Retinal

Molecule of the month, March 2009

Retinal - this molecule is the reason we are able to see.

Or at least one of them. Retinal, or, more correctly, 11-cis-retinal is a small molecule which fits into the binding site of a large protein called Opsin. Together they make up Rhodopsin, the structure of which is shown below (figure 1). This is where the terms ‘rods’ (think Rhodopsin) and ‘cones’ come from, referring to cells in our eyes which contain rhodosin and isodoposin pigments respectively.

Figure 1. The native form of opsin from bovine rod cellls. The pink bit at the bottom is retinal.

Have you ever noticed when you're in bed and can't sleep that once your eyes have become accustomed to the gloom, you can actually see the outlines of items in the room really quite clearly, but they all look grey and colourless? The reason we can see these outlines is because our rod cells are sensitive to very low levels of light, but can only respond to it in a black and white fashion. The cone cells, which respond to the whole spectrum of colours, require a much higher threshold of light than is present in the dark room to be triggered.

So what makes Rhodosin special as a molecule - how is it that it allows us to see? Firstly, it's important to realise that there is, of course, not just one, but lots of rod cells (about 100 million) all over the retina of our eyes. You can think of them like pixels in a digital camera - each one can only ever be on or off, but when we consider all of the signals in unison we can see a picture.

Retinal itself is what chemists refer to as 'delocalised' - hopefully the graphic below (figure 2) will give you an idea of what we mean by this; the electrons contained in the delocalised system exist in a high energy 'cloud' above and below the plane of the structure.

Figure 2. 'Resonance structures' of retinal - the high energy electrons in the double bonds can flow quickly in the course shown by the arrows. In real-time, retinal exists as a 'resonance hybrid' (bottom) of the left- and right-hand structures.

When a light particle (photon) hits retinal, the double bond at the 11 position changes conformation from -cis to -trans (figure 3). It's obvious from the diagram above that this changes the shape of the molecule. This means it can no longer fit into the cleft into the protein. We can think of the protein 'relaxing', and what happens next is what's known as an enzyme cascade. In other words a complex series of events which ultimately lead to nerves in your brain firing and you seeing an image.

Figure 3. 11-cis-retinal changes shape when it absorbs a photon. The cis ­part comes from the fact that one of the double bonds (at the 11th carbon) has the two largest substituents (that is, the largest chains coming off it) on the same side. The other double bonds are all –trans, or with the bulky substituents positioned on opposite sides. A more modern nomenclature uses the letters E (from the German, entgegen; apart) and Z (from zusammen; together).


Retinal is part of a group of retinoids including retinol (aka vitamin A) and their parent molecule beta-cartotene (figure 4). These compounds are not made in animals, but plants produce lots of them. Interestingly olives, which are distinctly not orange, also contain high concentrations of these molecules (2). This is where the old saying ‘carrots help you see in the dark’ comes from - unless humans get enough retinoids in their diets, they cease to be able to produce retinal. This can result in conditions like the scary sounding ‘night blindness.’ Relax though: this is hard to contract on a sensible diet.

Carrots - a good idea to include in your lunch box, that is if you want to avoid 'night-blindness'.

Figure 4. The retinoids retinal, retinol and beta-carotene (so called because it gives carrots their intense orange colour) are all inter-linked by biosynthetic pathways. NADPH is a biological source of negatively charged hydrogen (hydride).

You may be scrathing your head at this point, thinking, 'where have I been hearing about retinol recently?' Well, since L'Oreal have recently been inundating us with reports of how wonderful Pro-retinol A, their latest miracle skin cream is, this is probably not suprising.

These pro-retinols break down to retinol on exposure to the skin. Vitamin A itself is what does all the work - it is a chemical messenger, one function of which is to instruct cells to begin multiplying more uniformly, and to produce more elastin and collagen: two protein building materials essential in healthy, young-looking skin cells.

I will make no further comment about anti-ageing creams however. Largely because if you're the sort of person who's concerned about whether skin creams are really worth the money (as opposed to assuming they aren't), you're probably not the sort to be reading molecule of the month anyway.

Do take care of your skin though readers, you only get the one.

References

(1) O. P. Ernst et al., Nature, 2008, 454, 183 – 187.

