Posts Tagged ‘genetics’
epigenetics and imprinting 5: mouse experiments and chromosome 11
So we were looking at how we – mammals amongst others – are engaged in a kind of battle for the best way to ensure our genetic survival into the future, beyond our insignificant little selves. This battle begins in the very early phase of life, as zygotes multiply to form a blastocyst.
Remember from my last post on this topic, the male mammal is interested in the offspring above all else. He’s even happy to sacrifice the mother for the sake of the child – after all there’s plenty more fish in the sea (or mammals in the – you know what I mean). The female, on the other hand, is more interested in self-preservation than in this pregnancy. She wants more than one chance to pass on her genes.
So, by the blastocyst stage, cells have differentiated into those that will form the placenta and those that will form the embryo itself. Experiments on mice have helped to elucidate this male-female genetic struggle. Mouse zygotes were created which contained only paternal DNA and only maternal DNA. These different zygotes were implanted into the uterus of mice. As expected, the zygotes didn’t develop into living mice – it takes DNA from both sexes for that. The zygotes did develop though, but with serious abnormalities, which differed depending on whether they were ‘male’ or ‘female’. In those in which the chromosomes came from the mother, the placental tissues were particularly underdeveloped. For those with the male chromosomes, the embryo was in a bad way, but the placental tissues not so much.
In short, these and other experiments suggested that the male chromosomes favoured placental development while the female chromosomes favoured the embryo. Thus, the male chromosomes are ‘aiming’ to build up the placenta to drain as many nutrients as possible from the mother and feed them into the foetus. The female chromosomes have the opposite aim, resulting in a ‘fine balance’ in the best scenarios.
Further work in this area has identified particular chromosomes responsible for these developments, and some of the epigenetic factors involved. For example, mouse chromosome 11 is important for offspring development. When the offspring inherits a copy of chromosome 11 from each parent, the offspring will be of normal size. If both copies come from the mother it will abnormally small, while if both come from the father it will be abnormally large. These experiments were carried out on inbred mice with identical DNA. Nessa Carey summarises:
If you sequenced both copies of chromosome 11 in any of the three types of offspring, they would be exactly the same. They would contain the same millions of A, C, G and T base-pairs, in the same order. But the two copies of chromosome 11 do clearly behave differently at a functional level, as shown by the different sizes of the different types of mice. Therefore there must be epigenetic differences between the maternal and paternal copies of chromosome 11.
So this means that chromosome 11 is an imprinted chromosome – or at least certain sections of it. This is the same for other chromosomes, some of which aren’t imprinted at all. But how is it done? That’s the complex biochemical stuff, which I’ll try to elucidate in the next post on this topic.
Footnote: the photo above shows a bi-maternal mouse with healthy offspring, and further work in deleting imprinted genetic regions has allowed researchers to create healthy bi-paternal mice too. There’s a fascinating account of it here.
References:
Nessa Carey, The epigenetics revolution, 2011
https://www.the-scientist.com/news-opinion/first-mouse-embryos-made-from-two-fathers-64921
A DNA dialogue 1: the human genome
Canto: I’m often confused when I try to get my head around all the stuff about genes and DNA, and genomes and alleles and chromosomes, and XX and XY, and mitosis and meiosis, and dominant and recessive and so on. I’d like to get clear, if only I could.
Jacinta: That’s a big ask, and of course we’re both in the same boat. So let’s use the magical powers of the internet to find answers. For example, here’s something that confuses me. The Human Genome project, which ended around the year 2000, involved a mapping of the whole human genome, and that includes coding and non-coding genes, and I think it was found to contain 26,000 or so – what? Letters? Genes? Coding genes? Anyway there’s a number of questions there, but they’re not the questions that confuse me. I don’t get that we now, apparently, have worked out the genetic code for all humans, but each of us has different DNA. How, exactly, does our own individual DNA relate to the genome that determines the whole species? Presumably it’s some kind of subset?
Canto: Hmmm. This article from the Smithsonian tells us that the genetic difference between human individuals is very tiny, at around 0.1%. We humans differ from bonobos and chimps, two lineages of apes that separated much more recently, by about 1.2%….
Jacinta: Yes, yes, but how, with this tiny difference between us, are we able to use DNA forensically to identify individuals from a DNA sample?
Canto: Well, perhaps this Smithsonian article provides a clue. It says that the 1.2% difference between us and chimps reflects a particular way of counting. I won’t go into the details here but apparently another way of counting shows a 4-5% difference.
Jacinta: We probably do need to go into the details in the end, but clearly this tiny .1% difference between humans is enough for us to determine the DNA as coming from one individual rather than 7 to 8 billion others. Strangely enough, I can well believe that, given that we can detect gravitational waves and such – obviously using very different technology.
Canto: Yeah the magic of science. So the Human Genome Project was officially completed in April 2003. And here’s an interesting quote from Wikipedia:
The “genome” of any given individual is unique; mapping the “human genome” involved sequencing a small number of individuals and then assembling these together to get a complete sequence for each chromosome. Therefore, the finished human genome is a mosaic, not representing any one individual.
Of course it would have to be a mosaic, but how can it represent the whole human genome when it’s only drawn from a small number? And who were these individuals, how many, and where from?
