Chemistry World Podcast - August 2010

00:12- Introduction

01:31- First graphene touch screen  

03:10- Microspheres help restore eyesight   

06:08- Miles Congreve from Heptares Therapeutics talks about targeting G-protein-coupled receptors to develop new therapeutics

14:15- microRNAs may hold key to cocaine addiction 

17:28- Wood mimics packaging polymer 

19:54- Mark Johnson from Yale University, US, sings the praises of physical chemistry

26:57- Cleaning up organic pollutants 

29:43- Magnetic micro-machines made from liquid iron 

(00:12 - Introduction)

(Promo)

Brought to you by the Royal Society of Chemistry, this is the Chemistry World Podcast.

(End Promo)

Interviewer - Meera Senthilingam  

This month how microspheres could help restore eye sight; how RNA could be the solution to cocaine addiction; and an environmentally friendly way to create plastics using wood.   We also discover a potential new way to clear up organic pollutants very relevant with the current BP situation and how the field of physical chemistry is bringing fundamentals about water into the limelight.

Interviewee - Mark Johnson

Water becomes almost always part of the reaction because the OH bonds are stretching and deforming and changing partners that creates an opportunity for spectroscopy because we can follow these highly energized features that only happen when you have that special condition in water, where it's flexible as a solid.  

Interviewer - Meera Senthilingam  

Yale University's Mark Johnson will be explaining how this insight into water and the method of cryogenic mass spectrometry used to get there could provide hope for fuel cells as well as the catalytic industry.   All that to come in this August edition of Chemistry World with me Meera Senthilingam and contributors, Mike Brown, Matt Wilkinson and Nina Notman.

(Promo)

The Chemistry World Podcast is brought to you by the Royal Society of Chemistry. Look us up online at chemistryworld dot org.

(End Promo)

Interviewer - Meera Senthilingam

First up this month, the first graphene touch screen. Nina.

Interviewee - Nina Notman 

Indeed a group of researchers in Korea have managed to convert films of graphene into touch screen panels.   They made films of graphene , which is the material which is the one atom thick carbon sheets, which is tens of centimetres across is significantly larger than any graphene film that had been made before and they have engineered these into transparent electrode first and then used these electrodes in touch screen panels.   And this is a real leap forward in the potential use of graphene for consumer products. Potentially in two years time, we'll be able to see this on our shop shelves.  

Interviewer - Meera Senthilingam

How did they set about actually producing this?

Interviewee - Nina Notman

There are a number of steps here, first of all they grow the graphene on a copper foil using a known technology called chemical vapour deposition and next using a roller, they pressed the graphene onto adhesive polymer support.   The copper foil was then etched off and the graphene wrote onto a different polymer called PET.   The next step is to remove the initial adhesive polymer by heating and then finally they additionally doped the graphene using nitric acid and in this form it is suitable to be used as the electrode.

Interviewer - Meera Senthilingam

Now what makes this better than current touch screens that are in production?

Interviewee - Nina Notman

Current touch screens are made using indium tin oxide, which tend to be quite fragile and added to that carbon is obviously a much more environmentally friendly source than indium and tin.

Interviewer - Meera Senthilingam

Is this likely to be produced soon as a natural touch screen product?

Interviewee - Nina Notman 

At the moment, they're talking about to taking around two years for it to hit our shop shelves.

Interviewer - Meera Senthilingam

Okay, well moving away from consumer products now, to a potential treatment for age-related macular degeneration, Mike.

Interviewee - Mike Brown

Yeah that's right.   So research team in Southampton are taking biodegradable microspheres that you can attach stem cells to and then deliver them into the eye to treat this disease that affects a lot of people in the western world.  

Interviewer - Meera Senthilingam

And how is AMD caused and are there any current treatments for it?

Interviewee - Mike Brown

Okay, so AMD is basically a disease that attacks the photoreceptors in the retina and results in the central vision of the eye being lost.   At the moment, there aren't really many treatments for this disease and that's why it's such big problem.   There is research around that is focussed on these biodegradable polymers but no one so far has done any research with these spheres, so that's the new bit.

Interviewer - Meera Senthilingam

So this essentially is a new way to deliver the stem cells to the correct area of the eye.

Interviewee - Mike Brown

Yeah, basically.   So what you've got is two different polymers, which are blended together, the first is poly(L-lactide) and the second is poly(DL-lactide-co-glycolide) and depending on the blend that you get, you get different surfaces on the microspheres, so when the ratio is in favour of poly(DL-lactide-co-glycolide) you get very rough surfaces and what the research team has found is that rough surfaces tend to stick stem cells better.

