pp.143-152 (mijn onderlijning - zie het boek voor voetnoten en afbeeldingen.)
To appreciate the problem, consider the adult human brain. Its 1,5-kilogram mass contains up to a hundred billion neurons and ten times as many supporting cells, known as glia, surrounding them. This cell mass is highly structured. It is divided into numerous functionally specialized regions, and in each region the cells are arranged in a highly ordered pattern. Thus the surface of the brain is formed by a thin highly convoluted 'skin', about 4-6 millimetres thick — the cerebral cortex (grey matter). The cortex is packed with neurons arranged like a layer cake in six 'strata'; the pattern is readily observable in side view through an optical microscope if the cells are appropriately stained. Less well observable is the fact that, as viewed from the cortex's uppersurface, the cells are also organized into an array of functionally distinct columns. Closer examination of neurons reveals that they also show a number of distinct shapes, resembling pyramids, stars, baskets, and so on. As if this were not enough, each neuron is connected to others, some its neighbours, some distant from it, by fine fibres that radiate out from the cell body. Some of the fibres (dendrites) collect incoming signals, and at least one of them (the axon) transmits the information carried by these signals onwards to the other neurons, making contact with their dendrites by way of junctions called synapses. Any one neuron may carry up to a hundred thousand of these synaptic connections. Some of the connections are internal to the brain, enabling neurons to communicate with their colleagues. Others — such as the great cable of axons that runs from the eye down the optic nerve, first to a region deep inside the brain called the lateral geniculate, and from there to the 'visual' regions of the cortex — carry inputs from the external world. Still other nerve tracts lead out from the brain, connecting via the spinal cord with the body's musculature and internal organs.
This enormously complex structure must be generated within nine months of the moment of fertilization, so as to be largely functional by the time of birth. Of course, there's a lot of post-natal development still to go. Many of the glial cells are not yet in place at birth. And, even more important for the functioning of the brain, synapses are still sparse at birth. During the next few years of development, no fewer than 30,000 synapses a second will be created under each square centimetre of cortex, until the full complement of a hundred trillion (10^14) are present and functioning. To put that number into perspective, it is about 20.000 times more than the entire human population of the planet.
But even to get to the stage of the brain at birth requires the creation of about a million cells an hour, day in day out, throughout the entire gestation period — a formidable enough challenge if the brain were simply growing smoothly, like a steadily inflating balloon. But it isn't. The first observable step is taken when the embryo is no more than eighteen days old and 1.5 millimetres long, when the hollow ball of cells that constitutes the gastrula develops a groove along its surface, thickened and enlarged at the forward end, which will in due course become the brain. As development proceeds the groove deepens and its walls rise higher, move towards one another, touch and seal over; the groove has become the neural tube. By twenty-five days, when the embryo is about 5 millimetres in length, the tube begins to sink below the surface of the embryo. Its central cavity will become the central canal of the spinal cord and form the fluid-filled spaces within the brain itself (the ventricles). The head end of the tube begins to swell, and to show the beginnings of the three major divisions of fore, mid-and hind-brain.
In the next few months of embryonic development, precursor cells to all the billions of neurons and glia which will ultimately constitute the brain begin to separate from the neural tube. The precursor cells are thus not formed in the developing brain at the sites at which they will end up as mature neurons and glia, but in the vicinity of the neural tube and ventricles. They are then required to migrate from their places of origin to their ultimate locations, distances which may be tens of thousands of times their own length — equivalent to a human navigating a distance of 20 kilometres. How do they find their way? Does each cell know where it is going, and what it is to become before it arrives at its final destination? Is it equipped with a route map, or is it, as in the instructional model of the immune system, a general-purpose cell which can take on any appropriate form or function, depending on its final address within the brain? To many of these vital questions there are still no complete answers; as I pointed out in the previous chapter, the great expansion of genetic knowledge in recent decades has yet to be matched by a comparable increase in the understanding of development. But several mechanisms are known to play a part. In the developing brain it is the glial cells that begin the migratory pattern. As they move away from their sites of origin and towards what will become the cortex, they spin out long tails, up which the neurons can in due course climb. As Edelman and others have shown, the cell membranes of both neurons and glia contain a particular class of proteins called cell adhesion molecules (CAMs). In the developing tissue the CAM molecules work rather like crampons: they stick out from the surface of the membrane and cling to the matching CAM on a nearby cell. The neurons are thus able to clutch the glia and ratchet themselves along their tails. As a further trick, the migrating cells also lay down a sort of slime trail of molecules related to the CAMs — substrate adhesion molecules (SAMs) — which provide additional guidance for the cells following along behind.
