12 Genes, environment and their interactions (i.e. heterozygous) both gene products may be formed or the abnormal may inhibit the production of the normal. Between genes are large portions of DNA that do not actively code for proteins. Some parts of this are the site where molecules called transcription factors bind with DNA to signal to a gene whether it should be activated or not. Within genes there are also portions of active (exonic) and inactive (intronic) transcribable DNA that offer further complexity in regulation and allow one gene to code for more than one protein. DNA is packaged in chromosomes. In multi-cellular organisms there are two copies of each chromosome, except the sex chromosomes, in each mature cell, and one copy in the gametes. In species that use chromosomes for sexual determination (birds and mammals), in one gender (females in mammals, males in birds) the two sex chromosomes are identical, and in the other gender there are two different sex chromosomes (X and Y chromosomes in mammals) in each non-gamete cell. There are only about 35 000 genes in the human genome – but 35 000 protein switches are not in themselves enough to regulate the complex range of body func- tions that need to be regulated, particularly if they are just on/off switches. The complexity is created in a number of ways. Firstly, while there may be only 35 000 genes, there are various mechanisms to switch on or off part of the alphabet within agene (generally called splicing variants) so as to produce more than one pep- tide from a gene. Secondly, transcription factors not only turn a gene on or off, but can regulate the degree to which it is turned on (i.e. expressed) or turned off. 9 Thirdly, after the protein is made, theintracellular machinery may lead to enzymatic processing, breaking it up into smaller bits or leading to addition or subtraction of phosphate groups (which is a way in which molecules transfer energy) or by addition of sugar moieties to the protein. These latter processes are called post- translational (i.e. occurring after the translation of the genetic code) modifications and lead to a very large number of possible proteins. It is this complex orchestra of processes – translational and post-translational – that leads to the complexity of biological processes in the human body. Variations in genotype There is much variation in the individual genome (i.e. genotype) and it is this variation that is the genetic basis of our differences in function and appearance. For 9 Forexample, while every cell has the gene for making insulin, it is only in the cells of the pancreatic islet that transcription factors act to turn the gene for insulin on. These transcription factors in turn are regulated by other transcription factors and by information coming from other cells near by or far away. In the case of the insulin-making cells of the pancreas, the transcription factors telling the cell to synthesise insulin were turned on at a critical point in development and from that point on the cells were activated to make insulin; non-islet cells were inactivated from making insulin. But throughout life other transcription factors, activated by high-or low-sugar levels and by hormones, continue to modulate the rate of insulin production and secretion by the islet cells. 13 Variations in genotype example, the genotype of a Bantu and of an Icelander are different in the genetically determined expression of genes that determine the amount of melanin present in skin. Both genomes can make melanin – otherwise the Icelander could never get a tan when he or she went on holiday to Tenerife – but under normal conditions the amount of melanin in the skin cells is very different and this is genetically determined. Another example is the genes coding for cell-surface proteins on blood cells, which are detected in blood typing. Siblings may be similar in many respects but have different blood groups, depending on the parental blood groups. These differences are due to differences in the genetic code in the genes responsible for the blood group antigens of the two individuals. The most common cause of genetic differences is a change in a single nucleotide in a gene. In some cases this sequence change causes overt disease. For example, in the case of phenylketonuria (PKU), a single change in the nucleotide sequence of one particular gene causes a change in the amino acid sequence of an enzyme that normally metabolises phenylalanine. As a result, toxic levels of phenylalanine build up in the infant’s body when he or she eats protein foods, and these toxic levels cause brain damage. 10 In many cases of individual genotypes for which single nucleotide changes have been found, there is little or no obvious functional significance of the change. 11 The different consequences of a single nucleotide change occur because achange in nucleotide may or may not lead to a change in the amino acid encoded: there is considerable redundancy in the genetic code, 12 and the amino acid change may not change the function of the protein. When the genetic change leads to an obvious change in function or appearance we term it a mutation. When the change is very subtle it is called a polymorphism. 