Narrative Science – making synbio histories

Hello you.

This post is 50% an opportunity to share some archival material that should be of interest to my synbio and history of bio readership, and 50% a reflection on the historicizing I have been getting up to. It comes off the back of a workshop I attended last week at Kent on ‘Synthetic biology and the public good‘, excellently organised by David Peace and Russell Moul, where I spoke to the title ‘When is synthetic biology? Which public’s good?’ I am in the process of putting together my first articles on the history of synbio and thanks to the Kent workshop, and a recent special issue of Studies A on ‘Narrative Science‘, I think I’m in a position to explain what it’s been like writing a history of emerging science. It’s been different!

First, the archival material.That button takes you to a PDF of a privately circulated report, written – as far as I can tell – by Prof. Hans Kornberg (then at the University of Leicester), on restriction enzymes and molecular biology, just as new potentials for genetic engineering began to become clear in the early 1970s. I cannot be certain of the author because it is unattributed, but as Kornberg was the person asked to prepare this kind of document ahead of the meeting it was written for, it seems a fair assumption. The meeting was the first of the newly established ‘Working Party on genetic engineering in microorganisms’ of the UK’s Associated Board of Research Councils, and the report was expressly written as a ‘child’s guide’ to molecular biology’s science and safety (the Committee Chairman, Sir Eric Ashby, used the child’s guide language when asking for it to be written). The WP had been established in response to the call for an international moratorium on particular forms of experimentation with DNA by the National Academy of Sciences (NAS) in the US, which they had announced earlier that same year.

The big story of the recombinant DNA controversy has been told and retold many times, and new insights and perspectives are emerging all the time. Only a few weeks ago I got to see Luis Campos present his research on the Asilomar conference(s!), and he shared a tonne of exciting new archival material. Watch his space! One of the things he showed us I have since been able to find online. It’s a film, ‘”Hypothetical Risk: Cambridge City Council’s Hearings on Recombinant DNA Research”, recorded in the US in 1976. This was a public meeting called to discuss the appropriateness of recombinant DNA research taking place within Cambridge (Massachusetts), as a result of the City Council issuing its own moratorium, doing so on their own grounds, beyond any recommendation from the NAS.  It shows the interaction of science and society in terms that are both familiar and unfamiliar. There’s no point describing it when you can just watch it, and I’m exceedingly grateful to Campos for highlighting it in the first place.

Back in the UK the controversy played out in ways closely linked with the US. What I have been looking at are papers that have become available since those first histories were written, and which allow us to push the story further, and further forwards, to bring in synthetic biology. Below I have transcribed the WP ‘child’s guide’ because it is a fascinating snapshot into how DNA recombination was being discussed at the time by those guiding the UK research establishment, precisely within a context framed as controversial, and also because of what it can tell us about narrative in/for/of science. For my synbio readers, have a think about how recent developments such as CRISPR and ‘human genome write’ have played out in comparison with (in the legacy of?) these kinds of Working Party, and about how long we have anticipated the ‘great value in the industrial use of micro-organisms to make materials quite outside their normal repertoire.’

For my historian readers, I want to say one or two things on narrative in the document, and also what it has been like historicizing an emerging science. I am able to articulate both better thanks to the Studies A special issue mentioned above.

Narrative matters a lot for the WP report, and in ways that only become easy to appreciate once we take narrative as our focus. First it establishes that there are two narrative timelines, one playing out in public (and involving grand fears, alarm, emergency measures from the NAS, and so on), and a second playing out in private amongst those in the know, who have been talking about the potential dangers for quite some time. Second, the report places the UK experience in a different position from that underway in the US, by highlighting how Paul Berg’s concerns appear to be narrower than those which the UK Working Party intends to address. So the WP narrative is again emphasised as related to, but different from, the alternative timeline (Berg was author of the NAS moratorium statement). Third, the author recognises that the language at hand, particularly that of ‘genetic engineering’, is not ideal, especially for the purposes of a report such as this. Nevertheless a narrative has been commissioned and so as “there is no obvious simple alternative to describe the whole range of operations now available for the manipulation of the hereditary material of organisms and cells”, then ‘genetic engineering’ will have to do. Fourth and last, the report’s author uses surprise and twists as a way to position the reader with regard to key biological phenomena. In particular restriction enzymes have ‘quirks’, and more broadly “Most genetic engineering…in particular, that which is the subject of recent public concern – has depended on the exploitation of oddities”. So we are assured that the new biological technologies are weird in and of themselves, regardless of any scientific research.

