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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"> <o:p></o:p></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Hb: The material forwarded below by Joel Isaacson is amazing.<SPAN style="mso-spacerun: yes"> </SPAN></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><SPAN style="mso-spacerun: yes"></SPAN></FONT> </P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><SPAN style="mso-spacerun: yes"></SPAN>But can I gloat for a minute?<SPAN style="mso-spacerun: yes"> </SPAN>You’ll find the bulk of these ideas proposed in paleopsych discussions that go back to at least 2001.<SPAN style="mso-spacerun: yes"> </SPAN>Not the RNA mechanisms--a huge part of the puzzle--but the general idea that junk dna provides the instructions for putting together the protein leggo blocks of complex creatures, and for changing the arrangement of those blocks over time.<SPAN style="mso-spacerun: yes"> </SPAN></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><SPAN style="mso-spacerun: yes"></SPAN></FONT> </P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><SPAN style="mso-spacerun: yes"></SPAN>The prime contributors to this thread have been Greg Bear, Eshel Ben-Jacob, and, ummm, this is gonna be obnoxious, me.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"> <o:p></o:p></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Below is the Scientific American article that Joel Isaacson, Shann Turnbull, and Cliff Joslyn are referring to.<SPAN style="mso-spacerun: yes"> </SPAN>A special thanks to Cliff for summing the material and its significance up so exquisitely.<SPAN style="mso-spacerun: yes"> </SPAN>Howard</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"> <o:p></o:p></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">In a message dated 11/27/2004 5:50:53 PM Eastern Standard Time, isaacsonj@hotmail.com writes:</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>From: "Shann Turnbull" <sturnbull@mba1963.hbs.edu></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Reply-To: pcp-discuss@lanl.gov</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>To: <pcp-discuss@lanl.gov></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>CC: <vturchin@bellatlantic.net></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Subject: RE: [pcp-discuss:] The likely Meta-System Transition in molecular </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>evolution</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Date: Sat, 27 Nov 2004 17:45:44 +1100</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>I also found the Mattick article exciting, but not being a biologist is was</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>not because that it challenged our thinking about the role of DNA but</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>because it indicated how the strategies found in nature for building </FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>complex</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>self-reproducing organisations might provide guidance on how to design</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>complex social organisations and perhaps even a "global brain".</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>It showed the need for an interdisciplinary approach to progress insights</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>into all the disciplines involved.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Regards</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Shann</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Shann Turnbull PhD http://www.aprim.net/associates/turnbull.htm</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Principal, International Institute for Self-governance</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>PO Box 266 Woollahra, Sydney, Australia 1350</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Ph+612 9328 7466 Mobile 0418 222 378, Papers at:</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>http://ssrn.com/author=26239</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>-----Original Message-----</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>From: owner-pcp-discuss@maillist.lanl.gov</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>[mailto:owner-pcp-discuss@maillist.lanl.gov] On Behalf Of Cliff Joslyn</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Sent: Saturday, 27 November 2004 4:28 PM</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>To: pcp-discuss@lanl.gov</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Cc: vturchin@bellatlantic.net</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Subject: [pcp-discuss:] The likely Meta-System Transition in molecular</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>evolution</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>I would like to draw everyone's attention to:</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Mattick, John: (2004) ``The Hidden Genetic Program of Complex</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Organisms'', Scientific American, v. 291:4, pp. 60-67</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>See also his technical papers:</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>"The evolution of controlled multitasked gene networks: The role of</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>introns and other noncoding RNAs in the development of complex</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>organisms", Mattick, JS; Gagen, MJ Source: Molecular Biology and</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Evolution; September, 2001; v.18, no.9, p.1611-1630</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>"Challenging the dogma: The hidden layer of non-protein-coding RNAs in</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>complex organisms."<SPAN style="mso-spacerun: yes"> </SPAN>Mattick, JS Source: BioEssays; October 2003;</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>v.25, no.10, p.930-939</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>"RNA regulation: a new genetics?"