13 Most polymorphisms are of no fundamental consequence. The large number of polymorphisms provide the basis of DNA-fingerprinting used by the police. How- ever, while polymorphisms do not necessarily cause disease they can influence the amount of a protein secreted, or the action of a protein. For example, milk pro- duction in dairy cows is stimulated by growth hormone, and the different milk 10 This is a very risky but treatable situation and it is why all newborn babies are screened for PKU by the heel-prick Guthrie test. 11 Such single point changes in sequence are often called SNPs (single nucleotide polymorphisms and pronounced as “snips”). 12 Forexample, both GGU and GGC code for the amino acid glycine so there is absolutely no difference in the functional outcome of a code reading GGU or GGC. On the other hand UGC codes for cysteine and UGG codes for tryptophan, so the protein readout for the one change (C to G) in the nucleotide can lead toachange in the amino acid sequence of the protein. 13 Mutations and polymorphisms are essentially overlapping terms. By custom, when the genetic change leads to overt disease it is called a mutation, when it merely leads to a non-obvious biochemical change, it is called a polymorphism. As we get better at genetic diagnosis we are finding that the definitions are not that easy to keep separate. Mutations also involve a broader range of genetic defects including deletions of pieces of DNAandDNAchanges that leadto premature stopping oftranscription etc.Both polymorphisms and mutations can involve alterations in single-base pairs or in the length of repeating pieces of DNA. 14 Genes, environment and their interactions production in two breeds of dairy cow is caused by a polymorphism in the growth- hormone receptor. This polymorphism is thus very valuable. The element of chance Sperm and eggs (ova) only have one copy of each autosome and one sex chro- mosome. At fertilisation the egg and sperm fuse to create a one-cell embryo containing – in humans – 46 chromosomes, which then has the capacity to develop fully into a mature human being. It is the mixing of genetic material at fertilisa- tion,aprocesstermedrecombination, that is central to the process of maintaining mammalian diversity and thus is crucial to evolution. 14 It provides one chance ele- ment in the evolutionary process, somewhat like shuffling the cards. The other is genetic drift. 15 This inter-generationally driven variation in genetic mix is the basis of variation on which evolutionary selective processes operate. Chromosomes line up in matched pairs during cell division in the cells that will form the egg or sperm. This lining up has the prime purpose of ensuring that the right number and the complete portfolio of chromosomes end up in each cell. Obviously one copy of each chromosome and one X chromosome must end up in each egg. The same happens in each sperm, except that there can be either an X or a Y chromosome present. Thus the correct and complete repertoire of 46 chromosomes forms the fertilised egg. If the individual has three copies of one chromosome, profound developmental abnormalities can occur – for example, many cases of Down’s syndrome are due to the fertilised egg having three copies of chromosome 21. Most abnormalities of chromosome number are fatal to the development of the embryo – the exceptions generally involve the sex chromosomes but abnormality of number always has phenotypic effects. 16 But this lining up has a second purpose: it allows genetic recombination by one-to-one swapping of genes between the two chromosomes of different parental origin, without losing the 14 Notall species reproduce in every generation in this sexual way in which genes from mother and father are mixed. For example, bacteria can reproduce by splitting in half – so that each daughter bac- terium is identical to its parent; as well as by sexual reproduction. The processes of reproduction across species and, in particular, in microbes and other single-cell organisms is fascinating but beyond this book. 15 Genetic drift is a concept largely outside the focus of this book. It is the process by which, in populations over time, the mean frequency of various alleles may shift by random chance. The rate of genetic drift depends on the population size (greatest when it is smallest), generation length (greatest when it is short) and litter size (greatest when small). Genetic drift arises because, particularly in small populations with low reproduction per generation, not all alleles pass by chance in equal proportion from one generation to the next. Thus over time some rarer alleles may get lost or in some cases, if carried by a dominant male for example, magnified. 16 Forexample, a person with 45 chromosomes with only one X chromosome has Turner’s Syndrome – the person is an infertile female with inactive ovaries and a number of skeletal and tissue abnormalities. 15 The element of chance integrity of the full repertoire of genes. 