Physicists confirm there's a second layer of information hidden in our DNA

[casper]

http://www.sciencealert.com/scientists-confirm-a-second-layer-of-information-hiding-in-dna

"...As you probably learnt in high school, Watson and Crick discovered in 1953 that the DNA code that determines who we are is made up of a sequence of the letters G, A, C, and T.

The order of these letters determines which proteins are made in our cells. So, if you have brown eyes, it's because your DNA contains a particular series of letters that encodes for a protein that makes the dark pigment inside your iris.

But that's not the whole story, because all the cells in your body start out with the exact same DNA code, but every organ has a very different function - your stomach cells don't need to produce the brown eye protein, but they do need to produce digestive enzymes. So how does that work?

Since the '80s, scientists have found that the way DNA is folded up inside our cells actually controls this process. Environmental factors can play a big role in this process too, with things like stress known to turn certain genes on and off through something known as epigenetics.

But the mechanics of the DNA folding is the original control mechanism. That's because every single cell in our body contains around 2 metres of DNA, so to fit inside us, it has to be tightly wrapped up into a bundle called a nucleosome - like a thread around a spool.

And the way the DNA is wrapped up controls which genes are 'read' by the rest of the cell - genes that are all wrapped on the inside won't be expressed as proteins, but those on the outside will. This explains why different cells have the same DNA but different functions.

In recent years, biologists have even started to isolate the mechanical cues that determine the way DNA is folded, by 'grabbing onto' certain parts of the genetic code or changing the shape of the 'spool' the DNA is wrapped around.

So far, so good, but what do theoretical physicists have to do with all this?

A team from Leiden University in the Netherlands has now been able to step back and look at the process on a whole-genome scale, and confirm through computer simulations that these mechanical cues are actually coded into our DNA. ..."


The research has been published in PLOS ONE.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156905

 

[Kisito]

Casper thank you, it seems like a great discovery. But as a Pandora's box, this leads us to ask other questions. What is the force that organizes its folds?

 

[casper]

This is the second, I am interested how many layers are there?

 

[luc]

Thanks casper, very interesting.

Here's the abstract of the study:

Abstract

Eukaryotic DNA is strongly bent inside fundamental packaging units: the nucleosomes. It is known that their positions are strongly influenced by the mechanical properties of the underlying DNA sequence. Here we discuss the possibility that these mechanical properties and the concomitant nucleosome positions are not just a side product of the given DNA sequence, e.g. that of the genes, but that a mechanical evolution of DNA molecules might have taken place. We first demonstrate the possibility of multiplexing classical and mechanical genetic information using a computational nucleosome model. In a second step we give evidence for genome-wide multiplexing in Saccharomyces cerevisiae and Schizosacharomyces pombe. This suggests that the exact positions of nucleosomes play crucial roles in chromatin function.

Maybe those researchers are on to something? Then again, they based their conclusions on a computer model, so I guess it would be good to be a bit careful? I don't know a lot about all this to be honest, but maybe those researchers are trying to solve the major problem associated with DNA, namely that despite all the hype around DNA and genes and so on it's still not clear how and why they produce this or that outcome. So they think in terms of mechanical properties to avoid other, more "esoteric" conclusions? But maybe the "mechanical evolution" they talk about is the process by which Sheldrake's morphogenetic fields manifest?

Sheldrake wrote about the Protein folding process as follows:

Protein folding

The pull of processes towards attractors is not confined to living organisms. The formation of chemical molecules is also a type of morphogenesis; molecules are forms or structures. Their forms can be represented by attractors that lie at the bottom of potential wells (Figure 5.1): the molecules are stable because they are minimum-energy structures. If they are perturbed, and pushed away from the bottom of the well, they soon return to it.

With simple molecules like carbon dioxide, there is a simple, straightforward minimum energy structure. But with large, complicated molecules, like proteins, the range of possible structures becomes enormous. Protein molecules are made of polypeptide chains, strings of amino acids that twist, turn and fold into complex three-dimensional forms (Figure 5.6). A given type of protein molecule folds up into a unique structure. In the laboratory, many proteins can be made to unfold by changing their chemical environment; they then fold again correctly when they are replaced in appropriate conditions.10 They return to a stable end-point.

