Monday, May 7, 2012

The human machine: biological batteries and motors

So far in my series of posts, I’ve tried to give you an appreciation for how war is fought on a microscopic level, which is to say: how invading pathogens try to consume our body’s resources, and how our immune system fights back. In my last post, I also tried to convey some of the contemporary research that is expanding our understanding of this system. While this is (to me at least!) a fascinating topic, I am going to put it to one side for the time being. The reason for this is that there are just so many enthralling topics to talk about when it comes to molecular biology! So, I have decided to concentrate a new series of posts on various interesting snippets of biology and biochemistry that I hope you will find intriguing and allow you to understand your own body a little better. In doing this, I don’t want to lose sight of the purpose of this blog – i.e. to convey a sense of the ongoing work taking place – and so will try to include cutting-edge research into each post whenever possible.

Preamble over, let’s get started...

Looking deeper and deeper

‘How does my body actually work?’ It’s a question that’s likely occurred to most of us at some point in our lives. Most people know how our skeleton is arranged and how our muscles tug at various parts of it to allow movement; similarly we all know how our hearts pump blood around this vast system, and what our various internal organs do. But science is all about finding something out and then saying ‘sure...but how does that work’ and then taking it down to the next level. When physicists discovered protons and neutrons, they weren’t content to leave it there; they took it to the next level and found out what those are made of, and then what the things they’re made of are made of, and so on to the present day. The same is true for biology – sure your muscles contract, but what are they made of, how do they contract and where do they get the energy from? It is this last point that we will deal with today: where does our body get energy from?

The simple answer to the above question is just: food. We all know we need to eat to have energy; if you’re a bit of an athlete or diet-enthusiast then you might know about the different components of food (carbs, fats, protein etc.) and how they affect the body. But have you ever wondered how all those varieties of different foods end up powering your body at the molecular level?

How much is that? ATP! (pause for laughter)

The system by which we are powered is staggeringly beautiful in its construction and efficiency. It runs every second of your life unwaveringly and faultlessly, and would do so forever if the more fragile components of our bodies didn’t eventually throw us over the edge of this mortal coil! The problem that must be overcome by our bodies (to which I alluded earlier) is that we eat all sorts of different molecules in our food, yet our cells must always work the same way. The way to get around this is a kind of cellular bureau de change, where the various currencies of the different foods are exchanged for a single energy currency that is good for use anywhere in the body. This single ‘currency’ is called ATP (or adenosine triphosphate if you want the full name), and is perhaps the most important single molecule in your body. ATP is used by almost all active processes that take place in your body; some of these are obvious, such as muscle contraction, but the vast majority take place in relative anonymity. There’s no possibility that I could list all of the myriad events that take place in every cell in your body that are powered by ATP; they range from alcohol metabolism in the liver, to light receptor recycling in the eye, to production of antibodies in B cells. In short, you use ATP for almost everything you do, including every thought and memory that you have, since ATP gives the energy to transmit signals down every neuron in your brain.

Adenosine Triphosphate. 80p, you say?

All of these processes devour ATP and break it up into its components ADP (adenosine diphosphate) and inorganic phosphate, so your cells are constantly sticking these two components back together to keep you supplied with ATP. If your body suddenly stopped making ATP (as happens with some poisons, as we’ll see later) then you would die within seconds. In fact, ATP is in such demand that even though there is only 250g of it in your body at any one time, you make roughly your entire body weight fresh every day, only for it to be used to up keeping you alive. This is equivalent to the energy released by roughly 1kg of TNT (i.e. 4.2 megajoules for a 70kg human), which means that over the course of a 70 year life you process enough ATP to release the equivalent energy of more than two GBU-43/B Massive Ordnance Air Blast Bombs (i.e 107,000 MJ, or around 25.5 tonnes TNT). It is, to put it lightly, quite important.

Human batteries 

While that’s all very interesting, I want to explain to you how ATP is made and how we convert all of our food into this single, vital molecule. If this is your first foray into bioenergetics then you might be somewhat taken aback to learn that we actually run on electricity; which is to say is it the generation of an electric current within our cells that allows the production of ATP, which in turn powers everything we do. In fact, the principle behind our own power is identical to that behind how energy is released from a standard battery! Better than that, in fact, we run on two types of current! If you’re not familiar with the details: electrical current is the movement of subatomic particles called electrons down an electrical potential - i.e. they move from where there are lots of electrons, to where there are few electrons. They do this because they are negatively charged and so repel one another and try to move apart if at all possible. Protons, on the other hand, are positively charged subatomic particles. Protons are (as Shaun can tell you in far greater detail than I) more complex than electrons but the overriding principle is the same: they will try to move apart because they all have like (positive) charges. We run on two currents; the first is an electrical current, the second is a proton current.

