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Discussion of Genome as Program

Gary Welz gwelz at panix.com
Wed May 3 12:03:47 EST 1995


Attached is the discussion of an earlier posting of mine: "Can the 
Genome be Thought of as a Computer Program"
-Gary Welz

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Correspondence re: "Can the Genome be thought of as a Computer Program?"

Gary Welz
Dept of Mathematics
John Jay College, CUNY
gwelz at panix.com


On April 13, 1995 I posted a note to the bionet.general and bionet.genome.
chromosome discussion lists concerned with the question of whether 
we could think of the genome as a computer program.  Since then I 
have received a great deal of very interesting mail from a number of 
scientists.  Here is my note along with a sampling of the discussion 
that it inspired.  I hope this dialogue will continue and be of interest
to readers of this discussion group.

April 13, 1995

I'm writing an article about the large scale structure of the genome.  
Does anyone besides me think that an organism's genome can be regarded 
as a computer program?  I mean that its structure can be presented as a 
flowchart with genes as objects connected by logical terms like "and" 
and "or" and, of course, "while" loops?  Of course conditional activity in 
the genome - the analog of "while" loop - has been studied for some time.

One development that might support this point of view is the recent 
demonstration (reported in last week's Science) that the eyeless gene 
can be inserted into various parts of the chromosome of a fly and cause 
it to have eyes grow on different parts of its body.  Is eyeless a free 
standing genetic object that can be plugged into any syntactically 
correct sequence and function as though it belonged there naturally? If so 
what is the nature of the programming language that makes this possible.

Gene Stanley and others at Boston U. and Harvard Medical School have 
done statistical analyses of non-coding DNA sequences (published in 
Physical Review Letters a few months ago) that suggest that there may be 
linguistic structures, i.e. words within them.  Are some of these 
non-coding sequences the terms of the genetic programming language?  

If this is interesting to you, or if you think its bogus, let me know.

Mr. Gary Welz
Dept. of Mathematics
John Jay College, CUNY


Date: Fri, 14 Apr 1995 09:31:54 -0400 (EDT)
From: Robert Robbins <rrobbins at gdb.org>
Subject: Re: Is the genome like a computer program?
To: Gary Welz <gwelz at panix.com>
Cc: biochrom at net.bio.net, gary at setn.org, Robert Robbins <rrobbins at gdb.org>
Mime-Version: 1.0

Gary,

This is an area to which I have given some thought (and in fact have even
written about it a bit and have added a discussion of the subject to a 
course I teach at Johns Hopkins).

The genome is like a mass storage device (with properties not shared by
current electronic mass-storage devices), but the programs that it encodes
differ significantly from current computer technology.

Each parent contributes one set of mass-storage devices (23 chromosomes)
so that the resulting single cell has two full sets of the programs (that
may, and do, differ from each other).  

Although the genetic code is without doubt a digital code, the level of
parallelism that exists in the expression of these codes is such that many
aspects of the system have more in common with an analog system than with
a digital one.  If we assume that the transcription of a gene, followed
by the synthesis of an enzyme is the spawning of an executing process,
then each single cell has millions of programs executing in a truly
parallel (i.e., independent execution, no time sharing) mode. 

By the time the single cell produced by the union of sperm and egg has
grown into an adult, there are probably well in excess of 10**13 cells,
each with two copies of the mass-storage devices, and each running
somewhere in excess of 10**5 to 10**6 processes in parallel.  Many of the
spawned processes affect the launching of other processes, so the level of
feed-back control is high.  Hormones produced in one cell may affect the
expression of genes (i.e., the launching of processes) in other cells, so
in principle the processes running in any of the 10**13 cells could affect
the launching o processes in any of the other 10**13 cells.  Proteins may
interact with each other, so processes may affect processes, and there is
certainly a lot of inter-process interaction.  

Taken all together then, the expression of the human genome involves the
simultaneous expression and (potential) interaction of something probably
in excess of 10**18 parallel processes.  

Given this, it is not likely that intuitions derived from an understanding
of the operation of programs on present computer architectures will
generalize well to the expression of the genome.

