Chemistry World Podcast - June 2011

1:20 - Fish in chips: growing embryos in microfluidic systems

3:20 - DNA origami yields tiny flask

5:42 - How similar are generic biological drugs to their patented counterparts, and how does that affect how they work? Pauline Rudd explains

13:20 - Nanodiamond aerogel hammered out on anvil

15:39 - Insecticide studies provide clues to bees' disappearance

19:10 - Joan Abbott discusses why we need a blood-brain barrier and how to get drugs across it

25:39 - Titanate cigarette filter

28:41 - Lignin cut down to size by nickel catalyst

32:06 - Trivia - it's 150 years since the first colour photograph. It worked, but it shouldn't have - find out why

(Promo)

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

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Interviewer - Chris Smith

Hello and welcome to the June 2011 edition of the Chemistry World podcast.   With me this month are Elinor Richards, Patrick Walter and Phillip Broadwith and we're discussing amongst other things DNA has been fashioned into a nanoscale flask; what you can do with a nanodiamond aerogel, my mind literally boggles and a revolution in cigarette filter technology; plus the risks you take with biosimilars, these are copycat molecules of major drugs.

Interviewee - Pauline Rudd

There are many, many types of erythropoietin that are being used illegally and perhaps being sold to patients illegally which are not efficacious. So they have the wrong sugars attached to the erythropoietin and so they're cleared in three minutes from the patient, where they should stay within the patient for three hours.

Interviewer - Chris Smith

We'll hear shortly how the regulators are tackling that one.   Hello I'm Chris Smith and this is the Chemistry World podcast.

(Promo)

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

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(1:20 - Fish in chips: growing embryos in microfluidic systems)

Interviewer - Chris Smith 

And up first fish-in  chips anyone, Eleanor.  

Interviewee - Elinor Richards

Well, this is actually fish in chips.   This is about growing embryos in micro fluidic systems.   So Michael Richardson from Leiden University in Netherlands and his team have placed zebra fish embryos in micro-fluidic chips.

Interviewer - Chris Smith 

Exciting, I heard of them raising zebra fish embryos in little dishes, normally scientists have them in little multi well dishes and these fish were attractive for research because they're transparent and you can see straight through them with the microscope in order to study them makes the research very easy.   So what's wrong with doing it that way?

Interviewee - Elinor Richards

The thing is this in these wells, you keep having to change the buffer solution in each individual well which means that this damages and causes stress to the zebrafish embryos.

Interviewer - Chris Smith

So, how have they done it?   What have they done that's different? 

Interviewee - Elinor Richards

So, the team made the device from three layers of borosilicate glass which contains an array of temperature controlled wells connected by channels, and each well holds this single zebrafish embryo and the buffer solution can flow through these wells, so you don't need to replacing it. 

Interviewer - Chris Smith 

So the idea is basically you have this pre-made research gadgets called the fish-in and the buffer flows over it and you can just subject them to whatever experiments and interventions you want to.   Any evidence that this is actually better or that it works at least as well as the traditionally what we are   doing?

Interviewee - Elinor Richards

They looked at the growth and development of embryos and after a five-day culture they saw that actually there was no significant increase in abnormalities, the body like which is it a little bit shorter, they did demonstrate the potential for application in drug screening assays, by releasing ethanol into the wells to induce embryonic abnormalities.

Interviewer - Chris Smith

And when will they be introducing this, is this available for researchers to use now?

Interviewee - Elinor Richards

Well, it's not available now, the chip is promising for drug discovery in which small quantities of compound are available, if the compound is very expensive but it is not ready yet.

(3:20 - DNA origami yields tiny flask)

Interviewer - Chris Smith

Well, thanks Elinor; that was very interesting stick to fish and chips for me I think will work but it's certainly an interesting step forward.   Now talking of things that are very small Phil, this is very exciting, DNA origami producing in a tiny flask.   Now I remember going back about five years or so when scientists actually made a little smiley acid house face out of DNA. Now they are actually going to the point where you can make physical objects out of it.

Interviewee-  Phillip Broadwith

Yes Chris, if you think of DNA as a long strand, it's actually not very stiff, it's quite flexible and you can make all sorts of shapes out of it and people have been making ever more complicated shapes by taking a long strand of DNA and then several short strands that they used to kind of staple and link it together and mostly those have been constrained to kind of flat things or combining several flat sheets together to make say a box, but what Hao Yan and his team at Arizona State University have done is to take a slightly different approach and used DNA like a worm coil pot that you might have made out of clay as a child.

