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‘Dark Matter’ in Biology

March 21, 2011

For the next few weeks, I plan to concentrate on a series of topics which could be all brought under the umbrella of so-called ‘biological dark matter’, or the current limits of biological knowledge. For biopolyverse, it seems like a good starting point to consider what things in biology we don’t know –as well as the huge amount that we do. This week,  I look at the notion of ‘dark matter’ in biology itself.

The scientific picture of life has crystallized from the onrush of molecular and cellular biology since the latter half of the 20th century. Now, this is not to say that our knowledge about living things is all wrapped up. Far from it, in fact. But this statement in itself begs the question: Are the remaining gaps in biological understanding just a matter of filling in details (even if there is a veritable ocean of detail yet to come), or are there more fundamental matters to be defined, perhaps including some which are not yet even recognized? The notion of filling in details vs. exploring new terrain has a long history in molecular biology itself. From the present perspective, many of us might think of 1963 as ancient times in this science, only a decade after the publication of the structure of DNA. Yet by then, some of those at the forefront of the field already regarded the ‘classic’ problems of molecular biology as solved in outline (or soon to be solved), and only needing the attention of a small army of competent workers to fill in the dots. At this time, the true frontiers were seen as the mechanisms of development of complex organisms and the higher-level operating principles of nervous systems, and so this remains today. Of course, vastly more is known about these biological phenomena now than was the case in 1963. And now, jumping the best part of 50 years onwards to the present, can we place these and other aspects of biology into the ‘details’ basket, or are there real gaps to cross first? And might there be anything hidden in such fissures of knowledge which might be utterly unanticipated ‘bolts from the blue’? Something unilluminated by knowledge…..something ‘dark’?

The term ‘dark matter’ of course has arisen within the science of physics, so a brief tour of the background to this is in order:

Dark Physics

Towards the end of the 19th century, most physicists were convinced that the essential nature of the universe was within their grasp. Diligent application of Newtonian mechanics had revealed much, and it was expected that most remaining details would soon be filled to complete the picture of a clockwork universe. The passage of time has, of course, shown that this attitude was utterly wrong. Tumbling out with the new century came radioactivity and subatomic structure, relativity, and quantum mechanics. The latter in particular produced experimentally verifiable interpretations of the behavior of subatomic particles which seemed to defy the common sense view of the macroscopic world, and a very different picture of the fundamental nature of the universe accordingly emerged.

By the end of the 20th century, progress in the physical sciences had been profound, but it would be true to say that there was nevertheless little of the smugness seen one hundred years before. The requirement for statistical interpretations of quantum behavior and the celebrated uncertainty principle in themselves do not permit the completely deterministic universal view embraced by 19th century physicists. But on the other hand, it was also clear that the universe still had many secrets remaining up its proverbial sleeve. This was powerfully revealed on the grandest of scales by the discovery that most of the mass of the universe could not be accounted for by ordinary matter. In fact, the ‘ordinary’ category of matter is a very small fraction of the total mass, on the order of only 4% , where the remainder is constituted by ‘dark matter’ and ‘dark energy’. As their name implies, these aspects of the universe by definition interact weakly with ordinary matter, but are predicted (and mandated) through certain physical observations. The notion of dark matter arose from studies of the expansion of the universe, which showed that large-scale galactic distributions could not be explained through their gravitational effects alone. A large component of additional matter, dark to observation but gravitationally interactive, was thus invoked. The observed acceleration of the universe’s expansion itself requires a universal ‘antigravity’ energy, which is inferred as equivalent to over two-thirds of the mass of the universe, but of an unknown nature. ‘Dark’ energy, then, indeed.

So these ‘dark’ physical entities have been revealed only through certain physical observations of the universe, and prior to this their existence was unsuspected. And while their existence as such has compelling logic, at present their specific natures are enigmatic, although numerous hypotheses have been put forwarded. It is only these ‘mystery’ features of dark matter and energy which need concern us further here, since for the present purposes the aim is not a rendition of the frontiers of cosmological physics. The inherent fascination of the ‘dark’ aspects of the universe easily lend themselves to analogies in other fields, and the use of analogy and metaphor as explanatory aids is a very old human trait. In fact, it has been proposed by some that such activities are the very essence of human cognition itself. If so, perhaps this fundamental analogical thought level drives the expression of higher-level analogies which serve to communicate one or more salient points about complex issues, from mind to mind. But like any explanatory aid, one must understand the limits of analogies as well as their strengths, for fear that their over-enthusiastic application might figuratively lead to ‘an allergy to analogy’ in the minds of would-be recipients.

