The Vital Question: Why Is Life the Way It Is?

[LoneShaman]

Electricians shocked to find out how DNA repairs itself

Scientists in America have shown that cells send electrical signals along their DNA to check its integrity.

If mutations or damage to DNA goes uncorrected, especially if it affects certain critical genes, the results can be disasterous for the viability of cells or whole organisms since one consequence of DNA damage is cancer. Thankfully cells are equipped with enzymes that can recognise genetic spelling mistakes made by mutations and can excise the incorrect letter and replace it with the right one.

But a key question is how this checking process can take place quickly enough, given that the average human cell contains more than 3 billion genetic letters - that's more than a pile of encyclopedias piled taller than a person. To find out, Caltech scientist Jacky Barton and her colleagues used E. coli bacteria to study the process.

The researchers focused on two enzymes in particular MutY and EndoIII, which are charged with identifying specific types of DNA damage. These proteins can walk along a DNA chain, checking the sequence,

Now for the cool part.

Now, in an elegant series of experiments in which the team made specific molecular tweaks to the structures of some of these repair enzymes, the researchers have shown that the repair enzymes work in pairs and signal to each other using the DNA between them like a telephone line. The process is incredibly simple: one repair protein lands on the DNA and activates itself. A second repair protein lands further along the DNA chain and releases a small amount of electric charge, which is conveyed along the DNA chain as if it were a wire. If it reaches the first protein this indicates that the DNA region separating the two proteins is intact and the sequence is correct. The first protein picks up the electrical charge and detaches from the DNA before binding somewhere else.

But if the sequence is wrong, as a consequence of mutation or damage for example, the signal does not transmit and the two proteins remain attached to the DNA and work their way slowly towards each other, laboriously checking each genetic letter as they go. When a fault is discovered and repaired, signalling between the two proteins is restored and they can depart to screen other parts of the genome. In this way, using electrical signalling, the entire genome can be checked and maintained in tiptop condition by using just a small number of repair enzymes.

The question is not if there is choice contingency, plans and purpose existent. But how the hell you possibly do without them!?
There is nothing but fairy tales to account, not science.

 

[LoneShaman]

Just chemistry? Just physical law?

 

[Arouet]

Tx LS. Once I've had a chance to go through those papers you linked to I'll respond.

 

[LoneShaman]

Here is a really nice overview of transcription and translation.

 

[malf]

My conclusions, are irrelevant though, I would prefer some honesty in accepting or attempts at understanding the issues rather than using just so stories. Selection dunn it. Evolution dunnit. Unguided process produce intent.

That is pretty much the sum of the defenders of the faiths arguments right there. You see there is more at work here than true scientific skepticism isn't there? The very same characters who stand for stringent protocols and empirical evidence, drop it all for stories and claim cybernetic programming arises from the prebiotic soup! Without reason. This is a fairy tale! They have there own spaghetti monster!

Political rhetoric.

That it is impossible?

No. We both agreed it was possible under certain conditions ("the fluke of life"). We both agreed the probability was very low.

Perhaps the gambit and.... cooperbottom terms, which I am unfamiliar with. Solidify? Absolutely.

And yes, the comparison for sure. Not because of Bernado's presentations but because I know of your attitude to such things. Which you acknowledge in your last post.

Sorry for any offence. I truly believe "everything is mind" is the best defence of your position ultimately, which is why you went there. I have a lot of sympathy for Bernardo's position but it does tend to kill the conversation.

The symbol matter problem extends to the mind body problem and the measurement problem, the difference between model and reality, the knower and the known. It is the fundamental dichotomy of reality. My points extend beyond biology to information and reality generally. In my opinion all information comes exclusively from mind. All information science is from the perspective of the temporal localised observer. If we are to talk of physics and semiosis. Then QM is where to look and the answers will not conform to your notions of reality. It is a pity you do not see the encompasing aspect here.

I agree that it is tempting to throw together a bunch of stuff we don't fully understand and think, firstly, that they are all connected, and secondly, that it is "god" that connects them. You may be right.

