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00:00This is how I
00:29all animal life begins, in a single fertilised egg cell. This one is human.
00:39Over the next nine months, it will divide and multiply many times.
00:59The embryo will fold and grow.
01:06The developing child will undergo a series of dramatic changes in shape and size.
01:20The developing child will undergo a series of dramatic changes in shape and size.
01:35By the time the child is born, the single egg cell will have become many millions.
01:44From it will have come all the complex organs and structures of the body, all in the right places.
01:51And perhaps the biggest question facing biologists is, how?
02:04I think that the way animals develop, including humans, is probably the most exciting area of modern biology.
02:12Because it's absolutely remarkable that we, and all the animals we see around us, come from one single cell, the fertilised egg.
02:22And how all the information for making noses, eyes, teeth and so forth, is contained within that single cell,
02:29and somehow emerges during development, is a truly remarkable phenomenon.
02:34The first important ideas about how animals' development came, like so many other things, from Aristotle.
02:40Aristotle.
02:41He likened it to making a fishing net, that you started off just with the raw materials and then it was built up.
02:48And he actually thought it was the male semen working on the female menstrual blood.
02:53And he called this process epigenesis.
02:55Aristotle's idea, that the embryo developed gradually, held sway until the 17th century.
03:03And then there was the counter-idea put forward, that everything was preformed.
03:08That is, that the egg and the early embryo really was a tiny individual in miniature.
03:15And that all that happened during development was growth, expanding these preformed structures.
03:22And there was a tremendous battle between these opposing schools.
03:25But nothing was really resolved until the last century, when it became clear that embryos were made up of cells,
03:33and that Aristotle was really right.
03:35That embryos developed gradually, and although he was right, I don't think...
03:40I think he was right because he was lucky, rather than because he really understood what was happening.
03:44That embryos were made out of cells was no longer in doubt.
03:55But how could those cells organise themselves into something like a human being?
04:00The discovery by Francis Crick and James Watson of the structure of DNA paved the way for a revolution in biology.
04:17The beautiful structure of the double helix contains all the instructions needed to build a body.
04:23The information is held in strings of chemicals, genes.
04:30The genes hold a recipe for making other chemicals, proteins, the building blocks of cells.
04:37Every activity of a cell, the way it grows, divides, moves or changes character, is dictated by the genes.
04:45Our genes determine the shape of our chins and noses.
04:52The colour of our eyes and hair.
04:57The keenness of our hearing and the power of our brains.
05:03In fact, everything that makes us individuals.
05:11The way genes control cells is really curious in the sense that genes are really rather passive.
05:17They really just contain information.
05:19The real wizards of the cell are the proteins.
05:23Genes code for proteins.
05:26Proteins, what proteins the cells have, that determines how the cell behaves, largely.
05:31There are other influences.
05:33But it's really the proteins that really characterise cells.
05:37It's proteins that determine how a cell moves, what molecules it has on its surface,
05:42whether it will make hemoglobin in red blood cells and so forth.
05:54Development starts as soon as an egg cell is successfully penetrated by a single sperm.
06:01The sperm sheds its tail, leaving the head containing genes from the father.
06:10These mix with those of the mother stored in the nucleus of the egg.
06:15The fusion creates the genes for the next generation.
06:20A few hours after the nuclei have fused, the fertilised egg divides for the first time.
06:33Divisions continue to occur every 12 to 15 hours.
06:37Each new cell takes with it an exact copy of the genes of its parent cell.
06:41Genes control how the embryo develops.
06:55But there's a problem, because all cells have just the same set of genes.
07:00So, how do different cells arise?
07:04If we are to understand development, we need to follow that, or need to understand that rather tortuous pathway
07:12between how a particular gene or set of genes is turned on in one cell,
07:18leads to production of a particular set of proteins.
07:21Those proteins change cell behaviour.
07:24Those cells interact with their neighbours,
07:27and ultimately we end up with a nose or an eye or an arm.
07:30So, it's that tortuous pathway that we need to understand.
07:33Four or five days after fertilisation, the single cell has been propelled into the uterus and divided into more than 60.
07:43This is known as the blastocyst.
07:46At this stage, two distinct groups of cells have emerged.
07:50The outer layer attaches to the uterus wall,
07:53and contained within it is the tiny mass of cells from which the embryo proper will develop.
07:59Specific genes in these two regions have now become activated.
08:04They make a protein which acts as a kind of glue.
08:08So, development begins as a single fertilised cell,
08:11and that cell divides, and even from the very beginning you have two cells.
