Francis Crick Was Misunderstood

The Central Dogma is not a "dogma," and it has never been broken.

By Matthew Cobb

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 Central Dogma states only that, “Once information has got into a protein it can’t get out again.”

Crick’s diagram also included two types of information flow for which there was no experimental evidence, but which he surmised might be biochemically feasible; namely, DNA → protein and RNA → DNA.

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.

The most significant part of Crick’s idea — and the part that Watson ignored in his oversimplification — was that there are three flows of information that cannot occur, due both to lack of experimental evidence and any plausible biochemical mechanisms. These were protein → protein, protein → RNA and, above all, protein → DNA.

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.

Despite the overarching simplicity of Crick’s idea, scientists, students, and journalists have struggled to grasp its precise meaning over the years. While there are many reasons for this confusion, a large part stems from the fact that Watson’s simplified version of the Central Dogma has been contradicted by a number of experimental results. We now know, for instance, that information in RNA can indeed be “reversed” back into DNA. We have also come to realize that Crick erred by naming his idea a “dogma” in the first place.

Not a Dogma

The Central Dogma is not actually a dogma — defined as “a belief that is laid down by an authority and cannot be challenged.” That would be antithetical to the scientific method itself, which uses experimental results, rather than the proclamation of an authority, as the basis for knowledge.

So it was that Crick’s chosen name was quickly criticized by his contemporaries. French geneticist Jacques Monod, for instance, said that Crick “did not appear to understand the correct use of the word,” as Crick recalled in his memoir, What Mad Pursuit. Crick later explained that he called his idea a “dogma” because he was using “the word in the way [he himself] thought about it, not as most of the rest of the world does, and simply applied it to a grand hypothesis that, however plausible, had little direct experimental support.”¹

Crick later acknowledged that he should have called his idea “the central hypothesis,” but he had already used the term “hypothesis” to describe another aspect of his vision of protein synthesis and did not want to repeat himself.²

Apart from its name, students are often confused about the Central Dogma (or, at least, Watson’s version of it) because experimental evidence has repeatedly shown that the information in a cell doesn’t only flow from DNA → RNA → protein.

In 1970, for example, several different research teams simultaneously discovered reverse transcriptase, a viral enzyme that creates DNA from an RNA template. One of those researchers, Howard Temin, first proposed the existence of such an enzyme in 1962 to explain the behavior of RNA viruses that infect chickens, called the Rous sarcoma virus. Temin showed that inhibition of DNA synthesis stopped the reproduction of this RNA virus, suggesting it somehow turned its RNA into DNA.

Upon the discovery of reverse transcriptase, the scientific journal Nature published an editorial entitled, “Central Dogma Reversed,” claiming it struck a major blow to the Central Dogma.

Unhappy with the editorial’s title, Crick published a rebuttal insisting that he never claimed that the flow of information went solely from DNA → RNA → protein or that the transfer RNA → DNA could not occur.

In 1964, for example, in answer to a question after one of his lectures, Crick insisted that the Central Dogma did not say that you cannot go from RNA to DNA. The Central Dogma, Crick explained in his editorial, was “a negative statement, saying that transfers from proteins did not exist.” To clarify his point, he redrew the diagram he had first created in 1956.

But by 1970, Crick began to wonder whether prion diseases — such as scrapie, mad cow disease, or Creutzfeldt-Jakob disease — might be an actual exception to the Central Dogma.

Stanley Prusiner, a neurologist and biochemist at the University of California, San Francisco, first coined the term “prion” in 1982. At the time, Prusiner suspected prion diseases were caused by pathological proteins that triggered cells to make new prion proteins, a process which would be in direct contradiction to Crick’s hypothesis. But Prusiner had no decisive evidence for this idea.

After a great deal of research over the subsequent decades, it was eventually shown in the early 2000s that prion diseases like scrapie or human Creutzfeldt-Jakob Disease, or similar conditions in plants and fungi, all involve a misfolded, pathological protein. Specifically, prion proteins do not change the sequence of amino acids; they instead transmit their pathological shape to otherwise “healthy” proteins, causing them to misfold in the same way. Prion diseases do not alter the validity of the Central Dogma because they don’t alter any genetic sequences.

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.

Francis Crick lecturing American students in 1977.

Epigenetic tags do change where and when genes are transcribed, and for how long. This shows that the genome is not the sole source of genetic information, a point that Crick actually agreed with. In 1970, he wrote: 

I do not subscribe to the view that all ‘information’ is necessarily located in nucleic acid. […] For example, the activating enzymes, the transfer RNA and the ribosomes are necessary for protein synthesis, and also define the genetic code, but they are not the sequence information itself, which resides in the mRNA.

In other words, 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.”

Breaking the Dogma

Throughout his life, Crick often rebuked those who misinterpreted his ideas — even when the person doing the misinterpreting was a Nobel Prize-winning scientist.

In 2003, near the end of his life, Crick heard that Phil Sharp (1993 Nobel Prize in Physiology or Medicine) was planning to mark the 50^th anniversary of the double helix’s discovery by giving a talk on exceptions to the Central Dogma. Crick fired off a sharp letter:

As far as I know there are no exceptions to the Central Dogma. However, there are to Jim Watson’s incorrect version of it. His version is simply DNA → RNA → protein. This is not the Central Dogma. The Central Dogma says, in simple terms, that reverse translation, from protein to nucleic acid, never occurs […] it was pointed out to me that Jim had used the term Central Dogma incorrectly. He still continues to do so. If, as I suggest, you intend to discuss Jim’s version, I strongly suggest you call it ‘Watson’s Dogma.’