I am not sure how you could suggest that by my conclusions the Aurora would be an encoded signal to light up the ionosphere when I have specifically addressed the difference between deterministic constraints and symbolic control. This is a little frustrating when the difference is quite apparent. A code is not physics! Again a little insulting.

I know you've been over this before yet I know I'm not the only one not getting what you are saying. You often use language that is either vague or inscrutable. It was a genuine question to help me understand... Specifically why is The Aurora not coded for. If you could be clear on this, I might be able to find a better example ;)

Then there is this doozy.
Hmmm... Surely if consciousness is all there is, reality is exactly and only as experienced, nothing more?

What could possibly be wrong with that sentence? It isconsistent with all being mind and a fundamental nature to consciousness. Read it again - I am sure this is the idealist position. Or maybe I misunderstand the definition of "fundamental"...

 

[Arouet]

In order to have a code, symbols must be interpreted. This was the big discovery of the DNA era. Crick was an old code cracker coincidentally enough.

You and Paul have had many discussions on this issue and I hope you'll forgive me for not wanting to retread that territory in this so far quite productive discussion we've been having. With your permission, rather than discuss whether all all codes involve symbol interpretation I'd like to focus on examining the processes that you suggest indicate that such interpretation is going on in the specific case of DNA.

This is where we have some misunderstanding, they are physical reactions. There is a chemical discontinuity between codon and amino acids that is bridged by the contingent structure of the aaRS enzymes.

Just to be clear, you are when combined with the structure chemical continuity is present?

That structure is defined by linear digital sequences. The complex interactions that are ultimately a series of checks in the enzymes is sometimes called the second genetic code.

The determinism is not derived from physical law but by formal rules, the code. Again this is actually logical. It has to be this way, there is no place for code in a chemical determined system.

So the bolded is what I'd really like to focus on. How precisely is the structure defined? How precisely does the rule interpretation get carried out? What parts of the structure are operating in a manner not related to the physical properties of the elements involved? I'd really like for us to be able to review a paper that sets this process out.

Ok, all good stuff. I think I answered some of those. Hopefully you recognize there is a chemical discontinuity to allow for formal operation into the system. The relationship is not derived from any property of atomic composition. The connection is made by a second arrangement of matter. This establishes the relationship between the physical stuff and it's effect. It preserves the discontinuity while bridging it allowing the system to make lawful effects not determined by physical law. Understand we have the code but a code requires sequence specificity and translation. Even the simplest system is irreducible.

I'm with you right up to "lawful effects not determined by physical law." I really think we need to have an example in front of us to clarify this issue. Up til then I understand that multiple physical structures interact to produce physical results that would not occur if they were separate. But I haven't seen anything in the material you've provided that explains where these non-phyiscally determined effects are occurring.

As for your questions. Symbol translation occurs all throughout the cell. There are other codes. And all machines seem to understand each other. The aaRS establish the rules of the code. But remember the are dozens and dozen of interacting enzymes just for translation alone. Maybe 50 or 60. Each one dazzling in it's seemingly intelligent operation. We are looking at but a tiny portion, and you can see how complicated this one aspect is, this one relationship. There are layers of code with enzymes marking sequences for gene regulation. It is all interconnected. Narrowing you vision is good for detail but you miss the big picture.

I'm trying to understand your position but I don't think you've quite answered my questions though. I'll set it out again:

Let me try and understand what you are proposing. Let's take a hypothetical example of Group A and Group B that lock onto Site X leading to Result 1. Are you saying that:

• it is not the particular physical qualities of A/B/X that produce precisely Result 1? (ie: direct physical one-to-one reaction)
• that the particular combination of A/B/X is a symbol that could pertain to Result 2, 3, 4, etc. but has been designated in some manner, unrelated to the constituent parts, to produce Result 1? (ie: symbol interpretation then separate process carrying out the instructions)

I understand that my hypothetical oversimplifies the situation but if we could can we keep it in this context? (you can add additional elements if you think it necessary. I'm still not clear on if you are proposing that the symbols could be assigned to any number of processes. For example, there's nothing about the word symbol that requires it to give the interpretation we give it. We have, through the development of language, assigned it a particular meaning, but there's nothing about the nature of the word that requires it to have the particular meaning it is associated with. That's what my hypothetical is designed to identify vis-a-vis your position on what is going on with DNA.