Interviewer - Meera Senthilingam

So this is a great idea, but have they actually tested it to see if the stem cells are actually delivered?

Interviewee - Mike Brown

Okay.   So at the moment, the team has just done in vitro studies with model retinal cells at the moment.   So, they haven't done any testing with the stem cells.   They've tested the stem cells to see whether they'd be compatible with the polymers, but they haven't actually been able to do that step yet, but they've been working in conjunction with a surgeon to design a method where the microspheres can be put into a suspension and then be injected under the retina.   So with minimal surgery, minimal invasive techniques, you can get the stem cells right where they're needed to basically treat the disease.

Interviewer - Meera Senthilingam

And then once these spheres have actually delivered the stem cells, what happens to them?

Interviewee - Mike Brown

Once the microspheres are in positions and they've orientated the stem cells in the right way, then over time, they will biodegrade.   So all you're left with are the stem cells doing the good work to restore the eyesight.  

Interviewer - Meera Senthilingam

So I guess, what   the next stage then with this to just take further and potentially actually test it in animals I guess?

Interviewee - Mike Brown

Yeah. So,   the researchers want to go to the next stage and test it with animal models, but they also want to also do further tests to check the compatibility between the stem cells and the microspheres as well.

Interviewer - Meera Senthilingam

Well, if it's compatible, the treatment would certainly be welcome, with certain forms of age-related macular degeneration currently having no available treatment at all.   Thanks Mike.  

Interviewer - Meera Senthilingam

Now an important and constantly developing area of chemistry is drug discovery.   Pharmaceutical companies across the globe invest billions of dollars into finding more efficient and reliable drugs to treat a wide range of conditions affecting the human body. The main method being structural drug design, where drugs are designed based on knowledge of the structure of a biological target such as an enzyme or a receptor and one group of receptors that pharmaceutical company, Heptares Therapeutics target are G-protein-coupled receptors or GPCRs, which mediate a wide range of physiological processes.   As the head of chemistry, Miles Congreve explained.

Interviewee - Miles Congreve 

GPCRs are signalling receptors.   So, they're in the membranes of cells and one of the major ways in which cells receive signals from outside of the cell to signal processes internally.   So, there are a whole range of different mediators from sort of peptide hormones through to neurotransmitters, ions, these molecules bind to the GPCRs and cause either an agonist effect, which is where the GPCR is essentially switched ON and through a complex signalling process inside the cell, this mediates the cellular response.   So GPCRs are critical to many signalling processes.   For example, inside the brain, things like serotonin, dopamine, all the sort of responses that we get the stimuli externally are mediated by GPCRs and also taste and smell, olfactory receptors are all GPCRs, so there's various estimated that may be up to 800 different receptors that all sort of mediate different process inside the body.   And I think also very importantly, it's been a very successful area over the years for drug research.   There are many licensed drugs which acts via GPCRs, you know, in particular antihistamine, anti-asthma drugs, etc.  

Interviewer - Meera Senthilingam

So these receptors clearly play a crucial role in a variety of physiological process, but how do you actually then set about designing a drug for a particular receptor?

Interviewee - Miles Congreve 

Well, historically people have either used a structure of the endogenous ligand such as serotonin or dopamine etc.   So that's where so many of the old fashioned drugs have come from, if you like, histamine etc. but now we're now in a position to start to use structural information. So there has been a number of protein ligand structures of GPCRs published from our own laboratories and also from other labs over the last few years.   Those structures are now allowing people to have a better understanding of how ligands bind to GPCRs and you can more rationally start to target the binding sites.   So this is really very exciting time in GPCR research.

Interviewer - Meera Senthilingam

So you mention these new methods are part of a new era then, so what is actually taking place?   What's the kind of cutting edge methods used at Heptares now then?

Interviewee - Miles Congreve 

We go through a process where we introduce mutations which don't affect binding of ligands, but improve the overall stability of the receptors and that's partly just generally making changes that the receptor can be taken out of the cell and will survive in detergents but also more specifically locks the receptor into particular conformation, usually the agonist or antagonist conformation and so by freezing out that conformational flexibility that helps to improve the stability of the system.   The other approach is that of lighter structures have relied on fusion proteins, either with antibodies or with a T4 lysozyme system and that approach has led to additional structures and so there are other approaches out there. The structures that have been come from fusion approaches have tended to be some of the more stable receptor systems, whilst, you know, we're introducing that stability and that means that we don't require any fusion protein or any other device to allow the proteins to crystallise.  