<SPAN style="mso-spacerun: yes"> </SPAN>Mattick, JS Source: NATURE REVIEWS</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>GENETICS; APR 2004; v.5, no.4, p.316-323</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>I saw Mattick give a technical plenary at the 2003 Intelligence</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Systems for Molecular Biology (ISMB 03, one of the two premier</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>bioinformatics conferences), and was really blown away. The Scientific</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>American article is a superb semi-technical distillation of his</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>work. He has a revolutionary, but simple and elegant, thesis, highly</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>coherent with the principles of evolutionary cybernetics, and most</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>importantly, highly likely to be TRUE, about molecular evolution. It</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>puts so much of what I know about biological systems in context, while</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>answering many current mysteries, and really opens up the kind of</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>explanatory paradigm we've been lacking for so long, but is so</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>obviously suggested by a cybernetic perspective.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>In brief, consider these facts:</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>*) <B>Most genomes are characterized by a VERY high degree (> 98%) of<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>genomic sequence which are not genes, that is, does not code for<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>>protein. </B>This includes introns and so-called "intergenic space".</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>*) However, recent evidence indicates that <B>much of this genome is<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>>actually expressed as RNA</B>, and moreover, <B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow">good chunks of it are<o:p></o:p></SPAN></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow">>identical among evolutionarily distinct orgnanisms</SPAN></B>. <B>This is a property<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>called "conservation", which indicates that it's functionally<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>significant for survival. And moreover, portions of non-coding DNA are<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>MORE highly conserved than proteins.</FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>*) <B>This is NOT true in prokaryotes (bacteria</B> lacking nuclei), but is</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>in eukaryotes.<B> Prokaryotes were the only life on earth for 2.5 B<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>years. But a few hundred million years after the emergence of<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>eukaryotes also saw the origin of metazoans (multi-cellular<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>>organisms)</B>, all of which are eukaryotes.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>*) <B>Nonetheless, prokaryotes have on the same order of magnitude of<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>>number of genes as eukaryotes.</B> The riddle that organismal size and</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>complexity (however measured, a different discussion) does not</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>correlate to the number of genes present is well noted, especially in</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>the wake of the genomic revolution.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>*)<B> BUT, total genome size, and in particular the RATIO of non-coding<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>to coding genome DOES more or less correlate with complexity.</FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>*) Finally, we note that <B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow">the standard hypothesis for explaining<o:p></o:p></SPAN></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow"><FONT face="Times New Roman">>regulatory organization of sufficient complexity to generate metazoans<o:p></o:p></FONT></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow"><FONT face="Times New Roman">>is that it is somehow embedded in the combinatorics of protein<o:p></o:p></FONT></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow"><FONT face="Times New Roman">>interaction, that is, proteins acting on each other to form regulatory<o:p></o:p></FONT></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B><SPAN style="BACKGROUND: yellow; mso-highlight: yellow">>networks.</SPAN></B> This is despite the fact that to a first approximation,</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>regulatory complexity must grow non-linearally with the number of</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>"components" controlled, on the order of the quadratic (to handle</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>pairs of proteins). And indeed, in PROKARYOTES the number of genes</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>increases with the square of organism size, up to a limit where the</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>number of regulatory genes is predicted to exceed the number of</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>functional genes, and the plateaus.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">><B>The conclusion is inescapable: there was a major evolutionary step at<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>2.5 B years where an RNA-mediated network for the regulation of<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>>protein function, encoded in "non-coding" DNA </B>(introns and</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>intergenic space), <B>arose, which resulted in the possibility of complex<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman"><B>>organisms,</B> including eukaryotes and especially the morphological</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>development of, <B>and cell differentiation</B> within, metazoans. <B>Mattick<o:p></o:p></B></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>uses the metaphor of genes as simply the "parts list" (a description<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>of the individual TYPES of "lego blocks"), and the rest as the<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>instructions for putting them together (how many blocks of which type<o:p></o:p></FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><B><FONT face="Times New Roman">>to use where and when in morphological development).