Chemistry World Podcast - March 2007
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Brought to you by the Royal Society of Chemistry, the Chemistry World Podcast.
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Interviewer - Chris Smith
Hello and welcome to episode 6 of the Chemistry World podcast with editor, Mark Peplow...
Interviewee - Mark Peplow
Hello!
Interviewer - Chris Smith
Science correspondent Richard Van Noorden...
Interviewee - Richard Van Noorden
Hello!
Interviewer - Chris Smith
And Victoria Gill...
Interviewee - Victoria Gill
Hello!
Interviewer - Chris Smith
I'm Chris Smith. This month: What's the future for generic drugs in India?
Interviewee - Victoria Gill
M?decins Sans Fronti?res are conducting a campaign to basically make Novartis back off. They say that this case will set a precedent that will threaten the ability of companies in India to make cheaper copies of drugs that are available to poor patients.
Interviewer - Chris Smith
We'll be taking with both players in that battle shortly, also a new break through in imaging.
Interviewee - Richard Van Noorden
This is what they are calling the ultimate microscope, so you don't need a lens at all to take very high-resolution pictures with x-rays and it could be used to take pictures of living biological cells.
Interviewer - Chris Smith
And an ultra-thin membrane that could hold the key to replacement kidneys.
Interviewee - Mark Peplow
Essentially, this is just a sieve for molecules. It's made of a very, very thin layer of silicon; just as they make computer chips out off. It's about 10,000 times thinner than a piece of office paper.
Interviewer - Chris Smith
More from Mark, with that story later. Also, a special Hello to members of ChemNet, which is the Royal Society of Chemistry's network for A-level students. This month you can win some HMV Vouchers. All you have to do is to send some review of this, the Chemistry World podcast. All the details of how to win it are in the March ChemNet newsletter. Firstly, if you listened to last month's Chemistry World's podcast you'll recall Sarah's quest for a constipation cure.
Interviewee - Sarah
As a doctor I've been wondering why it is that magnesium compounds like magnesium citrate and magnesium sulphate are such effective laxatives?
Interviewer - Chris Smith
Well thankfully, Sarah, relief is on its way to you. We've got the answer coming up later in the program. Firstly, to the bind bending chemistry of LSD, because researchers have sussed out how it triggers trips, Victoria.
Interviewee - Victoria Gill
Yeah, indeed, some researchers at Mount Sinai University in the States have looked into what the secret is of LSD? What its hallucinogenic secret is? LSD works on a serotonin receptor called 5-HT2A. Now it and other hallucinogens act on this receptor but so do non-hallucinogenic molecules they act on the same receptor. So the question they wanted to answer was why are compounds like LSD hallucinogenic and other compounds that act on the same receptor are not? So they did a number of tests, the first was with a knockout mouse, which had no 5-HT2A receptors. They gave that mouse hallucinogens - LSD, and found that it didn't produce an effect, so they confirmed that it was this receptor, then they did some biochemical tests and what the biochemical tests showed was that with another compound called lysergide, which acts on the same receptor but it is a non-hallucinogenic compound, you get a different downstream group of chemicals produced in the cell, in cell cultures.
Interviewer - Chris Smith
So, they both work at the same receptor but you get a different off-shoot or different effect of the stimulated receptor.
Interviewee - Victoria Gill
Yes, exactly.
Interviewer - Chris Smith
So how's that achieved?
Interviewee - Victoria Gill
Well the 5-HT2A receptor was called a G protein-coupled receptor and what they've discovered is that when the receptors on the cell membrane and when the compound activates the receptor, it can switch it into two ON phases. So it is sort of switches the receptor into one shape for hallucinogenics and a different shape for a non-hallucinogenics, so the receptor is still activated, it but it activates a different chemical pathway in within the cell.
Interviewer - Chris Smith
And that explains why you get this additional effects when the LSD is present?
Interviewee - Victoria Gill
Yes, exactly! So that's why it is hallucinogenic. You need the receptor to be in a specific ON position in order to get hallucinogenic effects.