Anything you eat, whether it’s carbohydrate, fat, protein, or other molecules, enters into your general metabolic network. This is a vastly complex series of chemical reactions whereby the structures of the various food molecules are shaped and changed into a small number of metabolic ‘standards’ that can be easily exploited for energy. I’m not going to go into the details of this now, it’s far too large a topic to cover here, but hopefully the figure below gives you some idea of just how vast and intricate this system is!

General metabolism - don't strain your eyes!

Throughout this whole process, the energy released by these chemical reactions is used to stick protons onto two key molecules: NAD (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide), to make NADH and FADH2, respectively. These are the molecules that power the electrical current that I mentioned earlier. NADH and FADH2 travel to specific structures in the cell called mitochondria where the whole process of ATP production begins.

Fully charged: mitochondrial lighting!

Mitochondria are fascinating things; they used to be separate organisms that lived independently as single-celled life forms, but were one day engulfed by a larger cell and formed a symbiotic relationship that has served them well and exists to this day. An artefact of this is that they still have some of their own genes in their own mitochondrial genome, and their own systems of DNA replication and protein production.

A stranger turned ally - mitochondria power our cells.

Mitochondria have an intricate internal structure, but the bit that is important for ATP generation is the ‘inner mitochondrial membrane’. A number of proteins are inserted into this membrane to form what is known as the mitochondrial ‘electron transport chain'. Four of these are responsible for converting the electrical current into a proton current, and are helpfully referred to as complexes I to IV. Complexes I and II are the entry points for NADH and FADH2, respectively. Complex I removes two electrons from NADH, converting it back into NAD and releasing it, while Complex II takes two electrons from FADH2, releasing free FAD. These electrons travel through the proteins in short hops between electron-binding sites formed by metal ions conjugated to the protein backbone, such as the common Iron-Sulphur clusters. This is analogous to the movement of electrons down a copper wire to power a light bulb or some other electrical device. However, unlike the free flowing electrons in the wire, the electrons in complexes I and II are only able to move from one site to the next within the protein because of the phenomena described in quantum electrodynamics, which allow electrons and other subatomic particles to move over short distances without passing through the space between. This is necessary in the electron transport chain because there are often no direct routes from one site to the next, and so the electrons have to be forced to hop along the chain by the electrons behind it being released by NADH orFADH2. It is intriguing to imagine that the fundamental physics of a quantum world so alien to everything we perceive is the basis of the most important process that takes place within our bodies!

Mitochondrial electron transport (complex II not shown; protons shown as H+)

Both complexes I and II pass their gained electrons on to a molecule known as coenzyme Q  that continues the steady march of the electrical current running through the mitochondrial membrane. However, complex I has an added role; during the movement of electrons through its structure, its shape is contorted and re-set over and over again. These shape changes cause it to act as an electron-driven pump that moves protons from one side of the membrane to the other via subtle changes in the environments of trapped water molecules. In total, complex I transports 4 protons from the mitochondrial matrix into the intermembrane space for every NADH that it processes. This is the first step in the production of a proton current over the membrane that will ultimately drive ATP synthesis.

The role of coenzyme Q is a complex one that I don’t want to discuss in too much detail here. Briefly, its job is to deliver the electrons on to complex III, but in doing so to move yet more protons over the membrane. It does this by a process known as the ‘Q cycle' in which it sequentially gains protons on the matrix side of the membrane and then loses then on the other. This moves even more protons up the gradient that is forming over the membrane. 

