Basic Concepts: The Central Dogma of Molecular Biology

The demise of the Central Dogma of Molecular Biology is becoming an annual event. Most recently, it was killed by non-coding RNA (ncRNA) (Mattick, 2003; 2004). In previous years the suspects included alternative splicing, reverse transcriptase, introns, junk DNA, epigenetics, RNA viruses, trans-splicing, transposons, prions, epigenetics, and gene rearrangements. (I’m sure I’ve forgotten some.)

What’s going on? The Central Dogma sounds like the backbone of an entire discipline. If it’s really a “dogma” how come it gets refuted on a regular basis? If it’s really so “central” to the field of molecular biology then why hasn’t the field collapsed?

In order to answer these questions we need to understand what the Central Dogma actually means. It was first proposed by Francis Crick in a talk given in 1957 and published in1958 (Crick, 1958). In the original paper he described all possible directions of information flow between DNA, RNA, and protein. Crick concluded that once information was transferred from nucleic acid (DNA or RNA) to protein it could not flow back to nucleic acids. In other words, the final step in the flow of information from nucleic acids to proteins is irreversible.

Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.

Crick restated the Central Dogma of Molecular Biology in a famous paper published in 1970 at a time when the premature slaying of the Central Dogma by reverse transcriptase was being announced (Crick, 1970). According to Crick, the correct, concise version of the Central Dogma is ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

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)

Announcing the (Premature) Death of the Central Dogma
The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein coding RNA (ncRNA) transcription in the higher eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of genetic regulatory systems in animals and plants may be incorrect.

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939.

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The central dogma, DNA makes RNA makes protein, has long been a staple of biology textbooks.... Technologies based on textbook biology will continue to generate opportunities in bioinformatics. However, more exciting prospects may come from new discoveries that extend or even violate the central dogma. Consider developmental biology. The central dogma says nothing about the differences between the cells in a human body, as each one has the same DNA. However, recent findings have begun to shed light on how these differences arise and are maintained, and the biochemical rules that govern these differences are only being worked out now. The emerging understanding of developmental inheritance follows a series of fundamental discoveries that have led to a realization that there is more to life than the central dogma.

Henikoff, S. (2002) Beyond the central dogma. Bioinformatics 18:223-225.

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It will take years, perhaps decades, to construct a detailed theory that explains how DNA, RNA and the epigenetic machinery all fit into an interlocking, self- regulating system. But there is no longer any doubt that a new theory is needed to replace the central dogma that has been the foundation of molecular genetics and biotechnology since the 1950s.

The central dogma, as usually stated, is quite simple: DNA makes RNA, RNA makes protein, and proteins do almost all of the work of biology.

Gibbs. W.W. (2003) The unseen genome: gems among the junk. Sci. Am. 289:26-33.

Unfortunately, there’s a second version of the Central Dogma that’s very popular even though it’s historically incorrect. This version is the simplistic DNA → RNA → protein pathway that was published by Jim Watson in the first edition of The Molecular Biology of the Gene (Watson, 1965). Watson’s version differs from Crick’s because Watson describes the two-step (DNA → RNA and RNA → protein) pathway as the Central Dogma. It has long been known that these conflicting versions have caused confusion among students and scientists (Darden and Tabery, 2005; Thieffry, 1998). I argue that as teachers we should teach the correct version, or, at the very least, acknowledge that there are conflicting versions of the Central Dogma of Molecular Biology.

The pathway version of the Central Dogma is the one that continues to get all the attention. It’s the version that is copied by almost all textbooks of biochemistry and molecular biology. For example, the 2004 edition of the Voet & Voet biochemistry textbook says,

In 1958, Crick neatly encapsulated the broad outlines of this process in a flow scheme he called the central dogma of molecular biology: DNA directs its own replication and its transcription to yield RNA, which, in turn, directs its translation to form proteins. (Voet and Voet, 2004)

If the Watson pathway version of the Central Dogma really was the one true version then it would have been discarded or modified long ago. In his original description, Watson drew single arrows from DNA to RNA and from RNA to protein and stated ....

The arrow encircling DNA signifies that it is the template for its self-replication; the arrow between DNA and RNA indicates that all cellular RNA molecules are made on DNA templates. Most importantly, both these latter arrows are unidirectional, that is, RNA sequences are never copied on protein templates; likewise, RNA never acts as a template for DNA.

Fig. 2. Watson’s version of the Central Dogma. This figure is taken from the first edition of The Molecular Biology of the Gene (p. 298).

Watson's statement is clearly untrue, as the discovery of reverse transcriptase demonstrated only a few years after his book was published. Furthermore, there are now dozens of examples of information flow pathways that are more complex than the simple scheme shown in Watson’s 1965 book. (Not to mention the fact that many information flow pathways terminate with functional RNA’s and never produce protein.)

Watson’s version of the Central Dogma is the one scientists most often refer to when they claim that the Central Dogma is dead. The reason it refuses to die is because it is not the correct Central Dogma. The correct version has not been refuted.

Crick was well aware of the difference between his (correct) version and the Watson version. In his original 1958 paper, Crick referred to the standard information flow pathway as the sequence hypothesis. In his 1970 paper he listed several common misunderstandings of the Central Dogma including ....

It is not the same, as is commonly assumed, as the sequence hypothesis, which was clearly distinguished from it in the same article (Crick, 1958). In particular, the sequence hypothesis was a positive statement, saying that the (overall) transfer nucleic acid → protein did exist, whereas the central dogma was a negative statement saying that transfers from protein did not exist.

The Sequence Hypothesis and the Central Dogma in 1957
My own thinking (and that of many of my colleagues) is based on two general principles, which I shall call the Sequence Hypothesis and the Central Dogma. The direct evidence for both of them is negligible, but I have found them to be of great help in getting to grips with these very complex problems. I present them here in the hope that others can make similar use of them. Their speculative nature is emphasized by their names. It is an instructive exercise to attempt to build a useful theory without using them. One generally ends in the wilderness.

The Sequence Hypothesis. This has already been referred to a number of times. In its simplest form it assumes that the specificity of a piece of nucleic acid is expressed solely by the sequence of its bases, and that this sequence is a (simple) code for the amino acid sequence of a particular protein.

This hypothesis appears to be rather widely held. Its virtue is that it unites several remarkable pairs of generalizations: the central biochemical importance of proteins and the dominating role of genes, and in particular of their nucleic acid; the linearity of protein molecules (considered covalently) and the genetic linearity within the functional gene, as shown by the work of Benzer and Pontecorvo; the simplicity of the composition of protein molecules and the simplicity of nucleic acids. Work is actively proceeding in several laboratories, including our own, in an attempt to provide more direct evidence for this hypothesis.