Interviewer - Chris Smith

I did indeed make one of those and also at school, how did they do it though?

Interviewee-  Phillip Broadwith

Okay, so if we think of DNA as like a worm pot, what you're trying to do is take a long strands of DNA and coil it and attach it to yourself as it coils, you can make each coil of DNA slightly bigger than the last one and fix it on and so you get like a spherical flask. It looks like a classical round bottom flask from a chemistry lab.

Interviewer - Chris Smith

Is that the picture of it you've got there, because that looks a bit like a sort of snake charmer's pot with a long neck, it's almost a volumetric flask, isn't it to strike a chemical analogy.

Interviewee-  Phillip Broadwith

Yes Chris,   that's exactly what it looks like and we did a quick calculation in the Chemistry World office and worked out using the dimensions that the team gave us that it has a volume of something like 24,000 cubic nanometres which should be enough to hold about 800,000 molecules of water.

Interviewer - Chris Smith

Apart from being elegant what do they say you could use the technique they've developed to do this for?  

Interviewee-  Phillip Broadwith

So, because we can make much more complicated shapes you can start thinking about making shapes that will trap specific things in them.   So templates for growing nanocrystals or capsules for drug delivery all that kind of thing but really completely tailor-made and because it's DNA, it's also functional so you have the opportunity to add extra bits on the outside or have it opened in response to a specific sequence of DNA and things like that.

(5:42 - How similar are generic biological drugs to their patented counterparts, and how does that affect how they work? Pauline Rudd explains)

Interviewer - Chris Smith

Phil Broadwith.   You might not have heard of a biosimilar, but that's how the industry is badging the generic forms of some of the more complicated and exotic protein-based drugs that have dominated the therapeutic scene in recent years, but are these biosimilars safe, in fact how similar actually are they to the drug they are designed to mimic?

Interviewee - Pauline Rudd

I am   Professor Pauline Rudd, so I am the NIBRT professor of Glycobiology at University College Dublin and part of my group is in fundamental research, the other part of my group works with the pharmaceutical companies to try to analyze and control glycosylation on biological drugs.

Interviewer - Chris Smith

Thanks Pauline, first of all can you tell us in the old days when we made a drug what happened as soon as that drug went off its patent?

Interviewee - Pauline Rudd

Well, these are usually small molecules which could be chemically synthesized and chemically defined so it was reasonable for other companies to be able to copy the drug absolutely and know that they have an identical chemical structure and the issue now is that the new drugs are proteins which are huge molecules which have their own particular folding characteristics, their own   particular modifications which are very complex.   And so for a company to copy the innovative drug exactly is really, well nigh   impossible I would say is hugely more complex than that used to be.

Interviewer - Chris Smith

And what could be the clinical impacts of that?

Interviewee - Pauline Rudd

Well, it depends upon what the differences are, so one important area of research is to define what we call critical features of the drug, so what do the critical characteristics of the drugs that would make it either unsafe or toxic or not efficacious anymore. For example in monoclonal antibodies we have specific features of glycosylation that makes the drug unsafe for example if it has something that has come from an animal cell which is antigenic to humans than that would make the drug unsafe.   If it had incorrect glycosylation that would mean that it couldn't enter the effective pathway that you wanted it to enter, then the drug wouldn't work.   So we tried to look at each molecule and understand which features are really critical for the safety and efficacy of the drug.

Interviewer - Chris Smith

Now, especially pharmaceutical companies must actually quite like that in the sense that their agent is hard to copy, because in the old days they had to make all their money when they have the patent in place and then the sinister generics came along, the price plummeted 20 to 30% off for the same agent.   Now if you've got something where it's really difficult to copy it the lifetime of that drug therefore must go well beyond potentially the lifetime of the patent.

Interviewee - Pauline Rudd

You're right; it's an advantage to be the innovator because they're not going to give that process information to somebody making a biosimilar.   I mean there are recent cases where the biosimilar company makes a drug that has higher activity that would do either, because this activity has to be exactly the same as the parent product. So it's a very complex area for drug regulators.

Interviewer - Chris Smith

Where does the law stand on this, do they need to do a complete set of clinical trials on the generics, presumably not because they can inherit some of the proof of concept from those? So what does the law say they have to do if you come up with the biosimilar?

Interviewee - Pauline Rudd

Well, it's not exactly a law, it's the regulators who license the drugs to be used in people.   It's a judgment for them to decide whether the new product is sufficiently different from the old one that it requires a new clinical trial.