The Q cycle

The electrons continue their march along the chain through complex III and into complex IV via an intermediate electron-binding protein called cytochrome c. Four molecules of cytochrome c bind to complex IV sequentially and donate their electrons to a central site where they await their final destination. In this centre, the electrons are finally donated onto a waiting oxygen molecule, which splits and forms two water molecules by snapping up protons from the matrix side of the membrane. Ever wondered what the oxygen you were breathing in was actually doing? Well this is it – it acts at the final electron acceptor in the mitochondrial electron transport chain. Moreover, the reaction also results in the uptake of protons from the matrix side of the membrane, and the dumping of other protons out into the intermembrane space. Cyanide and carbon monoxide both inhibit this final reaction and so kill you stone dead because the final electrons in the chain can’t be lost and so the whole thing backs up, meaning no proton pumping and so, as we’re about to see, no ATP production.

The motor: ATP synthase

So, we’ve seen so far how the electrical current running through our mitochondria is used to pump protons from one side of a membrane to another, but what use is that for making ATP? Well, as I said earlier, protons don’t want to be crammed next to each other because of their repelling positive charges. If there are more protons on one side of the membrane that the other, then they are going to want to cross it, and work energy can be extracted by letting them do so. It’s the equivalent of pumping water to the top of a water tower and then extracting work energy from its fall back to earth under gravity. In this case, the work energy will be used to make ATP by a truly remarkable protein complex called ATP synthase
Round, and round, and round she goes: where she stops, ATP comes out!

ATP synthase is a collection of proteins (hence the term ‘protein complex’) that harnesses the energy released by the movement of protons from the intermembrane space to the mitochondrial matrix and uses it to make ATP. It does this by acting, quite literally, as an engine, with moving components driven by a current. The key to this is its structure. ATP synthase has a ring component embedded within the membrane that is capable of spinning independently of the rest of the complex. Protons move through this ring in order to get back to the matrix and, for reasons I won’t go into, so cause the ring to spin furiously at up to 7000 revolutions per minute! The spinning ring is attached to another component of ATP synthase called the gamma subunit, that spins with the ring. The gamma subunit in embedded within the centre responsible for ATP production, called the alpha-beta complex. As the gamma subunit spins, it causes the alpha-beta subunit to change shape, since this does not spin. The shape changes cause alpha-beta to cycle through a series of stages where it binds ADP and Pi, then catalyses their conversion to ATP, then releases ATP, then begins again. And so, the movement of the ring in the membrane drives the synthesis of ATP by alpha-beta. It is a wonderfully elegant machine that whirs constantly in every cell in your body and powers everything you do.

ATP synthase in action - courtesy of YouTube

And so it is that we are all powered by microscopic motors spinning eternally within every cell in our bodies! Moreover, it is a power source shared by every life-form on Earth and an the varying complexity between different species is an excellent example of evolution in action. It's taken a huge effort to understand it in the detail that we do and the job is not over! As I mentioned earlier, we must now ask: 'sure, but how does that work'. Researchers are currently trying to delve deeper into the detail of how the proton pumps in the electron transport chain work and how the whole process is regulated under different conditions. This has significant implications in both the fields to synthetic biology (i.e. building cells up from scratch) as well in the treatment of a number of genetic disorders that lead to irregular mitochondrial regulation. A number of groups are also taking inspiration from ATP synthase and other related biological motors to design organic machines capable of extracting energy from chemical gradients, developments that may have significant implications for the future of energy policy and self-powering electrical equipment, such as those that may be required to probe environments without conventional energy sources, such as other planets.

Next time

I hope this has been an interesting post and that I've given you some insight into the beautiful engineering that makes up the technological marvel that is your body! Each post in this series will look at a different under-appreciated aspect of how your body works, so if there's anything in particular that you'd like me to focus on then please let me know!

The next post in this series can be found here.


  1. And at last I reach the present...

    I have quite a few comments about this one:

    - At the moment, we only know one level under protons, that is, quarks. As far as we're aware, quarks don't have constituents. Although, there are theories where quarks are composite particles.
    - I've always found it kind of surprising that the chemical we use to provide energy is so big and complicated. When life itself first evolved, I would have expected energy exchange to be one of the first, most important, things, so when all I knew about this was the burning of sugars I nodded my head comfortably. ATP however seems so fancy. Did mitochondria basically discover this method and then everyone else assimilated mitochondria because it was so ridiculously useful that anything that did assimilate mitochondria ruled the planet? How did mitochondria discover it? Is there any idea when, where "when" isn't so much measured in time but complexity of organisms around at the time (though time would be interesting too)?
    - Did one organism assimilate mitochondria and then we're all descendants of that organism, or did "assimilate mitochondria" become a trait for a while, where organisms could find mitochondria and assimilate them and pass that trait to descendants? And then that trait become redundant once everyone had mitochondria in them? Or something?
    -That MOAB really puts into perspective how explosive a nuclear bomb is. Even the "mother of all bombs" is more than a thousand times smaller than the *smallest* nuclear bombs
    - electrons don't actually travel freely down a wire. They're surprisingly slow. One electron will take hours to move one metre down a wire with a continuous current.

