Monday, January 19, 2009

Ribosomal Quality Control

In order to demonstrate the validity of viewing cells as computers that are able to manipulate information, consider the following finding.

The Ribosome: Perfectionist Protein-maker Trashes Errors

ScienceDaily (Jan. 9, 2009) — The enzyme machine that translates a cell's DNA code into the proteins of life is nothing if not an editorial perfectionist.
It turns out, the Johns Hopkins researchers say, that the ribosome exerts far tighter quality control than anyone ever suspected over its precious protein products which, as workhorses of the cell, carry out the very business of life.

"What we now know is that in the event of miscoding, the ribosome cuts the bond and aborts the protein-in-progress, end of story," says Rachel Green, a Howard Hughes Medical Institute investigator and professor of molecular biology and genetics in the Johns Hopkins University School of Medicine. "There's no second chance." Previously, Green says, molecular biologists thought the ribosome tightly managed its actions only prior to the actual incorporation of the next building block by being super-selective about which chemical ingredients it allows to enter the process.

Because a protein's chemical "shape" dictates its function, mistakes in translating assembly codes can be toxic to cells, resulting in the misfolding of proteins often associated with neurodegenerative conditions. Working with bacterial ribosomes, Green and her team watched them react to lab-induced chemical errors and were surprised to see that the protein-manufacturing process didn't proceed as usual, getting past the error and continuing its "walk" along the DNA's protein-encoding genetic messages.

"We thought that once the mistake was made, it would have just gone on to make the next bond and the next," Green says. "But instead, we noticed that one mistake on the ribosomal assembly line begets another, and it's this compounding of errors that leads to the partially finished protein being tossed into the cellular trash," she adds.
So what is being monitored by the ribosome? Information. Material representations (amino acid sequence vs DNA sequence) of information. But, it does not only monitor it, it manipulates it as a means to an end... fidelity.

To their further surprise, the ribosome lets go of error-laden proteins 10,000 times faster than it would normally release error-free proteins, a rate of destruction that Green says is "shocking" and reveals just how much of a stickler the ribosome is about high-fidelity protein synthesis.

"These are not subtle numbers," she says, noting that there's a clear biological cost for this ribosomal editing and jettisoning of errors, but a necessary expense.

"The cell is a wasteful system in that it makes something and then says, forget it, throw it out," Green concedes. "But it's evidently worth the waste to increase fidelity. There are places in life where fidelity matters."
The ribosome is optimized to manipulate information for fidelity.

Sunday, January 4, 2009

Preaching bad design: An argument from ignorance?

Over the years many people have come with arguments that systems in nature are sub-optimal, or sub-par. These arguments were used as a means to point out that they are "dumb" designs if it was the product of mind.

An example of such an argument is given by Richard Dawkins. Take his article:
The Information Challenge

Genomes are littered with nonfunctional pseudogenes, faulty duplicates of functional genes that do nothing, while their functional cousins (the word doesn't even need scare quotes) get on with their business in a different part of the same genome. And there's lots more DNA that doesn't even deserve the name pseudogene. It, too, is derived by duplication, but not duplication of functional genes. It consists of multiple copies of junk, "tandem repeats", and other nonsense which may be useful for forensic detectives but which doesn't seem to be used in the body itself.

Luckily science moves forward and these arguments from ignorance get left behind and the proponents of these arguments fade into history as proponents of ignorance trying to sell meaningless metaphysics.

Junk DNA is a myth.
Examples abound of research finding fascinating functions for these previously thought non-functional parts of the genome (out of ignorance and bad metaphysics-- Dawkins: "And there's lots more DNA that doesn't even deserve the name pseudogene.").

Model unravels rules that govern how genes are switched on and off

"Since the discovery of DNA's double helical structure more than a half century ago, scientists have focused much of their attention on understanding the 2 percent of the genome that is made up of classic genes, which code for the production of proteins.

However, the instructions for turning these genes on or off are generally not in the genes themselves. Rather, they are buried in the 98 percent of the genome that was once cast aside as little more than genetic "junk."

