Feature: is size everything?

Should the things we do ever make you fear that intelligent life has yet to arrive on Earth, it is cheering to recall that humans do in fact have unusually large brains for our size. If you doubt it, check with a mother who remembers giving birth. About 20 weeks into a pregnancy, the brain starts adding neurons at a startling rate, an expansion that continues until two years after the baby is born.

When the expansion falters, it makes for an easier delivery, but of a microcephalic – small-brained – infant. This condition, which is diagnosed by measuring skull size, can be caused by infection or serious alcohol abuse during pregnancy. Sometimes, though, it is due to a genetic alteration.

In a revealing series of investigations over the last ten years, Geoff Woods and his colleagues have been pinning down the genes involved. Their interest is clinical, but the work also raises intriguing questions about the human story. As primates evolved over the last few million years, when and how did the changes begin that lifted one lineage to a higher level of awareness? How did we come to be the ones who not just are products of evolution, but can ask questions about it?

A clinical issue

The recent clues are an unexpected by-product of the British textile industry's recruitment of workers from abroad. In the 1950s and 1960s, many people from rural Pakistan settled in Bradford. Over the next decades, health workers in Yorkshire became aware of a tradition of cousin marriage, which meant that some recessive genetic conditions were relatively common among some families. At the same time, these families often had little contact with health services.

Geoff Woods, a paediatrician moving into clinical genetics, arrived in neighbouring Leeds in the mid-1990s, just when the local health service was gearing up to deal with these problems better. An Asian genetic counsellor, soon joined by two more, helped to break down the communication barriers. And it became apparent that extended families, tightly genetically interwoven, had advantages for research. It has become feasible to map a disease-causing gene using just one of these closely interrelated families.

Dr Woods quickly noticed that he was seeing an unusual number of microcephalic children in his clinic: the incidence of what is formally designated autosomal recessive primary microcephaly (MCPH) is about 20 per million births among the Pakistani population, or ten times the rate normally seen in the UK. "We thought, they have been a relatively isolated population: we'll go and look for the gene."

In fact, the turbulent history of northern Pakistan meant that the population was much less isolated than he assumed. But marriage within families and clans did make the genetic analysis easier. Eight years and a lot of molecular biology later, he knows there are at least eight genes, maybe nine, and many different mutations. All seem to lead to the same condition. The children have small heads, and a nervous system that is reduced in size, especially the cerebral cortex. Structurally, everything looks quite normal. They grow up with mild or moderate learning difficulties. They learn to talk but find reading and writing difficult, and are slow learners, though are typically cheerful, easy going and well behaved. "In a rural setting in Pakistan," according to Dr Woods, "they fit in perfectly well, and can even have children."

The condition is more readily diagnosed in the UK, and the new genetics can now be used for prenatal testing or to help inform marriage choices: "What they really want is carrier testing," says Dr Woods. There are moves to make this available in Pakistan, too, although at the moment samples have to be sent to the UK for analysis. One or two affected children may not be seen as a serious problem. But Dr Woods recalls bringing together one large family in Pakistan for research sampling: when they all gathered for the first time in one house, it became apparent that there were no fewer than 11 individuals with microcephaly among them. "They decided there and then: no more marriage within the family."

Dr Woods has just moved from Leeds to the Cambridge Institute for Medical Research, where he is Wellcome Trust Clinical Research Fellow. The post is ideal, as it allows him to divide his time 50–50 between research and working with patients. He intends to work with the Pakistani populations of Peterborough, Luton and Bedford, to find the remaining MCPH gene products and the genes causing other neurodevelopmental diseases in these populations. The initial genetic identification is now more straightforward, he thinks: "Since the human genome has been properly annotated, our life has become so much easier".

Counting cells

Once a gene has been identified, its biological role can begin to be explored. This has revealed what may be the key process – control of cell division and, in particular, of the centrosome. "The centrosome is an organelle which has been a bit overlooked," says Dr Woods. As befits the name, it is at the centre of one of the most astonishingly orchestrated – and beautiful – processes in biology: the copying and relocation of the chromosomes during cell division.

Most of the time, the centrosome anchors an animal cell's array of microtubules, the protein filaments that it uses to drag things from place to place. When the time comes for the cell to divide, the centrosome is copied, and the centrosome pair organise their microtubules between them into the so-called mitotic spindle. It is this spindle that eventually pulls each set of chromosomes to opposite sides of the cell, ensuring each daughter cell ends up with one complete copy of the DNA – no more, no less.

A further twist is that cells in the developing embryo, including those involved in generating neurons, can divide symmetrically or asymmetrically. If a neural stem cell divides symmetrically, the result is two more neural progenitor cells. If it divides asymmetrically, it gives rise to one progenitor cell and a fully fledged neuron. The neuron then moves to the position in the brain where it can do its job after birth.

What decides whether a progenitor cell goes one way or the other? The process is poorly understood, but one clear difference is whether the mitotic spindle is oriented horizontally in the layer of neuroepithelial cells under development, or vertically.

Somewhere in all this, it is easy to imagine ways of controlling brain size, in the sense of the total number of neurons produced. And that idea is reinforced by the fact that three of the known MCPH proteins are found in the centrosome during cell division. "Our most obvious hypothesis would be that all these genes affect the ability to control the mitotic spindle axis," says Dr Woods. Exactly how is not yet known, but he speculates that the ASPM protein, for example, has the right structure to exert leverage when one end is latched on to a microtubule. "Perhaps it forms a kind of flying buttress, so that as the centrosome rotates, the spindle goes with it."

As well as this cellular work, Dr Woods will continue to focus on the clinical work and the genetic analysis, while building collaborations for evolutionary studies and work on flies and mice. Genetics is the starting point, but understanding what role the genes play in the brain means going deeper into cell biology and development. We may not be able to grow even bigger brains any time soon, but he is prepared to speculate that there may be results to come that will bring neural stem cell therapy a little nearer.

Further reading

• Bond J et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 2005;37(4):353–5.
• Woods CG et al. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 2005;76(5):717–28.
• Kouprina N et al. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol 2004;2(5):E126.
• Woods CG. Human microcephaly. Curr Opin Neurobiol 2004;14(1):112–7.