(2) http://www.lenntech.com/fruit-vegetable-vitamin-content.htm (Accessed 27.02.2009)

I have collaborated with Dr. Paul May of the School of Chemistry, University of Bristol to produce a slightly more 'fun' version of this article for a younger audience. This has been published on the School of Chemistry webpages. You can have a look by visiting www.chm.bris.ac.uk/motm/motm.htm and clicking on the relevant link (as of April the 1st).

Josh goes to Parliament

This week I strode off to the houses of parliament to attend the grandly named 'voice of the future, 2009'. This was essentially a bundle of Chemists and a smattering of Engineers and Biologists firing Question time-style questions at some of the people in and around government.

To my disappointment, it turns out that a third of the MPs are now housed in Portcullis house (referring to the portcullis on the house of commons logo) which is not the beatiful gothic structure tagged onto the side of Big Ben I had hoped for. A child-like excitement had filled me at the thought of getting in there. Emerging from Westminster tube station into the drizzle though, I wandered over to a police officer outside the commons and asked if he could 'point this portcullis place out to me'. He did so, towards a grey, dark building. I was a little disappointed. Admittedly, the place is extremely swish once you get inside, and indeed, is reputedly the most expensive office building in the world today. I especially loved the life-size picture of David Cameron I spotted hanging in one of the balconies.

Portcullis house - the one on the left that looks like a prison.

After 45 minutes of queuing I was scanned and frisked. I then entered the fray, heading to the Attlee suite.

The morning was taken up by a pleasing display of confidence from Lord Paul Drayson, a self-made bio-tech guru and current Science minister. Drayson spoke passionately of our need to 'play to our strengths during this time of economic difficulty' and 'get specific' on our plans do that this year. He also suggested our natural advantages in terms of tidal energy generation (we have a lot of coatline) could be coupled with our engineering experience in building off-shore rigs to fuel world-leading research into this type of tidal energy generation. I guess this is one way he wants us to 'get specific'. It does leave one wondering though, if one happens to work in an industry which the UK does not lead, will Drayson consider you a priority?

I also managed to glean an quick chat with Stephen Williams, MP for Bristol West and coincidentally shadow (Lib. Dem., if you want to know) minister for Universities, Innovation and Skills.I asked his opinion on the REF as a replacement for the RAE as a method of deciding on how much government funding an institution receives. Afficiandos of joshua-howgego.com will know some of my thoughts on this matter from my previous post on the subject of peer review. Stephen agreed the new proposals 'do seem to give poeple the chance to fiddle [the statistics]' and on the whole didn't seem too impressed with the scheme. In truth Stephen spent much of our 'interview' trying to work out who I actually was, at one stage plucking out a copy of my previous weeks email from his portfolio and studying it with brow furrowed, as if my explanation that I was a PhD Chemist who was interested in politics didn't quite convince him. Well fair enough I suppose.

You can find out more about the REF, if you're so inclined, here: http://www.hefce.ac.uk/Research/ref/

JH and Stephen Williams, MP for Bristol West

Lord Drayson, Science minister, speaks of his commitment to our scientific strengths

A post doctoral researcher grills the pannel

Shadow Science minister Adam Afriyie is an advocate of a 'scientific approach to policy making' - that is weighing up all the evidence before drawing conlusions in line with our current understanding. He has recently introduced a 'science induction' for all new MPs. Good work, Adam.

Aspartame and Audrey

Molecule of the Month, February 2009

To begin my story, I need to introduce you to Audrey my mother in law to be. A force to reckoned with at the best of times, Audrey is never less of a menace than when she broaches the subject of aspartame. 'Don't drink that,' she once cried, as I innocently lifted a bottle of my favourite carbonated beverage (lilt, mon) to my lips during the first year I was dating my newly betrothed. Smacking the plastic from my grasp, she launched into a tirade of abuse about how aspartame could give me a whole host of ailments. As I imagine most people would, I avoided drinking anything fizzy and pineapplely for a few days: or at least until I really fancied another can. Of course, I didn't forget Audrey's words of warning, but simply chose to ignore them on the grounds that I'm 22, in perfect health and refuse to accept that anything might ever change that.