Not sure about the last question, the code can be artificially manipulated, yes.
The actual assignment? That is tricky because it is most definitely not random.

By this do you mean that the assignment is determined by the physical structure?

Hopefully clarified, Actually it is not exclusive to biology, but an operational requirement of information transfer.
Hmmm.. I will think about some resources.

A paper would be great!

No problem. All good questions, I had the same ones, and sometimes the answers are not easy to find.
As long as you are truly trying to understand I am happy to discuss.

I am truly trying to understand. I understand the answers might not be easy to find but for me to be able to assess your position at all it really requires seeing some of the sources that you are basing it on.

 

[Arouet]

If you saw robots assembling machines would you invoke the laws of physics to describe there functions?
Enzymes are not lock and key mechanical fittings. I will give you some examples.
It is not the fact that it is programming being controversial. Well for some. It is the fact that programming is not the result of physical laws or random process, naturally.

I'm not clear on what you mean by this? I googled and found this old but hopefully accurate enough introduction to enzymes: http://www.worthington-biochem.com/introbiochem/enzymes.pdf.

Even if a bit out of date I don't see anything that remotely suggests non-physical operations? The article describes that different kinds of enzymes function in different manners:

1. Absolute specificity - the enzyme will catalyze only one reaction.
2. Group specificity - the enzyme will act only on molecules that have specific functional groups, such as amino, phosphate and methyl groups.
3. Linkage specificity - the enzyme will act on a particular type of chemical bond regardless of the rest of the molecular structure.
4. Stereochemical specificity - the enzyme will act on a particular steric or optical isomer.

The article describes differently reactions depending on what substance the enzyme is acting as a catalyst for.

It describes that enzyme affect the activation energy for reactions which determine how fast it speeds up the reaction.

The paper goes further into proposed mechanisms for enzymes. It suggests that at that point scientists were still working it out so maybe you are referring to something that was discovered later? I wasn't able to quickly find a more resent introduction to enzymes.

Yes. All of these conditions are easily satisfied all throughout the cell. In spectacular ways!
The rest of your post is the details of a particular aaRS, happy to go there but understand while it is a crucial point in the process it is part of a much bigger network. So don't loose site of upstream and downstream effects. But it seems the issue is about carrying out plans and goals? This is easily demonstrated by other proteins. I will post a few examples.

I'm happy to look at any example you provide. This example was from the initial paper you linked and that I summarized. With regard to this example do you agree with my characterization of what is going on?

I understand that all of this takes place within a complex network. What we're trying to do is identify specifically where in that network the non-physically determined processes are occurring.

Both big and small pictures are important, and we probably need to assess both in order to properly reach a conclusion on this question.

 

[Arouet]

Check this out. This is quite recent. And once again biology says think again.

http://www.newswise.com/articles/defying-textbook-science-new-finding-blurs-role-of-proteins

Thanks for the link. I tracked down the full paper here: http://biochem.stanford.edu/Publications(featuredfiles)/featured3/Science-2015-Shen-75-8.pdf

Although it has big implications, this is really just like many other examples constantly pouring from micro biology. There are some protozoa who can split there genome into a thousand pieces when stressed and reassemble it to adapt to new conditions. There are proteins who can detect bad folds in proteins, unfold and refold them. In fact many proteins require folding assisted by other proteins. Some proteins have been observed to unfold and refold for a new function. There are multiple levels of quality control.

In fact at times about a third of the cells entire resources are geared toward protein production and quality control. This shows how crucial, integrated and computationally rich the process is, and how difficult it is.

Unless you wish to say these enzymes are conscious, the conclusion is logical in the presence of digital code. They are programmed machines. It has purpose written all over it, it requires it.

