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README.md

@@ -168,6 +168,18 @@ This represents the most comprehensive bacterial cellular process collection eve
 
 This article serves as an accessible introduction to the Programming Framework methodology, bridging the gap between technical research and public understanding of computational biology.
 
+## 🏛️ Historical Foundation
+
+### **📜 [Gary Welz's Original 1995 Article: "Is a Genome Like a Computer Program?"](welz.genome0.shtml)**
+**HISTORICAL DOCUMENT** - The original 1995 article that first proposed the genome-as-computer-program metaphor. This foundational work from *The X Advisor* (July 1995) represents one of the earliest attempts to bridge computer science and molecular biology, featuring:
+- **Original 1995 Text** - Authentic historical document preserved from the Wayback Machine
+- **Beta-Galactosidase Flowchart** - First computational model of genetic regulation (lac operon)
+- **Interdisciplinary Dialogue** - Early discussion between computer scientists and biologists
+- **"Light's Better Syndrome"** - Insight about research funding priorities still relevant today
+- **Historical Context** - Published during early Human Genome Project, before systems biology emerged
+
+This article provides the historical foundation for modern computational biology and demonstrates how early interdisciplinary thinking led to significant advances in multiple fields.
+
 ## 🚀 Research Highlights
 
 ### **Programming Framework Implementation**

README_welz_1995.md

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+# Gary Welz's "Is a Genome Like a Computer Program?" (1995)
+
+## Historical Significance
+
+This dataset contains Gary Welz's groundbreaking 1995 article "Is a Genome Like a Computer Program?" originally published in *The X Advisor* (July 1995, Vol 1 No 2). This work represents one of the earliest attempts to bridge computer science and molecular biology, proposing that genomes could be understood and modeled as computer programs.
+
+## Key Contributions
+
+### 1. **Early Systems Biology Thinking**
+Welz proposed that computer scientists and biologists should collaborate to describe genomic processes as parts of a large computer program, using flowcharts with genes as objects connected by logical operators like "and," "or," and "while" loops.
+
+### 2. **Beta-Galactosidase Flowchart**
+The article includes one of the first attempts to represent a genetic regulatory network (the lac operon in E. coli) as a programming flowchart, demonstrating how complex biological processes could be modeled computationally.
+
+### 3. **Interdisciplinary Dialogue**
+The work sparked a lively discussion in the bionet.genome.chromosome and bionet.general newsgroups, involving prominent researchers like Robert Robbins (DOE Genome Database Project), G. Dellaire (McGill), and others.
+
+## Modern Relevance
+
+### Connection to Current Research
+This 1995 work directly foreshadows modern approaches in:
+- **Systems Biology**: Understanding biological systems as integrated networks
+- **Computational Biology**: Using programming concepts to model biological processes
+- **Synthetic Biology**: Engineering biological systems using programming principles
+- **Bioinformatics**: Analyzing genomic data with computational tools
+
+### The "Light's Better Syndrome"
+Welz identified a critical challenge in scientific research: the tendency to focus on easily answerable questions rather than tackling fundamental, long-term problems. This insight remains relevant today in discussions about research funding and scientific priorities.
