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Whole-cell in-silico emulations
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Prof Trevor Marshall
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 Posted: Fri Apr 1st, 2011 10:04

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Two interesting articles describe landmark in-silico emulation of the complete cytoplasm of a cell.

Of course their view of what the cell does is far too simplistic (for example, no consideration of transcription being the result of many separate symbionts), but nevertheless it does give a glimpse into the imponderable complexity of the processes in-vivo.

Article:
http://bit.ly/ft4bjU

Paper:
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002010

I noted particularly the emerging understanding that the processes in a cell are basically stochastic, a concept which Medicine is going to be unable to accept (IMO).

The entire pragma of interventional Medicine is based on cause and effect, without room for random variation...
 

Markt9452
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 Posted: Fri Apr 1st, 2011 10:20

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The concept of stochastic isn't working well for me because I don't understand it properly.

Is there a good explanation for this concept somewhere that I can read that will help me to understand your statement in precisely the same sense that you mean it.



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tammy1000
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 Posted: Fri Apr 1st, 2011 10:30

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Looks like a challenging read for the weekend.

At first, my ignorant mind was a bit apprehensive about the accuracy of your in-silico modeling with Olmesartan.

But after thinking it over, I completely agree that without a model -- as you have said -- you are grasping in the dark without a candle.

I remember an  early EE lab. One particular design project, I was having trouble getting my Pspice model to work. I was very frustrated and ignorant about circuits at the time. I made a comment something like "I think I am going to forget about Pspice, and just build my circuit."  The smug responder replied something about that if my model didn't work, then my circuit never would.

Reality is usually much more complex modelling. If we can't at least work things out theoretically -- we are completely in the dark about what is really happening. I sure wish doctors understood that, to reduce the harm they inflict on frail bodies.

 



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Prof Trevor Marshall
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 Posted: Fri Apr 1st, 2011 11:54

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Indeed, Tammy. My first Spice emulation was in 1977, with punched cards and a DEC-10 :) I was simulating a switched RF power amplifier as part of my Masters thesis. At that time, simulation was a difficult and expensive task. But it gave unparalleled insight into how a circuit operated.

A couple of years ago I simulated (with PSpice) an ultra-low noise preamp I was constructing with bipolar transistors for my conference recording tasks, and it really is quite amazing how much the tools have improved over the years, particularly in the area of GUI and Component libraries.

But it was success with the simulation of microwave antennas which set me off on my journey into in-silico emulation technologies:

http://trevormarshall.com/waveguides.htm

What engineering taught me was the necessity to test your model output. It is easy to make a tiny error which gives the incorrect output. Testing the concepts I had discovered in-silico by putting them into an in-vivo environment is primarily what distinguishes my in-silico work from nearly everything else being done at the moment :) :)
 

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 Posted: Fri Apr 1st, 2011 22:46

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Dr. Marshall,
Even though what you're talking about is way above my head...I can appreciate the fundamental idea and am more enthusiastic than ever that you are on the right track.
It is truly exciting to be a trail blazer.
For the past few days I have felt better than I have in over twenty years. When I try to recollect all the symptoms I used to have it is nearly impossible because there were so many. My entire system felt poisoned..nothing was working right.
Nowadays, a bad patch will consist of a limited number of symptoms. Annoying and I wish they were gone completely, but in comparison to bMP I am hardly even sick anymore.

My husband remarked on my lightness and happiness today. Even my smile has returned to what it used to be.
Words are inadequate but...thank you.



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ChrisMavo
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 Posted: Fri Apr 1st, 2011 23:50

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Great to hear of your fantastic progress on the MP Aunt Diana!  I hope that I'll be telling the same inspiring story when I reach the point you have! 

Right now it is very tough for me.. but you are RIGHT it feels so exciting to be a trailblazer! 

:D



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Ton
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 Posted: Sat Apr 2nd, 2011 03:01

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"A couple of years ago I simulated (with PSpice) an ultra-low noise preamp I was constructing with bipolar transistors for my conference recording tasks, and it really is quite amazing how much the tools have improved over the years, particularly in the area of GUI and Component libraries."

Dr. Marshall, you are right that over the years the simulations tools (Matlab, Simulink, LabView, Spice) have improved much and I fully agree that if you cannot calculate the properties of your system/model in an analytical way , simulation tools are of great help in understanding your model and it's behavior. However, one should always analyse carefully the answers/results. I notice that younger colleagues (and students) are not checking simple boundary results :( of the simulation tools and think that the simulation always produces the right answer. And of course that might be not true if the assumed pre-conditions of your model are wrong.:? 

