DNA – The Only Way?

I’ve been struggling to write a post about the new TV show ‘Pluribus’ but it’s actually huge and therefore hard to talk about in a single piece, so for now, and possibly instead of that, I’ll just be talking about a scientific point it raises and it isn’t really about the series. There’ll be spoilers for about the first ten minutes of the first episode and then I’ll be moving off the subject. Here goes.

At the start of the first episode of ‘Pluribus’, astronomers detect a signal from the TRAPPIST-1 system around 600 light years away in the constellation of Cygnus. It repeats every seventy-eight seconds and consists of a series of four types of signal which they quickly realise represent the four bases of RNA, cytosine, guanine, adenine and uracil. This makes sense, in a way, as RNA is used to send messages from DNA for transcription into proteins, and it’s doing the same job here. This made me wonder a couple of things. How did they know it was uracil and not thymine, and RNA but not DNA? Also, does this mean that RNA and DNA are universal codes for genetic information, everywhere there’s life, or is it individually customised for different recipients, in which case how did they know terrestrial life used that code? Seems like insider information is involved somewhere.

So, crystallising that thought, this is the situation. All known life here on Earth uses one of two complex types of molecules, deoxyribonucleic acid and ribonucleic acid, DNA and RNA. At this point I’m stuck because I have no idea how much is common knowledge. If I get this wrong, I’m going to lose a lot of people. So I’m going to assume that everyone knows the remarkable general double helix with rungs structure of DNA, how its coils are themselves in coils so that it’s packed together very closely most of the time, that most of it doesn’t carry genetic information but has other functions related to it, that it has sides made of alternating sugar molecules and phosphate groups and four types of bases which link up in specific pairs, adenine with thymine and cytosine with guanine. RNA is generated from DNA and has a different, simpler structure, again with a sugar molecule alternating with phosphate groups and again four bases, except that instead of thymine it has a base called uracil. RNA is used to transfer information to ribosomes, which are like playback heads except that instead of sound they produce proteins, one amino acid at a time. Although most species of animal, plant and other organisms use DNA to store their genes, many viruses use RNA instead. RNA is less stable than DNA, so for example whereas animal or plant remains from many millennia in the past can have their DNA information extracted in a form increasingly corrupted with their age, RNA is not the same and doesn’t last long.

This is important. Please tell me if I’m assuming too much and if I’m not writing clearly. I really struggle with brevity, clarity and trying to work out what people do and don’t know about things, and one way of addressing this might be to get some feedback. In a sense, this entire blog post is a test of my ability to communicate clearly and well at least as much as it is about DNA.

So, I have questions, some of which I know some of the answers to but most I don’t. DNA can be considered to have the following components: deoxyribose, phosphate, adenine, thymine, guanine and cytosine. RNA has ribose instead of deoxyribose and uracil instead of thymine. The question is, are any or all of these essential for any molecule carrying genetic information within an organic life form, or are there other possibilities? How rigidly restrained is this aspect of biochemistry? This could be framed as a question about alien life but in fact it’s as relevant to biochemistry as it’s actually known to be on this planet as it is to that possibility.

First of all, the bases. There are two types of these: purines and pyrimidines. Purines have two rings in their molecule and pyrimidines only one. I remember this by thinking that the long name describes the short molecules and vice versa. Purines include some other familiar compounds including caffeine and the related stimulants often found with it. A particularly prominent purine is guanine, which forms the reflective layer at the back of many vertebrate retinae such as dogs and owls and increases their visual sensitivity in low-light conditions, and also the white cross on the back of garden spiders. They tend to be broken down into uric acid, so a diet high in DNA can contribute to gout and kidney stones and also conditions involving a high turnover of DNA such as leukaemia can also have these effects. Pyrimidines strike me as more obscure. Vitamin B1, thiamine, is a pyrimidine, as the name of thymine suggests, but as I understand it, although they’re widespread most of them are not well-known. However, similar pyrimidines to the ones found in nucleic acids are used as anti-cancer and anti-viral drugs.

Hence we have a system with four bases of particular kinds which can pair up with each other and consecutive groups of three bases are known as codons, each encoding for a particular amino acid, which are the blocks of proteins, as well as acting as “punctuation” such as full stops marking the end of a protein synthesis sequence. That’s sixty-four possibilities. However, since other bases can exist, it’s hypothetically feasible that these data can be stored more densely and efficiently. In particular it seems odd that uracil occurs in RNA but not DNA, but the reason for this is that it’s less stable and therefore can’t reliably encode for a long period of time, so it’s not so much that it’s used in RNA as that it isn’t used in DNA, and maybe at some stage it was but wasn’t selected for. This, then, is the first identifiable factor in the structure of DNA which determines its nature. I think there are probably at least four more usable bases, and this would double their data density. What it might not do, however, is enable evolution, as it might be that these bases are less amenable to mutation. For all I know, the first life forms in our lineage may have had different bases but couldn’t evolve as fast and therefore wasn’t able to compete with other organisms and aren’t our ancestors, even though there was nothing wrong with the basis of their genomes.