+
+## Dataset Contents
+
+### Files
+- `welz_1995_genome_programming.html` - Clean, modern HTML version of the original article
+- `b-galchart2.gif` - Original 1995 flowchart from the article
+- `welz.genome0.shtml` - Original archived HTML from Wayback Machine (March 10, 1997)
+
+### Key Sections
+1. **Introduction**: The genome as computer program metaphor
+2. **Historical Context**: The 1995 online discussion
+3. **Beta-Galactosidase Flowchart**: First computational model of genetic regulation
+4. **The Challenge**: Call for interdisciplinary collaboration
+5. **Scientific Context**: References to Berg & Singer's "Dealing With Genes"
+
+## Impact and Legacy
+
+### Immediate Impact
+- Stimulated discussion between computer scientists and biologists
+- Introduced programming concepts to molecular biology community
+- Demonstrated potential for computational modeling of biological systems
+
+### Long-term Influence
+- **Precursor to Systems Biology**: The article's approach foreshadowed the emergence of systems biology as a field
+- **Computational Biology**: Helped establish the foundation for computational approaches to biology
+- **Interdisciplinary Research**: Demonstrated the value of cross-disciplinary collaboration
+
+### Modern Applications
+The concepts introduced in this article have evolved into:
+- **Gene Regulatory Networks**: Computational models of gene interactions
+- **Metabolic Pathway Modeling**: Software tools for analyzing biochemical pathways
+- **Synthetic Biology**: Programming languages for biological systems
+- **Machine Learning in Biology**: AI approaches to understanding genomic data
+
+## Technical Details
+
+### Original Publication
+- **Journal**: The X Advisor
+- **Date**: July 1995
+- **Volume**: Vol 1 No 2
+- **Author**: Gary Welz
+- **Copyright**: © 1995-96 Gary Welz, All Rights Reserved
+
+### Archive Information
+- **Source**: Wayback Machine
+- **Archive Date**: March 10, 1997
+- **Original URL**: http://landru.unx.com/DD/advisor/docs/jul95/welz.genome0.shtml
+
+## Usage Guidelines
+
+### Educational Use
+This dataset is valuable for:
+- **History of Science**: Understanding the evolution of computational biology
+- **Interdisciplinary Education**: Teaching the intersection of computer science and biology
+- **Research Methodology**: Demonstrating the importance of cross-disciplinary thinking
+
+### Research Applications
+- **Literature Review**: Historical context for modern systems biology
+- **Teaching Material**: Example of early computational biology thinking
+- **Citation**: Reference for historical development of the field
+
+## Related Work
+
+### Contemporary Context (1995)
+- Human Genome Project was in early stages
+- Internet was emerging as a research tool
+- Bioinformatics was in its infancy
+- Systems biology had not yet emerged as a formal discipline
+
+### Modern Connections
+- **Current Frameworks**: Modern biological programming languages and tools
+- **Systems Biology**: Established field building on these early ideas
+- **Synthetic Biology**: Engineering biological systems using programming principles
+- **Computational Biology**: Mature field with sophisticated modeling tools
+
+## Citation
+
+When using this dataset, please cite:
+
+```
+Welz, G. (1995). Is a Genome Like a Computer Program? The X Advisor, 1(2), July 1995.
+```
+
+## License
+
+This dataset contains copyrighted material used with permission. The original article is © 1995-96 Gary Welz, All Rights Reserved. Used With Permission.
+
+## Contact
+
+For questions about this dataset or the original work, please refer to the original author's contact information in the article.
+
+---
+
+*This dataset preserves an important piece of scientific history and demonstrates how early interdisciplinary thinking can lead to significant advances in multiple fields.*

welz.genome0.shtml

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+<center>
+<h2>COMING SOON</h2>
+
+<h2>THE DISCOVERY JOURNAL OF COMPUTING</h2>
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+
+<!-- line 2 -->
+<a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/cgi-bin/loghit?type=logo&amp;log=cline.lg&amp;sponsor=cline&amp;url=http://www.centerline.com" target="_top"> <img width="100" height="34" src="./welz.genome0_files/clinelogo.gif" border="none" alt="[CENTERLINE]"></a>
+
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+
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+
+<!-- line 3 -->
+<a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/cgi-bin/loghit?type=logo&amp;log=discovery.lg&amp;sponsor=discovery&amp;url=http://www.unx.com/DD/advertisers/discovery/javatrain.shtml" target="_top"> <img width="100" height="34" src="./welz.genome0_files/javatrn.gif" border="none" alt="[Java Training]"></a>
+<hr>
+</center>
+
+<h1>Peripheral Visions</h1>
+
+
+<img src="./welz.genome0_files/welz.gene.gif"><p>
+</p><h2>Is a Genome Like a Computer Program?</h2>
+
+<h3><em>by <a href="https://web.archive.org/web/19970310064130/http://found.cs.nyu.edu/found.a/CAT/misc/welz/">Gary Welz</a></em></h3>
+<h5>Copyright � 1995-96 Gary Welz, All Rights Reserved. Used With Permission.</h5>
+
+<center>
+<h4><pre><hr size="5">The X Advisor: <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/v1n2TOC.shtml">July 1995 - Vol 1 No 2.</a> <i> http://www.unx.com/DD/advisor/</i><p>
+</p><h5><a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/docs/whoarewe.shtml">DISCOVERY PUBLISHING GROUP</a><hr></h5></pre></h4>
+</center>
+
+
+
+An organism's genome is its set of chromosomes, its complete set of genetic
+information.   Many have compared the genome to a massive database - as a
+blueprint for every protein and organ in the organism.   Certainly it is an
+extraordinary storage device.  But can the computer analogy be taken
+further?  Can the genome be thought of as a program that controls the
+moment to moment functioning of the organism.  Can it be viewed as
+a "self-installing and self-launching application" that enables an organism 
+to develop or "build" itself?<p>
+
+In order to make this metaphor concrete, I propose that computer scientists
+and biologists begin attempting to describe the processes that the genome
+participates in as though they were parts of a large computer program.