This stable end-point is a minimum-energy structure at the bottom of a potential well. But this does not prove that it is the only structure with a minimum energy; there may be hundreds or thousands of other possible structures with the same minimum energy. Indeed, calculations to predict the three-dimensional structure of proteins, starting from the linear sequence of amino acids coded for by DNA, give far too many solutions.11 In the literature on protein folding, this is known as the ‘multiple-minimum problem’.12

There are persuasive reasons for thinking that the protein does not ‘test’ all these minima until it finds the right one. Christian Anfinsen, who won the Nobel Prize for his work on protein folding, put it thus:

If the chain explored all possible configurations at random by rotations about the various single bonds of the structure, it would take too long to reach the native configuration. For example, if the individual residues of an unfolded polypeptide chain can exist in only two states, which is a gross underestimate, then the number of possible randomly generated conformations is 1045 for a chain of 150 amino acid residues (although, of course, most of these would probably be sterically impossible ones). If each conformation could be explored with a frequency of a molecular rotation (1012 sec.-1), which is an overestimate, it would take approximately 1026 years to examine all possible conformations. Since the synthesis and folding of a protein chain such as that of ribonuclease or lysozyme can be accomplished in about 2 minutes, it is clear that all conformations are not traversed in the folding process. Instead, it appears to us that, in response to local interactions, the peptide chain is directed along a variety of possible low-energy pathways (relatively small in number), possibly passing through unique intermediate states, towards the conformation of lowest free energy.13

But not only may the folding process be ‘directed’ along certain pathways, it is also attracted towards one particular conformation of minimum energy, rather than any other possible conformations with the same minimum energy. The folding pathway can be thought of as a chreode in the morphogenetic field of the protein, and the final three-dimensional structure an attractor. Like biological morphogenesis, chemical morphogenesis is end-directed. [Mechanical?] Energy alone cannot select between these alternative possibilities and determine the specific structure taken up by the system.14

Maybe I'm getting this all wrong though

 

[Eboard10]

Thanks for sharing the article casper, very interesting to see that some progress is being made in the field.

But not only may the folding process be ‘directed’ along certain pathways, it is also attracted towards one particular conformation of minimum energy, rather than any other possible conformations with the same minimum energy. The folding pathway can be thought of as a chreode in the morphogenetic field of the protein, and the final three-dimensional structure an attractor. Like biological morphogenesis, chemical morphogenesis is end-directed. [Mechanical?] Energy alone cannot select between these alternative possibilities and determine the specific structure taken up by the system.14

The observations put forward by Rupert Sheldrake about how folding process is directed towards a select number of pathways of the myriad possible ones and is at the same time attracted to a conformation that requires minimum energy reminds does make sense IMO. He suggest the process as being driven by end-directed chemical morphogenesis (i.e. not subject to random change but intentionally directed towards specific pathways), which would imply some form of intelligence inherent in the folding process.

It looks like EZ Water may also play a part in the proper functioning of protein folding at a cellular level.

EZ Water, Protein dysfunction and pathologies

Cellular action occurs through the collective action of protein and water: as proteins fold, the interfacial water becomes transiently disordered, while subsequent unfolding brings reordering. If EZ water is central for folding, then long-term maintenance of EZ water must be critical for proper folding and function. Hence, any protein/EZ unit compromised by dysfunction or pathology requires EZ restoration to become functional. That is the central hypothesis on which this proposal builds.

EZ Water and Cellular Protein Functions - Proposal

It is known that without water, most macromolecules would collapse and precipitate; they could not function properly. This scientific premise underlies our hypothesis.

Many diseases have been recognized as dysfunctions of proteins or protein regulatory systems (Dobson, 2002; Wiggins et al., 2009). In this protein-centered framework, creating the dysfunction may involve two components: the protein, or the intimate EZ water that envelops the protein. Thus, a dysfunctional mitotic apparatus that endlessly drives cell division (cancer) may involve dysfunction not only in microtubules and motor proteins, but also of the surrounding EZ water. The state of interfacial water can be part of the problem — one that has received much less attention than the protein.

Reversing pathologies is a daunting task. Many approaches are palliative; i.e., drugs are given to reverse the effects of the pathology but not necessarily the cause. Depending on whether the cause lies with the protein or with the interfacial water, molecular hydration might alleviate the effects or perhaps even get to the root of the problem.

Stemming from our previous work aimed at characterizing EZ water, we recently began exploring a possible correlation between EZ water and biological function. In studies of muscle myofibrils using IR spectroscopy at the synchrotron beam line at UC Berkeley, we found that relaxed muscle contained mainly EZ (ice-like) water, while in contracting muscle the water transitioned to mainly bulk water (Yoo and Pollack, submitted). Thus, we could identify a change of state of water associated with functional state.

We also recently explored anesthetics — which compromise nerve function (and also unicellular organism function). Local and general anesthetics diminished EZ size. Lidocaine reversibly reduced EZ size in a dose-dependent manner; the dose required for achieving half-maximal size was ~0.6 mM, which is in the range of tissue concentrations for clinical application. Bupivacaine showed a 50% reduction of EZ size at ~0.2 mM. Similar reduction was seen with Isoflurane, a general inhalation anesthetic (Kundacina et al., submitted).

We also recently began studying agents that promote function (Kim and Pollack, in preparation). Aspirin promotes function by reducing fever, relieving pain, diminishing inflammation, etc. We found that aspirin substantially increased EZ size. The increase was as much as 300%.