17 Thus the variation in gene sequence can change from generation to generation. This is the power of recombination – it ensures ongoing variation in the phe- notype of each generation of the organism, but still complete functionality and integrity of the species. It is this variation created by polymorphism that is the infrastructure on which Darwinian selection occurs within a species. As we are learning, if the genotype varies between individuals then the nature of the gene– environment interaction can also vary across individuals for any given environ- mental stimulus. From genotype to phenotype We have already introduced the concept that genetic determinants alone do not generate the phenotype – there are important environmental influences. Through- out this book we will use the term ‘environment’ in a somewhat broader sense than its most obvious and traditional usage. The environment of an organism is the sum total of all factors that can affect the organism – we can call this the macro-environment. For example the amount and type of food available is an environmental factor, a high likelihood of predators in the neighbourhood creates a risk/stress environment etc. For a given cell, the micro-environment is determined by the concentrations of sugar and oxygen and other nutrients in the blood stream and the tissue space surrounding the cell. The cellular envi- ronment is further determined by the cells lying next to it – for example, a liver cell lying immediately next to a blood vessel has a different environment from a liver cell surrounded by other liver cells. The fetal environment, as we shall see in chapter 4, is largely determined by the function of the placenta, and in turn by the mother’s physiological function, which is in turn determined in part by her macro- environment. This book is about how and when the environment acts on the genome to lead to specific phenotypes, and how these processes generate health or disease. A major thesis of the book is that the most important of these interactions operate at the 17 Imagine two teams of rugby players wearing different uniforms but each in numbers from 1 to 15 according to their playing position. Each team is to swap two players with the other team and the swap occurs with the person lined up opposite. If the two number 9s and two number 15s changed, there still would be two complete teams each with one half back (number 9) and one fullback (number 15). Each could go off and play a good game of rugby. But if the teams did not line up properly at the start, then the number 15 in one team might have swapped with the number 9 in the other team, so that after swapping neither team would be fully functional. Recombination is this process of swapping when lined up correctly. Imagine the same exercise of aligned recombination going on after every game in a league. By the end of the season every team would still be an intact rugby team of 15 players covering every position but the membership of the teams would be very different. By chance, some teams may be very strong and some very weak but most would be of rather similar capability. 16 Genes, environment and their interactions earliest stages of life and that we have grossly underestimated the importance of these interactions. Disease and genes Few diseases are purely genetic. In those that are, the chromosome is abnormal or an important gene is critically disrupted in a major way. Down’s syndrome (trisomy 21) is an abnormality of chromosome 21: this can happen in two ways but in each case the critical feature is that there are three copies instead of two of some genes that are located on chromosome 21. One of these ways – carrying three copies of the chromosome 21 (usually two from mother and one from father) is greatly increased in mothers over 35, and this knowledge is important in reducing the risk of having a baby with Down’s syndrome. Other diseases are due to an abnormality of a single gene – for example, cystic fibrosis. This is a fatal disease in which the lungs and pancreas are particularly affected by very thick secretions of mucus. It occurs if both copies of the gene for a protein-channel within the cell wall that moves chloride between the outside and inside of the cell are abnormal. If one copy of the gene is normal, then so is the subject; if both copies are abnormal owing to a mutation (not necessarily the same mutation), then the disease is manifest. This is an example of an autosomal recessive genetic disease – i.e. the autosomes (chromosomes that are not the sex chromosomes) are involved; it is termed recessive because both genes (i.e. one from each parent) must be affected for disease to be present. Some diseases are dominant, in which case even if one allele is normal, it cannot block the devastating effect of the partner’s abnormal gene. An example of this is Huntington’s disease, which either affected parent has a 50 per cent chance of passing on to his or her progeny because disease arises if one copy of the paired alleles is abnormal at the relevant gene locus. Huntington’s disease is caused by a mutation in a section of a gene that codes for a protein in the brain, and this changes the number of repeats of the sequencethatcodes forglutamine. This leads toanabnormalformoftheprotein, particularly in part of the brain known as the basal ganglia and in the cerebral cortex.Itstimulates brain-cell degeneration in adult life and leads to a tragic and irreversible decline into dementia, movement disorder and death. 18 Each of these examples – trisomy 21, Huntington’s disease and cystic fibrosis – is a disease where destiny is cast from the point of conception and nothing that happens later will change it. 18 Huntington’s disease illustrates other points relevant to this book. Because the disease does not manifest until after reproductive age, there isno selection (other than conscious cultural/social selection) againstthe defective gene. While both parents can pass on the Huntington’s mutation, with a 50 per cent probability, children who inherit the gene from their father are more likely to get the disease earlier than if they inherit the gene from their mother. This demonstrates a degree of imprinting of the Huntington allele (for explanation see chapter 2). The Huntington-disease gene is found on chromosome 4 and the mutation is due to an insert of extra repeats of the nucleotide sequence CAG (which codes for glutamine) into a normal brain protein, making it abnormal. 