Chemistry World Podcast - May 2007

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Brought to you by the Royal Society of Chemistry: The Chemistry World Podcast.

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Interviewer - Azi Khatiri

Hello and Welcome to the eighth episode of the Chemistry World podcast with me Azi Khatiri sitting in for Chris Smith while he is enjoying the sunshine down under.   But I am joined by Chemistry World's editor Mark Peplow 

Interviewee - Mark Peplow

Hello!

Interviewer - Azi Khatiri

With Deputy Editor Bea Perks... 

Interviewee - Bea Perks

Hello!

Interviewer - Azi Khatiri

And science correspondents, Victoria Gill... 

Interviewee - Victoria Gill

Hello!

Interviewer - Azi Khatiri

And Richard Van Noorden...

Interviewee - Richard Van Noorden

Hello!

Interviewer - Azi Khatiri

This month how nanoparticles help to light up the MRI scan

Interviewee - Victoria Gill

And the point of these nanoparticle contrast agents is that they are speeding up even more.   So you just got this really marked improvement in contrast

Interviewer - Azi Khatiri

And how researchers were able to identify soft tissue in the fossilized remains of a 68 million-year old T rex.

Interviewee - Bea Perks

The evidence right now to the best of our knowledge supports the fact that some of the material in the bone matrix is collagen produced by the cells of the dinosaur.

Interviewer - Azi Khatiri

And the quantum mechanics of green tea.

Interviewee - Richard Van Noorden

Because of this quantum tunneling the beneficial reaction occured so quickly that the lipids never even got to look in thankfully.

Interviewer - Azi Khatiri

That's also to come in the program, but first scientists at the Georgia Institute of Technology have developed a nano scale power generator that can harvest electricity from the environment.   The device relies on combination of tiny nano wires and a specially designed electrode to transfer vibrations into electricity.   Mark, tell us more about it. 

Interviewee - Mark Peplow

Well, these are tiny generators that work on the scale of just billions of a meter.   Scientists for years have been working on various nano machines, devices that work at this sort of scale thousands of times smaller than the width of a human hair, but researchers lagged behind on ways to actually power these machines, now these group of scientists at the Georgia Institute of Technology have found a way that might work.   Effectively what they've done is, created, if you like, a tiny, tiny hairbrush, where each of the bristles is made of, what's called a nanowire so it's a tiny thread, if you like, made out of zinc oxide.   This chemical is piezoelectric which means when you bend it, it actually creates a tiny electrical current, now what they've done is, is taken this brush of zinc oxide nano wires and over the top of it they have a corrugated surface made out of silicon coated with platinum, now what they found is that just from background vibrations or ultrasonic waves, the movement of this corrugated surface across the nano wires, across this brush, actually makes them generate a current.

Interviewer - Azi Khatiri

So how much power can they generate with that device at the moment.

Interviewee - Mark Peplow

Well, the current that they're outputting appropriately enough is nanoamps, so that's billionth of an amp and they recommend that there may be another three years of development in this before they are able to provide the source of powers that would be needed to actually power real world devices.

Interviewer - Azi Khatiri

So what sort of things could they use this device for?

Interviewee - Mark Peplow

Well, when we spoke to Zhong Lin Wang who leads this research team, he imagined that there was a variety of possible uses for this.   Some of the ones that he was talking about was implantable biosensors that may be to monitor blood pressure or blood sugar levels, for example, if you're diabetic or possibly even monitor for instance of cancer, perhaps.   He also suggested that there may be technical applications as well, for instance, remote sensing of gases or chemicals or even, I mean, given that this is powered by ultrasonic waves, it could also prove to be a way of detecting ultrasonic waves if you wanted to do that. 

Interviewer - Azi Khatiri

Thanks Mark.   Now from power-generating nanotechnology to even more nanotechnology.   Researchers in South Korea have used special nanoparticles as contrast agents in MRI or nuclear magnetic resonance imaging as well as showing up unprecedented details in the image.   These particles are also biocompatible, Bea.

