Keith: Frenetic cities use up energy often at an alarming rate, the city that never sleeps eats up power.
The methods that provide the gas and electricity to drive our cities undeniably involve a great deal of wasted energy.
And though we are now striving to improve on our sources of energy, we still have a long way to go before we reach efficiency levels found in cells.
There is however a new and somewhat surprising form of power station, which is analogous to the process inside a cell.
I’m in a modern straw burning power station. Ultimately all of this energy comes from sunlight. Used and fixed by green plants, by photosynthesis, into a useable form biomass.
Once upon a time that would have been fossil fuels, like coal. But today, this is last summer’s sunshine, being stored and fixed in the form of straw that is being burnt.
The power station works by burning the fuel, and converting it to heat, the furnace converts it into electricity, which can be distributed to where ever it’s needed.
Inside the cell there are also small power stations called mitochondria, generating chemical energy that powers most of the cells activities. They do this by burning fuel – usually sugars – transferring the energy released into molecules called ATP – the cell equivalent of rechargeable batteries.
This thin section of mitochondria shows they have a highly folded inner membrane containing most of the countless molecular turbines.
As each machine rotates the cells previously spent molecular batteries - small organic molecules – enter the turbine and are rejuvenated.
The recharged batteries – the ATP molecules - are then freely available for use within the cell.
Advances in 3D technology are however beginning to change our understanding of mitochondria.
Carmen Mannella, Wadsworth Center, New York State: The mitochondrion is organised in a very different way than we originally thought.
New data from electro microscopy is really causing people to rethink some of the basic understandings, or lets say, preconceptions, of how mitochondrion function.
Keith: Images from the electron microscope are initially, in themselves, unclear but computer modelling reveals their structure.
Carmen Mannella: Design is very important, the design has to allow for the very efficient uptake of the raw materials, the small organic molecules, for maximum release of the power, in this case ATP.
Keith: Scientists are also beginning to unlock the secrets of the tiny factories or manufacturing plants within the cell - Ribosomes.
The synchrotron at Berkeley in California is the size of two soccer pitches.
It can accelerate electrons energies of up to nearly 2 billion electron volts.
The synchrotron allows scientists to study the minuscule crystallised proteins of cellular structures like the Ribosomes – the manufacturing plants of a cell.
It’s the defraction pattern of protein that is used to reconstruct a ribosome down to sub-nanometer resolution.
Harry Noller, University of California, Santa Cruz: We have no idea until what our genes mean, until they are translated into proteins, and the ribosome carries out that job. It expresses the genetic information into a form that is biological.
Keith: At the Wadworths Centre in Albany, scientists are using the world’s most powerful and sophisticated electron microscope to study the ribosome.
Joachim Frank, Wadsworth Center, New York State: The ribosome is just a dumb machine. It translates anything that comes along. Including genetic information for bacteria, and viruses.
The ribosome is involved in translating the genetic information into proteins, and the way it works is that the genetic information results from DNA and then, piece by piece, the portions of the DNA are being transcribed into electrical messenger RNA.
And so, we have exactly the same information, as on the DNA, the difference is the MRNA is free to move, and it moves and finds itself a ribosome. And then it causes the ribosome to read it, and translate it into a string of amino acids. These amino acids are then put together, into a, a long chain, and that chain grows together, and bonds together to form a protein.
We can think about the ribosome as something like a factory, and essentially it makes a model according to instructions. And, in order to come out with a new model, the company does not tear down the factory, but rather it just feeds new information to these robbers. And out comes a company new model. And this is how we can see the ribosome. Throughout evolution ribosomes essentially remained the same.
Harry Noller, UCSC: In the early days o the ribosome field of the ribosome field, our understanding was fairly superficial.
The state we were in, I liken to the analogy of caveman who comes out of his cave one day, and discovers a Ferrari. And he, in his buddies get in, and they drive around in the Ferrari, and enjoy themselves. And eventually develop theories of the function and the structure of the Ferrari.
And those theories are followed up. The steering wheel, the gas pedal, the brakes, the clutch, the gear shift lever. Eventually though, they get curious and one of them pops the hood. Or the bonnets, as you say in England.