So I am in favour of first trying to calculate things analytically (in general this gives you more insight of the model and it’s properties) and if that does not work go for the simulation or emulations (In IC-design, the term emulation is used if part of the simulation or system is working real-time) 

I am not experienced in molecular simulations/emulations but I can imagine that these are too complex to do the analytical calculations, and if that is true are you able to simulatie boundary conditions easily? Like very high or very low dose simulation or looking at zero or infinity-time etc. Is that, or can that be done in this field?

Thanks,

Ton



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Markt9452
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 Posted: Sat Apr 2nd, 2011 10:28

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Maybe I am over complicating?  Maybe the term stochastic means the opposite of deterministic with regards to randomness?

If that's true -  it doesn't seem right to me.  :(  I will keep researching.  :)

I can see some difficulties here with definitions.  Where are our philosophers?  I know there are some here.  :?

In mathematics, a deterministic system is a system in which no randomness is involved in the development of future states of the system.[1] A deterministic model will thus always produce the same output from a given starting condition or initial state.[2]

 



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tammy1000
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 Posted: Sat Apr 2nd, 2011 11:56

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Ton,

You might want to watch Dr. Marshall's 2005 presentation to the FDA. I was at first concerned that the Marshall Pathogenosis was based on abstract theoretical ideas, but the more that I have the time to read and listen, the more it seems that Dr. Marshall's ideas conform to what going in biochemical and medical research. (I am an EE, so I have no background in these fields, but I am trying to learn.)

 

Markt,

I don't have a textbook definition for you, but here are some of my thoughts about a stoichastic process:

A stoichastic process is kind of like a normal statistical distribution, for example. You know what the expected result is, but many results vary a little from the expected value, and a few results will vary a lot from the expected value. A stoichastic process is not completely random because you know the expected value, but it does have an element of randomness.

I hope this hopes. Tammy  

 



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Marysue
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 Posted: Sat Apr 2nd, 2011 11:58

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Here is a quote from the wikipedia page for "stochastic process":

"In probability theory, a stochastic process, or sometimes random process, is the counterpart to a deterministic process (or deterministic system). Instead of dealing with only one possible reality of how the process might evolve under time...., in a stochastic or random process there is some indeterminacy in its future evolution described by probability distributions. This means that even if the initial condition (or starting point) is known, there are many possibilities the process might go to, but some paths may be more probable and others less so."
--------------------------------------------------------------------------------------------------------

I don't think it's too hard to get, and I do tend to overcomplicate things.  My understanding of what Dr. Marshall said is that in the medical/scientific community, there is too much assumption that cells are deterministic--meaning that every cell is going to behave in a specific defined way every time.  This is truly the most rediculous and simplistic assumption and yet so much of what we are taught in school is like this.  It's as though once we start drawing conceptual stationary models of biological things, we forget that they are living, "breathing", evolving forms that are obviously stochastic--meaning that there are an unlimited number of variables and options for each part of a cell to bump into and attract, repel, interact with, etc. and an equal number of imponderable outcomes.

Imagine a large room full of people who show up for a party.  Some of them represent proteins, some enzymes, some DNA, and so on....  The deterministic view is that we can define precise outcomes from that room full of people like who is going to do what every time.  Even the idea that you can recreate the exact group of people every time is pretty far-fetched.  And yet, that is how these concepts are taught.  The stochastic view is an understanding that (as defined above) "there are many possibilities the process might go to, but some paths may be more probable and others less so."

In the simplistic of words, stochastic means "multiple possible and variable outcomes."

Does that help?
:)
Marysue



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 Posted: Sat Apr 2nd, 2011 19:48

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Nice article.


Mark,

I tried to find out about the chemical master equation from the link below. :shock:, lol. Well at least I understood the introduction which explains stochasticity in gene epression.

https://www.cds.caltech.edu/~murray/wiki/images/d/d9/Khammash_master-15aug06.pdf




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 Posted: Sun Apr 3rd, 2011 05:54

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Marty,

Thanks for the link -- although a little over my head -- I also get the general idea that gene expression is a stoichastic process. I found the key points on slide 22 very interesting:

1) small subsystems can often be isolated

2) each protein binds to one or very few other molecules

3) Key molecules exist in small numbers (ex: in liver cells 97% of mRNAs are present at ~10 copies/cell)

To me, this means the process is truly stoichastic, but not completely random by any means.

Dr. M's paper link is also way above my understanding. But again a statement that gene expression is not deterministic. I very much like Figure 1, C. In our case it would seem that the bacteria is certainly a large part of the "environment".

The news article Dr. M linked to --is something we can understand. I had no idea that cells were "crowded". I always thought of them like a vast emptiness inside, such as outer space. I guess the Thomson "plum pudding" model of an atom -- might be kind of a good analogy for a cell.