In addition, narrative also helps explain my own work better.

One of the things that I have done by following synthetic biologists in a more ethnographic mode, is to pay attention to the ways in which history already matters for them,  be it in the ways they frame their research (for fellow scientists and for policy makers), where they see themselves in history, indeed even what kind of ‘biological time’ they see themselves operating with. All this history making by scientific actors is important in and of itself, but is also an entry point into a discussion of different kinds of narrative and who they work for. This was the theme of my talk at Kent, hence ‘When is synthetic biology? Which public’s good?’

As for my own history making, a nested Narrative Science discussion has been very helpful. Paul Roth draws attention to Allan Megill‘s analysis of Fernan Braudel‘s (told you it was nested!) The Mediterranean World in the Age of Philip II (1972 first English translation), and what it can teach us about narrative knowing and explanation. The way Megill unpacks the value of Braudel in the case of the Mediterranean captures a lot of how I have felt about synbio (obviously OBVIOUSLY Braudel is working on a far vaster, more complicated, and impressive scale than anything I have achieved. OBVIOUSLY).

The Mediterranean and the Mediterranean World is best seen, then, as a vast character analysis, in which Braudel broke down ‘the Mediterranean,’ which begins as an undifferentiated entity, into its constituent parts, with growing attention over the course of the book to the human processes that are carried out within this geohistorical space. … The Mediterranean tells us what ‘the Mediterranean’ was and, to some extent, what it still is. Braudel’s explanations are contributions to this end. The work is a vast recounting, into which explanations are stuck like pins into a pin cushion. It is likewise a vast narrative, though more an anatomizing narrative of character than a sequential narrative of action. ( Megill, 1989, p. 646, p. 646)

This has been how I have approached synbio, and it has often made me difficult for people (scientists, historians, social scientists) to understand, and has certainly made producing historical research slower and more difficult than anything I have attempted before. It is like picking up broken glass with your bare hands – you stand and stare, thinking for a long time about where to place your fingers.*

That’s all for now folks. Conference season beckons, and I’m a big fan of blogging as a way to think. You all just watched me do a bit of that. SORRY!

*No, I do not own a dustpan and brush.

Transcript: Briefing paper for ABRC [Advisory Board for the Research Councils] Working Party

  1. Background

In their recent public statement, a group of distinguished American molecular biologists, led by Paul Berg, drew attention to two classes of experiment which they felt presented particular hazards. Their first concern was with the experimental transfer of drug-resistance factors between bacteria; the second was with the linkage of animal viruses to other self-replicating systems, whether viruses or plasmids. They recommended that, to give time for a careful assessment of the problem, there should for the present, be a voluntary moratorium on such work. They further drew attention to the more general class of experiment, involving linkage of any animal DNA to plasmids or bacteriophages, and suggested caution in the planning and execution of such work.

There had been, for some time, a general awareness of the problem and, although the publication of the Berg statement precipitated rather dramatic action, discussions had already been going on, for example, within the MRC [Medical Research Council], about what level of hazard such work presented. Furthermore, as a consequence of the 1973 smallpox outbreak, a Government Working Party was set up, under the Chairmanship of Sir George Godber, the ex-Chief Medical Officer at DHSS [Department of Health and Social security], to consider the laboratory use of dangerous pathogens. That Working Party, partly as a result of representations made by the MRC’s representative on it, had already provisionally concluded that experiments similar to those envisaged by Berg should be carried out with precautions appropriate to the handling of pathogenic viruses. It seems likely that there will shortly be constituted a standing committee to draw up codes of practice appropriate to the handling of pathogens and no doubt the thinking of such a committee would be influenced by the outcome of this present ABRC Working Party’s deliberations.