I’m not one for drinking lots of Coke as a rule. I think this is based on the ‘experiment’ we conducted with Mrs. Webb when I was in class 3 at primary school. We immersed a tooth (these were in ready supply, us being at that age where you endlessly concoct barmy schemes for dislodging baby teeth involving loops of string around door handles) in a test tube of Pepsi for a week. Believe it or not, the tooth was a shell of its former self after this treatment, although on reflection perhaps this test might have over estimated the typical amount of time Pepsi spends in the mouth.

Even so, I do indulge in a cheeky Coke every so often and although what I might be doing to my teeth doesn’t really enter my mind, I do find myself wondering if Audrey had a point about Aspartame.

Aspartame (the structure of the molecule is shown above) is a synthetic sweetener, often found in diet soft drinks as a replacement for sugar. Aspartame is about 180 times sweeter than sucrose (i.e. the sugar monomer which you get in Tate and Lyle bags). This is great for dieters as soft drink companies can use 180 times less aspartame than sucrose, which means a lot less carbohydrate mass in the drink and so fewer calories.
The compound in question was discovered by Jim Schaletter in 1965. He made it accidentally whilst trying to prepare a dipepetide (that is two amino acids joined together) which was at the time thought to be a promising drug candidate for the treatment of gastric ulcers. He accidentally licked his finger after working with the compound and to his (pressumable) amazement it was as sweet as a biscuit!

Schaletter, man of sagely intelligence that he was, decided to scrape the contents of his round bottomed flask into his coffee the following morning, to make sure it really was the compound, and not some disregarded doughnut remnant from his after dinner indulgences of the previous night, which had caused the aforementioned sweetness. Typically a chemist who tempts fate in such a way might expect a short trip to a long stay in hospital as his wages, but Schalatter - the lucky so and so - on realising his coffee was sweetened to perfection, started a chain of events which led to his company making billions of dollars a year: You will now find aspartame in a huge range of products: diet and regular soft drinks, confectionary, cereals and even yoghurts.

So why are people concerned? It is well known that Aspartame breaks down to aspartic acid, phenyl alanine and methanol when ingested. Potentially this could be worrying, because:

1. When exposed to biological conditions methanol can be converted to formaldehyde (the stuff you see dead things floating in at a school science laboratory) which is a known carcinogen.

2. Phenylalanine and aspartic acid are both neurotransmitters which up- regulate the firing of the neurons in your brain. They are part of a complex metabolic system and can be converted into other neurotransmitters such as dopamine and adrenaline. The theory runs that ingesting extra phenylalanine will mess up the delicate neurotransmitter balance and could have unpredictable effects on your mood. Potentially, since phenylalanine is an up-regulator, if you have an awful lot of it you could go a bit haywire.

3. In a recent study, aspartame itself has been shown to be an intercalator of DNA (1), which means it jams itself snugly into the gaps in the DNA double helix. This causes problems when the DNA has to be 'unzipped' for copying when the cell replicates. We understand enough about DNA replication and its connections with cancer to know for certain that this is in theory bad news – but scientists don’t know how this particular intercalation might affect us at the moment.

The points above are facts, however the arguments for aspartame being safe say that the amount of these substances which actually reach a site in the body where they can do any harm is very, very small. In any case it is also true that we eat and drink foods containing far higher concentrations of these substances on a daily basis. For example an average glass of milk provides 6 times more phenylalanine and 13 times more aspartic acid than the equivalent amount of aspartame sweetend beverage (2).

In public, the debate about aspartame still rumbles softly. Indeed, ‘safer’ alternatives such as sucralase (marketed as splenda) have been developed to combat these public fears, whether they are realistic or not.

In fact, all the scientific evidence is against any issues with the safety of aspartame. Repeated toxicological studies on various animals and human subpopulations (infants, the elderly and diabetics for example) have failed to find any ill effects caused by the sweetener (2). Millions of people consume products with aspartame in everyday and it does not appear to do them any harm at all.

To finish with, and in the interest of preserving my engagement, I'd just like to add here that I may have embelished some of incidents in which I cite Audrey's involvement for comic effect. In fact she is a lovely woman and I can only remember her knocking a drink from my hand once, and this was in an aspartame-unrelated situation. Honest.


