All entries for Wednesday 12 January 2011

January 12, 2011

I simply remember my favourite things…

I have been banned from reading at work. This arises from an email I sent to my supervisor about a week ago, in which I asked him to help me try and understand a concept in a paper that I was trying to read. “No, no, no, Alice! No more reading! You’re working too hard and getting bogged down! Just concentrate on your lab-work and enjoy your research”. Oh, I have a cushy job. (Sometimes – for ‘twas only yesterday I was complaining about it).  Anyway, since indeed I was doing one hell of a lot of reading, I now find myself at a bit of a loose end this morning whilst I’m waiting for my experiment to quietly simmer away for the next hour or so. Rather than sit around on Facebook all day, I thought I’d tell you about my five favourite, most marvellous and exquisitely beautiful examples of biology that I have ever come across.  Indeed, one of the reasons I am writing this is because I am acutely aware that, now that I have graduated and no longer have to study anything except diabetes, I am rather likely to forget most of the detail that I learned through my degree. This idea saddens me very much, so I make it my aim to continue reminding myself of those topics that I don’t deal with any more.

Anyway, the five topics that I’m going to talk about are these:

·        Kinesin-mediated movement

·        Insulin signalling pathway

·        Nervous transmission

·        Gills of bony fish

·        Suckling reflex

If you’ve heard of one or two of them I’ll be impressed – I don’t think I knew any of them before A Level. Anyway, I hope you enjoy it, and I hope there is somebody else out there who can appreciate these little natural wonders, and hope that they will bring a smile to your face as they will always do for me.

KINESIN-MEDIATED MOVEMENT

The first on my list (in no order of preference!) is kinesin movement. In order to explain what this is, I need to go into a little bit of detail about cell biology.

Very generally, a cell is comprised a nucleus and various other smaller structures, all suspended in a jell-like fluid called cytosol, and all wrapped in a cell membrane. However, cells are not just shapeless, jelly-like blobs that flop around all over the place; they have a very highly organised structure which is constantly changing and reforming according to the cell’s needs. Cells need to be able to co-ordinate what goes on within them. They need to have mechanisms in place for transporting things from one place to another, making sure things get to – and stay in – the right places, disposing of waste products and a whole multitude of other things. They’re exceptionally complex – indeed, in many universities, cell biology is a degree subject by itself.

To keep things ordered and structured, cells have a phenomenal network of long protein filaments, collectively known as the cytoskeleton. This is literally a scaffolding network within the cell, and its job is to maintain the cell’s structural integrity. Think of this like the iron girders in a skyscraper. If you would strip away everything about the building to leave just the girders, you would see that they form a complex network all over the building which literally prevents it from collapsing under its own weight. This is exactly the function of the cytoskeleton; to prevent the cell from collapsing in on itself.

Structural integrity, is not, however, the only function of the cytoskeleton. It is also involved in movement of bulky items from one part of the cell to another, and this is where kinesin comes in. You’ve probably guessed that kinesin is a protein – everything awesome in biology is a protein! Kinesin has a complicated structure; it starts off with a round, head region which becomes a thin linker region. The linker joins the head to a thin stalk which ends once more in a rounded tail. The complete kinesin molecule comprises two such subunits with the stalks wrapped around each other, rather like a lollipop with feet.

Going back to my skyscraper, if I wanted to haul a piano from the ground floor right up onto the roof, one of the ways I could do it would be to get a giant, piano-sized rucksack and climb my way, bit by bit, along the girders right up to the roof. In the cell, this is the job of kinesin (although it’s more likely to be transporting new bits of cell machinery, not pianos). Kinesin moves along the cytoskeleton bit by bit.

Now, where the beautiful bit comes in is the way in which this movement is brought about. It’s so amazing; I’m grinning just thinking about it. Remember I said that the kinesin is made of two identical intertwined subunits? This means that there are two heads and two tails. The substance to be transported is tethered to the tails, while the heads are the interesting bits that do the moving.

