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Synthetic organelles


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#1 Lazarus Long

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Posted 25 March 2005 - 02:48 PM


Nanotech has been focused on creating artificial hemoglobin, eyelet cells and antibodies and so on and the thought has occurred to me that there are a few cells that might be easier than others to synthesis. One being mitochondria.

The reason I am suggesting this and I can make a couple of approaches involving different methodologies is that it might be easier than we imagine. I raised the question i the SENS discussion but I would like to invite a few of the leading nanomedical researcher to our forum to discuss this approach and I have already begun an outreach to Mike Treder at the CRN.

If this idea grows wings I would also like to see it formalized at the conference for a designated discussion.

Anyway as we are decrypting both the complete genomic and proteomic structure, function and integrative operation of mitochondria is it possible to consider a synthetic nanotech alternative for mitochondria, which could be manufactured externally to the body (as opposed to self assembled and implies a different set of problems but is also a separate possibility)?

Since we are close to possessing the full molecular composition of mitochondria, understand its biological role in the cell, are able to decode its isomeric structure and DNA *code* as well as its interactivity in cellular metabolism it seems to me that this proposal has a lot going for it to start with.

Obviously there is still a lot of room for investigatory R&D but the target parameters are all rationally obtainable within a relatively short time horizon (decade(s). Proteomics being one area that is garnering a lot of interest at this very moment.

I am curious of the perception of this problem and I intend to refine this question a bit but would love to hear some feedback on this nanomedical approach. I would also like to suggest a chimera.

As a second question: Could we create a xenotransplantation model for mitochondria that could use a surrogate species (unknown for the moment) for culturing mitos with target mtDNA from a specific host to initialize the repair process and produce harvestable mitochondria that could then be transferred to a recipient utilizing the various insertion techniques that are being developed?

I am putting this over here in nanotech because the discussion is about nanotech but will overlap the methodologies of developing a *synthetic* variant of mitochondria and also for alternative *synthetic* approaches for producing mitochondria that could be DNA matched to a host's mtDNA.

I must say I have been absolutely fascinated reading the dialog in the SENS discussion and when this idea came to me I thought it would be great to parallel track that discussion with a multidisciplinary approach that could allow the kind of interactivity between these two fields which may provide further ideas and incentives for both. Remember from my perspective at least genetics is nanotech anyway.

So all you bio-researchers please feel free to describe all the reasons this idea can't work and I will now try and invite some informed medical nanotech researchers to take the counter point.

#2 Lazarus Long

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Posted 25 March 2005 - 03:10 PM

Jay said in a different thread about this idea:

...I believe we'll increase the efficiency and effectiveness of many of our systems, leading to for example increased strength and endurance, controllable pain systems (since pain has its usefulness, I wouldn't eliminate it, but put it in our control; genetic tests have shown that some people are natural wimps when it comes to pain, due to neurotransmitter levels, while others are natural stoics. I suspect I'm one of those genetic wimps, based on my tolerance levels for just about any kind of pain).

To this, I would add limited types of augmentation, such as a BMI for interfacing with the net (I'm thinking along the lines of neural nanonics, for Peter F. Hamilton fans...), as well as possibly artificial muscles for increased strength, and fancy bone materials for increased strength and toughness and reduced brittleness. But as for my core biology, I suspect I'll remain biological at least into the next century.


But, I strongly want to see the synthetic versions pursued, and I'm interested in how uploading will work, or at least a full body prosthesis run by a person's transplanted brain and spinal cord. While I'm hesitant to upload now (based on my understanding of the relevant science), I am also confident that the problem will be solved in some capacity suitable enough for my liking (if for no other reason than to market this solution to holdouts like me who want it, but have reservations).

Anyway, a little off topic, but your comment about nano-engineering (I like the term geneering, again from Hamilton's work...) synthetic mitos got me thinking about it more...


So i am putting that initial comment here because I think it was serendipitously written while I was preparing the post it should address.

I also want to add another thing.

The use of surrogate species for manufacturing optimized synthetic mitochondria doesn't have as many problems as other forms of xenotransplatation because it does not utilize segments of the nDNA and doesn't confuse the larger genetic issues of tissue integration/rejection and prion/DNA viral infection as much.

