A New Dogma Of Molecular Biology: A Paradigm Shift

Thomas Kuhn, in his groundbreaking book The Structure of Scientific Revolutions, described a paradigm shift in science as a new understanding of nature that:

1. Is a sufficiently unprecedented theory to attract an enduring group of adherents.
2. A theory that is open-ended with many problems for the redefined group of practitioners to resolve.

This is precisely the nature of our new understanding of biology, which has occurred over the past twenty years and is now sufficiently advanced to offer a new paradigm.

The previous paradigm was given in what is called the central dogma.

DNA—> RNA—> Protein—> Phenotype

The dogma was enshrined in Jim Watson’s 1965 epic textbook The Molecular Biology of the Gene.

The theory holds that Gregor Mendel’s concept of a gene (a discrete heritable trait or phenotype) is the consequence of a change in the text of DNA that alters the function of a protein and, therefore, the phenotype. Sickle cell anemia is a prime example. A single-letter change in the DNA that encodes the hemoglobin protein changes the structure of the protein so that it aggregates to create sickle-shaped red blood cells, leading to the blood clots that define the disease. While true, we now view this paradigm as a special case of a broader reality. Why?

Anomalies

There is a need for a new paradigm to account for a series of anomalous observations.

Over the past twenty years, we have made impressive progress in reading the complete genome sequences of hundreds of thousands of humans and tens of thousands of other species. We have uncovered countless variations among individuals in their inherited DNA sequence and associated those changes with thousands of inherited traits, including inherited diseases.

A big surprise: The vast majority of changes in DNA sequence of consequence are not in the 2% of the human genome that specify proteins but rather in the 90% or more of the genome that does not. In other words, most of what Gregor Mendel described as a trait is usually NOT a change in the sequence of a protein.

If most genes are not proteins, what are they?

Another revelation has also emerged from genomic studies. Recent studies reveal that animal and plant cells copy the great majority of DNA into RNA. Humans copy at least 70% of our genome into RNA, vastly more than the 2% specifying protein. Previously, non-protein coding DNA was related to a trash heap called “junk DNA”. Additionally, many variants that affect heritable traits occur in other non-protein-coding regulatory regions, including RNA transcription start, stop, and splicing sequences.

A third anomaly has been apparent for some time. Very simple organisms possess versions of the great majority of the twenty thousand proteins similar to those of complex animals, including us. How do we account for the complexity of most multicellular organisms and ourselves?

In the early days of molecular biology, the universality of the genetic code prompted the Nobel Prize-winning biologist Jaques Monod to proclaim, “What is true for phage lambda is true for the elephant.” Elucidating the human genome and those of other species revealed an enormous complexity in the organization of DNA and RNA not evident in viruses or bacteria.

A New Paradigm

We are now in the midst of a very exciting revolution defining what role this new view of DNA and the plethora of RNAs play in defining our biology. A consensus is now emerging as a new biological theory. Whereas our twenty thousand proteins perform the necessary functions for life, it is the RNA, made mostly from the “junk DNA,” that controls when and where proteins are made.

I describe this new paradigm as the DNA/RNA Dogma, a description that assigns equal importance to both DNA and RNA, a focus on the control of protein expression as a key to understanding Mendelian inheritance. The DNA/RNA Dogma offers a more comprehensive and accurate picture of Mendel’s genes and our complexity.

The new dogma now reads.

DNA <—> RNA—> Control—> Protein—> Phenotype

The insertion of the word “control” denotes our rapidly expanding knowledge of the role RNA plays in controlling when, where, how many, and in what form proteins are made.

The new double arrow between DNA and RNA describes both the RNA-directed modification of DNA that affects RNA production and the reverse flow of genetic information from RNA not accounted for by the original central dogma. Like all diagrams, this one is oversimplified. For example, some non-coding RNAs affect phenotype.

Analogy may help. I now have extensive experience with Lego in building entire cities for my grandchildren. Lego sets come with a set of colored plastic parts and a set of instructions to assemble them. In this analogy, the plastic parts are the proteins, limited in number, each with a defined form. The instructions are the regulatory RNAs. With the same parts, you can build either a simple or complex structure. Change the instructions, and you change the structure. A single error in the instructions (or much less frequently in a building block) results in a fault in the final structure. There are many more words in the instructions than there are in the different types of building blocks. Most organisms produce very similar sets of proteins but differ markedly in the way those proteins are used. Kits for complex structures, like Ninjago sets, also include a minority of customized blocks analogous to specialized proteins.

The new Dogma meets Thomas Kuhn’s definition of a paradigm shift.

1. The DNA/RNA Dogma is sufficiently unprecedented to attract an enduring set of adherents. Indeed, many new studies elaborating on the discovery and details of new regulatory RNAs and genome structures are published each week.
2. T. he DNA/RNA Dogma is open-ended, with many problems to be resolved. The weekly accumulation of new discoveries highlights this theory’s open-ended nature.

I liken the shift to the DNA/RNA Dogma as akin to the paradigm shift between Newtonian physics and quantum theory. Newtonian physics explained much of what was then known about the physical world. Newtonian physics is not incorrect, but it is only a special case that applies to large objects. The original central dogma explained much of what was known about simple organisms, viruses, and bacteria but did not explain the biology of complex organisms.

New theories must not only explain vast new sets of observations and predict future observations, but they must also be accepted by most practitioners and the public. Thanks to COVID-19 RNA vaccines, the recent appreciation of the importance of RNA is now generally understood by the public. RNA biology is now also at the forefront of gene therapy, gene editing, and cancer therapies.