08:14Those two cells don't just float away from each other.
08:16They stay together. They divide again, so on and so forth.
08:19You get a clump of cells, ultimately a ball of cells.
08:22And right from the beginning you have the question of what's keeping those cells together?
08:25Why aren't they just floating apart?
08:27And not only what keeps them together, but what keeps them together as a very specific group of cells in specific orientation?
08:33And the answer is they're stick molecules, or glues, what we call cell adhesion molecules.
08:37Now imagine my hands are two cells. They bump into each other.
08:40Well, they bump in and bounce off.
08:42Except that there are molecules sticking out of these cells, these cell adhesion molecules.
08:46And they act much like a glue.
08:48In fact, you can think of them sort of as Velcro.
08:50That when two cells bump into each other, these things will lock onto each other and hold those cells together.
08:55Now, that keeps the two cells together, but something else has to happen.
08:59That the inside of the cell needs to know that the outside of the cell has bumped into an appropriate cell and has made some sort of contact, some sort of stickiness.
09:07And so there's also a part of these proteins that sticks inside the cell, in what we call the cytoplasm, and sends a signal to tell the inside of the cell,
09:14yes, I've bumped into the right cell, I've bumped into the right target, to make a decision.
09:19Either I'm going to stay stuck or it's time to move on.
09:22It's time to break that contact and crawl along and find another cell.
09:26The ability of cells to stick together goes some way to explaining how structures start to appear in the growing embryo.
09:35But just sticking together is not enough.
09:38It's vital that only the right sorts of cells accumulate into groups.
09:43To solve this problem, cell adhesion molecules can themselves change, altering their stickiness over time.
09:52The result is that cells can gather together or break away from each other, as and when needed.
10:01This selective stickiness guides the cells in the expanding blastocyst through their next moves.
10:10In the human embryo, once a blastocyst forms, those cells, that hollow ball of cells, has to make a decision.
10:16The cells make a decision among themselves what to become.
10:19It's believed, from guessing from our work in frogs and other organisms,
10:24that that decision involves dividing the cells up into three groups.
10:27The first group, the endoderm, would form principally the gut.
10:30The second group, the ectoderm, will form principally the skin,
10:34but can also form nervous system, if told to do so later on.
10:37And the third group, the mesoderm, forms the blood, the bone, the muscle, the kidney.
10:43We don't yet know if that's certain in human embryos, but it's a good guess that that's true.
10:49It's now thought that signals pass between cells in a process called induction.
10:55This means that a cell can change the way it develops in response to a signal received from a neighbour.
11:01Induction first occurs after about seven days, when the hollow ball of cells implants in the uterus.
11:08The uterus is stimulated to produce chemical signals.
11:11Among them are messengers that will activate certain genes in the cells.
11:16These genes tell cells which parts of the embryo they are destined to become.
11:21Chemical signals now probably pass along the embryo.
11:25The concentration would be highest around the cells nearest the head.
11:30Further away, the chemical will get weaker and weaker.
11:33Cells that are bathed in stronger concentrations of the chemical will make the right proteins to build the structures of the head.
11:40Cells exposed to a weaker signal will make the proteins needed to form the lower end.
11:46Those in between become in between.
11:49In the frog embryo, what we think happens is that the bottom portion of the embryo,
11:54the portion which will normally make just the gut, sends a signal, a peptide growth factor,
11:59to the overlying cells and changes the fate of those cells.
12:03The signal is not fully identified in that we know it's a kind of peptide growth factor,
12:08but whether it's one called an activin or another called an FGF or a third called a Wnt,
12:13we can't be absolutely certain yet.
12:15And it may be a conspiracy of the three, which tell the overlying cells now to become the mesoderm.
12:20Once that happens, then things really move quickly.
12:23These mesodermal cells now have been endowed with a new capacity,
12:27a capacity to move in a process called gastrulation.
12:31And then in addition, they can now start to form these new mesodermal body parts,
12:36the bone, the blood, the muscle.
12:42We don't understand how cells know when to produce the growth factor,
12:45but it could be a rather trivial timing mechanism,
12:48which is to say after the egg has been fertilized,
12:51the embryonic cells now begin to translate their messages and make the proteins,
12:57and that it's not strictly controlled,
12:59that they simply translate any available message.
13:02Another important aspect of this problem is the fact that not all of the cells contain the messages for these growth factors.
13:10Only some cells contain the messages and others don't.