Jacinta: The Wikipedia article does give more info on this. It tells us that the project isn’t really finished, as we’ve developed techniques and processes for faster and deeper analyses. As to your questions, when the ‘finished’ sequencing was announced, the mosaic was drawn from a small number of anonymous donors, all of European origin.
Canto: But we all originated from Africa anyway, so…
Jacinta: So maybe recent ‘origin’ isn’t so important. Anyway, that first sequencing is now known as the ‘reference genome’, but after that they did sequence the genomes of ‘multiple distinct ethnic groups’, so they’ve been busy. But here are some key findings, to finish off this first post. They found some 22,300 protein-coding genes, as well as a lot of what they used to call junk DNA – now known as non-coding DNA. That number is within the mammalian range for DNA, which no doubt surprised many. Another blow for human specialness? And they also found that there were many more segmental duplications than expected. That’s to say, sections of DNA that are almost identically repeated.We’ll have to explore the significance of this as we go along.
Canto: Yes, that’s enough for starters. Apparently our genome has over 3 billion nucleobase pairs, about which more later no doubt.
References
epigenetics and imprinting 3: at the beginning
A zygote is the union of two gametes (haploid cells), the sperm and the egg. It’s the first diploid cell, from which all the other diploid cells – scores of trillions of them – are formed via mitosis.
What’s interesting about this from an epigenetic perspective is that gametes are specialised cells, but zygotes are essentially totipotent – the least specialised cells imaginable – and all this has to do with epigenetics.
I’m not entirely clear about what happens to turn specialist gametes into totipotent zygotes, and that’s what I’m trying to find out. I’m not sure yet whether zygotes immediately start differentiating as they divide and multiply or whether the first divisions – in what is called the zygote phase, which eventually forms the blastocyst – form an identical set of zygotes.
The two-week period of these first divisions is called the germinal phase. During this phase zygotes divide mitotically while at the same time moving, I’m not sure how, from the fallopian tube to the uterus. Apparently, after the first few divisions, differentiation starts to occur. The cells also divide into two layers, the inner embryo and the outer placenta. The growing group of cells is called a blastocyst. The outer layer burrows into the lining of the uterus and continues to create a web of membranes and blood vessels, a fully developed placenta.
But, as Nessa Carey would say, this is a description not an explanation. How does this initial cell differentiation – into the outer layer (trophectoderm), which becomes the placenta and other extra-embryonic tissues, and the inner cell mass (ICM) – come about? Understanding these mechanisms, and the difference between totipotent cells (zygotes) and pluripotent cells (embryonic stem cells) is clearly essential for comprehending, and so creating, particular forms of life. This PMC article, which examines how the trophectoderm is formed in mice, demonstrates the complexity of all this, and raises questions about when the ‘information’ that gives rise to differentiation becomes established in these initial cells. Note for example this passage from the article, which dates to 2003:
It is now generally accepted that trophectoderm is formed from the outer cell layer of the morula, while the inner cells give rise to the ICM, which subsequently forms the epiblast and primitive endoderm lineages. What remains controversial, however, is whether there is pre-existing information accounting for these cell fate decisions earlier than the 8-cell stage of development, perhaps even as early as the oocyte itself.
The morula is the early-stage embryo, consisting of 16 totipotent cells. The epiblast is a slightly later differentiation within the ICM. An oocyte is a cytoplasm-rich, immature egg cell.
Molecular biologists have been trying to understand cell differentiation by working backwards, trying to turn specialised cells into pluripotent stem cells, mostly through manipulating their nuclei. You can imagine the benefits, considering the furore created a while back about the use of embryonic stem (ES) cells in medical treatments. To be able to somehow transform a liver or skin cell into this pluripotential multi-dimensional tool would surely be a tremendous breakthrough. Most in the field, however, considered such a transformation to be little more than a pipe-dream.
Carey describes how this breakthrough occurred. Based on previous research, Shinya Yamanaka and his junior associate Kazutoshi Takahashi started with a list of 24 genes already found to be ‘pluripotency genes’, essential to ES cells. If these genes are switched off experimentally, ES cells begin to differentiate. The 24 genes were tested in mouse embryonic fibroblasts, and, to massively over-simplify, they eventually found that only 4 genes, acting together, could transform the fibroblasts into ES-type cells. Further research confirmed this finding, and the method was later found to work with non-embryonic cells. The new cells thus created were given the name ‘induced pluripotent stem cells’, or iPS cells, and the breakthrough has inspired a lot of research since then.
So what exactly does this have to do with epigenetics? The story continues.
epigenetics and imprinting 2: identical genes and non-identical phenotypes
I’ve now listened to a talk given by Nessa Carey (author of The epigenetic revolution) at the Royal Institution, but I don’t think she even mentioned imprinting, so I may not mention it again in this post, but I’ll get back to it.
The talk was of course easier to follow than the book, and it didn’t really teach me anything new, but it did hammer home some points that I should’ve mentioned at the outset, and that is that it’s obvious that genetics isn’t the whole story of our inheritance and development because it doesn’t begin to explain how, from one fertilised egg – the union of, or pairing of, two sets of chromosomes – we get, via divisions upon divisions upon divisions, a complex being with brain cells, blood cells, skin cells, liver cells and so forth, all with identical DNA. It also doesn’t explain how a maggot becomes a fly with the same set of genes (or a caterpillar becomes a butterfly, to be a little more uplifting). These transformations, which maintain genetic inheritance while involving massive change, must be instigated and shaped by something over and above genetics but intimately related to it – hence epigenetics. Other examples include whether a crocodile hatchling will turn out male or female – determined epigenetically via the temperature during development, rather than genetically via the Y chromosome in mammals.
