As I’ve mentioned several times, Matthew Cobb has written what will likely prove the definitive biography of Francis Crick (1916-2004), co-discoverer of the structure of DNA and a general polymath. While writing it, Matthew came across some Crick material showing that biologists and historians have misunderstood Crick’s “Central Dogma” of molecular biology.

Matthew has corrected the record in the piece below from the Asimov Press. Click the headline, as it’s free to read:

You may have learned this dogma as “DNA makes RNA makes protein,” along with the caveat that it’s a one-way path. But Matthew shows that this was not Crick’s contention. I’ve indented Mathew’s words below:

The Central Dogma is a linchpin for understanding how cells work, and yet it is one of the most widely misunderstood concepts in molecular biology.

Many students are taught that the Central Dogma is simply “DNA → RNA → protein.” This version was first put forward in Jim Watson’s pioneering 1965 textbook, The Molecular Biology of the Gene, as a way of summarizing how protein synthesis takes place. However, Watson’s explanation, which he adapted from his colleague, Francis Crick, is profoundly misleading.

In 1956, Crick was working on a lecture that would bring together what was then known about the “flow of information” between DNA, RNA, and protein in cells. Crick formalized his ideas in what he called the Central Dogma, and his original conception of information flow within cells was both richer and more complex than Watson’s reductive and erroneous presentation.

Crick was aware of at least four kinds of information transfers, all of which had been observed in biochemical studies by researchers at that time. These were: DNA → DNA (DNA replication), DNA → RNA (called transcription), RNA → protein (called translation) and RNA → RNA (a mechanism by which some viruses copy themselves). To summarize his thinking, Crick sketched out these information flows in a little figure that was never published.

Crick’s figure is below. Note that the dogma is simply the first sentence typed in the diagram, implying that information from either DNA or RNA, translated into a protein, cannot get back into the DNA or RNA code again. Thus changes in protein structure cannot go back and change the genetic code (see the bottom part of the diagram).

As you see, the DNA—>RNA—>protein “dogma” is an extreme oversimplification of Crick’s views. And he meant the word “dogma” to mean not an inviolable rule of nature, but a hypothesis. Nevertheless, Crick was widely criticized for using the word “dogma”.

But getting back to the diagram:

The direct synthesis of proteins using only DNA might be possible, Crick thought, because the sequence of bases in DNA ultimately determines the order of amino acids in a protein chain. If this were true, however, it would mean that RNA was not always involved in protein synthesis, even though every study at that time suggested it was. Crick therefore concluded that this kind of information flow was highly unlikely, though not impossible.

Crick also theorized that RNA → DNA was chemically possible, simply because it was the reverse of transcription and both types of molecules were chemically similar to each other. Still, Crick could not imagine any biological function for this so-called “reverse transcription,” so he portrayed this information flow as a dotted line in his diagram.

We now know, though that the enzyme “reverse transcriptase” is used by some RNA viruses to make DNA to insert into their hosts’ genomes.

Here’s what Crick said he meant by the “Central Dogma,” and, in fact, this schema has not yet been violated in nature:

In other words, in Crick’s schema, information within the cell only flows from nucleic acids to proteins, and never the other way around. Crick’s “Central Dogma” could therefore be described in a single line: “Once information has got into a protein it can’t get out again.” This negative statement — that some transfers of information seem to be impossible — was the essential part of Crick’s idea.

Crick’s hypothesis also carried an unstated evolutionary implication; namely, that whatever might happen to an organism’s proteins during its lifetime, those changes cannot alter its DNA sequence. In other words, organisms cannot use proteins to transmit characteristics they have acquired during their lifetime to their offspring.

In other words, there can be no Lamarckian inheritance, in which environmental change affecting an organism’s proteins cannot become ingrained into the organism’s genome and thus become permanently heritable.

Matthew discusses several suggested modifications of Crick’s version of the Central Dogma. Prions, misfolded proteins that cause several known diseases, were thought by some to have replicated themselves by somehow changing the DNA that codes for them, but it’s now known that prions are either produced by mutations in the DNA, or can transmit their pathological shape by directly interacting with other proteins. Prion proteins do not change the DNA sequence.

Some readers here might also be thinking that “epigenetic inheritance”, in which DNA is modified by chemical tags affixed to its bases, might refute the central dogma, as those modifications are mediated by enzymes, which of course are proteins. But as Matthew notes, those modifications are temporary, while the DNA sequence of nucleotides (sans modifications) is forever:

In other cases, researchers have pointed to epigenetics as a possible exception to Crick’s Central Dogma, arguing that changes in gene expression are transmitted across the generations and thus provide an additional, non-nucleic source of information. But still, epigenetics does not violate Crick’s Central Dogma.

During an organism’s life, environmental conditions cause certain genes to get switched on or off. This often occurs through a process known as methylation, in which the cell adds a methyl group to a cytosine base in a DNA sequence. As a result, the cell no longer transcribes the gene.

These effects occur most frequently in somatic cells — the cells that make up the body of the organism. If epigenetic marks occur in sex cells, they are wiped clean prior to egg and sperm formation. Then, once the sperm and eggs have fully formed, methylation patterns are re-established in each type of cell, meaning that the acquired genetic regulation is reset to baseline in the offspring.

Sometimes, these regulatory effects are transmitted to the next generation through the activity of small RNA molecules, which can interact with messenger RNAs or proteins to control gene expression. This occurs frequently in plants but is much rarer in animals, which have separate lineages for their somatic and reproductive cells. A widely-studied exception to this is the nematode C. elegans, where RNAs and other molecules can alter inheritance patterns.

No matter how striking, though, none of these examples violate Crick’s Central Dogma; the genetic information remains intact and the epigenetic tags are always temporary, disappearing after at most a few generations.

That should squelch the brouhaha over epigenetics as a form of Lamarckian evolutionary change, as some have suggested that epigenetic (environmental) modifications of the DNA could be permanent, ergo the environment itself can cause permanent heritable change. (That is Lamarckian inheriance.) But we know of no epigenetic modifications that last more than a couple of generations, so don’t believe the hype about “permanently inherited trauma” or other such nonsense.

And there’s this, which again is not a violation of Crick’s “Dogma”:

. . . enzymes can modify proteins in the cell after they have been synthesized, so not every amino acid in a protein is specified in the genome. DNA does not contain all the information in a cell, but Crick’s original hypothesis remains true: “Once information has got into a protein it can’t get out again.”

Now Matthew does suggest a rather complicated way that the Dogma could be violated, but it’s not known to occur, though perhaps humans might use genetic engineering to effect it. But you can read about it in his piece.

It’s remarkable that Crick’s supposition that information in a protein can’t get back to the DNA or RNA code—made only three years after the structure of DNA was published—has stood up without exception for nearly seventy years. This is a testament to Crick’s smarts and prescience.

And if you remember anything about the Central Dogma, just remember this:

“Once information has got into a protein it can’t get out again.”