Well, as I see it, this relates to the issue I brought up with the error-correcting mechanism described in the first paper.
The question I raised there, and will raise again are we seeing the goal-oriented behaviour to achieve a particular result or non-planned results of the interacting physical mechanisms?

I'm not going to summarize the experimental aspects of the paper but will only set out any sections where they describe what they think is the mechanism that is going on. Please let me know if you think I get anything wrong..

• "We set out to determine the mechanism(s) by which relatively rare (5) proteins such as Ltn1p, Rqc1p, and Rqc2p recognize and rescue stalled 60S ribosome nascent chain complexes, which are vastly outnumbered by ribosomes
  translating normally or in stages of assembly."

(First, we should note that the paper starts with the same kind of purpose-laden vocabulary that we saw in the other paper: Is this purpose laden vocabulary meant to indicate the authors believe goal-oriented behaviour is going on? Or just image-driven lingo to help people picture the general process?)

• Analysis revealed:
• Rqc3p as transfer RNA (tRNA)
• binding protein occupies binding surface
• Ltn1p = elongated molecule that interacts with Rqc2p at the sarcin-ricin loop (SRL)
• Ltn1p has a terminus (N) that brings the SRL together with the Rqc3p
• conformation positions the C-terminal RING (really interesting new gene) domain near the exit tunnel
• this ubiquitylates (modify a protein by attaching ubiquitin molecules) stalled nascent chains

(So far what we're seeing described still seems to resemble the process in the other paper. This parts are always moving, and given the shape and other properties then react in different ways when they bump into each other. The process that modifies the stalled chains is always happening - if a stalled chain is there it will be ubiquitized (sounds better than the actual word!) but if no stalled chain is there then nothing will happen.)

• tRNA is positioned on P-site and makes "extensive contact" with Rqc2P.
• The Rqc2p has a "long coiled coil" that makes direct contact with the SRL and the P-stalk base.
• Rqc2p also binds to an A-side tRNA. This tRNA has a tail within the peptidyl transferase center of the 60S
• they were surprised to see this tail, because A-site tRNA interactions with large ribosomal subunits tend to be unstable unless they have mRNA templates and are a certain length.
• The Rqc2p interactions with the A site tRNA appeared to involve recognition (ability of one molecule to attach to another molecule having a complementary shape) between the anticodon loop and a globular N-terminal domain. Also the D-loop and T-loop interactions along Rqc2p's coiled coil

(Ok, so all of this seems to be strictly a function of how the moving parts interact. Despite being an interpretative-laden word, "recognition" in this context appears to refer to binding based purely on shape.)

• experimental results suggest that the reason the Rqc2p reacts specifically for these tRNAs is due in part to direct interactions between Rqc2p and positions 32 to 36 of the anticodon loop.
• some are "edited" in the mature tRNA.
• Adenosine in the anticodon in a couple tRNAs gets deanimated to inosine that leads to a "diagnostic guanosine upon reverse transcription".

(So despite the purpose laden language of "edited" and "diagnostic" they still seem to describe continuous processes that when bump up with other parts produce certain results. Nothing so far seems to describe anything that could be characterized as requiring interpretation. LS please tell me if you think I missed something.)

• cytosine in the tRNA is also deanimated to uracil 70% of teh Rqc2p
• when combined with the structure, this suggests that Rqc2p binds to the D-, T- and anticodon loop of teh A site tRNA
• recognition of edited motif accounts for Rqc2's specificity for these two tRNAs.
• they posit that the pyrimidine at position 36 could explain the discrimination

(So we're seeing, if I'm not mistaken, how the authors believe certain tasks that could at first blush appear to be deliberative are actually the result of a complex interaction of autonomous processes. The particular conformation produces the particular result. Again, I don't see any need for interpretation here.

I'm going to skip over the sections detailing the experiment and how they tested their hypothesis.