References

(1) G. A. Karikas et al., Clin. Biochem., 1998, 31, 405 – 407.
(2) H. H. Butchko et al., Regulatory Toxicology and Pharmacology, 2002, 35, 1 - 92.

Peer Review



It was this time in 2006 when Gordon brown announced his plans to overhaul the Research Assessment Exercise (RAE); the way in which the government decides on funding for science and technology research in the UK. There have been loud cries of alarm from all sides of the scientific community since then, ‘what’s wrong with the way we do things now,’ they ask?

The RAE is based on the system of Peer Review. It’s a ludicrous idea when one first hears about it – in what other subject would competing experts in a field, be allowed to critically review each others work, and advise the politicians how good it is? Some conflict of interest you would think, no? Yet this is the system the government has used for a hundred years and it’s also the way the editors of scientific journals decide which work they print - and which they bin.

It has been said of Peer Review that it is to Scientists like democracy was to Winston Churchill, that is, ‘the worst type of government, except all those other types that have been tried.’ So maybe the time has come to take a fresh look at Peer Review, and see if we can do any better.



The faults of Peer Review

We scientists can admit that the failings of Peer Review are not inconsiderable. The main objection (on the part of the government at least, who must foot the bill) is that task of coordinating the independent reviews is bureaucratic and costly. Journals have to pay the expenses this brings too, and they account for them by charging scientists large sums to read the intellectually valuable scientific goodies they contain. This seems somewhat unfair for hard-up developing countries and isn’t all that much fun for UK Universities struggling in the wake of the credit crunch either.

More fundamentally, Peer Review has been accused of slowing down the development of science – which is just not cricket. This is because well-known and well-respected experts (the people best placed to review a journal) can be old fashioned and loathe to accept radical new ideas which contradict with their accepted hypothesis. This means bright, radical, young 21st century Darwins (i.e. people with brilliant ideas which unfortunately go completely against the grain of the current accepted opinion) can go disappointingly unpublished.

Against Peer review is also the fact that it is no use whatsoever at detecting major fraud. If a researcher simply makes his graphs up, realistically, a reviewer (who could be on the other side of the world) can have no idea. This was exactly what happened in the memorable of case of Hwang Woo-Suk, the (ahem) celebrated Korean researcher and his work on the cloning of human embryonic stem cells. He published his work in the high impact journal Science in two ‘landmark’ papers in 2004 and 2005. His written experimental section, conclusions and experiments appeared totally sound; it was just a shame he never actually carried any of these out.

The fact is though, Peer Review does work well in 99% of cases – believe it or not. It is an excellent way of professionalizing and shaping up a paper; stopping the authors drawing rash conclusions, or over hyping their results. Reviewers can even offer input on a particular experiment which might prove the results more conclusively and make the research more convincing. Most importantly, scientists trust Peer Review (and indeed it is this mutual trust which allows the system to work at all) – changing the system will always be met with healthy scepticism.

Finally, we should remember that as Irene Hames, editor of The Plant Journal put it recently, ‘Peer Reviewed journals are not records of absolute truth, merely records of work carried out,’ and that in science you can only ever be right until someone proves you wrong.



The solutions

Browns new framework for dishing out cash to scientists, the research excellence framework (REF) will do away with all that filthy bureaucracy in one swipe, to replace it with a statistical system. Instead of using Peer review directly, the REF will generate a bibliometric evaluation of how good each research application is using figures such as the amount of publications a researcher has achieved in the past year say, or the amount of private funding they have acquired.

Many researchers argue this statistical approach is unfair; probably much worse than Peer Review ever has been. The thinking behind this objection being that great scientists could be given a poor rating if they have taken a career break (to have children or get over an illness say) and thus haven’t published enough work that year. Early-career researchers could loose out too, if they don’t make the breakthrough they need to get published before the REF comes around.

In my opinion, we clearly need to opt for including some form of Peer Review in the new procedure - it is vital in deciding scientific merit, and avoiding unfair prejudices.