Interviewee - Bea Perks

Nanoparticles are being used to make clearer MRI images.

Interviewer - Azi Khatiri

So how does MRI normally work then?

Interviewee - Bea Perks

Well the human body is about over 60% water and each of the hydrogen ions in those water molecules has a magnetic movement, so in a very powerful magnetic field, the molecules line up and in the scanner you have this enormously powerful magnetic field, but then you also have running in the other direction, radio waves and the radio waves reverse the magnetic field momentarily switched on and off and so these hydrogen ions flipping backwards and forwards, they emit little bit of radiofrequency themselves and that's what is picked up on the MRI scan.   You see amazing detail actually, but if depending on what you are looking for you might want some more detail and so there are these contrast agents that medics can use.

Interviewer - Azi Khatiri

So what exactly is the role of the contrast agent because when we're talking about contrast, this is not like a photographic image contrast when it comes to MRI, is it?

Interviewee - Bea Perks

No, absolutely not.   In an ordinary MRI scan or at least an MRI scan without a contrast agent what you are seeing is the hydrogen ions flipping between magnetic states and once you put a contrast agent in there, you're speeding up that flipping and it is the flipping that is being picked up basically on the image and if you can speed that up you're going to get a darker image or a brighter image perhaps, I should say, but a stronger image anyway and the point of these nanoparticle contrast agents is that they are speeding up even more, so you just get this really marked improvement in contrast and there are already some contrast agents in use and these are very successful, but some of them will cause kidney damage for instance and apparently these nanoparticles get around that issue.

Interviewer - Azi Khatiri

What are these nanoparticles actually made of?

Interviewee - Bea Perks

These nanoparticles are manganese oxide but they are coated in a biocompatible polyethylene glycophospholipid shell, they have only used this in mice so far, I should say, so it is very early days, but if it does work in higher and higher animals and eventually in humans, then you will be able to tell really slight differences especially at the early stages say of neurological diseases where you wouldn't see any damage with a conventional MRI scan.

Interviewer - Azi Khatiri

Just out of curiosity, how big are the actual particles?

Interviewee - Bea Perks

They are 25 nanometers across.

Interviewer - Azi Khatiri

And do they get metabolized inside the body or what actually happens to them once they're there?

Interviewee - Bea Perks

No they are not metabolized.   They are safely excreted.   So they don't do any damage to the body or at least they didn't do any damage to these mice.

Interviewer - Azi Khatiri

Well, from mice to dinosaurs now.   A team of scientists have discovered extraordinary preservation of soft tissue in the remains of a 68-million-year-old Tyrannosaurus rex.   The skull, vertebrae, femora and tibia of this dinosaur were recovered from the base of the Hell Creek Formation in Eastern Montana in USA.   Here is Dr. Mary Schweitzer of North Carolina State University.

Interviewee - Mary Schweitzer

We noticed exceptional preservation in this Tyrannosaurus Rex fossil and we reported the presence of 4 components that were not supposed to be present in dinosaur bone and these would be the fibrous matrix that in modern bone is collagen, what appeared to be transparent blood vessels and two cell populations.

Interviewer - Azi Khatiri

That's really interesting Mary, given that these fossils are quite old, aren't they?

Interviewee - Mary Schweitzer

Yes, this dinosaur was found at the very base of the Hell Creek Formation which puts it about 68 million years old plus or minus 200 thousand.

Interviewer - Azi Khatiri

Now that's quite old for a piece of fossil.   How is that that you found soft tissue in it.

Interviewee - Mary Schweitzer

Ah well! I found it by accident and we are not really sure at the present why this material is preserved or how it's preserved or even what it is for sure.   Just because it looks like vessels and cells, it does not mean that's what it is after 68 million years, until our chemical analyses verify that these are products of the original cells of the original dinosaur, they could be anything and at this point that is where we are at. We're trying to chemically and molecularly characterize these four different components.

Interviewer - Azi Khatiri

So, how're you trying to verify this?