13:13That's important because that means that the signal which changes the faith of cells
13:18is not presented throughout the embryo, but only in one portion.
13:22Because if it were presented throughout the embryo,
13:24then the whole embryo would become mesoderm, and that wouldn't be good either.
13:28We don't understand how a cell knows what signal it has received in terms of its quantity.
13:52And in fact, this cell which is receiving the signal may also contain information.
13:57In other words, the same concentration of an inducing molecule could tell cell A to become muscle,
14:03and cell B to become blood, because the responding cells have different information.
14:15Doug Melton has been able to prove the importance of growth factors
14:19by modifying the chemical environment of frog embryos during the early stages of development.
14:27A kind of experiment which can prove that a Wnt or an active end molecule can form the whole backbone,
14:35the head to tail part of the embryo, is to give the embryo an extra dose of it.
14:40We believe then that in normal development, the embryo has some active end or Wnt on one side,
14:46and that induces the mesoderm on that side to make the head to tail part of the embryo.
14:50But if by micro-injection we give it a second dose, and we can produce a whole second axis,
14:56a double-headed or a double head to tail embryo,
14:59that is good evidence that that molecule can do it normally.
15:03Although it was a chemical signal which produced these two-headed tadpoles,
15:09it was the animal's genes that provided the instructions for making the head.
15:18Until recently it was unknown which genes were responsible for which parts of development.
15:23But in the last few years, painstaking research has isolated a group of genes
15:28with a well-defined and vital function.
15:31They specify how the finished body will look.
15:34They're called homeobox genes.
15:38The homeobox genes contain a particular kind of DNA.
15:43Surprisingly, similar genes seem to be found in just about every animal.
15:47When the homeobox genes become active, they produce chemical signals
15:52which control the actions of many other genes.
15:56These other genes are the ones which specify how the body is put together.
16:02Homeobox genes exert such a powerful influence
16:05that they've even been called the master genes.
16:09Their discovery suddenly gave biologists powerful insights
16:12into how different parts of the embryo grow into head, body, arms and legs,
16:16in their proper places.
16:19In laying down the body plan,
16:22the cells have to be told which part of the body they're in,
16:25whether they're at the front end or the back end.
16:28And of course we don't know in detail how that happens.
16:31We don't really know in detail what signals are involved.
16:35But a really major advance has been to identify a set of genes,
16:39the so-called homeobox genes, originally identified in flies,
16:43which seem to act as labels giving the cells their position within the embryo.
16:51And so for example, depending on which homeobox gene is on,
16:55that will determine whether a particular group of cells is in the front of the brain
16:58or at the back of the brain.
17:00Or if you think of the limb,
17:02we know the different homeobox genes are expressed in different parts of the limb.
17:05And say for example, because there are different homeobox genes,
17:09in this part you'll make the little finger,
17:12whereas in this part you'll make the thumb.
17:14Homeobox genes are thought to be a kind of master control gene.
17:24Their expression, or when and where they're expressed in the embryo,
17:28is quite important because if they are not expressed in the embryo,
17:32they're not expressed in the embryo.
17:33Then the embryo doesn't know its front from its back, its top from its bottom.
17:37I'll give an example.
17:38In the frog embryo, if a homeobox gene is not expressed or present at high levels in the head,
17:43the head doesn't develop.
17:44Conversely, if it's not expressed or is expressed at the wrong levels in the head,
17:46the head doesn't develop.
17:47And so when I say that pattern is formed in the embryo, the head-to-tail pattern,
17:49we now think that the genes involved in that are the expression or the homeobox genes themselves.
18:17A good question then, if homeobox genes are so important for patterning the embryo, is
18:22what tells a homeobox gene to come on in the head or come on in the tail?
18:27Studies in the frog embryo have shown that it's the very molecules which induce the mesoderm
18:32which turn on and off homeobox genes.
18:35So to put it simply, early in the embryo, a peptide growth factor will tell cells to
18:40become mesoderm.
18:41And as part of that process, they tell that cell either to turn on or not turn on a certain
18:46kind of homeobox gene.
18:52The influence of chemical signalling on the genes is also responsible for the next great
18:57step in development, sending cells to the right places.
19:04Intricate folding is about to happen to the growing ball of cells in the process called
19:09gastrulation.
19:10Many of the movements during this very early stage, during gastrulation, are really complex.
19:22And trying to describe them is quite difficult.
19:25It's a little bit like trying to describe to someone how to tie a shoelace without letting
19:31them actually see it.
19:33And it's a great advantage to look at gastrulation in simpler organisms where it's much easier
19:40to understand.
