Saturday, July 26, 2008

Life's toolkits

Life has a genetic toolkit to build a wide variety of forms from just a few basic, simple and elegant body plans.

Take this into consideration and take a look at how stem cells become specialized.
Many Paths, Few Destinations: How Stem Cells Decide What They'll Become.
How does a stem cell decide what specialized identity to adopt -- or simply to remain a stem cell? A new study suggests that the conventional view, which assumes that cells are "instructed" to progress along prescribed signaling pathways, is too simplistic. Instead, it supports the idea that cells differentiate through the collective behavior of multiple genes in a network that ultimately leads to just a few endpoints -- just as a marble on a hilltop can travel a nearly infinite number of downward paths, only to arrive in the same valley.
The findings, published in the May 22 issue of Nature, give a glimpse into how that collective behavior works, and show that cell populations maintain a built-in variability that nature can harness for change under the right conditions. The findings also help explain why the process of differentiating stem cells into specific lineages in the laboratory has been highly inefficient.
"Nature has created an incredibly elegant and simple way of creating variability, and maintaining it at a steady level, enabling cells to respond to changes in their environment in a systematic, controlled way," adds Chang, first author on the paper.
The landscape analogy and collective "decision-making" are concepts unfamiliar to biologists, who have tended to focus on single genes acting in linear pathways. This made the work initially difficult to publish, notes Huang. "It's hard for biologists to move from thinking about single pathways to thinking about a landscape, which is the mathematical manifestation of the entirety of all the possible pathways," he says. "A single pathway is not a good way to understand a whole process. Our goal has been to understand the driving force behind it."
So stem cells have a built-in toolkit that responds to random changes, enabling then to respond to changes in their environment in a systematic and controlled way, ultimately leading to just a few endpoints. The toolkit harnesses random variation and selection to reach the same destination.
The stem cells are front-loaded (provided with a toolkit) to develop along a certain path while harnessing random variation and selection.

Key Regulator Of DNA Mutations Identified
As a general rule, your DNA is not something you want rearranged. But there are exceptions – especially when it comes to fighting infections. Since the number of microbes in the world far surpasses the amount of human DNA dedicated to combat them, specialized cells in the immune system have adopted an ingenious, if potentially disastrous, strategy for making antibodies. These cells, called B lymphocytes, intentionally mutate their own DNA to ward off invaders they have never seen before.
B lymphocytes have a toolkit that regulates mutations for the purpose of generating antibodies. Thus, here we have another toolkit that harnesses random variation and selection to intentionally generate variety for the purpose of producing novel antibodies.

How many more toolkits that harness quantum randomness and selection to generate controlled variety will we discover?

Genetic toolkits in action:
New Evidence That Ancient Choanoflagellates' Form Evolutionary Link Between Single-celled And Multi-celled Organisms
Evolutionary Origin Of Mammalian Gene Regulation Is Over 150 Million Years Old
Marsupials And Humans Share Same Genetic Imprinting That Evolved 150 Million Years

Thursday, July 24, 2008


Intelligence is associated with a property of mind.
From wiki:
From the first sentence:
Intelligence (also called intellect) is an umbrella term used to describe a property of the mind that encompasses many related abilities, such as the capacities to reason, to plan, to solve problems, to think abstractly, to comprehend ideas, to use language, and to learn.
Artificial intelligence
From this article a few essential traits of intelligence are considered:
1) Deduction, reasoning, problem solving
2) Knowledge representation
3) Planning
4) Learning
5) Natural language processing
6) Motion and manipulation
7) Perception
8) Social intelligence
9) Creativity
10) General intelligence

However, there is no universally accepted definition of intelligence.
So let's take what we do know about intelligence (the 10 criteria above) and compare the systems and machinery within cells to any intelligent AI system.

1) Deduction, reasoning, problem solving
Deduction: No
Reasoning: No
Problem solving: Yes. E.g. (from Nature;Vol 446;12 April 2007: Quantum path to photosynthesis)
Elsewhere in this issue, Engel et al. (page 782) take a close look at how nature, in the form of the green sulphur bacterium Chlorobium tepidum, manages to transfer and trap light’s energy so effectively. The key might be a clever quantum computation built into the photosynthetic algorithm.
The process is analogous to Grover’s algorithm in quantum computing, which has been proved to provide the fastest possible search of an unsorted information database.
And in the same issue: Evidence for wavelike energy transfer through quantum coherence in photosynthetic systems
When viewed in this way, the system is essentially performing a single quantum computation, sensing many states simultaneously and selecting the correct answer, as indicated by the efficiency of the energy transfer.
Who knows what other kinds of quantum computing we will discover in organisms? Perhaps a clever quantum “trick” together with coulombic interactions in the bifurcated electron transfer of bc1-like complexes through the Q-cycle? Microtubles, centrioles etc.?

