nothingsmonstrd

[nothingsmonstrd]

the goal for this year and for every year is to be kind and also to stop being scared of literally everything

[nothingsmonstrd]

From Red Plenty by Patrick Spufford

"The Unified System: 1970"

A cell. A lung cell. Tobacco smoke swirls by in the spired and foliated channel the cell faces. Its job is to take in oxygen from breath and keep out everything else, and on the whole it does well filtering the usual impurities in air: but this is not a designed mechanism, put together for a function by conscious plan, it is a dumb iteraion of all the features which have proved by trial and error to serve lung cells well in the past. The past did not include deliberately-breathed smoke. We could count an amazing number of different chemicals in the blue-grey vapour snaking through the tissue, altogether too many of which the cell does not know how to exclude. Formaldehyde, acetaldehyde, catechol, isoprene, ethylene oxide, nitric oxide, nitrosamine, the aromatic amines — not to mention the quinones, the semiquinones, the hydroquinones, a whole fanily of polycyclic aromatic hydrocarbons. We are watching for one of these last. Here it comes now, a drifting, tumbling molecule of benzopyrene. It sails into the cell's bulging curtain wall of fats and sticks there, like an insect caught in glue; then, worse, is dragged through, because the fat curtain is spiked here and there by receptors, and one of these has the benzopyrene in its grip. The receptor winches the benzopyrene through the curtain, hand over hand, atom over atom, wrapping it as it comes in a fold of the curtain, and then closing the fold behind it, so that when it reaches the inside, a little fatty envelope buds off from the inner wall of the cell with the benzopyrene sealed inside it. And floats free, into the warm liquid workspace where the body builds its proteins.

But it's all right. The cell has no specific defence against benzopyrene, but it is not defenceless. It has the powerful standard equipment all mammalian cells deploy when foreign bodies turn up where they're not supposed to. The package of fat is a flag, a label, an alert. Detecting it, up comes an enzyme to metabolise the contents. The enzyme munchs the benzopyrene into pieces of epoxide which other bits of the cellular machinery can flush safely away.

This has happened over and over again, every time Sergei Alexeyevich Lebedev lights a cigarette. There are billions of cells in the lungs. Lebedev has smoked thousands of unfiltered Kazbek a day for fifty years. So this has happened thousands of billions of times.

***

Another lung cell. The machines that Lebedev has made all build up their complicated behaviours from absolutely predictable little events, from valves and then transistors turning on and off. Definitely on; definitely off. Without any shading of degree. Without any ambiguity. The machine that makes Lebedev is different. The base layer of its behaviour, from which all the rest emerges, is various and multiple and uncertain. There is no binary simplicity. There is the slow bubble of many chemical reactions all happening at once, each continuing until a task is mostly done, probably done, done enough to satisfy a program which was itself only whittled out of randomness just well enough to get by. The enzyme’s destruction of benzopyrene, for example, only flushes most of it away. A fraction of the epoxides react again with the enzyme and become diol epoxides. That’s what’s happened here; instead of nice, inert, detoxified molecules, we have a version of the same thing which is lacking one electron on one of its atoms, and which consequently yearns to stick to any other molecule which will share an electron with it. The diol epoxides are aggressive gloop. Aggressive? One electron’s worth of electric charge doesn’t tow a molecule very fast through the soupy interior of a cell: it doesn’t send the diol epoxides streaming along at the speed of light like the electrons in a vacuum tube. But it does exert a tiny, persistent pull on them. It draws them along towards molecules they might stick to. It draws them everywhere in the cell, and so it draws some of them towards the cell nucleus, which has another wall of fats around it, but unfortunately is designed to let molecules rather like the diol epoxides in and out on the cell’s ordinary business. The hungry, electron-seeking blob of gloop slips through, and there in front of it are floating twenty-three pairs of tempting targets: the huge, fat, friendly, electron-rich chromosomes of human DNA.

