Monday, July 18, 2011

One gene one .... what? The problem with the 'Centra Dogma'...or any dogmas in science

One thing that has been found in recent years, and about which knowledge has been rapidly expanding is that the grand old 'Central Dogma of Biology', that one gene codes for one protein is, well, substantially wrong (to be kind to it).

Gene transcription, from The Mermaid's Tale, Weiss & Buchanan, 2009

The Central Dogma held that DNA is a string of codes that specifies messenger RNA (mRNA) that is translated in the cell into protein.  One gene, one protein.  That was how it looked when the nature of DNA was first being discovered.  But it's been decades since we knew that was not accurate.

A few of the reasons are
  1. genes are interrupted coding sequences (they have non-coding 'introns'),  
  2. introns are spliced out of mRNA by particular DNA sequence motifs,  
  3. genomes evolve by duplication of whole segments, 
  4. much more DNA is transcribed into RNA than was thought; 
  5. some of this RNA has complimentary sequences to protein codes and there is an elaborate mechanism for this, which is never translated into protein, to inhibit 'real' genes (this known as microRNA);  
  6. some non-protein RNA--copied from genes without the usual gene processing sequence elements, is nonetheless found attached to ribosomes in the cell as if it were being translated anyway; 
  7. gene usage is determined in part by the way DNA in the gene's part of a chromosome is packaged and chemically modified ('epigenetics'); 
  8. important aspects of variation are due to mutations that happen during the lifetime of the organism; 
  9. each cell uses only some of its genes, and sometimes only one of its two copies of a gene that it is using; 
  10. genes can be assembled via effects of genes from other chromosomes or even make mRNA that is a composite of pieces from two different chromosomes ; and (so we don't have to keep on and on), 
  11. some mRNA is 'edited' after being transcribed, in replicable ways sometimes conserved among distantly related species, in which one nucleotide copied from the DNA template is replaced by a specific other nucleotide, thus changing the function, including the protein code, of the mRNA.
These are among many other things that we now know to be parts of DNA function.  They don't change the basic idea that DNA specifies protein structure, but there are so many details, of so many sorts, that it is clear that the idea of the Central Dogma is essentially wrong.  Yet, why do we still have 'exome' sequencing in so many expensive studies, or gene 'for' this or that trait, in so many expensive studies, when we know how simplistic this is?

There are many answers, and we regularly harp on them.  Here, the main point is that these discoveries are real, their importance highly variable and mainly unknown, and that they always add to, but rarely if ever reduce, the complexity between DNA and the traits that it affects.  Promises of simple prediction have been aided and abetted by the addictive discoveries that really work like the genes Mendel studied in peas.  We do a lot of hand-waving to dismiss complexity, but we cling like drowning sailors to life-rafts to the simple, Central Dogma, in the fervent hope that we'll find the Big Gene Story.   Yet those who are thinking about science itself, rather than about what they have to do to maintain their careers, know very well that we know very little about the nature of genetic function.

Dogma should not be part of science.  But historians and philosophers of science have shown that it certainly is.  A new book, for example, shows how this has affected immunology for decades, as  investigators clung to a 'fictive' theory, the idiotype network theory, even though it never had much basis (the book, The network collective: Rise and fall of a scientific paradigm, edited by Klaus Eichmann, is reviewed in the July issue of Bioessays). There's no place for dogma in science, nor for the tribalism that accompanies it.  But, well, we're only human so purging the motivations that drive dogma, and the careers that are made on its basis, may not be in the cards.


jaxkayaker said...

Larry Moran's take on the Central Dogma conflicts with your presentation of it:

Ken Weiss said...

Yes, you present a nice view of things.

Various versions of the 'dogma' have been offered, and circulated around, and interpreted. The most common is one gene one polypeptide, I think, although the one-way movement of information is certainly a part of it.

Whether various things like methylation and so on that transfer information from cell state to DNA state should count as 'violations' is debatable, and perhaps even a part of scientists wanting to know better than their predecessors and modifying meanings accordingly.

Some feedback onto DNA sequence itself does occur, such as in gene excision in immune system genes in vertebrates, but those are not directed by specific environmental conditions.

If a misperception of some versions, or an incomplete understanding is widespread and is in many textbooks or courses (or even if students miss the key points), the idea of a dogma is a poor one (whether or not Crick was being tongue in cheek as some would say or as he said in a letter--I forget), and the educational system is too often not doing its job.

Could it equally be viewed as hiding behind a technicality to deny that epigenetic and other signal-based gene expression changes, which are clearly cell-experience derived, should count as as a back flow of information to the genome? After all, it may be that DNA sequence isn't changed, but the idea of back and forth information flow to the genome seems correct in that sense. I don't know how much that's relevant was known in the Dogma-stating time. But maybe it was OK for what was then known, but overstated in light of current knowledge.

While the point we made is that things are not so simple is, I think, correct, it is also correct (so far as anyone yet knows) that not everything anybody finds and lauds in science is as revolutionary as they often claim.

Maybe what we need is simply a more nuanced--and widely understood!--statement of principles of biology, than by a 'Dogma' of that sort, even if its basic points seem basically valid.

PJ said...

Unfortunately, this refutes the sequence hypothesis "one gene, one protein" hypothesis that was suggested by James Watson. This has been well disproved in the past (as mentioned). However, Francis Crick's model, the Central Dogma, still holds true: once information flows from nucleic acid to protein, it cannot flow back to nucleic acid.