Creating Order from Disorder?

Researchers from the Monash Biomedicine Discovery Institute (BDI) in Australia, have identified what they have termed “Structural Capacitance Elements” (abbreviated as SCEs hereafter) in mutated proteins that are associated with many different types of human diseases, often a range of cancers. These proteins are inherently “disordered,” having little definite structure. In fact, it has been commonly assumed that mutations associated with genetic diseases and cancers occur because they that have no ordered structure to begin with.

These intrinsically disordered proteins (IDPs) appear to be deliberately designed to be functional despite the fact that they are not structured. Using disorder to describe them is something of a misnomer since disorder implies something broken and non-functional. This is the opposite of what these “IDPs” actually are. In fact, they appear to have added functionality as they are more adaptable. The flexible structure and flexible structural segments of IDPs helps allow for a greater spectrum of binding targets. IDPs are highly abundant in regulatory processes such as transcription, regulation, recognition, and cell signaling. Furthermore, the disordered regions in polypeptide chains are important because such regions are essential for protein function. However, abnormally high numbers of, alteration of, or even long-lived IDPs are often associated with many diseases.1

These intrinsically disordered proteins (IDPs) appear to be deliberately designed to be functional despite the fact that they are not structured. Using disorder to describe them is something of a misnomer since disorder implies something broken and non-functional.

Saltatory Evolution

What the researchers wanted to determine was whether point mutations in disordered regions would generate localized regions of microstructure. In other words, they wanted to see if the mutations would impose a region of order to the disordered regions of certain proteins. They were able to identify (by combing through the human polymorphisms and disease mutations dataset2) that several changes at the level of individual proteins could potentially be generated, which might cause new structure and functionality. These new structures may be able to more readily fold and may induce other proteins to bind together with them at the SCE microstructural region. The authors’ contention is that these SCEs could be a mechanism for saltatory evolution rather than slow and gradual neo-Darwinian evolution.

Saltatory evolution was the original idea of evolution proposed by Anaximander around five hundred and fifty years before Christ.3 He proposed that life evolved in the ocean and man was birthed from some kind of fish since man requires nursing before being able to live on his own. The Greek writer Plutarch, best known for his biographies of ancient historical figures, embellished this idea to claim men were birthed from sharks.4 Until the time of Darwin, most evolutionists were proponents of saltation in some form. However, with the publication of The Origin of Species, saltatory evolution made way for a slow, progressive gradualism nearly unique to Darwin at the time. This Darwinian evolutionary dogma persisted unquestioned by most of its followers until 1972 when Stephen Jay Gould and Niles Eldredge published their seminal essay. This lengthy essay, entitled “Punctuated equilibria: an alternative to phyletic gradualism,” proposed that a process called “punctuated equilibrium" could explain the gaps in the fossil record.5 This sparked a trend, particularly in geology, of using punctuated equilibrium to explain away the gaps Gould freely admitted existed in the fossil record.6 Biology was not immune to the trend, with saltatory evolution becoming more appealing and popular as well. This idea of changes too rapid for the fossil record to capture appears to be the catalyst for this recent study in the areas of molecular biology and biochemistry.

According to a Journal of Molecular Biology article, even though the process remains “undescribed,” they believe that protein mutations, usually associated with cancer or other diseases, can somehow undergo a specific additional mutation, which not only would render them non-carcinogenic, but would actually cause them to be beneficial to the organism in a functional gain. According to the journal article:

We propose that in addition to canonical loss-of function mutations, disease-causing mutations may result in gain of function through the binary activation of cryptic SCEs . . . . However, here we distinguish mutations that disrupt disorder-based functional properties from those that induce microstructuralization and accompanying gain of function through the phenomenon of structural capacitance. It is possible that some of the D➔O mutations we have identified may induce pathological changes through disrupting known associations with interaction partners, for example, via premature microstructuralization.7

In contrast to loss of function through loss of structure in canonical disease-causing mutations, the complementary phenomenon of gain of structure and function through the introduction of microstructuralization into disordered or unstructured regions of proteins remains undescribed. The characterization of these changes is challenging due to the technical hurdles associated with resolving the structural properties of a structurally heterogeneous disordered population.8

Flawed Research Assumptions

The methodology of this research was to sort through several databases of human mutations. As a result, the researchers identified something they called “structural capacitance” as a mechanism for protein evolution. Their claim is that in proteins with long disordered regions (LDRs), point mutations could form their newly named “structural capacitance elements,” which could supposedly increase order and make microstructures. However, this was not borne out by the results of the study. The researchers recorded observations of hundreds of proteins in the lengthy supplemental information of the paper. Remarkably for a paper postulating carcinogenic mutations as a mechanism for saltatory evolution, not a single one of their results was positive. The results were without exception neutral or negative.