    I'm still confused (we've chatted about this before) about how quantum electrodynamics plays a particular role in ATP synthesis. All chemistry is based on quantum mechanics, so the bonding of all the elements in all of the molecules involved in life needs quantum mechanics. Surely, given that this stuff is occurring at the molecular scale, the passage of electrons down the chain is just a chemical process like all the rest and so no more or less "quantum". The electrons in a sugar molecule aren't ball-bearings hurtling around, but quantum wave-functions too.

    Also, it's not really full-blown QED that would be necessary to describe this process. QED certainly is the more general theory, but it is only really needed when there isn't a constant number of electrons (or photons if you're describing the light), so they must be treated as a field, rather than an individual particle. That might have been a bit confusing, I can elaborate if necessary. (by constant number of electrons I don't mean because some get lost, but because some get annihilated)

    I guess I'm nitpicking the specific mention that *this* is quantum. Everything you've talked about is quantum, because it is chemical. Even the immunology stuff is quantum, surely? The chemical processes by which T-cells recognise antigens is chemical and thus quantum, surely? How is this any more "quantum"?

    A non-quantum example would be the pressure in a blood-vein, or something...

  2. Oh, also... the time when mitochondria gets absorbed into our evolutionary tree would make an awesome back-story for the novel, either in a prequel, or a story told by a character to provide context.

    BTW, I am now 20% sure that I am part of a living organism. I just have to work out what my role is...

  3. Oh, also... if you're taking requests, how about genetic engineering, as well as the ethical implications of genetic engineering, and risks, etc.

    I'd be pretty keen to first read your thoughts and then ask you a bunch of questions about it. I'm not sure if it is within your range of specialisations though, so feel free to pass if it isn't.

  4. Ok, that's a lot to respond to. I'll go in the order you went in:

    1. It's true, ATP does look complicated, but it's actually not much more than a simple cyclic sugar to start with anyway; it just has the additional triphosphate and purine groups. The reason why it's used is almost certainly because it is a constituent of RNA synthesis. RNA was the primary organic molecule in very early life: it's thought that self-replicating RNA molecules were the first precursors to life. These RNAs would have a double function as the template for their own replication, and also the machinery by which it's achieved. Over time the system became more sophisticated and some RNAs would be free to take up new tasks, such as producing simple metabolic networks to allow more efficient self-replication. Eventually RNA was replaced by DNA in the data-storage capacity because of the greater chemical stability of DNA and also the need to partition transcription and translation to allow more subtle regulation of gene expression. Protein, on the other hand, took up the role of general cellular workhorse as it is made up of far more chemically diverse components and so is suited to a broader range of tasks. Nonetheless, RNA retained some catalytic role in the form of ribonucleoproteins and also reactive RNAs such as transfer RNA. The upshot of all this is that ATP and GTP (the two purinic RNA nucleotides) were originally used by catalytic RNAs in the production of more RNA and then later to power other reactions, and this is still the case today. ATP is by far the more important of the two but GTP is still required to catalyse some reactions, primarily phosphorylation reactions during cell signalling. ATP isn't inherently 'energetic', it's just that the cell keeps the ADP+Pi:ATP ratio a long way from equilibrium and so there's plenty of free energy to be extracted from its dephosphorylation.

    There are also lots of other examples of RNA nucleotides being used in important cofactors: e.g. Acetyl CoA, NADH, FADH2 etc.