So, to add to the description I gave last time, the histone proteins that the DNA wraps itself round come in batches or clusters of eight. The DNA wraps around one cluster, then another, and so on with millions of these histone clusters (which have much-studied ‘tails’ sticking out of them). And I should also remind myself that our DNA comes in a four-letter code strung together, out of which is constructed 3 billion or so letters.
The detailed description here is important (I hope). One gene will be wrapped around multiple histone clusters. Carey, in her talk, gave the example of a gene that breaks down alcohol faster in response to consumption over time. As Carey says, ‘[the body] has switched on higher expression of the gene that breaks down alcohol’. The response to this higher alcohol consumption is that signals are generated in the liver which induce modifications in the histone tails, which drive up gene expression. If you then reduce your alcohol consumption over time, further modifications will inhibit gene expression. And it won’t necessarily be a matter of off or on, but more like less or more, and the modifications may relate to perhaps an endless variety of other stimuli, so that it can get very complicated. We’re talking about modifications to proteins but there can also be modifications to DNA itself. These modifications are more permanent, generally. This is what creates specialised cells – it’s what prevents brain cells from creating haemoglobin, etc. Those genes are ‘tightened up’ or compacted in neurons by the modifying agents, so that, for example, they’re permanently unable to express the haemoglobin-creating function.
All of this is extremely fascinating and complex, of course, but the most fascinating – the most controversial and headline-creating stuff – has to do with carrying epigenetic changes to the next generation. The inheritance of acquired characteristics, no less. Next time.
References
What is epigenetics? with Nessa Carey – The Royal Institution (video)
The Epigenetics Revolution, by Nessa Carey, 2011
epigenetics and imprinting 1 – it’s complex
The last book I read was The Epigenetics Revolution by Nessa Carey, though I’m not sure if I’ve really read it. So much of it was about persisting with the next sentence though I hadn’t fully understood the previous one. Biochemistry does that to me – too many proteins, versions of RNA, transposons, transferases, suppressors, catalysers, adjuvants and acronyms. And in the end I’m not at all sure how much progress we’re making in this apparently tantalising field.
So I’m going to pick out imprinting for starters, as a way of familiarising myself a little more with the epigenetic process of leaving tabs or marks on specific genes.
I know nothing about imprinting. Isn’t it what female birds do with their offspring, even when they’re still in the shell? Here’s how Wikipedia introduces it :
Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. As of 2014, there are about 150 imprinted genes known in the mouse and about half that in humans. Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established (“imprinted”) in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.
This suggests that it’s not something life-forms do, it just happens. But there are a number of mysterious terms here that need exploring – ‘a parent-of-origin-specific manner’, ‘DNA methylation’ and ‘histone methylation’.
Briefly, to get all that DNA (between 2 and 3 metres to each nucleus) to fit inside that tiny space you need some expert packaging, and that’s where histones come in. They’re proteins that DNA gets wound around, like cotton reels, and together the histones and the DNA are called chromatin. They’re also divided into sections called nucleosomes.
DNA methylation is when a methyl group, derived from methane (CH3), is added to the DNA, affecting its activity, including repressing gene transcription. Histone methylation is when methyl groups are added to amino acids in histone proteins. Again these can repress or enhance gene transcription, depending on the amino acids and how they’re methylated.
The parent-of-origin thing is most interesting to me, and needs a bit more explaining. When a human sperm cell enters an egg cell, as the first step in fertilisation, it carries its load of 23 chromosomes in what is called a pro-nucleus. In a sense a sperm cell, much smaller than an egg, is nothing but a pro-nucleus surrounded by a membrane, with a tail for motility. Once inside the egg, the tail and the membrane are shed. The egg cell also has its load of 23 chromosomes in its pro-nucleus, but this is considerably larger than the male – and the human egg cell in its entirety has about 100,000 times the volume of a sperm cell. The point is that the differences in the male and female pro-nuclei have a lot to do with epigenetic effects including imprinting, which affect phenotypic traits, including disease prone-ness and structural effects in animals and plants. Tracing these effects in molecular terms to either parent therefore becomes a priority.
So, this is a little starter in what is an overwhelmingly complex topic. I shall return to it.
clever Charlie Darwin
A photo taken by me! King Charles seated in state in the Musuem of Natural History, London. It was a thrill to be granted an audience
I recently decided to reread Darwin’s Origin of Species, which was really reading it for the first time as my first reading was pretty cursory, and I could barely follow the wealth of particular knowledge he used for cumulative effect to adduce his theory. This time I’ve been doing a closer reading, and becoming increasingly impressed, and I’ve only read the first chapter, ‘Variation under Domestication’.