Deduction: No
Reasoning: No
Problem solving: Yes. (not quantum mechanically)

2) Knowledge representation
Default reasoning and the qualification problem: No?
Unconscious knowledge: Perhaps? Stored in any or all of the cellular codes?
The breadth of common sense knowledge: No.
Default reasoning and the qualification problem: No
Unconscious knowledge: Yes. The software contains the stored information
The breadth of common sense knowledge: No

3) Planning
Cells: Possibly yes!
Predictive Behavior Within Microbial Genetic Networks

We question whether homeostasis alone adequately explains microbial responses to environmental stimuli, and explore the capacity of intra-cellular networks for predictive behavior in a fashion similar to metazoan nervous systems. We show that in silico biochemical networks, evolving randomly under precisely defined complex habitats, capture the dynamical, multidimensional structure of diverse environments by forming internal models that allow prediction of environmental change. We provide evidence for such anticipatory behavior by revealing striking correlations of Escherichia coli transcriptional responses to temperature and oxygen perturbations—precisely mirroring the co-variation of these parameters upon transitions between the outside world and the mammalian gastrointestinal-tract. We further show that these internal correlations reflect a true associative learning paradigm, since they show rapid decoupling upon exposure to novel environments.
Emphasis mine.

Microarray transcriptional profiling was employed to determine whether gene expression correlates with the observed global cellular state and physiological responses. And indeed it does.
From the study it was determined that anticipatory transcriptional reprogramming occurs in response to aerobic and anaerobic environmental changes and these anticipatory transcriptional reprogramming events are as a result an “associative learning” paradigm. Is this an example of harnessing random variation and selection that allow for predictive transcriptional reprogramming in response to environmental change that gives the illusion of foresight? Creativity?

It should also be interesting to determine how big a part riboswitches play in this phenomenon.

AI:Yes if programmed to.

4) Learning
Cells: Yes, see "planning".
AI: Yes, certain artificial neural networks are capable of this.

5) Natural language processing
Cells: Yes and no. Yes because cells are able to communicate and process information from themselves and other cells (autocrine, paracrine, endocrine etc). No, cells do not consciously talk to exchange concepts and ideas.
AI: Yes and no. Yes because certain programs can interpret human language and systems of various platforms can communicate (Linux to Mac etc). No, AI does not consciously talk to exchange concepts and ideas.

6) Motion and manipulation
Cells: Yes, with the possibility that tubulin and other structural components of cells acting as quantum computers, motion and manipulation is directed, not stochastic, in even the simplest organisms.
Movement of organisms without a nervous system.
Also here:
Interesting site about cell intelligence and movement.
AI: Yes

7) Perception
Cells: Yes, cells communicate with the environment through surface receptors and relays information through signal transduction which in turn affects gene expression and protein activity which it turn results in predictive cell responses. Information from the environment is also processed via the multiples codes, e.g. histone code, ribosomal code and the standard genetic code.
AI: Yes

8) Social intelligence
Cells: Yes, even bacteria interact with other bacteria and can even mimic a multicellular organism through quorum sensing.
AI: Perhaps? AI neural networks?

9) Creativity
Cells: Perhaps? Harnessing random variation and selection to adapt?
AI: Perhaps? An example?

10) General intelligence
Cells: No (Only in humans so far)
AI: No

At present, even traditionally viewed simple cells outsmart our best efforts at AI.

I don't know where to put the following:
Cell's 'Quality Control' Mechanism Discovered
Is this an example of a non-passive selection system to remove mutated proteins from the population, even if the mutated proteins are functional? Perhaps a system that preserves a set of proteins? Unconscious knowledge (2)? Constrained creativity (9)?
This mechanism (system?) is not limited to eukaryotic cells. The ERdj5 enzyme operates in eukaryotes. The DnaJ enzyme is a homlogous chaperone protein in bacteria that carries out virtually the same function. Also known as heat shock 40 proteins (HSP40).
The DNAJ gene family.
DnaJ is also found in primitive eubacteria, indicating that the system was present VERY early on during evolution.
Most eubacteria are gram positive, and they are generally less structurally complex than other bacteria.
ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C
ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER.

Seems interesting nonetheless.

