were able to speed up the chemical reactions that define life. The ability of molecules like RNA to act as enzymes and to catalyse reactions was discovered in the early 1980s by Sidney Altman and Thomas Cech, who won the 1989 Nobel Prize in Chemistry for their work. If left to their own devices, the kind of reactions that take place in our cells would need billions of years to occur spontaneously; in the presence of RNA they take a fraction of a second.
¹⁰

At some point, perhaps after a period of evolution and competition between various biochemical types of life, the RNA world came into being.
¹¹
There are no direct traces of this world, so our views are based on strong suppositions rather than physical evidence. This was a very different kind of life. In the RNA world, RNA molecules were the basis both for reproduction and for biochemical interaction. In a world without DNA or proteins, the genetic information contained in an RNA molecule coded simply for that piece of RNA. There was therefore no code, in terms of the genetic material containing a representation of another molecule – the earliest RNA genes coded themselves and that was it. Reproduction involved the copying of RNA molecules that acted as enzymes to direct chemical reactions. These RNA molecules provided the raw material for natural selection to begin its long work of sifting between variants, eventually leading to the DNA-based life that now covers the planet.

The idea of the RNA world seems to have first been put forward by Oswald Avery’s colleague, Rollin Hotchkiss, at a symposium organised by the New York Academy of Sciences in 1957. Struck by the fact that some viruses use RNA and others use DNA, Hotchkiss suggested that

as a genetic determinant, RNA was replaced during biochemical evolution by the more molecularly and metabolically stable DNA. Cell lines have preserved the RNA entities which, evolutionwise, were primary to DNA and may have allowed them to store their information in DNA and thereby become subservient to it metabolically.

For many years it was difficult to see how RNA could have appeared spontaneously, because the biosynthetic pathways involved in its creation seemed to be too complex. But in 2009, John Sutherland’s group, then at the University of Manchester, showed that the RNA pyrimidines (U and C nucleotides) could appear through a relatively simple series of reactions, using as their starting point the kind of chemicals that could have been floating about in early Earth conditions.
¹³
We are getting closer to understanding how life might have appeared spontaneously. Already, researchers have been able to create artificial systems in which pairs of short RNA enzymes can grow and evolve in a self-sustained manner, each catalysing the growth of the other.
¹⁴

Although the RNA world no longer exists (but who knows what secrets lurk in the deep ocean?), we all carry its legacy within our cells. When our DNA-based life appeared, evolution did not redesign life from scratch: it used what was to hand, adapting existing RNA biochemical pathways and turning them into something new and strange. This explains why RNA is not simply a passive messenger between the two apparently fundamental components of life – DNA and proteins. It plays many roles, shuttling genetic information around the cell and shaping how it is expressed, just as it did in the RNA world. As the RNA biochemist Michael Yarus has put it: ‘Without RNA, a cell would be all archive and no action.’
¹⁵

RNA is involved in almost all of the cell’s machinery for getting the genetic information out of DNA and either creating proteins or controlling the activity of genes. In its many forms, RNA performs essential functions within the cell, even if it has lost its role as the embodiment of genetic information, replaced by the semi-inert double helix of DNA. The double helix – iconic, rigid and fixed – contrasts with the many physical forms that RNA can take, enabling it to carry out such a wide range of functions, which would have been such an important feature of the RNA world.

Just as we do not know when the RNA world appeared, so we also do not know when it finally disappeared. All we can do is trace the ancestry of modern, DNA-based organisms back to the Last Universal Common Ancestor (LUCA), a population of single-celled DNA organisms that lived perhaps 3.8 billion years ago. LUCA evolved out of the RNA world, eventually – perhaps rapidly – out-competing and replacing it.

The replacement of RNA as the repository of genetic information by its more stable cousin, DNA, provided a more reliable way of transmitting information down the generations. This explains why DNA uses thymine (T) as one of its four informational bases, whereas RNA uses uracil (U) in its place. The problem is that cytosine (C), one of the two other bases, can easily turn into U, through a simple reaction called deamination. This takes place spontaneously dozens of times a day in each of your cells but is easily corrected by cellular machinery because, in DNA, U is meaningless. However, in RNA such a change would be significant – the cell would not be able to tell the difference between a U that was supposed to be there and needed to be acted upon, and a U that was a spontaneous mutation from C and needed to be corrected. This does not cause your cells any difficulty, because most RNA is so transient that it does not have time to mutate – in the case of messenger RNA it is copied from DNA immediately before being used. Thymine is much more stable and does not spontaneously change so easily. The adoption of DNA as the genetic material, with its built-in error-correction mechanism in the shape of the two complementary strands in the double helix, and the use of thymine in the sequence, provided a more reliable information store and slowed the rate of potentially damaging mutations.