Canto: So in the last post, lymph glands, or nodes or whatever, got a passing mention, and I realise I’ve lived a pretty full lifetime without having much of an idea of this substance – is it a solid, liquid or gas, or is it delightfully ethereal, like qi?
Jacinta: Okay, let’s explore. The Better Health Channel, an Australian website, manages to give a point by point summary of the lymphatic system without really explaining what lymph actually is. For example, here are a couple of points that come close, but not very….
The lymph nodes monitor the lymph flowing into them and produce cells and antibodies which protect our body from infection and disease.
It maintains fluid levels in our body tissues by removing all fluids that leak out of our blood vessels.
From which we can deduce that it’s a fluid, since it flows.
Canto: The book we’ve been reading on CFS and its symptoms gives, en passant, this useful information on lymph nodes:
The lymph nodes are tender in multiple areas, such as in the front and back of the neck, armpits, elbows and groin…. One of the most characteristic symptoms is pain in the sub-auricular lymph nodes, the nodes located under the ear and behind the angle of the jaw.
Jacinta: Wow, they bin everywhere. And yes it does sound a bit like qi, some energy force that just needs to be needled at the nodes.
Canto: Time for some science. Lymph comes from Latin, lympha, ‘water’. So, very fluid. Here’s what Wikipedia says on its structure:
Lymph has a composition similar but not identical to that of blood plasma. Lymph that leaves a lymph node is richer in lymphocytes than blood plasma is. The lymph formed in the human digestive system called chyle is rich in triglycerides (fat), and looks milky white because of its lipid content.
Which sounds like the lymph nodes are where lymphocytes are produced. Lymphocytes are a type of leukocyte or white blood cell.
Jacinta: Well, here’s what I’ve come up with, to start things off.
The lymphatic system is the system of lymphoid channels and tissues that drains extracellular fluid from the periphery via the thoracic duct to the blood. It includes the lymph nodes, Peyer’s patches, and other organized lymphoid elements apart from the spleen, which communicates directly with the blood.
And what, you might ask, is the thoracic duct? Not to mention Peyer’s patches. The thorax, I think, is basically that part of the body covered by the rib cage, which includes the heart, the lungs and other organs, perhaps the spleen, perhaps the pancreas, the liver, the stomach, I’m very vague about it all. Anyway, the thoracic duct is an essential part of the lymphatic system, so here’s some more essential info about it:
The lymph from most of the body, except the head, neck, and right arm, is gathered in a large lymphatic vessel, the thoracic duct, which runs parallel to the aorta through the thorax and drains into the left subclavian vein. The thoracic duct thus returns the lymphatic fluid and lymphocytes back into the peripheral blood circulation.
So from this it’s clear that blood and lymph seem to circulate and work together in some respects.
Canto: It’s annoying that lymph is described as the ‘stuff of the lymphatic system’ or in the lymph nodes/vessels, etc etc. It reminds me of dormative virtue, somehow. Then again, it’s a bit like blood. What’s blood? It’s the stuff that comes out of us when we cut ourselves. Most people don’t know much beyond that – except for one key fact. It’s red, and it pools all over the floor in murder dramas. What colour is lymph? Have we ever seen a pool of it? Do we every lymph to death? Why can’t we turn lymph into a verb?
Jacinta: Okay, enough of the deepities. This really is a fascinating topic, and tracing the discovery of lymph, chyle, and the lymphatic system, starting with Hippocrates some 2400 years ago, would be the best, or at least the most interesting way to learn about the stuff, IMHO. I’ve found a recent series of pieces, The discovery of lymphatic system in the seventeenth century, which I’d love to read, but they’re behind a paywall, because we impoverished dilettantes need to be kept from accessing such things. They do give us access to the abstracts though. Here’s the abstract from part one:
The early history of lymphatic anatomy from Hippocrates (ca. 460–377 B.C.) to Eustachius (1510–1574). The presence of lymphatic vessels and lymph nodes was reported by ancient anatomists without any accurate knowledge of their true functions. Lymph nodes were described as spongy structures, spread over the whole body for the support of vulnerable body parts. Digestion was explained as being the resorption of clear chyle from digested food by the open endings of chyle vessels. The first insights into the place of lymphatic components within nutrition emanated from the medical school of Alexandria (fourth century B.C.) where vivisection was a common practice. Herophilus and Erasistratus described mesenteric veins [relating to the mesentery, a fold of membrane that attaches the intestine to the abdominal wall] full of clear liquid, air or milk. For Galen of Pergamum, (104–210) mesenteric lymph nodes also had a nutritional function. He described three different types of mesenteric vessels, namely, the arterial vessels, for the transport of spirituous blood to the intestines; the venous side branches of the portal vein, for the transport of nutritive blood from the liver to the intestines; and small vessels, from the intestines to the mesenteric lymph nodes (serous lymph vessels?). According to Galen, chyle was transported via the above-mentioned mesenteric venous vessels from the intestines to the portal vein and liver, where it was transformed into nutritive blood. This doctrine would be obliterated in the seventeenth century by the discovery of systemic circulation and of the drainage of chyle through a thoracic duct to the subclavian veins.
Canto: Hmmm. Chyle? Peritoneum? Subclavian?
Jacinta: Chyle’s a milky, fatty fluid (containing lymph), formed in the small intestine during digestion. It flows into those lymph vessels known as lacteals. These are special ‘lymph capillaries’ where the lipids ‘are colloidally suspended in chylomicrons’ My guess is that ‘chylomicrons’ are itty-bitty chyle bits. Colloidal suspension is ‘a stable phase showing little tendency to aggregate and separate from the aqueous phase’, according to ScienceDirect. The peritoneum is ‘the serous membrane that lines the abdominal cavity’. Other serous membranes are the pleura and the pericardium. They are two-layered membranes ‘lubricated by a fluid derived from serum’. The subclavian veins (and arteries) are those running from the neck down the left and right arms.
Canto: Serum?
Jacinta: Comes from the blood, and rich in proteins.
Canto: So it seems that lymph, or the lymphatic system, has a few functions. Three in particular are highlighted by a NIH website relating to cancer. First, it returns interstitial fluid – fluid that leaks from blood capillaries into the spaces between cells – to the venous blood. This is a sort of recycling process – a regular leakage and a regular return. The returned fluid is called lymph. The second function connects it to the digestive system. Fats and fat soluble vitamins are absorbed and transported to the venous circulation. This happens through those aforementioned lacteals. The small intestines are lined with villi, little finger-like projections, in the centre of which are blood capillaries, and lacteals, aka lymph capillaries. The blood and the lymph thus act together, with the blood capillaries absorbing most of the nutrients and the lymph capillaries absorbing the fatty stuff. And this high fat content lymph is called chyle. And the third function – the most well-known function according to my source – is immunological:
Lymph nodes and other lymphatic organs filter the lymph to remove microorganisms and other foreign particles. Lymphatic organs contain lymphocytes that destroy invading organisms.
Jacinta: A reasonably good dummies intro to lymph and the lymphatic system, IMHO, and it’s not really surprising that it took a while to work out what it was all about. We certainly don’t know ourselves, but we know a bit more than we did.
Canto: Yes, much more to learn, about lymphoid tissue, capillaries, vessels and that big thoracic duct. And since much of this info comes from the National Cancer Institute (in the US), the connection with cancer, positive or negative, might be worth exploring….
bonobos or chimps? Or both? Or neither? What’s in a name…?
