Quality AND quantity

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The Sea Change That’s Challenging Biology’s Central Dogma

[Via Discover Magazine | RSS]

For decades, RNA was seen as a simple slave to DNA. Newer research shows it has an active and critical role in every disease from Alzheimer’s to cancer.

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This is a great story about how a small group of focussed people working on a seemingly obscure problem can sometimes provide incredible insight. The author provides some really great insight into the path the research took, including the fact that the researcher who first published on this work, who was one of the key instrumental scientists involved, did not initially get tenure.

His work was viewed as too obscure.

The article does an excellent job of portraying these researchers as flesh and blood humans, rather than Promethean geniuses or lone wolfs.

The only thing a little off is that this work’s challenge to the Central Dogma (i.e. DNA to RNA to Protein) is a little more subtle than simply overturning it. It is more like the effect of Relativity on Newtonian mechanics.

It provides a more sophisticated explanation while leaving much of the framework intact.

In the Central Dogma, proteins are the really important things. They determine just what a cell does. DNA is simply the memory and RNA the transmitter. But proteins are the key.

The big challenge this work provides, where it does some real overturning of paradigms, are to some of the hypotheses regarding so-called junk DNA. Many people have had a feeling that this supposedly unused DNA might actually have a use. It has just been hard to figure out what it is. Now we have an idea of what some of it does.

It is there for a reason.

And what it does is really important. One area where the Central Dogma is influential is with the idea of genomic sequencing as an insight into disease. ‘If we want to know what the protein sequence is, we can look at the DNA sequence.’

However, it is really hard to determine the sequence of a protein, while it is easy to get DNA sequences. So genomic sequencing has been a surrogate for having protein sequences. The Dogma suggests that there is a one-to-one mapping of DNA sequence and protein sequence. With some small exceptions, this remains true.

This makes sense since mutations in DNA often produce alterations in proteins. A change in quality of one is seen in a change in the quality of the other. So we have been hearing a lot about getting everyone’s DNA sequenced. Then we will know what diseases they are likely to be susceptible to. At least in a simple world.

This is a leftover of the Central Dogma’s proposal that changes in proteins are reflected in changes in DNA sequences. But I have already discussed how epigenetic factors (here, here, here, here, here ) can break this relationship, producing different disease states without changing the genetic sequences.

Proteins are still important. But simply knowing what their sequence is – indirectly from DNA – does not describe fully the complex nature of a cell. More than just protein sequence is used to determine what a cell does.

The work on microRNA demonstrates that simply knowing a person’s genomic sequences does not tell the whole story. These RNAs are critical for controlling the amount of different proteins found in each cell.

And the quantity may be just as important as the quality.

Along with epigenesis, microRNAs show us that disease can be caused by the wrong amount of a protein.

So, the dogma of DNA to RNA to Protein is still present. Things are just a little more complex. What a cell does is not just determined by the quality of protein, its sequence that then determines its structure and activity.

It is also determined by the quantity of the protein. Some cells may have a protein that can prevent disease. But if microRNAs prevent it from being produced, then we have disease. Knowing the DNA sequence might not really help us much in this case.

Having too much or too little of a particular protein in a specific cell may well be the cause for many of the diseases we see today. Sometimes it will be because the protein itself is ‘wrong’ and sometimes it will be because the amount of protein present is wrong.

Knowing the genomic sequence of a person will be really important and useful to have. But it will be critical to know how much protein is produced. Knowing how microRNAs work will be critical for understanding this.

[Listening to: Stuck On You from the album “Elv1s 30 #1 Hits” by Elvis Presley]