Scientists at CSHL uncover new RNA processing mechanism and a class of previously unknown small RNAs

A very small fraction of our genetic material--about 2%-- performs the crucial task scientists once thought was the sole purpose of the genome: to serve as a blueprint for the production of proteins, the molecules that make cells work and sustain life. This 2% of human DNA is converted into intermediary molecules called RNAs, which in turn carry instructions within cells for protein manufacture.
"And what of the other 98% of the genome? It has been assumed by many to be genetic junk, a massive accumulation of “code” that evolution has rendered superfluous. Now, however, scientists are discovering that the vast bulk of the DNA in our genomes, while it does not “code” for the specific RNA molecules that serve as templates for protein synthesis, do nevertheless perform various kinds of work."

'Junk' DNA May Have Important Role In Gene Regulation

ScienceDaily (Oct. 20, 2008) — For about 15 years, scientists have known that certain "junk" DNA -- repetitive DNA segments previously thought to have no function -- could evolve into exons, which are the building blocks for protein-coding genes in higher organisms like animals and plants. Now, a University of Iowa study has found evidence that a significant number of exons created from junk DNA seem to play a role in gene regulation.

Well, it is not only supposedly "junk DNA" that was used for these kind of arguments. The vertebrate eye has been preached to be a bad design. Why? Why is it a bad design?

The human eye contain bona fide optical fibers to conduct light and here is a nice illustration. Besides the design arose 40-60 times during evolution, like evolution was biased (converged on an optimal design) towards such a structure. So why is it sub optimal? Are proponents of these arguments going to suggest a better design with all the blueprints? Thought not, arguments from ignorance are short on design. Mr. Green

Why was it suggested that the appendix is useless and functionless, instead of just admitting "we are still looking into it".
A few articles discussing its function:
1) Dasso JF. Howell MD. 1997. "Neonatal appendectomy impairs mucosal immunity in rabbits." Cellular Immunology. 182(1):29-37.
2) Dasso JF. Obiakor H. Bach H. Anderson AO. Mage RG. 2000. "A morphological and immunohistological study of the human and rabbit appendix for comparison with the avian bursa." Developmental & Comparative Immunology. 24:8:797-814.
3) Fisher, RE. 2000. "The primate appendix: a reassessment." The Anatomical Record (New Anatomist) 261:228-236.
4) Weinstein PD. Mage RG. Anderson AO. 1994. "The appendix functions as a mammalian bursal equivalent in the developing rabbit." Advances in Experimental Medicine & Biology. 355:249-53.
5) A more detailed survey of the evidence, with numerous references to other technical literature, showing that the appendix is not a vestigial organ can be found in J.W. Glover, The Human Vermiform Appendix—a General Surgeon’s Reflections, CEN Technical Journal, 3:31–38, 1988.

In short:
The appendix contains a high concentration of very specialized structures called lymphoid follicles (also found throughout the GIT). Lymphoid follicles in the appendix produce cells that produce antibodies that control which essential bacteria come to reside in the caecum and colon in neonatal life. The "strategic" placement of the appendix is important during the development of neonatal life in the setup of healthy intestinal flora therefore neonatal appendectomy will impair mucosal immunity.

"The appendix's job is to reboot the digestive system..." and "acts as a good safe house for bacteria,".

It might not be that important in later life and it can be removed, but so can your one kidney, your stomach, an eye, small intestines, reproductive organs etc. Are these bad designs then as well? See... these arguments have no force. Empty arguments from ignorance...

And the cilium? Until the 1990s, the prevailing view of the primary cilium was that it was merely a vestigial organelle, without important function (wiki). Seems like pretty high-tech structures to me?

Primary Cilium As Cellular 'GPS System' Crucial To Wound Repair

ScienceDaily (Dec. 25, 2008) — The primary cilium, the solitary, antenna-like structure that studs the outer surfaces of virtually all human cells, orient cells to move in the right direction and at the speed needed to heal wounds, much like a Global Positioning System helps ships navigate to their destinations.
What we are dealing with is a physiological analogy to the GPS system with a coupled autopilot that coordinates air traffic or tankers on open sea," says Soren T. Christensen, describing his recent research findings on the primary cilium, the GPS-like cell structure, at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.

Christensen and his colleagues at the University of Copenhagen in Denmark and the Albert Einstein School of Medicine in the Bronx studied the primary cilia in lab cultures of mice fibroblasts, the cells that along with related connective tissues sculpt the bulk of the mammalian body.

So we think we have designed GPS systems?