The Central Dogma. This states that once “information” has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163 quoted in Judson, H.F. The Eight Day of Creation, Expanded Edition (1979, 1996) p. 332.

So, how do we explain the current state of the Central Dogma? The Watson version is the one presented in almost every textbook, even though it is not the correct version according to Francis Crick. The Watson version has become the favorite whipping boy of any scientist who lays claim to a revolutionary discovery, even though a tiny bit of research would uncover the real meaning of the Central Dogma of Molecular Biology. The Watson version has been repeatedly refuted or shown to be incomplete, and yet it continues to be promoted as the true Central Dogma. This is very strange.

The Crick version is correct—it has never been seriously challenged—but few textbooks refer to it. One exception is Lewin’s GENES VIII (Lewin, 2004) (and earlier editions). Lewin defines the Central Dogma of Molecular Biology as,

The central dogma states that information in nucleic acid can be perpetuated or transferred but the transfer of information into protein is irreversible. (B. Lewin, 2004)

I recommend that all biochemistry and molecular biology teachers adopt this definition—or something very similar—and teach it in their classrooms.

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]

Darden, L. and Tabery, J. (2005) Molecular Biology

Lewin, B. (2004) GENES VIII Pearson/Prentice Hall

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939

Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci. Am. 291:60-67.

Thieffry, D. (1998) Forty years under the central dogma. Trends Biochem. 23:312-316.

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

Does the Central Dogma Still Stand?

Lots of people don't understand the Central Dogma of Molecular Biology and that's probably why there are so many articles announcing its death. The article and book by James Shapiro is just one example [Revisiting the Central Dogma in the 21st Century].

The correct version of the Central Dogma of Molecular Biology is .... [see Basic Concepts: The Central Dogma of Molecular Biology]

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

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)

Eugene Koonin has an article in Biology Direct entitled Does the central dogma still stand (Koonin, 2012).

The Central Dogma Dies Again! (not)

You expect IDiots to be idiots so it's not surprising that they consistently screw up their analyses of scientific papers. The latest is a post by David Taylor on the Central Dogma of Molecular Biology [Revisiting the Cental Dogma] [Revisiting the Central Dogma]. He has just noticed a paper published in 2011 where two scientists challenge the Central Dogma. Naturally, this is interpreted to mean that Intelligent Design Creationism is true.

It's frustrating to read yet another scientific paper announcing the demise of the Central Dogma of Molecular Biology. If you've been following the literature, you'll know that the Central Dogma is regularly killed off about ten times per year—a rate that's been fairly constant for thirty years. But to paraphrase Mark Twain, reports of the death of the Central Dogma are greatly exaggerated.

Let's look at the paper by Sarah Franklin and Thomas M. Vondriska from the David Geffen School of Medicine in Los Angeles California (USA) (Franklin and Vondriska 2011). This is a paper that specifically addresses the Central Dogma of Molecular Biology so you'd expect that the authors understand what they are attacking, right?

Readings from Trends in Biochemical Sciences on the Central Dogma

I'm re-reading The Inside Story edited by Jan Witkowski, the former editor-in-chief of Trends in Biochemical Sciences (TIBS). The book is a collection of essays that appeared in the journal. The collection centers around "the theme of the Central Dogma of molecular biology." Here's how Jan Witkowski describes the collection in the preface (page xii)...

When I came to look more closely, it was clear that the area the articles covered most comprehensively, where the most interesting selection could be made, was the Central Dogma, that is DNA, RNA, and protein synthesis. And the number of relevant articles was just right for the size of book we had in mind.

This explains the subtitle of the book, "DNA to RNA to Protein."

This is not going to be another complaint about misinterpretations of the Central Dogma. Quite the contrary, as we shall see.

The Forward was written by Tim Hunt who was the editor-in-chief from 1992-2000. He refers to "The General Idea."

"Jim, you might say, had it first. DNA makes RNA makes protein. That became the general idea." Thus did Francis Crick explain to Horace Judson years later, long after he had written with such clarity and force on the subject of protein synthesis in the 1958 Symposium on "The Biological Replication of Macromolecules" [see Crick, 1959). This article is celebrated for its prediction of the existence of tRNA (although by the time the article appeared in print, tRNA had been discovered), but it is chiefly worth reading and rereading, even today, for its enunciation of the two principles that together constitute the "General Idea." The first principle is the Sequence Hypothesis; the idea that the sequence of amino acids in proteins is specified by the sequence of bases in DNA and RNA. The second principle is the famous "Central Dogma"; not DNA makes RNA makes Protein, but the assertion that "Once information has passed into protein it cannot get out again." It isn't completely clear why one is a hypothesis and the other a dogma and the two together an idea. The Dogma stuck in some throats, mainly because it was called a dogma, with heavy religious overtones.

I quote Tim Hunt to show that there are some knowledgeable scientists who understand the Central Dogma [see The Central Dogma of Molecular Biology].

Hunt continues ...

Crick explains that calling it a dogma was a misunderstanding on his part: he thought the word stood for "an idea for which there was no reasonable evidence," blaming his "curious religious upbringing" for the error. But it probably wasn't that much of a mistake after all, for the Oxford Dictionary allows dogma to mean simply a principle, although the alternative "Arrogant declaration of opinion" is probably how most people who were not molecular biologists took it, considering its never modest author. That is probably how they were meant to take it, too. It was the most important article of faith among the circle of biologists centered on Watson and Crick and remained so for quite a long time until the mechanism of protein synthesis became clear. Crick said that if you did not subscribe to the sequence hypothesis and the central dogma "you generally ended up in the wilderness," although he did not offer alternative scenarios for public consumption, even though they probably played an important part in convincing him of the dogmatic status of the General Idea's second component.

This is the concept that I "grew up" with as a graduate student in the late 1960s. We saw the "General Idea" as an important concept and a way of understanding the data that was coming out of many labs working on DNA replication, transcription, and protein synthesis. We knew, especially after 1970 (Crick, 1970), that RNA could be used as a template to make DNA and that there were many types of RNA other than messenger RNA. We also knew that Francis Crick was a very smart man and it was unwise to disagree with him because he was usually right about big ideas.

Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.

At some point in the last 40 year the "General Idea" has been subverted in two ways.

1. The Sequence Hypothesis has come to be interpreted as the Central Dogma. This is mostly due to Jim Watson who propagated this misinterpretation in his Molecular Biology of the Gene textbook.
2. The Central Dogma is taken to mean that the ONLY important information in the genome is that which encodes proteins. It's assumed, incorrectly, that Crick meant to say that the role of all genes is to encode proteins.

