Broad Institute, Cambridge, Massachusetts

A biologist looks at new functions for non-coding RNAs.

The increasing study of small and large RNA molecules that do not encode protein — non-coding RNAs — is widening our view of their relevance, and of their roles in important developmental mechanisms such as gene silencing and X-chromosome inactivation. Nevertheless, our knowledge covers only a fraction of the non-coding transcripts produced from the mammalian genome.

Much of the non-coding RNA transcribed is associated with protein-coding genes: for example, the transcripts that are complementary or 'antisense' to the gene sequence. These can be created by 'bidirectional' transcription from either DNA strand. Kevin Morris of the Scripps Research Institute in La Jolla, California, and his colleagues have now shed light on the function of this type of transcription (K. V. Morris et al. PLoS Genet. 4, e1000258; 2008).

They focused on the gene encoding the tumour suppressor p21, transcription of which must be finely tuned, and show that an endogenous antisense transcript of p21 controls the amount of p21 mRNA made by silencing its promoter. This transcriptional suppression is dependent on Argonaute-1, a protein implicated in RNA-mediated gene silencing. Suppression correlates with bidirectional transcription within p21's promoter.

This observation is not limited to p21: a similar regulatory mechanism controls gene expression of the protein E-cadherin, suggesting that this balancing of sense and antisense transcription might be a common mechanism of transcriptional regulation.

The next challenge is to understand how RNAs can induce transcriptional gene silencing; information that will probably reveal just how much power RNA wields in the control of gene expression.

Posted by Brendan Maher at 06:22 PM | Permalink | Comments (0) | TrackBacks (0)

Burnham Institute for Medical Research, La Jolla, California

A structural biologist has great expectations for llamas' small antibodies.

Llamas aren't just unusual and exotic looking: their antibodies are also a reason for much excitement. Made entirely of heavy chains, they are about half the size of those found in humans and many other vertebrates, which are normally composed of both heavy and light chains. When it comes to therapeutic applications, these larger antibodies are hard to store and deliver. But llama and other camelid antibodies demonstrate superior heat-stability and solubility, without compromising affinity or specificity, making them an attractive alternative.

Robin Weiss of University College London and his colleagues isolated three llama antibodies, known as 'neutralizing' antibodies, that can broadly prevent multiple HIV subtypes from infecting cells (A. Forsman et al. J. Virol. 82, 12069–12081; 2008). They began by creating an antibody library from two llamas immunized with the HIV gp120 antigen. To select for neutralizing antibodies, antibodies were raised against one HIV subtype but cross-screened against multiple subtypes. The researchers also included a competitive elution step to select antibodies that can compete with binding by CD4, the primary HIV receptor on human T cells. It remains to be seen how these neutralizing antibodies fare in animal studies and where they bind in atomic detail.

Intriguingly, there have been reports of several potent, broadly neutralizing human antibodies (for example, F10 and CR6261 against influenza's haemagglutinin) in which only heavy chains are involved in antigen binding — reminiscent of the situation of llama antibodies. These studies corroborate that the heavy chain alone can mediate broad neutralizing activity, and invite speculation that this may be a special strategy engaged by the human immune system to reach cryptic binding sites. Llama antibodies may be even better suited for those hard-to-reach targets.

Posted by Brendan Maher at 01:55 PM | Permalink | Comments (1) | TrackBacks (0)

University of Southampton, UK

A stem-cell researcher considers an accusation of dullness.

How might hard-working scientists react to an accusation that 'modern scientists' are 'dull', as is provocatively postulated in a March editorial of the non-peer-reviewed journal Medical Hypotheses (B. Charlton Med. Hypotheses 72, 237–243; 2009). With offence? Humour? Ambivalence? Or, perhaps, in response to a jeremiad bemoaning our apparent insufficient intelligence and creativity, we might retort, "So what? Tell us something we don't know."

Because, it seems to me, most working scientists have either long since accepted that they are not of the 'revolutionary' type exemplified by greats such as Isaac Newton, Charles Darwin and Albert Einstein, or never strived to be. Gaining and retaining employment in academia is hard enough. Yes, we are of the persevering and conscientious 'normal' type — if we weren't, nothing would get done.

We know there is too much bureaucracy. And yes, there is a lot of repetitive, boring, tiresome, problematic work to be done that is unlikely to shift any paradigms (yet), but important nonetheless. Whether or not somehow creating more windows of opportunity for would-be geniuses possessed of the requisite levels of selfishness and creativity would lead to significant changes in direction is debatable. But the drudge is always necessary in a multidisciplinary collaborative enterprise.

It's not that scientists are dull per se. Rather, instead of being the 'clever crazy' type that might belong in an institution, we labour in an institutionalized occupation that demands we play by certain rules. We know we're not going to change the world, but we like to think we can contribute to the sum of knowledge. Providing we can first convince our peers. If it was easy, everybody would do it. One might add, complaining that modern science can be dull, although valid, isn't exactly a 'revolutionary' idea. Tell us something original, eh?

Posted by Brendan Maher at 03:01 PM | Permalink | Comments (2) | TrackBacks (0)

University of Delaware, Lewes

A microbial ecologist learns something new from an old-fashioned study.

What could be easier than learning about an organism simply by watching how it varies over time in its natural habitat? You'd think this would have been done long ago for marine bacteria, which are important in many biogeochemical processes, including the carbon cycle; in fact, they're the organisms running the biosphere. But it's not easy to follow microbes in the open ocean, far from the lab and beyond the reach of standard techniques.

Craig Carlson at the University of California, Santa Barbara, and his colleagues took on this challenge for the most abundant group of marine bacteria: SAR11. They examined variations in SAR11 over several years in the Sargasso Sea, where the group was first discovered nearly 20 years ago (C. A. Carlson et al. ISME J. 3, 283–295; 2009). Sequencing and other data had previously revealed that SAR11 bacteria are diverse and can account for almost 50% of microbes in a given marine environment; however, we still knew little about their natural history.

So Carlson's group looked to address a basic question: how do different members of SAR11 vary with depth and over time? They examined 13 years' worth of DNA samples, viewed 3 years' worth of preserved cells under the microscope, and then analysed the microbial data in light of what is known about SAR11's environment. Three SAR11 'ecotypes', they say, flourish differently at various depths and over a yearly cycle, which starts in spring, when deep mixing stops and photosynthesis speeds up.

The authors make good use of new genomic data from a lab-grown representative of SAR11 (Pelagibacter ubique) to understand Sargasso Sea populations, but the study's insight comes from the old approach of patiently watching organisms over time in their natural habitat.

Posted by Brendan Maher at 09:22 PM | Permalink | Comments (0) | TrackBacks (0)