The next issue is sugar. Two sugars are involved and give their initials to the first letter of DNA and RNA. They’re pentoses, like fructose, rather than hexoses like dextrose or disaccharides like sucrose. Again, the explanation for the difference is durability and stability. The hydroxyl group on the second carbon which is absent on the deoxyribose molecule means it’s more stable than ribose and less likely to be altered by water. The presence of this hydroxyl group on the ribose molecule makes it easier to break down, ensuring that protein synthesis stops when it needs to. However, three- and four-carbon sugars could form the basis of the backbone instead of ribose or deoxyribose. Any more than five carbons stops double helix working: it gets in the way of the shape, making packing into the coils and supercoils unfeasible, and also makes it more reactive and also encourages branching. The double helix arrangement isn’t just pretty. It makes it possible to pack it into a small space, such as in chromosomes. It is possible for hexose nucleic acids to form but they don’t become double helices. Fructose is of course another pentose but the position on its molecule at which nitrogens from the bases can form are in the wrong place and the arrangement would be too crowded. Inulin, which is the daisy family’s alternative to starch which tastes like Jerusalem artichokes because those are in that family too, and sucrose itself both contain fructose but it’s not used in nucleic acids for this reason. It’s also thought that the processes which led to living processes preferred pentoses over other types of sugar, so life built on what was available.

That leaves the phosphate groups. These keep the molecule regular in shape and enable the DNA to bind to histones, which are the proteins making up much of the chromosomes around which it winds. Obviously this doesn’t apply to RNA because it isn’t wound round anything. Actually, it doesn’t apply to prokaryotic organisms such as bacteria either because they don’t have histones, but they do have nucleoid-associated proteins which do similar jobs. Bacterial DNA is in loops called plasmids. Plastids (not plasmids) have less DNA than free-living prokaryotes because many of their genes have been transferred to the nucleus.

Surprisingly, phosphate groups are not essential to the structure of nucleic acids and are in fact weaker than other options. For instance, glycine, the simplest, and the only non-chiral amino acid, can bond the sugar molecules together. Amide bonds are an option. There are also some different arrangements with phosphorus itself. These stronger bonds, though, can’t cross membranes as easily. Now I’ve previously mentioned how phosphorus may be the dog in the manger which explains the Fermi Paradox, but this is clearly not to do with DNA or RNA as it’s entirely feasible for an adequate alternative to DNA to exist without phosphorus, but with glycolysis and the Krebs Cycle where so far as I can tell it really cannot be replaced. This does however open up the possibility of life existing in the Universe in places with rather less phosphorus than this solar system. Incidentally, a decade or so ago organisms were found in a lake which were thought to be able to substitute arsenic for phosphorus in their DNA, but it turned out they were just really good at finding phosphorus.

It does seem, then, that fairly dramatically different but still perfectly functional analogues to DNA and RNA could exist, and even that they might be more likely than those two to form in an environment with less phosphorus. Getting back to ‘Pluribus’, it’s exceedingly unlikely that it’s the kind of series for this to matter. It’s known that there’s a gene for the receptor which detects the odour of Convallaria majalis in the genome received, which is lily of the valley, and this is probably a throwaway reference to that storyline in ‘Breaking Bad’, and this receptor is also found in sperm cells and attracts them towards the ovum, although it’s thought nowadays that the ovum chooses the sperm rather than the other way around. But it leads to two organisms joining. I very much doubt whether any of this matters to the show. However, it is possible to push this further for the sheer scienciness of it all. Yeah, science!

OK, so here are two alternate scenarios regarding the origin of life on Earth. One is that life as we know it originated somewhere in the Universe before the birth of the solar system and spread through the Galaxy, including this solar system. The other is that life arose many times, in this solar system and elsewhere. In the first scenario, for which there’s actually quite a bit of evidence, it’s feasible for many worlds to have life with identical biochemistry, since all of it would have the same ancestry. In such a situation, the transmission of the RNA from TRAPPIST-1 makes sense and isn’t customised for life here, at least as far as genetic code is concerned. However, the fact that it uses the code for this receptor would seem to mean a remarkable degree of convergent evolution, the presence of the gene in the last universal common ancestor with the life in that system or detailed knowledge about life here. Another is that there are various different ways of storing and transferring genetic information, in which case it’s a mild coincidence that the signal happens to be RNA base-pairs. Given what I’ve suggested here, there seems to be no particular reason why the chemical basis of the genome should be the same. There are more complex possibilities, such as there being various different independent empires of life throughout the Galaxy, and this one happens to be the same as ours.