One of the essays in The Inside Story is "Forty Years under the Central Dogma," published in 1998. The authors are Denis Thieffry and Sahotra Sarkar (Thieffry and Sarkar, 1998).

Here's how they explain some of the confusion about the Central Dogma ...

The most obvious interpretation of Crick’s original (1958) formulation of the Central Dogma is in negative terms. The Central Dogma only forbids a few types of information transfer, namely, from proteins to proteins and from proteins to nucleic acids. However, after its rapid adoption by most of the biologists interested in protein synthesis, it was most often interpreted or reformulated in a more restrictive way, constricting the flow of information from DNA to RNA and from RNA to protein (Fig. 1).

Figure 1 The Central Dogma as envisioned by Watson in 1965. ‘We should first look at the evidence that DNA itself is not the direct template that orders amino acid sequences. Instead, the genetic information of DNA is transferred to another class of molecules, which then serve as the protein templates. These intermediate templates are molecules of ribonucleic acid (RNA)...Their relation to DNA and protein is usually summarised by the formula (often called the central dogma).'

According to Watson’s autobiography, he had already derived this ‘formula’ (Fig. 1) in 1952. In fact, such schemes were commonly entertained during the early 1950s, at least among the biologists interested in protein synthesis. ... Much more restrictive than Crick’s original statement, Watson’s formula was immediately confronted with a series of possible exceptions, some of which are mentioned below. Crick, meanwhile, remained rather cautious in his interpretation of the Central Dogma. On several occasions, he felt it necessary to come back to his original idea and explicate what he thought to be its correct interpretation. For example, in 1970, Crick devoted a paper specifically to the Central Dogma, including a diagram reportedly conceived (but not published) in 1958.[see the figure at the top of this page]

The authors recognize several challenges to the Central Dogma, at least to the version preferred by Watson. There were two discoveries in the 1960s that seemed to threaten the Central Dogma. The first was the discovery that the genetic material of some viruses (e.g. TMV) was RNA, not DNA. The second was the discovery that RNA could be copied into DNA by reverse transcriptase. This was not a problem for Crick ....

These findings prompted Crick to write his 1970 piece for Nature, in which he explicitly showed how the new facts fitted into his scheme.

It's difficult to evaluate the importance of the Central Dogma in the 21st century because so many scientists don't understand it. The incorrect version seems to mostly serve as a whipping boy to promote "new" ideas that overthrow the strawman version of the Central Dogma.

Back in 1998, the authors of this article asked Crick what he thought of the Central Dogma ...

In a recent answer to a question addressing the relevance of these challenges, Crick stated that he still believes in the value of the Central Dogma today (F.H.C. Crick, pers. commun.). However, he also acknowledges the existence of various exceptions, most of which he regards as minor. For him, the most significant exception is RNA editing. Still, according to Crick, simplifications of the Central Dogma in terms such as ‘DNA makes RNA and RNA makes protein’ were clearly inadequate from the beginning.

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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]

Thieffry, D. and Sarkar, S. (1998) "Forty years under the central dogma." Trends in Biochemical Sciences 23:312–316. [doi: 10.1016/S0968-0004(98)01244-4}

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.

The Central Dogma Strawman

Whenever you're trying to promote a new idea it's nice to have a scapegoat to beat up on. You're going to get a lot more attention if you can demonstrate that your latest results overthrow some key scientific concept that everyone took for granted. If you can't find a real "key concept" then the next best thing is to make one up.

For the past several decades that strawman target has been The Central Dogma of Molecular Biology. The Central Dogma is supposed to represent the key concept of molecular biology yet it gets "overthrown" on a regular basis every six months. Isn't that strange?

The latest example comes from a Nature review of a recent Science paper. The Science paper presents evidence that many mRNA sequences differ from the sequences in the exons that encode them (Li et al., 2011). RNA editing has been known for decades and every few years it is trotted out again as proof that the Central Dogma is wrong. The recent Li et al. (2011) paper doesn't present evidence for a new phenomenon but it does suggest that RNA editing may be much more common than previously suspected.

Here's what Nature staff writer Erika Check Hayden says about this paper ("Cells may stray from 'central dogma'" Hayden, 2011a).

All science students learn the 'central dogma' of molecular biology: that the sequence of bases encoded in DNA determines the sequence of amino acids that makes up the corresponding proteins. But now researchers suggest that human cells may complicate this tidy picture by making many proteins that do not match their underlying DNA sequences.

Now if that really was what the Central Dogma actually said then it would have disappeared thirty years ago.

The real Central Dogma of Molecular Biology is ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

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)

I've explained why this is the correct version in an old blog posting from 2007: Basic Concepts: The Central Dogma of Molecular Biology. A very similar definition can be found on the Wikipedia site: Central Dogma of Molecular Biology. The key point is that once information flows into protein it can't flow back to nucleic acid. The standard misconception of the Central Dogma is actually the normal information flow pathway or what Crick called the "Sequence Hypothesis." It's a generality that was never meant to be an inviolate rule like the actual Central Dogma.

Hayden has another article in this week's print version of Nature (Hayden, 2011b). The second article emphasizes the controversy surrounding the Li et al. (2011) paper—lots of people are skeptical—but she doesn't back off the implications.

If verified, the findings would require a rewrite of the 'central dogma' of molecular biology, which posits that the RNA transcripts that carry genetic information to the ribosome, where they are used as templates for protein assembly, are generally faithful matches to the original DNA.

There are two remarkable things about such a statement. First, RNA editing has been an established fact for almost thirty years so if the Central Dogma needed rewriting it would have been done a long time ago. Second, Hayden was informed in the comments to her first article that there was a problem with her definition of the Central Dogma. Maybe she didn't have time to change the second version that was about to be published.

To be fair, this isn't just a problem with science writers who don't do their homework. Hayden is right when she says that most science students learn an incorrect version of the Central Dogma of Molecular Biology. It's true that most textbooks promote the information flow pathway as the Central Dogma and they fail to point out that the real version only precludes reverse translation. I don't understand why so many textbook writers and teachers continue to teach something they know to be false as the "Central Dogma" of molecular biology.

Is it because they don't know about the exceptions?

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

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

Hayden, E.C. (2011a) Cells may stray from 'central dogma.' Nature Published online 19 May 2011 [doi:10.1038/news.2011.304.