Dark Bio-Analogies

But this cautionary note has certainly not inhibited biologists in the slightest, and analogies have been drawn between a variety of different unresolved biological issues and the existence of physical dark matter (References & Details).

In these instances, we could translate such biological ‘dark matter’ references as simply ‘unknown entities’, which at first glance seems fine. Yet if we really want to make an accurate analogy with the physical enigma of dark matter, this usage of ‘dark matter’ becomes a little wishy-washy. This is so since physical dark matter refers to something whose very nature is an unknown quantity, not merely its existence per se. All current examples of ‘biological dark matter’ cited in the literature are, in essence, uncharacterized manifestations of known types of entities. Consider the issue of ‘dark’ products of complex genomes, in the form of numerous transcribed RNAs with unknown functions. However exotic the biological roles of certain non-coding RNAs, the general chemical nature of any RNA molecule is very familiar (although of course a complete chemical description of any particular biological nucleic acid is not revealed until its base sequence is defined). And single-stranded RNA molecules which fold into definable structures with specific functions (binding other molecules or catalysis) have long been known.

In contrast, cosmic dark matter cannot be a result of some kind of reassortment of known ordinary matter, or ordinary matter behaving in hitherto unexpected ways, but something else entirely. This is clearly far more ‘dark’ than lacking the knowledge of what a particular RNA molecule does. The same kind of comment may be applied to other instances of ‘dark’ biological phenomena or discoveries which have been cited in the published literature (References & Details). To be fair, we should not forget that the ‘dark’ label has also connotations of recondite knowledge, of hidden things that may not even be understood as problems to be investigated. In this sense, the function of many regions of eukaryotic regions were indeed enigmatic initially, and are still far from being fully defined. But if it is accepted that many non-coding sequences function through transcription to RNA, then this primary step is no longer ‘dark’ in the sense that RNA itself is familiar, even though its ultimate functions may remain to be defined.

A strict analogical extension of cosmic to biological dark matter would then be the discovery of a biological effect that cannot be accounted for by ‘ordinary’ biological mediators or processes. And just as dark matter in the universe is a recent finding, such a hypothetical biological effect might itself be long unrecognized, rendering the agency involved truly obscured. Of course, if we attempted to exclusively apply this most stringent definition of ‘dark matter’ in biology, some onlookers would claim that there is little for it to refer to. That is to say, there may be no biological entities which (in the modern world) are sufficiently unknown to qualify as ‘dark’ to anything like the same degree as dark and mysterious cosmic matter.

In the end, this comes down to an exercise in semantics, and some opinion would also hold it to be rather pedantic to insist on the most stringent use of ‘dark matter’ as a biological term, especially when it has already been used in its more dilute form. But at very least, these considerations serve to make an important general point: there are levels and levels of ‘darkness’ in any area of investigation, not least of which is biology. In other words, a hierarchy of novelty / unfamiliarity / strangeness can be readily constructed when we consider new biological discoveries, and speculate upon their ‘outer limits’.

Real Biological Dark Matter

The ‘surprise factor’ in a biological discovery can be simply related to the degree of divergence of the new finding from the existing corpus of biological information. Of course, most new data simply slots in and extends the coverage of biology without having any effect on the ‘big picture’ scale. Some discoveries may provide interesting precedents for processes or structures hitherto unreported, but without causing too many eyebrows to be raised. Still other findings may indeed cause considerable supra-ocular hair elevation, yet fall short of seriously challenging key biological principles. With these considerations in mind, it is not difficult to categorize the experimental input of new biological information as a spectrum of sorts, as shown in the accompanying ‘Biological Dark Matter Hierarchy’ Table.