Canto: So we’ve been learning than we did it with Neanderthals, and that Neanderthals did it with Denisovans, and I remember hearing an anthropologist or palaeontologist saying that it’s likely that our split with our last common ancestor with chimps and bonobos – they call it the CHLCA (chimp-human last common ancestor, eliminating bonobos altogether, sigh) – wasn’t necessarily a clean break, which surely makes sense.
Jacinta: Well, yes, as we’ve read, the split was caused by the relatively sudden creation of the Congo River, but the word ‘relatively’, is, well, relative. So this raises the question of speciation in general. Think of those Galapagos finches that so intrigued Darwin. All about differently-shaped beaks, but it didn’t happen overnight.
Canto: Right, so here’s what a website with the rather all-encompassing title “Science” says about our topic:
Tens of thousands of years ago, modern humans slept around with Neandertals and swapped some genes. Now, it turns out one of our closest living relatives, chimpanzees, also dallied with another species. New research reveals that chimps mixed it up with bonobos at least twice during the 2 million years since these great apes started evolving their own identities. Although it’s not yet clear whether the acquired genes were ultimately beneficial or harmful, the finding strengthens the idea that such cross-species mating played an important role in the evolution of the great apes.
Jacinta: Interestingly this Congo River separation which led to a completely different species was repeated by other separations which led to four sub-species of chimps. Which leads me to wonder – what’s the difference between a new species and a sub-species? Why are bonobos ‘deserving’ of being called a different species?
Canto: Well the Science article has some fascinating further information. This was the work of Christina Hvilsom and colleagues, described as ‘conservation geneticists’. They were using any genetic differences they could find to work out where particular chimps were being caught or hunted. But, since the interbreeding of humans and Neanderthals, proven by DNA, had hit the headlines, Hvilsom wondered about the DNA of chimps. So, using the same methods that uncovered Neanderthal in humans –
she and her colleagues determined that 1% of the central chimpanzee’s genome is bonobo DNA. The genetic analysis indicates that this inbreeding happened during two time periods: 1.5 million years ago bonobo ancestors mixed with the ancestor of the eastern and central chimps. Then, just 200,000 years ago, central chimps got another boost of bonobo genes, the team reports today in Science. In contrast, the western chimp subspecies has no bonobo DNA, the researchers note, suggesting that only those chimps living close to the Congo River entertained bonobo consorts.
Jacinta: What this highlights, more than anything to me, is the importance and excitement of genetic and genomic analyses. Not that we’re experts on the topic, but it has clearly revolutionised the science of evolution, complicating it in quite exciting ways. Think again of those Galapogos finches. Separation, some interbreeding, more separation, less interbreeding, but with a few kinks along the way.
Canto: And we’re just beginning our play with genetics and genomics. There’s surely a lot more to come. Ah, to live forever…
Jacinta: So how did they know some inbreeding occurred? Can we understand the science of this without torturing ourselves?
Canto: David Reich’s book Who we are and how we got here tells the story of interbreeding between human populations, and how population genetics has revolutionised our understanding of the subject. With dread, I’ll try to explain the science behind it. First, the Science article quoted above mentions a split between bonobos and chimps 2 million years ago. Others I’ve noted go back only about a million years – for example a Cambridge University video referenced below. The inference, to me, is that there was a gradual separation over a fair amount of time, as aforementioned. I mean, how long does it take to create a major river? Now, I can’t get hold of the data on chimp-bonobo interbreeding in particular, so I’ll try to describe how geneticists detect interbreeding in general.
I’ll look at the human genome, and I’ll start at the beginning – a very good place to start. This largely comes from Who we are and how we got here, and the following quotes come from that book. The human genome consists of a double chain of 3 billion nucleobases, adenine, cytosine, guanine and thymine. That’s 6 billion bases (often called letters – A, C, G and T) in all. Genes are small sections of this base chain (called DNA), typically a thousand or so letters long. They’re templates or codes for building proteins of many and varied types for doing many different kinds of work, although there are segments in between made up of non-coding DNA.
Researchers have been able to ‘read’ these letters via machinery that creates chemical reactions to specific DNA sequences:
The reactions emit a different colour for each of the letters A, C, G and T, so that the sequence of letters can be scanned into a computer by a camera.
What anthropologists want to focus on are mutations – random errors in the copying process, which tend to occur at a rate of about one in every thousand letters. So, about 3 million differences, or mutations, per genome (3 billion genes, coding or non-coding). But genomes change over time due to these mutations and each individual’s genome is unique. The number of differences between two individuals’ genomes tells us something about their relatedness. The more differences, the less related. And there’s also a more or less constant rate of mutations:
So the density of differences provides a biological stopwatch, a record of how long it has been since key events occurred in the past.
As Reich recounts, it was the analysis of mitochondrial DNA, the tiny proportion of the genome that descends entirely down the maternal line, that became a corner-stone of the out-of-Africa understanding of human origins, which had been competing with the multi-regional hypothesis for decades. ‘Mitochondrial Eve’ – a rather ‘western’ moniker considering that the Adam and Eve myth is only one of a multitude of origin stories – lived in Botswana in Southern Africa about 160,000 to 200,000 years ago, given the variability of the genomic ‘clock’ – the mutation rate.
So, what does this have to do with chimps and bonobos? Well, The exact detail of how Hvilsom et al proved that their (slightly) more recent interbreeding events occurred is hidden behind a paywall, and you could say I’m a cheapskate but the reality is I’m quite poor, trying to bring up seven kids and a few dozen grandkids in a home not much bigger than a toilet, so… but truthfully I’m just getting by, and I just want to know in general the techniques used.
First, they have to find ancient specimens, I think. But, in a video referenced below, they raised the question – Can we ‘excavate’ ancient DNA from modern specimens? We’ve learned that many modern humans have a certain percentage of Neanderthal DNA, say around 2%, but each person’s 2% may be different. Aggregating those different segments can, if we analyse the genomes of enough humans, create a whole Neanderthal genome, though not one of any Neanderthal who ever lived! At least that’s how I’m reading it, in my dilettantish way. So what exactly does this tell us? I’m not at all sure – it’s a relatively new research area, and completely new to me.
The presenter of this video uses the heading, at least at the beginning of his talk, ‘A little Archaic introgression goes a long way’. So now I need to know what introgression means. A quick look-up tells me it’s:
‘the transfer of genetic information from one species to another as a result of hybridization between them and repeated backcrossing‘.
I’ve bolded two key words here. Hybridisation, in mammals, is ‘breeding between two distinct taxonomic units’. Note that the term species isn’t used, presumably because it has long been a questionable or loaded concept – life just seems too complex for such hard and fast divisions. Backcrossing seems self-explanatory. Without looking it up, I’d guess it’s just what we’ve been learning about. Canoodling after speciation should’ve ruled canoodling out.
But, looking it up – not so! It’s apparently not something happening in the real world, something like backsliding. But then… Here’s how Wikipedia puts it:
Backcrossing may be deliberately employed in animals to transfer a desirable trait in an animal of inferior genetic background to an animal of preferable genetic background.
This is unclear, to say the least. How could an animal, even a human, deliberately do this? We could do it to other animals, or try it, based on phenotypes. We’ve been doing that for centuries. What follows makes it more or less clear that this is about human experimentation with other animals, though.
Anyway, I’m going well off-topic here. What I wanted to do is try to understand the proof of, or evidence for, bonobo-chimp interbreeding. I accept that it happened, well after the split between these two very similar-looking species. What could be less surprising? Along the way I’ve been reminded inter alia, of homozygous and heterozygous alleles, but I’ve been frustrated that straightforward information isn’t being made available to the general public, aka myself. I’ll pursue this further in later posts.