19:42In this frog embryo, we can see how movement and folding of cells gives rise to the tube
19:48that runs right through all animals, the gut.
19:52This small circle on the surface will become one end, the anus.
19:58Growth and movement of cells will drive the tube right through the embryo to meet the mouth.
20:06By the end of gastrulation, cells really know pretty well what they're going to do.
20:11Perhaps not in detail, but they certainly know now whether they're going to form part
20:16of the brain or part of the gut.
20:19And they also have quite new relationships with their neighbours because they're really
20:22in the right place to make the organism.
20:28Gastrulation has been described as the most important thing that ever happens to an animal.
20:34But folding on its own can only take the embryo so far.
20:39Some other process of shaping is needed.
20:43In embryos such as mammals and birds and reptiles that either have a large yolk that they can
20:49get food from or a mother that they can get food from, there's another important process
20:53and that is cell growth and division.
20:56Cells divide, grow, divide again.
20:58And they can do so differentially so that you get changes in the shape of the embryo just
21:02based upon the differential growth.
21:09The information that codes for what we are is in the DNA and that's linear information.
21:36There's a sequence of chemicals that code for proteins.
21:42And those proteins become part of the structure of the animal and they control how the animal
21:46ultimately looks.
21:48Now there's a serious problem in how you convert linear information to three dimensional information
21:54in space and time.
21:55And at the cell level that consists of understanding how individual cells can get together in
22:01populations.
22:03How they can cooperate to actually make an embryo change shape.
22:09And you can visualize this as a bunch of cells that might be connected together like boxes.
22:14And if each one of them gets taller and narrower, the sheet will get more compact and much thicker.
22:25If on the other hand they become shorter and wider, the sheet will spread.
22:30If you had a bunch of them like that, it would change the shape of the whole population.
22:33The other thing that they can do is migrate or crawl.
22:36We use the term migration, but basically it is crawling or walking across this external
22:41substratum.
22:43Another is that they can crawl across each other to rearrange.
22:47And we call these kinds of walkings cell intercalations.
22:52And a good analogy would be to consider how cars merge on the freeway to make a longer narrow
22:57array.
22:58If you have a freeway that's four lanes wide and the cars merge to form two lanes, then
23:03the array gets twice as long.
23:06And in fact cells can crawl across each other to intercalate much like my fingers are intercalating
23:12here to form a longer narrower array.
23:23Lengthening and narrowing takes place again and again during development.
23:27At about three weeks the dance of the cells makes the embryo longer and thinner.
23:42At the same time an important change overtakes a group of cells running around the outside
23:51of the embryo.
23:57This frog embryo is about to acquire a most important organ, the brain.
24:04On the embryo's surface a new set of genes becomes activated.
24:09Proteins are made which foreshadow the development of nerve cells.
24:12The cells themselves change shape.
24:15The group then curves to form two ridges.
24:19The ridges come together rather like a pair of lips to make the forerunner of the spinal
24:24cord and brain.
24:29The story of development really is one of increasing commitment, increasing irreversibility.
24:40At the earliest stages anything goes, anything can develop fully.
24:44The later and later in the development of the embryo the more vital every bit has become
24:49and the more committed it's become and the less potential it has for taking the place of other bits.
24:55When the tiny embryo, the ball of cells, has moved into the uterus and is just about to take its position
25:01in the uterus wall, then the first stirrings of the development of the nervous system begin.
25:06It's the first stage in commitment.
25:09A group of cells on the surface of the embryo suddenly changes its identity.
25:16It responds probably to a chemical signal from the cells below.
25:20It starts to express or to produce a substance which makes that particular strip of cells stick together.
25:27That is the beginning of the formation of the whole of the nervous system.
25:31That row of sticky cells on the surface of the ball turns in on itself to form a tube, the neural tube,
25:39and that's the start of the formation of the brain, the spinal cord and all of the nervous system.
25:44The cells that lie within that tube are going to make all the nerve cells
25:48and all the other cells that contribute to the nervous system, the glial cells.
25:52As time progresses, three weeks, four weeks, parts of that tube begin to expand
25:57and they expand because the cells in that region are growing and being produced more quickly than in other regions.
26:03So you begin to see a little bulge at the top of the tube. That's going to be the brain.
26:08You see the long tail at the back of the tube. That's going to be the spinal cord.
26:12The really critical period in the development of this structure occurs between about a month of age
26:18and about three months of age in the growing human fetus.
