Duroquinone: A Parallelly Processing Chemical Computer

Dr Anirban Bandyopadhyay of the National Institute for Materials Science, Tsukuba, Japan, have developed a tiny chemical nano-brain, that could one day be guided by remote control. These machines could make surgery on human bodies easier and help revolutionize the computing power of future computers.

Scientists have built nanobots (nanoscale robots; nano means a billionth of a metre) previously but these bots could not be controlled by outside means. Dr. Bandyopadhyay has now devised a nanobot, a chemical one and not mechanical or electronic one, that can be controlled from outside.

This promising nanomachine, just 2 billionths of a meter across, consists of a molecule called duroquinone. A single nanomachine comprises of 17 duroquinone molecules; with one molecule at the center and remaining 16 surrounding it. All these molecules are connected by hydrogen bonding. As is shown in the figure, each duroquinone molecule has four spoke like arms jutting out from it, which can be independently rotated to represent four different states. Thus they can be made to represent four different 'logic states', bits: 0,1,2,3. While ordinary computers work on binary logic (0,1), computers using this technology would have four billion possible combinations with this chemical brain.

The molecule at the center, to which the rest are connected, can be controlled by a scanning tunneling microscope (STM). This machine is not only capable of 'manipulating/directing' their (nanobots') orientations, it is also capable of 'reading' the states they are in. They act rather like both a transducer and a receiver. By tweaking the central molecule, one could switch the nanobot's configurations. Comparable switches in electronic circuits include CD4066, a quad bilateral switch, electrical relays, transistors and others. But here, we are controlling a chemical device by using STMs. In future, we may be able to operate the duroquinone machinery by using the conformational properties of proteins, by optical devices like lasers and may be other electromagnetic devices too.

The researchers were inspired by the parallel processing circuitry of the glial cells in the brain.
Said Dr. Bandyopadhayay, "Doctors will inject molecular machines attached to similar control unit, the assembly will go to the target part inside our body through veins, and carry out bloodless surgery. Till now several molecular machines have been built, prior to this work, but there were no machine that could control them."

Recent Advances in Memory Research

Though how memory is formed, stored or retrieved has not been elucidated yet, things are beginning to unfold as new advances begin to break the frontiers. It was long thought that long term memories (memories such as the persons own name), which remain steadfastly seated in the brain, were etched permanently in the brain. But, recent advances in research has proved to the contrary. Long term memories are not like something as a computer's ROM (Read Only Memory, which once stored can not be erased and it does not need any maintenance current once the data had been entered; EPROM and EEPROM are exceptions), but it resembles a computer's RAM (Random Access Memory, which needs to be continuously fed with electricity in order to retain its memory).

In a classic experiment by Prof. Yadin Dudai, Head of the Department of Neurobiology at Weizmann Institute of Science, Israel, and colleagues had trained rats to learn to avoid certain tastes. This is called conditioned avoidance, a form of operant conditioning (learning that is influenced by environment). This is done by giving an unpleasant stimulus such as electric shock or injecting substances that cause discomfort, along with some foods. Thus the animals 'remember' to avoid these foods which are associated with bad accompaniments. Prof. Yadin Dudai had injected a chemical, an inhibitor of a protein called PKM zeta, into the rats' taste cortex. A single administration was found to erase the long term memories of those rats completely. The rats forgot which tastes they were to avoid.

PKM zeta (or Protein Kinase M zeta) is an isoform of protein kinase C, an enzyme present within the cell membrane. This molecule (PKM zeta) is necessary for an already learned and deep rooted response (long term memory) to remain long term. The constant ferrying activity of PKM zeta in the synapse (junction between two neurones) is needed for the memory to be retained, reminding us of the constant supply of electricity needed in the RAM of computers to retain its memory. Thus the long founded idea that long term memories were etched permanently into the brain is now being challenged and a new dynamically modeled approach such as this is emerging.

A process called long term potentiation (LTP) occurs in the brain which help us to learn. Repeated high frequency stimulation of a synapse strengthens it by LTP. It should be noted in this context that nicotine helps in memory formation since it stimulates the inhibitory inputs to layer V pyramidal cells. These cells exert a negative influence on LTP based learning. Hence suppression of these cells by nicotine helps in memory formation.

Another very useful discovery is the development of a new microscopic technique that has allowed us to 'see' memory traces in the brain. Using restorative deconvolution microscopy, scientists at the university of California at Irvine, has shown how the synapse had expanded after LTP. If you think of the synapse as the space between two balloons, you will realize that by pressing these balloons towards each other, the balloon ends will flatten, leading to a broader synapse with a larger contact area. Just as in Ohmic resistance of electricity, here also the apparent resistance will diminish, leading to a faster and better processing and storing.