Jacinta: What a mess. Phenotype isn’t everything my friend. To a bonobo, a chimp probably looks like a neanderthal – a real bonehead… They probably only had sex with them out of pity. ‘Boys, we’ll show you a good time – like you’ve never had before.’
Canto: So If Charles Darwin was alive today, he’d be gobsmacked at the facts derived from the ‘random variation’ end of his theory of natural selection from random variation. I’m talking about genes, DNA, genetic recombination and all that we know about meiosis and mitosis, spermatogenesis and oogenesis, genomics and epigenetics, mitochondrial DNA, ribosomes, mRNA, proteins and the like, none of which I’m particularly knowledgeable about – but surely even what I know about it all would make Darwin’s head explode.
Jacinta: Yes, and of course Darwin did all his studies on phenotypes, a term he would never have heard. He studied pigeons, finches, barnacles, fossils and a wide variety of plants. But he was never able to ‘crack the code’ of random variation. Why did offspring differ from parents? Why did those offspring vary from the utterly dysfunctional to the super-functional? For a time he considered pangenesis, his coinage, as a solution. This involved ‘gemmules’ inherited from both parents, blended together and somehow modified by the environment, presumably in a Lamarckian way. So Darwin never quite cracked the code of inheritance as we understand it today, but the work with plants which occupied his last years – allowing him to avoid the acrimony around human origins surrounding the publication of On the origin of species – produced important results for the understanding of plant reproductive biology. Take this quote from the Smithsonian magazine:
Darwin designed highly rigorous experiments and made predictions—which turned out to be correct—using his theory of natural selection. For example, he predicted that the myriad floral adaptations he saw existed to ensure that flowers were outcrossed, or fertilized by individuals other than themselves. He then tested this hypothesis with over a decade of pollination experiments and found that self-pollination leads to lower fitness and higher sterility. Inbred plants, like inbred animals, don’t fare well, at least over time—a phenomenon that’s now known as inbreeding depression.
Canto: Right, but let’s not get bogged down in the history of reproductive biology and the birth of genetics here, as it’s hard enough for me to comprehend meiosis and mitosis, gametes and zygotes and all the rest, as we understand it all today. We’ve previously written about meiosis, but I want to understand, or to begin to understand, in this post, how the process of producing gametes is so different in male and female mammals.
Jacinta: Okay, so we’re talking about gametogenesis. The male gametes are called sperm, the female gametes are called eggs, and so have two forms of gametogenesis, spermatogenesis and oogenesis. In this post I’ll focus on the male, saving the best for another post. So sperm is formed in the testes…
Canto: The ballsacks?
Jacinta: Uhh, well, the sack is just the sack, also known as the scrotum. Inside, you’ll find a testicle, hopefully. And as you well know there are, ideally, two of them. That is, two sacks, each with its testicle. And a testicle is about as complex as any other piece of biological machinery – a lifetime’s learning worth. Take this illustration, courtesy of ken hub.com:
Note the seminiferous tubules above. That’s where the sperm is formed, first by the mitotic division of a spermatogonial stem cell…
Canto: Eh what? How did they get in there?
Jacinta: Okay let me try to understand this for myself, but I may get more and more bogged down. It all begins at the beginning, during the early stages of male foetal development. The primordial germ cells differentiate in the testis, in these seminiferous tubules… But let me first fast forward to the end of the process and describe a complete, mature sperm cell or spermatozoon. That’s an active, motile sperm – plural spermatozoa, or just plain sperm. It’s divided into three parts, essentially, the head, the midpiece and the tail. At the head we find the acrosome and the tightly packed nucleus. The midpiece contains the mitochondria. which provides energy for the sperm’s motility, and the tail is essentially the flagellum, the sperm’s outboard motor, so to speak.
Canto: Okay, so that’s the end product – get back to the spermatogonial stem cells and the seminiferous tubules.
Jacinta: Fine. Spermatogonia are undifferentiated male germ cells, or sperm cells. It’s hard to find a simplified, but not overly simplified, explanation of how pluripotent or totipotent stem cells become germ cells, or any other cells for that matter, but it begins in the embryo. A cell signalling process in the embryo induces a small, transient proportion of the cell mass, the primitive streak, to become primordial germ cells (PGCs), along with other cells. This process is called gastrulation, in which the embryo begins to differentiate into distinct cell lineages. For the PGCs, according to a paper cited in Wikipedia, ‘The specification of primordial germ cells in mammals is mainly attributed to the downstream functions of two signaling pathways; the BMP signaling pathway and the canonical Wnt/β-catenin pathway’. This is essentially about regulatory proteins, I think.
Canto: This is getting too complicated for me. How come that second pathway is canonical?
Jacinta: See, you are paying attention. That Wnt/beta-catenin pathway gets a lot of attention in scientific papers, because we know that its deregulation is a problem in serious diseases and cancers. Basically these pathways are essential for embryonic development. The terms ‘canonical’ and ‘noncanonical’ are terms of art used to describe the standard production of Wnt proteins for development or homeostasis, and less well-known, or later-discovered pathways. I think. Anyway, let’s get back to spermatogonia, of which there are three types – A dark, A pale and B. The A dark spermatogonia are the reserves, and they don’t generally go through the mitosis process – they remain dormant. The A pale cells (so called because they have pale nuclei compared to the A dark cells) undergo mitosis to become the type B cells, which grow and develop to become primary spermatocytes, a process called spermatocytogenesis, truly. All of this occurs, as mentioned, in the seminiferous tubules of the testes, and begins at puberty.
Canto: Okay so how do these primary spermatocytes differ from spermatozoa, or how do they become spermatozoa?
Jacinta: The primary spermatocytes are diploid cells, so they need to undergo meiosis to become gametes. After meiosis 1, two haploid cells are formed, called secondary spermatocytes. And of course, being diploid cells undergoing that first process of meiosis, there’s this crossing over or recombination that occurs, shuffling the deck so to speak. And this is followed by meiosis 2, replicating the haploid cells, and so forth. But you ask how the spermatozoa are formed as an end product, so I need to take us back to those tubules in the testes. They’re packed with particular cells called Sertoli cells, and just outside the tubules are Leydig cells, which produce testosterone. Anyway, once these sperm cells have developed further they travel up to the epididymis via the rete testis, where they continue to mature, ready for ejaculation. They reach the rete testis, and presumably also the epididymis, by means of peristalsis, which you’ll know about from the intestines and other parts of the body.
Canto: Sort of. You think you know about stuff until you find out what you don’t know, which is overwhelmingly vast. Mais, continue..