No one in the world in 1970 understands in any detail how they work, and the ignorance is particularly bad in the Soviet Union, thanks to Lysenko. But the chromosomes work whether they are understood or not. The gloop drifts in; and at any and every point along the endless coiled helix where it happens to make contact, the gloop locks on. Where it jostles forward with its missing electron to embrace one of the DNA’s electrons, there’s a little chemical reaction, and the electron in question bonds to both the DNA and the gloop. The gloop is now an ‘adduct’, glued to the helix. But the helix is changed too, by having the blob of tobacco residue stuck to it. At the position where the adduct sits, the information in the DNA has been corrupted. Instead of the G, T, C or A that should be there, in the four-letter alphabet of the genome, it reads as one of the other letters instead. The adduct has written an error into the code.

But it’s all right. In the vast majority of positions along the genome where goo might attach itself at random, altering one letter won’t produce any significant mutation, even if the alteration lasts. The genome is Lebedev’s software, but unlike software written by humans, it is not a set of procedures packed end-to-end, all of which at least purport to do something. It is a jumble of legacy code spread out in fragments through a whole voluminous library of nonsense. Almost always, a random change of letter will either hit some existing nonsense, or turn some sense into new nonsense. And because the chromosomes come in pairs, with a version of every chromosome contributed by Lebedev’s mother floating there opposite a version from his father, if some sense on the version on one side turns to nonsense, the equivalent piece on the other version will go on making sense just fine. Dangerous mutations usually only happen in the rare cases where sense is accidentally turned into different sense. Which is not what has happened here. Here, the arriving molecule has glued itself where it makes no difference at all.

This has happened billions of times.

***

Another lung cell. The soft rainfall of gloop onto Lebedev’s DNA continues. By chance, this particular sticky drop in the statistical rain is one of the small minority that is going to land somewhere that matters. By chance, it is falling onto a stretch of code on Chromosome number 11 which scientists will know later as the gene ras, or hRas. The electrophile noses in; it suckers on; the guanine (G) it has suckered onto on the helix now reads, for all intents and purposes, as cytosine (C). And this time, it happens that changing G to C creates sense, not nonsense, in the code. Ras with a C in it at this specific position is a viable and functional piece of software. But much more of a change is in prospect than there would be if someone substituted a new programme for the one that was supposed to be running in a computer. Human-made software is only an informational ghost, temporarily given possession of the machine and allowed to change 0s to 1s and vice versa. The software of humans, on the other hand, actually builds the hardware it runs on. It creates the machine. So a mutation in the code means a mutation in the body too, if the error endures.

Ras is one of the genes that control cell growth and cell division. In adults, it switches on and off periodically to govern the normal cycle of the cell’s existence. You wouldn’t want it switched on all the time. Foetuses in the womb run ras continually to generate all the new tissue that the Build-A-Human program demands when a human is being first assembled. Otherwise, cell multiplication must happen when, and only when, the body part the cell is in needs a new cell. But it’s the switch that has been altered by having C where G used to be in this mutant version of ras. C instead of G at this one particular point jams the ras gene at ‘on’ – throws the lever for unstoppable growth, and then breaks the lever.

But it’s all right. This copy of ras may be corrupted, but the cell has a failsafe mechanism built into the shape of the DNA molecules. The helix is a double helix. On the other side of the double corkscrew there runs another strand of Gs, Ts, Cs, and As which carries all the information of the genome, only in reverse, like the negative of a photograph or the mould a jelly was turned out of; and the cell, which is used to operating in an environment of small chemical accidents, operates a handy editorial enzyme that moves up and down the chromosomes checking that the two strands remain perfect opposites. The editorial enzyme doesn’t find absolutely all of the changes the adducts gummed to Lebedev’s DNA have made, but it finds most of them, the harmless and the harmful alike, methodically correcting each little mutation. It finds this one. The new C in the mutant version of RAS on one side clashes with the existing C on the reverse side. C against C isn’t a legitimate opposite. A quick editorial snip, and there’s the original G again. Lebedev’s factory settings have been restored.

This has happened millions of times.