I wonder if the bacteria physically crowding the human cell plays a role in the dynamics. The infection of the bacteria occurs in the nucleus of the phagocyte, and not the cytoplasm, but it would seem that the crowding phenomenon would also exist in the nucleus. I also wonder what impact that the bacteria have on cell function outside the nucleus in the cytoplasm of the phagocyte. If the bacteria live in the nucleus, then they must also be in the cytoplasm. Please correct any errors in my level of understanding.

Thanks. 



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mvanwink5
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 Posted: Sun Apr 3rd, 2011 06:23

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Intracellular bacteria adding to the crowding also seemed an issue to me. We see from the modeling that crowding is a significant effect on cell functioning, so even if intracellular bacteria did nothing else, they would distort cellular chemical dynamics.

My coursework in chemistry was always with well mixed, very large number of molecules type chemical reactions. The chemistry of small number of molecules, with geometry effects, and effects of crowding is completely new. I can see where doctors might not have the correct view of what is going on in the body with new classes of drugs that work on nuclear receptors.

Very exciting, very strange and complex. Mathematics looks like a combination of abstract algebra, topology, and statistics.



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tammy1000
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 Posted: Sun Apr 3rd, 2011 06:53

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I guess math truly is the universal language. I have seen the different forms of math in the papers/presentations during my graduate courses in  engineering. That was a long time ago, but seem like yesterday when I look at the slides.

I may not understand the biochemistry, but at least the math is no stranger.



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Prof Trevor Marshall
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 Posted: Sun Apr 3rd, 2011 11:15

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If the bacteria live in the nucleus, then they must also be in the cytoplasm

Wirostko's TEM photos showed mainly bacterial inclusions in the cytoplasm. The Nuclei were damaged, but this could be biochemical action from the microbiota in the cytoplasm.
 

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 Posted: Tue Apr 5th, 2011 09:53

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Here is a quote from the wikipedia page for "stochastic process":

"In probability theory, a stochastic process, or sometimes random process, is the counterpart to a deterministic process (or deterministic system). Instead of dealing with only one possible reality of how the process might evolve under time...., in a stochastic or random process there is some indeterminacy in its future evolution described by probability distributions. This means that even if the initial condition (or starting point) is known, there are many possibilities the process might go to, but some paths may be more probable and others less so."

Oh I see - so putting vitamin D in the milk with a "one size fits all approach" would be a deterministic approach  - because it is good for everybody - as opposed to the stochastic idea that the supplementation will be harming some of the people.

I guess I was overcomplicating.

Well if the medicos don't get that we are all not the same and won't respond the same to their chemical cocktails  - I guess that is pretty stupid.

We call that "common sense" where I'm from. (a geographically isolated section of southern ontario - sometimes associated with canada).

I personally call the medical deterministic approach and it's unintended consequences on certain phenotypes/genotypes/haplotypes/etc  "genocide".

Some like to call it "evolution" or "survival of the fittest" but that's more deterministic thinking isn't it.



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 Posted: Tue Apr 5th, 2011 11:22

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Perhaps it is this project http://www.youtube.com/watch?v=j84sF_81gCo

It is a cut from nvidia gpu simulations http://www.nvidia.com/object/gtc2010-presentation-archive.html , at 50 minute of the second presentation. http://livesmooth.istreamplanet.com/nvidia100922/

I like watching those :D

Last edited on Tue Apr 5th, 2011 11:30 by wrotek



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Prof Trevor Marshall
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 Posted: Tue Apr 5th, 2011 13:34

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Wrotek, that is a wonderful link you have found.
I downloaded the Nvidia presentation this morning and will include the cell video into my presentation later this month in China. The video is clean in the Nvida video, much better than the hand-held camera version in the YouTube version.

I had been looking at this paper over the last few days, and so having the video is absolutely brilliant :) Thanks again :) :)

..Trevor..
 

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 Posted: Tue Apr 5th, 2011 13:45

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What a coincidence LoL. I was watching this conference  few days ago,found it after reading about Nvidia Tesla Teraflop processors.  Good i was watching carefully and remembered the segment. :)



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Teresa Green
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 Posted: Tue Apr 5th, 2011 17:26

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Trevor,

This cell simulation work is very important for conducting drug pharmokinetics research.   More so given the new understanding that cytoplasmic density impacts many of the stochastic processes of cellular functioning.

The most encouraging factor from all of this, is that the pharmokinetics of your "pure olmesarten" will be improved given that it is a smaller molecule than olmesarten medoxomil.

I watch this topic with great interest.

Regards

Teresa


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