Differences also exist in the mass-storage devices as well.  The genome
can be thought of as a mass-storage device based on a linked-list
architecture, rather than a physical platter.  All addressing is
associative, with multiple read heads scanning the device in parallel,
looking for specific START LOADING HERE signals.  When such a signal is
encountered, the read head starts transcribing DNA and continues doing so
until a STOP LOADING HERE signal is encountered.  [The resulting transcript
is like a *.EXE file, rather than a *.COM file.  On Intel systems, *.COM
files are perfect memory images that may be loaded verbatim into memory
and then execute when control is passed to the first byte.  *.EXE files,
on the other hand, are a mixture of instructions to the loader and
instructions to be executed.  After the loader instructions are executed,
the program (now different from that stored on the mass-storage device) is
placed in memory and control passed to it.]

Genome programs execute on a virtual machine that is defined by some of
the genomic programs that are executing.  Thus, in trying to understand
the genome, we are trying to reverse engineer binaries for an unknown CPU,
in fact for a virtual CPU whose properties are encoded in the binaries we
are trying to reverse engineer.

We do know that "genomic op codes" are probabilistic, rather than
deterministic.  That is, when control hits a particular op code, there is
a certain probability that a certain action will occur. This applies to
the associative addresses on the mass storage device as well.  Intuitions
from current hardware suggests that this would make for intermittent,
jerky behavior of the system.  However, in such a massively parallel
system, probabilistic op codes actually smooth out the behavior of the
system by providing some buffering capacity (in the chemical, not computer
I/O, sense of buffering). 

I could go on, but I hope my general point is made.  I offer some
additional comments below in response to your specific inquiries.

On 14 Apr 1995, Gary Welz wrote:

>I'm writing an article about the large scale structure of the genome.  
>Does anyone besides me think that an organism's genome can be regarded 
>as a computer program?  I mean that its structure can be presented as a 
>flowchart with genes as objects connected by logical terms like "and" 
>and "or" and, of course, "while" loops?  Of course, conditional 
>activity in the genome - the analog of the "while" loop - has been 
>studied for some time.

Flow charts describe the behavior of a non-parallel machine.  Although
some aspects of a massively parallel system can be expressed
(metaphorically) as a flow chart of linearly executing steps, care must 
be taken in interpreting that flow chart.  

>One development that might support this point of view is the recent 
>demonstration (reported in last week's Science) that the eyeless gene 
>can be inserted into various parts of the chromosome of a fly and cause 
>it to have eyes grow on different parts of its body.  Is eyeless a free 
>standing genetic object that can be plugged into any syntactically 
>correct sequence and function as though it belonged there naturally? If   
>so what is the nature of the programming language that makes this 
>possible.


The expression of single processes (like MAKE HUMAN GROWTH HORMONE or MAKE
HUMAN INSULIN) are fairly free-standing and can be inserted into almost
any syntactic interpreter, with the result that the desired protein is in
fact synthesized.  This is the heart of much of the bio-tech industry.

However, the parallel nature of genomic expression is such that major
developmental steps, like making eyes, involve so many processes acting in
concert that individual processes cannot be seen as free standing.  This
may seem to contradict the findings you mention above, but explaining the
subtleties involve would require more time and space than is available
here. 

>
>Gene Stanley and others at Boston U. and Harvard Medical School have 
>done statistical analyses of non-coding DNA sequences (published in 
>Physical Review Letters a few months ago) that suggest that there may be 
>linguistic structures, i.e. words within them.  Are some of these 
>non-coding sequences the terms of the genetic programming language?
>

There is an entire body of literature that treats the linguistic
properties of DNA.  If you are really interested, you should read a lot of
it before jumping to quick interpretations.  However, you should also bear
in mind that DNA involves the coding of a "language" on a mass-storage
device, it is not the direct expression of a language.  As an analogy,
consider the differences that programs designed to detect linguistic
features would exhibit of they were run first against, say, War and Peace
as straight ASCII text and then second, against the byte stream obtained
from a hard disk on which War and Peace was stored as, say, a WordPerfect
file with all of the embedded WordPerfect formatting codes and with lots
of file fragmentation thrown in.  I expect that the program would detect
linguistic features when run against the byte stream from the hard disk,
but they would be neither a clean set of features of English nor a clean
set of features from WordPerfect formatting codes, but rather a mixture of
the two, with some confusion thrown in due to the disk fragmentation.

> 
> If this is interesting to you, or if you think its bogus, let me know.

I think it's really interesting, but I also think that we need to be
careful not to oversimplify the analogies.  When I was the program officer
for Database Activities in Biology at NSF, I had many inquiries from
computer scientists who had acquired a Scientific-American-article level
of appreciation of genetics and who assumed that the well-known table
showing the determination of the sequence of amino-acids in proteins by
the sequence of nucleotides in DNA was more or less equivalent to the
table of op codes for some CPU.  This level of understanding led to some
very simplistic proposals. 