</FONT></B></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>The argument is so strong and so reasonable, and simply MUST be</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>accepted prima facie: "The implications of this rule are</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>staggering. We may have totally misunderstood the nature of the</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>genomic programming and the basis of variations in traits among</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>individuals and species." (Mattick, the Sci Am paper).</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>There's much more to this argument, including some fascinating</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>observations about further GENETIC specialty of primates, and even</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>humans. And while I've seen one of Mattick's technical talks, and read</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>the Sci Am piece, I have not studied his papers. Nor am I anything</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>like an expert in this area. My good colleagues here at LANL who are</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>molecular biologists say "yes, he's made a splash, but let's go slow".</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>And of course revolutionary ideas require the strongest evidence, and</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Mattick is suggesting nothing other than a major revision to, if not</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>an obliteration of, the Central Dogma:</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>"We may be witnessing such a turning point in our understanding of</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>genetic information. The central dogma of molecular biology for the</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>past half a century and more has stated that genetic information</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>encoded in DNA is transcribed as intermediary molecules of RNA, which</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>are in turn translated into the amino acid sequences that make up</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>proteins. The prevailing assumption, embodied in the credo 'one gene,</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>one protein', has been that genes are generally synonymous with</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>proteins. A corollary has been that proteins, in addition to their</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>structural and enzymatic roles in cells, must be the primary agents</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>for regulating the expression, or activation, of genes."<SPAN style="mso-spacerun: yes"> </SPAN>(Mattick,</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>the Sci Am paper).</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>But fortunately, I'm not a biologist, and so I can without hesitancy</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>say the following to this group of people interested in (and some</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>dedicated to) Turchin's Meta-System Transition (MST) theory.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Turchin's original evolutionary system begins with multi-cellular</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>organisms, and we have speculated for some time about extending the</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>ideas to earlier evolutionary times. The route is now open with the</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>origin of the control of genetic expression. In the MST schema, this</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>is "X is the control of genetic expression", and I don't really know</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>what X is, something like "protein mechanisms" or "protein</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>interaction". But the other hallmarks of am MST are there, in the</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>possible divergence and specialization of the components being</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>controlled.</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>-----</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>O---------------------------------------------------------------------------</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">> ></FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>| Cliff Joslyn, Research Team Leader (Cybernetician at Large)</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>| Knowledge Systems & Computational Biology; Computer & Computational</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>Science</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>| Los Alamos National Laboratory, Mail Stop B265, Los Alamos NM 87545 USA</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>| joslyn@lanl.gov<SPAN style="mso-spacerun: yes"> </SPAN>http://www.c3.lanl.gov/~joslyn<SPAN style="mso-spacerun: yes"> </SPAN>(505) 667-9096</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">>V All the world is biscuit-shaped. . .</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">________</FONT></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><FONT face="Times New Roman">Retrieved November 28, 2004, from the World Wide Web<SPAN style="mso-spacerun: yes"> </SPAN>NEW YORK PUBLIC LIBRARY-MID MANHATTAN Title: THE HIDDEN GENETIC PROGRAM of COMPLEX ORGANISMS ,<SPAN style="mso-spacerun: yes"> </SPAN>By: Mattick, John S., Scientific American, 00368733, Oct2004, Vol. 291, Issue 4 Database: Academic Search Premier<SPAN style="mso-spacerun: yes"> </SPAN>THE HIDDEN GENETIC PROGRAM of COMPLEX ORGANISMS<SPAN style="mso-spacerun: yes"> </SPAN>Contents Overview/Revising Genetic Dogma The Ubiquitous Junk From Parasites to Parallel Controls Regulating Development Controlling Complexity MORE TO EXPLORE<SPAN style="mso-spacerun: yes"> </SPAN>Biologists assumed that proteins alone regulate the genes of humans and other complex organisms. But an overlooked regulator based on RNA may hold the keys to development and evolution Overview/Revising Genetic Dogma<SPAN style="mso-spacerun: yes"> </SPAN>* <B>A perplexingly large portion of the DNA of complex organisms (eukaryotes) seems irrelevant to the production of proteins</B>. For years, molecular biologists have assumed this extra material was evolutionary "junk". * New evidence suggests, however, that this <B>junk DNA may encode RNA molecules that perform a variety of regulatory functions</B>. <B>The genetic mechanisms of eukaryotes may therefore be radically different from those of simple cells [prokaryotes].