"The really important discovery is that the primary cilium detects signals, which tell the cells to engage their compass reading and move in the right direction to close the wound," Christensen explains.

Purposefully communicating information as a means to an end... wound healing.

The researchers suspect this cellular GPS system plays roles other than wound healing. The primary cilia could serve as a fail-safe device against uncontrolled cell movement, says Christensen. Without chemical stimulation, the primary cilia would restrain cell migration, preventing the dangerous displacement of cells that is associated with invasive cancers and fibrosis, the scientists explain. On the other hand, defective primary cilia might fail to provide correct directional instructions during cell differentiation. This failure could be another link connecting primary cilia to severe developmental disorders, the researchers suggest.

Protruding through the cell membrane, primary cilia occur on almost every non-dividing cell in the body. Once written off as a vestigial organelle discarded in the evolutionary dust, primary cilia in the last decade have risen to prominence as a vital cellular sensor at the root of a wide range of health disorders, from polycystic kidney disease to cancer to left-right anatomical abnormalities.

Demonstrating the vacuity of preaching sub-optimal design... an idea from faulty Darwinian reasoning?

And taking clues from original design (cellular machinery) to design our own optimal nanotechnology? Does that make the original design optimal/above par/good?

Clockwork That Drives Powerful Virus Nanomotor Discovered

Because of the motor's strength--to scale, twice that of an automobile--the new findings could inspire engineers designing sophisticated nanomachines. In addition, because a number of virus types may possess a similar motor, including the virus that causes herpes, the results may also assist pharmaceutical companies developing methods to sabotage virus machinery.

Related article:
Biologists Learn Structure, Mechanism Of Powerful 'Molecular Motor' In Virus

One has to wonder were the next spate of these arguments are going to come from? Perhaps the low optimality of the genetic code? Perhaps not... Maybe the inefficiency of biomolecular machines? Maybe not...

Arguments from bad design should be taken with a pinch of salt as they are often made out of ignorance with hidden meaningless and mindless metaphysical propositions.

Thursday, January 1, 2009

Computers Making Computers?

An interesting article authored by Antoine Danchin from the Pasteur Institut was recently published and is sure to bring forth much discussion.
Bacteria as computers making computers

Various efforts to integrate biological knowledge into networks of interactions have produced a lively microbial systems biology. Putting molecular biology and computer sciences in perspective, we review another trend in systems biology, in which recursivity and information replace the usual concepts of differential equations, feedback and feedforward loops and the like. Noting that the processes of gene expression separate the genome from the cell machinery, we analyse the role of the separation between machine and program in computers. However, computers do not make computers. For cells to make cells requires a specific organization of the genetic program, which we investigate using available knowledge. Microbial genomes are organized into a paleome (the name emphasizes the role of the corresponding functions from the time of the origin of life), comprising a constructor and a replicator, and a cenome (emphasizing community-relevant genes), made up of genes that permit life in a particular context. The cell duplication process supposes rejuvenation of the machine and replication of the program. The paleome also possesses genes that enable information to accumulate in a ratchet-like process down the generations. The systems biology must include the dynamics of information creation in its future developments.

The quantum teleportation experiments have demonstrated that information can be viewed as a fundamental irreducible property of physics (informationalism). Systems biology is moving in that same direction, as viewing cells as computers with machinery and software makes it possible to view information as a fundamental category of nature and all future developments of systems biology can include this concept when looking at cells.

There are many interesting passages in this article. A few of these are going to be highlighted for discussion.

Historically, systems biology follows on from molecular biology, a science based on many concepts more closely linked to arithmetic and computation than to classical physics or chemistry. Molecular biology relies heavily on concepts such as ‘control’, ‘coding’ or ‘information’, which are at the heart of arithmetic and computation. To accept the cell as a computer conjecture first requires an exploration of the concept of information, in relation to the concept of genetic program.

Cellular processes are exquisitely controlled and carried out by remarkable biomolecular machines. The software needed to coordinate these processes is located in a fairly optimal genetic code that is optimized for evolution and maintains its own functional integrity.