+Specifically, create flowcharts with genes as objects connected by logical
+terms like "and" and "or" and, of course, "while" loops?</p><p>
+
+Schematic representation of genetic processes has a long history.  The 
+"Central Dogma" of genetics, as Francis Crick once glibly called it, is
+represented by:</p><p>
+
+</p><h3>DNA --&gt; RNA --&gt; Proteins</h3>
+
+This expresses the sequence of processes: <p>
+"DNA is transcribed by RNA and RNA is the template upon which proteins are 
+constructed."</p><p>
+
+We can begin to approximate it with the chart</p><p>
+
+</p><pre><h3>DNA --&gt; primary transcript --&gt; messenger RNA 
+
+--&gt;primary polypetide --&gt; processed polypeptide 
+
+--&gt;final protein --&gt; does stuff </h3>
+</pre>
+
+With each item in the sequence gives feedback to all the ealier items and DNA 
+even gives feedback to itself.<p>
+
+
+This past Spring I posted a note to the bionet.genome.chromosome and bionet.general 
+discussion groups concerning the question of whether a genome can be regarded as 
+a computer program and quite a lively discussion ensued that I want to make available
+to a larger audience.  Excerpts of the discussion are linked to my synopsis of it
+below.</p><p>
+
+It began with <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome1.shtml">my original posting</a> on April 13, 1995
+which was followed by a reply by a very thoughtful and detailed reply from
+<a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome2.shtml">Robert Robbins</a> of the US Dept. of Energy Genome 
+Database Project.  Robbins is a biologist with a serious interest in having
+computer scientists consider my questions.  He was encouraging while politely
+pointing out the naive errors in my thinking.</p><p>
+
+Robbins himself then heard from <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome3.shtml">G. Dellaire of McGill</a>
+who raised some interesting points of his own.  <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome4.shtml">Robbins 
+replied</a> in detail to Dellaire's comments.</p><p>
+
+David Baillie from the Institute of Mol. Biol. Biochem. at Simon Fraser University 
+in Burnaby, Canada, Vahe Bedian from the Univ. of Pennsylvania and Paul O'Neill 
+from the Univ. of Utah Computer Center offered some <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome5.shtml"> short 
+but useful comments</a>.</p><p>
+
+<a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome6.shtml">Tengleong Chew from the St. Louis University Medical 
+Center</a> replied in detail to my posting and closed with the tantalizing
+remark that "There are potential Nobel Prizes hidden in this field."</p><p>
+
+I sent a few people the collected comments and <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome7.shtml">G. Dellaire 
+replied</a> with some detail remarks on the comments of others.</p><p>
+
+Next, I posted my first attempt to create <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome8.shtml">a flow chart of a 
+genetic process</a>, the process of b-galactosidase, the gene that produces an enzyme 
+used for the digestion of lactose sugar in the bacterium e.coli. The gene is activated 
+if glucose is not present and lactose is.</p><p>
+
+The chart seemed fairly simple, but Keith Robison of Harvard pointed out that the 
+processes of detecting the presence of glucose and lactose took place in parallel, 
+not in a linear order as my chart implied.</p><p>
+
+ <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome9.shtml">I responded to Robison</a> saying basically that this type 
+ of discussion was precisely what I hoped would result from my posting.  This was not,
+ after all, an obvious fact to a naive non-molecular biologist. 
