Building Bodies and Mending Broken Hearts

The genome of the water mould responsible for Potato blight, and resultantly the great Irish famine, Phytophthora infestans, has been published in this week's Nature and there are some tantalising targets for attack.

When we talk about the potato famine, which famously hit Ireland between 1845 and 1852, it seems like an historical, rather than contemporary concern. But plant diseases like potato blight remain a threat to food security worldwide - current annual losses due to blight are an estimated $6.7 billion.

Preventing and treating blight has proven particularly difficult because it seems to adapt remarkably quickly to control methods, quickly taking hold in cultivars of potato that are, or rather were, genetically resistant to blight.  Now, with the publication of its genome, we can start to understand just how it adapts so quickly, and devise better ways to fight it.

Chad Nusbaum, from the Broad Institute of MIT and Harvard, Cambridge, Massachusetts and colleagues from all over the world analysed the genome and compared it to other species of Phytopthora.  They found a dense region of highly conserved genes, ones that the different species share, but the majority of the genome consisted of repeating regions.

This repetitive region of the genome was seen to contain genes that alter the normal biological processes in the plant, helping the blight to get past the plants defences.  It also contained bits of DNA known to move around the genome, known as transposons, and this ability to alter the genome quite dramatically is thought to be a key feature in the rapid adaptability of the disease.  Now that we know how it's doing it - we can start to identify targets for attack.

In a related paper in Current Biology this week, Dawn Arnold, from the university of the West of England, or UWE, reports on how the defences of the bean plant may be driving bacteria to become more pathogenic.Working with teams from Imperial College London & Reading University, the UWE researchers looked at Pseudamonas syringae, the bacteria that causes halo blight in bean plants.  They observed that the bacterium, in response to the bean plant's defences, ejects a region of their DNA, or a Genomic Island, which is then taken up by other bacteria.  This allows for horizontal gene transfer, which is thought to play a key role in the evolution of bacteria.

We know that bacteria can swap sections of their genome, and swapping of the pathogenic genomic island has been seen working in a few different ways in some pretty nasty characters - yersinia, which causes plague; the food poisoning bacteria salmonella and Vibrio cholerae, responsible for cholera.  However, this is the first time that it's been seen to happen within a host, and seems to be encouraged by the stress of host immune attack.

Looking at the rest of the genome, they were able to identify genes that were essential to allow this gene transfer to occur.  We may now be able to target these genes to help slow the development of pathogenicity and resistance in a range of bacteria, and make our disease control systems much longer lasting.

Addictive drugs hijack a brain reward mechanism to strengthen drug-related memories and perpetuate drug use, according to a paper published in Neuron this week.

It's already known that dopamine, the brain's feel-good reward chemical, plays a role in addiction, and also participates in a process called synaptic potentiation - the strengthening of nerve connections that happens during learning.

To find out if dopamine would encourage synaptic potentiation as a result of exposure to drugs, John Dani from the Baylor College of Medicine in Houston, Texas, and colleagues gave physiologically significant doses of nicotine to freely moving mice while recording brain activity.

They noticed increased synaptic potentiation that correlated with the mice learning to prefer a location that was associated with the nicotine dose.  They also recorded a local dopamine signal in the hippocampus, a region towards the centre of the brain that is critical for the formation of new memories, reinforcing the view that dopamine enables memories of specific events to be formed.

This starts a vicious cycle, where dopamine strengthens drug associated memories and thus attaches more importance to them, and increases the likelihood of future drug use.  In any normal situation, this dopamine signal would mark memories and feelings about the environment as important, and this would mark an important part of the learning process, but in the presence of an addictive substance, the system is subverted.

John Dani summarised the importance of this for understanding addiction:"When specific environmental events occur, such as the place or people associated with drug use, they are capable of cuing drug-associated memories or feelings that motivate continued drug use or relapse."  Understanding how drugs change our perception may help to develop treatments or means to prevent relapse, saving both money and lives.