17 The element of chance Environment, genes and disease However, most disease is not simply genetic, even if it has a genetic component. Most often, genetic make-up creates an altered risk or propensity for a disease, but it requires environmentalfactors to comeintoplayfor the disease to be exhibited.Even so-called purely genetic diseases can have an environmental component. For exam- ple, the most common genetic abnormality in the world is glucose-6-phosphate- dehydrogenase (or G6PD) deficiency. It is estimated that G6PD deficiency afflicts some 400 million people, particularly those of African, Mediterranean or Asian ancestry, but it does occur in about 1 in 1000 Northern Europeans. The disease is caused by an abnormality on the X chromosome in the gene coding for the enzyme G6PD. If you are female then both copies must be abnormal to produce the dis- ease. If you are male then you only have one X chromosome and so you cannot be protected from the disease by having a normal copy on the other chromosome, unlike in the female. This pattern of disease is called ‘recessive sex linked’, and other examples are haemophilia and red–green colour blindness. The enzyme G6PD is present in all cells but is particularly important in blood cells where it is essen- tial for making glutathione; this is one of the molecules we endogenously use as an antioxidant. 19 Depending on the precise mutation, the vast majority of peo- ple with G6PD deficiency have no symptoms unless certain environmental factors occur. If the individual with the mutation eats fava beans or is given a particular anti-malarial drug called primaquine, then the red blood cells break down and there is a severe attack of haemolytic anaemia 20 with multiple and sometimes fatal consequences. The point we are making is that G6PD deficiency is a genetic disease in which nothing usually happens unless there is an environmental trigger – the disease phenotype is precipitated by a specific interaction between the environment (e.g. fava beans) and the genotype (the faulty G6PD gene). This is a dramatic example of what is likely to be the most common way in which genetic factors predispose to disease – they change the way in which environmental factors impact on the function of the body. Genes have been related to many common diseases such as diabetes and heart disease. Usuallythereare multiple genes involvedand the genes are not in themselves causal. They create a risk situation in which a particular set of genetically determined changes in body function, together with environmental factors, creates disease. For example, many genes are known to alter the sensitivity of the body to insulin – but except in one or two very rare mutations, single-gene defects or changes do 19 Antioxidants scavenge the small amounts of highly negatively charged oxygen produced as a by-product of normal metabolism. This charged oxygen is highly toxic, and if it accumulates leads to too much oxygenation of fats and proteins and to cell death. 20 In haemolytic anaemia the red blood cells, which carry oxygen through the body, rupture. 18 Genes, environment and their interactions not actually cause ‘Type 2’ diabetes. 21 Instead, polymorphisms or mutations in the many components of the cell machinery affect the sensitivity of a cell to insulin. Generally the disease phenotype will not be exhibited, irrespective of genotype, without an environmental factor acting. For example, a high-fat and carbohydrate diet, obesity (which by stretching fat cells makes them more insulin resistant) and alack of exercise induce the appearance of diabetes. The genotype merely changes the sensitivity to the environmental interaction. As we shall see in chapter 4, the diabetes story is highly relevant as it is now clear that predictive adaptive responses play an important role in determining the sensitivity of this interaction. Phenotypes clearly affect the disease risks for an individual organism: the rabbit with short ears is at greater risk of overheating in a warm environment; short people appear to be at greater risk of heart disease; people with truncal obesity are at greater risk of diabetes. But phenotype can also confer benefits: tall people are more likely to get better jobs; lions with longer manes are more likely to be sexually dominant and attractive to the lioness; the bower bird with the most impressive dance and the most impressive collection of objects is more likely to attract a mate; the peacock with the longest tail is more likely to attract a mate; and being thin, not smoking and being physically fit reduces the risk of heart disease and diabetes. Some diseases are obviously environmentally determined and depend on a single environmental effect, but even in these there are variations – for example, thyroid cancer was markedly increased in people close to Chernobyl because severe irradia- tion causes cancerous changes in thyroid cells. But not every individual exposed to the same level of radiation got cancer – some other factors, perhaps environmental, perhaps genetic, changed the sensitivity of the