What they saw was something far more complicated than they had imagined. And this is very like what we felt like when we saw the ribosome for the first time.
We are looking into the heart of the beast. Most of what we saw, was new, exciting, mysterious. It was, of course, the things that we are now based on, but as we were trying to figure out how the ribosome works, in terms of its actual machinery.
Keith: Newly manufactured proteins are distributed to different places within the cell, but how on earth do they know, what that destination is? Well, it is a bit like posting a letter.
Protein just like letters have their own little built in zip code, or post code, that determines exactly where they will end up. Ten thousand million, different protein molecules in every cell, ten thousand different kinds, yet every one ends up in the right place, at the right time.
This idea of proteins each having their own postcode or zip code was once dismissed as fanciful. Yet Gunter Blobel proved that this was indeed the case. And he also discovered how and why post-codes for finding destinations within a cell.
Gunter Blobel, Rockefeller University, New York: The postal code is not sufficient. You need, also whole machinery and organisation to read the postal code.
The very large amount of cellular activity is dedicated to getting the protein at the right address, because of the limited lifetime of the protein.
Then, if it is not properly functioning, then the protein doesn’t function and you end up with a very large number of different diseases.
There are about one million events of molecular dialogue between the nucleus and the cytoplasm, per minute. This is done by zip codes, to get in, and you need a zip code to get out, and you need the machinery to decode this important information, to actually go into the nucleus and travel there.
We have recently discovered something like a subway system in the nucleus, because the nucleus is very crowded so that you can have rapid transit because the nucleus is very big, the molecule might die, between the cytoplasm and the nucleus. It is very important.
Keith: The need for various parts of a cell to move and communicate is essential.
Within eukaryotic cells - like the cells found in animals - there are highly dynamic structures that fill the cytoplasm. These form the cytoskeleton.
It’s largely made up of actin-filaments, intermediate filaments and microtubules.
On one level, they can be seen as the cell equivalent of footpaths, rail tracks and motorways.
They’re the structures that allow movement and stability within an animal cell.
A major organising centre for the microtubules is the centrosome.
Jordan Raff, University of Cambridge: People often think of the nucleus as the heart of the cell, but I often think of the centrosome as the real heart of the cell, the heart of the city.
A lot of molecules do meet at the centrosome, and then they assess what is going on and then spread back out towards the cell’s then. So, if you like, you can view it as a meeting place. It is a place where molecules can meet, and assess their, how each of them is behaving, should they modulate the behaviour, and then go back out into the periphery of the cell, and tell the rest of the cell what is going on.
Now, when you look at a centrosome, and you see all these microtubules, it is very tempting to sort of compare them, and an analogy with these tracks of microtubules, emanating from the centrosome like motorways, or highways. And in a way that is a very good analogy, because a lot of vesicles and organisms could have gone onto these tracks, and moved along.
So, it, it is a sort of track network. What is a bit misleading about this analogy, and what I don’t like about it, and what isn’t conveying in a picture like this, is actually this network of microtubules is incredibly dynamic. They are constantly growing and shrinking. And changing shape in response to what the cell is sensing.
For example the cell needs to eat. The microtubules will sense that, and reorganise themselves to send the traffic in the right direction. The analogy with the city, I think is a good one, but what is important to remember is they actually can take out these motorways and completely rebuild them, in a different way, very, very quickly. Microtubules last on average less than 30 seconds.
Individual ones. So, when I say they can be rebuilt and remodelled very quickly, it is on a timescale that is completely different to rebuilding roads of a city. And that is very important for the function of the cell.
Keith: All activity in a city, just like all activity in a cell results in waste. To stuff that has got to be got rid of. This material needs to go some where else in the city to be processed.
The raw waste is sent to sewage works for processing, then piped back to the rest of the city as safe, clean water.
A cell also sends its waste to be processed by specialised compartments called lysosomes that contain digestive enzymes.
Almost everything that has passed its sell-by date will be broken down and reused.
This is a large secondary lysosome containing a mitochondrion and another organelle, both of which are about to be disassembled. Cells are extremely sophisticated and efficient recycling machines.