All of this is most unlikely to have much to do with the plot of the series. I don’t know how ‘The Walking Dead’ ended but there was initially speculation about the origin and a possible cure for the Wildfire virus, but later on it seemed to become clear that these questions were irrelevant to the story. If this later changed, to my mind this would detract from the quality of the series. Whether the same is true of the ‘Pluribus’ virus remains to be seen but it doesn’t feel like treating it as a central mystery would add to the quality of the series, which is currently very high indeed of course because it’s Vince Gilligan. What’s occupying everyone’s minds right now, just after episode 5, ‘Got Milk’, is of course whether “Soylent Green is people”.

My Orphanhood And Science

I’ve been very quiet on here lately due to pressure of organising things related to my mother’s death and my father’s probate, so I’m coming back to report here on a particularly affecting thought about my mother which I think illustrates something about science as it relates to feelings. But first things first.

My father died last June. One of the last things he said was a series of names of more or less binary compounds such as ammonium sulphide. I’ve never heard of this kind of thing happening before, but this is similar to something which happened with the mother of a friend recently too, whose details I don’t remember. My father had, among other things, been an industrial chemist, and we won’t know until we get there I suppose, but it seems to me that this was a sign of how firmly ingrained his scientific knowledge was in his memory that this happened. I also found it notable that this particular compound, which is used in stink bombs, has the formula (NH₄)₂S. It may mean nothing, but it does have the same initials as National Health Service. Then again, maybe he could just smell something, or was perhaps hallucinating its odour. I really don’t know.

At the end of March this year, my mother also died. They were long since divorced, so there’s probably no direct connection between these two events happening in the space of a year. It isn’t like my mother missed her husband, for example, and the differences between their ages probably doesn’t mean that anything about their lifestyle when they were together would have resulted in their deaths being close together. I could imagine that my mother still held some deep, residual affection for my father of course, but I really don’t think she did. Going down this route would probably involve imagining patterns where there are none, and this brings me once again to science, which is in a way an attempt to find out which patterns are based in reality and which ones aren’t. Given this, my late father’s recitation of chemical formulae isn’t scientific but just part of the vocabulary of science. If he’d been at all musical, maybe he would’ve hummed a tune or something similar. It is true, of course, that centuries of understanding and investigation got humanity from atomic theory in the time of Democritus and the four elements of Empedocles to a point where we understood that there were around a hundred different main types of atom which joined together through the operation of electrical forces in certain numbers to form molecules and other compounds, which are expressed through such names as “ammonium sulphide”, but the actual name of the compound is more the culture of science than science itself. It’s almost like poetry. These things can be conjoured up in technobabble by using two surnames with a hyphen between them followed by a technical sounding word, so for example the Banks-Tortora Effect, Auerbach-Gould Analysis or the Brock-Pearson Principle. These are just surnames I read off nearby books, but don’t they sound clever and technical?

All that said, real scientific findings can have real emotional impact, and my recent bereavement is no exception.

My mother was a remarkably kind and selfless person, and a non-scientific but nonetheless true way of looking at her life would be to say she didn’t deserve the misfortunes which afflicted her. A few years ago, I was casting about for a neutral way to describe what pro-lifers call an “unborn child” and what pro-choicers tend to call a “fetus”, and thought about using the term “the products of conception”. This, however, was firmly rejected by mothers I knew who had had miscarriages, and the question is still open. The words we use to describe scientific phenomena matter when they are used by people who are directly emotionally affected by them. A notorious example is the tendency for genes to be referred to by whimsical names such as “sonic hedgehog”. This is a gene found in most species of multicellular animals. Now known as the SHH gene, this encodes a signalling protein responsible for regulating the formation of organs, the central nervous system and limbs in humans, and has similarly important roles in other animals, including fruit flies. If it malfunctions in fruit flies, it produces a spiny embryo, hence the name. However, as genetics became more advanced and applied to human medicine, the gene’s name began to crop up in conversations about a lethal fetal condition known as holoprosencephaly, where the brain doesn’t separate into two hemispheres in utero, which as well as being fatal can lead to horrific facial features which I’m not going to go into. Therefore, the practice of using these playful names came to an end. When scientific findings come up against personal life, things can get distressing and upsetting.