Also it may be possible to utilize methodologies that are more like cheese making or antibiotics than pig farming. The host species may not even have to be an *animal* if for example the mtDNA could be treated as as basic algae and tanked.

I just wonder if with mtDNA, as very complex as that alone is, if we are conflating it too much with the nDNA issues of complexity and in some respects could be treating it as simply a *subspecies* with much simpler parameters. When we take that perspective a number of alternatives begin to *seem* possible because it reproduces mitotically, has a vastly smaller and simpler DNA encryption, and the targeted functions are very specific, yet universally important for all the cells of the host.

I am only proposing this *prosthetic* alternative because the more I thought about it the more rational it seemed in our current *transitory* period of technology. We who are still of the old genome (which is all of us alive today) cannot simply rebuild our whole physiology but we might find whole varieties of methods for *augmenting* it with far less repercussions.

As another little thought experiment this idea came to me from contemplation of my fictional nanotech skin treatment, where I designed a method of integrating chloroplasts into synthetic mitochondria so as to make human skin tissue photosynthetic (albeit a bit green for St. Patty's day) and offset the nutrient requirement for our species by making us partially solar powered.

Now I know I shouldn't have included that fictional aspect but I couldn't resist getting those cerebral juices boiling for many of you.

#3 DJS

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Posted 25 March 2005 - 07:35 PM

This is an interesting line of inquiry, and one that I believe I have heard Prometheus (though not Aubrey) mention in biotech.

Lazarus

Nanotech has been focused on creating artificial hemoglobin, eyelet cells and antibodies and so on and the thought has occurred to me that there are a few cells that might be easier than others to synthesis.  One being mitochondria.


I think this is probably just a misstatement on your part, but I should emphasize that mitos are definitely not cells. They are organelles -- part of the body's cellular machinery -- which can not be separated and survive/reproduce on their own. Mitos are integrated sub units of a cell, the vestigial product of a endosymbiont merger more than a billion years ago. But what I assume you mean here (especially with your later reference to xenotransplantation) is that alien organelles could be bioenginerred and coopted for our own purposes. As I've said previously, this is a fascinating idea, but one that I think may suffer from a number of complication.

Anyway as we are decrypting both the complete genomic and proteomic structure, function and integrative operation of mitochondria is it possible to consider a synthetic nanotech alternative for mitochondria, which could be manufactured externally to the body (as opposed to self assembled and implies a different set of problems but is also a separate possibility)?


But we don't even really know all of the signaling processes (both within the nucleus and mitochondrion) or how they are involved in metabolic maintenance.

And how exactly does nuDNA regulate mito turn over? Granted, we understand in principle how this is done, via the cells ability to sense flux in aggregate ATP production, but how does the cell really do it? What are the specific mechanisms involved? IOW, how would one go about bio-engineering the requisite nuclear-mito intracellular communications apparatus necessary for proper homeostatic balance?

I have other challenges to the concept of creating synthetic organelles are well, but I think this is a big unanswered question to start with. We may understand how the mitochondrion fulfills its cellular obligations, but the regulatory mechanisms that are in place that keep it (and the cell) functioning properly, and which are nuclear encoded, are not fully understood at this time. In order for a proposal such as this to be in anyway feasible, we would not only have to have a better understanding of these processes, but also improvements in our ability to delivery the necessary genetic programming (probably via targeted gene therapy).

This is not to mention the fact that if we were going for redesign of an existing organelle, we would have to also be able to identify the relevant differences between itself and our mitos, and then reengineer them accordingly... All of this seems like quite a lot of added complication. I guess it is fine to look at alternative proposals as "back up" plans, but as far as our primary strategy for attacking the problem of mitochondrial mutations, I think our best course of action is still (of course ;) ) ablation and allotopic expression.

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#4 Lazarus Long

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Posted 25 March 2005 - 08:56 PM

I think this is probably just a misstatement on your part, but I should emphasize that mitos are definitely not cells. They are organelles -- part of the body's cellular machinery -- which can not be separated and survive/reproduce on their own.


Actually Don from a genetic perspective up instead of the host's down it is even more appropriate to compare mitos to *bacteria* (or perhaps even more a *virus*) and that is why I conflated the use of the word *cell.*

You are correct, and as I note in the title I am referring to *organelles* but there are no others that have their own genome and there is a very good evolutionary reason for that, mito's are a symbiotically assimilated organism. A fact which will be further discussed as I wonder how many different models for mtDNA there are as we cross species?