Jacinta: So the last transformations, making them those mobile little tadpole-like critters, occur in the epididymis. But returning to those tubules. There are lots of Sertoli cells in there, and the sperm is developed in the gaps between them, strangely enough, but they acquire nutrients from those cells to help them along. Their journey between the cells takes them from the outer membrane of the tubule to the lumen. At the beginning of this journey they’re called spermatogonia. They’re going to go through this differentiating process to finally become spermatozoa. Now I’ve already partially described the first step, when a spermatogonium divides by mitosis, into two cells, one of which is kept in reserve, the Ad or ‘dark’ cell. The Ap or ‘pale’ cells continue on the pathway between the Sertoli cells towards the lumen, somehow becoming B cells – don’t know how that happens, but it involves mitosis, perhaps with nutrients from the Sertoli cells. I think, because the process of mitosis is continuous, those reserve cells are left behind all along the pathway. Or maybe not. But that pathway is obstructed along the way by ‘tight junctions’ between the Sertoli cells, which create separate compartments as they open and close before and behind the sperm cells (which are now called primary spermatocytes) like locks in a canal. Now these compartments, called basal and lumenal compartments, aren’t empty, they’re full of chemicals, signalling proteins and such, a different mix for each compartment, which add to the spermatocyte’s development. So the sperm grows as it travels along this pathway, accumulating more cytoplasm. And the junctions close very tightly after the sperm moves through, to prevent leakage into the next chemical environment. Now, somewhere along this pathway between the Sertoli cells, the primary spermatocyte is ready to divide into two secondary spermatocytes via meiosis, a very different form of cell division from mitosis.
Canto: Yes, meiosis has those two parts, ending with four haploid cells from one diploid cell, and genetic recombination to make us all unique.
Jacinta; Okay, moving right along, so to speak, those four haploid cells are now called spermatids, and they continue to mature in the lumen. They’re still not motile, they’re rounded cells at first, but they go through lots of changes, to the conformation of the DNA, for example, with histone proteins being replaced by protamines. We’re now entering the final processes, known as spermiogenesis, which I think occurs after transportation to the epididymis. The cytoplasm is removed, the acrosomal cap is formed, and the other structures I mentioned at the outset, the mitochondrial spiral and the fibres that form the flagellum, all take shape. This whole process, from spermatogonia to spermatozoa, takes about 65 days.
Canto: Okay, that’s enough of all that, I don’t particularly want to learn about seminal fluids and ejaculation at this point, fascinating though that might be – I’m more interested in the female stuff, the generation of eggs, known as oogenesis.
Jacinta: So that for you to detail in a future post.
Canto: So I’m trying to get my head around meiosis in general, and how the parental chromosomes get assorted in the process. I understand that Mendel arrived at his law or principle of independent assortment by noting the resultant phenotypes from particular crosses, especially dihybrid crosses. He knew nothing about gametes and meiosis, an understanding of which didn’t get underway until a decade or more after his 1865 experiments…
Jacinta: Well, meiosis is a v v amazing process that deserves lots of attention, because if not for, etc….
Canto: But what is meiosis for, I don’t even understand that.
Jacinta: It’s for the production of gametes – the sperm and egg cells in mammals. And that’s interesting, because, according to Medical News Today, ‘Females are born with all the eggs they will ever have in their lifetime. The amount decreases until a person stops ovulating and reaches menopause’. According to a graph they present, the number of egg cells produced is at its peak long before birth, and has reduced about tenfold by the time of birth, to about one or two million. This number continues to reduce through life, though it remains relatively stable during the period of ‘optimum fertility’ from about ages 18 to 31, when the number of eggs is around 200,000, with a lot of individual variation.
Canto: So, meiosis occurs entirely while the infant is in the womb? For females at least. And what exactly is ovulation?
Jacinta: Yes, egg cells don’t regenerate like other cells. Remember, tens of billions of our somatic cells die every day, and are being replaced – mostly. As to ovulation, this occurs as part of the menstrual cycle, which occurs with females at puberty. During menstruation, mature eggs are released from the ovaries, which are on the left and right sides of the uterus and connected to it by the fallopian tubes.
Canto: What do you mean by mature eggs? Aren’t they always mature?
Jacinta: Hmmm. Detour after detour. Four phases are recognised in the menstrual cycle – menstruation, the follicular phase, ovulation and the luteal phase. It’s the follicular phase that produces mature eggs, through the release of follicle stimulating hormone (FSH) by the pituitary gland. Do you want me to go into detail?
Canto: No, let’s get back to meiosis – but I always knew there was something fshy about the menstrual cycle. So meiosis is about haploid cells producing more haploid cells? You mentioned that egg cells, which are haploid cells, are at their peak long before the birth of a female child, a peak of around 10 million. But where does the first haploid cell come from, when a child starts as one fertilised egg – a diploid cell? Haploid cells combining to form diploid cells is one amazing process, but diploid cells separating to form haploid cells?
Jacinta: Okay so here’s what I think is happening. A human being starts as a diploid cell, a fertilised egg. As cells differentiate, which happens quite early, some become germ cells. But they’re diploid cells, like all the others, not haploid cells. So meiosis starts with diploid cells.
Canto: Okay, so what differentiates a germ cell from other somatic diploid cells?
Jacinta: I don’t know, just as I don’t know what makes a pluripotent or totipotent cell become a brain cell or a blood cell or whatever. This presumably has a lot to do with genetics, epigenetics and the production of endless varieties of proteins that make stuff, including germ cells. Which presumably are not egg cells or sperm cells, which are haploid cells, or gametes. And these germ cells can undergo mitosis, to reproduce themselves, or meiosis, to produce gametes. So now, at last, we describe the process, and much of this comes from Khan Academy. There are two ’rounds’ of meiosis – M1 and M2 – each of which has a number of phases. In M1 the diploid cell is split into two haploid cells each with 23 chromosomes, and in M2 the haploid cells reproduce as haploid cells, so that at the end of the cycle you have four haploid cells. And in each of these ’rounds’ there are the four phases, prophase, metaphase, anaphase and telophase. PMAT is how to remember it. And then there’s interphase, where cells just going on being themselves and doing whatever they do – though it’s important to know what happens during interphase for these other stages.
Canto: The complexity of it all is fairly mind blowing. Molecules that have a code for making proteins that perform all these functions that produce a huge variety of cells every one of which – apart from the gametes – has a nucleus containing 23 chromosomes from your mother and 23 from your father. Trillions of them!
Jacinta: Yes, it’s certainly amazing – and billions of those cells die and are replaced every day. And not just in humans but in dogs and bonobos and cetaceans and whatnot.
Canto: But here’s a thing – we’re talking about gametes, also known as germ cells, which may be female or male – sperm cells or egg cells. But sperm are also known as spermatazoa, and they’re much tinier and less complex than egg cells, and also far more numerous. Is a spermatozoon a sperm cell, or do lots of spermatozoa live in one cell, or what? One ejaculation releases – how many of these tiddlers?
Jacinta: Well sperm counts can range from about 15 million or less per millilitre of semen (that’s a low sperm count) to somewhere between 200 and 300 million. An ejaculation can vary in volume of course – generally about a teaspoon, which might be as much as 5mls. And, yes, a single sperm or spermatozoon is a male gamete, much smaller than the female ovum. So, yes, male sperm, like male political leaders, make up in numbers for what they lack in complexity.
Canto: Okay so let’s get started with PMAT and all that.
Jacinta: Well it’s all very miraculous or mind-blowing as Salman Khan rightly emphasises – to think that this complexity comes from mindless molecules and all. But here goes, and it cannot help but be a simplified description. So we start with a germ cell – and I’m not sure how this particular type of diploid cell is distinguished from other diploid cells…
Canto: Or whether, even though it’s called a germ cell, it is essentially different in male bodies as compared to female bodies, since they produce such different gametes…
Jacinta: Yeah well I’ll keep that in mind as we progress. Now we start with the interphase, during which time the chromosomes in the nucleus are synthesised. Interphase is generally subdivided into three phases, Gap 1 (G1), Synthesis (S) and Gap 2 (G2). The cell itself experiences a lot of growth during interphase.
Canto: Too vague.
Jacinta: Well I’m just getting started, but I’m not writing a book here.