Interviewer - Chris Smith

The world is not just one marketplace. We've got different sets of regulations, different sets of rules and regulatory bodies in different countries.   Many companies do have a presence in many countries.   So what's actually happening geographically?   Is there a consensus of opinion as how to handle this?

Interviewee - Pauline Rudd

Well, the regulators talk to each other of course, I mean, in fact the EMA which is the European regulatory authority have licensed quite a number of biosimilars now.   I think the FDA at this moment has not licensed any.   So there's a difference.   I have just been at the FDA actually and there's such a huge responsibility here, because if they make a judgment which is wrong then there are lots of unforeseen side effects then of course they would fear really culpable so I can see why they would err on the side of caution.  

Interviewer - Chris Smith

But human life doesn't have a different value depending upon where there are one side of the Atlantic or the other; do you think they're right or wrong?

Interviewee - Pauline Rudd

The EMA are not, erm. They're also extremely cautious, they're not letting out drugs which they think are unsafe just that they perhaps they've made their minds up about the criteria rather earlier than the FDA, that's all.   For example there was a drug called Myozyme and when the manufacturers scaled up the production the glycosylation changed then when they presented these status to the authorities, the two authorities came to a different decision about whether they should have a nuclear control or not, this actually brought into focus I think the need for that be some more experimentation and some common understanding between the different regulators about what criteria should be monitored.

Interviewer - Chris Smith

And probably also some common sense because I mean I was rather shocked the other day I was talking to a pharmacologist who actually answered the question for me.   Well if Aspirin were invented today, 

Interviewee - Pauline Rudd

It wouldn't be like, yeah. 

Interviewer - Chris Smith

Would we end up giving it to patients and saving the millions of life it has and this person said to me absolutely no, Aspirin would never come within.

Interviewee - Pauline Rudd

No it wouldn't..

Interviewer - Chris Smith

A million years of getting near patient these days

Interviewee - Pauline Rudd

No, that's not the question because, you know, you can go on asking companies to do more and more alliances and more and more functional tests and then the drugs will be so expensive that nobody will be able to afford them.   But I think, you know, one thing that is quite rather more worrying because drugs that go through regulators are they are safe as human beings can make them safe, as the regulators agree that they should be sold I mean what's much more important is countries where there is a regulation or there are a lots of drugs being made illegally, because for example we did some work for the World Anti-Doping Agency.   There are many, many types of Erythropoietin that are being used illegally and perhaps being sold to patients illegally which are not efficacious.   So they have the wrong sugars attached to the Erythropoietin and so they cleared in three minutes from the patient where they should stay within the patient for three hours.   So they actually don't have time to upregulate the pathway which gives you more red blood cells.   If your are a patient and you get some of this material over the internet and then it's not properly analyzed or it's being analyzed for known to be a faulty glycosylation but they're selling it anyway, then, you know, you risk taking a drug which not only won't do any good but it might actually do you harm because you might raise antibodies against that and then you would lose not only the EPOs that you were taking, but the EPO that you were making yourself.   So I think, you know, the non-regulation of these things is something much more to worry about then that the great work that's being done by the regulators in Europe and in the US.

(13:20 - Nanodiamond aerogel hammered out on anvil)

Interviewer - Chris Smith

Professor Pauline Rudd from University College Dublin.   And now, to a girl's best friend, diamonds; although you would need to be a very tiny girl or perhaps a female nanodiamond specialist to appreciate these ones, Patrick.

Interviewee- Patrick Walter

Yeah, this is Peter Pauzauskie, at the Lawrence Livermore National Laboratory what they did was they compressed an amorphous carbon aerogel, so amorphous carbon is the non-crystalline form the kind of thing you put on your barbecue charcoal that kind of thing and then when they compressed it at high pressures they are able to turn it into a nanodiamond aerogel.

Interviewer - Chris Smith

But if you've got something which has got a lots of space and you put it under enormous pressure, doesn't all the space just crush down to make the diamond.

Interviewee- Patrick Walter

Right, well in this case what they do when they crushed in a diamond anvil, so using diamonds to make diamonds in this case, was that they deposited the amorphous carbon aerogel then they poured it in supercritical neon and the supercritical neon supports the structure.   So when the crushing is taking place at 20GPa this stops the whole structure collapsing. I mean 20GPa is a huge amount of pressure. It's equivalent to 200,000 times our own earth's atmosphere.