A not-that-bad-reversal of the analogy would have someone thinking that an
understanding of the ASCII code (41h = A, 42h = B, etc) is all that would 
be required to understand the workings of, say, an Intel Paragon or a 
Cray-4.

At the same time, I think that bringing computer-science insights to bear 
on the challenge of understanding genome operation has some potentially 
huge payoffs.  For example, it would be really interesting to think about 
the file-allocation-table system for a mass storage device that behaves 
like a redundant linked list, with only associative addressing (i.e., no 
physical addressing by sector-offset, but instead only addressing by 
offsets from recognizable landmarks).  It would also be interesting to 
think about the computational properties that might emerge in a system 
with probabilistic op codes and with as much parallelism as biological 
computers.

Bob

  Robert J. Robbins
  Bioinformation Infrastructure Program
  Office of Health and Environmental Research
  ER-72 GTN
  United States Department of Energy
  19901 Germantown Road
  Germantown, MD  20874-1290

  robbins at er.doe.gov



Date: Fri, 14 Apr 95 02:58:08 PDT
From: "David L. Baillie" <dbaillie at darwin.mbb.sfu.ca>
To: gwelz at panix.com
Subject: Re:  Is the genome like a computer program?

I think it sounds like I good idea, if you can carry the arguement far 
enough to make it convincing.  I think that the logical equivalent of 
the transcript-ional signals in the front of a gene can be modelled as 
a set of and, or, not statements for deciding when the gene is used.  
I suppose this is a just an extention of your arguement.

dave baillie
Institute of Mol. Biol. Biochem.
Simon Fraser University
Burnaby, BC
Canada


Date: Fri, 14 Apr 1995 08:48:48 -0400 (EDT)
From: dnasequence at MSCF.MED.UPENN.EDU (Vahe Bedian)
Subject: Re: Is the genome like a computer program?
To: Gary Welz <gwelz at panix.com>


Check out work done by Stuart Kauffman in the 70's published mostly in the
Journal of Theoretical Biology. He represented the gneome as a network of
interacting binary switches, and analyzed number and connectivity of
"steady states" available.

Vahe Bedian


From: Patrick O'Neil <patrick at corona.med.utah.edu>
Newsgroups: bionet.general
Subject: Re: Can a genome be analyzed like a computer program?
Date: Thu, 13 Apr 1995 19:22:26 -0600
Organization: University Of Utah Computer Center


On 13 Apr 1995, Gary Welz wrote:

> I'm writing an article about the large scale structure of the genome.
> Does anyone besides me think that an organism's genome can be regarded
> as a computer program?  I mean that its structure can be presented as a
> flowchart with genes as objects connected by logical terms like "and"
> and "or" and, of course, "while" loops?

You would also have to come up with a computer program terms like, "sort
of" and "sometimes" and "a little bit."  Not all genes act in an either
on or off configuration.  Dosage affects, epigenetic affects, etc, muddy
the water a bit.  Some genes can be a little bit on meaning that
sometimes a full gene product is produced, but other times an abortive
product is produced; or the gene might be on at a low level which differs
in different circumstances with the same signals floating about in the cell.

Patrick


To: RRobbins_DOE
From: gwelz at holonet.net (Gary Welz)
Subject: Parallel processes in Genes
Cc: 
Bcc: 
X-Attachments: 

Bob,
Certainly the "program" in the genome is a highly parallel one.  Perhaps 
it is reasonable to think of it's structure as being like an n-dimensional
lattice for a very large n.  (You mention "10**5 to 10**6 processes 
in parallel" in a single cell and 10**13 cells that could affect the launching 
of processes in any of the other 10**13 cells.)  While this 
is certainly a large number of processes to model, the picture is not 
so difficult to visualize.

    \|           |      \/      |              \|/ 
    / \----?----/|\    /\     /|\    |  ?  / \
   /\ |\   |   /|| \--/| \  |/\  \--/|\/| /| /\ ?
  /| ?  \ /|\ /\|\ /\  |--| | /\ ? /\ /\/\ | ?-\/

The basic components are: 
 | (1 substance or compound in and 1 out)
 
\|/ (multiple in and 1 out)

/|\ (1 in multiple out) 

\|/
/|\ (multiple in and multiple out)

? (originally a typo, but I left it in as a way of designating an 
indeterminate branch)

--- (some kind of relation between processes, a feedback type 
connection that did not have to be an exchange of substances.)