Hayden, E.C. (2011a) Evidence of altered RNA stirs debate. Nature 473:432. [doi:10.1038/473432a]

Li, M., Wang, I.X., Li, Y., Bruzel, A., Richards, A.L., Toung, J.M., and Cheung, V.G. (2011) Widespread RNA and DNA Sequence Differences in the Human Transcriptome. Science. 2011 May 19. [Epub ahead of print] [Science]

Breaking News!!! Wikipedia Is Wrong! (about the Central Dogma)

I shuddered when I spotted Razib's latest post in my aggregator [see The Central Dogma goes YouTube]. "Oh, no!" I thought, "Am I going to have to point him to my post on The Central Dogma of Molecular Biology?

Imagine my surprise when I saw that he has a link to the Wikipedia article on the Central Dogma. I said to myself, "This will set him straight because I wrote some of that article."

Oops! The Wikipedia article on the Central Dogma of Molecular Biology has been changed. Apparently I haven't looked at it for nine years since the important change was made by someone named Kierano back on September 15, 2006. Kierano describes himself (in 2011) as a Ph.D. student in bioinformatics.

Here's the opening paragraphs from before Sept. 15, 2006.

The central dogma of molecular biology was first enunciated by Francis Crick in 1958 and re-stated in a Nature paper published in 1970:

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.

In other words, 'once information gets into protein, it can't flow back to nucleic acid.'

The central dogma is often misunderstood. It is frequently confused with the standard pathway of information flow from "DNA to RNA to protein". There are notable exceptions to the normal pathway of information flow and these are often mistakenly referred to as exceptions to the central dogma.

The standard information flow pathway can be summarized in a very short and oversimplified manner as "DNA makes RNA makes proteins, which in turn facilitate the previous two steps as well as the replication of DNA", or simply "DNA → RNA → protein". This process is therefore broken down into three steps: transcription, translation, and replication. By new knowledge of the RNA processing, a fourth step must be included: splicing.

This has undergone some edits from what I originally wrote but the main idea is there. Strictly speaking, the Central Dogma of Molecular Biology (Crick version) says only that once information gets into protein it can't flow back to nucleic acid. I thought it was important to explain the main misconception; namely, that the Central Dogma means DNA to RNA to protein. This should be referred to as "the standard information flow pathway" or something similar.

The rest of the Wikipedia article talks about transcription and translation which, strictly speaking, are not part of the Central Dogma. However, the misconception is so widespread that many people expect these to be described under "Central Dogma."

The new version posted on Sept. 15, 2006 says ...

The central dogma of molecular biology was first enunciated by Francis Crick in 1958 and re-stated in a Nature paper published in 1970:

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.

In other words, 'once information gets into protein, it can't flow back to nucleic acid.'

The dogma is a framework for understanding the transfer of information between information-carrying biopolymers, in the most common or general case, in living organisms. There are 3 major classes of information-carrying biopolymers: DNA and RNA (both nucleic acids), and protein. There are 9 possible direct transfers of information that can occur between these. The dogma classes these into 3 general transfers (believed to occur normally in most cells), 3 special transfers (known to occur, but only under abnormal conditions), and 3 unkown transfers (believed to never occur). The general transfers describe the normal flow of biological information: DNA can be copied to DNA (DNA replication), DNA information can be copied into mRNA, (transcription), and proteins can be synthesized using the information in mRNA as a template (translation).

The central dogma is occasionally misunderstood as being a statement of absolute fact. If taken as such, it can be criticised, as there are well-described exceptions. It is also criticised by some systems biologists as being too reductionist.

This is the beginning of a change in emphasis. Kierano removed my statement that the basic meaning of the Central Dogma is often misunderstood. It's clear that he misunderstands it.

On March 10, 2012 someone named Nbauman addd the following statement; "Or, as Marshall Nirenberg said, 'DNA makes RNA makes protein.'" Nbauman cautioned that this was a reliable published source and should not be removed from the Wikipedia article. As far as I can tell Nbauman is not a scientist and has no training in science. In fact, she seems proud of the fact that she is ignorant of the subjects she edits. She does not seem to have noticed that her "authority" (Nirenberg) conflicts with another authority (Francis Crick).

Here's the complete version as of this morning. It's going to change as soon as I get around to it.

The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It was first stated by Francis Crick in 1958[1] and re-stated in a Nature paper published in 1970:

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 back from protein to either protein or nucleic acid.

Or, as Marshall Nirenberg said, "DNA makes RNA makes protein."[3]

To appreciate the significance of the concept, note that Crick had misapplied the term "dogma" in ignorance. In evolutionary or molecular biological theory, either then or subsequently, Crick's proposal had nothing to do with the correct meaning of "dogma". He subsequently documented this error in his autobiography.

The dogma is a framework for understanding the transfer of sequence information between sequential information-carrying biopolymers, in the most common or general case, in living organisms. There are 3 major classes of such biopolymers: DNA and RNA (both nucleic acids), and protein. There are 3×3 = 9 conceivable direct transfers of information that can occur between these. The dogma classes these into 3 groups of 3: 3 general transfers (believed to occur normally in most cells), 3 special transfers (known to occur, but only under specific conditions in case of some viruses or in a laboratory), and 3 unknown transfers (believed never to occur). The general transfers describe the normal flow of biological information: DNA can be copied to DNA (DNA replication), DNA information can be copied into mRNA (transcription), and proteins can be synthesized using the information in mRNA as a template (translation).

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Revisiting the Central Dogma in the 21st Century

James A. Shapiro is an interesting character. He claims that he is opposed to both neo-Dawinism and Creationism (upper case "C") and he claims to offer a "Third Way." That "third way" appears to be indistinguishable from Intelligent Design Creationism although Shapiro never admits to being an advocate of intelligent design. Instead, he prefers to let his "science" do the talking and points out that it's science that leads us to the conclusion that life is designed.

Shapiro has published scientific articles with Richard Sternberg who advocates a similar position but who has become one of the poster boys of the Discovery Institute and one of the stars of the movie Expelled: No Intelligence Allowed. Like Sternberg, Shapiro is admired by IDiots [Non-supernatural ID?: University of Chicago microbiologist James Shapiro works with ID guys, dismisses Darwinism, offers third way].

One of the characteristics Shapiro shares with the IDiots is attacking evolution. In this post I want to review a paper he published in 2009 on "Revisiting the Central Dogma in the 21st Century" (Shapiro, 2009).

The correct version of the Central Dogma of Molecular Biology is:

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

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)

In other words, the flow of information is from nucleic acid to protein and never from protein to nucleic acid.