Sian Harding is a Professor of Cardiac Pharmacology at the National Heart and Lung Institute at Imperial College, London and she's here in the studio with me now.  Now, Sian has been using stem cells to develop cardiac patches that could hopefully, one day, be placed on to damaged tissue damaged by a heart attack and basically send in the special cells to repair it.  Hello, Sian, thank you ever so much for joining us...

Sian -   Hello, Ben.  Hi!

Ben -   Now, cardiac repair sounds an incredible ideal that's something that we would obviously want to do. Heart disease is a very common killer.  What are the problems at the moment with cardiac repair?

Sian -   Well, first of all, I should say that there are trials, clinical trials, have been going on for some time using stem cells for cardiac repair and with some success as well.  They've been using bone marrow cells and injecting these into peoples' hearts.  And I think probably 400 or 500 people have been treated that way.  There's one going on in London now with John Martin and good things have happened with these but what appears to be happening is, if anything, a re-growth of blood vessels into the area.  But what appears not to be happening is a production of new actual beating muscle, the myocytes, the muscle cells of the heart. So this is one of the problems and this is what we've been trying to look at in more detail along with any other people about what's the best cell to produce a myocyte.

Ben -   So, although these new blood vessels are obviously a good thing: it'll help to keep heart oxygenated it'll help to keep the muscle that is there healthy.  It obviously won't mean that we can grow back, that we can actually regenerate heart tissue.

Sian -   That's right.  The capacity for the heart to regenerate itself even with these new blood vessels is really very low, especially as you get to the older ages.

Ben -   So, where do you think is the best source for stem cells, if the bone marrow isn't quite doing what we need to do, isn't doing the full job?  What should we be looking at?

Sian -   Well, the frontrunners, the ones that are really good at producing, contracting myocytes at the moment are the human embryonic stem cells and we have used these to produce beating muscle.  It's a very tough muscle. We've kept it in the laboratory beating for over a year in some cases.  You can send it through the post.  It will come out beating at the end.  It's really good tough stuff.  Now, I mean there are problems with this - some people have worried about the ethical problems.  It certainly is a problem about matching it to the immune system of the person.  So there are other possibilities.  One thing is the induced pluripotent cells by looking at what makes an embryonic stem cell an embryonic stem cell.  People have put those factors into skin cells and produced some cells that are really quite like embryonic stem cells and then there are adult stem cells that you can harvest from the heart and expand.  And all these are like coming up on the outside and could be very good but at the moment, they're just potential; whereas the embryonic stem cells are all the ones that are producing the most healthy and hearty tissue at the moment.

Ben -   It does seem that this is a field of great expansion, an awful lot of new interesting discoveries at the moment because there's a story only a couple of weeks ago about how we might be able to induce stem cells to come out of the waste from liposuction, from just human fat.

Sian -   Oh, yes and I'd be among many other ladies who are very happy with it.  The idea of this source of repair, certainly yes.  So there are lots of other stem cell sources.  Now, the problem we have is that if you have made a cell into a beating heart cell is getting it to the heart.  You can't put it down the blood vessels like you could for bone marrow cells because now they're too large, just block up the blood vessels.  So you have to find another way to do it.  And if you inject it into the heart, I think if anybody's ever seen a heart contract, you can see exactly what's going to happen.  You put a needle in, you inject your substance, your cells, the heart contracts and squeezes it right back at you so you lose a lot of your cells that way.

Ben -   Yes, I'd imagine that could be quite messy.  So you have come up with a slightly more elegant solution of using patches.

Sian -   That's right.  So we want to get some kind of ready-made patch to put to transfer the cells into place.  Most likely, over the scar that happens when you have the heart attack, the infarct scar.  So that's the best place to put it and really now, the interesting part is thinking about what's the best way to get the cells there.  There are natural materials that have sort of porous structure that cells can grow into.  They're one good thing.  But at Imperial College, we have this fantastic materials department and so, we've been trying to make some polymers that have perhaps some added benefits.  For example, one thing we're trying to do is make our polymer match the sort of contractile elastic properties of the heart so it can stop the scar from ballooning out and expanding so you can produce some extra benefit.  While the cells are getting into place and getting ready and growing, you can keep the heart from getting any worse during that time.