Wednesday, July 23, 2008

Biomolecular animations

Molecular Biology Visualization of DNA
ATP synthase
Chaperone assisted protein folding, 3D animation
mRNA Splicing
Protein Translation


One of the most intriguing group of proteins is a group of proteins that assist in the folding and unfolding of macromolecular structures into the correct 3D-architecture, prevents protein clumping and transport damaged or improperly made proteins to be recycled. The chaperones (a lot of them are also known as heat-shock proteins)

Great video

New Insights Into Hidden World Of Protein Folding

"Folding is one of the key steps for the health of the cell," Frydman said.

Virtually all proteins have to be folded-some in complex configurations-in order to function properly, and many are known to require a molecule called a chaperone to fold them. Frydman estimates that perhaps 10 percent of the proteins needing chaperones must have one that, like TRiC, is part of the subset called chaperonins. Other work done in Frydman's lab has shown that proteins that have very complex folds seem to require chaperonins.

"Many of the proteins that have these complex folds are the most important ones for life," Frydman said. "The proteins that control the cell cycle, tumor suppressers and the proteins that control the shape of the cell are dependent on chaperonins to get to the folded state.

"If the chaperones don't work well, then all these proteins that have been made become toxic," she said.
“One of the great mysteries of biology is how life could have evolved so rapidly,” says Lindquist. “This research gives at least one plausible explanation for the speed of evolution and for the evolution of complex traits affected by several genes.”
“One stressful event can affect many traits and allow previously unseen genetic variation to be expressed,” says Sangster. “We don’t know yet what is going on at the molecular level—why the HSP90-dependent traits are expressed when the plants are mildly stressed.”
Seeing that the structure and functionality of sliding clamps and clamp loaders (not an isolated case btw) are conserved across the three domains of life with very little sequence similarity it seems reasonable that chaperones played a part in conserving the structure and functionality of selected proteins over deep time while retaining flexibility and allowing sequence variability.
This ties in nicely with the robust Universal Optimal codon Code that allows for variation but also buffers against the effects of mutation.

The bc1-complex for electron transfer from dihydroubiquinone to cytochrome c through the Q-cycle.

The bc1-like complexes (Complex III in mitochondria) play a central role in the electron transport chains of respiratory and photosynthetic machinery.

Their function is to carry out a sequence of electron and proton transfer reactions to generate a trans-membrane proton motive force that supplies the energy for ATP synthesizing utilizing the ATP synthase (excellent video, funny clip) machinery. Protons and electrons are supplied by dihydroubiquinone which in turn is generated by complexes I and II of the electron transport chain.

How do the bc1-like complexes carry out their function?
First the structure:
Figure 1: Bc1-complex
The cyt bc1-complex contains two separate redox chains; High potential and low potential.
The high-potential chain connects the Qo-binding site with the cyt c1 through the Rieske Iron-sulphur-protein (RISP). The RISP is situated on a rotateable arm that is able to connect the cyt c1 component with the Qo-binging site.
The low potential chain connects the Qo-site with the Q1-site through the cyt BL and Cyt BH complexes.

Now the mechanism. A bifurcated electron transfer mechanism:
Figure 2: Bifurcated electron transfer the Qo-site of the bc1-complex.

1) The lipid-soluble dihydroubiquinone molecule binds at the Qo-site and liberates one proton into the intermembrane space and in the process forms a semiubiquinone radical.
2) The RISP swings around to receives an electron from the semiubiquinone and donates it to cyt c1 which in turn donates it to cytochrome c. Cytochrome c plays its part in energy transfer to complex IV of the electron transfer chain.
3) A second proton is liberates into the intermembrane space and an electron is donated to the low potential chain, resulting in the formation of ubiquinone
4) At the Q1-site the electron is donated to ubiquinone to form semiubiquinone, while a proton is donated from the mitochondrial matrix.
5) In order for the formation of dihydroubiquinone at the Q1-site, two dihydroubiquinones must bins at the Qo-site.
6) Thus the end result is the formation of 1 dihydroubiquinone, 2 quinones, 4 intermembrane protons and 2 ferrocyrochrome c proteins and loss of 2 mitochondrial matrix molecules after the binding of 2 dihydroubiquinones at the Qo-site.