Interviewee - Mary Schweitzer

By as many different means as possible and we started with collagen first of all because in bone that's the most prevalent protein and secondly collagen is so well studied across all modern organisms that we know its characteristic fingerprints quite well.   We needed to look for things like antibody binding, which is highly specific, we also did in-situ localized mass spec illustrating a lot of the amino acids in the tissues that are specific for collagen.   We did atomic force microscopy to illustrate the cross standing that's the hallmark of bone collagen and then we finally did mass spec sequencing which was part of the paper my colleague led.

Interviewer - Azi Khatiri

So what   have you concluded that these specimens actually are?

Interviewee - Mary Schweitzer

Well, the evidence right now to the best of our knowledge supports the fact that some of the material in the bone matrix is collagen produced by the cells of the dinosaur.

Interviewer - Azi Khatiri

Why do you think the collagen in such an old specimen is still intact?

Interviewee - Mary Schweitzer

Well, we have a lot of different ideas, but one of the main path that I'm working on right now is the role that iron may play in the preservation of this material and the literature suggests that iron under certain conditions becomes very, very reactive and triggers the formation of lot of protein crosslinks.   If the crosslinks are in the right place and of the right type, it basically removes the active sites of the molecule that enzymes can attack, it protects them.   What we found in our studies is that bone provides a large degree of protection from different degradative processes that's skin and muscles and guts don't have.   So I think you know the first component in preservation is the fact that this material is bone.

Interviewer - Azi Khatiri

Now if I can turn to the co-author Dr. John Asara from the Harvard Medical School.   John, how does your work link in with what Dr. Schweitzer has been doing.

Interviewee - John Asara

She has actually shown that the T. Rex fossil is exceptionally well preserved and contain soft tissues, then basically what we did was we attempted to actually find peptide sequences in the T. Rex fossil and it was a real struggle, there was very, very little peptide material to actually begin with.   When we got the bone extracts from her, it was more than 99.99% some sort of brown, gritty contaminant and we actually needed to use a lot of purification and a lot of chromatographic techniques in order to remove the contaminants from the actual peptide content and when we were actually successful at that we got seven total peptide sequences and these sequences barely crossed the detection level of the mass spectrometer.

Interviewer - Azi Khatiri

How did you overcome that problem?

Interviewee - John Asara

What we had to do was basically take all of what she had given us, which was about 30 to 40 mg and we had to purify all of that and concentrate it down to a few microliters of material and when we injected those few microliters we were able to actually get enough signal to successfully sequence pieces of the collagen protein and then when we get the sequences we can then search them against the protein database.

Interviewer - Azi Khatiri

How did you know that what you were looking at was actually remains of a 68-million-year-old species, because there wouldn't really be any indication of what the species should look like in the database, how did you overcome that problem?

Interviewee - John Asara

What we have to do is rely on matches of related species, so if you had, lets say, a common contaminant.   Let's say we were really sequencing a chicken bone, well then all of the sequences that we obtain would match chicken collagen.   If, let's say, we were sequencing a frog and not a T. rex then all of our sequences would then align perfectly with frog, but the fact is we got seven sequences, three which matched uniquely to chicken and then we got two which matched multiple organisms.   But then we got these two very interesting sequences one that only matched newt.   Nothing else in the database had this sequences except for newt and then we got the same things for frog, so that's how we knew that it was likely not frog, likely not newt and it was likely not chicken because of this unique newt and also this unique frog sequences and the fact that we were getting almost barely enough material to actually cross the threshold of the mass spectrometer.   If you had any sort of contamination even these smallest amount that you can barely see of modern collagen, it would overwhelm the instrument in terms of sensitivity.   So when you put all these factors together, especially the sequence alignment that's been held in the coffin here, overall picture was clear that it was from T. rex and obviously not a modern contaminant and the thing is things like newts were never native to the Hell Creek environment, so there is almost no way that it could really make a case for contamination.