Such long giant leaps are needed to achieve better nootropics (memory enhancers), treat and cure Alzheimer's disease and related conditions.

Protein Folding And Disease: Nature's Own Origami

Human body is like a very complicated computer. It's code (genetic) is written in 4 letters: Adenine, Cytosine, Guanine and Thymine, compared to 2 letters (0,1) in computers. But in our cases, this code is again translated into another language using 20 letters, the 20 amino acids, genes produce by the way of transcription and translation. This language of the proteins that forms, as a result of combinations (and permutations) of these amino acids, is not a word for word (verbatim) dictation by the human genome. Genes only tell the order in which one protein would arrange itself like the beads in a string, where the beads are individual amino acids.

Proteins then fold themselves (much like origami: the ancient Japanese art of paper folding), adding another dimension to this language. This folding is dictated by numerous factors like charge, hydrophilicity, hydrophobicity, van der Waals forces, hydrogen bonding etc. Once they fold upon themselves, they are accompanied by chaperone proteins, so that this configuration is preserved (like write protecting in computers). Any misfolding, due to aging or some other defect, is severely dealt with by a peptide consisting of 74 amino acids, called ubiquitin. It tags the defectively folded proteins to be destroyed, for removal, in a multi unit intracellular factory called proteasome, in much the same way a Windows computer would tag a file to be deleted to the recycle bin. Many diseases occur from misfolded proteins, Alzheimer's disease, Prion diseases like bovine spongiform encephalopathy or mad cow disease etc. In Alzheimer's for example, a protein named beta amyloid accumulates in the brain. We normally produce beta amyloid in our brains, but this amyloid is in soluble form. Proteins consist of both water dissolving (hydrophilic) and water non dissolving (hydrophobic) amino acids. In normal beta amyloid, the hydrophilic domains lie outward while the hydrophobic domains are kept in the interior. Thus, it remains soluble in the interstitial body fluids. But when this protein is misfolded, the hydrophobic domains are exposed, making it immiscible in water, allowing it to aggregate in clumps, called neurofibrillary tangles. This tangle presumably strangles the neurones and causes AD. Thus it is necessary that we understand the property of the tertiary structures (foldings) of proteins, in order to deal with such diseases.

Recently, scientists have developed a unique way to explore this. They are using atomic force microscopes (AFM) to have an understanding of this. They tied one terminal (end) of a protein to a substrate (serving as an anchor) and stretched the other end, which were tied to a very tiny cantilever, a part of the AFM itself. Then they released this (cantilever end) and measured the intermediate energy it released, as it went back to the equilibrium point (previous state), reminding us of the way we measured the energy stored in a spring (isn't it?). This 3D shaping as a function of energy, a measurable and objective quantity, would definitely help us decipher the enigmatic coils of proteins, thus help us tackle these deadly and disabling ailments effectively.

Cerebellum-Part3

Just as a phosphorescent object is best seen in absence of light, the functions of some organs of our body is best revealed when they are removed or malfunctioning. The best known example is perhaps that of Best and Banting's discovery of insulin on their pancreatectomized dogs, (i.e. dogs whose pancreas was removed). Likewise, cerebellar diseases reveal many of its functions/things, the healthy cerebellum apparently didn't.

In about 1% of alcoholics, there is degeneration of the cerebellum, particularly the vermis, a midline cerebellar structure. The person develops nystagmus (jerky movement of eyeballs), an increasingly unsteady gait; superimposed on an unsteady stance. Vitamins and other medications are of little use. However, this instance clearly signifies the cerebellum's role in maintaining posture and movement.

Other posture and movement abnormalities like intention tremor occurs. Distance measuring and rapidly alternating tasks are also hampered. The cerebellum analyzes the 'error voltage' and stores the best response in its memory: all this data are destroyed in cerebellar disease. Thus when a patient reaches out for the tip of his nose, with his index finger, for example, the finger overshoots and gets past the target. This occurs as the relevant database as to how much force to be applied and for how long, before the brake (activation of antagonist muscles) is applied; are destroyed. This is known as past pointing. Now the patient understands it and tries to correct the error. He past points again, and this process goes on. Intention tremor results.