The incorrect version of the Central Dogma of Molecular Biology is what Crick referred to as the "Sequence Hypothesis" and what we now know as a simplified version of the standard pathway for information flow from genes that specify a protein product. The incorrect version is often presented in textbooks as the real Central Dogma although that's slowly changing [The Central Dogma Strawman].

None of this should be a problem for someone who is writing a scholarly article for the scientific literature since we expect such a person to have read the relevant references (Crick, 1958; Crick, 1970). They should get it right. Let's see how Shapiro does when he says ...

The concept was that information basically flows from DNA to RNA to protein, which determines the cellular and organismal phenotype. While it was considered a theoretical possibility that RNA could transfer information to DNA, information transfer from proteins to DNA, RNA, of other proteins was considered outside the dogma and "would shake the whole intellectual basis of molecular biology [Crick, 1970].

That sounds pretty good but the first part is a little troubling. Which version does Shapiro actually believe he's "revisiting"?

Overthrowing the Central Dogma

I believe that the Central Dogma of Molecular Biology is widely misunderstood [Basic Concepts: The Central Dogma of Molecular Biology]. It is usually interpreted to mean that information must flow exclusively from DNA to RNA to protein. But he original definition by Francis Crick was ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.

I think we should retain the original definition.

A biology teacher has been discussing this issue with me and he points out that the term "Central Dogma" is defined by consensus. If the vast majority of scientists define it incorrectly, then that becomes the new definition. I agree, but I'm not yet prepared to concede defeat.

My correspondent made an interesting observation. He noted that the Nobel Prize committee has awarded three Nobel Prizes for, in part, overthrowing the Central Dogma of Molecular Biology. This is very interesting. What's the value of continuing to refer the the "Central Dogma" if it has, indeed, been refuted?

Here are the three examples. The first is from a 1975 press release announcing the Nobel Prizes to Howard Temin, David Baltimore, and Renato Dulbecco [The Nobel Prize in Physiology or Medicine 1975].

Howard Temin was since the end of the 1950ies concerned with studies of tumour viruses which contain the alternative type of genetic material, i.e. RNA. He noticed that certain characteristics of tumour cells arising after infection with this type of virus suggested a possible persistence of virus genetic material in them. It was very difficult however to understand how the genetic information of viruses containing RNA could form a part of the hereditary material of the tumour cells. In order to explain this Temin postulated that the genetic information of an RNA virus capable of giving transformation could be copied into DNA, and that this DNA in a manner similar to that described for a DNA tumour virus could become integrated into the genetic material of cells. This proposal by the overall majority of scientists was considered as heresy since it was in conflict with the central dogma accepted in the field of molecular biology in those days. This dogma implied that information transfer in nature occurred only from DNA to RNA and not in the other direction.

Note that Crick's original paper (see above) allowed for information flow from RNA back to DNA so Temin's work did not overthrow the original concept of theoretical information flow. It did conflict with the incorrect version of the Central Dogma that had been promoted by Jim Watson. It was Temin's work, and the subsequent hype about the Central Dogma, that prompted Crick to publish his 1970 paper.

The second example comes from the press release for 1989 Nobel Prizes to Sydney Altman and Thomas Cech in 1989 [Ribonucleic acid (RNA) - a biomolecule of many functions].

The genetic information in the DNA strand is arranged as a long sentence of three-letter words (e.g. CAG ACT GCC), each corresponding to one of the twenty amino acids which build the proteins. This means that there is a flow of genetic information from the DNA to the proteins, which in turn provide the structural framework of living cells and give them their different functions in the organism. However, this flow of genetic information cannot occur unless the DNA code is transcribed to another code in another type of nucleic acid - RNA (ribonucleic acid). This connection between the nucleic acids (the molecules of heredity) and the proteins (the molecules of structure and function) is what has been called the central dogma of the biosciences.
The genetic information in the DNA molecules determines the composition and function of the proteins. Altman and Cech have now modified this by showing that the RNA molecules not only transmit the genetic information but can also function as biocatalyst.

The third example comes from the press release of the 2006 Nobel Prize to Andrew Fire and Craig Mello for thier work on intrefering RNA [The Nobel Prize in Physiology or Medicine 2006]. In this case, the press release does not claim that Fire and Mello overthrew the Central Dogma but it does give an incorrect version of the Central Dogma of Molecular Biology. This is ironic since, according to the Noble Prize committee, the Central Dogma had been called into question in 1975 and 1989.

The genetic code in DNA determines how proteins are built. The instructions contained in the DNA are copied to mRNA and subsequently used to synthesize proteins (Fig 1). This flow of genetic information from DNA via mRNA to protein has been termed the central dogma of molecular biology by the British Nobel Laureate Francis Crick. Proteins are involved in all processes of life, for instance as enzymes digesting our food, receptors receiving signals in the brain, and as antibodies defending us against bacteria.

It is not true that Francis Crick referred to this process of information flow as the Central Dogma.

Is any of this important? Yes, I think it is. I think there is too much sloppiness in science these days. There are too many instances where sloppy thinking is acceptable. On this particular issue you can't have it both ways. Either the Watson definition of the Central Dogma of Molecular Biology was correct, in which case it has been discredited to such an extent that it's no longer useful. Or, the original Crick version is correct, in which case the work of Temin, Altman, Cech, Fire, and Mello have nothing to do with the Central Dogma.

If a scientist is going to write about the Central Dogma of Molecular Biology then they better be damned sure that they understand it. If they are going to quote the original papers (Crick 1958, 1970) then it might be a very good idea to read them.

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

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

The Ribosome and the Central Dogma of Molecular Biology

The Nobel Prize website usually does an excellent job of explaining the science behind the prizes. The STRUCTURE AND FUNCTION OF THE RIBOSOME is a good explanation of reasons why the 2009 Nobel Prize in Chemistry was awarded for work on the ribosome.

Unfortunately, the article begins by perpetuating a basic misunderstanding of the Central Dogma of Molecular Biology.

The ribosome and the central dogma. The genetic information in living systems is stored in the genome sequences of their DNA (deoxyribonucleic acid). A large part of these sequences encode proteins which carry out most of the functional tasks in all extant organisms. The DNA information is made available by transcription of the genes to mRNAs (messenger ribonucleic acids) that subsequently are translated into the various amino acid sequences of all the proteins of an organism. This is the central dogma (Crick, 1970) of molecular biology in its simplest form (Figure 1)

This is not the Central Dogma according to Crick (1970). I explain this in a posting from two years ago [Basic Concepts: The Central Dogma of Molecular Biology].

In both his original paper (Crick, 1958) and the 1970 update, Crick made it very clear that the Central Dogma of Molecular Biology is ....