If I could represent this with 3 dimensional graphics I could 
express the multidimensionality better.  The point is any strand 
can be connected to any other strand and all are probably connected 
to "spines" that are the master control processes for the entire 
cell and the entire organism. 

I've been getting some encouraging mail from biologists and 
computer scientists.

One of my respondents, Patrick O'Neil (U. of Utah Computer Center) wrote:
>You would also have to come up with a computer program terms like, "sort
>of" and "sometimes" and "a little bit."  Not all genes act in an either
>on or off configuration.  Dosage affects, epigenetic affects, etc, muddy
the water a bit.  Some genes can be a little bit on meaning that
>sometimes a full gene product is produced, but other times an abortive
>product is produced; or the gene might be on at a low level which differs
>in different circumstances with the same signals floating about in the cell.

David Baillie wrote:
> I think that the logical equivalent of the transcriptional signals in the 
>front of a gene can be modelled as a set of and, or, not statements for 
>deciding when the gene is used.  I suppose this is a just an extention of 
>your arguement.


Date: Sat, 15 Apr 1995 17:41:52 -0400 (EDT)
From: Robert Robbins <rrobbins at gdb.org>
Subject: Re: Parallel processes in Genes
To: Gary Welz <gwelz at setn.org>

On Sat, 15 Apr 1995, Gary Welz wrote:

> Certainly the "program" in the genome is a highly parallel one. Perhaps it
> is reasonable to think of it's structure as being like an n-dimensional
> lattice for a very large n.  (You mention "10**5 to 10**6 processes in
> parallel" in a single cell and 10**13 cells that could affect the launching
> of processes in any of the other 10**13 cells.)  While this is certainly a
> large number of processes to model, the picture is not so difficult to
> visualize.

My intuition may be all wet here, but my gut feeling is that you could
model the system this way, but that you would find the state space for the
system to be so huge that it would not be computable within the expected
lifespan of the universe (like the protein folding problem, only lots
tougher).  However, proteins fold and critters develop within real time,
so there is clearly some kind of heuristic going on that these exhaustive
models don't quite capture.

If this sounds like I missed your point, maybe I did.  If so, reword and
retransmit... 

> One of my respondents, Patrick O'Neil (U. of Utah Computer Center) wrote:
> >You would also have to come up with a computer program terms like, "sort
> >of" and "sometimes" and "a little bit."  Not all genes act in an either
> >on or off configuration.  Dosage affects, epigenetic affects, etc, muddy
> the water a bit.  Some genes can be a little bit on meaning that
> >sometimes a full gene product is produced, but other times an abortive
> >product is produced; or the gene might be on at a low level which differs
> >in different circumstances with the same signals floating about in the cell.

This is what I meant by probabilistic op codes...

> 
> David Baillie wrote:
> > I think that the logical equivalent of the transcriptional signals in the
> >>front of a gene can be modelled as a set of and, or, not statements for
> >>deciding when the gene is used.  I suppose this is a just an extention of
> >your arguement.

And this is what I meant when I said that the probabilistic op codes
extended to the associative START READ HERE signals...



Date: Sat, 15 Apr 1995
To: Robert Robbins <rrobbins at gdb.org>
From: gwelz at holonet.net (Gary Welz)
Subject: Re: Parallel processes in Genes

Bob,
You wrote:
>On Sat, 15 Apr 1995, Gary Welz wrote:
>
>> Certainly the "program" in the genome is a highly parallel one.  Perhaps it
>> is reasonable to think of it's structure as being like an n-dimensional
>> lattice for a very large n.  (You mention "10**5 to 10**6 processes in
>> parallel" in a single cell and 10**13 cells that could affect the launching
>> of processes in any of the other 10**13 cells.)  While this is certainly a
>> large number of processes to model, the picture is not so difficult to
>> visualize.
>
>My intuition may be all wet here, but my gut feeling is that you could
>model the system this way, but that you would find the state space for the
>system to be so huge that it would not be computable within the expected
>lifespan of the universe (like the protein folding problem, only lots
>tougher).  However, proteins fold and critters develop within real time,
>so there is clearly some kind of heuristic going on that these exhaustive
>models don't quite capture.
>
>If this sounds like I missed your point, maybe I did.  If so, reword and
>retransmit... 

I think I was just too vague.  The picture I drew is a representation of the processes themselves - all happening in parallel with some degree of interaction between some of the processes.  I don't think the state space of this system would ever have to be computed.  Maybe I missed your point.  