Interviewer - Chris Smith
Thanks, Victoria. Well from one toxic substance to another and it turns out the canny snakes are stealing toad's toxins, Mark.
Interviewee - Mark Peplow
That's right, most animals tend to stay well clear of poisonous toads, but scientists have found a species of Japanese snake, which actually seeks them out and eats them and they found that what it's doing is actually seeking out the poisonous toads, so that it can steal their poison and then use it to hunts it's own prey.
Interviewer - Chris Smith
The obvious question there Mark is why doesn't the snake succumb to the toxin in the first place?
Interviewee - Mark Peplow
Well this is one of the things that they've been investigating and through looking at the chemistry, all of the toxins that they are taking in, they've come over with a couple of theories to explain how this might work. Basically, what they've found is that the poison molecules in the snake are actually slightly different from those in the toad and what they think is happening is the snake is somehow chemically modifying these molecules, so that it makes it safe to store but it is still an active poison when it goes and hunts its prey.
Interviewer - Chris Smith
Do we know how the snake then re-deploys the poison, gets it from the right place in the body to where it needs it, i.e. in its venom gland?
Interviewee - Mark Peplow
They haven't looked at that at all. Really the point of this study was to first of all establish that the snake definitely was taking up the toad's toxin. The way that they did that actually was to look at populations of these snakes which you call Japanese colubrid snakes on two different islands around Japan, one of the islands has loads of these toxic toads hopping around and the other one has none and they found that the snakes on the island with all the toads tended to have this poison in their system and were poisonous snakes, whereas the snakes on the toad-free island weren't poisonous at all.
Interviewer - Chris Smith
And if you swap them around?
Interviewee - Mark Peplow
And if you swap them around -- they took the snakes that had not any toads in their diet ever and they fed them little toxic toads and they became poisonous snakes.
Interviewer - Chris Smith
Thus proving it's got to be something in the diet, rather than.
Interviewee - Mark Peplow
Absolutely, so they proved that the stuff is coming from their diets. They proved that it is coming from the toads and although you do see this sort of relationship in certain insects and eating other insects or eating plants to get their toxins. There is a tree frog, for example, that eats insects specifically so that they can get toxins. It is very unusual to see vertebrates like snakes eating other vertebrates like toads to get these poisons.
Interviewer - Chris Smith
Thanks Mark. Well back to drugs now and an international furore that's raging between Novartis and the Indian Government.
Interviewee - Victoria Gill
Yeah, what's happening is Novartis, the Swiss drug company Novartis make a drug called Glivec which is a cancer drug and they've tried to get this drug patented in India and the Indian Government have refused and Novartis are now are saying that since, India, in 2005 should have become compliant with the World Trade Organization rules on patentable drugs, they are breaking law. So Novartis are taking the Indian Government to court.
Interviewer - Chris Smith
Well, they are breaking the law aren't they?
Interviewee - Victoria Gill
Well it's a bit of a tricky area. What the Indian Government claim is that Novartis are trying to evergreen this drug, trying to extend the length of the time they have a patent on it. They already have a patent on the original compound that the Glivec is based on. Novartis claims that this is a new breakthrough drug. The Indian Government claim, no it is a compound that you already have a patent on with a minor change, so it doesn't count as new intellectual property.
Interviewer - Chris Smith
What do people think about this, do they think that this is a reasonable thing, do they think that Novartis have a case.
Interviewee - Victoria Gill
That's where the controversy comes in. An organization M?decins Sans Fronti?res who are a voluntary organization of medical workers who work a lot in India and in the developing world are conducting a campaign to basically make Novartis back off. They say that they depend on generic drugs and that this case will set a precedent that will threaten the ability of companies in India to make generic drugs, cheaper copies of drugs that are available to poorer patients.
Interviewer - Chris Smith
Thanks, Victoria. Well, to find out more I linked up with representatives of both MSF and Novartis to get their sides of the story.
