RNAi melts cholesterol

The powerful technique of RNA interference was put to use last month to regulate cholesterol levels in mice. Jürgen Soutschek et al. (Nature 432, 173–178) administered the RNA by intraveous injection, a route that had proven difficult in earlier studies.

The target was apolipoprotein B, a key regulator of cholesterol levels. RNAi treatment reduced levels of mRNA encoding apolipoprotein B by 50% in the liver and 70% in the jejunum, resulting in lowering of blood cholesterol comparable to that observed when the gene for apolipoprotein B is deleted.

Key to the success was a slight modification—the small RNAs were joined by a cholesterol group, which insured delivery to the correct tissues. But many hurdles still remain, as regular infusions of large quantities of RNA-cholesterol conjugates would be required to translate the findings, as they stand, to people. Whether conjugation with cholesterol can be used to silence other disease-related genes remains to be seen.

Consumption and cannibalism

The influence of autophagy—whereby components of the cytoplasm are degraded in the lysosome—expanded last month. One study implicated the process in defense against group A Streptococcus, and another in keeping newborn mice alive after birth.

Ichiro Nakagawa et al. (Science 306, 1037–1040) found that cells eliminate Streptococcus by enveloping the bacteria in cytoplasmic compartments, and killing them upon fusion with lysosomes. In autophagy-deficient cells the bacteria multiplied wildly, and burst from the cells. Perhaps other bacteria that accumulate in intracellular compartments, such as Listeria and Rickettsia, are also eliminated by autophagy, suggest the authors.

Akiko Kuma provide evidence that within minutes after birth, young mice begin to consume themselves (Nature, doi:10.1038/nature03029). Autophagy, a process laregly dormant during embryogenesis, initiates on a massive scale, and quiets down within 12 hours. Mice lacking a critical autophagy gene survive to birth with few overt defects. But they die within 12 hours after birth—an event that can be delayed if they drink milk. The authors propose that such cellular cannibalism provides nutrients to the vulnerable newborn while its systems are turning on and before it begins to suckle efficiently.

Antiviral tag team

The field of toll-like receptors (TLRs), molecules that recognize viruses and other pathogens, has exploded in recent years. But a few puzzles remain. One is this: activation of TLRs is important for inducing maturation of dendritic cells, and dendritic cells initiate T-cell responses. But most viruses do not infect dendritic cells.

In the 16 November PNAS, Ayuko Sato and Akiko Iwasaki begin to unlock this puzzle (101, 16274–16279). The researchers investigated mice infected with herpes simplex virus, which like many viruses infects nonimmune cells (stromal cells). They generated chimeric mice in which either the immune cells or the stromal cells were lacking TLR signaling; among other findings they showed that normal immune cells were not sufficient to mount an effective T-cell response against the virus. They suggest that virally infected stromal cells instruct dendritic cells to initiate the appropriate T-cell responses. The exact molecular details of this 'two-stage' recognition need to be worked out.

Identifying the enabler

The biological basis of nicotine addiction became clearer last month, with research showing just how central a nicotine-binding receptor is to mediating the drug's effects.

Nicotinic acetylcholine receptors, widely expressed in the nervous system, are activated by the neurotransmitter acetylcholine. There are eleven acetylcholine receptor subunits in humans and these combine variously to create different receptors, each containing five units. Receptors containing α4 and β2 subunits have been implicated in nicotine addiction. For instance, mice lacking the β2 subunit have reduced sensitivity to the addictive effects of nicotine. But how such receptors work and their importance has been hazy.

In the 5 November Science, Andrew Tapper et al. (306, 1029–1032) began to clear the air. They engineered mice to express a α4 receptor subunit, modified to have high affinity for nicotine. They reasoned that such mice should be more susceptible to the drug's effects. They found that this was the case, with lower doses of the drug needed to increase locomotor activity, and two aspects of addiction, sensitization and reward.

Artificial organoid

Artificial lymphoid organs contain the requisite cell types: T cells (red), B cells (green) and dendritic cells (blue), in the right proportions. Credit: Reprinted from Nature Biotechnology

Using a few tissue culture cells and a sponge-like scaffold, researchers have created an 'organoid' that resembles a lymph node (Nat. Biotechnol., doi:10.1038/nbt1039). What's more, this organoid can produce antibodies when transplanted into mice with severe combined immunodeficiency (SCID).

The key to success was a 'collagen sponge' scaffold made of the Achilles tendon of cattle. Sachiko Suematsu and Takeshi Watanabe embedded cells in the sponge that were designed to attract immune cells. These cells were engineered to express molecules, such as lymphotoxin-α, that seed the formation of lymphoid structures. A dose of dendritic cells enhanced the ability of the structures to generate lymphoid-like organs when transplanted into mice. The invention should help answer questions about how lymphoid organs are built.

Alien flu gene

An analysis of the deadly strain of the pandemic 1918 flu virus has uncovered a 'mystery gene' of unknown origin. The strain, which killed more than 20 million people, is being analyzed from archival material by several groups. These analyses suggest that many of the genes encoding the viral surface proteins originated in birds. Ann Reid et al. (J. Virology 78, 12462–12470) took a look at the viral nucleoprotein gene, which mediates viral transcription and replication, and is a major determinant of host specificity. The analysis showed that the 498–amino acid protein differed from bird consensus sequences at six amino acids. But there were more than 170 differences in the nucleic acid sequence, more than expected based on the rate at which changes accumulate in bird genes in human viruses. Further analysis hinted that the gene may not have a human origin, but came from some unknown source several years before the pandemic hit full force.

Written by Charlotte Schubert