+ </p><p>
+ 
+ <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome10.shtml">Vahe Bedian</a> commented more enthusiatically on the 
+ rough chart and Robison's remarks.</p><p>
+ 
+<a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome11.shtml">Guy Tantenzopf suggested</a> a few candidate organisms for 
+this type of analysis.  Ron Sapolsky gave <a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome12.shtml">references to two 
+papers by P.D. Karp</a> that deal with some of the same questions that I had raised.
+</p><p>
+
+This discussion has been very enriching.  First because of the intelligence
+and generousity of the electronic acqaintances I have made in the international 
+molecular biology community but also because it has made me realize that there
+is a place - perhaps even a need - for naive computer science thinking in the 
+world of molecular genetics.</p><p>
+
+
+As a sample of the kind of chart I have in mind, below is a flow chart 
+for the expression of the beta-galactosidase gene in E. coli.  This is 
+obviously a well known process, though perhaps not previously 
+represented in this kind of programming schematic.  </p><p>
+
+[added to The X Advisor article:  In "Dealing With Genes" by Paul Berg and Maxine Singer, University Science Books, 1992, pp 71-73, the process is described as follows:</p><p>
+
+</p><blockquote>The <i>E. coli</i> enzyme beta-galactosidase breaks down lactose (milk sugar) into two simpler
+sugars, glucose and galactose.  If <i>E. coli</i> is grown in the presence of glucose, its preferred nutrient, it does not synthesize beta-galactosidase; but the enzyme is produced if lactose is the only sugar available.  Several DNA sequences that preced the 5' end of the beta-galactosidase coding region on <i>E. coli</i> DNA serve to regulate transcription.   The RNA polymerase enzyme that will transcribe the gene binds to one, the <b>promoter</b>.  A second sequence, the <b>operator</b>, lies between the promoter and the start of the beta-galactosidase coding sequence.  The operator interacts with another protein, the <b>repressor</b>.  Binding of the repressor to the operator prevents RNA polymerase from initiating transcription.  
+</blockquote>
+<p>
+
+</p><blockquote>
+If lactose is supplied to the E. Coli, the sugar binds to the repressor protein, thereby altering the repressor's shape and preventing it from binding to the DNA.  This loss of operator-binding activity now allows (1) the RNA polymerase to transcribe the gene into mRNA, [messenger RNA], (2) the beta-galactosidase to be synthesized, and (3) lactose to be utilized as an energy source for growth...
+</blockquote>
+
+<blockquote>Besides the negative control provided by the repressor-operator interactions, beta-galactosides is also under positive control.  Thus, transcription of the beta-galactosidase gene can start only if a specific activator is present.  The activator is also a protein that functions only when it is joined with a special small molecule.  The special small molecule appears in the cell when there is no glucose available to the bacterium.   In a sense, the small molecule is a starvation signal...
+</blockquote>
+
+
+Here is my latest attempt to represent this graphically:<p>
+
+Flow Chart of the process of beta-galactosidase 
+gene expresssion in E. coli</p><p>
+
+</p><center>
+<hr>
+<img src="b-galchart2.gif">
+<hr>
+</center>
+
+(BTW, this chart was made using a program called "Inspiration" - normally used as 
+a business tool, but one that I think may be very helpful for biologists and 
+computer scientists alike.)<p>
+
+</p><h3>Our Challenge</h3>
+
+The entire genome of a the bacterium Hemophilus enfluenzae has recently been
+mapped at Dr. J. Craig Venter's <a href="https://web.archive.org/web/19970310064130/http://www.tigr.org/">Institute for
+Genomic Research</a> and the entire human genome is likely to be mapped
+within a decade.  Yet we still know relatively little about the big picture, i.e. 