Interviewee - Pierre Chirac
I'm Pierre Chirac and I'm working with M?decins Sans Fronti?res: Doctors Without Borders. Novartis is challenging a decision by the Indian patentists regarding their anticancer drug Glivec and more importantly they are challenging a crucial point of the Indian Patent Law. This is why MSF and others are worried by this trial and we're asking Novartis to drop the case, but I think it's important to give some details on the Glivec case. Imatinib freebase and its solid salts which is the active ingredient of Glivec, was patented since 1993-1994 in Europe and the US. At this time, India had no interaction or obligations regarding patents, so in fact there was no ground to ask India to consider the '93 patent on Glivec. Since India turned into WTO, World Trade Organization that this country asked to comply with World Trade agreements dealing with intellectual property. Then Novartis has asked India to recognize another patent on Glivec in 1998. India rejected this patent after a fair trial, where chemical experts have proven that the particular crystal covered by the '98 patent was in fact already covered by the '93 patent, so the Indian patentists concluded that the '98 patent could not be granted because of lack of novelty.
Interviewer - Chris Smith
Let's just take this opportunity to bring in Petra Laux who is from Novartis, Petra how do you respond to the points that Pierre Chirac has made.
Interviewee - Petra Laux
First it is very important to understand that Glivec is a real breakthrough treatment against a rare form of cancer disease, which is called chronic myeloid leukaemia and it makes sure that 95% of people who take the medicine, they still live 5 years after they've started treatment, so it is a worldwide recognized treatment.
Interviewer - Chris Smith
But I don't think Pierre is arguing about that, does he? The potency of Glivec isn't under scrutiny. It's actually whether or not India should be allowed to make it without having to pay Novartis lots of money?
Interviewee - Petra Laux
Let me get clear. We don't ask the 1993 patent to be recognized; however, patent that covers the active ingredient is not a medicine as such. It is this active ingredient, which can never be tried in humans. So we did more work on this molecule, we invented the form that is actually applicable into humans, so we've been asking for exactly the form that is part of the medicine to be patented.
Interviewer - Chris Smith
So, Pierre, there seems to be a valid point that Petra makes, which is that actually the medicine has been refined since the 1993 patent was laid down, 1998, they re-patented this new formulation. Why shouldn't India respect that?
Interviewee - Pierre Chirac
I would like to make two points. First one is that chemical experts during this trial said that, in fact, the most stable form of imatinib mesylate, which is covered by the '98 patent, is already covered by the '93 patent. The second point is that the certificate extending the patent term of Glivec issued by the US Food and Drug Administration in 2004 is a '93 patent.
Interviewer - Chris Smith
Petra, what does actually the failure of India to recognize your patent mean to Novartis and not just to Novartis but other companies like Novartis? What could it mean to you financially?
Interviewee - Petra Laux
Actually, by saying that you could only get a patent for a improvement of an existing compound, if it is to be shown that the compound is better, now there is a substantial problem these days because at the time when we trial for patent application there is no medicine available, we have nothing but a compound that we then use to make a medicine. So by the way the Indian Patent Law is phrased, companies have no chance. These clinical trials and efficacy data to really show that the improvements they are going for, are better, which means, in essence that there is no reliability because nobody can prove that the patent granted is important for patents for improvement, and this is not only about salts. Imagine India is a place where you have a very hot climate and many Indians also have diabetes. If they were to be a heat-stable insulin, which you would not need to put into the fridge, what an approvement this would be in India; however, heat-stable insulin would not be covered by the present day patent law because there was an approvement of non compound.
Interviewer - Chris Smith
Its sounds to me Pierre Chirac like, the Indian Government could be shooting itself in the foot because big companies like Novartis would actually find it very unattractive to do anything beneficial for India or if they're put over a barrel like this?