It should perhaps be emphasised that concern, as expressed in earlier discussions we have held in this office, has ranged rather more widely that the areas defined by Berg and his colleagues; Berg’s concern was with the consequences of recently-developed techniques, based on biochemical procedures applied to DNA molecules, for the transfer of DNA into new situations and associations while at the same time maintaining its role as a genetic template. But the same end – and, a fortiori, comparable hazards – can be achieved, deliberately or accidentally, in other ways. It may well be that the ABRC Working Party’s area of concern should not be assumed too readily to be identical with Berg’s.

 

  1. Cell Biology

Although the term ‘genetic engineering’ has become a cliche debased by overuse, there is no obvious simple alternative to describe the whole range of operations now available for the manipulation of the hereditary material of organisms and cells. Early work in this area relied on the direct microsurgical approach – the transplantation of nuclei from one cell to another, or the localised destruction of chromosomes by ultraviolet radiation – and there is still distinguished work exploiting this area. As a case in point, Gurdon at the MRC Laboratory of Molecular Biology has done a great deal to illuminate the interaction of nucleus and a cytoplasm, showing for example that a nucleus taken from a fully differentiated cell can, when transplanted to an enucleate egg, take over the characteristics and the role of an egg-cell nucleus. Perhaps brief consideration should be given by the Working Party to the implications of this work, partly because such direct techniques could well be used profitably in conjunction with more biochemical approaches.

Most genetic engineering, however – and in particular, that which is the subject of recent public concern – has depended on the exploitation of oddities. Thus a parainfluenza virus, the so-called Sendai virus, was observed to cause cells to sue to form giant cells and this quirk of behaviour has been very fully exploited, notably by Henry Harris at Oxford, to carry out, relatively quickly and simply, genetic analysis – for example the assigning of genes to particular chromosomes – which is inconveniently tedious if done by classical techniques of linkage analysis. Thus, if a mouse cell lacking some particular genetic competence, so that it will not survive in some medium adequate for normal cells, is fused with a human cell having the competence in question, the heterokaryon, as the product of fusion is called, will survive the challenge of exposure to the medium. As the cell undergoes mitosis there is a pull between the two rhythms of mouse and human nuclei and partitioning of the two sets of chromosomes will tend to be incomplete; most commonly, in mouse-human heterokaryons, progressive loss of human chromosomes occurs. By challenging the daughter cells, noting the correlation between loss of the capacity to survive in the challenging medium and loss of a particular human chromosome, the laboratory worker can assign the particular gene to a chromosome.

Although most work has been done so far on animal cells, Cocking at Nottingham has succeeded in digesting away plant cell walls, to leave naked protoplasts, thus allowing fusion of plant cells. Given the recently developed techniques of meristem culture, which apply the methods of tissue culture to the early stages of plant development, and which permit the growth of viable plants from meristematic cells, the way is now open to a sort of asexual genetic hybridization with all the advantages of being able to make crosses that would be impossible by normal fertilization methods and, by suitable challenges to the heterokaryons, of making selection for particular genetic characteristics.

As applied to animal systems the technique might appear to be limited by the problems of histoincompatibility. Thus, if a heterokaryon were introduced into the animal which had provided one of the cells used for fusion, the expression of the other cell’s characteristics might be expected to lead to rejection of the heterokaryon. But, again, an oddity has been identified that allows even this obstacle to be surmounted: the precursor cells of red blood cells, when used for fusion, do not contribute membrane antigens to the heterokaryon and are thus not recognised as foreign. This example perhaps illustrates the way in which research in this field, being so intensive, throws up ways to overcome apparently intractable difficulties; it would be dangerous to regard any manipulation as impossible.

Work on cell fusion, as with Gurdon’s on nuclear transplantation, is again not what is in Berg’s mind, but nevertheless achieves the same end result of bringing DNA, functionally competent, into new associations.

 

  1. Molecular Biology

To turn now to the more biochemical approaches: if one single event can be identified as precipitating the present concern it is the discovery of Berg at Stanford of the so-called ‘restriction enzymes’. These, in their natural role, are defensive enzymes which break down foreign DNA to stop its incorporation into the host. Each restriction enzyme breaks the DNA molecule only at points adjacent to certain sequences of bases; the parent organism does not have the particular sequences and is thus spared from attack by its own restriction enzymes.