Darwin’s argument here of course is that domesticated horses, dogs, birds and plants have been artificially selected over long periods of time, and often unconsciously, to suit human needs and tastes. This might seem screamingly obvious today, and to a degree it was recognised in Darwin’s time, but because of an inability to take the long view, and also because of the then-prevalent paradigm of the fixity of species, breeders and nurserymen tended to under-estimate their own cumulative powers, and to claim, for example, that dogs and pigeons had always come in many varieties. Even Darwin was uncertain, and was willing to concede – writing of course before the advent of Mendelian genetics, never mind the revolution wrought by the identification and analysis of DNA as the molecule of inheritance – that in some cases the breeders might be right:
In the case of most of our anciently domesticated animals and plants, I do not think it is possible to come to any definite conclusion, whether they have descended from one or several species.
He was even prepared to concede that it was ‘highly probable that our domestic dogs have descended from several wild species’, while at the same time arguing that the breeding of dogs, in Egypt, other parts of Africa and Australia (where, in his Beagle travels, he observed dingoes, which he may have seen as semi-domesticated by the Aborigines) extended back far further in time than most people suspected. We now know that Darwin’s concession here was ‘premature’. The latest research strongly suggests that our domesticated dogs trace their ancestry to a group of European wolves dating from 19,000 to 32,000 years ago, and probably now extinct. That’s a time-frame Darwin would’ve baulked at, and it’s both funny and kind of tragic that this is something I’ve ‘discovered’ after 30 seconds of selective internet searching. There’s no doubt, though that Darwin’s bold but always informed speculations were heading in the right direction.
Particularly informed – and bold – were his speculations about pigeons. This is hardly surprising as he spent several years studying and breeding them himself. Interestingly, he started doing so because he’d become convinced that all the fancy pigeons then on show were most likely derived from one common species, the rock pigeon or rock dove (Columba livia), a view already held by some naturalists but few breeders. He devotes several pages in Chapter 1 to arguing his case, for example pointing out that the ‘several distinct species’ argued for by breeders can be crossed with complete success, that’s to say with no signs of sterility or more than usually defective offspring.
So, as with dogs, I decided to look up what the latest research was on the ancestry of English carriers, short-faced tumblers, runts, fantails, common tumblers, barbs, pouters, trumpeters and laughers, to name some of the pigeons Darwin mentions in the chapter, and was excited to find that a piece of research published as recently as 2013 has confirmed Darwin’s hypothesis. Cheaper and faster genome sequencing technologies have enabled researchers to sequence the genomes of many wild and domesticated birds, and they’ve found that all of the latter are clearly closer to C livia than to any other wild species. It only took just over 150 years for Darwin to be proven correct.
Close reading like this really does reap some fun rewards, and I’ll finish with two more examples. Darwin wrote of how in the world of breeding, quite a drastic change can be brought about in one breeding step, as in the case of the fuller’s teasel with its hooks. He goes on:
So it has probably been with the turnspit dog; and this is known to have been the case with the ancon sheep.
Not knowing wtf he was talking about, I irritatedly decided to look up these unknown creatures. The turnspit dog is a now-extinct breed, bred specifically from around the 16th century to provide the dogpower to turn meat on a spit, the only conceivable way of cooking large joints of meat in your average fancy household for a couple of centuries. The dog, or dogs, because the system worked better if you had two of them engaged in shift work, turned a wheel by running inside it, rat-like, until the meat was cooked. They were known to be long-bodied and short-legged, but details of how they were bred aren’t known, as they were apparently beneath scholarly consideration. They certainly weren’t seen as cuddly pets – if you treat creatures as slaves it heightens your contempt for then (cf Aristotle) – and they were even taken to church as foot-warmers. They’d disappeared entirely by the end of the 19th century.
It’s a dog’s life?
The ancon sheep was a short-legged type, apparently bred from a single individual in the USA in the late nineteenth century, its short legs having the singular advantage, to some, of curtailing its hopes of freedom by jumping the fence. The term ‘ancon’ has since been used by breeding researchers to describe strains of creatures arising from an individual with the same phenotype.
What is a trisomy?
Canto: So I happened to watch an excellent video from the Royal Institute recently, a talk by the beautifully named and beautifully voiced Irish geneticist, Aoife Mclysaght…
Jacinta: How do you pronounce that?
Canto: It’s pronounced Aoife Mclysaght…
Jacinta: Oh right.
Canto: So the theme was that everything in biology makes sense only in the light of evolution, and she was illustrating this through her area of interest and research, gene duplication. And along the way she talked about trisomies, particularly trisomy 21, usually referred to as Down Syndome.
Jacinta: A trisomy involves having an extra copy of a chromosome, in this case chromosome 21.
Canto: Very good, and the extra copy is a perfectly good copy, but having that extra copy causes major problems, obviously.
Jacinta: The term ‘trisomy’ refers of course to three – having three rather than two sets of a particular chromosome. Humans normally have two sets of 23 chromosomes. I have a relative who has a rare and unnamed form of trisomy, or at least a rare form of chromosomal disorder, which, when looking into it, I decided must be a trisomy. But since then I’ve discovered that Williams syndrome – which I learned about from another person I know with that condition – isn’t a trisomy, but the result of genes missing from chromosome 7. So now I’ve gone from thinking that trisomies accounted for all or most sorts of genetic intellectual disabilities to… I don’t know.
Canto: To a position of deeper ignorance. So people with trisomies have 47 chromosomes, with Down syndrome being the most common. Others include Edward syndrome (trisomy 18) and Patau syndrome (trisomy 13). Interestingly, though, there’s another rarer form of Down syndrome that’s due to translocation – that’s when a part of a chromosome – in this case chromosome 21 – migrates to another chromosome, usually chromosome 14, during cell division
Jacinta: That complicates matters… So do we know what causes these trisomies, and these translocations? They seem to be very specific, occurring for only particular chromosomes, or bits of them.
