It would be tedious to recount the many false starts, the years wasted on the search for the organiser morphogen, the hecatombs of frog and newt embryos ground up in the search for the elusive substance, and then, in the 1960s, the growing belief that the problem was intractable and should simply be abandoned. ‘Science,’ Peter Medawar once said, ‘is the Art of the Soluble.’ But the soluble was precisely what the art of the day could not find.
In the early 1990s recombinant DNA technology was applied to the problem. By 1993 a protein was identified that, when injected into the embryos of African clawed toads, gave conjoined-twin tadpoles. At last it was possible to obtain – without crude surgery – the results that Hilda Pröscholdt had found so many years before. The protein was especially good at turning naive ectoderm into spinal cord and brain. With a whimsy that is pervasive in this area of biology, it was named ‘noggin’. By this time techniques had been developed that made it possible to see where in an embryo genes were being switched on and off. The noggin gene was turned on at the far end of the blastopore’s lip, just where the gene encoding an organising morphogen should be.
Noggin is a signalling molecule – that is, a molecule by which one cell communicates with another. Animals have an inordinate number of them. Of the thirty thousand genes in the human genome, at least twelve hundred are thought to encode proteins involved in communication between cells. They come in great families of related molecules: the transforming growth factor-betas (TGF-?), the hedgehogs and the fibroblast growth factors (FGFs) to name but a few, and some families contain more than a dozen members. The way they work varies in detail, but the theme is the same. Secreted by one cell, they attach to receptors on the surfaces of other cells and in doing so begin a sequence of molecular events that reaches into the recipient cell. The chain of information finally reaches the nucleus, where batteries of other genes are either activated or repressed, and the cell adopts a fate, an identity.
When noggin was first discovered, it was supposed that its uncanny powers lay in an ability to define the back of the embryo from the front – more precisely, to instruct naive ectodermal cells to become spinal column rather than skin. This was the simplest interpretation of the data. Noggin, the thinking went, spurred ectodermal cells on to higher things; without it, they would languish as humble skin.
The truth is a bit more subtle. The probability that a cell becomes spinal column rather than skin is not just a function of the quantity of noggin that finds its way to its receptors, but is rather the outcome of molecular conflict over its fate. I said that our genomes encode an inordinate number of signalling molecules. This implies that the cells in our bodies must be continually bathed in many signals emanating from many sources. Some of these signals speak with one voice, but others offer conflicting advice. Noggin from the organiser may urge ectoderm to become neurons, but as it does so, from the opposite side of the embryo another molecule, bone morphogenetic protein 4 (BMP4) instructs those same cells to become skin.
The manner in which the embryo resolves the conflict between these two signals is ingenious. Each signal has its own receptor to which it will attach, but noggin, with cunning versatility, can also attach to free BMP4 molecules as they filter through the intercellular spaces, and disable them. Cells close to the organiser are not only induced to become neurons, but are also inhibited from becoming skin; far from the organiser the opposite obtains. The fate of a given cell depends on the balance of the concentration between the two competing molecules. It is an ingenious device, only one of many like it that work throughout the development of vertebrate bodies, at scales large and small, to a variety of ends; but here the end is a toad or a child that has a front and a back. In a way, the embryo is just a microcosm of the cognitive world that we inhabit, the world of signals that insistently urge us to travel to one destination rather than another, eschew some goals in favour of others, hold some things to be true and others false; in short, that moulds us into what we are.
It is actually quite hard to prove that a gene, or the protein that it encodes, does what one supposes. One way of doing so is to eliminate the gene and watch what happens. This is rather like removing a car part – some inconspicuous screw – in order to see why it’s there. Sometimes only a rear-view mirror falls off, but sometimes the car dies. So it is with mice and genes. If noggin were indeed the long-sought organising molecule, then any mouse with a defective noggin gene should have a deeply disordered geometry. For want of information, the cells in such an embryo would not know where they were or what to do. One might expect a mouse that grew up in the absence of noggin to have no spinal column or brain, but be belly all round; at the very least one would expect it to die long before it was born. Oddly enough, when a noggin-defective mouse was engineered in 1998, it proved to be really quite healthy. True, its spinal cord and some of its muscles were abnormal, but its deformities were trivial compared to what they might have been.
The reason for this is still not completely understood, but it probably lies in the complexity of the organiser. Since the discovery of noggin at least seven different signalling proteins have been found there, among them the ominously named ‘cerberus’ (after the three-headed dog that guards the entrance to Hades), and the blunter but no less evocative ‘dickkopf’ (German for ‘fat-head’). This multiplicity is puzzling. Some of these proteins probably have unique tasks (perhaps giving pattern to the head but not the tail, or else ectoderm but not mesoderm), but it could also be that some can substitute for others. Biologists refer to genes that perform the same task as others as ‘redundant’ in much the same sense that employers do: one can be disposed of without the enterprise suffering ill-effects. At least two of the organiser signals, noggin and another called chordin, appear to be partially redundant. Like noggin, chordin instructs cells to become back rather than front, neurons rather than skin, and does so by inhibiting the BMP4 that filters up from the opposite side of the embryo. And, like noggin-defective mice, mice engineered with a defect in the chordin gene have more or less normal geometry, although they are stillborn. However, doubly-mutant mice, in which both the noggin and chordin genes have been disabled, never see the light of day. The doubly-mutant embryos die long before they are born, their geometries profoundly disordered. They can only be found by dissecting the mother in early pregnancy.
Hilda Pröscholdt’s results were published in 1924, but she did not live to see them in print. Halfway through her doctoral degree she married Otto Mangold, one of her fellow students in Spemann’s laboratory, and it is by his name that she is now known. In December 1923, having been awarded a doctorate, she gave birth to a son, Christian, and left the laboratory. On 4 September 1924, while visiting her Swabian in-laws, she spilt kerosene while refuelling a stove. Her dress caught alight, and she died the following day of her burns. She was only twenty-six, and in all ways a product of the Weimar. As a student, when not dissecting embryos, she had read Rilke and Stefan George, sat in on the philosopher Edmund Husserl’s lectures, decorated her flat with Expressionist prints, and taken long Black Forest walks. She had only really done one good experiment, but it is said by some that had Hilda Pröscholdt lived she would have shared the Nobel Prize that Spemann won in 1935.