• proposed model based on their observations:
• Ribosome stalling leads to dissociation of 60S and 40S subunits.
• This leads to recognition fo the peptidyl-tRNA-60S species by Rqc2p and Ltn1p
• Ltn1p ubiquitylates the stalled nascent chain which leads to Cdc48 recruitment for extraction and degrades the incomplete translation product
• due to specifically binding to Ala(IGC) and Thr(IGU) tRNAs, Rqc2p directs the template-free and 40S Free-elongation of the incomplete translation product with CAT tails
• the CAT tails induce heat shock response though an as yet unknown mechanism

Ok, I think that basically sums up the mechanisms described in the paper. From what I can tell, please correct me if I'm wrong, all of the processes described therein are physically determined. I'm not clear, LS, which part of the paper demonstrates the non-physically determined processes you referred to. It would be great if you could quote the relevant section and your interpretation of it.

Let's stick with the actual paper though. I appreciate that you might have only linked to news article about it because you thought it more accessible, but I think we should stick to primary sources wherever possible.

I'm finding this to be a really interesting exercise by the way! I had no idea how they actually went about figuring this stuff out! It's amazing how they can take this enormously complicated system such as this and piece by piece work out the various processes and how they all fit together. Fascinating stuff so thank you for the link!

 

[LoneShaman]

You and Paul have had many discussions on this issue and I hope you'll forgive me for not wanting to retread that territory in this so far quite productive discussion we've been having. With your permission, rather than discuss whether all all codes involve symbol interpretation I'd like to focus on examining the processes that you suggest indicate that such interpretation is going on in the specific case of DNA.

All codes do require translation. This basically implies that DNA is not a code. I am not willing to even argue this point. DNA follows the rules of the genetic code. The process of converting a nucleotide sequence to protein sequence is called translation. The machines need to interpret the sequences. The machines are the products of translation.

Just to be clear, you are when combined with the structure chemical continuity is present?

I am not sure what this means. There is no physical law determining amino acid assignment and placement. That is mediated by another arrangement of matter. 20 aaRS highly specific enzymes to combine, for twenty tRNA carrying anticodons and twenty amino acids. These define the assignments

The crucial structures are defined by a digital sequence. No physical law determines the sequences.

So the bolded is what I'd really like to focus on. How precisely is the structure defined? How precisely does the rule interpretation get carried out? What parts of the structure are operating in a manner not related to the physical properties of the elements involved? I'd really like for us to be able to review a paper that sets this process out.

The linear sequences are not defined by any physical law. There are only bonds along the backbone, there are no bonds defining the order in nucleotides.

The parts are assembled by and carry out coded prescriptive instructions, none of which is derived from the physical properties of the matter. Neither the code itself, nor the sequences are derived from the physical properties. You are not seeing the forest for the trees Arouet. See the video on transcription translation.

I'm with you right up to "lawful effects not determined by physical law." I really think we need to have an example in front of us to clarify this issue. Up til then I understand that multiple physical structures interact to produce physical results that would not occur if they were separate. But I haven't seen anything in the material you've provided that explains where these non-phyiscally determined effects are occurring.

They are determined by the code not physical determinism.
This is the issue I think Arouet. The forest and trees thing.

I understand that my hypothetical oversimplifies the situation but if we could can we keep it in this context? (you can add additional elements if you think it necessary. I'm still not clear on if you are proposing that the symbols could be assigned to any number of processes. For example, there's nothing about the word symbol that requires it to give the interpretation we give it. We have, through the development of language, assigned it a particular meaning, but there's nothing about the nature of the word that requires it to have the particular meaning it is associated with. That's what my hypothetical is designed to identify vis-a-vis your position on what is going on with DNA.

Yes that is right and in any communication system. It is just how it is. There are no physical laws relating the symbol to its representation.

Yes it is going on in DNA. It is bridged by the contingent structure of specified aaRS that is also a product of translation whose structure is defined in linear code. It is not my position. It is what has been discovered.

By this do you mean that the assignment is determined by the physical structure?

Yes, and the physical structure is determined by the code and sequence not physical law.

I am truly trying to understand. I understand the answers might not be easy to find but for me to be able to assess your position at all it really requires seeing some of the sources that you are basing it on.

