[Paleopsych] FW: RE:The likely Meta-System in Junk DNA

HowlBloom at aol.com HowlBloom at aol.com
Sun Nov 28 07:52:57 UTC 2004

Hb: The material forwarded below by Joel Isaacson is amazing.  

But can I gloat for a minute?  You’ll find the bulk of these ideas proposed 
in paleopsych discussions that go back to at least 2001.  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.  

The prime contributors to this thread have been Greg Bear, Eshel Ben-Jacob, 
and, ummm, this is gonna be obnoxious, me.
Below is the Scientific American article that Joel Isaacson, Shann Turnbull, 
and Cliff Joslyn are referring to.  A special thanks to Cliff for summing the 
material and its significance up so exquisitely.  Howard
In a message dated 11/27/2004 5:50:53 PM Eastern Standard Time, 
isaacsonj at hotmail.com writes:
>From: "Shann Turnbull" <sturnbull at mba1963.hbs.edu>
>Reply-To: pcp-discuss at lanl.gov
>To: <pcp-discuss at lanl.gov>
>CC: <vturchin at bellatlantic.net>
>Subject: RE: [pcp-discuss:] The likely Meta-System Transition in molecular 
>Date: Sat, 27 Nov 2004 17:45:44 +1100
>I also found the Mattick article exciting, but not being a biologist is was
>not because that it challenged our thinking about the role of DNA but
>because it indicated how the strategies found in nature for building 
>self-reproducing organisations might provide guidance on how to design
>complex social organisations and perhaps even a "global brain".
>It showed the need for an interdisciplinary approach to progress insights
>into all the disciplines involved.
>Shann Turnbull PhD http://www.aprim.net/associates/turnbull.htm
>Principal, International Institute for Self-governance
>PO Box 266 Woollahra, Sydney, Australia 1350
>Ph+612 9328 7466 Mobile 0418 222 378, Papers at:
>-----Original Message-----
>From: owner-pcp-discuss at maillist.lanl.gov
>[mailto:owner-pcp-discuss at maillist.lanl.gov] On Behalf Of Cliff Joslyn
>Sent: Saturday, 27 November 2004 4:28 PM
>To: pcp-discuss at lanl.gov
>Cc: vturchin at bellatlantic.net
>Subject: [pcp-discuss:] The likely Meta-System Transition in molecular
>I would like to draw everyone's attention to:
>Mattick, John: (2004) ``The Hidden Genetic Program of Complex
>Organisms'', Scientific American, v. 291:4, pp. 60-67
>See also his technical papers:
>"The evolution of controlled multitasked gene networks: The role of
>introns and other noncoding RNAs in the development of complex
>organisms", Mattick, JS; Gagen, MJ Source: Molecular Biology and
>Evolution; September, 2001; v.18, no.9, p.1611-1630
>"Challenging the dogma: The hidden layer of non-protein-coding RNAs in
>complex organisms."  Mattick, JS Source: BioEssays; October 2003;
>v.25, no.10, p.930-939
>"RNA regulation: a new genetics?"  Mattick, JS Source: NATURE REVIEWS
>GENETICS; APR 2004; v.5, no.4, p.316-323
>I saw Mattick give a technical plenary at the 2003 Intelligence
>Systems for Molecular Biology (ISMB 03, one of the two premier
>bioinformatics conferences), and was really blown away. The Scientific
>American article is a superb semi-technical distillation of his
>work. He has a revolutionary, but simple and elegant, thesis, highly
>coherent with the principles of evolutionary cybernetics, and most
>importantly, highly likely to be TRUE, about molecular evolution. It
>puts so much of what I know about biological systems in context, while
>answering many current mysteries, and really opens up the kind of
>explanatory paradigm we've been lacking for so long, but is so
>obviously suggested by a cybernetic perspective.
>In brief, consider these facts:
>*) Most genomes are characterized by a VERY high degree (> 98%) of
>genomic sequence which are not genes, that is, does not code for
>protein. This includes introns and so-called "intergenic space".