+how the genome works as whole, what the relationships are between processes 
+and how these relationships are controlled.<p>  
+
+I put this challenge to molecular biologists and computer scientists:  Work 
+together to describe the processes taking place in the genome.  Robert Robbins 
+once said to me that he suspected the reason few scientists had seriously looked
+at the question of the large scale functional structure of the genome was the
+"the light's better syndrome" now prevalent in science.  This refers to the story
+of the man who was searching for something small and difficult to see - say a contact 
+lense - and proceeded to look for it in a well-lighted area even though he'd lost
+it somewhere else.  When his friend asked why he was looking there, he said
+"because the light's better over here."</p><p>  
+
+In science, we tend to ask questions for which the answers seem readily obtainable 
+on a schedule of six months to a year - at least no longer than the grant cycle.  
+This means that we tend to obtain the answers to questions in well lighted areas and 
+seldom risk asking those questions for which clear answers or measurable progress 
+is likely to take decades if not lifetimes of research and thought.  But this must 
+not deter us.  The functioning of the genome is the greatest challenge of biology 
+and one of the greatest challenges of all science.  Let us not be too timid to ask 
+the big questions and posit theories that we know will inevitably be found 
+insufficient and flawed.  We must be brave enough to stumble forward into the darkness - 
+so that we can find the answers to most compelling and important questions before us.
+</p><p>
+
+<a href="https://web.archive.org/web/19970310064130/http://landru.unx.com/DD/advisor/docs/jul95/welz.genome13.shtml">Appendix of Genome Related sites</a></p><p>
+
+
+</p><hr size="3" width="30%">
+<h4>
+<em>
+<a href="https://web.archive.org/web/19970310064130/http://found.cs.nyu.edu/found.a/CAT/misc/welz/">Gary Welz </a>
+is a New York City based journalist, consultant and WWW designer.
+He's currently writing a book about online multimedia and can 
+be reached via email at <a href="https://web.archive.org/web/19970310064130/MAILTO:gwelz@scitv.com">gwelz@scitv.com,</a> 
+or come visit his home page at <a href="https://web.archive.org/web/19970310064130/http://found.cs.nyu.edu/found.a/CAT/misc/welz/">
+http://found.cs.nyu.edu/found.a/CAT/misc/welz/</a>
+</em>
+</h4>
+
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+    <title>Is a Genome Like a Computer Program? - Gary Welz (1995)</title>
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+    <div class="container">
+        <div class="metadata">
+            <strong>Original Publication:</strong> The X Advisor, July 1995 - Vol 1 No 2<br>
+            <strong>Author:</strong> Gary Welz<br>
+            <strong>Copyright:</strong> © 1995-96 Gary Welz, All Rights Reserved. Used With Permission.<br>
+            <strong>Archived:</strong> Wayback Machine, March 10, 1997
+        </div>
+
+        <h1>Peripheral Visions: Is a Genome Like a Computer Program?</h1>
+        
+        <div class="author">
+            <h3>by Gary Welz</h3>
+        </div>
+
+        <p>An organism's genome is its set of chromosomes, its complete set of genetic information. Many have compared the genome to a massive database - as a blueprint for every protein and organ in the organism. Certainly it is an extraordinary storage device. But can the computer analogy be taken further? Can the genome be thought of as a program that controls the moment to moment functioning of the organism? Can it be viewed as a "self-installing and self-launching application" that enables an organism to develop or "build" itself?</p>
+
+        <p>In order to make this metaphor concrete, I propose that computer scientists and biologists begin attempting to describe the processes that the genome participates in as though they were parts of a large computer program. Specifically, create flowcharts with genes as objects connected by logical terms like "and" and "or" and, of course, "while" loops.</p>
+
+        <p>Schematic representation of genetic processes has a long history. The "Central Dogma" of genetics, as Francis Crick once glibly called it, is represented by:</p>
+
+        <h3>DNA → RNA → Proteins</h3>
+
+        <p>This expresses the sequence of processes: "DNA is transcribed by RNA and RNA is the template upon which proteins are constructed."</p>
+
+        <p>We can begin to approximate it with the chart:</p>
+
+        <pre><h3>DNA → primary transcript → messenger RNA 