26:21That's the stage of maximum growth, astounding, staggering rates of production of cells.
26:27A quarter of a million nerve cells a minute being made through much of that period of time.
26:33A great factory the brain has become for churning out more and more of those cells
26:37and for them to race away to their final destinations to take their place in this growing and increasingly complex structure.
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30:39By six weeks, the embryo has rudimentary versions of all the organs of the body.
30:57The eyes have started to form.
31:06Blood is flowing inside transparent veins.
31:11The paddles that will become legs and arms are clearly visible and are starting to move.
31:26All the muscles, nerves, chambers and valves of the heart are in place and working.
31:35But the most dramatic changes are taking place inside the embryonic head.
31:41What people usually think of as being special about the brain is the numbers.
31:46A hundred thousand million nerve cells. Enormous, enormous numbers.
31:51But you know, that alone isn't so surprising.
31:54There are probably about that same number of cells in the liver.
31:57And although the liver is important, it's certainly not as spectacular as the brain.
32:02What's really special about the brain is how it's connected and how it's organised.
32:06It is this enormous biological computer with every single element connected intricately to hundreds, thousands or even millions of other elements.
32:17It's the specificity of the connections that make the brain so special and make behaviour what it is, make our intelligence and our perceptions and our thoughts work.
32:28That's what has to be explained. Not the numbers, but how they're connected together.
32:34If we look at the adult brain, it almost seems that the problem is impossible to solve.
32:39It is just so complicated in its organisation. It almost defies description or interpretation.
32:45If we go back to the early stages, then we find that it's not so complicated.
32:49We can begin to work out the rules by which one set of fibres, one set of nerve cells interacts with another when the structure is very simple in its organisation.
33:01The development of the brain takes place in several stages.
33:05The instructions contained in the genes are now directing the production of enormous numbers of nerve cells.
33:13They move towards their final positions and begin to assemble themselves into the structures of the adult brain.
33:20Then connections are formed between the nerve cells, many millions of them.
33:39The brain isn't just nerve cells. They're the ones that get all the publicity and all the glamour.
33:52But about 90% probably of the cells in the human brain are a cell type called glial cells.
33:59They don't transmit impulses. They don't carry the information from the sense organs. They don't move the muscles.
34:05They're called glial cells because glia means glue. They hold the brain together and many of them play a crucial part in development.
34:14In particular, one of these classes of glial cells forms a scaffold or an organised structure over which the developing nerve cells migrate.
34:26The brain initially is just a tube and the place where the nerve cells are being born is in the middle of the tube, on the centre wall of the tube.
34:34And yet, in the end, most of those nerve cells end up at the edges of the tube.
34:39If you look in the cerebral hemispheres or in the cerebellum, in the major divisions of the brain, the nerve cells are distributed at the surface.
34:46They form layers at the surface. And they've got there by moving upwards from the place where they're born, around the middle of the developing tube.
34:53To get there, they follow the processes, the long processes, of a certain class of glial cell called radial glia that stretch between the inner wall of the tube and the outer wall of the tube.
35:05Hundreds of millions of them linking the proliferative region to the place where the nerves will eventually be.
35:12Now, after the nerve cells have moved to their final position, the next essential step is to wire them up.
35:25And we see the beginnings of that, probably even before they've finished their journey.
35:32What starts out at the base of the radial glial cell, moving upwards towards the final position, is an uncommitted ball of a cell.
35:41Not obviously a nerve cell or a glial cell or any other type of cell.
35:45And on the way, it begins to start to differentiate, to become committed to one cell type or another.
35:52As it approaches its target, even at that stage, many of them begin to produce a fibre, an axon, a nerve fibre, pushing out, spinning out, off into the unknown.
36:05The cell takes its position, finally, in the layers of the cerebral cortex or the cerebellum, leaving behind it the fibre, which pushes off into the wilderness, looking for its target.
36:18For the brain to work properly, the connections between nerve cells have to be the right ones.
36:23This is a monumental problem, to find the correct target among the 100,000 million cells of the brain.
36:30It's been likened to navigating across America without a map.
36:34We're driving through the streets in the San Francisco Bay Area.
36:38We're trying to make a decision of which way to go.
36:41If we were a nerve cell growing in a developing nervous system in the embryo, this journey would have started in New York City.
36:49Days ago, we would have made the decision to get onto particular freeways, to take an interstate that would have taken us cross-country,
36:55and to finally wind up in California, getting off the freeway on an exit that would dump us off into Berkeley, into this particular residential community.