Canto: Are you going to explain how the chromosomes are ‘synthesised’?
Jacinta: Probably not, this is just a summary.
Canto: I want to know about chromosome synthesis.
Jacinta: Sigh. You’re right, it sounds pretty important doesn’t it. So let’s focus in detail on interphase, which I think is much the same whether we’re looking at mitosis or meiosis. If you consider a whole cell cycle, from its ‘birth’ – usually through mitosis – to its ‘death’ (through mitosis again? I’m not sure), 95% of its time is spent in interphase, during which it doubles in size. It is, in a sense, preparing itself for chromosomal replication and cell division. Here’s a quote from a text book, Concepts of Biology, which I found online, describing the first stage of interphase:
The first stage of interphase is called the G1 phase, or first gap, because little change is visible. However, during the G1 stage, the cell is quite active at the biochemical level. The cell is accumulating the building blocks of chromosomal DNA and the associated proteins, as well as accumulating enough energy reserves to complete the task of replicating each chromosome in the nucleus.
Canto: So it’s a clever cell, actively accumulating the material to build and replicate its particular and unique DNA – I mean unique to the particular soma that it somatically serves, along with several trillion others.
Jacinta: Actually, another source tells that the G stands for growth, which I think makes more sense. The next stage is the S or synthesis phase. Now at this stage, or the beginning of it, the chromosomes exist largely as chromatin, a kind of mixture of DNA and proteins. Histones, in particular are important proteins for packaging the DNA into a tight enough space to fit in the nucleus. I mean, 23 pairs of chromosomes doesn’t really tell you how much DNA and other molecules it all amounts to. Now, this S phase is really complicated, and summaries don’t do it justice. Here’s a quote from yet another source to kick things off:
The S phase of a cell cycle occurs during interphase, before mitosis or meiosis, and is responsible for the synthesis or replication of DNA. In this way, the genetic material of a cell is doubled before it enters mitosis or meiosis, allowing there to be enough DNA to be split into daughter cells. The S phase only begins when the cell has passed the G1 checkpoint and has grown enough to contain double the DNA. S phase is halted by a protein called p16 until this happens.
So you’re asking how these chromosomes are synthesised. Note how this says ‘synthesis or replication’, so it’s presumably about the same sort of process that occurs when cells and their chromosomes are replicated during mitosis? Here’s another passage from the same source, and I don’t pretend to understand it:
The most important event occurring in S phase is the replication of DNA. The aim of this process is to produce double the amount of DNA, providing the basis for the chromosome sets of the daughter cells. DNA replication begins at a point where regulatory pre-replication complexes are attached to the DNA in the G1phase. These complexes act as a signal for where DNA replication should start. They are removed in the S phase before replication begins so that DNA replication doesn’t occur more than once.
Canto: Wow. That explains not much. Obviously the key to it all is the ‘regulatory pre-replication complexes’ previously attached. How could I not have known that?
Jacinta: Well let’s just say that there are known mechanisms by which DNA replication is regulated, and prevented from occurring more than once in the S phase. I’m sure all those ‘pre-replication complexes’ have been named and studied in detail by scores of geneticists. So that’s enough for now about chromosome synthesis/replication. The S phase also involves continued cell growth and the production of more proteins and enzymes for DNA synthesis. Always looking to the future. And so we move to the next phase.
Canto: Ah yes, reading ahead I see that DNA synthesis is always much the same. The DNA double helix is kind of unzipped by an enzyme called helicase, and the two single strands can be used as templates to form new and identical double strands. I’m over-simplifying of course.
Jacinta: Yes there are different processes going on to ensure that everything goes more or less smoothly, as well as to maintain cell growth outside of the genetic material. A key enzyme, DNA polymerase, binds nucleotides to the template strands using the base pairing code – A binds to T, C to G. This creates an identical new double helix of DNA.
Canto: Apparently there’s a difference between DNA replication and chromosome replication. Please explain?
Jacinta: I’m not sure if I can, but we’re talking about the replication of chromosomes in the S phase, after which each chromosome now consists of two sister chromatids (halves of a chromosome), as you see below.
In the first circle, A and B are homologous pairs. That’s to say, they’re segments of DNA, chromosomes, from each parent, though they might code differently – they might be different alleles. This is a bit complicated. Sal Khan in his video puts it this way:
Homologous pairs means that they’re not identical chromosomes, but they do code for the same genes. They might have different versions, or different alleles for a gene or for a certain trait, but they code essentially for the same kind of stuff.
Make of that what you will. I suppose it means that the homologous pair might have, say, genes for eye colour, but mum’s will code for blue, dad’s for brown. But the same kinds of genes are paired. Anyway, after replication in the S phase, you get, as above, two male and two female chromosomes, joined together in a sort of x shape. They’re joined together at that circular sort of binding site called a centromere (it’s not actually circular). The images above are misleading though, in that there are short arms and long arms leading off the centromere. You could say the centromere is off-centre. So the whole of this new x-shaped thingy is called a chromosome and each half – the right and the left – is called a chromatid. And at the four ends of the x-shaped thingy – I mean the chromosome – is a cap of repetitive DNA called a telomere.
Canto: Ah yes, I’ve heard of those and their relation to ageing…
Jacinta: Let’s not be diverted. So all of this is occurring in the nucleus, and there’s also replication of the centrosomes. Okay they’re a new structure I’m introducing, one that seems to only occur in animal-type or metazoan eukaryotic cells. They serve as microtubule organising centres (MTOCs), according to Wikipedia, which is never wrong, and which goes into great detail on the structure of these centrosomes, but for now the key is that they’re essential to the future separation of the chromatids via microtubules during prophase I. And that’s the next phase to describe. And it’s worth noting that the developments described up to now could be preliminary to meiosis or mitosis.
So, in prophase I the nuclear envelope starts to disintegrate and the pair of centrosomes are somehow pushed apart, to opposite sides of the chromosomal material, and microtubule spindles start extending from them – presumably by the magic of proteins. And another sort of magical thing happens, though I’m sure that some geneticists understand the detail of it all, which is that the homologous pairs line up on opposite sides of a kind of equator line, guided by these spindles, forming a tetrad, and this is where a process called crossing over or recombination occurs, in which the pairs exchange sections of genes. And this recombination somehow manages to avoid duplication and to maintain viability, and indeed to increase diversity. The recombination occurs at points in the chromosomes called chiasmas.
So that’s the end of prophase I. Now to metaphase 1. In this phase the nucleus has disappeared, the centromeres have completed their move to the opposite sides of the cell, and the spindle fibres of microtubules become attached to chromosomes via the kinetochores – protein structures connected to the centromeres. Here’s an interesting and useful illustration of a kinetochore.
All of this is similar to metaphase in mitosis. Then in anaphase I the homologous pairs, which remember had come together and recombined, are separated, or pulled apart, which is different from anaphase I in mitosis, where the chromosomes are split into their separate chromatids. Next comes telophase I, when the separation is complete, the facilitating microtubules break down and cytokinesis, the final separation of the chromosomes and the cytoplasm into two distinct cells, occurs. Telophase I ends with two cells and two nuclei, each containing 23 chromosomes, half of those in the original cells. They’re called daughter cells, for some reason.
Canto: Probably because son cells sounds silly.