Mitos are integrated sub units of a cell, the vestigial product of a endosymbiont merger more than a billion years ago. 


Yes and this references the last question I asked. But even more importantly the relationship may not be as *vestigial* as you assume. The mtDNA is still responsible for most of the mitochondrial behavior NOT the nDNA.

It is a remarkably small genome of just a few hundred genes and obviously while there are still a lot of questions it is far easier to combine efforts and focus on just that aspect of the genome and reverse engineer a synthetic variant that is compatible with cell physiology than to try and re-engineer the nucleus and the entire host's genome in order to function with the characteristics of mtDNA.

I also wonder if part of the problem with the SENS model could be thermodynamic given what Mitos do and that one reason the function has never been absorbed into the nucleus anywhere in nature is that in addition to being closer to the process for nutrient absorption (fuel), conversion (ATP/ADP), and excretion of waste products that the *water* of the cytoplasm acts as coolant, transport, supplier, scrubber, and recycler to help regulate organelle operating temperature supply and general function?

Not to put too much of a *spin* on it but we are dealing with a form of energy generating plant that is converting sugar to usable energy and extracting the cellular waste products in the process and thus must adhere to the general laws of thermodynamics for the process to continue 27/7 in a regulated manner.

But what I assume you mean here (especially with your later reference to xenotransplantation) is that alien organelles could be bioenginerred and coopted for our own purposes. As I've said previously, this is a fascinating idea, but one that I think may suffer from a number of complication.


In regards to xenotransplantation I suspect it is a lot easier to insert human mtDNA into other animal oocytes with a lot less risk of cross species contamination because of the way mitos reproduce. This would allow cultivation and harvesting of a product that presents less risk from the xenotransplantation model if the end product can be delivered back into human cells.

#5 DJS

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Posted 25 March 2005 - 10:43 PM

Lazarus

Actually Don from a genetic perspective up instead of the host's down it is even more appropriate to compare mitos to *bacteria* (or perhaps even more a *virus*) and that is why I conflated the use of the word *cell.* 


LOL. ;) I sort of figure you were adding in some hidden meaning there. My main point was that normally cells maitain their own genome. This is a point I will go back to later in my post.

I wonder how many different models for mtDNA there are as we cross species?


I'm don't know the answer to that. I mean, I know that mtDNA (and mtDNA that has been tranfered over to the nucleus) varies significantly from one species to the next, but I'm not exactly sure what would constitute a "different model". Have you read the three articles linked here? Lots of good stuff in them, definitely improved my understanding.

The mtDNA is still responsible for most of the mitochondrial behavior NOT the nDNA.


From what I've read, mtDNA's predominately codes for proteins that maitain the redox balance within the mitos necessary for efficient cellular respiration. I'm not exactly clear on what you mean by 'behavior". Behavior in what sense, reproductive, internal regulation, etc?

It is a remarkably small genome of just a few hundred genes and obviously while there are still a lot of questions it is far easier to combine efforts and focus on just that aspect of the genome and reverse engineer a synthetic variant that is compatible with cell physiology than to try and re-engineer the nucleus and the entire host's genome in order to function with the characteristics of mtDNA.


The big issue here is really how to mitigate the harmful metabolic biproducts that are produced by anaerobic cells overwhelmed with mutant mitos. One way to address this problem is to attack it at its source -- the mutant mitos. Naturally, mutants are produced by mutations in mtDNA (I know I'm stating the obvious, but bear with me). The problem is more than likely what Aubrey suggests; the mutants enjoy a selective advantages brought about by the mutants being passed over by autophagic systems because the quality it targets (membrane damage, leakage, etc) is lacking in the mutants, which is of course a consequence of the mutant's dimished capacity to maintain OXPHOS.

The point is that mutants = bad. Since mtDNA damage is responsible for creating mutants, the goal is to stop this form occuring.

So where are you suggesting the sythetic variant's mtDNA be stored? The whole point of AE is to get the mtDNA away from the redox reactions and the ROS they produce. Synethic or not you still have one of two options, superior mtDNA maintenance and repair (which, I would argue, is a taller order than regular DNA repair because of its proximity to large quantities of ROS), or relocation to the nucleus and subsequent allotopic expression. Take your pick.