The Central Dogma. This states that once “information” has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

The diagram that's usually attributed to the central dogma is actually the Sequence Hypothesis. Crick was well aware of the confusion and that's why he wrote the 1970 paper. It was at a time when the so-called "Central Dogma" had been "overthrown" byt the discovery of reverse transcriptase.

Since then the false version of the Central Dogma has been disproven dozens and dozens of times—it's a minor cottage industry.

Here's what Crick says about this false version of the Central Dogma in his 1970 paper—the one quoted at the top of this page.

It is not the same, as is commonly assumed, as the sequence hypothesis, which was clearly distinguished from it in the same article (Crick, 1958). In particular, the sequence hypothesis was a positive statement, saying that the (overall) transfer nucleic acid → protein did exist, whereas the central dogma was a negative statement saying that transfers from protein did not exist.

Let's try and get it right. It will have the great benefit of stopping us from putting up with any new papers that refute the Central Dogma of Molecular Biology!

It will also encourage critical thinking. Haven't you ever wondered why there is a Central Dogma when reverse transcriptase, splicing, epigenetics, post-translational modification, chromatin rearrangements, small regulatory RNAs, and just about everything else under the sun, supposedly refutes it?

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

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

The illusions of James Shapiro

James A. Shapiro is a professor in the Department of Biochemistry and Molecular Biology at the University of Chicago (Chicago, USA). He made signficant contributions to our understanding if the function and structure of transposons but in later years he has become a vocal opponent of evolution culminating in his 2011 book Evolution: A View from the 21st Century. He is one of the founding members of The Third Way of Evolution.

I wrote a critical review of Evolution: A View from the 21st Century for the National Center for Science Education (NCSE) Reports but the issue is no longer visible on the web. Shapiro didn't like my review so NCSE published his rebutal and that's also unavailable. You can see my response at: James Shapiro Responds to My Review of His Book.

John Avise doesn't understand the Central Dogma of Molecular Biology

I've just read Conceptual Breakthroughs in Evolutionary Genetics by John Avise. Avise is a Distinguished Professor of Ecology & Evolutionary Biology in the School of Biological Sciences at the University of Califonia at Davis (Davis, California, USA). He has written a number of excellent books including, Inside the Human Genome: A Case for Non-Intelligent Design.

His latest book consists of 70 idiosyncratic "breakthroughs" that have changed the way we think about biology. Each one is introduced with a short paragraph outlining "The Standard Paradigm" followed by another paragraph on "The Conceptual Revolution." There are 70 chapters, one for each "breakthrough," and all of them are two pages in length.

Chapter 42 is entitled: "1970 The Flow of Information."

Here's the "standard paradigm" according to John Avise.

In biochemical genetics, the molecular direction of information flow is invariably from DNA → RNA → protein. In other words, DNA is first transcribed into RNA, which then may be translated into polypeptides that make up proteins. This view was so ensconced in the field that it had become known as the "central dogma" (Crick, 1970) of molecular biology.

It's true that the Watson version of the Central Dogma was "ensconced" by 1970 and it's true that the incorrect Watson version is still "ensconced" in the textbooks.

It is NOT TRUE that this is the version that Crick described in 1970 or in his 1958 paper [see Basic Concepts: The Central Dogma of Molecular Biology]. Here's how Crick actually described the Central Dogma.

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

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)

The version that John Avise refers to is the incorrect version promoted by Jim Watson.

I understand that many biologists have been taught an incorrect version of the Central Dogma but if you are going to write about it you are wise to read the original papers. In this case, Avise quotes the correct paper but he clearly has not read it.

Now let's look at the "conceptual revolution" according to John Avise.

Researchers showed that biochemical information could also flow from RNA → DNA. The key discovery came when Howard Temin and David Baltimore, working independently and on different viral systems, identified an enzyme (reverse transcriptase) that catalyzes the conversion of RNA into DNA, thus enabling the passage of genetic information in a direction contrary to the central dogma.

How do I know that John Avise has not read Crick's 1970 paper? Because here's what Crick says in that paper ...

"The central dogma, enunciated by Crick in 1958 and the keystone of molecular biology ever since, is likely to prove a considerable over-simplification."

This quotation is taken from the beginning of an unsigned article headed "Central dogma reversed", recounting the very important work of Dr Howard Temin and others showing that an RNA tumor virus can use viral RNA as a template for DNA synthesis. This is not the first time that the idea of the central dogma has been misunderstood, in one way or another. In this article I explain why the term was originally introduced, its true meaning, and state why I think that, properly understood, it is still an idea of fundamental importance.

Crick tells us that the discovery of reverse transcriptase did NOT conflict with the central dogma. Thus, John Avise's conceptual revolution never happened. What happened instead, at least for some biologists, is that the discovery of reverse transcriptase taught them that their view of the central dogma was wrong. Most biologists still haven't experienced that particular conceptual revolution.

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

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

The fuzzy thinking of John Parrington: The Central Dogma

My copy of The Deeper Genome: Why there's more to the human genome than meets the eye has arrived and I've finished reading it. It's a huge disappointment. Parrington makes no attempt to describe what's in your genome in more than general hand-waving terms. His main theme is that the genome is really complicated and so are we. Gosh, golly, gee whiz! Re-write the textbooks!

You will look in vain for any hard numbers such as the total number of genes or the amount of the genome devoted to centromeres, regulatory sequences etc. etc. [see What's in your genome?]. Instead, you will find a wishy-washy defense of ENCODE results and tributes to the views of John Mattick.

John Parrington is an Associate Professor of Cellular & Molecular Pharmacology at the University of Oxford (Oxford, UK). He works on the physiology of calcium signalling in mammals. This should make him well-qualified to write a book about biochemistry, molecular biology, and genomes. Unfortunately, his writing leaves a great deal to be desired. He seems to be part of a younger generation of scientists who were poorly trained as graduate students (he got his Ph.D. in 1992). He exhibits the same kind of fuzzy thinking as many of the ENCODE leaders.

Let me give you just one example.

SEED and the Central Dogma of Molecular Biology - I Take Back My Praise

 
On October 1, 2007 I praised SEED magazine for being one of the few science magazines to correctly define the Central Dogma of Molecular Biology. Here's what I said two months ago.

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One of my pet peeves is the misuse of the term "Central Dogma of Molecular Biology" [Basic Concepts: The Central Dogma of Molecular Biology]. Most people define it as the flow of information from DNA to RNA to protein. Many then go on to declare that the Central Dogma has been overthrown because of reverse transcriptase, alternative splicing, microRNA, epigenetics, or whatever.