</B> * This new theory could explain why the structural and developmental complexity of organisms does not parallel their numbers of protein-coding genes. It also carries important implications for future pharmaceutical and medical research.<SPAN style="mso-spacerun: yes"> </SPAN>Assumptions can be dangerous, especially in science. They usually start as the most plausible or comfortable interpretation of the available facts. But when their truth cannot be immediately tested and their flaws are not obvious, assumptions often graduate to articles of faith, and new observations are forced to fit them. Eventually, if the volume of troublesome information becomes unsustainable, the orthodoxy must collapse.<SPAN style="mso-spacerun: yes"> </SPAN>We may be witnessing such a turning point in our understanding of genetic information. <B>The central dogma of molecular biology for the past half a century and more has stated that genetic information encoded in DNA is transcribed as intermediary molecules of RNA, which are in turn translated into the amino acid sequences that make up proteins.</B> The prevailing assumption, <B>embodied in the credo "one gene, one protein,"</B> has been that genes are generally synonymous with proteins.<B> A corollary has been that proteins</B>, in addition to their structural and enzymatic roles in cells, <B>must be the primary agents for regulating the expression</B>, or activation,<B> of genes</B>.<SPAN style="mso-spacerun: yes"> </SPAN><B>This conclusion derived from studies primarily on bacteria such as Escherichia coli and other prokaryotes</B> (simple one-celled organisms lacking a nucleus). And indeed, it is still essentially correct for<B> prokaryotes</B>. Their <B>DNA consists almost entirely of genes encoding proteins, separated by flanking sequences that regulate the expression of the adjacent genes</B>.<B> (A few genes that encode RNAs with regulatory jobs are also present, but they make up only a tiny fraction of most prokaryotes' genetic ensembles, or genomes.)</B><SPAN style="mso-spacerun: yes"> </SPAN>Researchers have also long assumed that proteins similarly represent and control all the genetic information in <B>animals, plants and fungi--the multicellular organisms classified as eukaryotes</B> (having cells that contain nuclei). Pioneering biologist <B>Jacques Monod summarized the universality of the central dogma as "What was true for E. coli would be true for the elephant."</B><SPAN style="mso-spacerun: yes"> </SPAN>Monod was only partly right. A growing library of results reveals that the central dogma is woefully incomplete for describing the molecular biology of eukaryotes. Proteins do play a role in the regulation of eukaryotic gene expression, yet <B>a hidden, parallel regulatory System consisting of RNA that acts directly on DNA, RNAs and proteins is also at work.</B> This overlooked RNA-signaling network may be what allows humans, for example, to achieve structural complexity far beyond anything seen in the unicellular world.<SPAN style="mso-spacerun: yes"> </SPAN>Some molecular biologists are skeptical or even antagonistic toward these unorthodox ideas. But<B> the theory may answer some long-standing riddles of development and evolution</B> and holds great implications for gene-based medicine and pharmaceuticals. Moreover, the recent discovery of this system affords insights that could revolutionize designs for complex programmed systems of all kinds, cybernetic as well as biological. The Ubiquitous Junk<SPAN style="mso-spacerun: yes"> </SPAN><B>A DISCOVERY in 1977</B> presaged that something might be wrong with the established view of genomic programming. Phillip A. Sharp of the Massachusetts Institute of Technology and Richard J. Roberts of New England Biolabs, Inc., and their respective colleagues independently s<B>howed that the genes of eukaryotes are not contiguous blocks of protein-coding sequences. Rather they are mosaics of "exons" (DNA sequences that encode fragments of proteins) interspersed with often vast tracts of intervening sequences, or "introns," that do not code for protein.</B> In the nucleus, a gene is first copied in its totality as a primary RNA transcript; then a process called splicing removes the intronic RNAs and reconstitutes a continuous coding sequence-messenger RNA, or mRNA-for translation as protein in the cytoplasm. The excised intronic RNA, serving no apparent purpose, has been presumed to be degraded and recycled.<SPAN style="mso-spacerun: yes"> </SPAN>But if introns do not code for protein, then why are they ubiquitous among eukaryotes yet absent in prokaryotes? Although introns constitute 95 percent or more of the average protein-coding gene in humans, most molecular biologists have considered them to be evolutionary leftovers, or junk. Introns were rationalized as ancient remnants of a time before cellular life evolved, when fragments of protein-coding information crudely assembled into the first genes. Perhaps introns had survived in complex organisms because they had an incidental usefulness-for example, making it easier to reshuffle segments of proteins into useful new combinations during evolution. Similarly, biologists have assumed that the absence of introns from prokaryotes was a consequence of intense competitive pressures in the microbial environment: evolution had pruned away the introns as deadweight.<SPAN style="mso-spacerun: yes"> </SPAN>One observation that made it easier to dismiss introns--and other seemingly useless "intergenic" DNA that sat between genes--as junk was that the amount of DNA in a genome does not correlate well with the organism's complexity. Some amphibians, for example, have more than five times as much DNA as mammals do, and astonishingly, some amoebae have 1,000 times more. For decades, researchers assumed that the underlying number of protein-coding genes in these organisms correlated much better with complexity but that the relationship was lost against the variable background clutter of introns and other junk sequences.