Interviewer - Meera Senthilingam

So having got then the structures of these proteins and you've got them stabilized, how do you actually set about picking potential drugs that could then target then?

Interviewee - Miles Congreve 

Having learnt about how ligands are binding to the receptors systems then you can start to use stretch based design approaches, so you can either rationally design compounds or do virtual screening based approaches, where you know the shape of the binding pocket and you can in silica dock compounds into the receptor site and then you would select a number of those compounds for purchase and screening and that can give you novel star points.   The other thing that we're able to do with these star reagents is to use surface plasma and resonance screening methodology. So we can now isolate these receptors on chips and we screen compounds directly against the protein receptor without having any kind of coupled in vitro system.   And what that allows you to do is fragment based screening.   We can screen very small molecules at very high concentrations and look for either agonist or antagonist fragments which we can then take forward into crystallography.   Really, we're using those main approaches now either rational design or virtual screening approaches or fragment based screening approaches against targets of interest.

Interviewer - Meera Senthilingam

So, you've given examples of say historic drugs or drugs that have been targeting these proteins for long time, but now these new methods are available.   So what have been kind of recent finding or perhaps drugs that are in clinical trials at the moment that are hoping to target particular receptors and therefore treat, say a particular diseases or conditions?

Interviewee - Miles Congreve 

We've worked on A2A receptor for Parkinson's disease and that program has gone very well.   We're looking to license compounds from that program at the moment, for that program we used virtual screening, we're using structural information about the adenosine A2A system, the entomology modelling based approaches and also mutagenesis stage that we've developed in-house to understand how the ligands were binding to that system and then we used that do in silica dockings of potential ligands, identified compounds for purchasing and screened them and that gave us a number of hits. We then worked up in chemistry here and again using extensive mutagenesis and then later on crystallography. We were able to understand in fine detail how are ligands bound to the receptor and that led to being able to develop small efficient ligands that bind deeply in the binding site of the receptor.   You know that includes molecules which have efficacy in relevant in vivo models for Parkinson's disease.   It's been very much structure driven building understanding of how ligands bound to that particular receptor and then using that information to optimize them.

Interviewee - Meera Senthilingam

And Parkinson's is one of a long line of diseases hoping to be treated using drugs targeting G-protein-coupled receptors.   That was Miles Congreve, head of chemistry at Heptares Therapeutics. 

Jingle

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Interviewer - Meera Senthilingam

You're listening to Chemistry World with me Meera Senthilingam and still to come, how freezing molecules can give a step by step insight to chemical reactions, but first Matt, a new way to treat cocaine addiction.

(14:15 - microRNAs may hold key to cocaine addiction)

Interviewee - Matt Wilkinson 

Yes Meera, well scientists in the US managed to find a new way of interrupting the processes that could cause cocaine addiction and they do that by actually changing the amount of a chemical called a microRNA inside the brain.

Interviewer - Meera Senthilingam

So what are these microRNAs?

Interviewee - Matt Wilkinson 

Well, microRNAs are small segments of RNA and there are about 22 nucleotides in length and they've been found in recently to regulate gene expression and therefore the production of protein in various chemicals that those genes code for in the body.   So in this case what they've actually found is that a specific microRNA called miR-212 actually affects how much cocaine mice are likely to take when they have it available to them.

Interviewer - Meera Senthilingam

But how does this all, say   work together?   So when it comes to cocaine addiction, what causes an addiction?

Interviewee - Matt Wilkinson

Well nobody really knows the exact pathways or the entire story there, but cocaine addiction is believed to a psychological dependence and that can result in cardiovascular damages as well as brain damage and there's a whole plethora of pathways in the brain that cocaine interferes with.  

Interviewer - Meera Senthilingam

So who are the researchers looking into this and how did they actually go about testing then these microRNAs in addiction?

Interviewee - Matt Wilkinson

So the researches were led by Paul Kenney of the Scripps Research Institute in Florida and he believed that these microRNAs would influence the activity of the genes in this particular pathway.   So what he did was he found a rat model that mimics cocaine addiction, a model which when wrapped to give an extended daily access to the drug and he found that this particular microRNA 212, is actually upregulated or present in a lot higher concentration than in rats that only had a slight or small amounts of access to cocaine.  

Interviewer - Meera Senthilingam

So the presence of this microRNA seems to be reducing the addiction?

