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Saturday, January 03, 2015

Thinking critically about the Central Dogma of Molecular Biology

Our department is preparing to review our undergraduate courses and programs. Part of the review will be to examine our fundamental goals and objectives and determine if we are meeting them. In preparation for this exercise, I've been going over some papers that have been sitting around my office.

One of them concerns teaching the Central Dogma of Molecular Biology (Wright et al., 2014). It was just published last year. The authors have discovered that students have a "weak conceptual understanding" of information flow. Here's how they describe it in the abstract.
The central dogma of molecular biology, a model that has remained intact for decades, describes the transfer of genetic information from DNA to protein though an RNA intermediate. While recent work has illustrated many exceptions to the central dogma, it is still a common model used to describe and study the relationship between genes and protein products. We investigated understanding of central dogma concepts and found that students are not primed to think about information when presented with the canonical figure of the central dogma. We also uncovered conceptual errors in student interpretation of the meaning of the transcription arrow in the central dogma representation; 36% of students (n = 128; all undergraduate levels) described transcription as a chemical conversion of DNA into RNA or suggested that RNA existed before the process of transcription began. Interviews confirm that students with weak conceptual understanding of information flow find inappropriate meaning in the canonical representation of central dogma. Therefore, we suggest that use of this representation during instruction can be counterproductive unless educators are explicit about the underlying meaning.
This is a paper that interests me greatly because I think it's very important to focus on teaching important principles and concepts instead of trivial details.

Most of you know that I'm also interested in the Central Dogma [Basic Concepts: The Central Dogma of Molecular Biology]. I've been writing about it for almost two decades. There are two versions of the Central Dogma. The one you are most familiar with is the version promoted by Watson in 1965.
The discovery of reverse transcriptase a few years later prompted him to revise this version in subsequent editions so that now we often see double arrows going in both direction between DNA and RNA.

This is not the version that Francis Crick wrote about in 1958. He drew two diagrams illustrating all the possible directions of information transfer (left below) and the ones that may be permitted (right). The Central Dogma, according to Crick, is that "... once (sequential) information has passed into protein it cannot get out again."

Crick re-stated his original version in a classic Nature paper in 1970 after the discovery of reverse transcriptase. He pointed out that the synthesis of DNA from RNA is not a violation of the Central Dogma (original Crick version) because he explicitly mentioned that as a possibility. Furthermore, the Central Dogma says nothing about information flow between RNA and DNA it only forbids information flow from protein to nucleic acids.

He made this very clear in his 1970 paper.
The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)
Crick's papers are all about information flow. They have very little to do with transcription, reverse transcription, and translation.

I think it's important for students to understand this concept and to understand that information can't flow back from protein to nucleic acids. I think it's important for them to understand that the common version of the Central Dogma (DNA to RNA to protein) is a misrepresentation of Crick's original ideas. Correcting this misunderstanding is a good way to reinforce the concept.

Let's look at what Wright et al. (2014) have to say about the Central Dogma of Molecular Biology.
Indeed, the concept of information being stored in DNA molecules, copied into RNA intermediates, and expressed in proteins that carry out cellular functions, is known as the "central dogma" of molecular biology. Francis Crick first described the central dogma as "the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid" (Crick, 1970). The canonical interpretation of the central dogma is that genetic information (DNA) is used to generate transient messenger molecules (RNA) that are themselves used to direct synthesis of particular protein products and that the proteins are responsible for most cellular functions.
I don't think the authors have read the 1970 Nature paper very carefully because they misrepresent the main point that Crick was making in that paper. The information flow diagrams that Crick published are what he refers to as the "Sequence Hypothesis." This is NOT the Central Dogma.

It's going to be difficult to test student's understanding of information flow if it's not taught correctly. The authors may be testing whether students understand transcription but that's an entirely different topic—one that should be covered in several lectures on the role of RNA polymerase in copying DNA.