***

Another lung cell. There is a way for a blob of goo to cause a ras mutation that persists. The gummy electron-seeking missile has to arrive, and glue G into C in the exact right place, at the exact right moment in the life of the cell when for once the enzyme cannot compare ras to its negative. That is, when the lung cell is already busy dividing into two lung cells. The goo floats in, and finds inside the nucleus a double helix which has been unzipped into two separate strands, each of which is going to grow back into a complete copy of the genome. Of all the random blobs of goo in the random rainstorm, here comes the blob that suckers onto Chromosome 11 in the position to create the always-on version of ras, just as the unzipped halves of Chromosome 11 are waving loose. It’s too late for the editorial enzyme: there’s nothing to correct the mutant C against. Along the strand instead travels a polymerase, a construction enzyme, steadily building out the other half of a new double helix. And when it reaches the C, it obligingly supplies a new counterpart for the other side which is a match, which is a perfect opposite. The corrupted code has reproduced itself. After a while, there are two sets of completed chromosome pairs in the nucleus. They pull away from each other. The nucleus stretches, puckers out like dumb-bells, splits into two as well. Last the outside wall of the cell repeats the split, stretching and pulling and puckering back into a pair of separate fatty spheres. One contains ras in its original uncorrupted form, but beside it Lebedev now has a new lung cell with ras switched on in it forever. And immediately ras takes charge of the cellular machinery and starts the build-up to superfast cell multiplication. A cell running ras full-time won’t cooperate with nearby cells in any other task. It isn’t interested, for example, in being part of a lung. Binary at last, it only wants to become two cells, four cells, eight sixteen thirty-two –

But it’s all right. The body is used to occasional runaway accidents with ras. It has one last defence mechanism. As ras goes crazy, another gene, away over on Chromosome 17, detects the molecular signature of the build-up and neatly, swiftly, initiates cell suicide. The cell dies. With it goes the mutant ras.

This has happened thousands of times.

***

Another lung cell. Chance upon chance upon chance upon chance. Of all the billions of cells in Lebedev’s lungs, there will be some millions where the diol epoxide gum from his cigarettes stuck itself, not to ras, but to the gene on Chromosome 17 that initiates emergency cell suicide; and of those millions there will be some thousands where the crucial blob blew in just in time to land on a strand of DNA in the midst of cell division, and got itself copied. So, scattered here and there through the billions of cells whose little bulging windows of fat face the channels of the lung, there are some thousands, randomly distributed, where the suicide gene on Chromosome 17, later to be called P53, isn’t working. Here’s one of them. And into it, after fifty years of delicious Kazbek smoke, there flies one more random molecule of goo, and it travels straight to ras to scramble the vital G into C, and it arrives just in time, too, to evade the editorial enzyme and get copied into a new cell.

And it’s not all right. The new cell with mutant ras in charge of it is a tumor unbound, freed from the body’s safety systems to multiply and multiply, unstoppably, selfishly, altogether indifferent to its effect on Lebedev’s lung, and on Lebedev.

This only has to happen once.

***

NOTES

1 A cell. A lung cell: the molecular biology of this chapter is accurate as far as it goes, and I am assured that the dwindling probabilities of the molecular events in it are at least of the right orders of magnitude. But it should be remembered that the chapter only follows one possible route by which one toxin in tobacco smoke can induce one variety of lung cancer. There are many other routes, other toxins, and other cancers, so a realistic path towards carcinogenesis would be much less linear than the simple illustrative zoom I have selected here. It would trace its way in massive parallel through a massively forking labyrinth of probabilities. I drew heavily on – inhaled heavily from – Theodora R. Devereux, Jack A. Taylor and J. Carl Barrett, ‘Molecular Mechanisms of Lung Cancer: Interaction of Environmental and Genetic Factors’, Chest 1996, 109; 14–19; and on Stephen S. Hecht, ‘Tobacco carcinogens, their biomarkers and tobacco-induced cancer’, Nature Reviews Cancer 3, October 2003, pp. 733–44. I am also indebted to Dr Claerwen James for enlightenment via conversation and email.