I also wonder if part of the problem with the SENS model could be thermodynamic given what Mitos do and that one reason the function has never been absorbed into the nucleus anywhere in nature is that in addition to being closer to the process for nutrient absorption (fuel), conversion (ATP/ADP), and excretion of waste products that the *water* of the cytoplasm acts as coolant, transport, supplier, scrubber, and recycler to help regulate organelle operating temperature supply and general function?


? When you say "function absorbed into the nucleus" are you refering to mtDNA being transfered to the nucleus? If so, why would factors in the cytoplasm have any affect on mtDNA, or its transfer over to the nucleus? The CORR, HH and CDH seem adequate in their coverage of possible explanation (IM- very unexpert-O)

In regards to xenotransplantation I suspect it is a lot easier to insert human mtDNA into other animal oocytes with a lot less risk of cross species contamination because of the way mitos reproduce.  This would allow cultivation and harvesting of a product that presents less risk from the xenotransplantation model if the end product can be delivered back into human cells.


Yes, how mitos reproduce. This is the other point I wanted to touch on at the beginning of my post. Part of the distinction I was trying to make between mitos and cells or unicelluar organims is that the genetic code neccesary for a mito to build and maitain itself is mostly not located within the mitochondrion. There's no way mitochondria could reproduce ex vivo, they don't have the neccesary genetic information (its locked away in the cell nucleus). In fact, the entire process for mitochondrial reproduction is intimately tied to intracellular function. For instance, before mitotic division, pristine membrane is assembled and then added to the mitochondrion. This has the effect of diluting the level of damage being passed forward to the next generation of mitos, but my main point is this: the construction of this pristine membrane is being constructed by cellular machinery independent of the mitochondria themselves. This is why I keep saying that the mitochondria is not a cell, its a piece of cellular machinery with an assortment of cellular maitenance and repair apparatus that are potentially *unique* to each and every species. This is a problem -- and it would apply to virtually any attempt at using cross species organelles as modified synthetics. Now, if a sythetic organelle were built completely from scratch this would be a different story... but this would be getting into science fiction. :))

#6 Lazarus Long

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Posted 26 March 2005 - 12:10 AM

? When you say "function absorbed into the nucleus" are you referring to mtDNA being transfered to the nucleus? If so, why would factors in the cytoplasm have any affect on mtDNA, or its transfer over to the nucleus? The CORR, HH and CDH seem adequate in their coverage of possible explanation (IM- very unexpert-O)


It was not my opinion Don, it is how I understand a part of the SENS proposal, to encrypt the mtDNA *instructions* somehow into the nDNA but the mtDNA is the mitochondria and a part of how the organelle functions. Actually it is exactly your point toward the end of your post.

Not to jump around too much but I want to address the rest more in depth after one more quick response.

...my main point is this: the construction of this pristine membrane is being constructed by cellular machinery independent of the mitochondria themselves. This is why I keep saying that the mitochondria is not a cell, its a piece of cellular machinery with an assortment of cellular maintenance and repair apparatus that are potentially *unique* to each and every species.

This is a problem -- and it would apply to virtually any attempt at using cross species organelles as modified synthetics. Now, if a synthetic organelle were built completely from scratch this would be a different story... but this would be getting into science fiction. 


Actually no, this is not science fiction this is exactly what nanotech is all about and why I came at this idea from this dual perspective.

I am actually making two entirely different suggestions, one is to develop a xenotype methodology for cultivating mitos that are typed to human need and the second is to reverse engineer a synthetic prosthesis from the basic molecular structure on up by modeling a nanotech approach that treats the mtDNA as a targeted nanobot and the isomeric chemistry and proteomics as the process.

This is not as outlandish as you might think. We synthesized a polio virus not long ago and the comparison between these two ideas IMO is more reasonable than you credit. If we can develop a methodology for constructing a synthetic organelle then the next step is insertion and integration with cell physiology.

I understand this is just a form of mind-mapping at this stage but sometimes we must contemplate the improbable in order to recognize the possible.

#7 Lazarus Long

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Posted 26 March 2005 - 02:05 AM

Not to make too much of serendipity but it is quite fascinating that after starting this thread manofsan posted a link to a new technology that may contribute to exactly what I am talking about for reverse engineering.