Well, I am going to go there, mainly to show that science is not just this abstract thing which is “out there” and has no influence on how we feel about stuff.

I am my mother’s eldest child and have a younger brother. Between us, my mother gave birth to three children who were all premature but also potentially viable. In other circumstances, for instance paediatrics being a decade more advanced at the time, they would probably have survived, although each one was probably only conceived because the last one hadn’t been. This is the kind of sadness I almost feel shouldn’t be mentioned in public, and do feel shouldn’t be profited from. So I’ll state this as a cold, ruthless fact: my mother lost three babies between me and my brother. Not fetuses. Not that scientific term, and also not fetuses because of taking a position on the pro-choice/pro-life issue, but because they actually were babies. I don’t want to take away from anyone who has had a miscarriage either by denying that they too have lost a child, but I also want to assert that these were babies, born at the same stage of development as my brother, currently running marathons and living in the south of Spain with his partner, and in other circumstances it would be one of them who was doing something similarly “real person”-y today, although in that case it would be they who was my younger sibling rather than my brother. All of these are lives not lived, which ended perhaps a century earlier than they would, and which would’ve touched and resulted in other lives. But we’ll never find out because their remains are currently interred in a cemetery in Kent, and have been for over half a century. Perhaps my mother will have a memorial near them one day.

Okay, so a process of scientific enquiry led fairly recently to a surprising finding among people who had born children: some of those who had had boys were found to have XY diploid cells in their bodies, in a situation called “microchimerism”. It was found both that people whose cell lines had no Y chromosomes who had never been pregnant had no Y chromosomes in their bodies, which is hardly surprising, but that those who had had children with Y chromosomes did. This is not about sex or gender though. What this means is that cells from the fetus cross over into the maternal body and take up residence in their bodies, even in their brains, as stem cells and later develop into the appropriate cell, so for example they alter the microscopic anatomy of the brain and even participate in what is going on in that brain. It happens with female fetuses too: the only significance of the Y chromosomes here is that they happen to have indicated that something remarkable was happening with fetal cells and the maternal body. The interpretation of the fetal cells healing brain damage could go either way. It could be seen as the child controlling the parent’s mind or as a way the child is healing the parent.

The fetal cells don’t just occupy the brain. They have also been found in the pancreas, bone marrow, skin and liver. I may practically have been directly looking at my siblings when I looked at my mother. They also persist for decades, perhaps life-long. Hence it’s possible, and I choose to believe, unscientifically but still perhaps correctly, that part of my siblings was physically still with my mother until the day she died. Hence in that sense it’s possible that all of them lived into their fifties.

There’s something else though.

Another recent finding in human biology, and actually zoology in general, is what happens after an animal dies. A sketchy definition of death for vertebrates such as ourselves might be the point at which the respiratory centres of the brain irreversibly cease to respond to an increase in carbon dioxide levels in the blood. Now there are three sets of respiratory centres in the brain: in the pons, which is responsible for rhythm of breathing, the ventral centres in the medulla oblongata and the dorsal group in the nucleus tractus solitarius. It clearly isn’t a strict definition of death because artificial ventilation might keep the rest of the body functioning at this point, and clearly the rest of the brain might hypothetically continue to function even if they’ve been permanently damaged, and I don’t know if things ever happen this way round. Probably a better way to understand death would be irreversible cessation of brain stem function more generally. Note also that I’m saying “irreversible” rather than “permanent”, because permanent cessation of function may be irreversible without anything ever happening to reverse it, as with someone who doesn’t receive CPR or a defibrillator shock but might have, and therefore would’ve survived. Here again, the coldness of the scientific understanding is mixed with feelings of desperation and poignancy about someone who could’ve survived but didn’t because of the circumstances they found themselves in.

There’s a fragmentary memory here I have that individual cells from a human brain have been induced to function and divide, so presumably not neurones which can’t divide except in certain very localised regions, even twelve hours after death. This might hypothetically mean that a clinically dead body could have the injury repaired long after death as we understand it today, particularly in circumstances where metabolism and decomposition have been slowed or halted by such things as hypothermia. Maybe a body lying at the bottom of a frozen lake in winter or in a mortuary freezer, for example. But this all smacks of the bargaining stage of grief of course. The fact is that none of that now applies to my mother, who died in a hospital bed and whose corpse was still there several hours later before, presumably, being removed by the undertakers or going to the morgue.