I want to represent the relation between the processes.  They would have some string of DNA associated with them, but few would have connections with more than one or two other processes.  The average process might be only 4 or 5 steps long and take place in a fraction of a second - i.e. some kind of protein synthesis.  10**6 of these would be happening more or less independently at every moment.  

There would be heirarchies of regulatory processes nested within the large scale control processes of the cell or organism.  So between birth and death there are nested processes for all levels of development and all types of routine function.  The regulatory feed back would say "start", "stop" or "keep it going" in a fuzzy way.

>> One of my respondents, Patrick O'Neil (U. of Utah Computer Center) wrote:
>> >You would also have to come up with a computer program terms like, "sort
>> >of" and "sometimes" and "a little bit."  Not all genes act in an either
>> >on or off configuration.  Dosage affects, epigenetic affects, etc, muddy
>> the water a bit.  Some genes can be a little bit on meaning that
>> >sometimes a full gene product is produced, but other times an abortive
>> >product is produced; or the gene might be on at a low level which differs
>> >in different circumstances with the same signals floating about in the cell.

>This is what I meant by probabilistic op codes...

Yes, of course he's right.  Perhaps the lines should have probabilities written on them so that a particular pathway is 50% probable or 20% or whatever rather than a solid line.

>
>> 
>> David Baillie wrote:
>> > I think that the logical equivalent of the transcriptional signals in the
>> >>front of a gene can be modelled as a set of and, or, not statements for
>> >>deciding when the gene is used.  I suppose this is a just an extention of
>> >your arguement.
>
>And this is what I meant when I said that the probabilistic op codes
>extended to the associative START READ HERE signals...

Right.

So maybe a process looks more like:

        | 50%
        | 
        /\
   40% /  \ 60%

With a gene at the top that starts a process 50% of the time which has two outcomes that it generates 40% and 60% of the time respectively - maybe one of the outcomes is an aborted synthesis.  


Date: Sat, 15 Apr 1995 22:45:54 -0400 (EDT)
From: Robert Robbins <rrobbins at gdb.org>
Subject: Re: Parallel processes in Genes
To: Gary Welz <gwelz at setn.org>

On Sat, 15 Apr 1995, Gary Welz wrote:

> I think I was just too vague.  The picture I drew is a representation of
> the processes themselves - all happening in parallel with some degree of
> interaction between some of the processes.  I don't think the state space
> of this system would ever have to be computed.  Maybe I missed your point.

This is no doubt the kind of conversation best done live, with lots of
agitated interrupting and hollerings of "right, but..."


> Yes, of course he's right.  Perhaps the lines should have probabilities
> written on them so that a particular pathway is 50% probable or 20% or
> whatever rather than a solid line.

Yeah, some kind of weighted cyclic graph structure of fair global
complexity, but not that improbable locally...


To: Robert Robbins <rrobbins at gdb.org>
From: gwelz at holonet.net (Gary Welz)
Subject: Re: Parallel processes in Genes

On Sat, 15 Apr 1885 Robert Robbins wrote:
>On Sat, 15 Apr 1995, Gary Welz wrote:
>
>> I think I was just too vague.  The picture I drew is a representation of
>> the processes themselves - all happening in parallel with some degree of
>> interaction between some of the processes.  I don't think the state space
>> of this system would ever have to be computed.  Maybe I missed your point.
>
>This is no doubt the kind of conversation best done live, with lots of
>agitated interrupting and hollerings of "right, but..."

Yes.  What I'm trying to get at is a way to represent the overall structure of the relationship between the genes and the processes they control.  The key thing is that it should depict related serial and parallel processes.  Collections of these processes would be nested within other processes and the heirarchy of processes should extend from the developmental level to the elementary function level - from birth and death to eating and breathing. 

The next step should be to try to put pieces of the puzzle together - i.e. represent some well understood processes in this way and suggest how they might fit into a bigger picture.  

>> Yes, of course he's right.  Perhaps the lines should have probabilities
>> written on them so that a particular pathway is 50% probable or 20% or
>> whatever rather than a solid line.
>
>Yeah, some kind of weighted cyclic graph structure of fair global
>complexity, but not that improbable locally...

Right.  On the local scale, the program should resemble something like the program on the chips that control the workings of fancy Japanese cars.   You know, the ones  with fuzzy logic that control the internal temperature, the fuel mixture and the speed of the windshield wipers.