Canto: Well you’re right in that trisomies 21, 18 and 13 are relatively common – I mean rare but more common than a trisomy 9 or 15 or 19, just to pick out any numbers less than 23. We do know that trisomies become more common with older egg cells. As you know, your egg cells are as old as you are, and they become a little decrepit with age like yourself.
Jacinta: We’re both slouching to oblivion.
Canto: It’s also the case that most trisomies don’t survive to term, in fact they mostly miscarry so early that the mother doesn’t even know she’s been pregnant. So presumably those trisomies I just picked at random, if they occur at all, have more fatal consequences. It seems in any case that a trisomy occurs when cells divide but one chromosome somehow sticks to its homologue and is carried with it into the new cell. So maybe some chromosomes are more ‘sticky’ than others?
Jacinta: I think we need to do a deeper dive, as one pundit likes to say, into meiosis and aneuploidy.
Canto: Aneuploidy?
Jacinta: That’s just when you have an abnormal number of chromosomes per cell: it could be less or more. Actually trisomy 16 is the most common form, but fatal in its full-blown version. It can exist in mosaic form – when not all the cells have it.
Canto: So can you explain meiosis for us?
Jacinta: A long story but fascinating of course. It’s the basis of sexual reproduction for all eukaryotes. So before eukaryotic germ cells or gametes divide they need to replicate their chromosomes so that the resulting pair of cells has an equal share. This period of replication is known as the S phase.
Canto: Wait a minute, does this mean that in the S phase humans have 92 chromosomes per cell instead of 46?
Jacinta: Don’t bog me down with clever questions. Taking another step back, we have this whole process called the cell cycle, which we divide into phases. We can start anywhere, since it’s a cycle, if you know what I mean, but if you need a beginning it’s the prophase. Anyway, the S phase comes after the G1 phase and before the G2 phase. S, by the way, stands for synthesis, and G here stands for gap. Together these three phases make up the interphase, at the end of which we have the prophase of a new cell cycle, though actually meiosis isn’t a cycle the way mitosis (non-sexual reproduction or cell division) is. To be accurate, the next phase is called prophase 1, which is followed by metaphase 1, anaphase 1 and telophase 1 before we have prophase 2….
Canto: Stop cycling I’m getting dizzy.
Jacinta: Well yes believe me it’s complicated, and I haven’t begun yet. But you did ask for it.
Canto: Can you give the simplified version?
Jacinta: Not really.
Canto: Okay, we’ll leave that for another day. Focusing in on the part of meiosis when these trisomies and other anomalies occur, it seems that the problem isn’t so much stickiness as non-stickiness. Think of gametes. In mammals such as humans there are two types, egg and sperm cells. They’re differentiated by their sex chromosomes, chromosome 23…
Jacinta: And also by the fact that the egg cell is like the sun and the sperm cell is like the earth.
Canto: Well, sort of, in terms of volume. Now, after meiosis – which occurs in phases, meiosis 1 and meiosis 2, creating two daughter cells then four grand-daughter cells, so to speak – each of these grand-daughter gametes should be haploid. That’s to say, they should contain only one of each of the 23 chromosomes. But nothing’s perfect and sometimes there are errors, and we’re not clear about why, though the chances of error rise with the age of the female as mentioned before. Mostly the problem is that the chromosomes didn’t properly separate, a state called chromosome nondisjunction. Something to do with the spindle apparatus not functioning properly due to a lack of cohesion of the chromosome. This occurs rather more frequently in female meiosis, or oogenesis, than in male meiosis, or spermatogenesis, they’re not sure exactly why.
Jacinta: Well I must say that’s all very enlightening, and salutary, as it’s made me aware of how little I know about genetics in general. Now I know a teensy bit more. As to trisomies and other such chromosomal problems, what they know just makes me keen to know more about how we might detect them and possibly in the deep future rectify them at source. But the science is clearly a long way from that…
Canto: Well you never know. Genetics is a fast-moving field.
Jacinta: we must explore it more. It’s serious fun.
exercise, health, skepticism and my personal journey
‘Many of the most important benefits of exercise lie hidden deep inside your body.’ Michael Mosley
When it comes to diet and exercise, everyone seems to be an expert, and even a crank, to judge from many of the comments left on the SBS on demand site for its recent doco, ‘The Truth about Exercise’, presented by Michael Mosley. A scarily large number of these comments are of the ‘that’s all garbage, now I’ll give you the real lowdown’ variety.
And yet, considering how unique each person’s body and its requirements seems to be, maybe it’s not so surprising that general claims get up the noses of so many particular people.
So it’s good to be sceptical, though I was a bit surprised at the degree of scepticism about this doco when the subject came up recently – admittedly at a sceptics’ meet-up. So I’ve decided to take a closer look.
The program looked at a variety of surprising research findings, indicating, among other things, that your genes determine to a large degree whether intensive exercise will confer a benefit. There’s also controversial and counter-intuitive evidence that infrequent, sharp bursts of exercise, which get the heartbeat up and briefly racing, can provide a greater benefit than regular daily gym exercise. Offhand, I can think of an evolutionary basis for this finding, in that we evolved to combine a relatively indolent, social lifestyle with occasional energetic bursts to catch prey or run from predators. But what would I know?
