March 8, 2024, by Brigitte Nerlich

Genes, trains and eureka-moments

I was in the process of writing a blog post on metaphors in genetics and genomics which was getting longer and longer and I had some personal stuff to deal with. So, I stopped. I might come back to this another time. In the process of writing, I discovered that trains have been quite an important source domain for metaphorical inspiration in genetics and genomics. In this post I’ll give you three examples, but there might be more. If you know any, please let me know.

We all know that there are various metaphors that are fundamental for thinking and speaking about issues in genetics and genomics. Andrew Reynolds calls them ‘background metaphors’. They are rooted in what we know about language/information, agency and machines. These are very broad metaphorical source domains which have within them, in an almost fractal and evolutionary fashion, more and more source domains, depending on the state of the world and the state of technology.

The machine metaphor can draw its inspiration from anything mechanical; from automata and clockworks to gauges and pendulums, from steam engines to cars and assembly lines, from wireless telephones to digital computers. In amongst all these machines, we also find the train. And the train affords lots of other sources for metaphorical mappings; from the engine or locomotive to the carriages, from the driver to the passengers, from the rails to the networks, the switches and the points and probably many more.

I found a few train-inspired eureka-moments when rummaging around some relatively recent developments in genetics and genomics, but others must have used train metaphors in biology in the 19th century, when both biology and trains were all new…. If you know examples, let me know.

Julian Huxley and epigenetics

In 1956 Julian Huxley, an evolutionary biologist, eugenicist and brother of Aldous Huxley, wrote a review of Conrad H. Waddington‘s Principles of Embryology and expressed the hope that Waddington might write a sequel called Principles of Epigenetics.

Over the last decade or so ‘epigenetics’, in the guise of molecular epigenetics, has been much in the news. One of its long roots reaches back to Waddington’s thoughts on embryology and epigenesis. I can’t go into that long history here. Suffice it to say that Waddington established one of the most important visual metaphors in embryology in 1957 in his book The Strategy of the Genes. But it should be stressed that he had talked about that topic since the 1940s.

As James Ferrell pointed out in 2012 “Waddington’s epigenetic landscape is probably the most famous and most powerful metaphor in developmental biology.  Cells, represented by balls, roll downhill through a landscape of bifurcating valleys. Each new valley represents a possible cell fate and the ridges between the valleys maintain the cell fate once it has been chosen.” (One could argue that the valleys represent pathways towards a cell fate, not the cell fate itself)

A year before, in 1956, Waddington had published Principles of Embryology which Huxley reviewed under the title “Epigenetics” for Nature. This review is very complex and for a lay person like me difficult to understand. I’ll just quote what struck me as an interesting use of metaphor.

When talking about part 1 of the book, Huxley says “Throughout, the treatment is centred around the general concepts which are emerging from analysis on the epigenetic level, such as organizer action, induction, evocation, competence, individuation, gradient-fields, and canalized epigenetic pathways.”

He criticises Waddington for not taking more account of evolution and then points to “numerous epigenetic phenomena where a switch-mechanism is operative. In such cases, alternative causes or stimuli switch development into alternative pathways, each of which has been sharply delimited or homeostasized (stabilized) by past selection. As with a railway switch, there need be no instability, whether on the single pathway before reaching the switch, or on either of the alternative tracks along which the process may continue.”

It is interesting to note that Huxley’s switch metaphor is rooted in his experience of the railway, while modern metaphors for expigenetics tend to exploit our understanding of light and dimmer switches used to switch light on and off.

I wonder whether Waddington read Huxley’s review and whether he ever envisaged trains running through his epigenetic landscape. I suppose not. As somebody who knows a little bit more about these things just told me: the key thing about Waddington’s model is the loose control or influence exerted by the valleys on the path taken by the ball. The shape of the valleys influences the path the ball will take but does not absolutely determine it, and in some cases the ball can jump out of one valley into another. So unlike the railway switch there is still instability built into the model….

Interestingly, something else happened in 1957 which also was of great importance to biology and genetics. And again, trains played a role.

François Jacob and gene regulation

In 1957 François Jacob and Jacques Monod started a genetics research programme from which a radically new view of gene regulation emerged, known as the operon model.

As Reynolds explains in his 2022 book on metaphors in the life sciences: “In 1961 Jacob and Monod published a paper outlining a model for gene regulation that made an important distinction in two separate kinds of genes: ‘structural’ genes (so-called because they are implicated in the molecular organization or structure of the amino acids comprising the protein) and ‘regulatory’ genes whose products control the activity of structural genes by repressing or promoting their expression. […] The authors were proposing that the expression of certain genes (the ‘blueprints’ for protein synthesis) were controlled by mechanisms […] that acted like an electronic switch that could be activated by signals received from outside the cell. […] The activity of these switches they were suggesting were coordinated according to some plan or program that increased the organism’s adaptive function and response to its environment.” (pp. 34-35)

Here we can see the use of some important genetic metaphors, such as ‘blueprint’ and ‘program’. But, more importantly, Reynolds says: “Jacob explained that the idea for a switch mechanism occurred to him as he watched his son manipulate the on–off switch on his toy train set to regulate its speed”. But when did it occur to him? For this we have to turn to Mark Ptashne’s obituary of Jacob.