On the large scale, it's like the program that controls the workings of a whole factory - constantly monitoring local processes and seeking to bring about large scale objectives through a variety of alternative means - i.e. a large scale optimizer rather than a regulator - ready to shut a perfectly functioning process down in order to optimize the chances for survival e.g. stop digesting and run.

end of Part I


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Date: 15 Apr 1995 19:35:42 GMT
From: "G. Dellaire" <popa0206 at po-box.mcgill.ca>
To: biochrom at net.bio.net
Subject: Re: Is the genome like a computer program?

In article <Pine.3.07.9504140953.B28952-e100000 at dev.gdb.org>,
   rrobbins at GDB.ORG (Robert Robbins) wrote:

>
>Taken all together then, the expression of the human genome involves the
>simultaneous expression and (potential) interaction of something probably
>in excess of 10**18 parallel processes.  

Just curious, but how do you account then for the fact of imprinting and 
silencing of those parallel sets of instructions (i.e. alleles) such that 
you only actually have one "program" running.  This would bring to light
the idea of gene dosage, and what analog in informatics would pertain to 
such a mechanism?

>There is an entire body of literature that treats the linguistic
>properties of DNA.  If you are really interested, you should read a lot of
>it before jumping to quick interpretations.  However, you should also bear
>in mind that DNA involves the coding of a "language" on a mass-storage
>device, it is not the direct expression of a language.

On this point, it is becoming widely accepted that the actual structure of
genome and not just the linear sequence may "encode" sets of instructions
for the "reading and accessing" of this genetic code. Best illustrated
by large changes in genomic structure that affects the accessiblity of 
of various regions of the genome to be  "read" during development at specific
times and silenced afterwards.

Therefore, a second level of language is the overall code itself.  Sort of 
like the letters make up words (commands for the program), and different 
gene are like sentences... thus context is important for understanding the
code.  The context is provided by the supporting paragraphs which could represent
genetic domains with in the genome (context can be spatial, what tissue;
or temporal, what time of development).  And the overall story provides an 
impression and message in itself.
 

G. Dellaire
Exp. Medicine Mcgill
Red Cross Montreal
E-mail popa0206 at po-box.mcgill.ca
  

Date: Sat, 15 Apr 1995 17:33:25 -0400 (EDT)
From: Robert Robbins <rrobbins at gdb.org>
To: "G. Dellaire" <popa0206 at po-box.mcgill.ca>
Cc: biochrom at net.bio.net, Robert Robbins <rrobbins at dev.gdb.org>
Subject: Re: Is the genome like a computer program?


On 15 Apr 1995, G. Dellaire wrote:

> In article <Pine.3.07.9504140953.B28952-e100000 at dev.gdb.org>,
>    rrobbins at GDB.ORG (Robert Robbins) wrote:
> 
> >Taken all together then, the expression of the human genome involves the
> >simultaneous expression and (potential) interaction of something probably
> >in excess of 10**18 parallel processes.  
> 
> Just curious, but how do you account then for the fact of imprinting and 
> silencing of those parallel sets of instructions (i.e. alleles) such that 
> you only actually have one "program" running.  This would bring to light
> the idea of gene dosage, and what analog in informatics would pertain to 
> such a mechanism?

Note that I was referring to "processes", not to programs.  One program
on disk can result in many simultaneous processes being launched on a
parallel machine.  Indeed, I would consider each mRNA to be a process, and
each active enzyme also a process.

With regard to the selective silencing of some copies of some programs,
whether because of imprinting, or dosage compensation, or differentiation,
or some other cause, these could be interpreted simply as examples
of the behavior of the 10**13 virtual machines (i.e., cells) in which the
programs on "disk" are being executed.


> On this point, it is becoming widely accepted that the actual structure of
> genome and not just the linear sequence may "encode" sets of instructions
> for the "reading and accessing" of this genetic code. Best illustrated
> by large changes in genomic structure that affects the accessiblity of 
> of various regions of the genome to be  "read" during development at specific
> times and silenced afterwards.
> 
> Therefore, a second level of language is the overall code itself.  Sort of 
> like the letters make up words (commands for the program), and different 
> gene are like sentences... thus context is important for understanding the
> code.  The context is provided by the supporting paragraphs which could 
> represent genetic domains with in the genome (context can be spatial, what
> tissue; or temporal, what time of development).  And the overall story 
> provides an impression and message in itself.

This is a good point and demonstrates the multiple levels of subtlety and
conflation that must be taken into acciunt when trying to do linguisitic
analysis of DNA sequences.  The storage medium, DNA, has local chemical
and mechanical properties that are affected by the information encoded in
those local regions (melting points, etc.).  