Interviewee - Pierre Chirac
In fact the picture in the Indian patent is that Novartis is challenging, is saying that I'm quoting "salts, esters, polymorphs, metabolites, pure form, particle size, isoamyls, mixtures of isoamyls, complexes, combinations and other derivatives of non-substances shall be considered to be the same substance, and this differ significantly in properties with regard to efficacy." This definition has been pasted word for word from the European Directory of 2004 that is giving the new definition of generics in Europe and the meaning of these two definitions in India, is to avoid pharmaceutical industry to evergreen their patent in patenting mere differences in substances. We still remember that patents are supposed to be incentive for real innovation, not for cosmetic changes in substances.
Interviewer - Chris Smith
And Petra Laux, how would you respond to that that you are just trying to evergreen your patents?
Interviewee - Petra Laux
The provision you quoted Pierre is well ingrained in European Legislation Body but it is in the Data Exclusivity provisions and not in the patenting provisions and that's a fundamentally different point. Novartis is pretty much convinced that all the improvements we are working for, are supposed to deliver more value for patients and so we are very confident that if we had a chance to prove it would be improvement in efficacy or more safety, we would be able to adjust that due to the construct in this Indian Legislation where this concept has been taken from a regulatory concept into a patent environment makes no sense. There's another very important point to look at. I understand that MSF is very much concerned about access to essential medicines, now if it were true that we were just out there in to get patents for stuff that is not worth it, so if these things were not available to patients, why would this make any difference for you, because, by definition, you are saying the stuff is not worth any patent, so why do you need it then to treat the patients?
Interviewer - Chris Smith
I suspect that's a story that we'll be returning to in future. Thank you to Pierre Chirac from MSF and Petra Laux for Novartis. And now let's focus on how scientists are looking to build microscopes that promise to see better, brighter, faster, and further than ever before, Richard.
Interviewee - Richard Van Noorden
Yes, Chris. This is what they're calling the ultimate microscope, which means, a microscope where the wavelength that you can see is limited only by the wavelength of your incoming light. Now with normal, you know, optical light that's fine, we use a lens, very good lenses, to focus the light and we can get down roughly to the wavelength of the light that comes in. With x-rays and with electrons it's much harder to focus those type of beams, so the images are really about 100 times more blurred than you might think technically possible, if you could focus them perfectly. But a new technique introduced by John Rodenburg and colleagues, suggest that you don't need a lens at all to take very high-resolution pictures with x-rays, and it could be used to take pictures of living biological cells.
Interviewer - Chris Smith
So how now do you actually gather the light data, if you haven't got a lens?
Interviewee - Richard Van Noorden
Yeah, well you don't need a lens, you can actually diffract light through an object and out of the other side in a way it scatters tells you what the structure was. Now some people might be saying, "Well! Come on, they did this in the 1950s when they were told what the structure of DNA was."
Interviewer - Chris Smith
Crude x-ray crystallography, isn't it?
Interviewee - Richard Van Noorden
Exactly, but x-ray crystallography, because it's on a crystal, where the atoms have a regular structure and it's quite a well established to field to work out what the crystal's structure was from the way the rays were refracted, but when atoms are not arranged in a regular shape, there's no regular structure, it's much harder to work out what the atomic structure was
Interviewer - Chris Smith
So, like a living cell or something?
Interviewee - Richard Van Noorden
Yeah, something like a living cell and what Rodenburg's team have done is essentially they've got lot of fiddly computers and maths and as the rays pass through the structure, they interfere with each other after they pass through and by taking a series of overlapping diffraction patterns, say from overlapping areas of space, past the object that you are looking at, you can work out how they must have interfered with each other and actually work backwards from that to tell you what the structure was.
Interviewer - Chris Smith
So how long does it take to acquire an image then, and if you're looking at living things because I could think one reason this would be really powerful will be to, say look inside living cells, if it takes too long, won't the structures inside the cell potentially have moved and therefore blur the image?