Novel Ultrafast Laser Detection Of Cancer Cells Also May Improve Understanding Of Stem Cells

LOS ANGELES, Calif. - To investigate tumors, pathologists currently rely on labor-intensive microscopic examination, using century-old cell-staining methods that can take days to complete and may give false readings.

***

"There are hundreds of mitochondria, sometimes thousands, in a cell," says Gourley. "To see them in the old way requires a time-consuming process like fluorescent tagging or a chemical reagent. We've found we can see them immediately by light alone."

http://www.scienceda...50323123927.htm



This scanning process can provide an incredible amount of detail necessary to not only make the proposal of synthetic alternatives more possible but also to decipher the details of the interaction between the organelle and the nucleus.

#8 DJS

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Posted 26 March 2005 - 03:02 AM

Lazarus Long

It was not my opinion Don, it is how I understand a part of the SENS proposal, to encrypt the mtDNA *instructions* somehow into the nDNA but the mtDNA is the mitochondria and a part of how the organelle functions.


Indeed, but what does mtDNA's (possible) role in chemiosmosis have to do with the cytosol. ;)

I am actually making two entirely different suggestions, one is to develop a xenotype methodology for cultivating mitos that are typed to human need and the second is to reverse engineer a synthetic prosthesis from the basic molecular structure on up by modeling a nanotech approach that treats the mtDNA as a targeted nanobot and the isomeric chemistry and proteomics as the process.

This is not as outlandish as you might think. We synthesized a polio virus not long ago and the comparison between these two ideas IMO is more reasonable than you credit.  If we can develop a methodology for constructing a synthetic organelle then the next step is insertion and integration with cell physiology.

I understand this is just a form of mind-mapping at this stage but sometimes we must contemplate the improbable in order to recognize the possible.


Okay, let's let the ideas flow. :)

I'm sure you realize however that there is qualitative difference between a polio virus (some raw genetic code packaged in a capsid) and a mitochodrion (which carries out the immensly complex process of cellulary respiration). But all of this is besides the point, and I believe we are still talking past each other to a certain extent.

Every cell in the human body can have literally thousands of mitochondria. It would therefore logically follow that we will not be manufacturing all of these sythetic organelles for the body, but will be building them so that they can reproduce themselves independently. How exactly will these organelles reproduce? Surely a genetic template will be necessary to facilitate their reproductive processes. If so, where is the code going to be stored? Do you see? synthetic, nano, whatever -- we are still going to run into problems with the organellor genome (unless you are proposing AE). More over, just building the synthetic organelle is not enough. The code must also be devised.

I'll stop now and allow you to elaborate in case I'm missing something. [thumb]

#9 nefastor

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Posted 26 March 2005 - 10:02 PM

Hi all,

First, I must tell you I haven’t checked ImmInst in nearly a year. I wasn’t even aware of SENS before Lazarus brought it to my attention. I have a lot of catching up to do, so please don’t crucify me if I say something stupid.

All this time, I was obviously busy working on achieving immortality. I’m not there yet, but I’m making good progress.

For those who don’t know me (or don’t remember me), I’m advocating immortality through cybernetics. My motto is : “withstanding eternity requires a sturdier body”. As technology evolves, more and more organs now have artificial counterparts, prosthetics like the artificial heart, hip bone, teeth, arteries… I myself am researching a replacement part for the human brain and spinal cord.

Also, do keep in mind that I’m French. If something I say feels wrong or out of place, chances are it wasn’t supposed to be ;-)

Thank you for your invitation to this discussion, Lazarus. I must admit that before your e-mail I hadn’t considered cellular-level cybernetics. This is what I’d call the use of artificial mitochondria in natural cells.

I agree with you that mitochondria have a rather simple structure. If I remember my medical studies well, mitochondria have the relative simplicity of a bacteria. Their purpose is only to produce ATP. Indeed it would seem like something we could duplicate easily.

However, this would only make sense if our design is even simpler than existing mitochondria. This is a typical engineering truth : adding complexity to a system is like asking for trouble.

And speaking of trouble, we’d already have to manage the co-existence of natural and artificial mitochondria inside the same cell. This is possibly more complex than ensuring biocompatibility, as DonSpanton indicates. The artificial mitochondria will really have to behave exactly like the natural ones.