From: Tengleong.Chew at lambada.oit.unc.edu
Date: Sun, 23 Apr 1995 22:45:46 -0400
To: gwelz at panix.com
Subject: Re: Can a genome be analyzed like a computer program?

In article <3mka58$e2i at cmcl2.nyu.edu> you write:
>
>I'm writing an article about the large scale structure of the genome.  
>Does anyone besides me think that an organism's genome can be regarded 
>as a computer program?  I mean that its structure can be presented as a 
>flowchart with genes as objects connected by logical terms like "and" 
>and "or" and, of course, "while" loops?  

        It is not so much of computer program than it is of a circuit
board. A given gene is a function to be turned on or off by a switch
upstream of it in the genome. If the switch is turned on by some
mechanism, the gene is transcribed into messenger RNA, which then leaves
the nucleus and enter the cytoplasm of a cell where it is translated into
proteins that carry out the "real" biological functions.

>One development that might support this point of view is the recent 
>demonstration (reported in last week's Science) that the eyeless gene 
>can be inserted into various parts of the chromosome of a fly and cause 
>it to have eyes grow on different parts of its body.  Is eyeless a free 
>standing genetic object that can be plugged into any syntactically 
>correct sequence and function as though it belonged there naturally?

        All genes are free standing objects. That's the property exploited
by recombinant DNA technology in which genes from organism A are inserted
into organism B and be expressed under the control of the genetic switch
of organism B. 

        More examples come from the field of oncology. Oncogenes, for
instance, are cellular genes that encode extremely important regulatory
proteins which governs cell growth. When a person is infected by
retroviruses, there is a chance, albeit slim, that the retrovirus somehow
picks up the human gene and inserts it somewhere else in the body. In
doing so, places the gene under the control of a wrong switch and thus
screw up the expression of the regulatory gene, ultimately giving rise to
cancer.

        BTW, Barbara McClintock won a Nobel Prize for her discovery of
"Jumping Gene" or in correct term, Transposons. Transposons are genes that
have the capability to excise themselves out of one region of the genome
and insert themselves back in some other places. 

>Gene Stanley and others at Boston U. and Harvard Medical School have 
>done statistical analyses of non-coding DNA sequences (published in 
>Physical Review Letters a few months ago) that suggest that there may be 
>linguistic structures, i.e. words within them.  Are some of these 
>non-coding sequences the terms of the genetic programming language?

        Yes. The mentioned non-coding DNA sequences are called "junk DNA"
in biomedical field. However, they are not really junk. 

        They are beginning to get a lot of attention from scientists. Many
of these junk DNA are important regulatory elements which not only
dictates the turning on/off of a given gene, but also governs the turnover
(degradation) rate of a piece of RNA, especially those RNAs that code for
critical biological molecules whose level has to be fine-tuned precisely. 
Recently, Helen Blau at Stanford showed for the first time that one of these
"junk sequences" is actually a tumor suppressor (the 3' untranslated region
of tropomyosin mRNA). So junk is actually treasure. 

>If this is interesting to you, or if you think its bogus, let me know.

        This is no way bogus. There are potential Nobel Prizes hidden in
this field. 

 - T. L. Chew

Molecular Pathology,
St. Louis University Health Science Center


Postscript, Gary Welz, April 30, 1995.  A picture is beginning to emerge of the genome initiating and controlling a huge number of probabilistic processes, running in parallel with many having effects upon others.  I want next to examine a process or two that might fit into this large scale scheme and see how well it fits the model.  I might consider the process engendered by the eyeless gene of the fruitfly.  I would put the gene itself at the top of the diagram and two or more eyes it encodes at the bottom.  I would want to see what processes contribute to the growing of eyes and what genomic structures - such as the central nervous system are tied into it.  

Readers, your comments and suggestions are welcome.

regards,
Gary Welz
gwelz at holonet.net   


equired to understand the workings of, say, an Intel Paragon or a 
Cray-4.

At the same time, I think that bringing computer-science insights to bear 
on the challenge of understanding genome operation has some potentially 
huge payoffs.  For example, it would be really interesting to think about 
the file-allocation-table system for a mass storage device   |
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Date: Sun, 30 Apr 1995 20:08:49 -0400
Subject: Re: Dialogue re Genome Program
To: gwelz at setn.org (Gary Welz)
X-Mailer: AIR Mail 3.X (SPRY, Inc.)

