[BBF Standards] systemic limitation of biobricks for combinatorial logic?
Dr. Markus Schmidt
markus.schmidt at idialog.eu
Tue May 20 07:46:15 EDT 2008
Thanks JC for bringing the issues back into the disussion. The system-
wide visibility of all gate outputs is a serious obstacle to the
development of the standardized biopart concept. When I posted the
message on lacking specifity in February there was hardly any
reaction, which really surprised me. Sure as long as the experimental
phase of biobricks now runs systems that contain only few parts, all
these problems do not arise, but thinking about the future and about
the prospect of this approach we should dedicate a susbstantial amount
of time and energy to come up with solutions.
If we take electronic integrated circuits as an example (and not as a
metapher), than producing compartiments is the goal.
Which ways are there to produce compartiments?
To begin with I would say there are spacial, chemical, sematic or time-
based compartiments.
1. Spacial:
1.1. new organelles. This is a nice idea but how many organelles can
you engineer into a cell? Tens, hundreds, but certainly not millions.
1.2. cell-cell communications. of course this is an option but it is
basically the same situation as in the organelles, although with the
option to increase the number of differnet cells without the packing
problems of organelles. Basically the way by wich the cells
communicate is the bottleneck.
2. Chemical:
2.1. Number of molecules to be used as an information carrier is
extremely large but at the cost of reduced specifity and increasing
cross talk.
2.2. Quorum sensing. This is done by molecules and only because it
involves the extracellular environment it doesn't mean it solves the
problem of open logic gates.
3. Semantic:
3.1. I guess the zinc finger story comes in here, an approach that
target the genetic code. The information you can store on a lets say
x bp long DNA is 4^x (may be reduced for some mutation-robustness
meassures) and could provide enough specifity to deal with ultra large
scale circuits. This is actually a promising approach, programming an
RNA computer
4. Time-based
4.1. PoPS, for Polymerase Per Second. This is a nice idea (and the
comic is fun) and transcends/converts the problem of chemical
specifity to a unambigous signal unit. OK, lets say you found a way to
meassure the PoPS rigt on the DNA. Say you meassuered x PoPS. Then you
have a subsequent PoPS analyzer that makes e.g. the following
decision: if x<y output=0; if y<x<z output undefined; if z<x output=1.
Problem solved, isn't it? Well it is but only in the case if the PoPS
analyzer (counter) sits right after the PoPS relevant piece of DNA,
otherwise you would have to transfer the result x into a chemical
signal to transport it to another part of DNA or elsewhere and then
you run into the same problem of open logic gates. So if you avoid
that and realize a linear logic line (a Ford like assembly line) you
are quite limited in running your software.
However, what I think can be done is to combine all these approaches
in order to push the limit of the maximum number (Nmax) of realizable
"logic gates" or operations a little bit. Maybe each approach can help
us to push the Nmax by a factor of 100 or 1000 (or maybe more).
However, this is way a different story than with Moore's law, where
basically the reduction of size ( and packaging) of logic gates was
and is the main driving force to improve the number of transistor per
chip.
Cheers, Markus
Am 20.05.2008 um 05:35 schrieb Drew Endy:
> As background information relevant to your discussion:
>
> 1. there is a common signal carrier for gene expression devices. it
> is called PoPS, for Polymerase Per Second. read about it here: http://openwetware.org/wiki/Adventures
>
> 2. biochemical cross talk within a self mixing volume can be handled
> via the specificity of molecular interactions. look up zinc finger
> DNA binding proteins. read Reshma Shetty's dissertation from MIT
> (this year). Also read Zarrinpar A, Park SH, Lim WA., PMID: 14668868
>
> 3. new organelles could be created thereby providing engineered
> additional spatial insulation. see the 2007 UCSF iGEM team's second
> project (here: http://parts.mit.edu/igem07/index.php/UCSF/Organelle_Intro)
> . Also read Barry Canton's dissertation from MIT (this year).
>
> 4. cell-cell signaling can be used to communicate across bacteria.
> read Weiss and Knight (http://www.princeton.edu/~rweiss/papers/rweiss-dna6.pdf
> ) and more recent papers from Ron's lab at Princeton (see http://weisswebserver.ee.princeton.edu/pubs.html)
> .