<SPAN style="mso-spacerun: yes"> </SPAN>But investigators have since sequenced the genomes of diverse species, and it has become abundantly clear that the correlation between numbers of conventional genes and complexity truly is poor. The simple nematode worm Caenorhabditis elegans (made up of only about 1,000 cells) has about 19,000 protein-coding genes, almost 50 percent more than insects (13,500) and nearly as many as humans (around 25,000). Conversely, the relation between the amount of nonprotein-coding DNA sequences and organism complexity is more consistent.<SPAN style="mso-spacerun: yes"> </SPAN>Put simply, the conundrum is this: less than 1.5 percent of the human genome encodes proteins, but most of it is transcribed into RNA. Either the human genome (and that of other complex organisms) is replete with useless transcription, or these nonprotein-coding RNAs fulfill some unexpected function.<SPAN style="mso-spacerun: yes"> </SPAN>This line of argument and considerable other experimental evidence suggest that many genes in complex organisms-perhaps even the majority of genes in mammals--do not encode protein but instead give rise to RNAs with direct regulatory functions [see "The Hidden Genome," by W. Wayt Gibbs, SCIENTIFIC AMERICAN, November and December 2003]. These RNAs may be transmitting a level of information that is crucial, particularly to development, and that plays a pivotal role in evolution. From Parasites to Parallel Controls<SPAN style="mso-spacerun: yes"> </SPAN>THE CLUE to understanding this point may lie in a new interpretation of introns. Contrary to early assumptions that introns generally date back to the dawn of life, evidence amassed more recently indicates that these sequences invaded the genes of higher organisms late in evolution. Most likely, they derived from a type of self-splicing mobile genetic element similar to what are now called group II introns. These elements are parasitic bits of DNA that have the peculiar ability to insert themselves into host genomes and to splice themselves out when expressed as RNA.<SPAN style="mso-spacerun: yes"> </SPAN>Group II introns are found only occasionally in bacteria, and it is easy to see why. Because bacteria lack a nucleus, transcription and translation occur together: RNA is translated into protein almost as fast as it is transcribed from DNA. There is no time for intronic RNA to splice itself out of the protein coding RNA in which it sits, so an intron would in most cases disable the gene it inhabits, with harmful consequences for the host bacterium. In eukaryotes, transcription occurs in the nucleus and translation in the cytoplasm, a separation that opens a window of opportunity for the intron RNA to excise itself. Introns can thus be more easily tolerated in eukaryotes.<SPAN style="mso-spacerun: yes"> </SPAN>Of course, as long as introns needed to splice themselves in and out of genomes, their sequences could not have deviated much from that of group II introns. But a further leap in intron evolution may have accompanied the evolution in eukaryotes of the structure called the spliceosome. This is a complex of small catalytic RNAS and many proteins; its job is to snip intron RNA out of messenger RNA precursors efficiently.<SPAN style="mso-spacerun: yes"> </SPAN>By freeing introns from the need to splice themselves, the spliceosome would in effect have encouraged introns to proliferate, mutate and evolve. Any random mutation in an intron that proved beneficial to the host organism would have been retained by natural selection. Intronic RNAs would therefore be evolving independently and in parallel with proteins. In short, the entry of introns into eukaryotes may have initiated an explosive new round of molecular evolution, based on RNA rather than protein. Instead of being junky molecular relics, introns could have progressively acquired genetic functions mediated by RNA.<SPAN style="mso-spacerun: yes"> </SPAN>If this hypothesis is true, its meaning may be profound. Eukaryotes (especially the more complex ones) may have developed a genetic operating system and regulatory networks that are far more sophisticated than those of prokaryotes: RNAs and proteins could communicate regulatory information in parallel. Such an arrangement would resemble the advanced information-processing systems supporting network controls in computers and the brain.<SPAN style="mso-spacerun: yes"> </SPAN>Functional jobs in cells routinely belong to proteins because they have great chemical and structural diversity. Yet RNA has an advantage over proteins for transmitting information and regulating activities involving the genome itself: RNAs can encode short, sequence-specific signals as a kind of bit string or zip code. These embedded codes can direct RNA molecules precisely to receptive targets in other RNAs and DNA. The RNA-RNA and RNA-DNA interactions could in turn create structures that recruit proteins to convert the signals to actions.<SPAN style="mso-spacerun: yes"> </SPAN>The bit string of addressing information in the RNA gives this system the power of tremendous precision, just as the binary bit strings used by digital computers do. It is not too much of a stretch to say that this RNA regulatory system would be largely digital in nature.<SPAN style="mso-spacerun: yes"> </SPAN>The evidence for a widespread RNA-based regulatory system is strong, albeit still patchy. If such a system exists, one would expect that many genes might have evolved solely to express RNA signals as higher-order regulators in the network. That appears to be the case: thousands of RNAs that never get translated into protein (noncoding RNAs) have been identified in recent analyses of transcription in mammals. At least half and possibly more than three quarters of all RNA transcripts fit this category.<SPAN style="mso-spacerun: yes"> </SPAN>One would also expect that many of these RNAs might be processed into smaller signals capable of addressing targets in the network. Hundreds of "microRNAs" derived from introns and larger nonprotein-coding RNA transcripts have in fact already been identified in plants, animals and fungi. Many of them control the timing of processes that occur during development, such as stem cell maintenance, cell proliferation, and apoptosis (the so-called programmed cell death that remodels tissues). Many more such small RNAs surely await discovery.