Dear Gary,

I have no objections at all with your use of my comments.

I Regret that I do not have a copy of the comments you mentioned
it seems that recently I had cleaned out my E-mail and they have
been erased.  As well, "Mr." is more appropriate as I have not
completed my PhD. (but if you require some letters you can use
BSc. Hon. Biochem after my name <g>).

As well some comments on the text you sent me

>> One of my respondents, Patrick O'Neil (U. of Utah Computer Center) wrote:
>> >You would also have to come up with a computer program terms like, "sort
>> >of" and "sometimes" and "a little bit."  Not all genes act in an either
>> >on or off configuration.  Dosage affects, epigenetic affects, etc, muddy
>> the water a bit.  Some genes can be a little bit on meaning that
>> >sometimes a full gene product is produced, but other times an abortive
>> >product is produced; or the gene might be on at a low level which differs
>> >in different circumstances with the same signals floating about in the cell.

>This is what I meant by probabilistic op codes...

-Yes, of course he's right.  Perhaps the lines should have probabilities
-written on them so that a particular pathway is 50% probable or 20% or
-whatever rather than a solid line.

It is not so much a probability on the expression it has a developmental and 
temporal quality to it.  At certain times the level of expression of a gene 
may increase, but what may be hard to model is that there is more than one 
way to increase the product (ex. protein) in the cell.  You can alter the 
expression as discussed at infinitum, but also the translation
of the mRNA to protein and as well an alteration in the half life of the 
protein... the later two processes are independent of the expression and 
therefore are independent of the decision to "turn" on that gene.  The 
protein as well may not have a direct function in the "program" but may
contribute to the execution of tasks that are already queued by expression 
of some other gene(s).  

For example you have a gene that only functions when it is phophorylated by 
another protein (acting as a kinase), so the command to produce the protein
may occur well before the decision to execute the "programmed" function
of that gene product... as well of course that same protein may have 
several levels of interaction as both effector and inhibitor of many
processes (programs) within the cell.  Think of the a given process in a
cell as a culmination of a hierachy of decisions (switches perhaps) and 
these hierarchies overlap... components from one may have roles in other 
processes.


From: Tengleong.Chew at lambada.oit.unc.edu

>        All genes are free standing objects. That's the property exploited
>by recombinant DNA technology in which genes from organism A are inserted
>into organism B and be expressed under the control of the genetic switch
>of organism B.

Interestingly... there are also uncloneable genes or regions that require
the instructions from the host system to express (i.e. on a simple level  
the promoters, enhancers etc.  but may involve vast regions of DNA on the 
order of 10,000- 100,000 bases... which is beyond the capacity of cloning 
in anything other than yeast using artificial chromosomes).  As well,
there are regions of the human genome which can not even be cloned into
YAC's as they carry some inherent property that prevents this either by
killing the yeast host or by being very unstable (i.e. will not remain 
within the artificial chromosome intact).  So genes are not so cut and paste 
<g> in there properties.  The context of a gene (i.e. the surrounding
sequences) therefore is very important... and may actually contain the
instructions for accessing the region at the proper time or in response to
regulated signals.  The analogy would be for instance if you were the "house 
painter gene," your ability to paint the house would not be obviously 
exploited if you had not built the house yet... thus genes
without proper context placed haphazardly in the genome may not carry
out functions that they have been ascribed to them through evolution of that 
organism. 
        Finally if a gene is incorporated in a region that is permanently
turned "off" (i.e. heterochromatin) such as regions near the centromere
and telomere of chromosomes you may get no expression at all.  


>        More examples come from the field of oncology. Oncogenes, for
>instance, are cellular genes that encode extremely important regulatory
>proteins which governs cell growth. When a person is infected by
>retroviruses, there is a chance, albeit slim, that the retrovirus somehow
>picks up the human gene and inserts it somewhere else in the body. In
>doing so, places the gene under the control of a wrong switch and thus
>screw up the expression of the regulatory gene, ultimately giving rise to
>cancer.

You also can have similar results if the retro viral genome integrates
into a region near a proto-oncogene.  The retro virus genome contains
a constitutive promoter (switch continually in the on position) that
can confer habitual expression of the proto-oncogene and cause 
transformation of that cell, resulting in a tumor
 
Seeya

Graham Dellaire

g a huge numberext to examine a number of processes, please send me suggestions of ones that could be put into this type of schematic analysis.
gwelz at panix.com

More to come.

Gary Welz

.  P  robbins at er.doe.gov
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