The Austrian mathematician Kurt Godel showed that arithmetic (the science of whole numbers) can make statements about itself. To substantiate this remarkable claim, which implies that just manipulating whole numbers with the rules of arithmetic can generate novel information, G¨odel used a simple trick. He coded the words used in Number Theory as integers (e.g. four, which is quatre in French, vier in German and tessera in Greek, can be coded by 4) and used the corresponding code to translate propositions of arithmetic. This generated a large whole number, which could be manipulated by the rules of arithmetic, and after a sequence of operations, this manipulation generated another whole number. The latter could be decoded using the initial code. Godel’s trick was to drive the sequence of operations modifying the initial statement, to lead to a very particular conclusion. When decoded, the manipulated sequence translated into a particular proposition, which, briefly, stated: ‘I am impossible to prove’. In other words, arithmetic is incomplete, i.e. some propositions of arithmetic can be understood as valid; yet they cannot be proven within the frame of arithmetic. But this ‘incompleteness’ can also be seen as a positive feature; it is what allows the creation of new information – in Godel’s case, the statement of a fact of which the world was previously unaware. In his book, Hofstadter showed that the genetic code, which enables the world of nucleic acids to be translated into the world of proteins, which in turn manipulate nucleic acids, behaves exactly as Godel’s code does. This implies that manipulating strings of symbols, via a process that uses a code, can generate novel information. Of course, in the case of nucleic acids and proteins, there is no Godel to drive the process, and no need for one: while Godel knew what he was aiming at, living systems will accumulate information through recursivity, without any design being required. We only perceive a design because the end result is familiar to us, and thus seems more ‘right’ than any other possible result. But what we commonly term the ‘genetic program’ because it unfolds through time in a consistent manner is not a programme with an aim – it is merely there, and functions because it cannot do otherwise.

Why can't the function of the program be to actively manipulate information as a means to an end... self-replication and preservation. Later in the article something similar to this is actually suggested:

The reluctance of investigators to regard information as an authentic category of Nature suggests that, at this point in the present review of the literature, it may still be difficult for the reader to accept that a cell could behave as a computer. Indeed, what would the role of computation be in the process of evolution? We have already provided some elements of the answer to the question: Turing showed that the consequence of the process of computation along the lines he outlined is that his machine would be able to perform any conceivable operation of logic or computation by reading and writing on a data/program tape. Stated otherwise, and in a way that is easier to relate to biology, the machine manipulates information and, because arithmetic is incomplete [as illustrated in the introduction above (Hofstadter, 1979)], it is able to create information. The machine is therefore in essence unpredictable (Turing, 1936–1937), but not in a random way – quite the contrary, in a very interesting way, as lack of prediction is not due to lack of determinism, but due to a creative action that results in novel information. If the image is correct, then it shows that living organisms are those material systems that are able to manipulate information so as to produce unexpected solutions that enable them to survive in an unpredictable future (Danchin, 2003, 2008a).

There we go, organisms can be viewed as entities that are able to manipulate information as a means to an end. Why would it be difficult to accept that cells to behave like computers? Yet, cells are capable of more than computers, e.g. self-replication and autonomous manipulation of information.

A form of endogenous adaptive mutagenesis (EAM) is also being alluded to in the article:
Living organisms are, therefore, infinitely far removed from the clockwork mechanicism that superficial opponents of molecular biology associate with the widespread analytical stance they call ‘reductionism’ (Lewontin, 1993). It is important to emphasize here that, in the Turing machine, the machine is not only allowed to read the program but also to write on it. If, then, the conjecture of the cell as a Turing machine is valid, apparent paradoxes such as the controversial ‘adaptive mutations’ that enable the cell to invent novel metabolic pathways should not be unexpected (Cairns et al., 1988; Danchin, 1988b).

There is also room for drawing parallels between evolution, memetic algorithms and designed molecular docking programs.

Finally, we must note that the algorithmic approach, presented when considering the genetic program as an authentic program in a Turing machine (Danchin, 2003), identifies two completely different levels: the level of the program and the level of the machine.

The article continues to discuss at length the parallels between our own created information processing systems (computers) and molecular processes fundamental to life. The article is sure to provide information for many more interesting blog discussions.

Friday, December 5, 2008

The Kinesin Motor Machine.

ScienceDaily (Dec. 4, 2008) — MIT researchers have shown how a cell motor protein exerts the force to move, enabling functions such as cell division.
Kinesin, a motor protein that also carries neurotransmitters, "walks" along cellular beams known as microtubules. For the first time, the MIT team has shown at a molecular level how kinesin generates the force needed to step along the microtubules.
Microtubules, quantum physics, and consciousness? Microtubules form tracks for neurotransmitters to be transported and can possibly act as quantum computational structures.