>*) However, recent evidence indicates that much of this genome is
>actually expressed as RNA, and moreover, good chunks of it are
>identical among evolutionarily distinct orgnanisms. This is a property
>called "conservation", which indicates that it's functionally
>significant for survival. And moreover, portions of non-coding DNA are
>MORE highly conserved than proteins.
>*) This is NOT true in prokaryotes (bacteria lacking nuclei), but is
>in eukaryotes. Prokaryotes were the only life on earth for 2.5 B
>years. But a few hundred million years after the emergence of
>eukaryotes also saw the origin of metazoans (multi-cellular
>organisms), all of which are eukaryotes.
>*) Nonetheless, prokaryotes have on the same order of magnitude of
>number of genes as eukaryotes. The riddle that organismal size and
>complexity (however measured, a different discussion) does not
>correlate to the number of genes present is well noted, especially in
>the wake of the genomic revolution.
>*) BUT, total genome size, and in particular the RATIO of non-coding
>to coding genome DOES more or less correlate with complexity.
>*) Finally, we note that the standard hypothesis for explaining
>regulatory organization of sufficient complexity to generate metazoans
>is that it is somehow embedded in the combinatorics of protein
>interaction, that is, proteins acting on each other to form regulatory
>networks. This is despite the fact that to a first approximation,
>regulatory complexity must grow non-linearally with the number of
>"components" controlled, on the order of the quadratic (to handle
>pairs of proteins). And indeed, in PROKARYOTES the number of genes
>increases with the square of organism size, up to a limit where the
>number of regulatory genes is predicted to exceed the number of
>functional genes, and the plateaus.
>The conclusion is inescapable: there was a major evolutionary step at
>2.5 B years where an RNA-mediated network for the regulation of
>protein function, encoded in "non-coding" DNA (introns and
>intergenic space), arose, which resulted in the possibility of complex
>organisms, including eukaryotes and especially the morphological
>development of, and cell differentiation within, metazoans. Mattick
>uses the metaphor of genes as simply the "parts list" (a description
>of the individual TYPES of "lego blocks"), and the rest as the
>instructions for putting them together (how many blocks of which type
>to use where and when in morphological development).
>The argument is so strong and so reasonable, and simply MUST be
>accepted prima facie: "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." (Mattick, the Sci Am paper).
>There's much more to this argument, including some fascinating
>observations about further GENETIC specialty of primates, and even
>humans. And while I've seen one of Mattick's technical talks, and read
>the Sci Am piece, I have not studied his papers. Nor am I anything
>like an expert in this area. My good colleagues here at LANL who are
>molecular biologists say "yes, he's made a splash, but let's go slow".
>And of course revolutionary ideas require the strongest evidence, and
>Mattick is suggesting nothing other than a major revision to, if not
>an obliteration of, the Central Dogma:
>"We may be witnessing such a turning point in our understanding of
>genetic information. 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. The prevailing assumption, embodied in the credo 'one gene,
>one protein', has been that genes are generally synonymous with
>proteins. A corollary has been that proteins, in addition to their
>structural and enzymatic roles in cells, must be the primary agents
>for regulating the expression, or activation, of genes."  (Mattick,
>the Sci Am paper).
>But fortunately, I'm not a biologist, and so I can without hesitancy
>say the following to this group of people interested in (and some
>dedicated to) Turchin's Meta-System Transition (MST) theory.
>Turchin's original evolutionary system begins with multi-cellular
>organisms, and we have speculated for some time about extending the
>ideas to earlier evolutionary times. The route is now open with the
>origin of the control of genetic expression. In the MST schema, this
>is "X is the control of genetic expression", and I don't really know
>what X is, something like "protein mechanisms" or "protein
>interaction". But the other hallmarks of am MST are there, in the
>possible divergence and specialization of the components being
> >
>| Cliff Joslyn, Research Team Leader (Cybernetician at Large)
>| Knowledge Systems & Computational Biology; Computer & Computational
>| Los Alamos National Laboratory, Mail Stop B265, Los Alamos NM 87545 USA
>| joslyn at lanl.gov     http://www.c3.lanl.gov/~joslyn     (505) 667-9096
>V All the world is biscuit-shaped. . .