The authors seem to recognize that the Watson version of the Central Dogma has some problems.
In a recent review "revisiting" the central dogma, Shapiro (2009) wrote, "The idea of a ‘dogma’ in science has always struck me as inherently self-contradictory. The scientific method is based upon continual challenges to accepted ideas and the recognition that new information inevitably leads to new conceptual formulations." The discoveries of reverse transcription, catalytically active RNA molecules, and posttranscriptional modification of RNA molecules are examples of a few of the many exceptions to the central dogma. And while the traditional representation of the central dogma (Figure 1) suggests a very simplistic mechanism for information flow, in reality, the processes that direct the synthesis of each macromolecule are numerous and complex. Most postsecondary educators would likely agree that concepts related to the central dogma are crucial to their curricula in courses such as those in introductory biology, cell and molecular biology, genetics, and developmental biology, as well as in many others. As the fields of genomics and bioinformatics continue to be revolutionized by advancing technologies such as whole-genome sequencing (Ng and Kirkness, 2010; Mavromatis et al., 2012), it is critically important that we prepare our biology students to think deeply and carefully about information flow.
I've posted a critique of Shapiro's article at:Revisiting the Central Dogma in the 21st Century. He's another scientist who quotes Crick's Nature paper without understanding it.

Here's the problem. While there is general agreement that we should be concentrating on teaching fundamental concepts, there's less agreement on what those concepts are. I've also noticed a disturbing trend in the pedagogical literature. Many teachers of biochemistry and molecular biology will advocate their version of fundamental concepts but far too often those concepts are flawed.

As Wright et al. put it, "As the fields of genomics and bioinformatics continue to be revolutionized by advancing technologies such as whole-genome sequencing, it is critically important that we prepare our biology students to think deeply and carefully about information flow." I'm sure we all agree with that sentiment.

They also seem to be aware of the fact that students will often begin a class with misconceptions and misunderstandings and good teachers will make an effort to correct those misunderstanding. They say ...
In Science Teaching Reconsidered: A Handbook, conceptual misunderstandings are described as phenomena that occur when students are not forced to confront the discrepancies between their own preconceived ideas and real-world observations. The failure to critically examine one's own mental models leads to weak, faulty models, with little confidence behind them. Conceptual misunderstandings are problematic, because their existence often interferes with learning new concepts, especially if the misconceptions seem rational and useful to the learner at the time ...
I don't think we are doing enough to alert teachers to the fact that they, themselves, might suffer from this problem. I agree with their conclusion ...
... it is crucial that we, as educators, are careful about our language with students and demand that students be equally precise. Without such rigor, we cannot evaluate their mental models or prevent the creation of new misconceptions.

Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163 [PDF].

Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]

Watson, J.D. (1965) The Molecular Biology of the Gene. W.A. Benjamin. Inc. New York

Wright, L.K., Fisk, J.N., and Newman, D.L. (2014) DNA --> RNA: What Do Students Think the Arrow Means? CBE-Life Science Education 13:338-348. [doi: 10.1187/cbe.CBE-13-09-0188]


Anonymous said...

I don't think Crick's Central Dogma is a concept that needs to be enshrined. Its an interesting footnote in the history of ideas that advanced molecular biology. Of course sequence information can't be extracted from a protein but I don't think this has to be the case. I can imagine some proteosome-like structure that unfolded a protein and then had a mechanism for matching each aa to codons that were ligated together. I'd never claim that such a reverse-translation system could have ever evolved - it would need to be far more complex than translation- but I don't think there are any physical principles that preclude it. For this reason its just another fact of life that's the result of historic contingency and being aware of it doesn't count as a deep understanding of biochemical principles. You've discussed issues in the past- kinetics, energy and evolution that I think are far more important examples.
And why are students having all these difficulties with the flow of information in a cell? I don't think the concepts are that difficult to grasp. I suspect the students spend so much time on the details that they never step back and think about the big picture, but I think that most are bright enough that if they had any motivation to do so they'd have a reasonable understanding.
......for some reason as I contemplate pushing the 'Publish' button I have an ominous sense of foreboding

Unknown said...