An inherent feature of biology which renders it quite distinct from physics and general chemistry is that its subject of study currently is entirely bounded by this planet, and all known biological entities are clearly of same general ‘life type’ – that is, their most fundamental replication systems point to a shared evolutionary heritage, to a universal common ancestor in the remote past. Proof of the existence of fundamentally alien organisms from elsewhere in the universe (combined with the opportunity to examine them) would be a revelation in its most literal sense. But for the time being, we are restricted to ‘Life 1.0’ as the cornerstone of all biological investigations.

This point, obvious enough at one level, provides a clear division between two broad groupings of potential biological dark matter. In the first category are found any unsuspected and unprecedented structures or processes necessary to comprehensively understand all aspects of the living systems with which we are familiar. In this, we must include all biological phenomena, certainly not excluding consciousness and intelligence.  Any remaining deficiencies in complete biological understanding represent gaps in knowledge, although some schools of thought question whether human intelligence alone can comprehend consciousness itself (a likely topic in itself for future biopolyverse posts). Again, much of this gap-filling exercise will give straightforward results, yet some findings by their divergence from the norm may at least approach a ‘dark matter’ label.  The second broad category might be labeled ‘Life 2.0’, by dint of its lying beyond the standard biological boundaries as normally defined on this planet.  Any generalized discussions about Life invariability return to its physical meaning, although (as noted in the previous post) comprehensive definitions of Life have historically been surprisingly difficult to nail down. For the present purposes a key feature of living systems must be highlighted: life must have the capability of self-replication, or reproduction. Without this, an organized system could not persist and evolve through significant periods of time, nor could it diversify or attain high levels of complexity.  So in terms of the ‘dark’ label, replication is indeed a major focus of interest. Organisms using Life 2.0 biosystems would by definition be ‘dark replicators’, until their biologies were dissected at the molecular level and understood.

It should be emphasized that the ‘hierarchy’ Table is provided here to show levels of ‘darkness’, and does not of course include every potential arena in biology. For example, the issues of development and neurobiology (noted above in the context of discussions of molecular biologists in 1963) are still far from completely understood. But a good case can be made that ultimately they will be functionally defined entirely within the existing biological framework (or paradigm, if you prefer). If so, they will not yield any true instances of ‘dark matter’, no matter how convoluted and intricate their functional deployment turns out to be.

This could be wrong, of course, but it is hard to pin down. Once again, researchers may completely overlook an utterly novel biological feature if they have nothing directing their attention to it. If you don’t specifically look for some things, you may not see them. Decades ago, before evidence for cosmic dark matter accumulated, a different model of the universe existed, but one that was fundamentally flawed through a lack of knowledge about even the existence of a major universal component. (This could be expressed as a variation on the old attribution of profound ignorance, ‘He don’t know what he don’t know’).

More on this and related areas next week and continuing. In coming posts, certain features of the ‘hierarchy’ Table will be referred to and further explained and extended.

To conclude, a short but relevant (biopoly)verse, but this is not going to become a pattern…

Is biology just a walk in the park?

Is biocomplexity really a lark?

Have we a complete

Life systems fact-sheet?

Or is our outlook still enshrouded in dark?

References & Details:

By topic, in order:

Essence of molecular biology known by 1963:   In correspondence with Max Perutz, in 1963 the (later Nobel-prize winning) molecular biologist Sydney Brenner wrote:

“….It is now widely realized that nearly all the “classical” problems of molecular biology have either been solved or will be solved in the next decade. The entry of large numbers of American and other biochemists into the field will ensure that all the chemical details of replication and transcription will be elucidated. Because of this, I have long felt that the future of molecular biology lies in the extension of research to other fields of biology, notably development and the nervous system. This is not an original thought because, as you well know, many other molecular biologists are thinking in the same way. ….”

Letter to Max Perutz, 5 June 1963. Quoted in William B. Wood (Ed.), The Nematode Caenorhabditis Elegans Cold Spring Harbor Monograph Series 17 (1988), x-xi.

Dark matter, physical:   Many popular books and articles deal with the general topics of dark matter and dark energy. For example, see Brian Greene (The Fabric of the Cosmos, Penguin 2005); Paul Davies (The Goldilocks Enigma, Allen Lane 2006), whose books discuss dark matter and energy along with other cosmic topics. For an article on the role of dark energy in shaping the universe, see C. J. Conselice, The Universe’s Invisible Hand, Sci. Am. 2007 24-31.