    2. The role of mitochondria in all this is very interesting and is explained beautifully in Nick Lane's wonderful book: 'Power, Sex, Suicide: Mitochondria and the meaning of life'. The incorporation of mitochondria into a larger cells is arguably the most important step in the evolution of eukaryotic cells (i.e. us). Bacteria generate ATP in the same way as us, except that since they have no mitochondria they generate their proton gradient over their inner membrane, which places an inherent limit on their size because as they get bigger the surface area of their membrane decreases relative to their volume. For a cell to get large enough to have complex internal organisation the role of energy producer must be packaged up into subcellular compartments in order to get around the surface area:volume problem; i.e. mitochondria. The incorporation event is thought to have a been a one-off that then gave rise to all eukaryotes, but they had such an evolutionary advantage that they quickly diversified into myriad forms. A similar event then allowed the incorporation of a cyanobacteria into these proto-eukaryotes to give rise to chloroplasts and subsequently plants. It's worth noting, however, that both of these events will not have been clean-cut, and there was most likely a very long time where mitochondria existed partly as separate organisms and partly as symbiotes. Nick Lane gives a very nice explanation of the kind of stages that might have occurred to strengthen the symbiosis over a very long period of time.

  5. Saying that organisms with mitochondria 'rule the planet' is a bit much, however, since the vast majority of lifeforms on Earth (in terms of both numbers and biomass) and prokaryotes and so have no mitochondria. One of the things evolutionary biologists are up to at the minute is comparing the mechanisms of ATP synthesis in different species of prokaryotes in the hope of shedding more light on the evolution of ATP synthase and the electron transport chain. One theory is that the bacteria that became mitochondria lived in an environment with a naturally occurring pH gradient that they then exploited (as some still do) to make ATP. When they were incorporated into another cell, the proton gradient had to be generated artificially and so got tied into sugar metabolism etc.

    3. I'm not trying to imply that ATP synthesis is inherently more 'quantum' than anything else - it can't be since it's made of the same components as the rest of the universe. I'm just pointing it out as an example of the point at which you can no longer explain biology with Newtonian physics. You can talk about antigen-recognition in Newtonian terms and it basically is correct, even though it's obviously just as quantum as anything else, but the electron transport chain would not work if electrons were entirely discrete particles with a finite position. I appreciate that the same is also true for all chemical reactions, but that's another area where most people think of it in conventional terms. The electron transport chain is just cool.

    4. If I do a mitochondrial back-story to my immunology novel then I think I'd have to include all other key moments in the evolution of cellular complexity! For this I'd recommend another of Nick Lane's books: 'Life Ascending: the ten great inventions of evolution'.

    5. Sure, I'll do a post in the not too distant post about what genetic engineering actually is and the (perceived and real) risks involved.

  6. On a separate note linked to your comment about the MOAB; when I first did the calculation I went a bit wrong and came up with the conclusion that the energy that passes through your body over your lifetime is the equivalent of over 20 B83 nuclear bombs (i.e. 25.5 megatons, rather than 25.5 tons), which raised an eyebrow prompting me to check the figures. It would have been cool if true, though!

    1. Thanks James...

      I hadn't appreciated that ATP played a role in RNA synthesis. That makes it much less surprising that it is the thing responsible for energy transfer.

      Also, it is agreed, the electron transport chain is cool.

      I wonder if I should go back and do a degree in Biochemistry...

      Finally, I wouldn't have believed you if you had claimed that the energy passing through my body in a life time was 25.5 megatons. I've just done my own calculation and for an 80 year lifespan that is the equivalent to 40 megawatts of power, which according to wikipedia is not that much less than the power of a small nuclear reactor). A corollary is that if we've both done our calculations correctly, a human being has about 40 watts of total power! That information must be shared...

      P.S... "your" novel..?

  7. I've actually understated it a touch, ATP is PART of RNA rather than just a precursor. RNA, like DNA, has 4 bases (A,C,G and U) - the A is just ATP minus two phosphate groups.

    So, just to check my working:
    The hydrolysis of ATP to ADP+Pi has a Gibbs free energy of -30.5kJ/mol. ATP has a molecular weight of 507g/mol, so 70kg is just over 138 mol, which would therefore give 4211 kJ/day. This gives 48.7W power for a human at rest.

    I wanted to calculate how much time if would take for enough energy to flow through a human to power the kind of 'finger lightning' used by the Sith lords in Star Wars, but my physics wasn't quite up to it!

    Don't worry, you'll be in the acknowledgements.

    1. The Sith Lords are probably extracting power directly from the vacuum or something using blah blah quantum key word blah blah zero point energy blah the force.

    2. Fair enough.

      I assume dark energy must be much bigger in their part of the multiverse. Our universe's cosmological constant wouldn't be particularly useful as an evil force given that it wouldn't even come close to being able to lift the lightest feather.