37:03A whole set of navigational decisions that are going to take us, ultimately, to the correct target.
37:08Now, as I come up on each one of these intersections, there's a whole series of choices.
37:13They're all roadways. They're all paved with asphalt.
37:16And yet, we're able to make a distinction, to make the decision of whether we want to turn left, go straight ahead, or turn right.
37:21Well, nerve cells are capable of doing that just as well.
37:24And they can make that decision based on a whole series of labels.
37:27In some cases, we think the street signs, or the roadway signs, are actually molecules that are painted, in a sense, on the surface of the roadways.
37:35In your brain, those roadways are glial cells. They're the surface of other neurons.
37:39And they're painted, in a way, with labels that allow nerve cells, as they're navigating, to make decisions of which way to go.
37:46But I don't really have the information of exactly which house I'm going to.
37:50Rather, when I get to the particular block, when I get to the particular neighborhood, I'm going to stop, I'm going to walk up,
37:56ring each of those doorbells, and have a conversation with each one of the people in those homes to find out which house I actually want to be at.
38:02And that's much the way the nervous system is put together.
38:05There's a whole series of navigational cues, a whole series of choices, and ultimately, cells wind up in the right neighborhood.
38:11Now, the only place where the analogy breaks down is the sense that this road was here yesterday, it's going to be here tomorrow, it's going to be here a week from now.
38:19But in the case of the nervous system, these roadways can be very dynamic and very transient.
38:24This road might have been constructed a few hours ago, and it might be that it's going to be bulldozed and destroyed in a day or two.
38:30What happens is there are certain time windows when nerve cells are able to grow along the particular guides and the particular pathways,
38:37the particular fibers of glia and other neurons that guide them.
38:41And during that time, they're able to make their decisions of which way to grow.
38:52So much of the development of the brain depends on timing, and that's true in the rest of the body as well.
38:58We actually don't know quite how that's controlled.
39:02It could be, and it probably is, that each cell has a kind of life clock ticking away inside it somehow,
39:10which regulates what the genes will do, and therefore what the cell will become.
39:14But there's another way that time can impress itself in a growing structure.
39:19Because, of course, each cell is in an environment which is the product of the cells that are around it.
39:27So depending on what those cells are doing at that time, any particular cell can be influenced.
39:33There's a very good way of studying the importance of timing in the growing nervous system,
39:39and that is to use techniques for putting together bits of the nervous system at inappropriate times.
39:47It's a very powerful tool to determine whether time is important.
39:51There are now methods available for growing tiny explants, fragments, of different parts of the nervous system together in tissue culture,
40:11and allowing them to form connections, and seeing whether those connections follow the normal rules that they would if they were in the developing brain.
40:19For instance, if you combine from a rat fetus two tiny fragments of tissue,
40:27one from the cerebral cortex at around the time of birth,
40:30and another from the group of nerve cells which would send its fibres up to the cortex in the developing animal,
40:36those two things will indeed interconnect.
40:39However, whether they connect properly,
40:42and in particular whether the nerve fibres growing upwards stop at the correct layer within the cortex,
40:48depends critically on the age of the receiving tissue.
40:51Even a day can make a difference.
40:53It appears that in the rat, just two or three days after birth,
40:58although that corresponds to a period sometime before birth in human beings,
41:02the cells of the correct layer in the cortex suddenly begin to turn on a chemical signal that says,
41:08stop here.
41:09And if the chemical signal isn't being turned on,
41:12the fibres growing into the brain will race past,
41:15will search endlessly for a target that they never find.
41:20To make sure that the nerve cells do find their targets,
41:23the developing brain provides a guide.
41:26The supporting glial cells connect together into a sort of scaffold.
41:30The scaffold then provides a template along which the nerve cells move.
41:35This very clever trick of creating a scaffold, a guidance structure,
41:42over which the nerve cells can migrate to their correct position,
41:47is used again.
41:49It's used, at least in part,
41:51to guide the growth of the nerve fibres from those cells to their targets and back.
41:57So, it's a general trick that's used in the growing brain,
42:01to lay down a primitive structure, a scaffold, rather like building a building.
42:06You organize a scaffold around it, arrange things over the scaffold,
42:11and then, like a building, when the growth is complete, you take the scaffold away.
42:16In the developing brain, many of the scaffolds that guide nerve fibre growth to connect one area to another,
42:31many of those scaffolds are themselves made up of nerve fibres,
42:36what are called pioneer fibres.