Early on, we’re given a simple and salutary lesson about exercise and weight loss. Mosley, the program’s host and chief guinea pig, is monitored by a respiratory device on a relatively gentle [6mph] run around a training track. The device measures the amount of oxygen and carbon dioxide exhaled. Looking at the ratio between the two gases enables us to estimate the amount of fat and carbohydrate, or calories, being burned, apparently.
Mosley was measured as burning some 16 calories per minute during his run. It was then pointed out to him that, at that rate, it would take him 55 minutes to burn off the calories consumed in a cappuccino and a blueberry muffin [which he proceeded to consume after his run], plus a banana. Sounds like bad news.
Some questions about this. How close to average is Mosley’s calorie-burning level at a speed of 6mph? If I did the same run, would I burn off more calories, or less? A lot more? A lot less? How wide is the range? And do you burn off less calories if you’re much fitter? How much less?
The basic lesson here, though, is, if you want to lose weight, eat less. Exercise isn’t likely to do it for you, but it will certainly confer other benefits.
The next section of the program looks at fat levels in the blood. Mosley is treated to a hearty Glasgow breakfast of baked beans, sausage, bacon, black pudding [I think], some sort of creamed egg concoction [I think] and toast. As we’re told, the fat in this meal will be processed though the gut into the bloodstream, inducing metabolic processes which will determine the amount of fatty deposits forming on the walls of the blood vessels.
Four hours after the breakfast, a blood sample is taken and placed in a centrifuge to separate out the fat. This is compared to a blood sample taken before the breakfast, and we see that the amount of fat in the post-breakfast sample is about double the pre-breakfast one. Note that this is one sample – double the amount in the whole bloodstream, and you’re talking quite a load of fat.
As the Glasgow researcher, Dr Jason Gill, points out though, a key factor here is where this fat ends up. Sub-cutaneous fat is much less damaging than visceral fat, fat around organs such as the liver and pancreas. Unfortunately, many of us, like myself, don’t know where our fat is going, or what percentage of visceral fat we have. Mosley does know, however, that his percentage of visceral, or abdominal fat is disturbingly high. A high load of this kind of fat makes you susceptible to insulin resistance and type 2 diabetes and other problems. Mosley’s father suffered from type 2 diabetes, adding to his disturbance. How much of a part do your genes play here?
Mosley is given another big Glasgow breakfast the next morning, but this time he takes a long but seemingly leisurely walk the night before (Mosley describes it, though, as ’90 minutes of pretty hard walking’). This walk should have triggered the production of an enzyme that in turn should affect the way this second breakfast is metabolized.
Again, Mosley is blood-tested four hours later, and although the interaction is a bit confusing to me here, it seems that the sample this time contains about a third less fat than the one the day before.
More questions. We don’t know what Mosley did the night before he had his first breakfast, so we can’t compare it to the exercise of the night before his second breakfast. We also don’t know, on either occasion, what he did in the four hours between eating his breakfast and being tested.
In any case the fat in the blood vessels has substantially reduced, because it has been taken up into the muscles where it will be mostly burned off.
This is a remarkable finding, and the key enzyme or protein is lipoprotein lipase, or LPL. But most people would begrudge, or simply not have time for, 90 minutes of solid, swift walking of an evening. Any alternatives?
Well, British government guidelines make a general case for 150 minutes of moderate exercise per week, or 75 minutes of more vigorous exercise – and, unsurprisingly, most of us don’t manage this.
So, Mosley visits Prof Jamie Timmons in Nottingham whose team is looking at exercise differently, seeking to fit exercise regimes to particular individual needs. These researchers are looking at the wide variation of response to and benefit from exercise. They conducted a four-year study with a thousand subjects who exercised 4 hours a week for 20 weeks. Not surprisingly, average fitness improved, but it was the variation within the range that was the focus of the research. They found a spectrum with about 15% being ‘super-responders’, and about 20% at the other end recording ‘no change’. From this research [obviously there’s quite a bit of science missing from the explanation here] they were able to isolate 11 genes. This has further enabled them to devise a genetic test to determine which group a person belongs to, or where he sits on the spectrum.
More questions. So what if you’re one of the no-change types – is there really no benefit at all for them from this exercise schedule? That sounds almost crazy. And if this doesn’t have any effect, what will? The program doesn’t quite deal with this issue. Mosley states that the non-responders will benefit [which is essentially contradictory] but doesn’t say how. Which leads to the question – what exactly is being measured here? Obviously, a response to exercise, but what kind of response? Weight loss? Changed metabolism? Conversion of fat to muscle? Blood sugar levels, blood lipid levels? Sense of well-being?
Presumably it’s a combination of these elements, but the general point is clear – presenting benefits by means of averages doesn’t really help the individual, considering the massive individual variation revealed by this and other studies.
Personalised medicine and personalised exercise based on genetics may be the way of the future, but I wonder how easy, and how expensive it would be for each of us to access our genetic profiles. Of course the host of our program has no problems with that because he gets his genetic tests paid for presumably by the BBC.