Jacinta: Good point. So now these daughter cells start on a whole new PMAT process, which is a lot more like mitosis. Prophase II involves the disintegration of the nucleus once more, the two centrosomes start to move apart as microtubules are formed – and remember this is happening simultaneously in the two daughter cells – and then we’re into metaphase II, where the centrosomes have migrated to opposite ends of the cell, and the chromosomes line up at the ‘equator’, and the spindle fibres attach to the kinetochores of the sister chromatids. Next comes anaphase II, in which the spindle fibres draw the chromatids away from each other, as in anaphase during mitosis. And at the end of this journey they’re now treated as sister chromosomes. And all of this is happening in those two daughter cells, which start to stretch and cleave, which of course means that, in telophase II, you have cytokinesis, and the creation of new nuclear membranes, and the cytoplasm – remember that all the cytoplasm and its organelles have to be replicated too, to make, in the end four, complete haploid cells, or gametes. So that’s the potted version. There’s lots of stuff I’ve excluded, like the difference between centrosomes and centrioles, and lots of details about the cytoplasm, and there’s no doubt much more to learn (by me at least) about the crossing over that’s so essential to provide the variation that Darwin searched for in vain. Anyway, that was sort of fun and thank dog for the internet.
Canto: But I’m still confused about sperm cells and egg cells… If sperm cells are just those little tadpole things – a bunch of DNA with a flagellum, they don’t have any cytoplasm to speak of, do they?
Jacinta: Ah yes, something to look into. There’s spermatogenesis and there’s oogenesis… for a future post. It just never ends.
She has her mother’s laugh, by Carl Zimmer , science author and journalist, blogger, New York Times columnist, etc etc
content hints – inheritance and heredity, genetics and epigenetics, Darwin and Galton, the Hapsburg jaw, eugenics, Hugo de Vries, Theodor Boveri, Luther Burbank, Pearl and Carol Buck, Henry Goddard, The Kallikak Family, Hitler’s racial hygiene laws, morons, the five races etc, Frederick Douglass, Thomas Hunt Morgan, Emma Wolverton, PKU, chromosomal shuffling, meiosis, cultural inheritance, mitochondrial DNA, Mendel’s Law, August Weismann, germ and soma, twin studies, genetic predispositions, mongrels, Neanderthals, chimeras, exosomes, the Yandruwandha people, IVF, genomic engineering, Jennifer Doudna, CRISPR, ooplasm transfers, rogue experiments, gene drives, pluripotency, ethical battlegrounds.
the only image I can find that I really understand
In the previous post in this series I wrote about the connection between two serious disorders, Angelman syndrome and Prader-Willi syndrome, their connection to a missing small section of chromosome 15, and how they’re related to parental inheritance. These syndromes can sometimes also be traced back to uniparental disomy, in which the section of chromosome 15 is intact, but both copies are inherited from the mother (resulting in PWS) or the father (resulting in AS).
So the key here is that this small section of chromosome 15 needs to be inherited in the correct way because of the imprinting that comes with it. To take it to the genetic level, UBE3A is a gene which is only expressed from the maternal copy of chromosome 15. If that gene is missing in the maternal copy, or if, due to uniparental disomy, both copies of the chromosome are inherited from the father, UBE3A protein won’t be produced and symptoms of Angelman syndrome will appear. Similarly, PWS will develop if a certain imprinted gene or genes aren’t inherited from the father. Other imprinting disorders have been found, for example, one that leads to Beckwith-Wiedemann syndrome, though the mechanism of action is different, in that both copies of a gene on chromosome 11 are switched on when only the paternal copy should be expressed. This results in abnormal growth (too much growth) in the foetus. It too has an ‘opposite’ syndrome, Silver-Russell syndrome, in which the relevant protein expression is reduced, resulting in retarded growth and dwarfism.
But now to the question of exactly how genes are switched on and off, or expressed and repressed. DNA methylation, briefly explained in my first post on this topic, is essential to this. Methyl groups are carbon-hydrogen compounds which can be bound to a gene to switch it off, but here’s where I start to get confused. I’ll quote Carey and try to make sense of it:
… it may be surprising to learn that it is often not the gene body that is methylated. The part of the gene that codes for protein is epigenetically broadly the same when we compare the maternal and paternal copies of the chromosome. It’s the region of the chromosome that controls the expression of the gene that is differently methylated between the two genomes.
N Carey, The epigenetics revolution, 2011 p140
The idea, I now realise, is that there’s a section of the chromosome that controls the part of the gene that codes for the protein and it’s this region that’s differently methylated. Such regions are called imprinting control regions (ICRs). Sometimes this is straightforward, but it can get extremely complicated, with whole clusters of imprinted genes on a stretch of chromosome, being expressed from the maternally or paternally derived chromosomes, and not simply through methylation. An ICR may operate over a large region, creating ‘roadblocks’, keeping different sets of genes apart, and affecting thousands of base-pairs, not always in the same way. Repressed genes may come together in a ‘chromatin knot’, while other, activated genes from the same region form separate bundles.
Imprinting is a feature of brain cells – something which, as of the writing of Carey’s book (2011), is a bit of a mystery. Not so surprising is the number of expressed imprinted genes in the placenta, a place where competing paternal-maternal demands are played out. As to what is going on in the brain, Carey writes this:
Professor Gudrun Moore of University College London has made an intriguing suggestion. She has proposed that the high levels of imprinting in the brain represents a post-natal continuation of the war of the sexes. She has speculated that some brain imprints are an attempt by the paternal genome to promote behaviour in young offspring that will stimulate the mother to continue to drain her own resources, for example by prolonged breastfeeding.
N Carey, The epigenetics revolution, 2011. pp141-2
This sounds pretty amazing, but it’s a new epigenetic world we’re exploring. I’ll explore more of it next time.
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.
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.
filched from Wikipedia – don’y worry, I don’t understand it either – at least not yet
Statins are HMG-CoA reductase inhibitors, according to Wikipedia’s first sentence on the topic. HMG-CoA reductase is an enzyme – a macromolecule that accelerates or catalyses chemical reactions in cells. The enzyme works in the mevalonate pathway, which produces cholesterol and other terpenoids (terpenoids are very common, varied and useful forms of hydrocarbon).
So what does HMG-CoA stand for, and what’s a reductase?
3 hydroxy -3 methyl-glutaryl coenzyme A, which may be explained later. A reductase is an enzyme which catalyses a reduction reaction, and I’m not sure if that refers to redox reactions, in which case reduction involves the gaining of electrons…
But let’s look at cholesterol, which statins are used against. Sterols are lipid molecules with a polar OH component, and ‘chole’, meaning bile, comes from the liver. So cholesterol is a type of lipid molecule produced largely by the liver or hepatic cells of vertebrate animals. Cholesterol is essential for life, and it’s synthesised in the cell via a complex 37-step process (the mevalonate pathway makes up the first 18 of these). It makes up about 30% of our cell membranes, and its continual production is necessary to maintain cell membrane structure and fluidity. In high food-intake countries such as Australia and the US, we ingest about 300mg of cholesterol a day on average. We also have an intake of phytosterols, produced by plants, which might vary from 200-300mgs. Of course, this is massively dependent on individual diets (increased phytosterol intake may reduce LDL cholesterol, but it comes with its own quite serious problems).
The (very basic) structure of cholesterol is shown below.
The body of the molecule (centre) contains 4 rings of carbon and hydrogen – A, B and C are 6-carbon rings, while D has 5. The bonds between rings A and B, and C and D, represent methyl groups. On the left is a hydroxyl group, which is hydrophilic and polar, though the massive body of the molecule is extremely hydrophobic, which is reinforced by the cholesterol tail connected to the D ring. The hydroxyl polarity creates a binding site, which builds structure as the molecule binds to others.