Interviewer - Azi Khatiri

So when you wee looking at these T. rex proteins you were finding sequences that match with chicken, some with frog and some with newt, so how would you then be able to distinguish that it's not another species but specifically a T. rex.

Interviewee - John Asara

So you are saying that may be this bone was from something that we don't know about that's not T. rex, but sort of also matched all of these things uniquely the way that we had it all aligned up, I guess Mary and also Jack Horner know based on the structure of the bones, the size of the bones, where they come from that its got to be a T. rex and certainly nothing smaller, don't forget that this was a huge femur bone that actually needed to be broken in order to put inside a helicopter, so I don't think when you take into account the shape and all of their experiences, I don't think there is any question that it was actually a T. Rex.

Interviewer - Azi Khatiri

What do you think these findings will actually show us? How will they help us in the future?

Interviewee - John Asara

The biggest thing that you can get from this is now we have established a methodology that we can use to actually probe proteins from extinct organisms and if we acquire sequences from these extinct organisms and even if it is only from collagen you can start to make evolutionary relationships based on sequence, then we can start to, may be, fit this extinct organisms better in evolution.

Interviewer - Azi Khatiri

Dr. John Asara on how the team have managed to sequence the oldest ever protein specimen.

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Interviewer - Azi Khatiri

On the way, how traditional Chinese medicine may provide a safe alternative to hormone replacement therapy and how quantum mechanics can explain the beneficial effects of green tea, but first the case of a disappearing sunset, Richard tell us more.

Interviewee - Richard Van Noorden

Well if I can just sort of digress on the chemistry conversation a bit and tell you about art.   Winslow Homer is a very famous American painter, I hadn't heard of him before. I stumbled across this little bit of research, where the Art Institute of Chicago -- in fact they are launching a major exhibition of his work in Spring 2008.   Homer painted some paintings including a lot of pastoral scenes.   One of them, for example, 'For to be a Farmer's Boy' which I'll attempt to describe here.   Obviously you can see it on our web site. It's a little farmer's boy in a pumpkin field and there's a white sky behind him, but when researchers looked at the painting, they realized that invisible to the naked eye but just visible under the microscope with tiny orange and red dye pigments which probably meant that the original white sky was in fact a sunset, unfortunately the original dyes that Winslow Homer used were unstable in light and very quickly degraded leaving almost nothing.

Interviewer - Azi Khatiri

When you say very quickly, how long are we actually talking?

Interviewee - Richard Van Noorden

While he painted it around the 19th century, so of course, I'm talking about 100 hundred years and obviously they've been kept in reduced light levels, within 20 years   they would've degraded to almost nothing.

Interviewer - Azi Khatiri

So what's the dye actually made of?

Interviewee - Richard Van Noorden

The dye known as red lake pigments and is made by precipitating an organic dye stuff like madder or cochineal from insects onto some kind of inorganic binder like chalk or alumina and its those kind of dye stuffs which UV lights breaks down.

Interviewer - Azi Khatiri

So what are these researchers trying to do at the moment?

Interviewee - Richard Van Noorden

Well, normally what a chemist would do to work out what a dye is Raman's spectroscopy which is a kind of you fire a certain wavelength of light at your sample of interest and some of the light scatters off different wavelengths scatter off in different directions and that will sort of give you a fingerprint that you could compare to a known substance.   Unfortunately, these organic dyes have been very little studied and one reason is that they are extremely fluorescent and that just completely swamps the signal for traditional Raman's spectroscopy and to make things worse, these dyes aren't really available now because painters just don't use them.

Interviewer - Azi Khatiri

So if Raman's spectroscopy isn't going to work, what other techniques can they use?

Interviewee - Richard Van Noorden

Fortunately, a technique called surface-enhanced Raman spectroscopy.   In surface-enhanced Raman spectroscopy you put your dye molecules, for example, on a substrate of silver nanoparticles which on top of some kind of alumina spheres and plasmon resonances, which are electron waves excited on the surface.   When you shine your laser light then, they resonate and improve the signal.   So what they got is they have got a library of these pigments, they have got to say, you know, cochineal normally looks like this under surface-enhanced Raman spectroscopy, madder looks like this brazilwood would looks like this then they have to somehow workout a way of taking the red pigments off the painting comparing them to their library and hopefully recreating what the sunsets would have looked like.