(An aspirin sidelight: Aspirin reduces fever. Fever is associated with elevated temperature, which means increased generation of infrared energy. Infrared energy builds EZs. Therefore, by building EZs, fever may be one of nature’s internal ways of reversing dysfunction.)

All three types of experiments above show correlation between EZ size and biological function, and hence the possible biological relevance of EZ water. These preliminary results triggered the hypothesis that restoration of function might be brought about by manipulations of the water around malfunctioning proteins. One might call it a functional repair through EZ restoration. This hypothesis is warranted not only by the exploratory studies mentioned above, but also by the fact that many simple, traditional therapies include factors that were found to increase EZ size.

To wit, consider heat (infrared) and light — two forms of electromagnetic energy. Both build EZs (Chai et al., 2009); and both are used for therapeutic purposes. Heat therapy has broadly recognized therapeutic value for pain relief from arthritis, muscle spasms, and migraines; heat also combats edema, bursitis, fibromyalgia, and even some cancers. Light helps reverse depression and sleep disorders; and it is often used to treat dementia, bulimia, acne, juvenile jaundice, psoriasis, pre-menstrual pains (PMS), attention deficit disorder, bipolar disorders, high blood pressure, circadian disorders, pain, hair loss, reproductive disorders, Parkinson’s disease, and wounds (for a representative review on wound healing, see Peplow et al., 2012). Regarding depression, an interesting report is by Lam et al., (2006), a multi-center, double blind randomized controlled trial that found bright-light therapy to be equally effective as Prozac, with faster results and fewer side effects.

While all of this has been known for some time, our studies raise the new question whether heat and light exert their therapeutic effects through water: through the buildup of EZs. This is the hypothesis that we propose to investigate. Do heat, light, and several other agents affect biological function through a common mechanism of building EZ water? And, is EZ water buildup not merely correlative, but causal? Those are the questions we wish to answer.

And, if the answers turn out to be “yes,” then this research would lead naturally to the question of what is the detailed mechanism underlying this causal effect of EZ water buildup on function.

Another piece of the puzzle maybe?


EDIT: changed paragraph as I got confused between author of the article and the Sheldrake quote.

 

[TetrahedronJourneys]

Hi ! I'd like to comment/make some suggestions to the information provided in the original post. I'm a biologist who's main point of study is evolution and genetics :) I also teach courses in biology.

1 "The order of these letters determines which proteins are made in our cells. So, if you have brown eyes, it's because your DNA contains a particular series of letters that encodes for a protein that makes the dark pigment inside your iris."

It was stated above that the letters are A T C G but they are molecules refered to as nucleotide base pairs( Google images those who are interested ) As a teacher students get confused when we just call them " letters ". They get misconceptions about the structure and chemical make up of DNA

2 "But that's not the whole story, because all the cells in your body start out with the exact same DNA code, but every organ has a very different function - your stomach cells don't need to produce the brown eye protein, but they do need to produce digestive enzymes. So how does that work?"

This is correct. Every single body cell ( vs. sex cells ) have a complet copy of all of your DNA, all 23 pairs ( 46 all together) and every organ has specialized cells that only use certain genes to preform thier specific functions. Like you said stomach cells, although they contain all 46 chromosomes, will not be producing brown pigment proteins located even though the stomach cells do contain the gene for brown pigment.

3-"Since the '80s, scientists have found that the way DNA is folded up inside our cells actually controls this process. Environmental factors can play a big role in this process too, with things like stress known to turn certain genes on and off through something known as epigenetics.
And the way the DNA is wrapped up controls which genes are 'read' by the rest of the cell - genes that are all wrapped on the inside won't be expressed as proteins, but those on the outside will. This explains why different cells have the same DNA but different functions."

3- Do you have a place where I can read more about this last statement. I have never heard of multiple configurations for DNA wrapping. What I am understanding from this is that The chromosome ( the wrapped DNA) is wrapped differently depending on which cell it is in. That Stomach cells will have the genes that it needs on the outside for example and eye pigment on the inside since it will never use it. I'm very interested in reading about that. In my understanding this is simply not true. I say this because genes are found at specific locations( called loci) along the chromosome. We have identified these positions with accuracy. We know that on every Y chromosome in the male body, be in a skin cell or a blood cell, that the gene coding for testestrone will at that exact loci on that Y chromosome but only cells within the male reproductive organs will be able to express that gense, turn the gene on and send it to be translated into proteins, folded etc. It is regulatory factors that control the opening and closing of the chrosome and expose the gene that is needed. The loci for the testestrone gene, from my understanding does not shift its position because it's in an eye cell.

If my knowledge is incorrect or I'm misinterpreting lets discuss ! Because if what I think your saying is in fact true, you've blown my mind !