42:39Certain nerve cells send their fibres out at a very, very early stage
42:43to lay down a scaffold, an organized structure,
42:46over which later waves of fibre growth can occur.
42:50And when these cells have done their job,
42:52when the fibre system of the scaffolds is no longer needed, the cells die.
42:57Knowing that, initially, there are too many nerve cells and too many connections,
43:03we have to ask, how do the unwanted ones get eliminated?
43:08And there are probably several mechanisms involved there,
43:10but much the most interesting is one that depends on activity.
43:15It turns out that, at least in certain parts of the brain,
43:18connections that are used a lot, that have many impulses passing through them,
43:23tend to be strengthened.
43:25And if pathways aren't used, the fibres can be lost and the cells can actually die.
43:31Now that gives the brain a remarkable capacity.
43:34It gives it the capacity to control itself, to regulate its own connections
43:39and therefore its function, on the basis of the way in which it is used.
43:44And this can happen before birth and does.
43:46We know, for instance, that in the eye, in the retina of the eye,
43:50there are already nerve impulses going on long before the animal can see,
43:54long before birth in a human being.
43:56There are already patterns of impulses across the retina.
43:59Those impulses are passing down the optic nerve into the brain
44:02and they're regulating the formation of connections
44:05from the incoming nerve fibres to the cells that those fibres reach.
44:09That process undoubtedly happens in many other parts of the brain as well.
44:13It continues after birth.
44:15And that gives the animal the possibility to adjust and refine and reprogram its brain
44:21depending on what's happening to it, what the outside world is doing to it.
44:25Now, when you think about it, that's a remarkable thing
44:28because it means that this mechanism built into the brain by the genes
44:33gives the brain the capacity to reorganise itself
44:38on the basis of what is happening to the individual animal.
44:41The animal has become liberated from the constraints of the information present in its own genes.
44:48And it can now adapt to its environment.
44:51It can learn. It can remember.
44:53The genes have made the capacity to change the brain.
44:57And that, I think, is the pinnacle of evolution.
45:00It is the most remarkable achievement of the process of natural selection.
45:06The embryo is now more than eight weeks old
45:09and it's taken on a much more human appearance.
45:12It's still only about four centimetres long, but every organ is now in place.
45:22The next stage of development is one of dynamic growth.
45:34A very peculiar feature, or a special feature of embryos,
45:37is that everything is laid down initially,
45:40the patterning is done on a very small scale,
45:42and then gets bigger via growth.
45:45It's not that there hasn't been any growth earlier,
45:47but it's really much less.
45:49So if one thinks of one's arm,
45:52one's whole arm is laid down initially,
45:55all the patterning, when it's only about much less than a centimetre big,
45:58much less, I would say.
46:00And yet it grows into this quite large structure, and that's all growth.
46:04And this growth process is very reliable,
46:07because once two arms are laid down independently,
46:11tiny size, grow for 16 or 17 years,
46:15and hopefully, usually, they end up about the same length,
46:18and that's really rather remarkable,
46:20because there's no connection whatsoever between them.
46:22It's like setting off two rockets or two trains
46:25and looking 18 years later,
46:27there they've got exactly the same distance.
46:34If all that's left for most of the organs of the body is just to grow,
46:38for the brain, things are rather different.
46:41It's tempting to think that development just involves growth.
46:45You start with something very small,
46:47you end up with something very large,
46:49so it's obvious it must just get bigger and bigger and bigger,
46:52more and more cells being produced until it's perfect,
46:54and then it stops.
46:56Well, I think that one of the most interesting things
46:58that we've discovered in the last few years
46:59is that the brain isn't like that.
47:01What happens is that too much brain is produced at first,
47:05that what the genes do is make too many nerve cells,
47:09too many connections, too much brain,
47:12and then the unwanted bits are lost.
47:15That may seem very strange,
47:17but, in fact, I think it's very clever.
47:19What it presumably means is that the genes, the genetic control,
47:23can't make an absolutely perfect brain.
47:26It can't anticipate all the demands,
47:28it can't specify all the connections precisely.
47:31There are only two sorts of mistakes that you can make.
47:34You can either make too little or too much,
47:36and it would be a disaster to make too little,
47:38so the genes make too much,
47:40and they rely on other selective mechanisms
47:43to get rid of the connections and the cells that aren't needed.
47:46How growth is controlled is a central problem in biology.
47:49After all, cancer is really about growth going wrong.
