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Paradigms and Biological ‘Dark Matter’

March 28, 2011

Another way of looking at the nature of current biological unknowns, whether we attach the ‘dark’ label to them or not, is to think of them as the material for potential future ‘paradigm shifts’. This term, popularized through the influential book The Structure of Scientific Revolutions by Thomas Kuhn in 1962 can be applied to many recalibrations of scientific perspectives, and the Table below lists some significant changes to biological ‘paradigms’ since the 19th century. Once the old biological world-view, or paradigm, is overturned by undeniable evidence, a new paradigm is then set in place – and thus a ‘paradigm shift’ occurs. Whether all these items qualify as true ‘shifts’ of course depends on the strictness of one’s definition of ‘paradigm’ itself. In Kuhn’s usage, it referred to the theoretical background framework for a whole scientific field, as with physics just prior to the introduction of Relativity by Einstein. A shift (or major restructuring of such a paradigm) would then require a radical alteration in the accepted viewpoints of that scientific field, virtually by necessity.

Very often, though, in biological and other contexts one sees ‘paradigm’ (by itself, or combined with the ‘shift’ tag) applied to much more restricted matters, often in very specialized contexts which might seem mundane to outside observers (See References & Details). Any defined area of investigation, of course, can undergo such ‘shifts’ if you set the terms narrowly enough. But here, let’s at least approach a more Kuhnian stance and look at a high-altitude picture of biology. With this in mind, we can put this into the context of where a new so-called ‘dark matter’ finding might indeed trigger a seismic shift of paradigm-shaking proportions.

Even when attempting to do a big-picture analysis, though, it soon becomes clear that making such assignments is not entirely straightforward. It could be objected that some possible candidate ‘shifts’, while important and interesting, do not cause any major alterations in the ‘dominant paradigm’ of biology. So the impacts of the different discoveries in the paradigm-Table are certainly not all equal. But some are real ‘shifters’, by almost any measure.

Evolution, the first within this list, is the best case in point. The controversies arising from the public dissemination of Darwin’s book The Origin of Species are well-known, and the general acceptance of evolution by the end of Darwin’s life certainly marks a profound shift in biological thought at a very fundamental level. And evolution by natural selection remains by far the most important single organizing principle in biology.

On the other hand, it is important to note that this snapshot of biological scientific history is based on their deviations from the expected patterns of biological behavior at the time, which is not identical to their relative rankings for importance as scientific advances in their own right. For example, even biological dilettantes might point out that the paradigm-Table has notable omissions from the great biological achievements of the second half of the 20th century.  What about the deciphering of the genetic code, the unraveling of the mechanisms of protein synthesis and DNA replication and transcription, to name many possible examples? These are of unquestionable importance, but generally lack the ‘surprise’ factor of the advances which have been included in this Table.

These are all findings that apply at the molecular level, although they may carry implications that apply to many higher planks of biological organization (as of course evolution does). Certainly discoveries of unprecedented high-level biological effects themselves might in principle qualify as paradigm shifts, but to date there seem to be few examples, and these are arguable. For example, the discovery of eusocial behavior in the naked mole rat rewrote the view that only certain insects manifested this type of system, where carefully tended queens are the reproductive center of a group. A paradigm shift? – maybe, but not likely to universally regarded as such.

An original dictionary meaning of ‘paradigm’ was ‘exemplar’, so let’s take a case from the paradigm-Table as an old-style exemplar / paradigm of the Kuhnian sense of the word…..

A Dogmatic Example

In comparison with the earthquake shock of evolution, the other examples in the paradigm-Table are less dramatic, but each in their own way prompted revolutions in biological thought of varying magnitude.  (Some of the more recent items such as epigenetic inheritance remain controversial as to their ultimate biological and evolutionary significance, or are still in the process of being fully unraveled.) For example, after the structure of DNA it was soon understood that the essential process of protein synthesis was mediated by a messenger RNA copy of the DNA template. This gave rise to the simple aphorism ‘DNA makes RNA makes protein’, which has very often been referred to as ‘the central dogma’ of biology, given its fundamental biological applicability. (This is usually attributed to Francis Crick, but what he actually wrote had important distinctions from this. For a little additional material, see References & Details).