Mosley is also tested for a couple of other things. First, he’s given a sugary drink (presumably glucose not fructose – the difference between these two sugars has become something of a dietary issue lately) to measure his insulin sensitivity. Insulin removes sugar and controls fat in the blood, and if there’s a problem with its production or activity you can become diabetic. After the drink, Mosley has his blood regularly examined to determine how effectively his insulin is doing its job. As it turns out, his results are not so good – the blood-sugar level shot up after the drink of course, but it drifted down only slowly to a point just below ‘impaired glucose tolerance’, putting him only just in the healthy range. The plan is to introduce him, and us, to some exercise that might improve his situation.
Before that, though, he has to undergo his second test, to check out his aerobic fitness, also known as VO2 max, with V standing for volume and O2 for oxygen. In other words, maximum or peak oxygen uptake and capacity.
Perhaps amazingly I’ve never heard of VO2 max before, in my fifty-odd years on this planet, but it’s probably all the rage amongst modern-day gym junkies. It’s a measure of heart and lung efficiency at getting oxygen pumping through the body. It’s not really clear what the number measured indicates, but it correlates pretty well with general fitness. The number for Mosley was 37mls per kg, after scaling for body weight. Top athletes get up to 75, and the much less fit are down in the twenties. As someone who’s become quite interested in weight loss, exercise and fitness recently, I’d be very interested to discover my own VO2 max, but as the program shows, people are put through a punishing exercise test to determine the number, which itself could be quite dangerous, if you’re elderly or have heart issues. So this is an issue I’ll come back to as I try to get more info on myself.
After these tests, Mosley’s introduced to the high intensity training (HIT) protocol, which represents one of the most exciting and controversial developments in ‘exercise science’, if there is such a thing. On an exercise bike, he’s asked to do three short (20 second) bursts of give-it-all-you’ve-got cycling, with rests in between. That’s a minute of HIT, to be undertaken 3 times a week – so, 3 minutes a week. Not worth going to the gym for. Actually the principal attraction the gym held for me, during the short period when I regularly attended, was the sight of athletically lissom females. Sadly, I got rid of my exercise bike, reluctantly, a couple of years ago. Now I’ll have to buy another, because I’m definitely keen on this HIT stuff.
So why does HIT work? The science isn’t clear, but it definitely does work, as shown by many labs around the world. This HIT regime is enough to break down the glycogen stores in the muscles – the store of glucose. This is a key signal from the muscle to the bloodstream saying ‘I need more glucose’, which presumably results in the sugars, the calories being sucked out of the blood into the muscular tissue. This sort of thing happens on a low level with any activity, such as simply walking, but HIT sends out this message from a far higher percentage of the muscle tissue than walking or other mild activities. So for those at risk of diabetes, HIT appears to be an excellent approach
HIT is also good for increasing your VO2 max, presumably because it primes the body to expect, every now and then, short sharp bursts of intense effort, as our evolutionary development might have done. As the researcher says, the sense, after only 20 seconds, that you’ve engaged in a thorough-going, lung-bursting, heart-pumping workout, is a good indication of the VO2 max benefits. The benefits of HIT are not immediate, but after about six weeks the effects should become clear.
So Mosley commits to trying HIT for a month or two, and in the meantime he checks out some more research, this time on NEAT, another low-cost, no gym fees way of keeping healthy. NEAT stands for Non-Exercise Activity Thermogenesis, a neat acronym for avoiding sitting around on your butt all day, which many people spend twelve hours or more a day doing. NEAT basically means the calories you burn in all your everyday activity and movement, apart from deliberate exercise, whether inside or outside a gym.
Mosley is asked by James Levine, of the Mayo Clinic, to put on a pair of ‘fidget pants’ or NEAT underwear, which are ‘wired up’ to register all daily, and nightly, movements. A bit embarrassing, thinks I, if you’re known to sleep alone and you register some suspicious nocturnal rhythms, but hey, if it keeps you healthy… In fact doctors recommend…
The point is that just about any activity will increase your metabolic rate – though I’m a bit sceptical of the numbers Levine throws around here – ‘this guy’s walking slowly, about 1mph, that’s okay though, he’s doubling his metabolic rate, and look that guy’s walking twice as fast, so he’s tripling his metabolic rate..’ Really? Sounds like this is based on averages again, and even at that, I doubt if just doubling your walking speed doubles your metabolic rate. But hey, picky picky, it’s surely all doing some good.
Mosley and two other subjects are to have their daily activities tested via the pants. One works in a busy cafe, the other is a writer, particularly on health issues, who goes regularly to the gym.
The three subjects are measured over a 24-hour period, and the results are presented a bit sketchily – a problem with cramming so much in in an hour-long doco. The cafe worker is described as gold medal material from a NEAT perspective, because she’s constantly active, as her graph shows – but in fact only in the morning. There follows a period of complete inactivity according to the graph, but this doesn’t get a mention. The health writer’s graph is sporadic, with occasional bursts of high-level activity, including a very fast and reasonably long walk from one building to another, which Levine doesn’t seem much impressed by (he simply says at the end that the cafe worker produced impressive NEAT results, while the other two failed, essentially). Mosley’s own results indicated regular but quite low-level movement, which didn’t add up to much. So he did an extra 24-hour session with the fidget pants, this time making a concerted effort to sit less, and to generally be more on the move. Levine tells him that his much-improved graph means that he’s burned off 500 calories more than in the first session, so potentially he could be burning off 500 calories daily.
