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Development

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Slide 1Two linked themes for today:- Single-cell and multicellularorganisms, and the advantages in being multicellulardevelopment: how individual human life begins (as a single cell); how our development from single cell to fetus parallels some of the changes in evolution; similarities between embryos or fetuses of all vertebrate species; how organ systems develop

Slide 2 - ScaleHow many bacteria can sit on the point of a pin? Here is an electron micrograph of a standard domestic pin at several different magnifications. Bacteria are a fraction of a micrometre in length (a micrometre is a thousandth of a millimetre). Your cells are somewhat larger, with the largest being just visible with the naked eye.

Slide 3Introducing multicellular life. The main advantage to an organism in being multicellular is that it can control the environment of its cells, because the environment of each cell is the inside of the animal. This is the concept of the “internal environment” as first noted by Claude Bernard; multicellularorganisms keep their internal environment constant, as far as possible. They do this by specialisation of cell functions.

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Slide 4How did multicellular life originate? Which were the firstmulticellular organisms to specialise their cell functions? The simplest ones that survive today are sponges, which have several specialised types of cells including structural cells andchoanocytes, which have beating cilia which move water into the interior of the sponge so that the sponge can draw nutrients from the water.

Slide 5Wilson’s 1907 experiment referred to here consisted of passing a sponge through a sieve to separate it into single cells. When this was done, the cells spontaneously re-assembled into a new sponge. In doing this, they first went through a stage in which they were no longer specialised (de-differentiation). Each cell in a sponge is able to re-create a whole sponge, i.e. they are all germ cells. In contrast, most of our body cells (somatic cells) have irreversibly differentiated into their specialised types. Only a few cells in our body have the potential to create a new person: these are our germ cells, either sperm or egg cells.

Slide 6Differentiation in our bodies produces many different cell types and these are organised on many levels. Cell types (2) are organised into tissues (3), and several tissues make up each organ (4). Organs assemble into systems (5), each with a particular role in maintaining the constancy of the internal environment. The systems level of organisation is the most useful for our understanding of physiology. It is one level below the whole person (6).

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Slide 7Developmental biology is one of the most exciting and productive fields in modern biology. It concerns itself with how a single-celled embryo develops into an adult. This is the story of differentiation, how cells change from undifferentiated embryonic stem cells into the cell types characteristic of each tissue and organ system.Much of this work is being done in organisms that are much simpler than we are. These “model organisms” include simple vertebrates and invertebrates. One might wonder what relevance these have to humans: humans and mice are after all quite easy to tell apart.

Slide 8However, at the early embryo stage, all vertebrates look more or less alike. This observation, first made by Haeckel (see picture), indicates that many developmental pathways are shared. Some are shared in surprising ways. For instance, a major gene that controls eye formation in Drosophila is very similar to a gene with similar function in humans: this is surprising, not only because our eyes are so different and our common ancestor lived at least 500 million years ago, but even more so because that ancestor probably didn’t have eyes! (the answer to this surprising problem might be that the gene originally controlled a rudimentary light-sensitive structure that evolved to become the very different eyes of insects and mammals)

Slide 9The two questions each cell has to “ask itself” are:•where am I in the organism? and•what should I do now that I am here?Developmental biologists are finding the signals that answer these two questions.In general terms:•location is specified by gradients, often of some diffusible substance (e.g. moreretinoic acid is found in proximal than in distal regions)•cells respond by switching on and off the appropriate genes corresponding to the location they are in.

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Slide 10The most important theme of this lecture is your own development: how does a human baby form from the initial components, an egg cell and a a sperm cell?The first step is fertilisation. One sperm enters the egg; at that moment a reaction of the egg (see Seeley if you want the details) prevents any other sperm from entering. The sperm and egg nuclei are the male and female pronuclei and these fuse to become the nucleus of the fertilised egg.

Slides 11/12Expanding on slide 10:

The male and female pronuclei each contain 23 chromosomes. including an X (female pronucleus) and either an X or a Y (male pronucleus). The nucleus, after fusion, thus contains 46 chromosomes in 23 pairs; one pair is either XX (the fetuswill develop female) or XY (the fetus will develop male).

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Slide 13After fertilisation, the egg divides; each division takes about a day. The slide shows embryos at the one, two, four and eight-cell stage.

Slide 14The processes shown in the previous slides happen as the egg makes its journey from the ovary towards the uterus. Fertilisation happens towards the top end of the Fallopian tube. The embryo divides on its way down the Fallopian tube, and implants (see slide 20) when it has already divided several times

Slide 15Implantation is an active burrowing of the embryo into the lining of the womb (theendometrium). Nutrients are absorbed in a way that does not differ greatly from the nutrition of a single-celled organism. This is the stage oftrophoblastic nutritionwhich lasts for about 10-12 weeks.

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Slide 16Introduces the next major stage in embryonic development, which is in many ways the most important: the point where the embryo becomes larger and develops recognisable structures which will become its organ systems. It is no longer feasible to get nutrition by simple diffusion and here the circulation becomes essential. The embryo thus makes the transition from a relatively undifferentiated group of cells, surviving by diffusion, into amulticellular organism made up of specialised systems working together to ensure the survival of the whole.

Slide 17The formation of the embryonic disk at this time immediately precedes the development of the first structures. The disk divides two fluid compartments: the yolk sac and the amniotic sac. These names are important, especially the latter: sampling of amniotic fluid (amniocentesis) is one of the approaches used in pre-natal diagnosis of inherited disease.

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Slide 18One of the first recognisable structures is the primitive streak. This runs across the embryonic disk. It will become the nervous system (see following slides).