Another good analogy is a car breakers yard, where old bangers to when they come to the end of their useful lives.
If a protein is no longer required, it’s disassembled into the amino acids, which are the building blocks of protein, and then they are reused to make ribosomes, and then new proteins.
It’s exactly the same with cars, when they are disassembled, the different kinds of metals, the different components are all sorted, and as far as possible, reused.
Without all this highly efficient recycling, a cell would rapidly fill up with junk material.
These stacks are a by-product of the seemingly unstoppable proliferation of cars in our cities. In fact cities themselves are ever growing and increasing in number.
Cells too are keen to increase their numbers. And to do this they need to undergo cell division.
Paul Nurse, Cancer Research UK: I can imagine a city as a good metaphor for cell division. In thinking of a large city that is growing, and then establishes suburbs on it’s fringes.
Because what you can imagine, is the city grows, and then when it gets to a certain size, it needs to establish new community centres, shopping malls, town halls, and the like. And these are built in the periphery of the major city, and are like, sort of cell division, where established new towns, create a new suburb.
And you could also imagine that the plans that were used in the middle of the city, to be transferred to that outer part of the city. And it could be like the genes, the coding book, or the genetic information, or in this case it would be the town planners, or the town planning office, and the plans that they all have.
The metaphor of the city, however, can break down. Because there is something very special about biological reproduction. You have these genes that control everything that the cell does, and you duplicate those genes and separate them to opposite ends of the cell, and then the cell gathers around it, the two new cells, all the stuff that was in the original cells.
Cities don’t really behave like that, and then they split and lead their individual lives, so, that is a very special sort of process.
Keith: In preparation for cell division identical metre long strands of DNA condense.
Enzymes and structural proteins engineer a sequence of packing, folding and coiling.
They super-coil into micrometer sized packs of genetic information known as chromosomes.
Mitosis, the most dramatic event in cell division has begun.
Now, pairs of sister chromosomes and a spindle of arching microtubules occupy the centre of the cell.
Located halfway along the chromosome is a disc-like anchorage known as the kinetochore where the microtubules fasten to the chromosome.
Pulled by the connected microtubules the replicated chromosomes suddenly split apart – creating two identical sets of chromosomes.
A contractile ring pinches the cell across its middle forming two identical daughter cells. The cell cycle – cell division is complete.
Harold Varmus, Sloan Kettering Institute, New York: We have this image of the ideal city where everything is running properly, building go up where they are supposed to,.
And we have, boats rowing in and out, cars proceed normally faster, and the whole place is operating in a reasonably functional way, with happy, happy communities all around the city.
Everyone is feeling that if you’re down here in the industrial park, you’re selling your goods, and people over here, in Consumerville, the local hall is working well, we have our warehouses, and everything is working in a kind of balanced co-operative way.
However, this behaviour by even single individuals, can totally disrupt the functioning of efficient mechanisms. People drive too fast, or, fail to regulate its zoning for example. And buildings built across the street. We don’t have open freeways and parks or open space. Adequate number of bridges.
A runaway building programme, or too many people in one part of the city, can destroy patterns of communication and transportation, and make a city malfunction.
That is basically what happens when an individual develops a cancer, and cells overrun and destroy the functions of other clusters of cells. What kills people is the dysfunction of the whole organism as a result of this misbehaviour of cells.
Lee Hartwell, Fred Hutchinson Center, Seattle: Another very important and fundamental characteristic of cancer cells is that they evolve rapidly. They mutate, and they change their genes. If it weren’t for that, I don’t think we’d get cancer.
How does a cell normally maintain the accuracy of its division and what can go wrong to make it less accurate?
Keith: It was these questions about Cancer growth that lead Lee Hartwell to begin experimenting with humble yeast – He pioneered the genetic study of the cell cycle, identifying numerous specific genes, the hereditary instructions, that control cell division.
Lee Hartwell, FHCRC: Technology continues to drive what we can do. But I think one of the things that is very satisfying about a lot of yeast cell biology is that it’s been done with really quite simple technology. With petrie dishes, and velvet cloth, toothpicks.