Since the process of making an RNA copy from a DNA template (through normal Watson-Crick base-pairing rules) is known as transcription, it follows that an enzyme which can perform such an activity can be referred to as a transcriptase.  More formally, such enzymes are template-dependent polymerases, since they link nucleotide building blocks into long polymers, the sequence of which is dependent on the ‘instructions’ of the DNA template strand. A transcriptase copying an RNA strand from a DNA template then is a DNA-dependent RNA polymerase, and the ‘central dogma’ might be represented as:

In addition to the messenger RNA (mRNA) copy of a DNA which acts as a protein coding sequence, many other factors are required for the complex machinery of protein synthesis. For the present purposes, it should be noted that transfer and ribosomal RNAs (tRNAs and rRNAs respectively) are fundamentally important. Yet an indefinite number of functional factors could be introduced without affecting the directionality of the overall scheme. In other words, if we consider the arrows in the above diagram as showing a flow of information (taking the encoded DNA sequence into corresponding protein sequence), then there is no suggestion that the flow is anything but a one-way street. In fact, from early days it was obvious that functional loops were formed, since the agents which enable (catalyze) this information flow are themselves proteins (mainly) and certain RNA molecules. So proteins transcribe DNA sequences into mRNA molecules, which encode proteins, including those which transcribe and replicate DNA. In addition, it is now clear that certain RNA molecules, large and small, have major functional role in the regulation of gene expression. The feed-back dotted lines in this diagram then represent functional interactions, rather than direct information flow. This is the essence of the ‘entanglement’ of nucleic acids and proteins, so hard to account for during the origin of life. But this ‘loopiness’ aside, the direction of information flow was seen to pass from DNA to proteins via RNA intermediaries, and never in the reverse direction. To be fair to Francis Crick’s ‘dogma’, his main point was that once information gets into proteins, it can’t get back out (References & Details). Specifically, he was envisaging that the base-pairing of nucleic acids acts a biological means for transmitting information, but no such templating is possible with protein sequences themselves.

Biology, though, tends throw in additional levels of complexity the more one learns. In 1970, two independent workers (David Baltimore and Howard Temin) found that certain viruses produce enzymes that turn at least the DNA à RNA component of the ‘Central Dogma’ on its head. These protein catalysts have the ability to use RNA strands to synthesize a DNA copy, and thus are RNA-dependent DNA polymerases. Since the conventional pathway of transcription is reversed by this operation, such enzymes are very often referred to as reverse transcriptases. The viruses which encode these hitherto novel polymerases have RNA genomes, which are reverse-transcribed to DNA copies as a necessary step for enabling their integration into the host cell genomes. As a consequence, viruses of this general type are referred to as retroviruses, of which HIV is undoubtedly the best–known example, but certainly not the first described. But how revolutionary was this, in reality? Overturning a so-called ‘dogma’ might be defined as a paradigm shift, but hardly in the same sense as the theory of Evolution was.

The existence of RNA-dependent DNA polymerases in the retroviral world is not at all the end of this biological story. The once iconoclastic finding of reverse transcription crops up as a near-universal feature in eukaryotic cells, as a fundamental requirement for maintaining chromosomal integrity. Linear chromosomes, as found ubiquitously in eukaryotes, have a special problem of keeping their ends (telomeres) stable and intact. By the nature of double-stranded DNA replication, linear chromosomes have an inherent tendency to shorten after each round of replication. Even if this progressive depletion of end nucleotides was acceptable during the lifetime of an organism, clearly it could not be tolerated through successive reproductive generations. And so, it was predicted that an enzymatic activity must exist for telomere restoration, and this telomerase function was duly discovered in 1985. It later emerged that a key feature of telomerase activity is reverse transcription. A cellular RNA molecule forms an integral part of telomerase, and this RNA serves as a template for the reverse transcription of part of its sequence which allows telomere extension and reconstitution. In principle, the reverse transcriptase activity of telomerase could have evolved independently of the enzymes used by retroviruses (convergence), or both could have arisen from a common ancestor separated by wide gulfs of evolutionary time (divergence). While not absolutely certain, telomerase and retroviral reverse transcriptases share certain structural features, and some evidence suggests that telomerases may have evolved from parasitic retroelements. It is then far from absurd to suggest an evolutionary relationship between a fundamental enzymatic function of such widely disparate organisms as retroviruses and humans.

But this is all to emphasize that reverse transcriptases are hardly biologically insignificant entities restricted to obscure viruses, when they are fundamentally required for germline cell maintenance in higher organisms, including ourselves. Unlike the original descriptions of RNA-dependent DNA polymerases, the association of such a functional enzymatic activity with telomerases was nothing as dramatic in its impact. While of course very interesting from many points of view, by then the notion of reverse transcription itself was completely old hat. Indeed, commercially available cloned reverse transcriptases are routinely used for generation of complementary DNA (cDNA) strands from mRNA templates, to allow direct cloning or (more usually) amplification by the polymerase chain reaction.