individuals to the same environ- mental stress. Similarly, food poisoning is almost purely environmental but there may be individual variations in the degree of susceptibility to the infection or in response to the toxins. Conversely, some diseases are predominantly genetic – for example, thalassaemia or cystic fibrosis – but the disease course in such illnesses is influenced by the individual’s external and internal environment. So not every one who is obese gets diabetes, not everyone who is short gets heart disease, not everyone who smokes gets lung cancer, just as only those with a 21 Type 2 diabetes mellitus is caused by insulin resistance. Type 1 diabetes is caused by insulin deficiency. Insulin is a hormone secreted by the pancreas into the circulation. It acts to reduce blood glucose by actions on fat cells, liver cells and muscle cells – which, under insulin stimulation, turn glucose into fat and incorporate it into muscle and liver, where the glucose is stored as glycogen. Insulin acts on cells by binding to receptors. Receptors for hormones are proteins either on the cell surface (in the case of insulin and other protein hormones) or inside the cells (in the case of steroid hormones) – they are equivalent to alockandkeywherethe hormone is the key and the receptor is the lock. Just as the lock only works with the key in it, the receptor is only activated by the hormone binding to it. This starts a train of intracellular events that ends in altered gene transcription. Insulin resistance can be relative or absolute but is the phenomenon whereby for a given amount of insulin, less activity in terms of metabolic or other actions is seen. Insulin resistance can be caused by faults anywhere along the pathway of insulin action. 19 How the environment influences phenotype particular genetic make-up will have an adverse reaction to eating fava beans. Yet, some thin and fit non-smokers have heart attacks. What is going on? How can we explain this complexity? While much of this variation has been rightly explained by genetic polymorphisms, it is now clear that earlier environmental influences can have an echo throughout life. This is the dominant theme of our book. How the environment influences phenotype We have seen that the genotype is determined when the conceptus is formed, and both genotype and phenotype determine the propensity to disease. It thus follows that gene–environment interactions that determine phenotype must be critical elements in determining the destiny of an individual. Indeed that is the basis of evolutionary processes. 22 The Darwinian framework, which has stood the test of time, involved several key ideas. First, species are adapted to the environments in which they live. Because of genetic variation (although Darwin did not know about genes, he had the key idea), somespecieswouldbemore suitedforoneenvironmentandothersless.Those that were more suited would survive and be able to reproduce (natural selection). Gradual changes would make the species more likely to survive comfortably in a specific ecological niche and the appearanceofthe species would thus gradually change. The famous example of natural selection wasthe finches of the Galapagos Islands. They led Darwin to recognise that some beak shapes were better suited to certain food sources in the different environmental niches across the islands. Darwin recog- nised that if there were genetic variation in the determinants of beak shape, then over time those better-nourished birds having the right beak shape would be more likely to survive. We could predict that their genes would come to dominate in the gene pool. Over time all the birds would end up with the optimal beak shape. Te c hnically, naturalselectioncan be defined as an altered frequencyof a particular genetic allele in a given population. At the point at which the diversity in the gene 22 Evolution was an idea that developed quite quickly. It was not just one person’s idea – several thinkers and scientists including Darwin’s grandfather,Erasmus, had started to grapple with theideas of geological time, changing environments, the fossil record, and the stability of species. These had created real challenges to the then dominant, purely theological model of creation. In the 1830s and 1840s Darwin gradually formulated his ideas of the processes that drive evolution. They were based in part on the climate of thinking and the impact of Malthus, in part from observations made on the relationship between fossils in aregion and the current species found in the same region, and in part through his studies on geographical isolates such as the species found in the Galapagos. These ideas, while known to the cogniscenti, remained largely unknown to the public for nearly 20 years. Then Alfred Wallace, Darwin’s contemporary and friend, in writing to him in 1858 showed that he had essentially developed a similar set of ideas. Darwin was spurred to publication–abehaviour not unfamiliar to modern scientists! Both of these thinkers, by marrying experimental observation with some brilliant insights, expounded a complete theory in what was the most critical and compelling paradigm shift that has ever occurred in biological thought. 20 Genes, environment and their interactions pool was such that the paternal and maternal chromosomes from newly evolved variants could not align properly to allow cell division and gamete formation with the other variants, then a new species would have emerged. 