But what provides the map references for such cellular route marches? Both distant and local signals must be involved. One way of signalling direction is to have already in place some target cell or tissue towards which the migration can be directed. Suppose the target is constantly secreting a signalling molecule, which then diffuses away from it. This will create a concentration gradient, highest at the targetand progressively weaker at increasing distances. If the migrating cell can sense the signalling molecule and move towards it, rather as bacteria can swim towards sources of food, then it will eventually arrive at the target. In the 1950s Rita Levi Montalcini identified one such signalling (or trophic) molecule, which she called nerve growth factor; by the time she was awarded her Nobel prize for the discovery, in 1986, it had been recognized as but one of a growing family of such molecules.
Trophic factors can provide the long-range guidance which enables the growing axons of motor nerves to reach out and find their target muscles, or the axons from the retinal neurons which form the optic nerve to track their way to their first staging post within the brain, the lateral geniculate. However, the migrating cells or growing axons also need to keep in step with one another — each has to know who its neighbours are. The diffusion of a local gradient molecule, together with the presence of some types of chemosensor on the axon surface, could enable each to determine whether it has neighbours to its right and left and to maintain step with them. The entire troop of axons would then arrive in formation at the lateral geniculate and make appropriate synaptic connections, thus creating in the geniculate a map – albeit a topographically transformed one – of the retina, rather like the relationship between the London Underground or New York subway system and the maps of them on display at stations. Indeed, the brain holds many such maps, multiple maps for each of its input sensory systems and output motor systems, maps whose topology must be preserved during development.
The process just described would be compatible with an instructionist model. Each axon is kept on course by instructions from its environment, both the trophic factor diffusing from the target region and the relationships with its nearest neighbours directing it to its final site. There is some evidence that a considerable part of the nervous system's development can be accounted for in such a model. However, Edelman drew attention to another vital feature of development. During embryonic development there is a vast overproduction of cells: many more neurons are born than subsequently survive. Since more axons arrive at their destination than there are target cells to receive them, they must, argues Edelman, compete for targets. Those that do not find them wither away and die. The argument actually goes further: it is not only neurons and their axons which are overproduced, but the synapses too. There is a superabundance of synaptic production, a veritable efflorescence. But if synapses cannot make the appropriate functional connections with the dendrites of the neurons they approach, they too become pruned away and disappear. In this model of development, because there is competition for scarce resources – trophic factor, target cell, synaptic space – there is also selection. And now we have only to imagine that it is in some way the 'fittest' of the neurons and synapses that win out in the competition, and we arrive at Edelman's 'neural Darwinism'.
Selection in this sense can account for local but not distant processes. Long-range order, the migration of cells and the growth of axons over long distances, would seem to require something more - the execution of some internal programmes of both individual cells and the collectivity of cells acting in concert. Even though synapses from only one particular neuron may end up making successful connections with its target cell, if the others had not been present during the long period of growth and migration it is doubtful whether a single nerve axon would have been able even to reach the target. The survival of one depends on the presence of the many. Overproduction and subsequent pruning of neurons and synapses may at one level of magnification look like competition and selection; viewed on the larger scale, they appear as cooperative processes.
As a comparable example, it takes only one sperm to fertilize an ovum. In the vulgarly macho language that one has come to expect from some popular writers about biology, combining ultra-Darwinist rhetoric with sexual prurience, this 'fittest' successful sperm is often interpreted as being the 'winner' of a competition amongst the many hundreds of millions in an ejaculate. In fertilization, the head of the sperm cell — containing the nucleus — fuses with the egg. Yet introduce just this single 'fittest', sperm into the vagina and the chance of it surviving to reach and fertilize the ovum are minuscule; a high sperm count improves fertility, helping more sperms to survive their passage through the vagina, even though only one will ultimately enter the ovum and complete the fertilization. The single 'fittest' sperm must in fact cooperate rather than compete with the rest if fertilization is to occur at all. (Furthermore, it is increasingly apparent that the ovum is not merely the passive recipient of the victorious sperm, but plays an active part in the process. Fusion requires the sperm's enzymes to be activated by secretions from the female reproductive tract, and sometimes also by the protrusion from the egg's surface of small membranous 'fingers' that draw the sperm into the egg.
Instructive and selective mechanisms are thus only part of the picture of development. The maintenance of stability requires the entire ensemble of cells to cooperate, to act collectively. In a non-trivial way, each depends on the others in the creation and preservation of the dynamic pattern of connections which maps the world onto the sense organs, the sense organs onto the brain, and then, viathe brain and the musculature, imposes new patterns on the world beyond. This is why I want to argue that we need to transcend both instructionist and selectionist metaphors. Development is essentially a constructivist process; the developing organism, in its being and its becoming, in its specificity and its plasticity, constructs its own future.