In computer terms this is called “backwards compatibility”, and we all know what it means : the tolerance of inefficiencies in favor of compatibility. As we see with PC technology, a dozen generations down the line inefficiencies make the system completely unreliable and non-deterministic.

I have a solution, I think :

The body already contains the necessary mechanisms for producing mitochondria. Wouldn’t it be simpler and more efficient to control these mechanisms and increase the production of mitochondria in-vivo ?

Lazarus, you aren’t the only one to have thought of integrating chloroplasts into the human skin. Japanese artist and visionary Masamune Shirow once “created” an hybrid girl named Greenpeace, her purpose was to be a “prototype for the next mankind”, a species which could survive and clean-up Earth’s atmosphere in an age of extreme pollution. It wasn’t specified, however, if Greenpeace would use photosynthesis as a source of energy.

Jean

#10 Lazarus Long

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Posted 27 March 2005 - 05:40 PM

Thanks for joining the discussion Jean.

I have a solution, I think :

The body already contains the necessary mechanisms for producing mitochondria. Wouldn’t it be simpler and more efficient to control these mechanisms and increase the production of mitochondria in-vivo ?


Besides that being the obvious intent of SENS and the Neo-SENS debate I have left alone for good reason, they are proceeding into stimulating debate on their own; I am introducing optional nanotech and xenotransplantation models so as to encourage some out of the box lateral thinking and I may later open a separate thread for the xeno cultivation & trasnplantation discussion as well if that idea begins to attract more serious interest.

Another part of the reason and to answer your question directly Jean, is that the body's relationship with its mitochondria is not as simple as with all other aspects of physiology because of the introduction of independent genetic characteristics and this is one reason why I think nanotech is appropriate to introduce to the discussion because this independent AND interdependent genetic relationship of endosymbiotic character is one that implies a complex relationship that may allow a redesigned synthetic variant of an endosymbiote that introduces an *organic assembler* (DNA based) into the discussion.

The cross species approach is actually a separate topic onto itself and addresses the broader evolutionary questions of just how different are the separate genetic variant of mitochondria as we begin to do a comprehensive cross species analysis?

One reason for this is to address the different manner for example by which reptilian DNA directs mitochondrion behavior to how mammals do.

IMHO the inde/interdependent relationship of mtDNA to the host makes examining the option of a *new and improved* synthetic prosthetic variant of mitochondria more reasonable than I think is being credited but then again such a *radical alternative* approach should not be easily acceptable and no one including myself should take it for granted as easy.

Nevertheless the possibilities for making this a nanotech track are also far too interesting to ignore.

#11 Lazarus Long

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Posted 27 March 2005 - 06:16 PM

There's no way mitochondria could reproduce ex vivo, they don't have the necessary genetic information (its locked away in the cell nucleus). In fact, the entire process for mitochondrial reproduction is intimately tied to intracellular function. For instance, before mitotic division, pristine membrane is assembled and then added to the mitochondrion. This has the effect of diluting the level of damage being passed forward to the next generation of mitos, but my main point is this: the construction of this pristine membrane is being constructed by cellular machinery independent of the mitochondria themselves.


That covers the reason for both the use of alternative species cells Don and also for comparing the reverse engineering process to the methodology of creating synthetic viruses.

The mitochondrion and chloroplast as independent entities

In addition to their remarkable metabolic capabilities, both mitochondria and chloroplasts synthesize on their own a number of proteins and lipids necessary for their structure and activity. Not only do they contain the machinery necessary for this, but they also possess the genetic material to direct it.

DNA within these organelles has a circular structure reminiscent of bacterial, not eukaryotic DNA. Also as in bacteria, the DNA is not associated with histones. Along with the DNA are protein-synthesizing ribosomes, of bacterial rather than eukaryotic size, that are sensitive to bacteria-inhibiting antibiotics.

Only a small portion of the mitochondrion's total number of proteins is synthesized within the organelle.At least 90 proteins are encoded and made in the human cytoplasm specifically for export to the mitochondrion, while the mitochondrial DNA encode only 13 different proteins. The proteins that do contain components synthesized within the mitochondrion often possess, in addition, components synthesized in the cytoplasm. Mitochondrial and chloroplastic proteins synthesized in the cytoplasm have to enter the organelle by a complex process, crossing one or more membranes. Why this is possible for most, but not all, proteins is not known.