Initially, one of the heads binds to a site on one of the cytoskeletal filaments. This causes some structural changes to occur within this head, which leads to the other head being forcibly thrown forward where it can then bind to another binding site, further along the filament. Once again, changes occur in this head, and the first head is then thrown forward again. See? By this mechanism, the kinesin molecule quite literally ‘walks’ along the filament, repeatedly putting one head in front of the other until it reaches its destination. So beautiful!!

Now, if I were going to lug that blasted piano all the way up to the roof of my skyscraper, I’m going to need a hell of a lot of energy! Surprisingly enough, the kinesin molecule also requires a lot of energy in order to carry out this job if it’s got a big fat chunky bit of machinery stuck to the end of it.

In biology, energy is stored in the form of a molecule called ATP; adenosine triphosphate. This is simply a chemical molecule called adenosine with a chain of three phosphate groups attached to it. When the cell requires energy, it just nips off one of the phosphate groups from the ATP molecule. The resulting molecule is ADP – adenosine <span>DI</span>phosphate. The reason this works is because when the bond between two phosphate groups is broken, it releases a lot of energy, and this is used to power whatever is going on in the cell.

So how is ATP actually involved? Well, in the resting state, the kinesin heads are tightly bound to ADP. When the head encounters the binding site on the cytoskeletal filament, this is quickly exchanged for ATP. Now, when ATP binds the head, some magical things happen which cause changes in the way the heads behave. ATP is converted to ADP, and energy is released. The linker region that I spoke about earlier tightly zips up along the side of the bound head, and it is this action which throws the second head forward. The second head now binds to the next binding site. Meanwhile, the first head is now bound to ADP, and releases from the filament. Now, we’re back to the same position we started in, except for being one notch further along the filament. The whole process starts again, and continues over and over again until eventually, the transportee (is that a word?!) reaches its destination. It’s so awesome!!

Kinesin movement is extremely detailed, and I know it’s probably a bit difficult to picture just from this explanation…take a look at this video (it’s got some cool sound effects)

http://www.youtube.com/watch?v=686qX5yzksU

INSULIN SIGNALLING PATHWAY

Wow, that took me longer than I thought it would do. I thought I’d only need a few paragraphs. Anyway, I’m finished on that topic now – the second beautiful mechanism on my list is the insulin signalling pathway. Since I am doing a PhD in this topic, I do get pretty fired up on this once I get started, so stop me if I get too over-excited.  Right, where to start.

Insulin; most people have heard of it, but few could accurately describe what it does. “regulates blood sugar, innit?!” well flatly, yes, but it’s not quite as simple as that. And besides, what does that MEAN?  Insulin is a hormone which is secreted into the bloodstream from the pancreas following food intake. Its job is to cause cells to take up glucose from the blood, thus lowering the amount of free sugar floating around in the blood.

I’ve just come off my lunch break, and, befitting our jobs as obesity and diabetes researchers, we’ve just eaten a shamefully large amount of Quality Street. Oh, I wish I had some willpower, but chocolate seems to evaporate it all! Anyway, as we are MORE than aware, chocolate contains a lot of sugar. The increase in the concentration of glucose in my blood as I digest that sugar is detected by my pancreas, which will progressively release insulin. As this insulin starts to do its job, more sugar is taken up into my cells, and before long the concentration of sugar in my blood will be pretty similar to what it was when my stomach was rumbling before lunch. It’s absolutely astounding, really. It doesn’t matter how much chocolate you eat, or how little you eat, or how big a meal you’ve just had, or how old, young, big or small you are: if I simultaneously tested the sugar of everybody reading this post and compared it to mine, I bet you there would be hardly ANY variation between them; all of us would have blood sugar levels (glycaemia, as it’s known in the trade) within very close values of each other. That’s awesome in itself! I find it absolutely astounding that blood sugar levels can be fixed to within such narrow limits, all down to the action of ONE HORMONE! Absolutely fascinating! Such a beautiful, simple, ingenious mechanism for regulating something to within tiny ranges despite anything you might throw at it.