47:55We really don't understand at this stage
47:57how in development growth is controlled,
48:00and it's really very important
48:02because when, for example, the face grows,
48:05just one more cell division
48:07can make all the difference, I think,
48:09between a beautiful nose and a less beautiful nose.
48:13I like the idea of beauty, as it were,
48:15being just one cell division away.
48:18We think it will be controlled by genes,
48:22like the homeobox genes,
48:24but at this stage we simply don't know.
48:28Finding out could be very important.
48:30Recent research is showing that how much growth takes place
48:34during the late stages of pregnancy
48:36has a profound effect on health 50 or 60 years later.
48:39It can even determine susceptibility to diabetes, stroke or heart attack.
48:45At the very least, we now know the stages through which a developing embryo passes.
48:51But being able to describe something and really understanding it are radically different.
49:01We really understand quite a lot about development.
49:04And the bits we understand are probably those in early development.
49:09But there's still quite a big gap between, as it were, assigning positions to cells
49:15and how cells use that information, as it were, to make a nose or an eye or even the details of the fingers.
49:25So, in terms of sort of having what I could persuade you as a real understanding of development,
49:34I think we're about halfway there.
49:36We're doing quite well at the early stages,
49:38but there's still a long, hard slog to go to understand the later ones.
49:55There's tremendous excitement at the moment.
50:08First of all, because of the molecular work that gives us insights.
50:12But it's not just that basic mechanisms have been conserved.
50:16It's that the same genes seem to be involved in laying down the body plan in flies
50:23as in ourselves.
50:26And that's a tremendously encouraging generalization.
50:30I would like to think that the principles of development are going to be universal and very beautiful.
50:47The reason I think it's important to understand how animals develop,
50:51it is, after all, a miracle which we all observe,
50:54an egg and a sperm combined to make us all, to make a baby.
50:58I would dearly like to know how that's done.
51:00How does an animal develop?
51:02In our culture, we rightly think it's worth knowing basic facts about the universe.
51:06How was the universe born? How did the universe form?
51:09I think it's equally important to understand how babies develop.
51:13There's also the medical issues, that an awful lot of the problems that humans suffer from,
51:28a lot of the diseases, many of them are congenital problems.
51:31Many of them are mistakes and problems that took place during embryology.
51:35And if you understood how an embryo developed, how you finally came up with a mature organism,
51:40you'd have a much better understanding of how to solve some of these diseases.
51:44In a complicated process, things can go wrong, and they often do go wrong.
52:06We know that many childhood disorders are essentially disorders of development.
52:11If we look at the brain, for instance, things like cerebral palsy,
52:14maybe dyslexia, possibly schizophrenia, spina bifida,
52:18many, many serious disorders are failures of the coordination of development.
52:23But we're not going to understand that by looking at the body as it is in the adult.
52:27We have to go back to the beginning to understand those very important medical problems
52:31and ultimately to treat and cure them.
52:34But of equal significance to my mind is the intellectual challenge.
52:38We know that every cell in the human body has this amazingly limited repertoire of instructions,
52:43just 50,000 genes, 50,000 separate signals,
52:48which together tell the body how to build itself.
52:52To my mind, the greatest intellectual challenge in biology
52:55is to understand how those signals are read out
52:58and how they create something of the complexity and the magnificence
53:02of the whole of the human body.
53:16It's far from clear what advantages understanding development in detail would bring us.
53:23I don't want to promise that if we really understood development
53:28and therefore we'd also understand regeneration, for example, in newts,
53:33that we would then be able to find some way for people to regenerate lost limbs.
53:40I don't want to promise that if we really understood development
53:43that we'd be able to get rid of all congenital abnormalities.
53:47I simply don't know what benefits really understanding development will bring.
53:52But it's such a basic problem, and it's so fundamental to our very existence,
53:57I think it's absolutely essential that we understand it.
54:00You have to be able to understand your words of this world.
54:01But it's just like music , you know,
54:03some of the pleasures of this world,
54:06you have to be able to balance all the way for people to�.
54:07I will listen and enjoy your work.
54:09I will listen to the visual effects of this world,
54:11but I will listen to the visual effects of that.
54:13I believe you do.
54:14How will I have to be able to develop?
54:16The conclusion of this world is telling you that
54:17you have to be able to give us some of the details of this world to be able to.
54:19Because I'm ready to share this world,
54:21I believe you're just wanting to see the future.
54:22And I believe I have today with you.
55:24Map out a new picture of the land in a new series that profiles the wildlife which inhabits the British Isles.
55:31Celebrate Wild Britain, Tuesday at 8.30 on 4.
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