23 Darwin recognised that there was another form of selection, which we now call sexual selection. As selection is essentially all about preferential passage of one’s genes, then genetically determined characteristics that make that more likely to happen will be selected. Thus the male lion’s mane evolved because a long mane was meant to show the female that a particular male was stronger and thus his progeny were more likely to survive. One theory is that the mane is heavy and, like a thick scarf in a warm climate, having a long mane was presumably meant to illustrate to the female that the male was sufficiently strong to put up with such impediments. Indeed there are good scientific data that male lions with long manes are more likely to survive and have fewer injuries. But more importantly, for whatever reason, females were more willing to mate with male lions who had genes that somehow code for longer manes, and thus over time all male lions came to have longer manes. The same argument has been used to suggest why peacocks have developed long heavy useless tails, which presumably make flying more energy sapping. It is interesting to speculate which attributes in male and female humans might have originated in a similar way! So evolution can be defined as the process by which genetic characteristics that have been selected as being advantageous are amplified by mating advantage, cre- ated either by greater survivability or by sexual attraction. But the environmental factors are both physical (e.g. food supply) and social (e.g. attractiveness to the other gender). Selection is, at one level, an example of the genotype–environment interaction leading over generations to an altered phenotype. At another level it can be seen as the process by which a species manages to adapt to an environmental change. Presumably the finch with the curved beak evolved because its ancestors flew to a new environment with a food supply which had changed from one that was easy to eat with a straight beak to one easier to eat with a curved beak; or maybe the birds did not move but the food supply changed because of some environmental change. Either way, gene pool survival in the face of an environmental change is made possible by the process of evolution. Much of the latter part of this book will be concerned with the speed, direc- tion and permanency of environmental change. The time-base of the response also varies greatly. For example, when we get overheated we sweat. This is a normal physiological response to an acute environmental change and is an example of homeostasis, the minute-by-minute changes in body function we make to the myr- iad of environmental influences to which we are exposed. At the other extreme are 23 Species definition remains a complex and controversial topic, but it is not one for this book. 21 How the environment influences phenotype the adaptations brought about by Darwinian processes, which lead essentially to permanent changes in phenotype and which enhance reproductive fitness. These are the true adaptations 24 – for example, the altered beak shapes of finches. Interme- diate between these are changes that are induced during development by environ- mental influences. But all these responses have an immediacy in that the response is obviously and immediately advantageously linked to the concurrent environmen- tal selection. 25 Alternatively it is possible that the environmental response has no immediate advantage but has its advantage at some later time. The changed coat thickness of the meadow vole had no advantage to the fetus but clearly only has advantage later in life – as we will see this is the central characteristic of a predictive adaptive response. Environmental changecanobviously be permanent or transient, acute orchronic, and the implications of these differences will become obvious. If the change is very rapid and large and there is no phenotypic variation, then species extinction is likely if homeostatic mechanisms cannot cope. But if the environmentalchange is gradual, or ifthepossibility ofsurvival of the lessfitisrealistic,thentheenvironmentalimpact on the species may be very different. Darwinian selection is based on the inherent presence of variation, and on the presumption of some advantage of one phenotype over another; in addition, there must be a genetic heritable element to the origin of the phenotype that confers advantage. But short-term catastrophic environmental changes do happen. Asteroid impacts created the equivalent of nuclear winters overnight and are thought to have led to the extinction of the dinosaurs. But not all species died out in those catastrophic periods – for example, proto-mammals survived. Similarly many species are faced with changes in food supply as a result of drought or flood or other transient environmental change. For a species to survive this kind of transient and remote environmental change it cannot rely on evolution, because evolution acts over many generations to produce a significant phenotypic change. As we shall see, predictive adaptive responses are a non-genomic mechanism that can be used. Through them, a mother can inform her fetus of a future adverse environment; the fetus makes a phenotypic change that is adaptive for the predicted environment and thus survives to reproduce. 