(Brittannica 2003)


IOW’s we are definitely discussing an overlap of genetic information AND function. We are also addressing some pragmatic reasons why a presence in the cytoplasm may be necessary for mitochondria to function or have an entirely new alternative transport system re-engineered into the entire cell.

However SOME proteins are produced inside the mitochondrion and this along with the possession of their own ribosomes and more importantly what is called a SEMI-AUTONOMOUS reproductive ability describes a more complex *relationship* than you implied but I agree and have always agreed that the mitochondria depend on the nDNA for a lot of their reproductive ability but the nature of that dependence is not merely instructional, it is that nDNA have created cytoplasmic subsystems that provide many of the necessary proteins that mtDNA can no longer produce on its own to support independent mitochondrial function AND reproduction but the mitochondria do internally to the cell reproduce during its life cycle.

That is why mitochondria are still considered to be semi-autonomous and I think many are perhaps overlooking that aspect of its *symbiotic* nature.

The endosymbiont hypothesis

Mitochondria and chloroplasts are self-dividing; they contain their own DNA and protein-synthesizing machinery, all of the bacterial type. Chloroplasts produce ATP and trap photons by mechanisms that are complex and yet similar to those of certain bacteria. These phenomena have led to the hypothesis that the two organelles are direct descendants of bacteria that entered primitive nucleated cells in a number of infections.

Among billions of such infective events, a few could have led to the development of stable, symbiotic associations between nucleated hosts and bacterial parasites. The hosts would provide the parasites with a stable osmotic environment and easy access to nutrients, and the bacteria would repay by providing an effective oxidative ATP-producing system or a photosynthetic energy-producing reaction. The further development of genetic techniques may make it possible to identify the classes of bacteria that took part in these putative events.

Wilfred D. Stein


However returning to thermodynamics, the membrane issue is precisely related to mtDNA and why both the encryption and expression of it as BOTH construction and function for the Mito are probably related I suspect.

"Radical theory" of oxidative phosphorylation and photophosphorylation.
http://www.ncbi.nlm....itool=iconabstr


A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules.
http://www.ncbi.nlm....9&dopt=Citation

Cytosol-to-membrane redistribution of Bax and Bcl-XL during apoptosis
http://www.pubmedcen...cgi?artid=20498

#12 Lazarus Long

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Posted 27 March 2005 - 06:19 PM

Signaling Pathways for Monocyte Chemoattractant Protein 1-Mediated Extracellular Signal-Regulated Kinase Activation
http://molpharm.aspe...stract/64/3/773

We show that ERK activation by MCP-1 involves heterotrimeric Gi protein subunits, protein kinase C, phosphoinositide-3-kinase, and Ras. On the other hand, the activity of cytosolic tyrosine kinases, epidermal growth factor receptor transactivation, or variations in intracellular calcium levels are not required for the mitogenic activation elicited by MCP-1. In addition, we find that internalization of CCR2B itself is not necessary for efficient MCP-1-induced activation of ERK, although a dynamin mutant partially inhibits ERK stimulation.

These results suggest that different parallel pathways are being activated that lead to the full activation of the mitogen-activated protein kinase cascade and that internalization of other signaling proteins but not of the receptor is required for complete ERK activation.


All animal cells have the mitochondria present, in fact many prokaryotes like yeast too. The differences between how mitochondrions are constructed across different species are not *controlled by the nDNA* as much as *the relationship* between the mtDNA and nDNA I suspect.

I suspect a symbiotic parallel to the parasitic relationship of viral pathogenesis and one that developed out of the complex relationship of bacteriophages and their early ability to absorb episomal immune responses at the prokaryotic level evolutionarily. If correct this may offer a novel manner of determining where to look in the nDNA for the instructions that controls autophagic responses in mtDNA for example.

And to return to the xenotype option it is why another alternate idea is to a substitute human mitochondria for the type in an alternate species that can sustain them and reproduce. I suspect the process could be through the intentional transcription into a much simpler species like even an algae in the manner that human and antibiotic genetic characteristics are transcripted into such genomes.

However in this case it so as to create a surrogate species that can support human mitochondria and cultivate them at rates that far greater than human cells and also to fine tune the product to be both stronger for life expectancy and more resistant to mutation while subject to apoptosis quicker to prevent malignancy.