<SPAN style="mso-spacerun: yes"> </SPAN>These RNA signals, by finding targets on other RNAs, DNA and proteins, could influence a cell's genetic program in many ways. For example, they could inform various genes that a particular protein-coding sequence has been transcribed, and that feedback could trigger a host of parallel adjustments. More important, however, the RNA signals could serve as a powerful feed-forward program embedded in the genetic material that controls the trajectories of gene expression. If so, they could explain some of the deep mysteries surrounding cell differentiation and organism development. Regulating Development<SPAN style="mso-spacerun: yes"> </SPAN>CONSIDER WHAT HAPPENS during human embryonic development: a single fertilized cell progresses to become a precisely structured, beautifully sculptured organism of an estimated 100 trillion cells with distinct positions and functions. The pattern of gene expression that makes this transformation possible relies heavily on two phenomena: modification of chromatin and alternative splicing.<SPAN style="mso-spacerun: yes"> </SPAN>Chromatin is the material that makes up chromosomes; it consists of DNA complexed with proteins. Within cells, small chemical tags (such as methyl and acetyl groups) can attach to segments of the DNA and to the chromatin proteins and thereby determine whether the genes in the associated DNA will be accessible for transcription or will stay silent. Recent results indicate that RNA signaling directs the tagging of the chromatin and thus gene expression. Indeed, a number of complex chromosomal processes, such as mitosis (cell division) and meiosis (the formation of sperm and egg precursors), as well as a range of complex genetic phenomena appear to depend on biochemical pathways that affect RNA processing.<SPAN style="mso-spacerun: yes"> </SPAN>Alternative splicing generates divergent repertoires of RNAs and proteins in the cells of a body's different tissues, all of which share a common set of genes. Most protein-coding transcripts are alternatively spliced in mammals. When intron RNA is spliced out of a gene's transcript, the protein-coding RNA regions may be assembled in more than one way to yield more than one type of protein. The phenomenon is of fundamental importance to animal and plant development, but no one yet understands how cells specify which form of a protein they will make. Few protein factors that control the alternative splicing of specific genes have been found. Consequently, researchers have usually supposed that subtle combinations of general factors activate or repress alternative splicing in different contexts. But no strong evidence has backed up that presumption.<SPAN style="mso-spacerun: yes"> </SPAN>A more likely and mechanistically appealing possibility, however, is that RNAs regulate the process directly. In principle, these molecules could exert exquisitely flexible control by tagging or grabbing particular sequences in primary gene transcripts and steering how the spliceosome joins the pieces. In keeping with that idea, DNA sequences at the intron-exon junctions where alternative splicing occurs are often resistant to change during evolution. Also, a number of laboratories have demonstrated that artificial antisense RNAs designed to bind to such sites can modify splicing patterns in cultured cells, as well as in whole animals. It is perfectly plausible that this phenomenon occurs naturally in vivo, too, but has just not yet been detected. Controlling Complexity<SPAN style="mso-spacerun: yes"> </SPAN>SUCH CONSIDERATIONS lead naturally to a more general consideration of what type of information, and how much of it, might be required to program the development of complex organisms. The creation of complex objects, whether houses or horses, demands two kinds of specifications: one for the components and one for the system that guides their assembly. (To build a house, one must specify the needed bricks, boards and beams, but one must also have an architectural plan to show how they fit together.) In biology, unlike engineering, both types of information are encoded within one program, the DNA.<SPAN style="mso-spacerun: yes"> </SPAN>The component molecules that make up different organisms (both at the individual and the species levels) are fundamentally alike: around 99 percent of the proteins in humans have recognizable equivalents in mice, and vice versa; many of those proteins are also conserved in other animals, and those involved in basic cellular processes are conserved in all eukaryotes. Thus, the differences in animals' forms surely arise more fundamentally from differences in the architectural information.<SPAN style="mso-spacerun: yes"> </SPAN>Protein-coding genes obviously specify the components of organisms, but where does the architectural information reside? Biologists have widely assumed that the instructions for assembling complex organisms are somehow embedded in the diverse combinations of regulatory factors within cells--that is, in the permutations of regulatory proteins interacting with one another and with the DNA and RNA. Yet, as Daniel C. Dennett of Tufts University has observed, although such combinatorics can generate almost endless possibilities, the vast majority will be chaotic and meaningless-which is problematic for biology. Throughout their evolution and development, organisms must navigate precise developmental pathways that are sensible and competitive, or else they die. Generating complexity is easy; controlling it is not. The latter requires an enormous amount of regulatory information.<SPAN style="mso-spacerun: yes"> </SPAN>Both intuitive and mathematical considerations suggest that the amount of regulation must increase as a nonlinear (usually quadratic) function of the number of genes. So, as the system becomes more complex, an increasing proportion of it must be devoted to regulation. This nonlinear relation between regulation and function appears to be a feature of all integrally organized systems. Therefore, all such systems have an intrinsic complexity limit imposed by the accelerating growth of their control architecture, until or unless the regulatory mechanism changes fundamentally.<SPAN style="mso-spacerun: yes"> </SPAN>In agreement with this prediction, the number of protein regulators in prokaryotes has been found to increase quadratically with genome size. Moreover, extrapolation indicates that the point at which the number of new regulators is predicted to exceed the number of new functional genes is close to the observed upper limit of bacterial genome sizes.