Retrieved November 28, 2004, from the World Wide Web  NEW YORK PUBLIC 
Mattick, John S., Scientific American, 00368733, Oct2004, Vol. 291, Issue 4 
Database: Academic Search Premier  THE HIDDEN GENETIC PROGRAM of COMPLEX 
ORGANISMS  Contents Overview/Revising Genetic Dogma The Ubiquitous Junk From Parasites 
to Parallel Controls Regulating Development Controlling Complexity MORE TO 
EXPLORE  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  * A 
perplexingly large portion of the DNA of complex organisms (eukaryotes) seems 
irrelevant to the production of proteins. For years, molecular biologists have 
assumed this extra material was evolutionary "junk". * New evidence suggests, 
however, that this junk DNA may encode RNA molecules that perform a variety of 
regulatory functions. The genetic mechanisms of eukaryotes may therefore be 
radically different from those of simple cells [prokaryotes]. * 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.  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.  We may be witnessing such a turning point in our 
understanding of genetic information. 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. The prevailing 
assumption, embodied in the credo "one gene, one protein," has been that genes are 
generally synonymous with proteins. A corollary has been that proteins, in 
addition to their structural and enzymatic roles in cells, must be the primary 
agents for regulating the expression, or activation, of genes.  This conclusion 
derived from studies primarily on bacteria such as Escherichia coli and other 
prokaryotes (simple one-celled organisms lacking a nucleus). And indeed, it is 
still essentially correct for prokaryotes. Their DNA consists almost entirely 
of genes encoding proteins, separated by flanking sequences that regulate the 
expression of the adjacent genes. (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.)  Researchers have also long assumed that 
proteins similarly represent and control all the genetic information in 
animals, plants and fungi--the multicellular organisms classified as eukaryotes 
(having cells that contain nuclei). Pioneering biologist Jacques Monod summarized 
the universality of the central dogma as "What was true for E. coli would be 
true for the elephant."  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 a hidden, parallel regulatory System 
consisting of RNA that acts directly on DNA, RNAs and proteins is also at work. This 
overlooked RNA-signaling network may be what allows humans, for example, to 
achieve structural complexity far beyond anything seen in the unicellular world.  
Some molecular biologists are skeptical or even antagonistic toward these 
unorthodox ideas. But the theory may answer some long-standing riddles of 
development and evolution 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  A DISCOVERY in 1977 
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 showed 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. 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.  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.  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.  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.  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.  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  
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.  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.  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.  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.  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.  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.  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.  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.  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.  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  
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.  
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.  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.  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  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.  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.  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.  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. 
 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.  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.  
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.  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.  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.  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.)  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.  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 est
ablished in the community they and their descendants progressively became 
part of its dynamic--changing, contributing and evolving with it.  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.  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.  
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  Darwin's Dangerous Idea. Daniel C. Dennett. Simon and 
Schuster, 1995.  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.  The Unseen Genome: Gems among the Junk. W. Wayt 
Gibbs in Scientific American, Vol. 289, No. 5, pages 46-53; November 2003.  
Noncoding RNAs: Molecular Biology and Molecular Medicine. Edited by J. Barciszewski 
and V. A. Erdmann. Landes Bioscience/Eurekah.com, Georgetown, Tex., 2003.  
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  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.  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.  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.  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.  ~~~~~~~~  By John S. Mattick  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 
PROKARYOTES  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  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  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.  DIAGRAM  DIAGRAM  DIAGRAM Copyright of 
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Howard Bloom
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
Visiting Scholar-Graduate Psychology Department, New York University; Core 
Faculty Member, The Graduate Institute
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.
For information on The International Paleopsychology Project, see: 
for two chapters from 
The Lucifer Principle: A Scientific Expedition Into the Forces of History, 
see www.howardbloom.net/lucifer
For information on Global Brain: The Evolution of Mass Mind from the Big Bang 
to the 21st Century, see www.howardbloom.net
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