So now that you know what insulin does, how does it DO it? This is where the insulin signalling pathway comes in. When insulin is released, it circulates in the bloodstream. Now, one of the main sites of insulin activity is the liver (but almost all cells can respond to it). So insulin happily circles round in the blood until it reaches the liver. Here, it binds to RECEPTORS on the surface of liver cells.  As is insulin, these receptors are proteins, so it goes without saying that they have some amazing properties. The receptors are the proteins responsible for translating a signal from the OUTSIDE of the cell to the INSIDE, where the effects of the original signal are felt.

When there’s no insulin around, these receptors are on their own just floating around in the cell membrane and not really doing very much. However, all of this changes when insulin comes along. Insulin binds to its receptor, and the receptor then aggregates with another receptor in the membrane to form a molecule made of two subunits – it’s called a DIMER. This aggregation causes a striking shape-shift in the part of the receptor on the inside of the cell, and it then becomes an active enzyme. (An enzyme, if you’re not sure, is another type of protein which hastens (or permits) a chemical reaction in a cell). This is the first crucial stage in the insulin signalling pathway. The change in shape of the receptor also causes lots of smaller molecules, called IRS-1, inside the cell to bind to the receptor on the inside. From the IRS-1 molecules, the signal is further conveyed through a great long cascade of proteins. It’s like a chain reaction; IRS-1 allows activation of other proteins and enzymes, which in turn activate further proteins and enzymes, which activate further proteins and enzymes. This cascade eventually culminates in the movement of glucose transporter proteins onto the cell membrane. These glucose transporters (GLUT4, they’re called) are incorporated into the membrane, and their job is to facilitate glucose entry into the cell from outside.  Ah! So now we know how insulin does its work.

So, to summarise the insulin signalling pathway;

Insulin binds to its receptors on the cell surface, and these dimerise and change shape. This activates a long cascade of events within the cell, eventually causing glucose transporters to appear on the membrane. Thus, the cell’s capability to take in glucose is increased. And so I come to the end of my second explanation. I’m impressed I’ve kept it to a few hundred words!

NERVOUS TRANSMISSION

Ah! The nervous system! After an awful, utterly traumatizing and wholly disastrous final year project in neuroscience, I never again thought I’d live to see the day when nerves actually became interesting again. Funny really, since the final year neuroscience course was unquestionably my favourite final year module. The bits of neuroscience that I enjoy are the nitty gritty details of how nerves actually WORK; I’m not interested in any of the psychological or behavioural shit, or what happens when they don’t work properly – I think they’re pretty fascinating just as they are. So, how does a nerve work?

A nerve is a bundle of neurones – the individual cells that make up the nervous system.  Nerves are the main way by which the brain communicates with the rest of the body. Communication about the state of the body is sent back and forth via electrical impulses along NERVES. The patterns, frequency and timing of these electrical impulses can co-ordinate the responses of the body.

I’ll give you an example. In a short while, I am going to have to make the short journey out of my warm, comfortable office out into the fresh air to go to the Café to buy some coffee. It’s freezing outside, and, because I was a little late this morning, I forgot to bring my coat with me. I can tell it’s gunna be an unpleasant experience! When I go outside, the temperature-sensing nerves in my skin will be triggered to fire impulses by the change in temperature. My brain will interpret these impulses and will send out further nervous impulses to various muscles in my body to make them shiver in the attempt to make myself warmer again. (And, indeed, the very thought that I am already dreading it tells me that there is nervous transmission going on between the different areas of my brain, telling me that I should associate cold with unpleasantness. (Although that’s not quite so simple – the guy who figures out how that works will win the Nobel Prize!)).

So okay, you get why nerves are important – I won’t bore you any longer. But what is really really reallllllly awesome about them is how the electrical impulse is actually brought about. Normally, if you gave an electric shock to a cell, it would kill it, so how are nerves different?

Neurones are loosely comprised a cell body, one or more long extensions known as axons, and lots of branches called dendrites. A neurone is stimulated by a change in its VOLTAGE, and essentially this voltage change initiates a wave of electrical activity in the neurone, and this shoots down the axon at high speed. So now let’s go into a bit more detail.