That is the basic general mechanism, however research is ongoing into how bypass reactions are avoided.
For example:
Why do the electrons flow in only one direction in the low electron transport chains?
Why aren't both electrons donated to the high-potential chain in the first place?
Radical hypotheses have been proposed including (From Cape et al. 2006 Trends Plant Sci. 2006 Jan;11(1):46-55.):
(i) A complex that can either stabilize the intermediate semiubiquinone, rendering it inert and invisible through some unknown mechanism, or that can use the unprecedented tactic of destabilizing its reactive intermediates.
(ii) A kinetic ‘water-park’ that tunes reaction activation enthalpies or entropies to route ‘water’ (electron) flow into productive channels.
(iii) A nano-machine that gates the electron and proton transfer reactions of semiubiquinone according to its recognition of the different redox and/or conformational states of the complex.
(iv) An extraordinary, and unprecedented, double concerted oxidation of dihydroubiquinone that simultaneously distributes two electrons and at least one proton between at least three different acceptors.
Options II and III do not exclude the possibility of quantum mechanics and coulombic interactions playing a role.

All-in-all a brilliant solution for a bifurcated electron transfer mechanism in order to generate a proton motive force from dihydroubiquinone.

Interestingly, the intermediate (semiubiquinone) generated at the Qo-site is believed to be a major contributor to the formation of reactive oxygen species by donating it's free electron to oxygen and thereby resulting in the formation of superoxide. Superoxide formation causes damage to various molecules including DNA, RNA, proteins and lipids.

Figure 3: Semiubiquinone

Paradoxically though, reactive oxygen specie generation at the Qo-site as a result of semiubiquinone formation is increased during periods of hypoxia (low oxygen). Hypoxia is a major initiator of cancerous growth because it activates various pro-growth signaling pathways. Hypoxia in cells usually occur as a result of poor circulation and delivery of oxygen. Obesity, lack of exercise and poor diet all contribute to these circumstances.

Thus, the bc1-complexes connects bad health choices with higher incidences of cancers and other mitochondrially related diseases through reactive oxygen species formation as a result of hypoxic conditions within various systems of the body.

Exercising and eating right are good for oiling your biomolecular machines. :)

Saturday, July 19, 2008

Sliding clamps, clamp-loaders and helicases.

Sliding clamps, clamp-loaders and helicases.
Sliding clamps are ring-shaped proteins that some refer to as the “guardians” of the genome or others name them as the “ringmasters” of the genome.
Interestingly these clamps are structurally and functionally conserved in all branches of life and crystallographic studies have shown that they have almost superimposable three-dimensional structures, yet these components have very little sequence similarity (Figure 1) [1].

Figure 1: Sliding clamps eukaryotes, bacteria, phages and archaea.

What do they do?
The picture below is taken from the Molecular Biology Visualization of DNA video (2:14) from the site (Figure 2).
Great video!
Figure 2: Replication machinery.

The following components can be seen.
Sliding clamps (PCNA in eukaryotes): Green circular shaped
Clamp loader (RFC in eukaryotes): Blue-white component in the middle
Helicase: Blue
DNA polymerase: Dark-blue components attached to the sliding clamps
Primase: Green component attached to helicase
Leading strand: Spinning off to the right
Lagging strand: Spinning off to the top

They are not ringmasters for nothing. Sliding clamps participate and control events that orchestrate DNA replication events in the following ways:
  • Enhancement of DNA polymerase activity.
  • Coordinate Okazaki fragment processing.
  • Prevention of rereplication
  • Translesion synthesis
  • Prevents sister-chromatid recombination and also coordinates sister-chromatid cohesion
  • Crucial role in mismatch repair, base excision repair, nucleotide excision repair
  • Participates in chromatin assembly
Other functions include:
  • Epigenetic inheritance
  • Chromatin remodeling
  • Controls cell cycle and cell death signaling

The true ringmasters.

Clamp loaders are another group of interesting proteins (see video and figures 3-4).
Figure 3: Structures of Proliferating Cell Nuclear Antigen connected to
Replication factor C (Front).

Figure 4: Structures of Proliferating Cell Nuclear Antigen connected
Replication factor C (Side).

Interestingly again, their functional and structural architecture are conserved across the three domains of life with low-level sequence similarity [2]. At the replication fork during replication, they load the sliding clamps many times onto the lagging strand (after DNA priming) and only once onto the leading strand. They also act as a bridge to connect the leading and lagging strand polymerases and the helicase. Which brings us to another interesting group of proteins; the helicases.