Interestingly, the need for cholesterol synthesis varies with temperature, or climate. This has to do with fluidity and melting points. People who live in colder climates require less cholesterol production because, in cold weather, solid structure remains intact. Hotter climates cause greater fluidity and increased entropy, so more cholesterol needs to be synthesised to create and maintain structure.
So now to the 18-step mevalonate pathway, by which the liver produces lanosterol, the precursor to cholesterol. Well, on second thoughts, maybe not… It’s fiendishly complex and Nobel Prizes have been deservedly won for working it all out and I’m currently thinking that physics is easy-peasy compared to biochemistry (or maybe not). What I’m coming up against is the interconnectivity of everything and the need to be thorough. For example, in order to understand statins we need to understand cholesterol, and in order to understand cholesterol we need to understand lipids, lipoproteins, the liver, the bloodstream, the digestive system… So I sometimes feel overwhelmed but also annoyed at the misinformation everywhere, with chiropractors or ‘MDs’ announcing the ‘truth’ about statins, cholesterol or whatever in 500-word screeds or 5-minute videos.
Anyway, back to work. Cholesterol is a lipid molecule, and lipids are generallyhydrophobic (they don’t mix with water, or to be more exact they’re not very soluble in water), but cholesterol has a hydrophilic hydroxyl side to it. Lipids that have this hydrophilic/hydrophobic mix are called amphipathic. Phospholipids in cell membranes are an example. and they interact with cholesterol in the ‘phospholipid bilayer’. As an indication of the complexity involved, here’s a quote from an abstract of a biochemical paper on this very topic:
Mammalian cell membranes are composed of a complex array of glycerophospholipids and sphingolipids that vary in head-group and acyl-chain composition. In a given cell type, membrane phospholipids may amount to more than a thousand molecular species. The complexity of phospholipid and sphingolipid structures is most likely a consequence of their diverse roles in membrane dynamics, protein regulation, signal transduction and secretion. This review is mainly focused on two of the major classes of membrane phospholipids in eukaryotic organisms, sphingomyelins and phosphatidylcholines. These phospholipid classes constitute more than 50% of membrane phospholipids. Cholesterol is most likely to associate with these lipids in the membranes of the cells.
Anyway, perhaps for now at least I won’t explore the essential role of cholesterol in cell structure and function, but the role of ingested cholesterol, the difference between LDL and HDL cholesterol, and how it relates to saturated fats and heart disease, particularly atherosclerosis. As Gregory Roberts explains it in a Cosmos article, saturated fats (found in butter, meat and palm oil) definitely raise total cholesterol…
But what is saturated fat, as opposed to polyunsaturated or mono-unsaturated fat? Most of us have heard of these terms but do we really know what they mean? Here comes Wikipedia to the rescue (because there’s a lot of bullshit out there):.
A saturated fat is a type of fat in which the fatty acid chains have all or predominantly single bonds. A fat is made of two kinds of smaller molecules: glycerol and fatty acids. Fats are made of long chains of carbon (C) atoms. Some carbon atoms are linked by single bonds (-C-C-) and others are linked by double bonds (-C=C-). Double bonds can react with hydrogen to form single bonds. They are called saturated, because the second bond is broken and each half of the bond is attached to (saturated with) a hydrogen atom. Most animal fats are saturated. The fats of plants and fish are generally unsaturated. Saturated fats tend to have higher melting points than their corresponding unsaturated fats, leading to the popular understanding that saturated fats tend to be solids at room temperatures, while unsaturated fats tend to be liquid at room temperature with varying degrees of viscosity (meaning both saturated and unsaturated fats are found to be liquid at body temperature). Various fats contain different proportions of saturated and unsaturated fat. Examples of foods containing a high proportion of saturated fat include animal fat products such as cream, cheese, butter, other whole milk dairy products and fatty meats which also contain dietary cholesterol. Certain vegetable products have high saturated fat content, such as coconut oil and palm kernel oil. Many prepared foods are high in saturated fat content, such as pizza, dairy desserts, and sausage. Guidelines released by many medical organizations, including the World Health Organization, have advocated for reduction in the intake of saturated fat to promote health and reduce the risk from cardiovascular diseases. Many review articles also recommend a diet low in saturated fat and argue it will lower risks of cardiovascular diseases, diabetes, or death. A small number of contemporary reviews have challenged these conclusions, though predominant medical opinion is that saturated fat and cardiovascular disease are closely related.
Saturated Fat, Wikipedia. I’ve removed links and notes – they’re just too much of a good thing! Apologies for the lengthy quote but I think this is essential reading in this context.
High density lipoprotein (HDL) cholesterol can be a problem if your levels are low. HDL absorbs cholesterol and carries it back to the liver, from where it’s removed from the body. So generally high levels of HDL will reduce your chances of heart attack and stroke.
As Roberts notes, from the 1950s, heart disease has risen to be a major problem. Heart attack victims have been regularly found to have arteries clogged with ‘waxy plaques filled with cholesterol’. Further proof that cholesterol was to blame came with studies of people with a genetic disease – familial hypercholesterolemia (FH) – which meant that they had some five times the normal levels of blood cholesterol, and suffered heart attacks even as children or teenagers. Also, the rise in blood cholesterol levels and the rise in heart attacks, and heart disease generally, were correlated. This was unlikely to be coincidental.
But what’s a lipoprotein and why the different densities? Here we get into another area of extraordinary complexity. Lipoproteins are vehicles for transporting hydrophobic lipid molecules such as cholesterol, triglycerides and phospholipids through the watery bloodstream or the watery extracellular fluid (blood plasma – the yellowish liquid through which haemoglobin and lipoproteins etc are transported – is a proportion of that fluid). They act as emulsifiers, ‘encapsulating’ the lipids so that they can mix with and move through the fluid. Lipoproteins don’t just come in HD and LD forms – we classify them in terms of their density much as we classify colours in the light (electromagnetic) spectrum. According to that density classification we recognise five major types of lipoprotein in the bloodstream.
Cholesterol arrives in the blood via endogenous (internal) and exogenous (external) pathways. Some 70% of our cholesterol is produced by the liver, so, though diet is an important facet of changing cholesterol levels, finding ways of modifying or blocking liver production was clearly another option. Through studying the way fungi produced chemicals such as penicillin that break down cell walls (a large part of which are cholesterol), Akira Endo was the first to produce a statin from a mould in oranges – mevastatin. That was the beginning of the statin story.
Canto: So we’ve done four blogs on Palestine and we’ve barely scratched the surface, but we’re having trouble going forward with that project because, frankly, it’s so depressing and anger-inducing that it’s affecting our well-being.
Jacinta: Yes, an undoubtedly selfish excuse, but we do plan to go on with that project – we’re definitely not abandoning it, and meanwhile we should recommend such books as Tears for Tarshiha by the Palestinian peace activist Olfat Mahmoud, and Goliath by the Jewish American journalist Max Blumenthal, which highlight the sufferings of Palestinian people in diaspora, and the major stresses of trying to exist under zionist monoculturalism. But for now, something completely different, we’re going to delve into the fascinating facts around kin selection, with thanks to Robert Sapolski’s landmark book Behave.
Canto: The term ‘kin selection’ was first used by John Maynard Smith in the early sixties but it was first mooted by Darwin (who got it right about honey bees), and its mathematics were worked out back in the 1930s.