This month's issue of SEED has a tear-out summary (cribsheet) of "Genetics." In one of the boxes titled "The Central Dogma of Molecular Biology" there's a drawing of the major pathways of information flow [Cribsheet #12]. The caption says.

There are nine ways information can theoretically flow between DNA, RNA, and protein. Of these, three are seen throughout nature, DNA to DNA (replication), DNA to RNA (transcription), and RNA to protein (translation). Three more are known to occur in special circumstances like viruses or laboratory experiments (RNA to RNA, RNA to DNA, and DNA to protein). Flows of information from protein have not been observed. The trend is clear: information flow from DNA or RNA into protein is irreversible. This is known as the "central dogma," and forms the foundation of molecular biology.

Yeah! As far as I know this is the only popular magazine to get it right.

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I take it all back.

This month's issue has an article by Philip Ball outlining another revolution in molecular biology that overthrows the Central Dogma of Molecular Biology. This time it's microRNAs that have done the dirty deed [Redefining Genes].

Philip Ball is a London (UK) based freelance science writer with a Ph.D. in Physics. He has written 10 books on science and many articles for the news section of Nature. Philip Ball blogs at homunculus.

Here's what he says on page 29 of the current newsstand issue of SEED.

For nearly 50 years, the central dogma of molecular biology has been that genetic information is contained within DNA and is passed by rote transcription through RNA to make proteins. ...

The central dogma is being eroded, and it now appears as if DNA's cousin, the humble intermediary RNA, plays at least an equal role in genetics and the evolution of the species.

Philip Ball then gives two recent examples of work showing the involvement of noncoding RNA in gene expression. Then comes the revolution ...

These and a host of other recent findings are rewriting the textbooks of molecular biology. They are beginning to show not only that RNA is more fundamental to genetics than once believed, but also that it can directly affect evolution and elucidate the differences between species. The result is a story that looks a lot messier, but potentially a lot more interesting, than anyone ever guessed.

This is deeply insulting to all biochemists and molecular biologists. What in the world must people like Ball be thinking of us when he writes such nonsense? Does he really believe that for over half a century we have been slavishly adhering to the dogma that genes only make proteins? I know lots of scientists who think the Central Dogma refers to the general pathway of information flow (DNA → RNA → protein) but I never met a biochemist or a molecular biologist who thought that this pathway ruled out genes whose final product was RNA.

That idea is total nonsense, of course, and Philip Ball would know this if he only bothered to read any of the textbooks of molecular biology. Not only have we been teaching about ribosomal RNA, and transfer RNA for 40 years, we've also covered all of the small RNAs involved in splicing, telomeres, signal recognition particle, RNAse P etc. etc. Does he think we're completely ignorant of the Nobel Prizes awarded to Sidney Altman and Tom Czech in 1989 "for their discovery of catalytic properties of RNA"?

Furthermore, we've been teaching about regulatory RNAs for almost as long. The classic examples are the antisense RNAs in bacteriophage λ, attenuation in the trp operon and small RNAs that control the initiation of DNA replication at plasmid origins.

If you were to believe Philip Ball, molecular biologists have clung to his version of the Central Dogma of Molecular Biology in spite of all these counter-examples. Only now are they waking up to the fact that some genes make RNA as their final product. How stupid is that?

Science writers have a special obligation when writing for a general audience. Not only do they have to explain things in simple language but they have to be accurate as well. Pert of being accurate in science is having enough knowledge of the subject to be able to sort out the hype from reality. Philip Ball does not know anough about molecular biology to make that call. He should have read the cribsheet.

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More confusion about the central dogma of molecular biology

I was doing some reading on lncRNAs (long non-coding RNAs) in order to find out how many of them had been assigned real biological functions. My reading was prompted by the one of the latest updates to the human genome sequence; namely, assembly GRCh38.p3 from June 2015. The Ensembl website lists 14,889 lncRNA genes but I'm sure that most of these are just speculative [Ensembl Whole Genome].

The latest review by my colleagues here in the biochemistry department at the University of Toronto (Toronto, Canada), concludes that only a small fraction of these putative lncRNAs have a function (Palazzo and Lee, 2015). They point out that in the absence of evidence for function, the null hypothesis is that these RNAs are junk and the genes don't exist. That's not the view that annotators at Ensembl take.

I stumbled across a paper by Ling et al. (2015) that tries to make a case for function. I don't think their case is convincing but that's not what I want to discuss. I want to discuss their view of the Central Dogma of Molecular Biology. Here's the abstract ...

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer.

This is getting to be a familiar refrain. I understand how modern scientists might be confused about the difference between the Watson and the Crick versions of the Central Dogma [see The Central Dogma of Molecular Biology]. Many textbooks perpetuate the myth that Crick's sequence hypothesis is actually the Central Dogma. That's bad enough but lots of researchers seem to think that their false view of the Central Dogma goes even further. They think it means that the ONLY kind of genes in your genome are those that produce mRNA and protein.

I don't understand how such a ridiculous notion could arise but it must be a common misconception, otherwise why would these authors think that non-coding RNAs are a challenge to the Central Dogma? And why would the reviewers and editors think this was okay?

I'm pretty sure that I've interpreted their meaning correctly. Here's the opening sentences of the introduction to their paper ...

The Encyclopedia of DNA Elements (ENCODE) project has revealed that at least 75% of the human genome is transcribed into RNAs, while protein-coding genes comprise only 3% of the human genome. Because of a long-held protein-centered bias, many of the genomic regions that are transcribed into non-coding RNAs (ncRNAs) had been viewed as ‘junk’ in the genome, and the associated transcription had been regarded as transcriptional ‘noise’ lacking biological meaning.

They think that the Central Dogma is a "protein-centered bias." They think the Central Dogma rules out genes that specify noncoding RNAs. (Like tRNA and ribosomal RNA?)

Later on they say ....

The protein-centered dogma had viewed genomic regions not coding for proteins as ‘junk’ DNA. We now understand that many lncRNAs are transcribed from ‘junk’ regions, and even those encompassing transposons, pseudogenes and simple repeats represent important functional regulators with biological relevance.

It's simply not true that scientists in the past viewed all noncoding DNA as junk, at least not knowledgeable scientists [What's in Your Genome?]. Furthermore, no knowledgeable scientists ever interpreted the Central Dogma of Molecular Biology to mean that the only functional genes in a genome were those that encoded proteins.

Apparently Lee, Vincent, Picler, Fodde, Berindan-Neagoe, Slack, and Calin knew scientists who DID believe such nonsense. Maybe they even believed it themselves.