Ben - And would you also be able to, as well as attaching your stem cells, can you attach all the different factors that you might need to encourage them to really become part of the existing heart tissue and to develop properly?

Sian -   That's right and one of the benefits of the polymers again or even some hydro gels is to allow slow release of these kind of factors. For example, factors to encourage blood vessels to grow into the cell patch that you've put on or factors to protect the cells. Because if you the patch on when the heart attack has just happened, it's a very hostile environment, very inflamed so you need some kind of inhibitors of that inflammation to protect them.  So even though they are tough, you need something to protect them.

Ben -   It's always nice to hear of a scientific endeavour that is so multi-departmental and you have the material scientists and, obviously, you'll have people working on the medicine side but how-once you've made a patch, how is it actually delivered?  I assume you don't need to be quite as invasive as you would do if you're fully opening up the heart.

Sian -   Well, in this case at the moment, we are looking at opening up the heart because you need to put it on top of, underneath the pericardium that wraps around the heart.  There are a lot of robotic technologies being developed at Imperial, which have potential for later on.  They're putting amazing things like valves even by robotic technologies.  So there's the potential there, but at the moment, we would need an open-heart surgery.

Ben -   Well, clearly, this is relatively early days.  Where abouts are we at the moment, how far do you think it's going to be before we can really start looking at putting these into people and seeing them actually working out in people on the street.

Sian -   Well, there are parts of this puzzle that have already got into the clinic or have been approved for clinical use.  There's a patch of fibroblasts that can be put on the heart that's been approved.  The human embryonic stem cells have been approved to go into a trial for brain so that's there and so the polymers that we're using are derivatives of ones that are used in other kinds of tissue engineering solutions that have already been put into the body in some form or other.  So, out there, the parts of the puzzle are just getting into the clinic.  It's putting it all together is what we need to do now.

Ben -   Well, this sounds incredibly promising.  It must be a very exciting field to work on as well.

Sian -   Oh, extremely exciting.  There's a new thing for stem cells to do every week, a new way of getting them more things that they can make, yeah.

Ben -   Fantastic.  Well, thank you ever so much for joining us.  That was Sian Harding from the National Heart and Lung Institute, Imperial College, London.

Kat -   Now, we've covered all sorts of nanotechnology on our show before and an exciting new area is so-called "Soft Nanotechnology", or is it all that new?  The cells in our bodies are fantastic examples of soft machines that work at the nanoscale and now scientists are attempting to copy some of that cell technology to build mini machines of their own.  Now we're joined by Professor Tony Ryan from Sheffield University.  He's one such scientist.  Hello, Tony. 

Tony -   Hello, Kat.

Kat -   Hello.  So what exactly do we mean when we talk about soft nanotechnology?

Tony -   It was great in the introduction when you said we learn from biology and from cell biology in particular because I'm a physical chemist and I've drawn my inspiration for this research and my colleague Richard Jones, basically from cell biology books.  So cells, all the cells in your body are put together by a process called self-assembly and that's where the molecules have information written into them to form structures whether they be membranes or little machines and the self-assembly is done by the molecules wiggling around, under the control of or not under the control of, by Brownian motion. So, soft nanotechnology uses self-assembly with molecules that contain information and Brownian motion to build structures just like biology does.

Kat -   So would this be like proteins that kind of fold under their own steam.  They've got the right kind of bonds in them that make them work?

Tony -   If only we were that clever.  Proteins have 21 building blocks and fantastic sequence and actually most of a proteins there, if a protein's a thousand units long, most of a proteins there to hold four or five units in a specific configuration and that's really, really hard to predict ab inicio so we make much simpler molecules with maybe, one or two or three different units, where we can program pattern formation and structures.

Kat -   And are you using things based on amino acids, based on the sort of things that we see in nature?