<SPAN style="mso-spacerun: yes"> </SPAN>Throughout evolution, therefore, the complexity of prokaryotes may have been limited by genetic regulatory overhead, rather than by environmental or biochemical factors as has been commonly assumed. This conclusion is also consistent with the fact that life on earth consisted solely of microorganisms for most of its history. Combinatorics of protein interactions could not, by themselves, lift that complexity ceiling.<SPAN style="mso-spacerun: yes"> </SPAN>Eukaryotes must have found a solution to this problem. Logic and the available evidence suggest that the rise of multicellular organisms over the past billion years was a consequence of the transition to a new control architecture based largely on endogenous digital RNA signals. It would certainly help explain the phenomenon of the Cambrian explosion about 525 million years ago, when invertebrate animals of jaw-dropping diversity evolved, seemingly abruptly, from much simpler life. Indeed, these results suggest a general rule with relevance beyond biology: organized complexity is a function of regulatory information--and, in virtually all systems, as observed by Marie E. Csete, now at Emory University School of Medicine, and John C. Doyle of the California Institute of Technology, explosions in complexity occur as a result of advanced controls and embedded networking.<SPAN style="mso-spacerun: yes"> </SPAN>The implications of this rule are staggering. We may have totally misunderstood the nature of the genomic programming and the basis of variations in traits among individuals and species. The rule implies that the greater portion of the genomes in complex organisms is not junk at all--rather it is functional and subject to evolutionary selection.<SPAN style="mso-spacerun: yes"> </SPAN>The most recent surprise is that vertebrate genomes contain thousands of noncoding sequences that have persisted virtually unaltered for many millions of years. These sequences are much more highly conserved than those coding for proteins, which was totally unexpected. The mechanism that has frozen these sequences is unknown, but their extreme constancy suggests that they are involved in complex networks essential to our biology. Thus, rather than the genomes of humans and other complex organisms being viewed as oases of protein-coding sequences in a desert of junk, they might better be seen as islands of protein-component information in a sea of regulatory information, most of which is conveyed by RNA.<SPAN style="mso-spacerun: yes"> </SPAN>The existence of an extensive RNA-based regulatory system also has ramifications for pharmacology, drug development and genetic screening. Traditional genetic diseases such as cystic fibrosis and thalassemia are caused by catastrophic component damage: one of the individual's proteins simply doesn't work. Yet many, if not most, of the genetic variations determining susceptibility to most diseases and underpinning our individual idiosyncrasies probably lie in the noncoding regulatory architecture of our genome that controls growth and development. (Noncoding RNAs have already been linked with several conditions, including B cell lymphoma, lung cancer, prostate cancer, autism and schizophrenia.)<SPAN style="mso-spacerun: yes"> </SPAN>Such defects will not be easy to identify by molecular genetic epidemiology, nor will they necessarily be easy to correct. But understanding this regulatory system may ultimately be critical to understanding our physical and psychological individuality, as well as trait variation in plants and animals. It may also be the prelude to sophisticated strategies for medical intervention to optimize health and for truly advanced genetic engineering in other species.<SPAN style="mso-spacerun: yes"> </SPAN>Aside from introns, the other great source of presumed genomic junk--accounting for about 40 percent of the human genome--comprises transposons and other repetitive elements. These sequences are widely regarded as molecular parasites that, like introns, colonized our genomes in waves at different times in evolutionary history. Like all immigrants, they may have been unwelcome at first, but once established in the community they and their descendants progressively became part of its dynamic--changing, contributing and evolving with it.<SPAN style="mso-spacerun: yes"> </SPAN>Good, albeit patchy, evidence suggests that transposons contribute to the evolution and genomic regulation of higher organisms and may play a key role in epigenetic inheritance (the modification of genetic traits). Moreover, this past July Erev Y. Levanon of Compugen and colleagues elsewhere announced an exciting discovery involving a process called A-to-I (adenosine-to-inosine) editing, in which an RNA sequence changes at a very specific site. They demonstrated that A-to-I editing of RNA transcripts is two orders of magnitude more widespread in humans than was previously thought and overwhelmingly occurs in repeat sequences called Alu elements that reside in noncoding RNA sequences. A-to-I editing is particularly active in the brain, and aberrant editing has been associated with a range of abnormal behaviors, including epilepsy and depression.<SPAN style="mso-spacerun: yes"> </SPAN>Although RNA editing occurs to some extent in all animals, Alu elements are unique to primates. An intriguing possibility is that the colonization of the primate lineage by Alu elements made it possible for a new level of complexity to arise in RNA processing and allowed the programming for neural circuitry to become more dynamic and flexible. That versatility may have in turn laid the foundation for the emergence of memory and higher-order cognition in the human species.<SPAN style="mso-spacerun: yes"> </SPAN>Finally, understanding the operation of the expanded and highly sophisticated regulatory architecture in the genomes of complex organisms may shed light on the challenges of designing systems capable of self-reproduction and self-programming-that is, true artificial life and artificial intelligence. What was dismissed as junk because it was not understood may well turn out to hold the secrets to human complexity and a guide to the programming of complex systems in general. MORE TO EXPLORE<SPAN style="mso-spacerun: yes"> </SPAN>Darwin's Dangerous Idea. Daniel C. Dennett. Simon and Schuster, 1995.