On the discovery of a ‘second code’ within DNA

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Although with my entire being I believe the title for this piece should be ‘An example of sensationalist columnists getting out of hand’, it’s a better opportunity to educate people on exactly how news gets out of hand and the science behind it in general. First, a primer for anyone who has forgotten, or has never known, their basic biology. All eukaryotic living cells (like those that make up humans) contain DNA. This DNA can freely replicate itself as DNA during cell division, or be transcribed into mRNA, which in-turn is then translated into a protein. The central dogma of biology states that all three structures – DNA, RNA and Proteins – interact to give rise to all life, and in many ways share their properties themselves between one another to fulfil various functions (for example, recent research suggests Protein epigenetic DNA modifications can be inherited, passing adaptations between generations at a pace quicker than evolution).Researchers from the University of Washington, or rather the PR department for the University at least, claim to have discovered a ‘second code’ within DNA (paper1– paywall warning) that redefines the way with which DNA expression and protein regulation occur within the cell. They think this is critical enough to be referred to in the same breath as the Crick and Brenner paper2 that announced the discovery of codons as DNA’s fundamental translational unit, and tout it as a medical break-through for the rest of our lifetimes. In reality, there have been discoveries that are this critical since 1961, and here’s how they’re different from the one announced this week:

  • The discovery of Alternative Splicing3: This is as close to a second language within DNA as we have found until this point. Basically, even though a single gene can be converted into a single transcript, by splicing different parts of the mRNA transcript (exons being the critical coding parts), multiple proteins can be formed. Recently, alternative splicing has been implicated as possibly being the dominant inter-generational transmission method of genetic defects in up to 60% of all hereditary diseases4.
  • The discovery of RNA Interference5: While not directly related to the reading of the genetic code, this discovery, and the subsequent research that found siRNA and miRNA, have been critical in understanding the degradation of RNA once it is transcribed from the DNA. There are many clinical trials testing intravenously-delivered interfering RNA as a therapeutic method for certain diseases (HIV, Hepatitis). This remains the only method technically feasible for post-transcriptional therapy.

And these are just the critical, field-defining discoveries when it comes to mRNA control and degradation within the cell. Many other levels of gene expression regulation exist, including (but not limited to) RNA localization, translational control, protein localization and protein degradation.

The main cellular method for regulating gene expression exists at the transcriptional level, however. This is due to the evolutionary need for the cell to never waste resources on transcripts it doesn’t need to create or utilize. The DNA itself is structurally regulated by only being uncoiled during its transcription, and is chemically regulated through methylation for silencing and acetylation for activation of transcription. The process of transcription itself is governed by a few additional fail-safes, including the necessity for the aggregation of multiple specific transcriptional factors, the absence of any operator repressors (or, alternatively, the presence of enhancers).

It is here that the UW discovery is critical – as a discovery about the double-use of codons in the tertiary expression hurdle in but one (the first) of the 8 or 9 major regulatory mechanisms the cell uses in the regulation of gene expression (in contrast with the studies in the bullet points above, which explain primary ways with which one of the major regulatory mechanisms operates). The study shows that up to 15% of codons in exonic regions direct transcriptional regulation. This is not a novel concept and, in fact, this is in-line with our understanding of operator sites. It is the prevalence and identity of these sites that has never been clarified with such detail in the past.

However, general practitioners, and the medical community at large, should have no interest whatsoever in this discovery. Even for the vast majority of researchers studying gene expression this doesn’t change a lot considering controls in those experiments are predicated on mostly post-transcriptionally observable changes that are standardized (usually through experimentally relying on a single operator site across multiple samples). This study does however affect researchers studying transcriptional control within the cell and how they might consider creating new specific synthetic polyamides (for silencing certain genes) (although, this technological advantage is at least a decade or two away from clinical relevance), or accounting for and detecting new variables in controlling expression in the preliminary phases of transcription.

While there’s nothing else to say on the scientific side of things, it may be worthwhile to consider how the news spread like a fire, with many of the articles only ever so slightly paraphrasing each other, in a scramble to accrue as many clicks as possible. But that’s an argument to be made by someone who understands the numbers behind newsreporting. Responsible, educated reporting is another thing, however, and it was unfortunately severely ignored in this case, in favour of reposting a PR speech. Some of the blame surely lays with scientists who themselves know that a catchy title or label to their paper, discovery or abstract will go viral with news outlets and yet they socially engineer their output in such a way that it piggy-backs on mainstream media for extra exposure.

For more information on the progress of the field of DNA/RNA biology, and their therapeutic ramifications, these wikipedia entries are actually great starting points.

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