Interviewee - Richard Van Noorden
Yes. I don't know how long it takes to acquire them because they've not tried on living cells yet, but I believe its a matter of hours and the crucial advantage of other diffraction techniques is that you don't need to vacuum, you don't need to focus on a very small isolated part of the sample, the way the overlapping diffraction patterns of the end work is that you can take a sample of any size or shape which is a big advantage. So far they haven't really got down to the cells; they haven't got down to the point 1 nanometres that they say is theoretically possibly. They have only shown a proof of principle demonstration that you can do this to around 15-nanometre resolution, which is still very good, that the principle is there and it could go much further.
Interviewer - Chris Smith
Thanks Richard. Well sticking with the very small, scientists have come up with an ultra thin membrane peppered with tiny perforations and this might hold the key to building replacement kidney, Mark.
Interviewee - Mark Peplow
Yeah essentially this is just a sieve for molecules. Its made of a very, very thin layer of silicon, just as they make computer chips out off and its about 10,000 thousand times thinner than a piece of office paper and its got tiny little holes in it. Now compared with the sorts of membranes that you normally see in dialysis machines, which are essentially just filtering your blood, they speed up the separation of proteins and also blood by at least an order of magnitude. Now the holes in the nanocrystalline silicon are essentially just gaps left between tiny, tiny crystals of silicon. They're about a 100,000 times smaller than the holes that you'd normally see in a kitchen sieve and what they allow you to do essentially is to very quickly get small molecules filtered out of the liquid, leaving big chunky molecules like proteins behind.
Interviewer - Chris Smith
Which is why we think they might have very great use, say, dialysis membranes and things like that?
Interviewee - Mark Peplow
That's right and normally when some one is undergoing dialysis it might take them 3 or 4 hours. What's essentially happening is that in the blood you are leaving behind large protein molecules and filtering through very small waste molecules, like urea, it's like something that your kidneys do for you normally. And now what the researchers who invented this membrane, who're based at Rochester University in New York, what they found was that they could achieve similar sorts of separations in about six and a half minutes. To test this, they separated a really big chunky protein called bovine serum albumin from fluorescent dye and they found that, yeah, you got complete separation in just over 6 minutes.
Interviewer - Chris Smith
How did they make the membranes in the first place?
Interviewee - Mark Peplow
Well, they actually stumbled across a method to do this by chance; it's quite interesting. They were just trying to find out how silicon crystallises and when its sandwiched between two layers and they found that because of the way that the crystals grow, it's almost like points growing open as they come together, they start to touch and in between those almost circular crystals, you get these little holes appearing and they found that by tweaking the conditions of that crystallisation, you can very precisely tailor the exact size of the hole, so that you're filtering out exactly the size of molecule that you want.
Interviewer - Chris Smith
So you could sort out bigger ones and smaller ones, just by tailoring the way in which you grow these sheets.
Interviewee - Mark Peplow
That's right. They tried some different conditions and they found that they were actually able to separate two different types of protein, so both big chunky molecules, one of them, slightly bigger than the other and actually managed to separate one four times as much as the other. Now they think they are optimizing this through tuning the conditions of the crystallizations just right, they can get the precise, perfect size hole that you can filter just about any biological molecule away from each other.
Interviewer - Chris Smith
Thanks Mark and now to the slopes of the Alps, where it turns out that in order to make slushy snow more skiable, large amounts of ammonium nitrate, which is also a potent fertilizer, are being sprinkled on the snow. The downside is that, of course, when the snow melts, it all ends up on the ground and in watercourses and Christian Rixen has been looking at the potential impacts.
Interviewee - Christian Rixen
Ammonium nitrate is being used on the snow surface to make it harder, to make it hazy. In case the snow is too warm, you can apply ammonium nitrate on the surfaces that leads to a cooling of the snow surface, to make it harder and to actually make ski race happen.
Interviewer - Chris Smith
So how do you know that ammonium nitrate's been added to the snow, and what are the possible consequences of that?