Judging by the frequency with with such statements appear in the scientific literature, I can only assume that this belief is widespread among biochemists and molecular biologists. How in the world did this happen? How many Sandwalk readers were taught that the Central Dogma rules out all genes for noncoding RNAs? Did you have such a protein-centered bias about the role of genes? Who were your teachers?

Didn't anyone teach you who won the Nobel Prize in 1989? Didn't you learn about snRNAs? What did you think RNA polymerases I and III were doing in the cell?

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Ling, H., Vincent, K., Pichler, M., Fodde, R., Berindan-Neagoe, I., Slack, F.J., and Calin, G.A. (2015) Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene (published online January 26, 2015) [PDF]

Palazzo, A.F. and Lee, E.S. (2015) Non-coding RNA: what is functional and what is junk? Frontiers in genetics 6: 2 (published online January 26, 2015 [Abstract]

Proponents of the Extended Evolutionary Synthesis (EES) explain their logic using the Central Dogma as an example

There's a group of biologists who think that the current version of evolutionary theory is insufficient. They want to create an extended evolutionary synthesis that incorporates evo-devo, plasticity, niche construction, evolvability, epigenetics, and other things.

You might be wondering how these things could be incorporated and what that would do to "classic" evolutionary theory. Fortunately, we have a road map provided by Massimo Pigliucci and Gerd Müller in chapter one of Evolution: The Extened Synthesis. They help us out by providing an analogy.

As we will see in the rest of this volume, several of these tenets [of the Modern Synthesis] are being challenged as either inaccurate or incomplete. It is important, however, to understand the kind of challenge being posed here, in order to avoid wasting time on unproductive discussions that missed the point of an extended evolutionary synthesis. Perhaps a parallel with another branch of biology will be helpful. After Watson and Crick discovered the double-helix structure of DNA, and the molecular revolution got started in earnest, one of the first principles to emerge from the new discipline was the unfortunately named "central dogma" of molecular biology. The dogma (a word that arguably should never be used in science) stated that the flow of information in biological systems is always one way, from DNA to RNA to proteins. Later on, however, it was discovered that the DNA > RNA flow can be reversed by the appropriately named process of reverse transcription, which takes place in a variety of organisms, including some viruses and eukaryotes (through retrotransposons). Moreover, we now know that some viruses replicate their RNA directly by means of RNA dependent RNA polymerases, enzymes also found in eukaryotes, where they mediate RNA silencing. Prions have shown us how some proteins can catalyze conformational changes in similar proteins, a phenomenon that is not a case of replication, but certainly qualifies as information transfer. Finally, we also have examples of direct DNA translation to protein in cell-free experimental systems in the presence of ribosomes but not of mRNA. All of these molecular processes clearly demolish the alleged central dogma, and yet do not call for the rejection of any of the empirical discoveries or conceptual advances made in molecular biology since the 1950s. Similarly, we argue, individual tenets of the Modern Synthesis can be modified, or even rejected, without generating a fundamental crisis in the structure of evolutionary theory—just as the Modern Synthesis itself improved upon but did not cause rejection of either Darwinism or neo-Darwinism.

I thank Pigliucci and Müller for giving us a clear idea of the logic behind their attack on the Modern Synthesis.

... I must correct a wrong idea that has been spreading for the past three or four years. It was discovered some years ago that in some cases, the transcription step from DNA to RNA works in the reverse direction. That is nothing surprising. ... it could be predicted that such events could occur. They do occur, indeed, but this must not be taken to mean that information from protein could possibly go back to the genome. ... I am ready to take any bet you like that this is never going to turn out to be the case.

Jacques Monod (1974) p.394The original, and correct, version of the Central Dogma of Molecular Biology was stated clearly by Francis Crick in 1958. Crick restated the Central Dogma of Molecular Biology in a famous paper published in 1970 at a time when the premature slaying of the Central Dogma by reverse transcriptase was being announced (Crick, 1970). According to Crick, the correct, concise version of the Central Dogma is ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

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)

Jim Watson published the well-known, but incorrect, version in his 1960s textbook but anyone who does even a little bit of research will discover that the Crick version is the original [see: The Central Dogma of Molecular Biology].

Here's the summary provided by Francis Crick in his 1970 Nature paper.

Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.

This is important because whenever someone attacks the Central Dogma you can get a good idea of their academic ability by seeing if they understand the concept they attack. In this case, there's a question about proponents of the extended evolutionary synthesis and whether they have a sufficient grasp of evolutionary theory to be challenging it. Pigliucci and Müller have tried to convince us that they know what they are talking about by giving us an analogy; namely, the "demolition" of the Central Dogma of Molecular Biology.

They didn't do their homework. That doesn't inspire confidence in their ability to overthrow modern evolutionary theory.

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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]
Monod, J. (1974) "On the Molecular Theory of Evolution" reprinted in Mark Ridley (editor) Evolution (1997) p. 389

Why is the Central Dogma so hard to understand?

The Central Dogma of molecular biology states ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958).

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).

This is not difficult to understand since Francis Crick made it very clear in his original 1958 paper and again in his 1970 paper in Nature [see Basic Concepts: The Central Dogma of Molecular Biology]. There's nothing particularly complicated about the Central Dogma. It merely states the obvious fact that sequence information can flow from nucleic acid to protein but not the other way around.

So, why do so many scientists have trouble grasping this simple idea? Why do they continue to misinterpret the Central Dogma while quoting Crick? I seems obvious that they haven't read the paper(s) they are referencing.

I just came across another example of such ignorance and it is so outrageous that I just can't help sharing it with you. Here's a few sentences from a recent review in the 2020 issue of Annual Reviews of Genomics and Human Genetics (Zerbino et al., 2020).

Once the role of DNA was proven, genes became physical components. Protein-coding genes could be characterized by the genetic code, which was determined in 1965, and could thus be defined by the open reading frames (ORFs). However, exceptions to Francis Crick's central dogma of genes as blueprints for protein synthesis (Crick, 1958) were already being uncovered: first tRNA and rRNA and then a broad variety of noncoding RNAs.

I can't imagine what the authors were thinking when they wrote this. If the Central Dogma actually said that the only role for genes was to make proteins then surely the discovery of tRNA and rRNA would have refuted the Central Dogma and relegated it to the dustbin of history. So why bother even mentioning it in 2020?

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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]

Zerbino, D.R., Frankish, A. and Flicek, P. (2020) "Progress, Challenges, and Surprises in Annotating the Human Genome." Annual review of genomics and human genetics 21:55-79. [doi: 10.1146/annurev-genom-121119-083418]