The researchers are acutely aware of the problem mutations pose for their proposal and even acknowledge it. “Most p53 mutations are loss-of-function mutations impacting the DNA-binding domain through interference with p53–DNA contacts or structural destabilization.”9 However, undeterred by the bare facts, they go on to speculate, without any observable evidence that there is a possibility of a gain of function (as in the first quote above). They are claiming that pathogenic mutations can activate their postulated SCEs and cause the mutated protein to gain a new function.

There are several massive problems in asserting that pathogenic mutations could be a source of saltatory evolution. The most glaring are the assumptions that IDPs are disordered and that they can gain order. The medical definition of disorder is “a disturbance of function, structure, or both resulting from a genetic or embryological failure in development . . . .”10 This definition does not fit unmutated IDPs since they have both a function and increased utility as evidenced by another paper, which they reference.

There are several massive problems in asserting that pathogenic mutations could be a source of saltatory evolution. The most glaring is the assumption that IDPs are disordered and can gain order.

Often the disordered regions [of IDP’s] fold upon association to their binding partners, and this coupled folding and binding provides several advantages. Flexibility can allow proteins to conform to the shape of a binding partner thereby increasing complementarity, such as with colicin and TolB. The flexibility can allow the protein to adopt different structures for different binding partners, as is the case with p53, which has been observed in helical, b-strand, or extended structures with different binding partners. Coupled folding and binding can influence the binding kinetics; for example, in the fly-casting mechanism, an unfolded protein binds faster than a well-structured protein because the unfolded protein has a larger capture radius than the folded protein.11

This assumption of disorder also does not fit unmutated IDPs since they have both a normal structure and function until they are interfered with by mutation. This assumption underpins the whole study, evidenced by the fact that the researchers frequently speak of mutations moving from disorder to order or just D-O. However, based on the previous medical definition of a disorder, it is the mutations that are creating the disorder on the previously ordered IDPs. Mutations do not create order, by definition or observation.

The second major issue comes from the complete lack of a demonstrable positive change. The best the study could come up with was a neutral mutation, despite examining thousands of LDR sequences. This lack of positive change, even something situationally beneficial, seriously undercuts the point of the study, leaving the researchers to speculate about possible future studies. As stated in their conclusion:

Although the reported mutations discussed here are associated with diseases representing a number of different pathogenic types including metabolic, vascular, neoplastic, and congenital, the subset of O➔D and D➔O mutations appears more likely to have a significant causal role and to be “drivers,” than O➔O and D➔D mutations in which there is no accompanying loss or gain of microstructural change. Given the theoretical nature of this work, we hope that it will prompt experimental validation and further exploration. In summary, the phenomenon of structural capacitance has implications ranging from the ancestral diversification of protein folds to the engineering of synthetic proteins with enhanced evolvability.12

A further issue is that the researchers assume the existence of proteins (or peptides for that matter) to begin with. The article does nothing to explain why proteins exist. No known process exists to form proteins from nothing. This faulty assumption undermines the whole purpose of the paper. Even if the proposed mechanisms could work, they would still be insufficient to explain the origin of proteins, which is the critical question that must be answered.

A further issue is that the researchers assume that proteins already exist. The article does nothing to explain why proteins exist. No known process exists to form proteins from nothing. This faulty assumption undermines the whole purpose of the paper.

Correcting the Conclusions

That there are proteins that appear somewhat "unstructured" comes as no surprise to creationists. In fact it makes sense that some proteins would have regions of “disorder” since proteins are simply long chains of amino acids folded together. It makes sense, from a biblical perspective, that some of these chains could be folded together in different ways that would still be functional. This would also increase the functionality of the genome as the same information could be used to produce multiple functional forms of a protein that could serve different functions.

Looking at the evidence presented in this paper leads to the inescapable conclusion that there actually is no evidence for evolution. The researchers seriously misinterpret the IDPs, postulating disorder when there is none. They then extrapolate from that proposed disorder to find a mechanism that could create order out of disorder. Unfortunately for them, their chosen mechanism, saltatory mutations, have been proven to only create disorder, not order. As with most other evolutionary postulations, the mechanisms for one works the opposite direction that it needs for evolution to occur.