As I mentioned earlier, cells are surrounded by a membrane, and it is the membrane that encloses all the cell contents and controls what enters and leaves the cell. This latter function is exceptionally important for all cells, but particularly so in neurones. A neuronal membrane is encrusted with these proteins known as ion pumps. These do exactly what they say on the tin: they pump chemical ions across the membrane.

What’s an ion? Argh, it’s difficult to explain without getting into A level chemistry territory (and let’s face it, nobody wants to go there). The omniscient Wikipedia – my most trusty resource – defines an ion as:

“An atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge”.

Basically, atoms consist of positive protons, negative electrons, and neutral neutrons. Usually an atom has exactly the same number of electrons as it does protons, so there is no overall electrical charge on the atom. However, there are many circumstances under which this is not the case, and an atom can gain or lose electrons, thus giving it either a positive or negative charge.

So, why is this important? Well the membrane-bound ion pumps that I was talking about specifically deal with two ions: Sodium (Na+) and potassium (K+). In a resting state, the ion pumps actively pump Na+ outside of the cell, and actively pump K+ into the cell. However, for every one K+ ion pumped inside, three Na+ ions are pumped outside. So, we have a situation in which there is way more Na+ outside the cell than there is inside the cell, and slightly more K+ inside the cell than there is outside. Because of this imbalance, the overall charge on the membrane is NEGATIVE – there are more positively charged ions on the outside than on the inside, so the inside of the cell is MORE NEGATIVE than the outside. In this state, a cell is all set up to fire an electrical impulse when stimulated.

Okay – I expect I’ve confused you! Picture in your mind two big rooms separated only by a locked door. One of the rooms is absolutely packed full to the rafters of great big fat people called Nathan, and the other has a few skinny little Kevins floating around. Because the Nathan room is packed, it’s all hot and sweaty in there and everybody is uncomfortable. On the other hand, the Kevin room is cool, calm and definitely the place to be. So what do you think will happen if the security guard comes along and unlocks the door? There’s going to be a mass exodus of Nathans into the Kevin room!

When the neurone is stimulated, “gates” in the membrane open which allow Na+ to freely enter the cell. Remember, it’s negatively charged in there, thus the positive Na+ ions are attracted inside. This causes a change in the cell’s voltage which causes sequential opening of more and more gates all the way along the axon, and the electrical impulse zips along the axon.

Okay, so once all the Nathans have descended onto the Kevins, the security guard thinks it might be a good idea to open another door back into the first room to ameliorate some of the crowding. The problem is that the door he’s just opened is only big enough for the skinny Kevins to fit through. So, while all the Kevins can leave again, the Nathans have to stay put.

When these K+ gates open in the membrane, the efflux of K+ once again restores the membrane to its original voltage – negatively charged. Slowly but surely, the pumps once again restore the membrane to its resting state in which the Na+ is on the outside and the K+ is on the inside, and the whole system is poised to respond as it was before.

I’d love to be able to explain the physics of this, but frankly, I’ve spent the last ten minutes or so trying to construct a paragraph that accurately explains it without getting the facts wrong, but I simply don’t understand it well enough (I SUCK at physics!). Forgive me. You’ll just have to do with the biology instead which, as I know you’ll agree, is way more interesting anyway.

For those of you, like me who find animations much more helpful when trying to imagine something, this video explains the nerve impulse very well. Take a look:

http://www.youtube.com/watch?v=yrsJ9HlnZ5s&feature=related

So once the electrical impulse has reached the end of the axon, what happens next? The axon of one cell typically makes contact with another neurone. When the impulse reaches the end of the axon, it reaches what is known as a SYNAPSE; a point where the axon of one cell comes into very close proximity with the cell body of another (they never touch, but come very, very close). When the electrical impulse reaches the synapse, a neurotransmitter substance is released by a complicated – but ingenious – mechanism. This neurotransmitter then binds to its RECEPTORS on the second cell. This receptor binding causes another chain of events that causes the electrical impulse to be propagated in the SECOND cell, and so it continues.