The researchers, led by Matthew Lang, associate professor of biological and mechanical engineering, report their findings in the Nov. 24 online early issue of the Proceedings of the National Academy of Sciences.

Because kinesin is involved in organizing the machinery of cell division, understanding how it works could one day be useful in developing therapies for diseases involving out-of-control cell division, such as cancer.

The protein consists of two "heads," which walk along the microtubule, and a long "tail," which carries cargo. The heads take turns stepping along the microtubule, at a rate of up to 100 steps (800 nanometers) per second.

In the PNAS paper, Lang and his colleagues offer experimental evidence for a model they reported in January in the journal Structure. Their model suggests — and the new experiments confirm — that a small region of the protein, part of which joins the head and tail is responsible for generating the force needed to make kinesin walk. Two protein subunits, known as the N-terminal cover strand and neck linker, line up next to each other to form a sheet, forming the cover-neck bundle that drives the kinesin head forward.

"This is the kinesin power stroke," said Lang.

Next, Lang's team plans to investigate how the two kinesin heads communicate with each other to coordinate their steps.

Lead author of the PNAS paper is Ahmad Khalil, graduate student in mechanical engineering. Other MIT authors of the paper are David Appleyard, a graduate student in biological engineering; Anna Labno, a recent MIT graduate; Adrien Georges, a visiting student in Lang's lab; and Angela Belcher, the Germehausen Professor of Materials Science and Engineering and Biological Engineering. This work is a close collaboration with authors Martin Karplus of Harvard and Wonmuk Hwang of Texas A&M.

The research was funded by the National Institutes of Health and the Army Research Office Institute of Collaborative Biotechnologies.
Few videos describing the motor:
Kinesin Transport Protein
Kinesin Explanation

Mice with a few kinesin mutations? Look like there is something wrong with their neurphysiology, almost like they are not interacting with the environment in the correct way?
Kinesin mutations in mice

Ever wondered how cellular machinery causes replication of cells?
Awesome video:
Inside the cell
And it does not even remotely cover the intricate mechanisms controllong the process.

Another video of mitosis:
Active cyclinB/cdc2 plays a part in nuclear envelope breakdown, and destruction of cyclinB and abolition of cdc2 activity allows nuclear envelope formation.

In real life it looks something like this:

Idle Control Units and Metabolomics

Well designed cars have well designed idle control units that spontaneously kick in to maintain the speed of the crankshaft within a pre-set range (usually >200rpm). An interesting study has demonstrated that 4 single celled organisms in two domains of life (bacteria and eukaryotes) uses the same number of biochemical reactions when optimizing growth.

Spontaneous Reaction Silencing in Metabolic Optimization
From the article:
Performing numerical optimization in glucose minimal media (Materials and Methods), we find that the number of active reactions in such optimal states is reduced by 21%–50% compared to typical non-optimal states, as indicated in the middle bars of Figure 2. Interestingly, the absolute number of active reactions under maximum growth is, 300 and appears to be fairly independent of the organism and network size for the cases analyzed. We observe that the minimum number of reactions required merely to sustain positive growth [7,8] is only a few reactions smaller than the number of reactions used in growth-maximizing states (bottom bars, Figure 2). This implies that surprisingly small metabolic adjustment or genetic modification is sufficient for an optimally growing organism to stop growing completely, which reveals a robust-yet-subtle tendency in cellular metabolism: while the large number of inactive reactions offers tremendous mutational and environmental robustness Papp:2004dn, the system is very sensitive if limited only to the set of reactions optimally active. The flip side of this prediction is that significant increase in growth can result from very few mutations, as observed recently in adaptive evolution experiments.
Reaction irreversibility and spontaneous cascading (article) of inactivity are described as built-in mechanisms that mediate these metabolic adjustments. The authors also point out that 638 out of the 931 reactions in the E. coli glucose metabolic network can be removed whilst maintaining a maximum growth rate in glucose. The mutational robustness as a result of inactive reactions under maximum growth thus act as a sort of preadaptation whereby different pathways can be spontaneously activated under shifting environmental conditions.