How could we make Peer Review even better, though? To stop the those radical young scientists with great ideas getting sidelined from reputable journals, some have called for the introduction of so-called double blind reviewing, in which neither the reviewer nor the author of papers know the identity of the other. This might mean prejudice against radical newcomers is minimised.

What about the price of the journals? Could we open up science to the developing world and make the whole process more transparent to boot if we adopted an open access system? This would mean all journals were freely available to view (on the internet for example), and authors themselves would have to pay to have them published. This would be a radical reform indeed, and forcing scientists to pay to be published might lead to authors simply creating blogs of their work online, which would be equally free to view, but somehow less trustworthy.

In conclusion, it appears that Churchill was right. Peer Review might not be perfect, but it is the best idea we have. Perhaps we can eventually learn to see it as what it really is; the (ever so slightly flawed) arbiter of scientific quality.

To read more about Peer Review, find out how it works and join the debate try visiting:

//www.senseaboutscience.org.uk/index.php/site/project/29/

Awful Organic?

This is an article I wrote around a year or so ago, which I sent off to 'Spark*', the University of Reading student newspaper (fortunately for me they'll publish just about anything!) I was really embarrassed with how arrogant my first draft sounded (can't believe I sent it off sounding like that...) but I've now given it a few tweaks so hopefully it sounds a lot less preachy this time around!



Awful Organic?


It seems like these days we can’t so much as walk down the street without some kind of advertisement presuming to tell us what we should and shouldn’t eat. The British public seem to be obsessed with food and as symptom of this it appears new, weird and wonderful eating disorders are appearing on an almost daily basis. My new favourite amusing, food-related condition is orthorexia; a state where sufferers are obsessed with eating only foods which they see as ‘pure’.

But what do we mean by pure? I guess different people have different definitions: Foods with a low GI, low saturated fat content, foods which include whole grains and food which is certified organic – and there are others. It’s organic food that I want to talk about in this article however because – I’m going to go ahead and say it - I think it’s (at the very best) extremely over-hyped.

Firstly, organic food is only ever organic if an accredited body, the best known being the SA (Soil Association), say it is. The SA was set up by Defra (the government department for rural affairs) and is generally well respected. One of their more recent items certified as a faux pas for organic foods though are scientifically trendy nanoparticles. Their view however is that any synthetic nanoparticles are banned whereas natural nanoparticles (such as soot, for example present in foods grown next to a power station) are deemed fine. Is it me or does this just not conjure up a picture of purity and wholesomeness? The trouble is they can pretty much create whatever list of acceptable chemicals they like and these may then be used on organic crops. The key word is always natural – as long as something is natural is can pretty much go onto organic food.

My view is that this rule of thumb seems a bit dodgy to say the least. This may make me sound like a bit of a heretic, but let me explain using an analogy! We use synthetic medicines to keep human bodies healthy and in the vast majority of cases these days we have sufficient scientific knowledge to make these medicines safe. If we were to use natural remedies to cure our ailments they would be in general not as effective. This is they key, because the same is true of plants. In general natural pesticides and fertilisers are much, much less effective than synthetic types. Don’t forget, this is not the 50s and we don’t use DDT anymore; agrochemical companies spend literally millions each year testing their products and ensuring they will do us no harm and that they are so effective that the amount needed for several hectares of lands can be quoted in grams.

With the global credit crunch and the fact that in lots of regions of the world there are clearly not enough crops to feed the population, is such a wasteful method of farming as organic really ethical? The only advantage it appears to yield is a vague warm feeling that when we pay that extra 50p for our carrots we are somehow doing the environment good and getting healthier produce. Is it worth it?

Ok, so I’ve given a pretty negative view of organic farming, and it’s true that conventional methods aren’t exactly perfect either. The fact that they create monocultures which reduce biodiversity is clearly not their most redeeming feature. And of course it takes many a long year, and lot of money and a lot of energy to take a pesticide or herbicide from conception to market, so in the process of making farming more efficient in this way we are also stamping down with a large to, frankly, enormous sized carbon footprint.

Read more about organic food and see what the Soil Association have to say for themselves at http://www.soilassociation.org/

Time for Richard Dawkins

Richard dawkins is this week, retiring from his post as Charles Simonyi (in case you're wondering, a very rich man who used to work for Microsoft) chair for the Public Understnding of Science at Oxford. What follows is therefore quite an apt article, which I wrote earlier this autmn.