Slide 19The primitive streak becomes the neural tube, by forming a fold then joining the edges of the fold. The tube closes over first in the middle then at the two ends. Note that closure is at an advanced stage 20 days after fertilisation, one of the earliest processes in development.

Slide 20Sometimes the closure is not complete at the distal end, and then spina bifidaresults.

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Slide 21The digestive system also forms as a fold which becomes a tube. The tube is closed somewhat later than the neural tube, by about 30 days.

Slide 22The face develops later still. Note the structures that must join, and where they join. Failure to join properly causes cleft lip or cleft palate, either of which will cause speech problems.

Slide 23Summary of the phases of development. Note that the nervous system begins to develop before the others and continues to develop longer than any other system.An important message here concerns the effects of teratogens in the environment. In the first two weeks, the embryo is highly vulnerable and likely to die as a result of exposure to any toxic chemical. However the mother may not be aware she is pregnant at that stage. The period of greatest practical danger in terms ofteratogen exposure is from 2-12 weeks, because that is when the major organ systems are developing. Exposure in this period may not kill the embryo, but may well cause malformation in one or other organ system (or limb malformation). Later in pregnancy, the fetus is gradually less and less vulnerable.

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Slide 24As the embryo develops, trophoblasticnutrition is no longer adequate to supply its needs. At about 10-12 weeks the placenta takes over nutrition.

Slide 25A reminder of slide 21 on implantation. The structures that will form the placenta are already in place during trophoblasticnutrition (see also next slide)

Slide 26Early stages in placenta formation. Maternal blood vessels approach thetrophoblast, while embryonic blood vessels are also forming and approaching the interface with the mother. Thesyncytiotrophoblast is the barrier, anacellular layer which is also not antigenic i.e. it doesn’t produce an immune reaction in the mother. This barrier remains in the placenta.

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Slide 27Fully formed placenta. Chorionic villicarrying fetal blood push into the placenta and are surrounded by maternal blood; thesyncytiotrophoblast is still present and still forms the effective barrier between mother and fetus. The chorionic villicontain fetal blood vessels which pick up nutrients and oxygen from the mother into the fetal blood, and release waste products from the fetal blood into the mother’s circulation. The placenta is connected to the fetus by the umbilical cord, which contains fetal blood.

Slide 28Formation of the heart. Clearly there has to be a pump for the fetal circulation, developing at about the same time as the placenta. Initially the pump is a simple thickening of the muscle around the aorta (20 days) but shortly after that the recognisable shape of the heart is present (35 days). Importantly, at that stage, there is no division between the two sides. Before birth, the ventricular septum closes to complete the separation between the two ventricles. If this does not happen, the resulting ventricular septal defect (“hole in the heart” will cause disability if not corrected. Surgical correction of ventricular septal defect is now a well-established procedure. At birth, there is still a functional connection between the left and right atria (the foramen ovale; see later).

Slide 29Stimuli for birth come to a large extent from the fetus itself: stress caused by lack of space is an important factor. This stress is increased by the rhythmic contractions of the uterus, and cervical dilatation caused by pressure of the fetus’s head provides an additional stimulus increasing uterine contractions.

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Slide 30The circulation changes profoundly immediately after birth. The changes are not obvious on this diagram from Seeley (see the red boxes; before birth on the left, after birth on the right). The lower slides from another textbook show the changes more clearly.

Slides 31 and 32Before birth (31) and after (32).

Before birth, blood flows from right atrium to left atrium through the foramenovale, and bypasses the lungs through theductus arteriosus. The lungs are collapsed and full of amniotic fluid. The numbers represent the percentage of blood that flows through each pathway. Note the small amount going into the right atrium, and the small fraction of that which goes into the lungs. Most of the blood flows around the systemic circulation and especially the placenta.

After birth, the placenta is no longer present, and the two connecting pathways (foramen ovale and ductus arteriosus) close up. Now, all the blood entering the right atrium flows into the right ventricle, and none of it into the left atrium. All the blood coming out of the right ventricle now flows into the lungs. The right and left half of the circulation are now completely separate and blood flows through one then the other.

See also next slide (taken from lecture 6). Lecture 6 will have more on the circulation.

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Slide 33Adult layout of the circulation. Note that blood flows sequentially through the four regions shown.

Slide 34Corresponding to the major change in the circulation, with blood flowing through the lungs for the first time, we also have the first breath: air enters the lungs for the first time. The force required to get this air in is enormous, far greater than any other breath of our lives. This is because the lungs are filled with fluid; introducing air into them produces a surface (air/fluid interface), and we have to pull against surface tension to get air in. Note the great suction that must be applied (-40 mmHg) before the lungs even begin to expand.

Slide 35Health of newborns is assessed using theApgar score. Named after Virginia Apgarwho introduced it, but her name is also a useful mnemonic for the five aspects of newborn health that are assessed. You can find more on the Apgar score in the Best & Bee textbook as well as in Seeley. It’s important to have a clear idea of what is measured and why it tells us about the baby’s health. In brief, the measures either tell us about the adequacy of oxygen supply (appearance/pulse/respiration) or about nervous system function (grimace/activity).

Slide 36Definition of prematurity. Prematurity has many consequences, and the earlier a child is born, the more serious the problems are likely to be. The problems are caused by immaturity of multiple organs.The most serious and life-thresteningconsequence of moderate degrees ofprematurity is respiratory distress syndrome. This will be explained further once I’ve explained about the respiratory system in a couple of weeks.

Suggested readingThe Boyd & Bee suggestion is intended if you want to read more deeply into early development. It is a very nice, readable book that contributed a number of the slides used today, but the essential material is already in the Seeley series textbooks.