Related article: Cerebellum, electronically speaking
The Cerebellum- Part 2

The Cerebellum-Part2

Quite a few of us are acquainted with the fact that in Windows XP, the start menu items that display, when we click the start button, organize themselves continuously (dynamically), as we use them. The programs we use most frequently, are placed on the top; while the least used items settle down at the bottom. A similar hierarchy is followed by the brain too. The tasks we have inherited from our ancestors, phyllogenetically, are kept at the bottom of our memory/program cache while more recent skills are placed at the top. As we go on acquiring new knowledge, they first locate in the cortical areas;- once the task have been mastered, they settle down deeper, into the cerebellum and so on. It seems we have our own stack registers. For example, much of our basic and posture maintenance algorithms are kept in lower brain areas such as the spinal cord, medulla, the midbrain rather than the cerebral cortex. They are old programs, evolution wise, and hence kept in the lower shelves. In early neonates, and in diseases of neuronal pathways e.g. in upper motor neuron lesion, midbrain lesions, spinal cord lesions the functional architecture/hierarchy is lost, as the higher centers are not yet or no longer active.That is, now, the sophisticated programs of the cerebral cortex are no longer working, the phylogenetically/ evolutionarily old programs resurface. Babinski reflex in UMN lesions, Moro's reflex are two examples.

In addition to the above mentioned address lines, there is this real time integration and differentiation that goes on constantly within the brain. The much awed calculus is their regular cup of tea!

To be contd.

Cerebellum: Electronically Speaking

Sometimes journeying into physiology textbooks can be a deja vu in electronics. The other day I was studying the way cerebellum learns from its past 'karma' and memorizes the best setting for an action. I was surprised to find that its learning resembled a lot with the op-amp (operational amplifier) ic's (LM741, for example) and its memorizing resembled to that of the EPROMs (erasable programmable read only memory, a picture of which is shown here on the left).

The cerebellum has one of the largest nerve cells of the body, the Purkinje cells, in addition to other types of cells. Purkinje cells have numerous tree-like branching dendritic processes. They receive two types of electrical connections; from the mossy fibers (about 250000 to 1 million fibers for each Purkinje cell) and climbing fibers (ONLY one for each cell).

The cerebellum fine tunes the movement that accompanies a certain task in the following way. The brain (lateral portions of the cerebellum and the basal ganglia) 'plans the action' even before we start an action. After the task has been executed, the cerebellum calculates the 'error', the difference between the planned trajectory and the achieved output in much the same way a does.

In the figure on the left, the op-amp is configured as a negative feedback, through resistance R2 which feeds a portion of output voltage back into its inverting input (since input is fed into its - terminal) amplifier. This way, the op-amp can have both a fraction of the output and input at the same pin, thereby the gain and other parameter remain 'stable'.


A still better analogy is that of the phase locked loop, the output phase of which 'locks' to the input frequency (diagram on the left). Likewise, the cerebellum too matches its expected action with that of the resulting action. The cerebellum is 'happy' with the performance when the error is minimum. At this moment of bliss, the climbing fibers fire for a long duration and with a characteristic waveform: a spike followed by a long trail. Now the information is written permanently.

Doesn't our experience of programming a 2716 (EPROM) tell a similar story; a peak programming voltage and a normal working voltage? When we wanted to program an EPROM, we needed to give it a high programming voltage in the beginning, followed by a steady 5 voltage thereafter till the EPROM 'learned'.

It doesn't end here. In the cerebral cortex, memory is consolidated in sleep, when it receives a spike voltage: the k-complex in the NREM stage of sleep. It seems that we have a micro, or may be a pico-controller in our brain.

To be contd.

Can't Spam The Ovum

Do you have the courage to ask your friends to spam your email inbox? I guess not. Though I will not be talking about e-mails in this post, I'll only compare the challenges a tiny ovum throws to a spam (flock) of sperms and wins the challenge too.

During procreation, sperms from the males are ejected (ejaculated) through the external urethral meatus. They get vigor (energized, by the action of fructose, a simple carbohydrate found in the vagina; a process called capacitation) in the female genital tract. Spirited and intoxicated, as they become, they (actually, millions of them) now charge towards the lonesome ovum like a raging bull (of Spain!). But this microscopic ovum is quite fussy in choosing just one (among say those 200-300 million!) .

Whether the ovum chooses the sperm or any random sperm or the fittest sperm chooses the ovum is something I do not know. Nobody knows for certain. But the accepted theory says it is the random sperm that hits the bull's eye. As it takes two to tango, the sperm and the ovum dance a jig and they drop their "veils" (polar bodies). They kind of, have a one to one talk, before they finally unite to achieve their goal (zygote).

Meanwhile the 'other' sperms continue their ova-ward journey, but now that the ovum has activated it's own firewall, it dodges them very efficiently. This firewall called zona pellucida is active once one sperm has unloaded its DNA in the ovum.

May be we can improve our own computer's firewall if we learn the ova's dialect. We have learned a few things like AI (artificial intelligence) from our knowledge of the brain and the plasticity of its synapses.

What happens next is very interesting. The 'ball of cells' (blastocyst) metamorphoses into the animal that are us. This is what Embryogenesis is about.