How to Build a Human: Adventures in How We Are Made and Who We Are. Philip Ball

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       The Waddington landscape. The balls represent the trajectories of different cell lineages, which begin in the single valley of totipotency as the zygote first begins to divide, and end in valleys representing different types of mature, differentiated cell.

      Differentiation begins early. Indeed, it has happened even in the pluripotent embryonic stem cells of the epiblast, which have lost the totipotency of the earliest cells made from the dividing zygote. Already some of those first cells have been directed down the valley in Waddington’s landscape that leads to a placenta or a yolk sac, not to a part of the fetal body. The cells that make up the three layers of endoderm, mesoderm and ectoderm in the gastrulated embryo have undergone a further degree of differentiation, a further narrowing of choice.

      It’s because of this specification of cell “fates” early in embryogenesis that the germ cells need to be formed so soon. Evidently a barely formed embryo doesn’t yet “need” eggs or sperm – but it must put aside the cells from which they will grow before they lose too much of their pluripotency. The germ cells, after all, have to make a totipotent zygote, so it won’t do if their chromosomes have already been heavily modified and silenced. Germ cells do have some epigenetic silencing of genes, although this too must be stripped away when the gametes combine to make a totipotent zygote.

      This special dispensation for germ cells aside, epigenetic changes appear to be one-way. They partly account for how our body tissues remember and maintain their identity as they grow: why skin cells divide to produce more skin cells, and don’t spontaneously become muscle cells or stem cells. In other words, cell replication is somewhat more complex than merely a matter of copying the chromosomes. It’s necessary also to copy the epigenetic chromosomal modifications that give the cell its identity.

      What this means is that each cell in our bodies, like each one of us, has a lineage: an ancestral history that starts with the zygote – and, except for a handful of germ cells (if we have children), ends in the grave. A liver cell has arisen from an embryonic stem cell via a succession of ancestors with intermediate characteristics, reflecting an ever greater specialization and loss of versatility. This notion of cell lineages was first articulated clearly by August Weismann when he drew up his fundamental distinction between somatic (“mortal”) and germ (“immortal”) cells.

      When we tell the story this way, a new possibility becomes apparent. In cells during development, just as in organisms during evolution, genes can change. Every time a cell divides, there is a chance that some of the three billion base pairs in the genome will be miscopied – that the daughter cells will acquire mutations. Cells put a great deal of effort into avoiding such mistakes, employing a kind of molecular proofreading to check for errors in replication. All the same, the numbers are so vast that mutations are inevitable. It’s estimated that distributed within the chromosomes of our 37 trillion or so cells are about ten thousand trillion genomic mutations.¹³ Every one of our genes experiences somatic mutations at some point in our lives.

      Most of these mutations, fortunately, don’t matter – they don’t affect a gene’s ability to do its job(s). But some have consequences. Most notoriously, gene mutations can lead to the cell dysfunctions that cause cancer (see here). Even potentially harmful mutations, though, might not matter if they happen late in development and so appear only in a few cells. Somatic mutations that arise during early embryo growth, on the other hand, may be passed on to all subsequent cells in that lineage, making the developing body a patchwork or “mosaic” with slightly but perhaps significantly different genomes. There are many diseases related to “mosaicism”, of which cancer is just one class. Somatic mutations leading to mosaicism are particularly common in brain neurons, and they are thought to be responsible for a range of brain and cognitive disorders, including some types of autism. Even benign mutations can manifest themselves in outward appearance (that is, phenotypically): for example, causing striped skin pigmentation called Blaschko’s lines or the red skin blotches called port-wine stains.

      One particularly unusual but very rare kind of mosaicism happens when a cell in a male embryo fails to pass on its Y chromosome to the daughter cells, which, inheriting only the X, then develop as “female cells” by default. This can lead to a mixture of male and female characteristics in the embryo. Rare it may be, but this condition serves to remind us of the cell’s autonomy. Even in a body “meant” (to judge from the zygote) to be male, there is no global command that cells obey, and the “feminized” cells will feel no obligation to conform to the nature of their “male” neighbours.

      Genetic СКАЧАТЬ