Interviewee - Christian Rixen
The use of ammonium nitrate can be common practice in some ski resorts during ski races to enable the ski race. What we are little worried at the moment is during snow melt, ammonium nitrate will run off in one large rush and part of this will probably end up in the vegetation in the ground and this could be a potential problem.
Interviewer - Chris Smith
So, which bits of the mountainside and where exactly have been affected by this?
Interviewee - Christian Rixen
The area we're talking about is at Lauberhorn in the Swiss mountains where famous ski race happens every year.
Interviewer - Chris Smith
And is this practice allowed or is it a covert practice that's just being done and isn't allowed or isn't something or that should be regulated?
Interviewee - Christian Rixen
This is something that has to be found out at the moment, whether there are laws actually applying to this case or whether this is an area that is not being covered by laws at the moment. This is being worked at, at the moment.
Interviewer - Chris Smith
So in order to get it stopped, what is it going to take? Is it going to take you proving that sufficiently large doses of, what amounts to very potent fertilizer, are finding their way into waterways or are we going to have to wait until something actually physically dies until someone will do something?
Interviewee - Christian Rixen
First we have to find how much ammonium nitrate is actually used. Is this a very special case that happens now or is it something we see regularly on ski slopes? The second question is how much is actually used and how much of the ammonium nitrate used will end up in waters and how much does this compare to what happens during fertilization in normal agricultural use? Its going to depend largely on that whether there is a need for action or not.
Interviewer - Chris Smith
Certainly a chilling thought. Christian Rixen is trying to find out what impact, if any, combating slushy snow with ammonium nitrate could have on Alpine ecosystems. And now sticking with the environment, are biofuels not all they are cracked up to be then, Richard.
Interviewee - Richard Van Noorden
Well talking specifically about getting ethanol from corn, which the US really love, it sounds great. You reduce your dependence on foreign oil; you support your farmers and you may be reducing greenhouse gases, but scientists have been warning that actually ethanol from corn is not such a great idea. You don't reduce that many greenhouse gases, you don't get much energy benefit, because you're putting so much into growing the crop in the first place, all your fertilizers, all your pesticides, when you take the whole life cycle of the corn into account, you're not getting much reduction in greenhouse gases and you're not getting much net energy gain.
Interviewer - Chris Smith
But what about countries like Brazil? There has to be an argument made that getting ethanol from sugarcane there does make economic and also environmental sense because it grows in great perfusion?
Interviewee - Richard Van Noorden
Yes, in fact if you get ethanol from sugarcane, it's a much high yield and Brazil already has a very well thought out distribution process and of course a much smaller population. So, although America's output 5 billion gallons of ethanol last year is about equal to Brazil's output; the two countries are not so similar at all. Nonetheless in America, George Bush is pushing for 35 billion gallons of renewable fuels by 2017 so there's certainly a quite a lot of biofuels to get that.
Interviewer - Chris Smith
But you could argue that by encouraging people to embrace the biofuel movement then you are much more likely to stimulate the field and squeeze it upon the industry and therefore you will see improvements, which have environmental benefits in the long run.
Interviewee - Richard Van Noorden
Yes, in fact there are close to 200 or going to be close to 200 ethanol plants set up in the US and although I've just said that ethanol from corn might not be such good idea, they are actually paving the way for a probably superior, what's called second generation biofuels technology, where instead of getting ethanol from corn which also cause impacts on the food supplies, you're actually getting it from the woody waste, corn, straw, prairie grasses, the so called cellulose and hemicellulose materials.
Interviewer - Chris Smith
Is it easy to get energy from that? Is it going to be actually economically and energetically viable to try and do that?
Interviewee - Richard Van Noorden
Well it's much harder to do that and very hard to break that down, but nonetheless some of the companies are attempting to do it commercially and you know BP, Abengoa in Spain, they're all trying to get in on the act and people of Chemistry World totally suggested that if government were prepared to put in subsidies and if entrepreneurs were to prepare to put in enough money and have a go at it, cellulosic ethanol technology could be commercially viable within the next 5 years.
Interviewer - Chr
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