+→ primary polypeptide → processed polypeptide 
+→ final protein → does stuff</h3></pre>
+
+        <p>With each item in the sequence gives feedback to all the earlier items and DNA even gives feedback to itself.</p>
+
+        <div class="highlight">
+            <h3>Historical Context</h3>
+            <p>This past Spring I posted a note to the bionet.genome.chromosome and bionet.general discussion groups concerning the question of whether a genome can be regarded as a computer program and quite a lively discussion ensued that I want to make available to a larger audience.</p>
+        </div>
+
+        <p>It began with my original posting on April 13, 1995 which was followed by a very thoughtful and detailed reply from Robert Robbins of the US Dept. of Energy Genome Database Project. Robbins is a biologist with a serious interest in having computer scientists consider my questions. He was encouraging while politely pointing out the naive errors in my thinking.</p>
+
+        <p>Robbins himself then heard from G. Dellaire of McGill who raised some interesting points of his own. Robbins replied in detail to Dellaire's comments.</p>
+
+        <p>David Baillie from the Institute of Mol. Biol. Biochem. at Simon Fraser University in Burnaby, Canada, Vahe Bedian from the Univ. of Pennsylvania and Paul O'Neill from the Univ. of Utah Computer Center offered some short but useful comments.</p>
+
+        <p>Tengleong Chew from the St. Louis University Medical Center replied in detail to my posting and closed with the tantalizing remark that "There are potential Nobel Prizes hidden in this field."</p>
+
+        <p>I sent a few people the collected comments and G. Dellaire replied with some detailed remarks on the comments of others.</p>
+
+        <p>Next, I posted my first attempt to create a flow chart of a genetic process, the process of β-galactosidase, the gene that produces an enzyme used for the digestion of lactose sugar in the bacterium E. coli. The gene is activated if glucose is not present and lactose is.</p>
+
+        <p>The chart seemed fairly simple, but Keith Robison of Harvard pointed out that the processes of detecting the presence of glucose and lactose took place in parallel, not in a linear order as my chart implied.</p>
+
+        <p>I responded to Robison saying basically that this type of discussion was precisely what I hoped would result from my posting. This was not, after all, an obvious fact to a naive non-molecular biologist.</p>
+
+        <p>Vahe Bedian commented more enthusiastically on the rough chart and Robison's remarks.</p>
+
+        <p>Guy Tantenzopf suggested a few candidate organisms for this type of analysis. Ron Sapolsky gave references to two papers by P.D. Karp that deal with some of the same questions that I had raised.</p>
+
+        <p>This discussion has been very enriching. First because of the intelligence and generosity of the electronic acquaintances I have made in the international molecular biology community but also because it has made me realize that there is a place - perhaps even a need - for naive computer science thinking in the world of molecular genetics.</p>
+
+        <h2>Beta-Galactosidase Flow Chart</h2>
+
+        <p>As a sample of the kind of chart I have in mind, below is a flow chart for the expression of the beta-galactosidase gene in E. coli. This is obviously a well known process, though perhaps not previously represented in this kind of programming schematic.</p>
+
+        <div class="flowchart">
+            <h3>Flow Chart of the process of beta-galactosidase gene expression in E. coli</h3>
+            <img src="b-galchart2.gif" alt="Beta-galactosidase gene expression flowchart - Original 1995 version">
+            <p><em>This chart was made using a program called "Inspiration" - normally used as a business tool, but one that I think may be very helpful for biologists and computer scientists alike.</em></p>
+        </div>
+
+        <blockquote>
+            <p><strong>From "Dealing With Genes" by Paul Berg and Maxine Singer, University Science Books, 1992, pp 71-73:</strong></p>
+            <p>The <em>E. coli</em> enzyme beta-galactosidase breaks down lactose (milk sugar) into two simpler sugars, glucose and galactose. If <em>E. coli</em> is grown in the presence of glucose, its preferred nutrient, it does not synthesize beta-galactosidase; but the enzyme is produced if lactose is the only sugar available. Several DNA sequences that precede the 5' end of the beta-galactosidase coding region on <em>E. coli</em> DNA serve to regulate transcription. The RNA polymerase enzyme that will transcribe the gene binds to one, the <strong>promoter</strong>. A second sequence, the <strong>operator</strong>, lies between the promoter and the start of the beta-galactosidase coding sequence. The operator interacts with another protein, the <strong>repressor</strong>. Binding of the repressor to the operator prevents RNA polymerase from initiating transcription.</p>
