applying aging to the OpenWorm

[vahid ghayoomi]

Hi everyone,

I'm working on systems biology of aging in C. elegans.

Searching for finding a framework to model and simulate aging mechanisms of aging in C. elegans introduced me with this interesting project.

I was wondering if there is any possibility to include aging in this project.

As you know, aging is a complex phenomenon which affect different tissues and cell types of an organism.

C. elegans is a leading model system for studies of aging and there are many studies reporting the age-related changes in this organism:

But the most obvious manifestation of senescence in the aging worm is that it moves ever more slowly and eventually stops moving altogether.

And this is the subject I'm interested to collaborate to this project with.

I know that the OpenWorm project, in its current state is just going to simulate the locomotion of a worm and mostly includes neurons and cell muscles of the worm which can not cover the complexity of the aging worm, but after reading a study which was recently published in the Cell press, it came to me that it is possible to start the simulation of aging in the OpenWorm project using such studies.

In this study, using a quantitative approach, Liu et al. probed the intricacies of functional aging in C. elegans. They show that motor neurons exhibit a progressive functional decline beginning early in life (~day 5).

Using electrophysiological recordings, they measured the frequency of spontaneous neurotransmitter release from pre-synaptic motor neurons, which reflects the activity of the motor nervous system in the body of the worm.

The earliness of the observed decline led the authors to infer that it is aging in the nervous system that largely drives the decay in locomotory activity.

After that they started to find how synaptic release in motor neurons becomes compromised during aging.

Further analysis revealed that motor neurons first develop a deficit in synaptic vesicle fusion, beginning in early life, which is followed by a defect in quantal size and vesicle docking/priming at later ages.

The point in this study is that these analysis are mostly based on quantitative approaches which is very useful in modeling and simulation.

For applying such studies to the OpenWorm project, at the first place, I need to know if it is possible to design and develop an extension to the current project which is capable of simulating the locomotion of the worm in a time-based dynamic approach instead of a single-state adult worm.

Also, I need such biological entities to be included to simulate such study:

• ventral nerve cord
  
• motor neurons
  
• muscles cells
  
• muscle receptors (for amplitude of PSCs)
• excitatory nicotinic acetylcholine receptors (nAChRs) 
• inhibitory GABA receptors
• neuromuscular junctions (NMJs) in the ventral nerve cord
  
• Pre-synaptic motor neurons
  
• neurotransmitters
  
• muscle receptor channels
  
• post-synaptic currents (PSCs)
  
• amplitude and frequency of PSCs
• synaptic vesicles
  
• neurotransmitter uploading to synaptic vesicles
• quantal size
• the amount of neurotransmitter released from synaptic vesicles
• vesicle docking/priming
• the size of the readily releasable pool (RRP)
• vesicle fusion

Also, I have to say that although I have a B.Sc in computer and M.Sc in Biology and I am familiar with both programming and biological modeling, I'm not alone in this project. One of my friends who is expert in Java development, is also interested in contributing to this project. So I hope we could do our best to contribute effectively to this project. 

Sorry for the long topic, but it is really important for me, and I would really appreciate it if you could help me through this.

[InterIntelligence Research]

Vahid:

 

I'm sure others will lend their comments but let me say that you have pegged the project well. There are two approaches going on whereas we have the overall project being developed in a top-down approach but the ultimate goal is to create a simulation in a bottom-up method that (again) ultimately would be able to read a gene sequence and start the simulation. Much of what you are proposing has to do with Systems Biology and this is the step up from gene expression. Even with our more top-down approach, the way in which the worm body and mechanics are being programmed will lend itself very well with added systems biology. Therefore, if you are looking for something we could do regarding aging in the next couple of months, we are not there, but if you wish to join in on the fun for the long haul and start working on the systems biology, you are welcome and much needed.

 

As an example, your outline on synaptic vesicles are still a way aways from our current development; i.e. our synaptic transmission would be more in line with mathematical modeling and the electrical properties than simulating physical globules at this time. But as I indicated, ultimately, we would like to simulate the globules so we can tinker with the chemical makeup and predict what happens. Same with the Innexins and resulting gap junctions. Neuropeptides are an ever present thought for us because we feel our simulation won't be accepted by the biology community until we account for the systems biology that produces neural activity. We have much to do and much to cover and always wanting more talent to assist in our development.