>
> Drew
>
>
>
> On May 19, 2008, at 10:42 PM, James Lawson wrote:
>
>> Hi folks,
>>
>> This might be a little from left field, and I don't have the
>> solution, but I have had this idea since I became familiar with the
>> gene-centric abstraction level that the entire Biobricks / standard
>> parts systems is based on. I don't think the level that we're
>> designing these systems at is helping us here, particularly with
>> respect to this system-wide visibility of gate outputs. We have no
>> 'encapsulation' mechanism. The non-nucleated cells we're using as
>> chassis for these systems don't have any mechanism for membrane-
>> based compartmentalisation, so any all the 'computation' is done in
>> pretty much the same compartment. Nucleated, compartmentalised cells
>> are able to get a step further by creating an encapsulation
>> mechanism, where some kind of reaction or transformation of species
>> may be contained within a delineated zone.
>>
>> Leveraging any of these membrane compartmentalisation (or membrane
>> mircodomain) based systems of encapsulation would require some
>> pretty extensive engineering and standardisation of the transport
>> and cytoskeletal systems within a cell, so I guess it isn't really
>> tractable for a while.
>>
>> To add to Herbert's comments:
>> In unicellular organisms, one could say that quorum sensing systems
>> are analogous to neural networks in multicellular organisms as a
>> solution to this problem of encapsulation and input/output
>> visibility management we're talking about. I have heard quite a lot
>> about people doing engineering with quorum sensing systems and I
>> think this is probably where the synthetic biology community will
>> continue to look to. I don't really know how much we know about
>> heterogeneous bacterial colonies - perhaps someone could enlighten
>> me on the state of the field?
>>
>> Kind regards,
>> James Lawson
>>
>> Herbert Sauro wrote:
>>> Funny you should mention this solution:
>>>
>>>> Can this be solved by using single cells for each circuit, then
>>>> somehow providing inter-cell communication?
>>>> (Also seems quite difficult, correct?)
>>>
>>> Because this is how evolution got round the problem by inventing
>>> neural circuits.
>>>
>>> Herbert Sauro
>>>
>>> J C wrote:
>>>
>>>> Hi all,
>>>> I have been reading about biobricks for some time,
>>>> I am a computer engineer.
>>>>
>>>> For combinatorial logic, it seems the limitation of biobricks
>>>> is the system-wide visibility of all gate outputs, is this correct?
>>>> In circuits with multiple gates, each gate must employ a unique
>>>> input signal and output signal, otherwise the multiple outputs
>>>> will conflict with the inputs.
>>>>
>>>> How is this being addressed other than by finding unique
>>>> signals to feed to each gate?
>>>>
>>>> This is not a scalable solution for larger circuits, i.e. adders
>>>> or latches (RAM storage for more than 1 bit).
>>>>
>>>> Can this be solved by using single cells for each circuit, then
>>>> somehow providing inter-cell communication?
>>>> (Also seems quite difficult, correct?)
>>>>
>>>> There was a similar comment on this recently, though I didn't
>>>> see any solution discussion?
>>>> http://biobricks.org/pipermail/standards_biobricks.org/2008-February/000034.html
>>>> "The lack of physical separation of signals, as is the case in
>>>> microelectronics, could be one of the biggest limitations to the
>>>> standardized bioparts concept. "
>>>>
>>>>
>>>> The idea offered in that thread,
>>>> "Actually this could lead to a design process where you operate
>>>> e.g. on a
>>>> system level and design your nice circuit, but depending on the
>>>> circuit the
>>>> design computer programme chooses one of different devices (and
>>>> finally
>>>> parts) that interact in the way you like."
>>>>
>>>> This is actually quite impossible for multi-gate designs. A multi-
>>>> bit adder
>>>> or memory storage would require far too much complexity. The
>>>> components
>>>> (i.e. "transistors") need to have completely compatible outputs so
>>>> that
>>>> any output can connect to any input. Otherwise they are not
>>>> "generic parts".
>>>> Similar issues led to much complexity in the early days of
>>>> semiconductor
>>>> fab.
>>>>
>>>> --
>>>> Cheers!
>>>>
>>>> _______________________________________________
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>>>> Standards at biobricks.org
>>>> http://biobricks.org/mailman/listinfo/standards_biobricks.org
>>>>
>>>
>>>
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>>
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