Well much of this I would call common sense, and much, such as the nature of the genetic code and DNA is not controversial and has been known for around 60 years. No offense here. But we will need to get past this.

I'm not clear on what you mean by this? I googled and found this old but hopefully accurate enough introduction to enzymes: http://www.worthington-biochem.com/introbiochem/enzymes.pdf.

Even if a bit out of date I don't see anything that remotely suggests non-physical operations?

I'm happy to look at any example you provide. This example was from the initial paper you linked and that I summarized. With regard to this example do you agree with my characterization of what is going on?

You are not seeing the full picture. The medium is not the information. Where do enzymes come from? They are the product of translation. Forest and trees again Arouet. The physical operations you observed are specified functions of computational organization.

I understand that all of this takes place within a complex network. What we're trying to do is identify specifically where in that network the non-physically determined processes are occurring.

I am not sure why this is so hard to get. Code is not physically determined! Self evidently! Through inert configurable switches (physical representations of formal programmed choice contingency) physical laws are channeled to functional utility.

There is and can be no law between symbol and representation. The code is formal and not physical. The sequences are not determined by physical law. Information is not matter or energy.

Thanks for the link. I tracked down the full paper here: http://biochem.stanford.edu/Publications(featuredfiles)/featured3/Science-2015-Shen-75-8.pdf
(First, we should note that the paper starts with the same kind of purpose-laden vocabulary that we saw in the other paper: Is this purpose laden vocabulary meant to indicate the authors believe goal-oriented behaviour is going on? Or just image-driven lingo to help people picture the general process?)

Like I said microbiology is full of teleological lingo. You cannot help it. Do you think it is an illusion? It has hard to justify as stuff bumping into each other don’t you think? Really?

Ok, I think that basically sums up the mechanisms described in the paper. From what I can tell, please correct me if I'm wrong, all of the processes described therein are physically determined. I'm not clear, LS, which part of the paper demonstrates the non-physically determined processes you referred to. It would be great if you could quote the relevant section and your interpretation of it.

You are wrong, sorry; none of the functional utility can be described and derived from things bumping into each other. Are all these things just moving around and bumping into each other in coordination for a crucial repair service? How is that possibly an explanation?

The organizational functional utility of multiple interacting parts for a purposeful function is a result of the coded sequence that make up those interacting parts. All individual parts are products of translation.

What you are missing is that lock and key fittings are interpretative, not only for the correct recognition but for identifying incorrect identities. The structures are predefined in code. They represent predefined choices. As you see there are other means of recognition besides these though. And yes they are physical. But you are missing the point. You see when we say translation in the mechanical sense. The physical protocols doing the bumping and moving are predefined choices in the hardware coordinated with coded signals to implement programmed actions. And as I mentioned must be dynamically inert to allow programmed determinism over law determinism. A lock and key is dynamically inert. What defines it shape? A specified sequence that is enCoded.

What do you expect to see in automata translating code? Are you are looking for something nonphysical and wonder why you can’t SEE it?

Once again I could use your remarks in my robot factory and nothing changes. There is no sign of anything nonphysical and stuff is just bumping into each other.

I'm finding this to be a really interesting exercise by the way! I had no idea how they actually went about figuring this stuff out! It's amazing how they can take this enormously complicated system such as this and piece by piece work out the various processes and how they all fit together. Fascinating stuff so thank you for the link!

No worries. And we have only scratched the surface!

I think you are missing some real fundamental things though. Basically that a code is not physics. Information is not actually the medium that carries it. It is the information that is determining the relationships. The code of life. You are not seeing the formal operation in the physical mechanisms. Not seeing the mental in the physical.

We could boil all of this down to one thing really. What is the casual explanation for how these machines can interact, recognize, build, repair, copy and unknowingly perform vital functions that balance life on the head of a pin? What is the casual cause for a factory of automated robots assembling other machines?

They are programmed machines. This may be a reasonable level of agreement?

It might be hard for some to swallow, and I don’t think you are there yet. But that is what microbiology has been showing us for some time.