+        </blockquote>
+
+        <blockquote>
+            <p>If lactose is supplied to the E. coli, the sugar binds to the repressor protein, thereby altering the repressor's shape and preventing it from binding to the DNA. This loss of operator-binding activity now allows (1) the RNA polymerase to transcribe the gene into mRNA, [messenger RNA], (2) the beta-galactosidase to be synthesized, and (3) lactose to be utilized as an energy source for growth...</p>
+        </blockquote>
+
+        <blockquote>
+            <p>Besides the negative control provided by the repressor-operator interactions, beta-galactosidase is also under positive control. Thus, transcription of the beta-galactosidase gene can start only if a specific activator is present. The activator is also a protein that functions only when it is joined with a special small molecule. The special small molecule appears in the cell when there is no glucose available to the bacterium. In a sense, the small molecule is a starvation signal...</p>
+        </blockquote>
+
+        <div class="challenge">
+            <h3>Our Challenge</h3>
+            <p>The entire genome of the bacterium <em>Hemophilus influenzae</em> has recently been mapped at Dr. J. Craig Venter's Institute for Genomic Research and the entire human genome is likely to be mapped within a decade. Yet we still know relatively little about the big picture, i.e. how the genome works as whole, what the relationships are between processes and how these relationships are controlled.</p>
+
+            <p>I put this challenge to molecular biologists and computer scientists: Work together to describe the processes taking place in the genome. Robert Robbins once said to me that he suspected the reason few scientists had seriously looked at the question of the large scale functional structure of the genome was the "the light's better syndrome" now prevalent in science. This refers to the story of the man who was searching for something small and difficult to see - say a contact lens - and proceeded to look for it in a well-lighted area even though he'd lost it somewhere else. When his friend asked why he was looking there, he said "because the light's better over here."</p>
+
+            <p>In science, we tend to ask questions for which the answers seem readily obtainable on a schedule of six months to a year - at least no longer than the grant cycle. This means that we tend to obtain the answers to questions in well lighted areas and seldom risk asking those questions for which clear answers or measurable progress is likely to take decades if not lifetimes of research and thought. But this must not deter us. The functioning of the genome is the greatest challenge of biology and one of the greatest challenges of all science. Let us not be too timid to ask the big questions and posit theories that we know will inevitably be found insufficient and flawed. We must be brave enough to stumble forward into the darkness - so that we can find the answers to most compelling and important questions before us.</p>
+        </div>
+
+        <div class="links">
+            <h3>Related Links</h3>
+            <p><strong>Original Discussion Threads:</strong></p>
+            <ul>
+                <li><a href="#">Original posting (April 13, 1995)</a></li>
+                <li><a href="#">Robert Robbins' response</a></li>
+                <li><a href="#">G. Dellaire's comments</a></li>
+                <li><a href="#">Additional discussion threads</a></li>
+            </ul>
+            <p><strong>Modern Context:</strong></p>
+            <ul>
+                <li><a href="#">Current genome programming frameworks</a></li>
+                <li><a href="#">Systems biology approaches</a></li>
+                <li><a href="#">Computational biology tools</a></li>
+            </ul>
+        </div>
+
+        <hr>
+        <p><em>Gary Welz is a New York City based journalist, consultant and WWW designer. He's currently writing a book about online multimedia and can be reached via email at gwelz@scitv.com, or visit his home page at http://found.cs.nyu.edu/found.a/CAT/misc/welz/</em></p>
+    </div>
+</body>
+</html>