A new paper in Science blurs the central dogma. Protein-making protein:

AllanMiller said...

It might help if people had a better grasp of the fact that RNA and DNA are essentially minor variants of each other - an oxygen atom present or absent every residue, ditto a methyl group on 1 in 4, and the odd exotic base, are all that separate them. Only the latter influences the 'information' content.

TheOtherJim said...

How exactly is a protein-based mechanism to clear a stalled ribosome. a contradiction of the central dogma?

Larry Moran said...

Nonribosomal peptide synthesis is covered in most biochemitry textbooks. It's been there for at least 25 years. The best known examples are the peptide antibiotics produced by many bacteria. These are small proteins with a specific amino acid sequence made in the absence of mRNA or ribosomes. Google "nonribosomal petide synthesis."

This has nothing to do with the original (correct) version of the Central Dogma but it might be confusing to those who interpret it to mean that all proteins/ peptides have to be made from RNA.

Unknown said...

Non-ribosomal peptide synthesis, as the name suggests, does not involve any ribosome or tRNAs.
But this case involves a protein, Rqc2p, which interacts with both the A-site and P-site on the 60S ribosomal subunit and recruits tRNAs specific for alanine and threonine adding them to a nascent peptide chain, all in the absence of mRNA and the relevant codons. This shows, for the first time, that ribosomal protein synthesis can occur without an mRNA code.

Jonathan Badger said...

It's important that students understand information flow, of course, but I don't really see how which version of the Central Dogma taught really matters. Or if it is taught at all outside a history of science class. Yes, it was an important idea in the development of molecular biology, but that doesn't mean that it a fundamental concept worth teaching. One can quite easily explain how DNA and RNA are interconvertible (and as Allan says, just variants of each other) and that translation is one way based on the actual science involved rather than because it is according to a so-called "dogma".

Larry Moran said...

@Vimal Ramachandran

Gimme a break. This is not nearly as big a deal as the synthesis of complete peptides with a defined amino acid sequence in the absence of mRNA and ribosomes. Besides, I'm going to wait until the data has been confirmed before accepting it as a fact.

Unknown said...

Sure, it's only a peptide tail and not a full-fledged protein that's being synthesized here. But this phenomenon went undetected since the advent of molecular biology and the central dogma doesn't seem that much dogmatic now. There may be more flexibility in the system than what we had assumed. A closer look at protein synthesis is warranted. Here's a popular article on the discovery:

Claudio said...

Let's not be dogmatic

frankly said...

No it doesn't. I posted a half dozen cases of "proteins altering the primary sequence of a protein" on WEIT: inteins, ubiquitination, selenocysteine (rather close to what goes on here), etc.

frankly said...

I think undergraduate courses need a much stronger understanding of biochemical information theory in general - e.g., Tom Schneider's papers. That would help in understanding the Central Dogma, gene regulation, and a whole lot more.

Unknown said...

Matthew Cobb has a good piece about this story on WEIT:

Frankly, I saw your comment in response to Matthew's post. But ubiquitination, SUMOylation, phosphorylation, inteins etc are post-translational modifications of proteins. The insertion of selenocysteine occurs at the level of translation, but requires the mRNA UGA codon and selenocysteine insertion sequence. On the contrary, here we're dealing with translation that's occurring independent of the mRNA, with the recruitment of tRNAs mediated by a protein. This was never considered possible according to Crick's central dogma.

frankly said...

Actually it was considered possible. For a long time (6 or so years) after the publication of the Central Dogma, it was hypothesized that the release factor(s) could be a specialized tRNA. Instead it's a protein that fits into the A-site.

Kariuki Sam said...

I concur with Vimal Ramachandran. I think these exemptions are far too many. I also wrote about the central dogma here:

Larry Moran said...

Your blog post is ridiculous. You haven't been paying attention to any of the discussions about the meaning of the Central Gogma.