 

Thanks

 

Tim

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[vahid ghayoomi]

Thanks for reply.

Of course, I'm interested in working on systems biology aspect of this project (preferably on aging and mathematical modeling) as long as possible.

As you know the aging process is a multidimensional concept, which consists of patterns from molecular/cellular to physiological. So, both the top-down and bottom-up approaches are applicable for modeling aging.

My idea was to start with the current biological entities of the OpenWorm project and model aging where applicable (i.e. look for what you have done and how aging could affect them) and continue it as the project goes on.

Of course, right now, this project is not ideal for my purpose, but my goal is to integrate them as much as possible and also continue it in the future (if the team found my work qualified and useful).

So, if you think the modularity and flexibility of this project lets me do what I proposed, I am glad to work on this, otherwise, I'm open to your suggestions for other kind of works on systems biology.

[InterIntelligence Research]

Vahid:

 

We are in dire need for more systems biology work and effort as we continue to develop the overall worm architecture and simulation. The premise of an open source team like ours is that you give a lot and we hope you gain something from it as well. At this stage I can't tell you we have much to offer you other than being involved in some very satisfying and exciting efforts but I think we would have much to gain from someone like yourself. I think everyone on the team can say that they have enhanced their love of science and the fields they particularly study. As an open source team, there are no assignments, their is no pressure for you to put in any particular time, it is all on you to contribute what you can when you can, and of course you have a front row seat to whatever the team produces.

 

It is always up to you as to whether our team dynamic and work efforts fit what you want to gain from the experience.

 

Tim

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[vahid ghayoomi]

Thanks Tim,

Is there any documentation/plan specific to the biology of the project? 

I've already started reading about different aspects of systems biology in C. elegans, but I'm not sure where should I start from in the OpenWorm.

[Stephen Larson]

Hi Vahid,

   Hope all is well with you.  I wanted to add on to what Tim had said now that we have had some recent progress with the project that seems very relevant.

 Hopefully you've had a chance to see some of the recent versions of the simulation (here and here).  I believe this is what you are looking for when 

you reference a "time-based dynamic approach"?  If so, it is very interesting to consider looking at aging as you suggest.

  We are soon to release some new documentation for the project, which also just got completed.  I wanted to point you at the

page that describes the modeling approach we are currently taking.  

   I believe what you are describing sounds like it would be a means of making changes to the dynamics of the nervous system model

once we get it up and running.  While this is still a significant effort that we are in the process of getting ourselves organized around

I think it may not be too early to start having a look at what this would mean.  I'd suggest you have a look at the docs and 

see if this matches with your ideas or not.  I'd love to take the idea forward from there.

Thanks,

  Stephen

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[vahid ghayoomi]

Hi Stephan,

Congratulations for your great work, and thank you for your attention.

Actually what I was meaning by a "time-based dynamic approach" was a worm that could move differently as it age. For example if your prototype's movement is based on the locomotion of a real worm in 1 minute of its life, we can simulate the movements of the worm for a whole life (e.g. ~20 days) in fast-forward. To simplify the application of this idea, we can start with the main three phases of its lifespan (week 1, week 2, and week 3) which in different studies, the progressive decline in motor activity during these phases has been measured.

In order to apply this idea, based on your model, to begin with a top-down approach, we need these requirements in different components of the project:

1. At data layer, we need entities I mentioned at my first post.

2. In the Sibernetic part, we need to add different kinds of movement based-on these three phases. (e.g. we need to add/change components, variables and algorithms to act differently at these phases)
3. In the Geppetto, again we need to simulate these three phases to show the progressive decline.
4. In the Movement Validation part, we need to gather quantitative information from published papers and DBs based-on different ages of the worm in order to apply the progressive decline and validate the results.

Although I had a look at the documentations which were very helpful, I'm going to spend more time on details (specially biological entities I need).

So, if you think, these kind of changes are applicable (even as a different project which can be integrated in the future), I'm very interested in contributing to the project.

Thanks,
Vahid