Interviewer - Chris Smith

It's certainly a tremendous amount of pressure and when you apply that what do you get, what happens?

Interviewee- Patrick Walter

So, at the other end you get a nanodiamond aerogel.   This is an aerogel where the carbon is being compressed so much that it has turned into diamond, but you can still only get a very small amount of material the moment, you're talking micron size pieces.

Interviewer - Chris Smith

And what do we think we could do with them and why are they important?

Interviewee- Patrick Walter

So the researchers suggest various possible uses.   So these kinds of aerogels would have excellent strength, they would also have excellent thermal insulation and they could also be used as anti-reflection coatings for things like glasses because they have a tuneable refraction index.

Interviewer - Chris Smith

Are they economically viable to make, because 20GPa or so on is not trivial, so can we make these on an industrial scale and therefore use them for the kinds of applications you're suggesting insulation and so on?

Interviewee- Patrick Walter

Right at the moment this is a proof of concept trial but the researchers are looking into ways to produce it more economically.   So what they are aiming for now is just to produce as fast as possible.   So they're putting it under huge amounts of pressure; they weren't trying to workout what kind of lower pressures could work.

(15:39 - Insecticide studies provide clues to bees' disappearance)

Interviewer - Chris Smith

Interesting material and want to keep an eye on, now you better be careful Elinor you're going to talk about insecticides and the humble honey bee.

Interviewee - Elinor Richards

Yes, we have heard a lot in the news about the bee population being in decline and this has an effect on plant pollination and in turn this affects the yields from crops, so scientists are trying to find out why, and they studied the role of pesticides, habitat loss and disease.   Now one theory said insecticides are passed to bees in pollen but there's a new theory that's put forward by Andrea Tapparo at the University of Padua in Italy and he suggests that bees may pickup a lethal dose of insecticides by grazing on sap produced by crop plants that's present on the leaves.

Interviewer - Chris Smith

So where does the insecticide come from in those crop plants?

Interviewee - Elinor Richards

Well, these are near neonicotinoid insecticides that are used to  coat the  seeds before the plants are planted and it saw that the insecticides go way up the plant through water and end up on the leaves in the water droplets. 

Interviewer - Chris Smith

Has he got evidence if that's the case that's really happening?

Interviewee - Elinor Richards

Well, they've used HPLC, High Performance Liquid Chromatography to study the content of the sap on the plant and yes they have seen high levels of neonicotinoid insecticides on the leaves.

Interviewer - Chris Smith

Devil's advocate here, farmers have been putting insecticides on plants for a long time with foliar application and put it straight on to the leaves, so if it was going to be a case of bees drinking stuff off the leaves that might be contaminated. Is this not likely to already have been the case and still therefore doesn't explain this very abrupt and sudden   decline in bee population that we're seeing?.

Interviewee - Elinor Richards

Yes it's just one theory, I mean Tapparo himself doesn't think the mechanism identifies the primary cause, he says the bee decline could be down to many different factors but he says that it can't be ignored, you know, the insecticides are in these droplets. 

Interviewer - Chris Smith

It's also interesting that the amount of what they're calling CCD, Colony Collapse Disorder is actually relatively rare in some places and relatively common in others but the agricultural practices are quite common to both which suggests that it may not just be hinging on one thing and some bee experts, I have spoken with, have certainly expressed doubt that it's just one cause and they think that actually it could be a combination of sort of killer factors such as feeding bees on a monotonous diet of sugary water and stealing all of the honey that they would normally eat themselves and feeding it to humans of course, so I mean this may be one thing, one contributor but certainly maybe not the whole cause.

Interviewee - Elinor Richards

No, Tapparo has said that he thinks the biologists and people in the field that are studying the bee decline, it's not always possible for them to have access to the mass spectrometer instrumentation, so his application in the use of HPLC is an easier way to detect these compounds in the water on the leaves. So it's a simple procedure really that he is recommending.

Interviewer - Chris Smith

Is it adequately sensitive then to do that with?

Interviewee - Elinor Richards

It seems to be yeah, the results they've had to say that this large concentration of these insecticides in the sap and they say that they're high enough to kill bees within a few minutes.

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Interviewer - Chris Smith

You're listening to Chemistry World with me, Chris Smith.   Still to come a superior cigarette filter; and a new catalyst to get more energy out of waste wood.   First though time to open your mind.   Joan Abbott from King's College works on why we need a blood-brain barrier.