<SPAN style="mso-spacerun: yes"> </SPAN>Challenging the Dogma: The Hidden Layer of Non-Protein-Coding RNAs In Complex Organisms. John S. Mattick in BioEssays, Vol. 25, No. 10, pages 930-939; October 2003.<SPAN style="mso-spacerun: yes"> </SPAN>The Unseen Genome: Gems among the Junk. W. Wayt Gibbs in Scientific American, Vol. 289, No. 5, pages 46-53; November 2003.<SPAN style="mso-spacerun: yes"> </SPAN>Noncoding RNAs: Molecular Biology and Molecular Medicine. Edited by J. Barciszewski and V. A. Erdmann. Landes Bioscience/Eurekah.com, Georgetown, Tex., 2003.<SPAN style="mso-spacerun: yes"> </SPAN>More information and lists of publications will be found at the author's Web site [under construction] at http://imb.uq.edu.au/groups/mattick<SPAN style="mso-spacerun: yes"> </SPAN>GRAPH: NONPROTEIN-CODING SEQUENCES make up only a small fraction of the DNA of prokaryotes. Among eukaryotes, as their complexity increases, generally so, too, does the proportion of their DNA that does not code for protein. The noncoding sequences have been considered junk, but perhaps it actually helps to explain organisms' complexity.<SPAN style="mso-spacerun: yes"> </SPAN>DIAGRAM: PROPOSED PRECURSOR molecule for microRNAs is a primary RNA transcript that may produce multiple small RNAs. The structure of the precursor might guide the excision of these small RNA signals.<SPAN style="mso-spacerun: yes"> </SPAN>DIAGRAM: UNICELLULAR LIFE, primarily prokaryotes, ruled the earth for billions of years. When multicellular life appeared, however, its complexity rose with dizzying speed. The evolution of an additional genetic regulatory system might explain both the jump to multicellularity and the rapid diversification into complexity.<SPAN style="mso-spacerun: yes"> </SPAN>PHOTO (COLOR): BACTERIA AND HUMANS differ greatly in their structural and developmental complexity, but biologists have long assumed that all organisms used the same genetic mechanisms. Yet new work hints that complexity arises from an additional program hidden in "junk" DNA.<SPAN style="mso-spacerun: yes"> </SPAN>~~~~~~~~<SPAN style="mso-spacerun: yes"> </SPAN>By John S. Mattick<SPAN style="mso-spacerun: yes"> </SPAN>JOHN S. MATTICK, born and raised in Sydney, today is a professor of molecular biology at the University of Queensland and director of the Institute for Molecular Bioscience. Formerly he was also foundation director of the Australian Genome Research Facility. His accomplished career includes the development of Australia's first genetically engineered vaccine. In 2001 Mattick was appointed an Officer in the Order of Australia, and in 2003 he was awarded the Australian government's Centenary Medal. Married with three sons, he enjoys walking and body surfing as time permits.<SPAN style="mso-spacerun: yes"> </SPAN>AN EVOLVING VIEW OF GENE ACTIVITY<SPAN style="mso-spacerun: yes"> </SPAN>GENE ACTIVITY IN PROKARYOTES<SPAN style="mso-spacerun: yes"> </SPAN>Prokaryotes (bacteria and other simple cells] have DNA that consists almost entirely of protein-coding genes. When those genes are active, they give rise to RNA transcripts that are immediately translated into proteins, which in turn regulate genetic activity and provide other functions. TRADITIONAL VIEW OF GENE ACTIVITY IN EUKARYOTES<SPAN style="mso-spacerun: yes"> </SPAN>In the DNA of eukaryotes (complex organisms), individual genes comprise "exon" sequences that code for segments of protein separated by noncoding "intron" sequences. When a gene is active, it is entirely transcribed as RNA, but then the intronic RNA is spliced out and the exonic RNA is assembled as messenger RNA. The cell translates the messenger RNA into protein while breaking down and recycling the intronic RNA, which serves no purpose. NEW VIEW OF GENE ACTIVITY IN EUKARYOTES<SPAN style="mso-spacerun: yes"> </SPAN>Some of the intronic RNA and even some of the assembled exonic RNA may play a direct regulatory role by interacting with the DNA, other RNA molecules or proteins. By modifying protein production at various levels, these noncoding RNAs may superimpose additional genetic instructions on a cell.<SPAN style="mso-spacerun: yes"> </SPAN>DIAGRAM<SPAN style="mso-spacerun: yes"> </SPAN>DIAGRAM<SPAN style="mso-spacerun: yes"> </SPAN>DIAGRAM Copyright of Scientific American is the property of Scientific American Inc. and its content may not be copied or e-mailed to multiple sites or posted to a listserv without the copyright holder`s express written permission. However, users may print, download, or e-mail articles for individual use. Source: Scientific American, Oct2004, Vol. 291 Issue 4, p60, 8p Item: 14394130 Top of Page Formats: CitationCitation<SPAN style="mso-spacerun: yes"> </SPAN>HTML Full TextHTML Full Text No previous pages 1 of 1 No additional pages Result List | Refine Search PrintPrint<SPAN style="mso-spacerun: yes"> </SPAN>E-mailE-mail<SPAN style="mso-spacerun: yes"> </SPAN>SaveSave Items added to the folder may be printed, e-mailed or saved from the View Folder screen.Folder is empty.<SPAN style="mso-spacerun: yes"> </SPAN>© 2004 EBSCO Publishing. Privacy Policy - Terms of Use<SPAN style="mso-spacerun: yes"> </SPAN></FONT></P></FONT></DIV>
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<DIV><FONT lang=0 face=Arial size=2 FAMILY="SANSSERIF" PTSIZE="10">----------<BR>Howard Bloom<BR>Author of The Lucifer Principle: A Scientific Expedition Into the Forces of History and Global Brain: The Evolution of Mass Mind From The Big Bang to the 21st Century<BR>Visiting Scholar-Graduate Psychology Department, New York University; Core Faculty Member, The Graduate Institute<BR>www.howardbloom.net<BR>www.bigbangtango.net<BR>Founder: International Paleopsychology Project; founding board member: Epic of Evolution Society; founding board member, The Darwin Project; founder: The Big Bang Tango Media Lab; member: New York Academy of Sciences, American Association for the Advancement of Science, American Psychological Society, Academy of Political Science, Human Behavior and Evolution Society, International Society for Human Ethology; advisory board member: Youthactivism.org; executive editor -- New Paradigm book series.<BR>For information on The International Paleopsychology Project, see: www.paleopsych.org<BR>for two chapters from <BR>The Lucifer Principle: A Scientific Expedition Into the Forces of History, see www.howardbloom.net/lucifer<BR>For information on Global Brain: The Evolution of Mass Mind from the Big Bang to the 21st Century, see www.howardbloom.net<BR></DIV></FONT></DIV></BODY></HTML>