Time for Richard Dawkins

Eminent and prolific, Professor Richard Dawkins has been a symbol for all that is scientific, intelligent and English for many a year now. The scientific community will wish him well this year, as he reaches the age for mandatory retirement from his post as Simonyi chair for public understanding of science at the University of Oxford.

In the aftermarth of his most recent and controversial (to say the least) book, ‘The God Delusion’ how can us lesser intellectual mortals engage with what has become known as the Oxford God debate? As I have considered this question I have begun to ask, are there some things which science - and even Richard Dawkins - will simply never be able to explain?

Firstly, it is imperative that we have a sound grasp of what it means to a scientist to explain something. For example, it is apparent that we exist in a universe with extremely complex laws of nature, intelligent life and beauty in many places. How do we explain the fact that it exists at all? What this boils down to in a scientific sense is that the existence of our universe is improbable without a cause. So any explaining theory which makes the existence more probable is initially a reasonable one. The best thing science has got at the moment is the Darwinian theory of evolution, as propounded by Dawkins in books like ‘The Blind Watchmaker’ .

The Watchmaker analogy says that something with complex inner workings such as a watch (or a human person) is so complex that it necessitates a designer; a watchmaker (or a God). The Blind Watchmaker theory, as explained so eloquently by Richard Dawkins, postulates that if the watchmaker was blind (i.e. not an intelligent being) a watch might still eventually get finished if the watchmaker (evolution) was allowed enough time to try lots of different combinations. This makes life on earth seem much more probable – in fact, given that the time period is something like one billion years I makes it almost certain – and so is a very good scientific theory.

Theologians, for the most part, accept this as good science, and most likely the truth. Where some experts disagree with Dawkins is where the universe came from in the first place. Professor Dawkins believes that something as complicated as our universe must require a cause which is at least as complicated as the universe. It can never, in his view, therefore be an explanation because it in turn requires an even more complex explanation. Was God created by a super-God and he in turn by a hyper-God?

Ex-Regius professor of Divinity at Oxford University, Keith Ward, points out in his recent work that this paradox does not really exist. Since physicists agree the Universe is composed of not merely space, but Steven Hawkin-esque ‘space-time’ then this, surely, is what God (if we suppose for a minute that there is one) must have created. If God created time, then it is clear he can not have a cause – the question, ‘what came before God then?’ has no meaning when we take time out of the equation.

The more we discover about the laws which govern our Universe the harder it becomes for us to conduct experiments to test our theories and make our observations – the switching on of the Large Hadron Collider in Geneva has had to be delayed over until after winter; unfortunately if they switched it the super conducting magnets on now they would suck enough power out of the French national grid that the French would have nothing left to heat their homes!

Realistically speaking we are beginning to reach the boundary of testable science when we deal with Bosons and quarks.

Are these the lengths we have to go to in order to get answers about cutting edge science? Let us not give up the search for understanding, but let us also be humble enough to admit that we may simply not have the capacity to make the measurements necessary to uncover the innermost secrets of the cosmos.

'Modelling the Cell' article

What follows is the original text I wrote for an article recently published in Chemistry Review, a magazine published at the University of York, and aimed at A Level Chemistry students. I don;t know an awful lot about pharmacological research really, I just thought I'd have a go at writing something after I did a summer research project on a topic related to that discussed in the article. The only problem is I haven't had time to sort out how to add in the diagrams yet! Watch this space..





Modelling the Cell

Disease is still a serious problem in the 21st century. Statistics now show that one in three people will develop cancer at some point during their lives. Chemists have always played an important role in developing drugs to combat disease and they continue to do so in modern science.

Have you ever considered how easy it is just to swallow a pill to relieve a headache or clear your sinuses? It’s very convenient for us to take drugs orally; imagine if you had to inject a syringe-full of paracetamol into your forehead each time you had a headache! Medicinal chemists have worked long and hard to design drugs which can enter our gut, pass through our cell membranes, dissolve in the blood and arrive at the site of action in large enough concentrations to actually do some good. It’s quite amazing when you think about it. For example, one problem that faces chemists is that the pH of the stomach is generally between about 1 and 3, depending on what’s been eaten recently. Unfortunately, lots of potentially great drugs contain acid-sensitive functional groups; under such highly acidic conditions amine groups will become protonated and esters may be hydrolysed. These are serious problems as the structure, and therefore the activity, of the drug is altered. The job of the medicinal chemist is to find ways of getting round these problems.