So there you have it. That’s how nerves communicate with each other, and I’ve reached the end of explaining my third biology miracle.

GILLS OF BONY FISH

My fourth is a little less complicated; you’ll be pleased to know. It is so wonderfully simple and seemingly insignificant that you may wonder why I’m even mentioning it here amongst the great wonders of the biological world. But nonetheless, this made me laugh out loud when I discovered it – it’s so, SO simple, yet makes such unbelievable, perfect sense.

As we all know, fish have gills which enable them to access oxygen that is dissolved in water. Gills are actually quite fascinating; they are beautiful, elaborate structures which are honed to perfection to carry out their job in a way more fantastically efficiently than any man-made machine.

The concentration of oxygen dissolved in water is decidedly lower than that in the air we breathe, yet by virtue of their gills, fish are still able to extract colossal amounts of oxygen from water in order to meet their demands. Humans wouldn’t stand a chance under water – our lungs are just not set up to be able to absorb oxygen at such low concentrations.

Gills consist of very thin filaments of tissue, all stacked on top of each other like stacks of paper. Each filament consists of comb-like structures known as lamellae, and are intertwined with an extensive capillary network. Together, the massive surface area and blood supply mean that the gill structure is optimised for maximum gaseous exchange. The whole gill structure can be found on either side of the head, covered by a scaly flap of skin known as the operculum.

I used to keep a goldfish in a little tank whilst I was at school, and I remember learning about this mechanism and then staring for ages at the movement of my goldfish’s gills, and marvelling at their simplicity. You must have seen fish open their mouths repeatedly, as if they were gulping down water? Well, when the fish opens its mouth, the operculum and the buccal cavity (the floor of the mouth) move outwards and downwards. This creates a negative pressure in the mouth, which draws in water. The fish then closes its mouth and the operculum, and the water pressure increases, forcing the water back over the gills. Then the exciting bits happen.

The simple concept behind gaseous exchange is this: a substance will always move from an area of its high concentration to an area of its low concentration. Simple, really. So simple that without this seemingly insignificant physicochemical phenomenon, there would be no life on earth. The difference in concentration between one area and another is called the diffusion gradient: the steeper the gradient, the more diffusion will happen. Got it?  Anyway, water is passed over the gills from front to back. As water passes through the gill, more and more oxygen is absorbed from it, and so the concentration of oxygen in the water steadily decreases from left to right. Yes? Concurrently, it could be expected that the concentration of oxygen in the blood INCREASES from left to right. Right? Wrong.

Think about this for a second. If blood were to enter the gill system on the left hand side, same as the water, then what would happen? Initially, large amounts of oxygen would happily diffuse into the low-concentration blood. But quickly, as the amount of oxygen in the water was depleted and the amount in the blood was increased, there would soon reach a point where the concentrations in both water and blood were equal, and no further oxygen exchange would be able to happen. What a waste! There is still quite a lot of dissolved oxygen in the water, but the fish can’t access it because there’s no more diffusion gradient!

Of course, inefficiency isn’t in the vocabulary of Mother Nature; of course she’s come up with a way to elegantly circumvent this little problem. Suppose the blood entered the gill system from the right, not the left. As before, the water that comes in has a high concentration, so it will easily diffuse into the blood. But instead of reaching this equilibrium point somewhere in the middle, this counter-current mechanism allows oxygen to keep diffusing out of the water into the blood right the way along the length of the gill. Think about it: although water on the right hand side of the gill has a lower concentration before, the blood that is on the right hand side has only just entered the gill: its concentration of oxygen is also exceptionally low! In fact, the concentration of oxygen in the blood is still considerably lower than that of the water, despite the latter having been already depleted of much of its oxygen. So, gaseous exchange will still occur. Thus the diffusion gradient is maintained all the way along the gill surface, and the fish is able to extract the maximum amount of available oxygen from the water. So simple, so ingenious! I love it!