(19:10 - Joan Abbott discusses why we need a blood-brain barrier and how to get drugs across it)

Interviewee- Joan Abbott

Yes, the whole point is that nerve cells require a much more regulated environment than almost every other cell in the body and particularly because they work on a combination of   electrochemistry and chemistry,   the fine membranes that form the nerve cell conduct electricity through ion movement through small channels and that whole process, ionic movement through membranes is what sets up the electrical activity of the brain and that whole process requires the fluid environment of the brain to be very stable otherwise it could also produce extraneous electrical activity and chemical activity which would disturb the signalling.   So the whole point of that the blood-brain barrier is to keep this brain environment very regulated and very stable and then the nervous activity can work in a very reproducible and reliable way to give you, for example, very precise vision, motor control, all things that our brains do.

Interviewer - Chris Smith

On the one hand that's great for the reasons you have outlined, but then when something goes wrong in the nervous system and you want to get a drug in there then if you have this impenetrable barrier or near-impenetrable barrier or a selectively penetrable barrier like the blood-brain barrier is then you've got a problem.

Interviewee- Joan Abbott

Yes, well I think one certainly mustn't get the impression that is some un-impenetrable barrier, it does allow through relatively easily things that are soluble in lipids so for example the obvious one is alcohol, ethanol gets in easily, so of course many drugs that had been produced over the years have made use of this, you could make things like barbiturates and especially use anaesthetics get into the brain because the membranes allow the barbiturates to diffuse through, so that's steady straight forward.   But there are other things that for example more recently we could make very complex molecules which could be useful in the brain in fact antibodies which we know would be very useful if we could get them to right target.   But the big problem then is that the blood-brain barrier is almost certain to impose some kind of restraint on getting these things in and that's part of its natural function, it actually doesn't want these large peptides and proteins and complex molecules in the brain plus these things could have damaging effects on normal activity.

Interviewer - Chris Smith

In some cases the molecules have help in   hand because there are natural   transporters there that will shift things into the brain and so some drugs can pretend to be one of the things the brain wants to import across the blood-brain barrier and they get in that way.   I suppose that's quite a good strategy.

Interviewee - Joan Abbott

It is going to be a very   useful one and there are lots of these different transporters and for all sorts of molecules that the brain does need and a whole range of other transporters that get rid of waste products in the same sort of ways and you might say okay, well if you want to get a drug in why don't we make it piggyback on one of these natural transporters. And the obvious example is yes it does work and things like L-DOPA which have been used to treat Parkinson's quite successfully use that principle, the L-DOPA goes in on what's called the l-amino acid carrier.   But that route has turned out not to be quite as successful as one might guess, particularly because a lot of these transporters are very specific.   They will only handle molecules which have a very good fit with the natural agents that are transported.   So it has turned out be somewhat disappointing for drug companies who thought this might be a way to re-engineer things to use transporters and also it's quite hard to make sure that things like the doses are right because it's harder to predict how much will get transported on the carrier than would be moving by a simple diffusion for example.

Interviewer - Chris Smith

You mentioned drug companies, so what is the drug pipeline actually looking like in this domain?

Interviewee - Joan Abbott

Well, I think many times these drug companies have the same problem but plans are looking not very encouraging, there have been some disappointments.   So, for example you might say, well stroke is a major problem, we should by now have found drugs that would be able to improve the condition of stroke but that whole area has been quite disappointing and many companies have given up on the stroke field because it's pretty quite hard to accomplish something that's really useful.

Interviewer - Chris Smith

So what sorts of strategies are people trying, the adventurous ones having given up, what are they doing?

Interviewee - Joan Abbott

As such there are two approaches, one is to try and reduce the symptoms as much as possible and that's pretty effective for things like multiple sclerosis and others where you can dump down the disease, the other is to begin to try and move the whole recognition of the disease much earlier so you look for very early signs of the dysfunction and you try and treat very early on before too much damage has been done and that may be the way to go.   The companies are beginning to put in a lot more effort into early diagnostics looking for biomarkers of disease and that may give them a much better chance of treating, because going in early when you have lost too much brain material and neurons; but then I felt throughout this there are still some very difficult diseases like brain tumours and I think that may turn out to be a more encouraging field because, yes people are beginning to find quite active agents that will very specifically kill particular types of tumour cells, you just need to get them into the brain and that's where more intelligent approach is being used trying to use as many of the different natural mechanisms that deliver into the brain as possible and to shape the drugs so that not only will