24 Adaptation is a word that causes some problems and confusion. In common parlance adaptation is a response to the environment that has immediate advantage. However, part of this book is about evolution, and in evolutionary biology adaptation has a particular meaning – the advantage must be demonstrated in terms of an improvement in reproductive performance (i.e. fitness). By and large we have avoided the common use of the word and tried to stick to the evolutionary definition. Certainly this is the case in any section concerned with evolutionary biology. But to make things easier for the reader, occasionally, as here, we have used it in its more commonly understood sense. Hopefully there will be no confusion to either lay or technical readers! 25 Homeostasis is another form of immediate response to the environment, but acting over a very short time base. [...]... describe the basic processes of development The timetable of development The word development means different things to different people, including scientists To the embryologist, it implies the processes of laying down the key components of the body – the genesis of the limbs, the primitive brain and the internal organs such as the heart and gut The genetic code for these processes, and the ways... through Asia and Europe a million years earlier but eventually died out 28 Mother and fetus A C D Fig 2. 1 B E F Early embryo development The first division of the fertilised egg gives rise to two cells (A) which divide to four cells (B) and divide again (C) to eight cells (D), and so on At the 3 2- cell stage (E) the cells of the inner cell mass which will form the embryo are at the bottom, with the blastocoele... uterus into the mother’s blood vessels supplying the uterine wall By 12 to 14 weeks the placenta is fully functional and mature It is important to note that maternal and 33 The fetal environment fetal blood are never in direct contact Nutrients from the mother, such as oxygen and glucose, must leave the maternal blood vessels, enter placental tissue, and then pass through this tissue into the fetal blood... (placental lactogen and placental growth hormone) made by the placenta and secreted into the mother’s blood stream Fetal survival The placenta has a limited capacity to deliver oxygen, glucose and other nutrients to the fetus Furthermore the placenta itself is a major consumer of these two key fuels and can use between 40 and 60 per cent of the fuels extracted from the maternal circulation As the placenta... at the fetal tissues All these processes, and the potential problems that may arise with them, have to be borne in mind when considering fetal nutrition (Derived from Bloomfield and Harding: Fetal and Maternal Medicine Reviews, 1998.) to make large amounts of oestrogens from precursors produced by the fetus – so in a sense the fetus is telling the mother what to do The metabolic changes of the mother... evolutionary terms) that the mother survives so as to be able to reproduce in future If the mother were to die, the fetus would die and the mother’s gene line would not be preserved Thus there is a hierarchy of demand created and regulated through pregnancy If energy is limited, fetal growth is compromised first, followed by the placenta (which must function if the fetus is to survive) and the mother last In extreme... of the fetus in late gestation, as nutrients from the fetus are pulled back to support the placenta But there is another potential conflict – that of fetal growth and maternal pelvic size If the fetus can outgrow the maternal birth canal, then both mother and fetus will die in the associated obstructive labour (in the absence of medical intervention) Thus the mother must have mechanisms to limit fetal. .. Oxygen diffuses through the eggshell to that outgrowth Some non-mammalian species do give ‘live birth’ but in most of these cases the egg is merely incubated within a specialised organ in the mother and there is no nutritional connection between the mother and the egg The exception are some lizards and skinks in which a placenta forms by which nutrients pass from mother to the fetus This reptilian... to their structure and how many layers of membranes and tissues separate the maternal and fetal circulation But all placentae subserve the same functions – transferring nutrients to the fetus, extracting waste from the fetus, secreting hormones to alter maternal physiology to 29 The pre-implantation embryo The developing conceptus has by this stage travelled down the Fallopian tubes into the uterus The. .. the face of an inadequate fetal placental–maternal collaboration is not advantageous for the species and is a waste of resources in the short term Maternal fetal ‘conflicts’ From conception, the interests of the mother and her fetus11 are not always aligned The fetus and mother are not genetically identical because the fetal genome is an admixture of maternal and paternal genes These genetic differences . cell, the micro-environment is determined by the concentrations of sugar and oxygen and other nutrients in the blood stream and the tissue space surrounding the cell. The cellular envi- ronment. sci- entists. To the embryologist, it implies the processes of laying down the key com- ponents of the body – the genesis of the limbs, the primitive brain and the internal organs such as the. ways. They must all achieve the objectives of developing tissues, organs and control systems, and of fine-tuning this development in relation to 25 26 Mother and fetus the environment in which the