Ptashne noted that an important insight into gene regulation came “from Jacob’s chance observation that his son could vary the speed of his toy train over a wide range depending on the frequency with which he flicked the on-off switch. Armed with this insight, Jacob confronted the usually impenetrable barrier of Monod’s critical intellect. The barrier weakened and then fell, and starting in 1957, together they designed and performed a glorious series of genetic experiments that ‘proved’ the idea.”

So, a leap of imagination led from a model train to a new model of gene regulation. And in 1965 Monod, Jacob and André Lwoff won the Nobel Prize in Physiology or Medicine “for their discoveries concerning genetic control of enzyme and virus synthesis”.

So far, tracks and switches have been the main source domain for our biological thinkers. In our next excursion we turn to locomotives and drivers.

Chris Curtis and gene drives

The Royal Society defines gene drives as: “systems that bias the inheritance of a particular DNA sequence. They can be used to increase the persistence of an introduced trait that would otherwise disappear from a population very rapidly because the introduced trait puts the organism at a disadvantage.” But why call them a drive, I wondered.

Reading an article on early gene drives by the science writer Oliver Morton led me to the metaphorical source of ‘gene drive’ (I believe). Morton reported on research carried out by Austin Burt at Imperial College London, especially on his 2003 article entitled “Site-specific selfish genes as tools for the control and genetic engineering of natural populations.” What fascinated Morton was that “Strange properties of DNA sequences called homing endonuclease genes (HEG) can be used to eradicate the whole species of mosquito. These genes have the capability to evade the normal rules of heredity, exploiting a loophole to get extra copies of themselves into the next generation.”

As Matthew Cobb pointed out in his 2022 book The Genetic Age, Burt did not coin the term ‘gene drive’, but he certainly laid the seeds for that naming. Cobb even talks about Burt realising “that by hitching one of these endonuclease genes to a gene that would alter the target animal – for example by inducing sterility or making a mosquito immune to malaria – it would be possible to drive that character into the population”, using metaphors related to the train metaphor to which we come now.

Morton wrote in 2003 that “Burt is not the first person to consider messing around with mosquito genes in order to tackle malaria. Chris Curtis of the London School of Hygiene and Tropical Medicine, has been publishing on the subject since the late 1960s, and recently the field has been positively swarming with ideas.”

Let’s see what Morton says about Curtis…. And what Curtis has to say about trains. In my little collection this is the most extensive and extended use of the train metaphor. One should keep in mind, however, that Curtis seems to use drive(r) in two ways: in the sense of driver as the ‘pusher’ or motive power of something and in the sense of the guide or steerer.

“To solve this problem [spreading genes that make mosquitoes less likely to transmit malaria through a population at large], the resistance genes need to be hitched to a ‘driver’ – a piece of DNA that spreads for some other reason. Various drivers have been discussed, including transposons and parasites that live within the mosquitoes’ cells, but they all share a significant drawback. ‘The crunch problem,’ says Curtis, ‘is how you make sure that the thing you want driven remains linked to the driving system.’ If you think of the driver as a locomotive and the things you want driven as the carriages, he says, then if the coupling between them breaks, the locomotive will drive off into the distance while the carriages start to roll backwards. There’s always a risk that a new mutation will uncouple the driver and its carriages, and even if the chances of this happening are very small, it’s still a fatal flaw. Work by some of Curtis’s colleagues suggests that if the engineered mosquitoes are just 20 per cent less fit than wild ones, and even if the chance of uncoupling is as low as one in a million, the locomotive always runs away and the resistance genes die out. To Curtis, that looks like the end of the line. ‘If we don’t have a reasonable prospect of driving those genes into wild populations, there’s no point.’” (Italics added)

I am not sure whether Curtis actually used the term “gene drive” itself, which the Oxford English Dictionary says first appeared in 2004 in an article on Wolbachia as “as a gene drive system for mosquito genetic replacement”.

However, only with the advent of the gene editing tool called CRISPR/Cas9 could gene drives ‘take off’, and edited genes can now potentially be ‘driven’ in the sense of ‘forced through’ a whole population of insects relatively easily. However, there are many ethical issues with that – have a look at Cobb’s book for that.

Trains, trains, trains

Once I had found these train-inspired eureka moments in my three cases of Huxley, Jacob and Curtis, I began to see trains everywhere… For example an article on cancer evolution notes that the “commuter train provides a convenient metaphor here; much like a selected cell lineage in a cancer, a commuter train has many passengers and only one driver”. In cancer research, there is also is talk of driver and passenger mutations etc.

In an article trying to explain Friedreich’s ataxia, a rare, inherited, degenerative disease, we find the sentence: “The metaphor for FXN gene function is a train with five compartments. The train engine functions to make sure all the segments (exons) of the FXN gene are made for adequate frataxin protein production.”

I am sure there are more examples!

Image: Swanage heritage train going through Corfe (photo taken by David Clarke)

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