It may be said parenthetically at this stage that the evolution of such a system is perhaps something which could have been encompassed effectively only by a micro organism, with enormous populations and rapid multiplication. Used as we are to the massive timescale of evolution in higher organisms, it is hard to appreciate how rapidly random change in micro organisms can produce adaptations significant for survival. This rapid adaptability is one of the crucial elements in the present problems.

To revert to restriction enzymes; one quirk of some of these enzymes is that they do not cut the two threads of the ‘double helix’ at the same point but instead make nicks some way apart. The consequences of enzyme action is thus to leave a single-threaded ‘sticky’ end to each DNA fragment which will readily recombine with the matching ‘sticky’ end of another fragment. A given enzyme acts only where there is a particular sequence of bases; so no matter what the source of the DNA, the sticky ends produced by cleavage with a given enzyme will all be of one or other matching base sequences and will therefore be able to recombine to form hybrid molecules of DNA. This oddity immediately provides a technique by which DNA’s from different sources can be ‘spliced’ together to form new molecules that ben be replicated to form identical copies, or translated to form the equivalent RNA’s and so used to code for the homologous protein molecules.

The full exploitation of the potentials of this ‘splicing’ techniques depends on the availability of other methods for selecting and handling the various DNAs before and after splicing; again useful natural systems have been identified.

One example is the use of ‘reverse transcriptases’. The existence of such enzymes, which allow the synthesis from an RNA molecule of the complementary DNA, was predicted on the basis that RNA tumour viruses can cause changes in the genome of the host cell. What reverse transcriptase allows in the laboratory is the use of RNA as a template for the synthesis of what are in effect genes. Thus, if erythroblasts, red blood cell precursors, are taken, their RNA will be predominantly that which leads to globin synthesis. RNA isolated from these cells can then be used for the synthesis, with the aid of reverse transcriptase, of a globin gene. Similar stratagems could be applied to any situation where the protein synthesis of a cell is stereotyped and biassed towards a single protein and thus would allow the production of DNA predominantly coding for a specific protein.

Three further techniques rely on natural mechanisms for introducing DNA into cells; first, some viruses can enter cells and there become incorporated into the cell’s genome (as can, in suitable circumstances, ordinary, non-viral DNA); second, bacteria may carry, in addition to their single chromosome, extrachromosomal genetic particles (plasmids) and by a process of sexual conjugation can transfer plasmids to other bacteria; thirdly, bacteriophages can, rather similarly, inject DNA into bacteria. Although many ‘phages are virulent and destroy the host bacterium, others simply replicate and form hereditary particles in the cell. By various combinations of these techniques the potential applications are generated.

Perhaps the simplest example would be to splice together DNA from two viruses; the consequence would be unpredictable but, given the large number of combinations of DNA possible, there must be a chance of producing recombinant hybrids showing particularly advantageous or hazardous characteristics. Host specificity in viruses appears to depend on the viruses’ protein coats, and if these were to be removed or changed the infectivity of the recombinant virus might be enhanced. We may therefore envisage a recombinant virus having, say, the infectivity of influenza or chickenpox and, at the same time producing diseases or disorders to which man is not normally susceptible. This sort of experiment is, of course, one which might be carried out by chance if the investigator accidently contributed viruses to which he himself was host.

It should perhaps be emphasised that experiments involving the incorporation, in a functional state, of DNA from Xenopus and from Drosophila into bacteria have already been successfully carried out; the essential feasibility of such procedures has therefore been validated beyond doubt.

There is a great deal of relevant detailed technology associated with this sort of operation; for example, some ‘phages have been isolated – the so-called defective ‘phages – which will be more infective, and replicate freely inside the host cell, if they have extra DNA spliced into them; normally this extra DNA is taken up from the host bacterium’s chromosome but could be spliced in by the restriction enzyme technique. Thus there is a built-in selection in favour of those ‘phages into which foreign DNA has been successfully spliced.