According to the author Horace Judson (References & Details), Crick later stated that he used ‘dogma’ in ignorance of the full ‘dogmatic’ implications of the actual meaning of the word. He added that he might well have used ‘Central Hypothesis’ instead. What about, ‘Central Paradigm’, then? While perhaps not quite up to the mark in the full Kuhnian sense, it certainly would beat many much weaker applications of ‘paradigm’ in contemporary scientific usage.

That which is outside the existing ‘Central Paradigm’ could be viewed as the realm of biological ‘Dark Matter’, if such new information could indeed shake the paradigmatic foundations of the field. As noted in the previous post, while the accuracy of the ‘dark matter analogy between physics and biology is poor, it has taken root as a metaphor for general biological unknowns or uncertainties. Anything remotely approaching a ‘shift’ in paradigms must then necessarily impinge upon the ‘dark’ areas of biology – although this is rather obvious if ‘dark matter’ simply equates with ‘unknowns’. But this leads to the topic of biological limits, which (among other things), will be picked up next post.

To conclude, a little (biopoly)verse somehow sneaks in:

Is abuse of the word ‘paradigm’

Approaching a scientific crime?

But words are erratic

And seldom dogmatic

When their meanings dilute out with time

References & Details

(In order of citation):

Usage of ‘paradigm’ and ‘paradigm shift ’: One way to look at this is to systematically search the free PubMed database. If one restricts a search to article titles only, as of this time 8062 hits are found for ‘paradigm’. In some of these (especially in the small number published before 1962) the usage of paradigm reflects its original meaning as ‘exemplar’, etc. To avoid this, I used “paradigm shift” as the search term, whereupon no hits are found before 1980. By about 2000, they start to accelerate, with a combined total of 658 hits to the present time. Of course, the total number of PubMed entries is continuously increasing per year (now approaching 1 million annual entries), but ‘paradigm shift’ has clearly increased in popularity at a much greater rate than can be attributed to general publication growth (See the graph below). So ‘paradigm shift’ seems to been undergoing an upward shift itself in recent times. From this trend alone, it would seem that the modern use of ‘paradigm shift’ could not possibly be in accordance with the Kuhnian ‘radical change’ connotations. (Scientific progress is certainly accelerating, but the whole basis of biology , or any subsection of it, is not continually overthrown 50 or more times each year!) Inspection of specific cases where ‘paradigm shift’ is used in publication titles bears out this conclusion.

(Note that technically, using the available PubMed service, this is an imperfect analysis, since PubMed coverage of a minority of journals is not complete over the timespan shown. For example, coverage of the major physics journal Physical Review extends only to 1985. Still, this is most unlikely to affect the simple conclusion of the above graphical compilation).

evolution….. marks a profound shift in biological thought at a very fundamental level’: Note that this is referring to the biological (and general) scientific community, not global populations as a whole. It is also well-publicized that ‘creationist’ lobbying against the teaching of evolution in schools regrettably continues to this day, especially in the US. Despite this obfuscation, no biologist of repute disputes the fact of evolution, although fine details of how it proceeds continue to be debated.

Some details for the paradigm-Table: (Obviously it is not possible to give a full rendition of each item here, but some details for some of the topics are given here where it may be useful).

Cell Theory: To most people, the notion that even the largest organisms are composed of discrete units termed cells is so commonplace as to seem obvious, but of course this was not always so. The 1839 date given here corresponds to the publication of a German monograph on the whole area by Theodor Schwann (1810-1882), which is a convenient point to use as a marker. But it would be wrong to consider Schwann the sole or even the main originator of the Cell Theory, towards which many took part. The full development of the concepts of nuclear cell division and cell differentiation took longer, dating to the latter part of the 19th century. See The Birth of the Cell (by Henry Harris, 1999, Yale University Press) for an excellent rendition of this history.

Genetic Inheritance: The ‘1866/1900’ entry reflects the fact that the early discoveries of Gregor Mendel (published in 1866) were generally ignored until rediscovered by three independent workers in 1900.

Epigenetics: A ‘starting point’ of sorts is taken as a paper by Robin Holliday in 1987. He originated neither the term ‘epigenetics’ nor the field itself, but this paper has been seen as a major stimulus for the current era of intense interest in epigenetics / epigenomics.

Genomic imprinting: The roots of this are complex in origin, since knowledge of the requirement of both paternal and maternal chromosomes in development preceded demonstration (in 1987) that this was associated with methylation. (See Reik et al. 1987; Sapienza et al., 1987; Swain et al., 1987).