Jacinta: What’s immediately interesting to me is that we humans tend to think we alone know who our kin are, especially our extended or most distant kin, because only we know about aunties, uncles and second and third cousins. We have language and writing and record-keeping, so we can keep track of those things as no other creatures can. But it’s our genes that are the key to kin selection, not our brains.
Canto: Yes, and let’s start with distinguishing between kin selection and group selection, which Sapolsky deals with well. Group selection, popularised in the sixties by the evolutionary biologist V C Wynne-Edwards and by the US TV program Wild Kingdom, which I remember well, was the view that individuals behaved, sometimes or often, for the good of the species rather than for themselves as individuals of that species. However, every case that seemed to illustrate group selection behaviour could easily be interpreted otherwise. Take the case of ‘eusocial’ insects such as ants and bees, where most individuals don’t reproduce. This was seen as a prime case of group selection, where individuals sacrifice themselves for the sake of the highly reproductive queen. However, as evolutionary biologists George Williams and W D Hamilton later showed, eusocial insects have a unique genetic system in which they are all more or less equally ‘kin’, so it’s really another form of kin selection. This eusociality exists in some mammals too, such as mole rats.
Jacinta: The famous primatologist Sarah Hrdy dealt something of a death-blow to group selection in the seventies by observing that male langur monkeys in India commit infanticide with some regularity, and, more importantly, she worked out why. Langurs live in groups with one resident male to a bunch of females, with whom he makes babies. Meanwhile the other males tend to hang around in groups brooding instead of breeding, and infighting. Eventually, one of this male gang feels powerful enough to challenge the resident male. If he wins, he takes over the female group, and their babies. He knows they’re not his, and his time is short before he gets booted out by the next tough guy. Further, the females aren’t ovulating because they’re nursing their kids. The whole aim is to pass on his genes (this is individual rather than kin selection), so his best course of action is to kill the babs, get the females ovulating as quickly as possible, and impregnate them himself.
Canto: Yes, but it gets more complicated, because the females have just as much interest in passing on their genes as the male, and a bird in the hand is worth two in the bush…
Jacinta: Let me see, a babe in your arms is worth a thousand erections?
Canto: More or less precisely. So they fight the male to protect their infants, and can even go into ‘fake’ estrus, and mate with the male, fooling the dumb cluck into thinking he’s a daddy.
Jacinta: And since Hrdy’s work, infanticide of this kind has been documented in well over 100 species, even though it can sometimes threaten the species’ survival, as in the case of mountain gorillas. So much for group selection.
Canto: So now to kin selection. Here are some facts. If you have an identical twin your genome is identical with hers. If you have a full sibling you’re sharing 50% and with a half-sibling 25%. As you can see, the mathematics of genes and relatedness can be widened out to great degrees of complexity. And since this is all about passing on all, or most, or some of your genes, it means that ‘in countless species, whom you co-operate with, compete with, or mate with depends on their degree of relatedness to you’, to quote Sapolsky.
Jacinta: Yes, so here’s a term to introduce and then fairly promptly forget about: allomothering. This is when a mother of a newborn enlists the assistance of another female in the process of child-rearing. It’s a commonplace among primate species, but also occurs in many bird species. The mother herself benefits from an occasional rest, and the allomother, more often than not a younger relation such as the mother’s kid sister, gets to practice mothering.
Canto: So this is part of what is called ‘inclusive fitness’, where, in this case, the kid gets all-day mothering (if of varying quality) the kid sister gets to learn about mothering, thereby increasing her fitness when the time comes, and the mother gets a rest to recharge her batteries for future mothering. It’s hopefully win-win-win.
Jacinta: Yes, there are negatives and positives to altruistic behaviour, but according to Hamilton’s Rule, r.B > C, kin selection favours altruism when the reproductive success of relatives is greater than the cost to the altruistic individual.
Canto: To explain that rule, r equals degree of relatedness between the altruist and the beneficiary (aka coefficient of relatedness), B is the benefit (measured in offspring) to the recipient, and C is the cost to the altruist. What interests me most, though, about this kin stuff, is how other, dumb primates know who is their kin. Sapolsky describes experiments with wild vervet monkeys by Dorothy Cheney and Robert Seyfarth which show that if monkey A behaves badly to monkey B, this will adversely affect B’s behaviour towards A’s relatives, as well as B’s relatives’ behaviour to A, as well as B’s relatives’ behaviour to A’s relatives. How do they all know who those relatives are? Good question. The same researchers proved this recognition by playing a recording of a juvenile distress call to a group of monkeys hanging around. The female monkeys all looked at the mother of the owner of that distress call to see what she would do. And there were other experiments of the sort.
Jacinta: And even when we can’t prove knowledge of kin relations (kin recognition) among the studied animals, we find their actual behaviour tends always to conform to Hamilton’s Rule. Or almost always… In any case there are probably other cues, including odours, which may be unconsciously sensed, which might aid in inclusive fitness and also avoiding inbreeding.
Canto: Yes and It’s interesting how this closeness, this familiarity, breeds contempt in some ways. Among humans too. Well, maybe not contempt but we tend not to be sexually attracted to those we grow up with and, for example, take baths with as kids, whether or not they’re related to us. But I suppose that has nothing to do with kin selection. And yet…
Jacinta: And yet it’s more often than not siblings or kin that we have baths with. As kids. But getting back to odours, we have more detail about that, as described in Sapolski. Place a mouse in an enclosed space, then introduce two other mice, one unrelated to her, another a full sister from another litter, never encountered before. The mouse will hang out with the sister. This is called innate recognition, and it’s due to olfactory signatures. Pheromones. From proteins which come from genes in the major histocompatibility complex (MHC).
Canto: Histowhat?
Jacinta: Okay, you know histology is the study of bodily tissues, so think of the compatibility or otherwise of tissues that come into contact. Immunology. Recognising friend or foe, at the cellular, subcellular level. The MHC, this cluster of genes, kicks off the production of proteins which produce pheromones with a unique odour, and because your relatives have similar MHC genes, they’re treated as friends because they have a similar olfactory signature. Which doesn’t mean the other mouse in the enclosure is treated as a foe. It’s a mouse, after all. But other animals have their own olfactory signatures, and that’s another story.
Canto: And there are other forms of kin recognition. Get this – birds recognise their parents from the songs sung to them before they were hatched. Birds have distinctive songs, passed down from father to son, since its mostly the males that do the singing. And as you get to more complex species, such as primates – though maybe they’re not all as complex as some bird species – there might even be a bit of reasoning involved, or at least consciousness of what’s going on.
Jacinta: So that’s kin selection, but can’t we superior humans rise above that sort of thing? Australians marry Japanese, or have close friendships with Nigerians, at least sometimes.
Canto: Sometimes, and this is the point. Kinship selection is an important factor in shaping behaviour and relations, but it’s one of a multiple of factors, and they all have differential influences in different individuals. It’s just that such influences may go below the level of awareness, and being aware of the factors shaping our behaviour is always the key, if we want to understand ourselves and everyone else, human or non-human.
Jacinta: Good to stop there. As we’ve said, much of our understanding has come from reading Sapolsky’s Behave, because we’re old-fashioned types who still read books, but I’ve just discovered that there’s a whole series of lectures by Sapolsky, about 25, on human behaviour, which employs the same structure as the book (which is clearly based on the lectures), and is available on youtube here. So all that’s highly recommended, and we’ll be watching them.
References
R Sapolski, Behave: the biology of humans at our best and worst. Bodley Head, 2017