 

  1. Potential applications:

One [aborate?] possibility would be to attach DNA, from whatever source, to a bacteriophage and to use the ‘phage to infect bacteria. The bacteria could then be used to make large quantities of DNA or, by extension, the protein for which the DNA codes. It is at this point that the commercial implications loom large because there must be a theoretical possibility of making proteins, for example, insulin, which are at present made by unsatisfactorily ‘messy’ extractions from animal tissues.

An extreme example of what might, conjecturally, be possible using a range of the techniques so far mentioned would be directed towards the cure of human anaemias characterised by defective globin production. From erythroblast RNA from a normal subject’s cells, globin DNA could be made by the use of reverse transcriptase. By means of restriction enzymes this DNA could be spliced into a defective ‘phage and the ‘phage used to convey the DNA into a bacterium for synthesis of larger quantities. The DNA might then be incorporated into the cells of an anaemic subject or could be attached to some virus that would assist incorporation, and thus carry the globin gene into deficient cells. Although the scheme may seem rather far-fetched, this particular programme of experiments is actually being planned.

The hazards of experiments such as this last are perhaps limited to the anaemic subjects exposed to the globin DNA rather than being widespread (and there is at least a reasonable possibility of validating the method by animal experiments before applying it to a human subject). An obvious danger would be that genes other than the globin gene might be introduced into the host’s cells. Or the ‘new’ globin gene might fail to respond to the control mechanisms and lead to uncontrolled synthesis of globin in all, or many, of the cells of the body.

 

  1. Plasmids

When we turn to bacterial plasmids, the situation is basically a simple one. Plasmids represent extrachromosomal elements which may interchange between bacteria and which represent a pool of genetic versatility, ever changing and interacting with the environmental factors. They represent an important adaptive resource in allowing populations of bacteria rapidly to come to terms with new situations. There is no reason why plasmid DNA should not be subject to splicing procedures with restriction enzymes and used, in the same way as ‘phage, to introduce new DNA into bacteria.

Unintentional genetic engineering has already greatly influenced bacterial capabilities; the indiscriminate use of antibiotics, in medical practice and in animal husbandry, has led to the widespread occurrence of drug-resistance plasmids. It is therefore perhaps surprising at first sight that experiments in this area should head the embargo list proposed by the US Academy’ of Sciences; certainly it would be strange if work intended to tackle the problems of drug-resistance were to suffer. Indeed, given the extreme versatility of bacteria, it might perhaps be thought that the hazards of experimental intervention are small, but nevertheless a realistic possibility might be the experimental transfer of resistance factors to an unrelated species of bacteria not normally possessing them. An injudicious experiment of this sort might seriously weaken the clinician’s armentarium of drugs.

 

  1. Perspectives:

It might be thought immediately attractive to compare the possible hazards of these procedures with those of work with radioactive materials. But there are two fundamental differences. First, radioactivity is inherently self-limiting whereas the biohazards in question are, potentially at any rate, self-propagating. Second, there is a possibility in the biological system of mutation, either spontaneous or caused by deliberate exposure to chemical or other mutagens, which could convert something innocent into a hazard. The problems may be especially serious where a laboratory has large numbers of cultured cells, especially if or human origin, which could act as a reservoir for replication and mutation of DNA.

The potential benefits of such techniques, quite apart from their enormous value as research tools, would be to alter and select genetic characteristics in animals and plants far more readily and purposively than by conventional techniques of breeding. In addition to the agricultural implications of such possibilities there may also be great value in the industrial use of micro-organisms to make materials quite outside their normal repertoire.

The hazards, quite apart from those immediately suffered by the experimenter or by experimental subjects – who must be assumed to be aware of the risk – are the creation and dissemination of new pathogens, whether of man, animals or plants. It should be borne in mind that the cost of the 1973 outbreak of smallpox, quite apart from the loss of life, was reckoned by the Committee of Inquiry to run into millions of pounds. Outbreaks of foot-and-mouth disease have been similarly costly. It might be argued that a single unfortunate experiment in genetic engineering could have consequences of the same, or greater, order of magnitude.

 

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