Interviewee - Matt Wilkinson

Well,   the presence of it seems to be protecting against it, but interestingly what they found was that when they then injected rats with virus specifically designed to boost the expression of miR-212, the animals that had been addicted, gradually took less and less cocaine, suggesting that the microRNA actually protects against the addicted behaviour.  

Interviewer - Meera Senthilingam

So how are they going to take this further in order to potentially use this then for humans that are addicted to cocaine?

Interviewee - Matt Wilkinson

Well, there's two ways to take this forward.   I mean, at the moment they've really just looked and found a new series of targets that you could look to hit with a number of different types of strategies.   You could look to actually upregulate the microRNA in cocaine addicts' brains, but that could be quite difficult because putting any kind of protein into the body and specifically into brain is a pretty difficult thing to do.   The other thing you could try to do is also to try and find out the drugs that target specific points along that pathway and that might be a simpler thing to do in the short term.

Interviewer - Meera Senthilingam

Okay.   Well thank you very much Matt.  

(17:28 - Wood mimics packaging polymer)

Interviewer - Meera Senthilingam

But now moving away from addiction to things like cocaine to the common human addiction to the use of fossil fuels as Nina, there's now a potential eco-friendly replacement to a common polymer that uses fossil fuels.

Interviewee - Nina Notman

Indeed so the polymer PET is the one that we normally use in our food packaging and as you just mentioned, it, derived from petroleum.   So everybody is waiting to looking for an environmentally friendly alternative.   The problems turned to be, these alternatives don't perform in the same way as PET.   So this team of researchers that have developed a new type of polymer, which behaves in the same way as PET and also has the same thermal properties, which is one of the big issues with the other biodegradable polymers.  

Interviewer - Meera Senthilingam

And what component of wood is it actually using?

Interviewee - Nina Notman

It's using lignin which is the natural organic polymer, which is found in wood.   So lignin is used in paper manufacture and one of the by-products, one the things that lignin breaks down to is vanillin and it's the vanillin which is being used to make the polymer.

Interviewer - Meera Senthilingam

So, how reliant are we on PET and so how big a difference could this make?

Interviewee - Nina Notman

So PET equates around about 80% of the world polymer production, which is around 50 million metric tons a year.   So if we were able to replace all of that, I guess with a bio-renewable polymer would have big environmental impact.

Interviewer - Meera Senthilingam

And what team or what researchers have actually been looking into this?

Interviewee - Nina Notman

So this work is being led by Stephen Miller at University of Florida and they published this work in the Journal, Green Chemistry.

Interviewer - Meera Senthilingam

And they found this component then, this vanillin from lignin but what stages is this actual research at now.   Is it likely that we're going to see perhaps bottles made of this anytime soon?

Interviewee - Nina Notman

Yes so the vanillin that they've got, they've managed to combine with acetic anhydride to make their monomer and therefore they've managed to polymerize it.   So they have their actual plastic, but they haven't tried moulding it into any shape yet and next they're going to try moulding it into for example the plastic water bottle.   They've also been looking at degradation because their interest is, a nice term that researchers use, they want their product to have green birth and a green death.   Obviously the green birth is the way that it is created from a green birth material and the green death meant it degrade to benign monomers.   So they pave way for that research at the moment and it looks like indeed it does have a green death.

Interviewer - Meera Senthilingam

So in terms of the environment it's definitely a good way forward.

Interviewee - Nina Notman 

It looks that way at the moment, yes.

Interviewer - Meera Senthilingam

Sounds promising, thanks Nina.  

Interviewer - Meera Senthilingam

Well moving into fundamental chemistry now, more specifically physical chemistry where scientists such as Mark Johnson from Yale University have created a new method of investigating how molecules such as water interact in certain reactions by freezing them in action.   The technique is cryogenic mass spectrometry and Mark explained what's possible using this technique and how it came about.

Interviewee - Mark Johnson

Innovation that happened I think that creates new opportunities to look at the spectra and therefore structure of interesting objects starts in the late 1980s with Yuan T. Lee the Nobel Prize winner who realized you could freeze ions down using supersonic jets and that allows us to get things very cold and when they're cold they have well defined structure and those structures give very nice vibrational patterns that we can use in order to see what the chemical signatures are telling us about that structure.

Interviewer - Meera Senthilingam

And then how you've then taken this one step further in your lab? What are the methods you use?