Polymer therapeutics

Diseases like cancer and HIV/AIDS present us with fresh challenges and in some cases polymer therapeutics could offer a way forward. Polymer therapeutics comprise a series of medicines where a drug molecule and a polymer are combined. In essence, the advantage of these medicines is that the polymer wraps around a drug molecule and protects it from degradation, such as via the stomach acid we just mentioned. One obvious property of such polymer-drug conjugates is their large size – much larger than standard drug molecules because of the polymer chains wrapped around them – leading to their other, somewhat more fashionable name nanomedicines. It has recently been shown that tumours produce large amounts of permeability factors, (compounds which make the lining of blood vessels more permeable). This essentially means that the blood vessels surrounding a malignant tumour are permeable to nano-sized molecules, whereas those surrounding healthy tissue are not. Polymer-drug conjugates are therefore a promising candidate for new anticancer medicines because they will differentiate between healthy tissue and cancerous tissue. The drug will accumulate at high concentrations at the tumour site, providing a two-fold advantage; it will be more effective in dealing with the tumour and will yield fewer side effects in healthy tissue.

Safe polymers?

Before we begin doling out spoonfuls of polymer to hopeful patients we must, of course, be convinced that the polymers of interest are not toxic to humans! One important way to look at this is to study the interaction of polymers with cell membranes – if the polymers disrupt the membrane, the contents will begin to spill out and the cell will die. Cytotoxicity studies (where the analyte is introduced to a cell culture) are performed by biologists and these are a very realistic way of looking at toxicity of a compound. Cell culture studies often give us simply a ‘yes’ or ‘no’ to questions about toxicity. If we want to understand the biophysical interactions taking place the Langmuir technique can be very useful. It allows us to create a simplified model of cell membranes and investigate which types of molecule have an interaction with them. Using a modelling technique has the advantage that one can control parameters such as pH and see their individual effect on polymer – lipid interactions. So while the Langmuir technique is a simplification (it does not take into account the copious protein channels and other moieties on the cell surface for example) it is an invaluable tool.

In real life, cell membranes are composed of a bi-layer of phospholipid molecules. The Langmuir technique enables chemists to create reasonable model of this; a uniform phospholipid monolayer. The phospholipids are not miscible with water (i.e. they do not mix) because they are amphiphillic. This means their hydrophobic tails stick up out of the water and their hydrophilic heads are aligned side by side in the surface of the water (see box 1). Once the monolayer is stable the polymer is injected through the bottom of the shallow trough into the buffer solution. Troughs are equipped with a special surface pressure sensor, so any changes in surface pressure can be measured. These give us indications about what is happening on a molecular level. For example, if there is an increase in surface pressure it indicates that the polymer is inserting itself into the monolayer, forcing the lipid molecules apart. If we did see an increase in surface pressure, it might lead us to conclude that were the polymer interacting with a real cell, it would be interfering with the cell membrane which could cause irreparable damage. Of course further studies would be needed, but the technique gives us a insightful starting point.

Dendrimers; the next generation of polymer therapeutics

Box 2 shows PEG and PEI two polymers used in drug conjugates at the moment. These are both certified as non-toxic and approved for use in humans. Of course the search for new drugs is on-going and an impressive new candidate for use in polymer therapeutics is a class of compound known as dendrimers. These novel polymers are monodisperse, spherical polymers grown outwards from a central core. Their hollow core area has the potential to act as a protective storage area for drug molecules. Their monodispersity makes them an attractive candidate as a delivery vector too, as it means their action in the body can be more easily and accurately predicted. The functionalised arms however mean that they are likely to have an interesting and novel interaction with cell membranes. The Langmuir technique will be one way in which chemists try to discover the nature of this interaction. if dendrimers are not toxic, we could have the makings of an excellent drug delivery vector.