Interviewer - Azi Khatiri

Now from disappearing sunsets to disappearing memories.   Researchers have identified a potential target for a memory-enhancing drug, Victoria.

Interviewee - Victoria Gill

This is some research that has come out of a University in Montreal, Nahum Sonenberg and his team have engineered a genetic knockout mouse that can't phosphorylate this particular protein called elF2? and elF2? stimulates the production of a new protein that prevents the making of new memories, so you need certain proteins to build memories to strengthen synapses, the junctions between your neurons, and certain proteins that inhibit the production of new memories and so the phosphorylation of elF-2-alpha inhibits the formation of new memories.

Interviewer - Azi Khatiri

So does that mean that they've effectively found the way of stopping memories being made?

Interviewee - Victoria Gill

Yeah! They tested the mouse with a molecule that increases the phosphorylation of elF2 , so what they basically have is a drug that makes the smarter mouse forget, so the opposite of what they would want to achieve with the potential memory-enhancing drug, the idea being that because they have a molecule that does this, then technically you can get a molecule that does the opposite and that would be your memory-enhancing drug.

Interviewer - Azi Khatiri

Does this actually mean that one day we might be able to buy a bottle of memory-enhancing pills just like some people might do with vitamin supplements.

Interviewee - Victoria Gill

There has been lots of speculation about the idea of being able to improve our memories and improve our learning ability, but from the perspective of these researches, this is a potential medical treatment, so you have neurodegenerative diseases like Alzheimer's disease or Parkinson's that affect your memory, particularly Alzheimer's disease, so the idea would be to have a molecule that you could give to patients to stop them from suffering this quite debilitating memory loss.

Interviewer - Azi Khatiri

Thanks Victoria.   Now from time to time, traditional botanical remedies are investigated for the beneficial properties for use in conventional medicine.   Professor Yong of the National University of Singapore is researching commonly used Chinese herbs in the hope of developing safer alternative drugs for the treatment of menopausal symptoms.

Interviewee - Eu Leong Yong

Menopausal women traditionally take synthetic estrogens to relieve their symptoms and to improve their bone health, but in recent years the hormone preparations or hormone replacement therapy had been shown to cause an increase in adverse effects like breast cancer, strokes, cardiovascular disease and even increased incidental Alzheimer's disease.   Though a lot of women worldwide now have stopped taking these traditional hormone replacement therapy and they are increasingly turning to botanical.   The problem there with botanical or herbal extract is that there is very little data on the bioavailability on how they act and whether they are actually safe in medication, so I wanted to examine in a very scientific way whether these botanical alternatives are really efficacious and safe?

Interviewer - Azi Khatiri

So what types of plant have you been looking at?

Interviewee - Eu Leong Yong

We examined about two dozen plants and found that a particular plant called Epimedium has a high concentration of granulated flavonoids and now flavonoids are the chemicals that give plants its colour and usually they protect the plant against fungal infection among other things, but flavonoids have recently being shown to have quite favourable effects on various cell systems.   For example, the flavonoid from, the soya beans has been reported to improve cholesterol level if you take them in time, in enough quantity.   Now this particular flavonoid from Epimedium is special, in that it has prenyl chain and may improve the bioavailability and also it has a flavone group which makes it a very strong estrogen-receptor alpha activator.

Interviewer - Azi Khatiri

So, what exactly is Epimedium and what does it look like?