If such an intentional mutant were able to be developed this way then one obvious alternative would be to substitute the alternative mitochondria into the oocytes of a primate (or mouse for the MMP) instead of the mothers’ and then proceed to term after IVF and implantation.

This is not cloning or significantly altering the nDNA but utilizing clonal modification techniques ex-vivo for modifying mtDNA into some archetypal alternative (yet to be determined obviously) that is developed after the full analysis of its basic genome and that relationship with the intended host’s genome.

By this method instead of altering the nDNA (with all the eugenics arguments) we could simply alter the mtDNA and provide the next generation with an alternative that could drastically elongate their *natural* lifespan.

As a separate but related treatment if these alternative mtDNA *recombinant xenotype* organelles can then be substituted into the body’s cells through a kind of staged therapy that first destroys or assimliates all mtDNA and quickly provides a profected alternative then even those of us alive now may benefit from such a treatment to prolong our lives or even reverse many aspects of aging that we current experience.

#13 Lazarus Long

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Posted 27 March 2005 - 08:08 PM

OK for the sake of making this a more cross disciplinary discussion I am going to include some basic but nicely descriptive sites that will help autodidacts and lay persons alike come to grips with the basic biology and very rudimentary chemistry and genetic encryption aspects. To start with:

The Virtual Cell
Posted Image

and

Mitochondria
from above:
Posted Image

What are mitochondria?

Mitochondria are the cell's power producers. They convert energy into forms that are usable by the cell. They are the sites of cellular respiration which ultimately generates fuel for the cell's activities.

Posted Image
The double membranes divide the mitochondrion into two distinct parts: the intermembrane space and the mitochondrial matrix. The intermembrane space is the narrow part between the two membranes while the mitochondrial matrix is the part enclosed by the innermost membrane. Several of the steps in cellular respiration occur in the matrix due to its high concentration of enzymes.

Mitochondria are semiautonomous in that they can divide and grow to make more of themselves. They also have their own DNA and ribosomes.


I understand these are extremely basic images and sites but I consider them accurate and a good beginning. I would ask that any of the more advanced scholars here please feel free to offer any better links and any corrections to the information provided that you may consider important to note.

#14 nefastor

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Posted 27 March 2005 - 11:30 PM

I must say I feel out of my league here, as my knowledge of mitochondria is far too limited compared to yours. I will therefore limit myself to technical and technological considerations, since this is my area of expertise.

In light of your latest posts, Laz, I see that mitochondria are far more complex than I realized. Therefore designing a simpler, more efficient replacement does seem possible.

The application of nanotech to biotech has been discussed a lot on Nanogirl’s nanotech mailing list, and I sometimes joined. We mostly agree that biochemistry is the most efficient way to do what biochemistry does (agreeing on the obvious… that’s always a good start) and that medical nanotechnology will probably remain the stuff of sci-fi movies such as “Jason X”.

But we haven’t considered the inefficiency of evolved biology compared to engineered technology. So let’s see what nanotechnology could provide us with…

“Nanochondria” technology would have four distinct aspects :

- production of nanochondria : this would be done outside the body, therefore in a machine as large as necessary. There should be no problem with making and conditioning large amounts of nanochondria.

- transport to the host cells : that’s the hard part. Unless the nanochondria are significantly smaller than mitochondria, will they be able to pass through the cellular membrane without destroying it ? Or triggering an immune system reaction ? Also, how do you ensure proper distribution throughout the body ? Or do you wish to target specific cells, like the muscles’ ?

- integration to the host cells : the nanochondria must behave as much as possible like mitochondria. They must fit in the same regulation loops, understand the same chemical messages… in computer words, they must have the same interface. I gather that we don’t know everything about this interface, but is what we know enough for our purposes ?

- disposal of nanochondria : once they are worn out or become undesirable, they will have to be disposed off, since their components might not be compatible with or reusable within the cells. Disposal will have to be engineered very carefully, in particular the self-dismantling of nanochondria into safe “waste” which could be processed by human metabolism.

As I’m sure you know, C-60 and nanotubes cause cancer. That is why disposal is going to be very important. Vital, indeed.

I’d like to read your suggestions or remarks regarding the four aspects of nanochondria I have outlined. Did I leave something out ?

Jean

(P.S. please forgive any spelling mistake, it's getting awfully late here. No rest for the whicked, I think you say ? ;) )




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