RNAi: The phenomenon of RNA interference was in fact first discovered in plants in 1990, and later analyzed in animal cells by Andrew Fire and Craig Mello (See this 2006 review for further details). Fire and Mello later received the 2006 Nobel prize for this discovery, which was not without controversy owing to the perceived lack of recognition of the original work in plants. (For example, see correspondence to Nature). This very point illustrates the difficulty which sometimes occurs when trying to assign a single source to a scientific advance.

…..eusocial behavior in the naked mole rat’: See Jarvis 1981.

Details for A Dogmatic Example:

‘Central dogma’ and Francis Crick : For a detailed consideration of this, see a posting in Larry Moran’s Sandwalk blog.

It might be added here that the loosening of the meanings of both ‘paradigm’ and ‘dogma’, as considered in this post, is not at all unprecedented. Another example that comes to mind is ‘nanotechnology’, as promoted by K. Eric Drexler, initially in his book, Engines of Creation. The Coming Era of Nanotechnology (Doubleday, 1986). Although he was preceded by Richard Feynman in 1959 in terms of discussing the potential of nano-scale operations, Drexler envisaged ‘nanotechnology’ as referring to machines and assemblers which operate on a nanometer scale. Yet in recent times the term has been ‘hijacked’ to cover much less ambitious technology, such as using simple nanoscale objects for drug delivery. The above limerick refers to this general trend.

In 1970, two independent workers….’ See Baltimore 1970 and Temin 1970.

HIV is undoubtedly the best–known example, but certainly not the first described: The first reverse transcriptases described were encoded by avian or murine RNA tumor viruses (Baltimore 1970; Temin 1970).

this telomerase function was duly discovered in 1985 ‘ See Greider & Blackburn 1985.

which allows telomere extension and reconstitution…’ (telomerase reverse transcriptase activity) See Cech 1997.

…..telomerase and retroviral reverse transcriptases share certain structural features…’ For example, see ; Lingner 1997; Autexier & Lue 2006.

….telomerases may have evolved from parasitic retroelements….’ This refers to mobile genetic elements usually referred to as ‘retrotransposons’, whose transference between host genomic sites is mediated through a reverse transcription step via an enzyme encoded within the mobile element itself. These elements are thus molecular parasites, which are replicated along with the host chromosome into which they insert themselves. While they share this feature with retroviruses, retrotransposons do not form infectious viral particles during a ‘lytic’ phase, when host cells are forced to become viral factories and are destroyed. For further information on telomerases and retroelements, see as examples Nosek 2006; Gladyshev 2007.

……reverse transcriptases are hardly biologically insignificant entities…..’: In retrospect, it does not seem that amazing that an RNA strand could act as the template for DNA synthesis, if an enzyme capable of catalyzing this template-directed polymerization existed. But of course, just because one can conceive of a process does not mean that a biological ‘real-life’ counterpart exists. An example of this comes from nucleic acid polymerization itself. RNA or DNA single strands have chemically distinct ends, referred to as 5’ and 3’ based on the numbering system of the ribose sugar ring moiety of nucleoside building blocks of nucleic acids. During the polymerization reaction, successive nucleotide building blocks are added on as directed by base-pair matching with the complementary template strand. As such, at any given time there is an end to the growing chain which serves as the site for the addition of the next appropriate nucleotide. This successive addition dictates that chain elongation has a directionality: if nucleotides are successively added to the 3’ end, then the new chain is growing in a 5’ –> 3’ direction (towards the 3’ end), and conversely, if continuously building upon the 5’ end, the chain growth would occur in a 3’ –> 5’ direction. In principle, one might imagine that either could occur, and there is no inherent chemical reason why this should not be the case. Yet all known biological polymerases act only in a 5’ –> 3’ direction.

In the same context, it should be noted that the absence of a molecular function from natural circumstances does not necessarily imply that it is impossible, and human ingenuity might in the future produce novel catalysts which indeed have the ‘missing’ features.

With respect to the role of reverse transcription in telomere extension, it is interesting that alternative routes for this vital biological activity exist, based on recombinational mechanisms. These pathways allow continued cell division in the absence of telomerase, and are exploited by some tumor cells (See Bryan et al. 1995).

germline cell maintenance…’: Telomerase is not usually expressed in normal somatic cells (as opposed to tumors), but an exception is the case of rapidly-replicating immune cells. (For further details, see Hathcock et al. 2005).

Judson, Horace. The Eighth Day of Creation. Makers of the Revolution in Biology. 1st Edition Simon & Schuster, 1979. 2nd Edition, Cold Spring Harbor Laboratory Press, 1996.

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