Acid test for marine biodiversity

Much of the carbon dioxide released into Earth’s atmosphere by human activities is absorbed by the oceans. When dissolved in water, CO2 forms carbonic acid. Anthropogenic carbon emissions are therefore leading to global acidification of the surface ocean, with uncertain consequences for marine life. On page 96 of this issue, Hall-Spencer et al. describe conditions off the island of Ischia near Naples, Italy (Fig. 1). Here, the release of CO2 from under-sea volcanoes causes local acidification of sea water by as much as 1.5 pH units below the average ocean pH of 8.1–8.2. Although surrounded by a diverse rocky shore community with abundant calcareous organisms, the CO2 venting site is impoverished in sea urchins and coralline algae, and is bare of stony corals. The shells of snails found in this area are weakened, and snail juveniles are completely absent. Are these changes a foretaste of the fate of the oceans in general? Adverse effects of ocean acidification, particularly on organisms that build shells and skeletons from calcium carbonate, have been reported from experiments on individual species and enclosed communities. Such experiments rely almost exclusively on abrupt and short-term changes in CO2 concentrations, raising questions about the relevance of the observed responses to marine ecosystems exposed to high CO2 and low pH over periods of years or decades. This includes uncertainties about the ability of marine organisms to adapt to the projected ocean acidification, and whether species sensitive to high CO2 and low pH might be replaced by more robust forms of life without jeopardizing the overall functioning of the ecosystem. Hall-Spencer et al. take research in this field an important step forwards by investigating the long-term biological effects of permanent exposure to high CO2 concentrations on a natural ecosystem. In addition to confirming laboratory-based results on individual species, they see a substantial shift in the benthic community composition, with no indication of adaptation or replacement of sensitive species by others capable of filling the same ecological niche. As predicted from previous work, however, there are winners as well as losers in ocean acidification and carbonation. Although calcareous groups generally decline in abundance or vanish completely, photosynthetic groups such as sea grasses and brown algae benefit from the higher CO2 availability by increasing their biomass. that facilitating DNA demethylation in incompletely reprogrammed cells — using a chemical inhibitor of the DNA-methylating enzyme DNMT1 — leads to a considerable response. After treatment with the inhibitor, a sizeable fraction of the stable intermediate cells exhibit three iPS-cell-like characteristics: significant demethylation of the pluripotency genes; reactivation of genes normally expressed in ES cells; and an ability to form teratomas (benign tumours) composed of all three embryonic cell layers when injected under the skin of adult mice. There was also a time-dependent aspect to the inhibitor’s effect. Incorporating this demethylating agent into the early stages of the reprogramming protocol interfered with reprogramming, whereas its addition at later stages increased the number of ES-cell-like colonies fourfold. But the demethylating agent was much more effective at enhancing reprogramming than a theoretically more specific inhibition of DNMT1 using the technique of RNA interference (RNAi). The demethylation results therefore remain open to interpretation, because the drug might have indirect or nonspecific effects, and/or the specific RNAi approach might be much less efficient at decreasing methylation. In one of the stable intermediate cell lines, inhibitor-induced DNA demethylation alone was not sufficient to increase reprogramming efficiency. This suggests that the other potential impediment — incomplete repression of genes specifying a particular cell type — may block full reprogramming in these cells. But inhibiting the expression of several such genes with RNAi did not help. Only when RNAimediated inhibition of transcription factors was combined with chemically induced DNA demethylation did these intermediate cells become more amenable to reprogramming. The authors conclude that incomplete suppression of such genes and failure to demethylate DNA both interfere with reprogramming of adult cells, and that removing these impediments will enhance the efficiency of direct reprogramming. It remains to be seen whether the iPS cells generated from this more efficient protocol can contribute to the germ line when injected into a blastocyst (70–100-cell embryos), a rigorous test of their functional similarity to ES cells. Research into direct reprogramming is advancing rapidly. Reprogramming protocols that exclude the cancer-associated gene c-myc have been developed. Differentiated human cells have now been reprogrammed with the same four-gene cocktail, including cells from young and older individuals. And the therapeutic potential of iPS cells has been demonstrated in a ‘humanized’ mouse, in which globin genes were replaced with human globin genes so as to model sickle-cell anaemia. It will be interesting to know whether the DNA demethylating agent or inhibition of cell-type-specific factors that Mikkelsen and colleagues describe will improve the efficiency of the reprogramming protocols used for human cells, and of protocols lacking c-myc (refs 5, 13). iPS cells and the relatively simple methods used to generate them are of fundamental importance to biology. Reprogramming shatters the long-standing concept that the identity of differentiated adult cells is indelible. That DNA demethylation is essential for direct reprogramming is particularly interesting as this process is also strictly necessary for reprogramming by nuclear transplantation, and is a common mechanism in human cancers. Although we know very little about how DNA demethylation happens naturally, or how to manipulate it in a gene-specific way, this process clearly guides several essential cellular transition events. Another puzzle is whether DNA demethylation associated with direct reprogramming involves just a few crucial genes, or occurs genome-wide. Given the current international investment in comprehensively mapping DNA methylation and other epigenetic modifications genome-wide, the ‘red-hot’ iPS cells will undoubtedly garner even more attention. On research into iPS cells, E. E. Cummings might have commented “into the strenuous briefness, again”. ■