The tremendous robustness of these systems raises an interesting question regarding the origins of these non-essential pathways under maximum growth rates. The authors provide a testable hypothesis:
An alternative explanation would be that in variable environments, which is a natural selective pressure likely to be more important than considered in standard laboratory experiments, the apparently dispensable pathways may play a significant role in suboptimal states induced by environmental changes. This alternative is based on the hypothesis that latent pathways provide intermediate states necessary to facilitate adaptation, therefore conferring competitive advantage even if the pathways are not active in any single fixed environmental condition.

This alternative is based on the hypothesis that latent pathways provide intermediate states necessary to facilitate adaptation, therefore conferring competitive advantage even if the pathways are not active in any single fixed environmental condition. In light of our results, this hypothesis can be tested experimentally in medium-perturbation assays by measuring the change in growth or other phenotype caused by deleting the predicted latent pathways in advance to a medium change.
Even more intriguing is the fact that metabolic adjustments are also controlled by anticipatory transcriptional reprogramming in response to environmental changes. It is posited to be as result an “associative learning” paradigm.

Looking at the motor industry again, anticipatory systems and structures have been designed in order to optimize the structure stiffness for a particular crash scenario. Pre-crash sensing is used to adjust structural stiffness and crumple zones in response to a particular deceleration scenario in order to maximize the crash worthiness of the vehicle. It seems this kind of anticipatory programming is an ancient invention, a few billion years old.

Using this information, another core element can be added to an initial state: Robust metabolic networks with tremendous adaptability that "idle" under maximum growth conditions.

Figure 1: An initial state. Reverse engineer ubiquitous core components of various life forms at present. Will it repeatedly produce similar endpoints after evolutionary processes, irrespective of its origin?

Tuesday, November 25, 2008

Protein folding, Nanotubes and Engineering

More on protein folding:
Many proteins have intricate folds and one of these fold types include the figure eight knot fold. A team of researchers tried to figure out how these proteins are folded. At present, it is only known that the knot is formed quickly soon after polypeptide chain formation, with an unknown mechanism. The researchers tentatively propose:
"an early threading event may be the defining feature of a polypeptide-knotting with the ensuing folding occurring in a similar fashion to unknotted proteins; the folding of a knotted protein differs only with an initial knotting event in a denatured-like state."

Perhaps an an as of yet undiscovered knot-folding machine?
Article: Exploring knotting mechanisms in protein folding

And nanotubes? Bah, old news... a few hundred million years old...
Tunnelling nanotubes: Life's secret network
The closest animal equivalents to plasmodesmata were thought to be gap junctions, which are like hollow rivets joining the membranes of adjacent cells. A channel through the middle of each gap junction directly connects the cell interiors, but the channel is very narrow - just 0.5 to 2 nanometres wide - and so only allows ions and small molecules to pass from one cell to another.

Nanotubes are something different. They are 50 to 200 nanometres thick, which is more than wide enough to allow proteins to pass through. What's more, they can span distances of several cell diameters, wiggling around obstacles to connect the insides of two cells some distance apart. "This gives the organism a new way to communicate very selectively over long range," says Gerdes. It is a previously unknown way in which cells can communicate over a distance

Soon after they first saw nanotubes in rat cells, he and Rustom saw them forming between human kidney cells too. Using video microscopy, they watched adjacent cells reach out to each other with antenna-like projections, establish contact and then build the tubular connections. The connections were not just between pairs of cells. Cells can send out several nanotubes, forming an intricate and transient network of linked cells lasting anything from minutes to hours. Using fluorescent proteins, the team also discovered that relatively large cellular structures, or organelles, could move from one cell to another through the nanotubes
Their work, published in May, shows that nanotubes are not just an artefact of the methods used to grow cells in culture, as some have suggested. And what they have seen is spectacular: some of the longest tunnelling nanotubes ever observed, more than 300 micrometres long, connecting dendritic cells in the cornea (The Journal of Immunology, vol 180, p 5779). "We can see them their whole course, spindling all the way through the cornea," says McMenamin. "It's fantastic."

"I'll bet you that within weeks to months, people will start noticing them in other tissues. It's just a case of how you look," he adds. "You've got to know what you are looking for. It's a bit like being a good bird-watcher. A hundred people will see a flock of seagulls, and it's only a very good bird-watcher who will spot this one tern flying in that flock."