Importance of analogy in human thought:   see Hofstadter, Douglas, Analogy as the Core of Cognition. In The Analogical Mind: Perspectives from Cognitive Science, edited by Dedre Gentner, Keith J. Holyoak, and Boicho N. Kokinov, Cambridge MA: The MIT Press/Bradford Book, 2001, pp. 499-538.

Dark Matter in biology:   Many remaining gaps in biological information have been referred to as ‘dark matter’, including uncertainties in genetic links with disease(Melhem & Devlin 2010) or cancer (Galvan et al. 2010), missing links in protein-protein interaction networks (Ranea et al. 2010), and defining the range of protein folds used in nature (Taylor et al. 2009). But two major areas within which authors have alluded to ‘dark matter’ are of particular interest. Firstly, as noted above, much transcription of RNA within complex genomes yields RNA products with unknown functions. ‘Tiling’ microarray experiments initially indicated that a major portion of eukaryotic genomes was actively transcribed (Johnson et al. 2005), necessarily including extensive tracts of non-coding RNAs (RNAs which do not code for proteins, and excluding the long-known non-coding ribosomal and transfer RNAs). Observations like these from various labs prompted proposals that an important and hidden function of the genome must be related to these RNA transcripts, and hence the ‘dark matter’ parallel again rears its head (ugly or otherwise) (Michalak 2006; Collins & Penny 2009; Scaruffi 2011). It has been pointed out, though, that before jumping to conclusions, roles for putative functional non-coding RNAs should be defined (Ponting & Belgard 2010). Recent evidence in fact strongly suggests that the great preponderance of genomic ‘dark matter’ RNA is associated with coding sequences after all (Van Bakel et al. 2010). Still, the latter paper does not deny that novel non-coding RNAs exist (only that they are much less abundant that other authors have claimed), and many other studies with specific instances of both long and short non-coding RNAs have firmly established their biological significance. But by then, they are certainly no longer so ‘dark’, are they?

The second ‘dark matter’ area of interest concerns unknown microbial organisms, because this can be directly related to the above ‘hierarchy’ Table. Most of the advances here have been enabled by the ability to amplify genomic DNAs from environmental sources through the polymerase chain reaction (PCR), a relatively new field known as metagenomics (more information on both PCR and metagenomics can be found in supplementary material for Searching for Molecular Solutions in its accompanying ftp site). The reason this is a revolutionary development is simply that only a very small proportion of microbes are amenable to laboratory culturing. So, metagenomics can reveal hitherto unknown organisms, or (you guessed it) microbial ‘dark matter’ (Galperin 2007; Marcy et al. 2007) from a range of environments (including marine ecosystems, soils, and human mouths and guts). Now, a DNA genomic sequence obtained through metagenomic analyses might indicate a new organism which fits within previously-defined groups (the intersection of ‘Unicellular Organisms’ and ‘Simple Extensions Within Existing Framework’ of the above Table). But a more exciting prospect is that something quite novel might turn up, from a new phylum (large scale biological group within one of the major [top-level classification] ‘domains’ of life) or even (possibly) a new domain itself (Wu et al. 2011). This would take the ‘Unicellular Organisms’ column of the ‘hierarchy’ Table to its intersection with ‘Complex Extensions Within Existing Framework’, but still does not produce true ‘dark matter’ by the more stringent criteria. The same applies to recent proposals that certain giant viruses (‘giruses’) are so distinct that they warrant their own kingdom (only one classification level down from domain) (Van Etten 2010).

But before finishing up, it must be noted that studies of environmental microbes could in principle reveal true, honest-to-God, real-McCoy biological Dark Matter. And that’s the ambit of so-called ‘Life 2.0’ or ‘weird life’ (as in the bottom of the ‘hierarchy’ Table above), and a topic for subsequent posts…..

Difficulties in definitions of life:   For example, see Cleland & Chyba 2002, also Chapter 10 of Searching for Molecular Solutions.

Note that these references are meant to serve as a guide for further information, and are not intended to be comprehensive.

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