Helicases are also known to be ring-shaped motor proteins, typically hexamers (see figure 5) and separate double-stranded DNA into single-stranded templates for the replication machinery.
Figure 5: Helicase

Replication occurs at about 1000 base pairs per second due to the highly efficient combination of sliding clamps and the polymerases. Thus, helicases need to unwind DNA at at least that speed. Unwinding DNA too slowly and the replication machinery might break down . Unwind the DNA too fast or untimely and harmful mutations might occur as single-stranded DNA is prone to degradation and cytosine deamination.

The speed at which helicase unwinds DNA is no accident though, as it is intrinsically controlled. As helicase is bound to the lagging strand, it unwinds the leading strand in a separate direction. Applying a pulling force on the leading strand leads to a 7-fold increase in the speed of DNA unwinding by helicase [3, 4]. The highly efficient DNA polymerase/sliding clamp combination provides this controlling force on the leading strand. This forms a robust unwinding/polymerization interaction whereby polymerization controls and prevents unwanted DNA unwinding.

Altogether, the replisome machinery provides a robust way for DNA replication to prevent unnecessary DNA damage and mutation.

1. Vivona JB, Kelman Z. The diverse spectrum of sliding clamp interacting proteins. FEBS Lett. 2003 Jul 10;546(2-3):167-72.
2. Jeruzalmi D, O'Donnell M, Kuriyan J. Clamp loaders and sliding clamps. Curr Opin Struct Biol. 2002 Apr;12(2):217-24.
3. Ha T. Need for speed: mechanical regulation of a replicative helicase. Cell. 2007 Jun 29;129(7):1249-50.
4. Johnson DS, Bai L, Smith BY, Patel SS, Wang MD. Single-molecule studies reveal dynamics of DNA unwinding by the ring-shaped T7 helicase. Cell. 2007 Jun 29;129(7):1299-309.

Biomolecular machines

Let's have a look at the recent interesting discoveries regarding the intracellular biomolecular machinery that are crucial for life to exist.

Intracellular biomolecular machinery include the following:
1) DNA replication and repair machinery (replisome)
2) DNA transcription machinery and RNA processing and translation machinery (Spliceosomes and ribosomes)
3) Cell cycle signaling network (pRB, e2F, CDKs)
4) Programmed cell death machinery (Apoptosis, autophagy, mitotic catastrophe etc.)
5) Protein processing machinery (Chaperones, ubiquitin-proteasome system)
6) Intracellular signaling networks (protein kinases and phosphatases)
7) Mechanical machines for intracellular shuttling of biomolecules and cellular movement (Microtubule network, kinesin, dynein)
8) Energy production machines (Electron transport chain, F0F1 ATP synthase)



During the last few years I have become increasingly interested in the philosophical debates and metaphysics. The evolution vs intelligent design debate seems like a recent manifestation between religion and science. It is not. It goes as far back 500BC where two opposing groups of scholars have dueled it out. In the one corner you have the teleologists and in the other corner you have the non-teleologists. Famous teleologists from Greece include Aristotle, Plato, Diogenes, Socrates and non-teleologists include Democritus, Leucippus, Empedocles and Epicurus [Teleology and science]. More modern examples of teleologists include Kant, Darwin, Paley and Aquinas while non-teleological examples include Hume, Locke and Dennett.

It does not look like the debate is going to be settled anytime soon. So what to do? I like this:

Take the analogy of a duck and a rabbit:
From The Design Matrix p123:
Evolution is supported by a vast amount of evidence. If it walks like a duck, quacks like a duck, looks like a duck, it is a duck. So let us view non-teleological evolution as the Duck. In contrast, Intelligent Design is rooted in a long tradition of thinking, but supported mainly by suggestive clues. Following the trail of Intelligent Design may be akin to chasing Allice's rabbit down the rabbit hole. Let us think of Intelligent Design as the Rabbit.

Of course, in the end, any particular biological feature either arose through non-teleological evolution or it was intelligently designed. Yet if the situation is ambiguous, where both the Duck and Rabbit can be seen, we have a choice. We can choose to follow the rabbit, let us not worry about killing the duck or attempting to convince ourselves there never was a Duck. Instead, let us keep out eye on the Rabbit and see where it goes.

How deep does the rabbit hole go?

Have fun, enjoy the ride!

Addendum (01/06/2010): I have become increasingly interested in peripatetic philosophy, especially the Aristotelian-Thomistic (A-T)version. Thus, future posts will include terminology asociated with A-T naturalism. These include:
Essence and Existence
Potency and Act
Prime matter, proximate matter, accidental form, substantial form.
Substance and Accident
Four causes: material, efficient, formal and final.
Powers, ends and inclinations
Immanent and transcendent causation etc.