Gerdes, meanwhile, continues to marvel at what is unravelling before his very eyes. "Whatever one can think of has been done by nature," he says. "It is unbelievable what the cell is able to do."
One striking feature that makes us different from other primates is our innate ability to develop a theory of mind at around 4-6 years. We start to develop the remarkable ability to simulate what other people are thinking and understand their thoughts through our own thinking. We also create our own model of the world in our own minds that leads to understanding of concepts.

Attempting to unravel nature's mysteries by trying to look at it from another engineering Mind's eye seems to make sense when one marvels at the engineering feats in cells. Why not?

Replication Machinery and Transcription Factories

How DNA Is Unwound So That Its Code Can Be Read
ScienceDaily (Nov. 24, 2008) — Researchers at The Scripps Research Institute have figured out how a macromolecular machine is able to unwind the long and twisted tangles of DNA within a cell's nucleus so that genetic information can be "read" and used to direct the synthesis of proteins, which have many specific functions in the body.
"This is a fundamental processes that takes place countless times inside each of our cells every day, but how it happens had not been understood." says the study's lead investigator, Francisco Asturias, Ph.D., associate professor in the Department of Cell Biology at Scripps Research. "The structure we have solved provides important clues into one of the first steps in gene expression regulation."
Anybody interested in some of the 3D-structure, go to

"Remarkable Unpacking and Repacking"

To understand the complexity of the process, it is important to know that if the DNA in each cell were stretched out, it would be more than three feet long—and given the trillions of cells within a human body, it has been calculated that a single individual's DNA could stretch to cover the distance to the sun and back many times over.

So DNA must be packaged into tidy little chromosomes. The DNA in each gene first assembles into what looks like a string of beads: the string is the DNA and to compact its length, it is wrapped two times around a spool-like bead of histone protein, to form a nucleosome. But there is so much DNA in a single gene that each gene is packed into a necklace of nucleosomes on a DNA string. These beads then become further compressed into twisted ropes that eventually form chromatin, in which DNA is compacted about 10,000 times from its extended length.

What the Scripps Research scientists set out to do is to understand how the RSC complex unwinds DNA from the many histone beads within a gene so that other molecular machines can read the genetic code.

RSC is a huge complex of 13 different proteins and the scientists first found that it holds an individual nucleosome in what looks like a vise grip. They then found that RSC creates a little bulge in the DNA that can be propagated around the nucleosome and make possible translocation of the DNA with respect to the histones, exposing the DNA so that it can be read.

"Imagine a rubber band wrapped twice around a water glass. The easiest way to move the band is to pull a little of it away from the glass and then slide it" Asturias says. "By using energy from an external source (ATP hydrolysis) RSC can repeatedly pull DNA away from the histones and eventually expose all of the DNA."

The researchers believe that by translocating a nucleosome along the DNA, RSC eventually slides into the next adjoining nucleosome, causing the histones to be ejected and exposing the DNA. "Interestingly, although its DNA is gradually exposed, the nucleosome to which RSC is bound remains intact," Asturias says.

The structure RSC interacting with a nucleosome explains how previously observed DNA bulges formed by chromatin remodeling complexes are formed, and why a single intact nucleosome appears to be left on a fully activated gene before other cellular machinery scoop up the histones and repack the DNA until it needs to be read again.

"Every time your cell expresses a gene, it goes through this remarkable unpacking and repacking," he says. "We are happy to have provided some clarity to the process."
Published article:
Structure of a RSC–nucleosome complex and insights into chromatin remodeling

Nice video showing DNA wrapping.

An interesting blog entry (and an interesting blog worth a read) describes how the transcription machinery is assembled and disassembled in a few sites in cells.

Yet another twist in the world of gene expression - transcription factories

First of all I will ask you, did you know that transcription only happened at a few sites within the nucleus? In mouse cells from the animal there are between 100-300 of these but in cultured cells such as HeLa cells there are many more. Transcription factories also known as RNAPII foci are where most, if not all mRNA is produced. This amazed me and raises the obvious questions of why and how. The why may be obvious. It is a good idea to keep the nucleus as I see it ‘tidy’ but in more technical terms it is a way of keeps gene expression organised and regulating it (see below). The how this work I don’t think has been addressed! All I can say is watch this space.
There is more there.