Tony -   So in our research, we've particularly tried to not use anything natural, okay?  So what we're trying to learn are the design principles.  So we've used more or less extensively synthetic polymers.  So we make our own molecules that show some of the features of proteins but they're completely and utterly synthetic then we don't have this kind of Frankenstein fear of the grey goo taking over the world and things.

Kat -   And how small are we actually talking?  What sort of size can you go down to? 

Tony -   Well, so we can exercise control at the level of molecules at the nanometre level, that so it really is nanotechnology.

Kat -   And what sort of things are you using these for?  What sort of applications do you think they could have?

Tony -   Well, I was out with some neuroscientists earlier this week and we were discussing delivering molecules across the blood-brain barrier, which is a particularly hard thing to do.  You know, the enduring image of nanotechnology is of this miniature submarine that swims around in your body, you know, a bit like the Fantastic Voyage.  And it's a very appealing movie and it's got Raquel Welch in a scuba diving suit and things, but that really wouldn't work.  All the physics of how things happen at the level of cells, below the micron scale, mean that materials and objects behave very differently.  So, a miniature submarine wouldn't work but something that looks like a bacteria or a sperm might work to do that job of cell-by-cell delivery.

Kat -   Excellent.  So we could say, deliver drugs across the blood-brain barrier or maybe specifically into tumours or something like that?

Tony -   Well, tumours are actually, relatively easy so...

Kat -   They love nanoparticles.

Tony -   Well, they do but that's because the blood supply to tumours is generally very, very leaky.  So if you put something in the blood supply then it will fall out of the blood supply where there are holes and generally there are holes around tumours so to address something to a tumour is actually done now.  You can get things called stealth liposomes, okay?  So they're liposomes just like a famous cosmetics company might try and sell you, because you're worth it.  So this is a bag that's decorated with molecules that stop the immune system attacking it and then that bag comes out of the blood supply around a tumour and just naturally collects there and that's used to deliver doxorubicin in the clinic now.

Kat -   Yeah because liposomes are another example of something that just sort of assembles itself if you get the water and the fat right, isn't it?

Tony -   Yup.  So our molecules basically learn from liposomes.  So we learn from lipids how to make a membrane.  So what we've been doing is making molecules.  They're called blocko polymers.  So if you think of the polymer as a piece of string, then we have a piece of string that maybe red one side and blue the other, and the red bits have water and the blue bits love it.  So it makes a bi-layer so all the red bits cluster together and the blue bits protect them from the water and then they make a big sheet and the sheet wraps up to make a bag.  And then as you wrap the sheets up, you can put things in the bag, okay?  And these bags will float around and we've even designed them so that if they get taken into a cell, they go into a thing called an endosome and the endosome changes the pH and then the changing pH makes the bag explode.

Kat -   Ah, very clever.

Tony -   And deliver the contents and we've used that to transfect, actually to do gene therapy to make green fluorescent protein in a whole range of human and animal cells.  And now the thing is, can we attach a little tail to one of these bags to make it swim?

Kat - I think it should be possible. There's certainly some evidence that I think anti-depressant drugs can change the turnover of cells. It would be interesting to see if Sian's got any views on this.Sian - Yeah. That's certainly true that depression reduces the turnover of cells in the brain. So certainly from that point of view, the regeneration might have a possibility and things like repairing the pathways that are changed in epilepsy, you could see that would be very amenable to this kind of stem cell regeneration.

Kat - I think you would still see the motion of the ball and you'd still see the ball. You just might not see the colour of it.Ben - It has a very different texture to grass, of course.Kat - Yeah.Ben - And on the forum, there was quite a bit of a chat about this Lyner, RD and Bored Chemist all making very good points about it and Bored Chemist pointed out of course that blind people also play cricket. So whether or not you can actually see the ball may not necessarily be a hindrance when playing cricket. But if you are colour blind and if you'd like to let us know how you cope with playing cricket then please do get in touch. You can drop us an email to chris@thenakedscientists.com.