Despite his fiery letter, Crick was not opposed to thinking through ways to break the Central Dogma. In 2002, he came up with a proposal to use genetic engineering to do precisely that.

Crick’s idea relied upon the fact that the genetic code is redundant. Each amino acid in a protein is encoded in DNA or RNA by a sequence of three bases, called a codon.³ Many amino acids are encoded by several different codons, whereas just two amino acids are encoded by a single codon. For example, the codons UUA, UUG, CUU, CUC, CUA, and CUG all encode the amino acid leucine. The amino acid tryptophan, however, is encoded only by UGG. Therefore, two proteins with identical amino acid sequences could be encoded by distinct nucleic acid sequences.

Crick suggested that this redundancy might have made it possible to overcome the Central Dogma and pass information from a protein back into the genome:

Obviously one cannot easily translate backwards to the exact original nucleic acid sequence. But Nature might have devised a mechanism in which only one codon, for each amino acid, was used to translate backwards. This would have given, to a good approximation, a new nucleic acid sequence that when translated forward again would give the identical protein. 

Recent advances in gene-editing now offer a method by which to test this theory.

Imagine that there are two different forms of an enzyme, A and B, each of which acts upon a different substrate. Now, imagine that the two enzymes differ by a single amino acid. It is possible to engineer a microbe such that the DNA encoding enzyme A could be altered to encode enzyme B depending upon which substrate is in the environment.

Base editing, a gene-editing tool first reported in 2016, can be used to swap individual base pairs in the genome. One could presumably use base editing to change a single base pair in the gene for enzyme A, thus turning it into a gene encoding enzyme B. If the base editing tool was made in such a way that it’s only active when a particular substrate is in the environment, then the cells would conditionally alter their genomes based on “experience.” In other words, for such a system, information would flow from the outside world into the nucleic acids, thus breaching the Central Dogma.

This little thought experiment tells us two things. Firstly, it reinforces the conclusion that the Central Dogma is simply a description of existing transfers of information used by life. There is nothing magic about it.

But second, it raises the question of why biology has not evolved to alter DNA to swap between two forms of a protein.⁴ The answer, I think, is relatively simple: changing DNA is a relatively slow and “permanent” way to respond to an environmental shift. If the environment suddenly changes again, the cell might die before it can alter its DNA to respond.

A much safer solution, therefore, is for a cell to have both enzymes A and B encoded in DNA, with the expression of each being controlled by a system that detects the substrate in the environment. That is pretty much exactly what happens in many microbes; gene regulation responds to environmental stimuli. Rather than changing DNA, organisms keep copies of genes that are only expressed under certain circumstances.

This highlights two points: DNA is metabolically cheap to make, even if it does nothing (which explains why our DNA is full of meaningless repetitive sequences) and, to paraphrase the words of the French molecular biologist François Jacob, evolution does not design, it tinkers. Better to have a conditional expression system, with genes that are only rarely required, rather than continually rewriting DNA in response to changing environmental conditions.

From this point of view, breaching the Central Dogma is not only biochemically complicated but rather pointless. Nature has found a workaround that enables organisms to respond to changing environments without changing their DNA.

Understanding the precise nature of Crick’s Central Dogma is important because it not only explains how protein synthesis occurs but also reveals something profound about the origin of the variation in organisms that can be sifted and transmitted through natural selection.

So even if scientists one day create cells — or discover new lifeforms — that contradict the Central Dogma, their discovery will not cause the complex edifice of modern molecular biology to come tumbling down. After all, Crick’s idea was never a “dogma” at all, but rather a powerful hypothesis about the fundamental mechanisms that explain how information flows through life.

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Matthew Cobb is a Professor Emeritus in the School of Biological Sciences at the University of Manchester. His biography of Francis Crick will be published in 2025 by Profile Books in the UK and by Basic Books in the USA.

Cite: Cobb, Matthew. “Francis Crick Was Misunderstood.” Asimov Press (2024). DOI: https://doi.org/10.62211/98er-31po

1. Crick first heard Sol Spiegelman, a professor at the University of Illinois, describe the link between DNA, RNA, and protein as a “dogma.” But Spiegelman was being provocative, wanting researchers to test the truth of this supposed dogma by doing more experiments. Crick heard Spiegelman’s talk and his ears pricked up at this fancy term, which he then used in his 1957 lecture.

2. As Crick said: “The Central Dogma is only a hypothesis. In every context it has to be shown to agree with experiments.”

3. Most cells use 20 different amino acids to build proteins. These amino acids are encoded by 64 different codons, including codons that signal the “start” or “stop” of translation.

4. This is not strictly true. Genes encoding antibodies, a part of the adaptive immune system, are changed at the DNA level through several processes, including VDJ recombination, class switch recombination, and somatic hypermutation. Somatic hypermutation occurs specifically in response to an environmental stimulus, triggering cells to mutate variable regions of immunoglobulin genes. However, these mutations are not passed on to the organism’s offspring; Crick’s Central Dogma remains intact.