Scepticism time again. The 500 calories thing is again based on an average. Metabolism varies enormously, and if it’s true that there are super-responders and no-changers when it comes to gym exercise, why wouldn’t it be true for NEAT activity? Also, is it really about calories?
Well, Levine answers that last question, sort of, in the next segment. Regular movement just keeps the system going, in terms of blood sugar and blood lipid levels and various other indicators, in a way that long sedentary hours, followed by a burst of activity, even at a gym, doesn’t. At least that’s what recent research seems to be telling us. It’s the sedentariness, according to Levine, that seems to be ‘the killer’. Sitting around in a chair all day is killing millions, is his stark assessment.
So Mosley continues on his journey among the researchers, while working on his HIT, and improving his NEAT. His next stop is the University of Brighton, where Dr Emma Ross is working on brain activity and fatigue. Mosley is asked to do some cycling in a hypoxic chamber, where the oxygen level is lowered (these are the in thing for pro distance cyclists, who often have to compete at altitude). The chamber shows a 14.2% oxygen level, compared to 21% outside the chamber. The idea is raise the fatigue level more quickly, but also the ‘brain concern level’, if you will. Mosley lasts only a few minutes. The oxygen saturation in his blood drops to 82% – presumably from 100%? The significance of this figure, and its effects, aren’t explained. Immediately afterward, he’s strapped into a chair, has electrodes placed on his thighs and has his leg strapped with a strain guage, to measure his kick strength. First he’s asked to push his muscles as hard as he can, then a trans-cranial pulse is attached to his head. This delivers a magnetic pulse to his leg, and the result of all this isn’t too easy to follow, but it seems as if the brain is communicating with the muscles and telling them not to strain so hard. That’s to say, the brain seems to be in ‘somewhat concerned’ mode, creating a safety margin for your exertion, which can be reduced through awareness and training. By reducing that safety margin, you can improve your overall fitness and health benefit.
We’re nearing the end. Mosley returns to Nottingham to see how his HIT schedule has worked out – though there’s a slight problem, as one expert has noted, in that Mosley has confounded the results by engaging in NEAT and other fitness experiments in the interim. This would tend to enhance the findings.
Never mind, it’s all good, and Mosley found that his insulin efficiency had improved by 23% since his previous test. So it seems that, with a combination of HIT and NEAT, you can’t lose…. Except that the test on Mosley’s aerobic capacity revealed no change, and this was in keeping with his genetic test. So, as the program concluded, good for science, bad for Mosley, at least so far as his VO2 max was concerned.
So my overall view of the program was that the science was persuasive, and quite exciting, especially re the ‘HIT protocol’.
On a personal level I find this very interesting, and in tune with my intuitions. When I was young I was a skinny thing who had little interest in food, in fact I actively disliked most of it, and my mother despaired of finding any kind of food I liked. In my teen years I was quite sporty and active but I hated exercise. I loved sport for the competition, not the exercise. In my early twenties I worked for a few years in a really good restaurant and discovered the joys of food and cooking, but I still quite active and sporty and rode a bike everywhere, but as the twenties moved into the thirties, sport became less of an activity and more of a spectacle, and I got my driver’s licence and could afford to eat out more, and my weight, as I got into my forties, began to creep up. In my teens and twenties I was around 69 or 70 kilos, just within the normal rate for my height (168cm), according to the BMI. In my thirties and early forties this crept up to the low to mid 70s, and then in the late forties it started to climb a bit alarmingly, reaching a maximum of 83.4 – that’s about a kilo below the obese range – in November -December last year. It’s probably fair to say that in the ten years leading up to that high, I’d exercised very little.
This morning, after a year, not of dieting, but of eating less and exercising a bit more – regular walking and some simple, non-strenuous CSIRO exercises, my weight was 72.9 and falling. I actually allow myself to feel hungry and quite enjoy it. I try to get back to the mindset of my youth when food didn’t matter to me. It’s not easy but it does work for periods. I also feel the benefits. I was over-eating and suffering gastric and digestive problems. They’ve disappeared this year.
So, although it’s unlikely that I’ll get genetically tested for my response to exercise – unless the test becomes freely available in the foreseeable – my guess is that I’m closer along the spectrum to the super responders than to the no-changers.
I also find the NEAT results are in keeping with my personal intuitions. As I got older and stopped playing sports, I became conscious of the dangers of sitting around all day. I’m a big reader, and a regular writer, so obviously sitting has played a big part in my whole adult life. When I lived alone, I used to read while pacing about in my flat. Nowadays, with podcasts, I can time a solid evening walk with a 70 minute or so episode of the SGU. When I visited people, I got mild complaints that I wouldn’t ‘sit and relax’, but preferred to chat while on my feet. That was more in my forties (I’m now 56). In recent years, before 2012, I kind of gave up, and relaxed into pudgy middle age. But 2012 has brought a change, in my dietary and activity habits, and it’s been all to the good. I’m only two and a half kilos from being out of the overweight range and into the normal range. Ultimately my aim is to get down to under 70ks again, perhaps for the first time in 30 years, and I’m on target to achieve that. Importantly, without strain. I’m aiming for a kilo a month, so my target is to be below 72ks by the end of January, and below 70ks by the end of March.