Interviewee - Mark Johnson

We've got a cryogenic mass spectrometry and what we did is pack ions of interest typically reaction and immediate, so protons, extra electrons or something like that that's hard to define when you have a whole sample and we froze out the centre part of it with a ice ball of argon, kind of an argon, ice arrangement in a mass spectrometer and then we use that ice in order to burn it in a manner of speaking, so that we could trap a lot of structures of water molecules as they start to form in a primary hydration environments around these species and then once we've had them cold, we could get the structures using vibrational spectroscopy.

Interviewer - Meera Senthilingam

What does this allow you to see that perhaps just traditional mass spect count?

Interviewee - Mark Johnson

Well mass spect you've seen obviously tells you, it weighs it and you get a mass discharge ratio, it doesn't tell you anything about what the structure of it is. We were able to use these techniques in order to create most importantly reaction intermediates and look at how the chemical transformations are occurring by freezing out each intermediate as it goes on its march from reactants to products.

Interviewer - Meera Senthilingam

And what kind of reaction intermediate are you looking at then?

Interviewee - Mark Johnson

Right, now we just had a science paper that came out in February where we were looking at how the movement of protons controls, how a covalent bond forms and that's the key thing that happens when you want to do photosynthesis for example to turn water into oxygen you have to get that O-O bond to form and it happens by making water into an acid and so the proton leaves as an acidic thing will do in water and then as it leaves it makes the covalent bond formed.

Interviewer - Meera Senthilingam

Well then the fact that you're looking in to that touch down the fact that you concentrate a lot on water as a molecule, don't you and the various reactions that water is involved in?

Interviewee - Mark Johnson

Water is important, and a lot of people care about it and it does a lot of curious and unusual things, if you choose a solvent to run your reaction and like super critical CO₂ or something, CO₂ is pretty stable, it's a good solvent it minds its own business, and it just crowds around,.   Water becomes almost always part of the reaction and that's why it's been difficult to track it down and because the OH bonds are stretching and deforming and changing partners that creates an opportunity for a spectroscopy because we can follow these highly energized features that only happen when you have that special condition in water where it's flexible as a solid.

Interviewer - Meera Senthilingam

And so this is an area of quite fundamental kind of physical chemistry but it does have its applications, doesn't it? You're in fact using this method and this understanding so far in the field of fuel cells.

Interviewee - Mark Johnson

Yeah, so we're involved with a large team of workers that have been assembled by the US National Science Foundation called Fueling the Future.   Its purpose is to look at how protons move through media, obviously I've just told you about how we like to think about the local structures that water adopts when you put a proton into it.   It   turns out that the translocation people say   just as a proton is moving between molecules it's a feature that it comes up a lot; it comes up in how vision works for example, bacteriorhodopsin transfers protons when you see things through a membrane in a cell.   Another membrane that's important is transfer a proton through what's called a proton exchange membrane in a fuel cell and so Nation is the medium, it's a waxy kind of substance that you can buy when you make a fuel cell because the electrons go through the wire and the protons have to go somewhere to keep the charge balanced and they go through these exchange membranes and the exchange membranes aren't good enough for general purpose fuel cells but that you know the population, because the current fuel cells run too high for Nation because it works with water as the transfer medium.   And so we've been working on developing Amitrole and other kinds of molecules which are stable at high temperature which you can use as the proton exchange membrane active agent.

Interviewer - Meera Senthilingam

So what stage is this at now, is it likely to be kind of incorporated or tested soon?

Interviewee - Mark Johnson

Sadly, I guess our team wasn't the first I think, there was a report earlier in the year of looking at this Amitrole based agents from Japan that looks like it could be very promising indeed.   So, this is a worldwide effort and I guess we are a small piece of it trying to contribute some mechanistic information on how these things work.

Interviewer - Meera Senthilingam

What would you say then your next area is, so fuel cells are one particular application of all of this knowledge but what's are other potential applications are there or what else is needed to be looked into?

Interviewee - Mark Johnson

Well, we are very committed to turning our efforts towards catalysis, you know the world market for chemicals made by tailored catalysts is huge, and understanding the mechanism of those catalytic reactions is the kind of thing that we think we can get into.   This is a very much more difficult proposition and simple systems we've been looking at because they're metal centred typically.   So we'll be using, we have just started installing new generation mass spectrometers and so on at Yale in order to trap as I mentioned we wanted to trap that O-O bond formation by proton transfer, well we would like to see that happen when it's being activated by a real catalyst, so that's where we are pointing our efforts.

Interviewer - Meera Senthilingam

So whilst you're able to at the moment see various stages in a reaction, you want