LACTATION AND BREASTFEEDING

I know I said that there was no order of preference for my writing these five mechanisms, but I have left my favourite until last. For some, intangible reason, I can’t put my finger on exactly why I find this so overwhelmingly beautiful, but I do. I remember very clearly learning about this in a second year lecture. I remember the lecturer, where I was sitting, and who I was sitting with. I also remember being more than a little bit embarrassed at being so emotionally affected by hearing the description for the first time. Okay, I’m a loser – get over it!

Have you ever stopped to think about how a newborn baby instinctively knows how to suckle and swallow milk from its mother? A tiny little baby that can’t do anything for itself, can’t control its breathing, can’t control its bladder, and can’t look after itself. A little baby is absolutely dependent on its parents for survival, yet instinctively, the moment it is born it knows exactly what a breast is for, and how to extract milk from it. I find that so breathtaking I can’t even describe. This behaviour is caused by the rooting and suckling reflexes.

A reflex is an action that is performed involuntarily or automatically. Other examples of reflexes include closing your eyes when you sneeze or encounter bright light, and that weird kick thing you do if the doctor uses the hammer just below your knee.

The rooting reflex is the term used to describe the phenomenon by which a newborn baby will turn its head to the side when something strokes its cheek or mouth – such as the mother’s breast. The baby will search for the object by turning its head in movements of increasing size until the object is found. Furthermore, what is even more beautiful is that there is refinement of this reflex if the baby is continually exposed to the stimulus. Once a child has been breastfeeding for a few weeks, it will move directly to the nipple without needing to display these rooting movements – it has learned where the nipple is, and doesn’t need to keep searching.

The suckling reflex follows the rooting reflex. Once the baby has found the mother’s nipple, the suckling reflex is activated when anything touches the baby’s lips, and stimulates the baby to grasp the nipple between its gums and start sucking. The tounge is used to also draw milk out of the breast.

These reflexes are the same in all newborn babies, so for me, this begs the obvious question of HOW does it do that? What’s causing it? It’s frustrating, I can’t seem to find the answer in any of the literature – it MUST be there somewhere, but I can’t find it. I have a few ideas, but I don’t know for certain. I can, however, find some information on how the baby’s suckling stimulates the mother’s breast to let out milk. The two maternal reflexes involved in suckling are the milk production and milk ejection reflexes, respectively controlled by two hormones called prolactin and oxytocin. You may have heard of oxytocin; the media like to call it the “love hormone”, because it is thought to be responsible for partner bonding, feelings of love, trust and sexual pleasure. It is also the hormone that they give to pregnant women to induce labour if the baby is overdue. Anyway, its role in breastfeeding is thus. When a baby suckles, it stimulates nerve endings in the nipple, and these fire impulses to the pituitary gland (in the brain). This is the body’s factory for various hormones – eight, in fact (one of my second year exam questions was to list them!). Anyway, two of these eight are prolactin and oxytocin, and these are subsequently released into the bloodstream, where they reach the breast tissue.

In exactly the same way as insulin has its receptors on liver cells, prolactin and oxytocin have their receptors on breast tissue cells. Binding of these hormones to their receptors triggers a great long cascade of events inside the cells (using very similar mechanisms to the insulin signalling pathway), which eventually culminate in production and ejection of milk. So amazing! The very action of a baby suckling can cause such profound changes in the way the mother’s breasts behave that she can feed her baby on demand, at any time, whenever necessary.

(Interestingly, as a side note here – you know I mentioned that the insulin signalling pathway and prolactin/oxytocin signalling pathways are very similar? Well actually all signals act in similar ways. The specifics do vary, but essentially it is the same molecules involved in all kinds of diverse and unrelated signalling processes in the body. What’s MORE intriguing is that these molecules are found across ALL OF EVOLUTION! Often it is exactly the same molecules that are found in frogs, snails, worms, humans, elephants, monkeys and mice – don’t you think that’s pretty awesome? One universal, flawless language that unites almost all life forms on earth).

So there you have it; my five favourite bits of biology. I admit, there are many, many others that I can instantly think of that are just as amazing, but for me, these certainly stand out above the others. Right, daydream over for the day, I’ve now got to go and develop my Western Blot!


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