However, there is more. Around the beginning of the twenty-first century, it was discovered that – well, I’m going to need to set out how genes work to maximise the chances of this making sense. DNA unravels and one of the strands is copied using transfer RNA, which then moves to the ribosomes of the cell and is turned into proteins. Like most processes in the cell, this requires energy, which is usually liberated from glucose and linked to the metabolic processes in the cell via adenosine triphosphate, hence my blog post ‘Sodding Phosphorus!’ a few entries back. Most of the energy liberated is helped by oxygen, which is why we need it, and of course free oxygen is not available to most of the body after someone has stopped breathing. This seems to have taken us quite a long way from the emotional side of what I’m talking about, although as I write this description I’m acutely aware than my mother did stop breathing forever a few weeks ago, so there is that. Anyway, due to the fact that most of this process benefits dramatically from the availability of oxygen, it might be concluded that it stops when someone dies. But, as I was saying, around the beginning of the twenty-first century, it was discovered that some genes continue to be expressed after death. This is known as the “thanatotranscriptome”, from the Greek “θανατος”, meaning “death”, and “transcriptome” by analogy with “genome”: all of the RNA transcriptions which occur in the internal organs of the body after death. Some of these are simply ongoing processes, but some are long since inactivated which spring back into action. This goes on for up to forty-eight hours after death. In “cold-blooded” animals it can be even longer.

Clearly cells are really complicated, and quickly break down as the carbon dioxide builds up, makes their internals more acidic and the temperature changes, usually by falling, but given that there are so many cells in the human body, not all of them just conk out immediately after death and some of those which do will have bits of their machinery still active. Significantly, one set of genes that does stop working is the suppressor genes, which are there to prevent other genes from expressing themselves and causing cancer, i.e. the oncogenes. Other genes which have stopped working seemingly permanently are the ones involved in fetal development and in the ovum. These two briefly come back into action after someone dies. Mammals, being “warm-blooded”, don’t express quite as many of these genes as, for example, fish, presumably because our bodies don’t just need oxygen but also higher temperatures than in most corpses to function, but even in us, more than five hundred genes will still be “working” out of the total genome of around twenty-odd thousand, so that’s actually more than two percent of them, which seems like a lot to me considering they’re in a dead person. Some of the genes are involved in inflammation and the immune system, which is not surprising as death is a very serious injury with the decomposition presumably being interpreted as infection. Here again I feel a sense of urgency and futility, and a kind of mixed feeling of despair that my mother’s dead body made some last-ditch attempt to defend itself against its decomposition and cried for help, as it were, which could never come. That’s grim.

This, though, was a body which had been pregnant several times, and which may, and this is not certain but I have a hunch that it did, have contained minute parts of the bodies of my dead siblings, lying almost dormant since the start of the 1970s, in the form of isolated fetal cells. In particular, considering that it is fetal genes that specifically ramp up after death, these cells would briefly, for maybe a couple of days, in a sense, and a very broken manner, resume the development which was interrupted by their untimely deaths all that time ago, and for a short period of time my mother’s other babies would in a sense be in a kind of half-living state during which they would vainly attempt to continue the development which would’ve enabled them to survive if they had been born later. In fact, considering that each time one of them was born, their chances of survival may have been higher than their elder siblings, just maybe these fatally injured cells would have in some ways reached the stage when they would have survived if they had been born. For instance, maybe there were lung cells secreting the surfactant which enables a baby’s lungs to expand properly at birth which actually had genes reach that stage and begin to manufacture that life-saving substance, only fifty-two years too late.

And then it was to no avail, because my mother’s body ended up at the undertakers, in the mortuary, in a casket, and now of course cremated, and all this in any case in an 89-year old body which had failed to stay alive.

I find this thought most disturbing. There might be things it’s better not to dwell on, but maybe if someone dwells on this for long enough in the right way, it will save lives. Even if not, it serves as an illustration of how apparently abstract and obscure scientific findings do not necessarily leave one cold if one can bring them sufficiently into focus in everyday or real life (or real death) terms. When I studied pathology, I was left with the impression that it’s primarily about the body’s desperate attempts to keep healthy from an initially very tiny imbalance that just ends up snowballing. This has a similar kind of feel to it, in that it made me sad to think of my mother’s body’s, and her children’s bodies’ including mine and my brother’s, efforts to do what they were “supposed” to do against impossible odds.

And that last bit, the realisation that some of my own cells died with my mother, means that part of me literally died with her sometime between her clinical death on 29th March and my father’s first missed birthday on 2nd April 2023.