One of the advantages of the budding yeast, for cell cycle studies, is that you can tell by looking at cells, where they are in the cell cycle. That process of cell division, normally takes about two hours, but it’s vastly speeded up, here.
And you see the bud growing in size, and that two, four, eight, sixteen, thirty-two, sixty-four, will go forever, as long as there are nutrients available. And that is how you make a lot of beer.
All of the cells on that little spot came from one single cell. And there is now probably ten to a hundred million cells in that little colony.
Keith: While yeast geneticists were cracking the control genes, biochemists were also puzzling over what controls the cell cycle by looking at proteins.
If genes are the script, then some proteins can be thought of as the actors.
Tim Hunt was experimenting with what seemed to be a very different model cell - sea urchins.
Tim Hunt, Cancer Research UK: I was a real pioneer, I discovered something completely by accident, and very early on, which sort of gave the game away. It revealed something, which the yeast genetics would never have revealed.
What I found was a protein that suddenly disappeared. The going away of this protein, which I call Cyclin, because actually it, it’s level does go, tick, tick, tick, like a clock in the sort of cell cycle, it sort of times the divisions.
And it was this one here that caught my attention, because you can see, you can just about see… they get stronger and stronger and stronger, and then just suddenly, it fades away. And all the others, just carry on getting stronger and stronger, and stronger. Which is what you’d expect. So it’s that kind, there, that, the Cyclin B as we would now call it.
The actual experiment was completely a eureka moment. I mean it was, once the gel was dried, you could see it, that was the, that was the result. No. People thought I was crazy. I mean, the people thought, no.
The basis of cell division, it can't be that simple, no way it could be that simple. One protein coming and going, don’t be silly. Life is much more complicated than that. But, that is how it was. That is how it still is.
Keith: Tim Hunt had revealed another fundamental controlling factor, but yeast geneticists including Lee Hartwell were still curious how a cell could maintain and repair itself during the cell cycle. He introduced the concept of checkpoints.
Lee Hartwell: The major paradox that emerged, once the controlling proteins of the cell cycle were discovered. Was that, the controlling protein was a kinase that seemed to turn on and off during the cycle.
And yet, the image we had from our studies of the yeast cell cycle, was a pathway of events. And even if you got part way along, if the event didn’t occur, you stopped.
If something goes wrong, during the progress of the cell cycle, there is a feedback, a signalling system, which stops the progress of the cell cycle. Checkpoints are a traffic cop.
Tim Hunt: Not only do they control the flow of traffic but they also make sure that if the traffic is going in this direction, you don’t, have stuff coming at right angles, which of course, is a disaster. And it is exactly the same in the cell cycle. I mean, if you’re doing replication, that has got to go through to completion, and you’ve got to finish that before you do cell division. And if you do do cell division at the same time as replication, what happens is indeed, you, you, of course, crash. And of course the chromosome breaks into little pieces. It’s really a rather good analogy.
Keith: The key regulators of the cell cycle were revealed. But one startling discovery was to prove the value of basic research to understanding cell division.
Paul Nurse: I know we use these corny phrases like, eureka moments, but this was one. At least it was a eureka moment for me.
We lined up on a computer, the structure of the yeast gene, and the human gene. The idea was, are these similar or not?
We saw in fact, that 60%, nearly two thirds of the letters that make up the protein, that is the CDC2 gene, were the same. And that just had to mean that the human gene was doing the same job as the yeast gene.
This was incredibly exciting… very, very important. And that meant that every living thing, not only yeast, not only human beings, but also your dog, flies, the roses in your garden.
All are, the cells that make all those organisms up, are controlled by the same genes.
Keith: This fundamental understanding of how the cell cycle is controlled is now making a huge impact on medical research, in particular our understanding of cancer - with the development of new targeted drugs and treatments. But what of the future?
Paul Nurse: Overall I'm optimistic, we are going to see cures. But we’re not going to see a single cure, it is not going to be the result of a single breakthrough. It will be much more bricks in the wall… building the wall until we have better and better treatment, and people’s fear of cancer can gradually get less, and less, and I think that will happen over the coming decades.