Interviewee - Eu Leong Yong

Intriguingly, this is a wild plant growing in various parts of China.   If you want a description, it's a little shrub that has three stems, and the three stems will have three little leaflets and three little branch stems will bear leaf with three leaflets, you see, so it's three plus three plus three -- it's a very beautiful plant.   The colloquial name in Chinese is Yin Yang Huo.   In the web it's shown as horny goat weed and that's exactly what Yin Yang Huo means in Chinese.   Now, the reason why it's called horny goat weed is that apparently goats in the field who are feeding on this particular weed, Epimedium, became very sexually aroused and it's sold on the web as the male Viagra, so these compounds are quite complex, because, besides being estrogenic they can activate other systems, you see, and that's the fascination of natural compounds.

Interviewer - Azi Khatiri

So, now that you're identifying active ingredients in these plants, what is the next step?

Interviewee - Eu Leong Yong

Plant extract is bit like a wine.   You have various wines, cheap wines, good wines, some have high alcoholic content, some are bitter, some are tannins and so what we wanted to do was to have the highest quality possible botanical extract, so we need to know the species like whether it's a bordeaux or whether it's a champagne and we need to know whether its Chat?au Lafite where its grown and under what conditions it's harvested and prepared and we wanted the chemical content to be known like tannin content, alcohol content, in the case of wine.   So we wanted to do it for the herbs so that we have a standardized, high quality preparation and we are doing it with a European company, so once we have a standardized preparation, we will be then in the position to screen animals and we have founded actually the chemicals and activities present in sufficient concentrations for us to explain a biological effect and then the final step will be to translate that to the human, so we'll be doing that very shortly.

Interviewer - Azi Khatiri

Professor Eu Leong Yong from the National University of Singapore.   Now staying with the far east, we have even more news for you.   Mark, tell us more.

Interviewee - Mark Peplow

That's right.   While we have various scientists investigating traditional Chinese medicine as we've just been hearing about, over in china, there is an ongoing bribery and corruption scandal dogging their state's Food and Drug Administration, the former head of this Food and Drug Administration, Zheng Xiaoyu was detained on corruption charges back in December.   This month some more details about this case have emerged and essentially it's been widely reported that he has been taking bribes from various Chinese pharmaceutical companies to approve their medicines, shepherd them for the approval process.

Interviewer - Azi Khatiri

So, what exactly is the Food and Drug Administration doing about this issue?

Interviewee - Mark Peplow

Well, they have a new head in place, Shao Li Ming, who told our reporter in late March that his agency is now revising the drug registration regulations to try and tighten up the criteria for new drugs.   One of the interesting things is that it has been very, very easy for Chinese pharmaceutical companies in the past through this process to get drugs approved as "new" whereas in fact there may really be very little novel about those drugs at all.   So that's part of the process, which is likely to be tightened up and that's something actually that's going to be welcomed by the increasing number of international pharmaceutical companies that is setting up bases in China and starting to collaborate with scientists out there.

Interviewer - Azi Khatiri

Of course, this issue is important for pharmaceutical companies because they have patents to protect, but how does it actually affect people and are there any indications of safety margins being sacrificed with these new drugs.

Interviewee - Mark Peplow

This is obviously extremely important to the people of China who are taking drugs that had been approved by this agency because if a drug is classified as new the company basically able to price it in a different way, which effectively means that they can make more profits from these things, but there haven't necessarily been the checks and balances that one would expect in assessing that they are completely safe for medical use and there is now an enormous investigation to go back and recheck, about more than a 100,000 drugs that were approved between 1999 and 2002.

Interviewer - Azi Khatiri

Well, we hope no one is adversely affected by these drugs.   Now Richard, what is this about quantum effects and green tea?.

Interviewee - Richard Van Noorden

Yeah!   Well, of course quantum effects run the core of everything, but they are also in the core of green tea and scientists have used quantum mechanics to account why green tea is good for you.   Green tea has always been associated with good health and long life and that's because it contains chemicals called catechins or possibly catechins depending on how you want to say them, but anyway they act as antioxidants and they disrupt a damaging chain reaction that can happen between free radicals in your body and lipids.   Now you knew about that before.   So, now ?ngels Gonz?lez-Lafont and her collages at the University of Barcelona in Spain, they've worked out why green tea catechins can mop up the free radicals and it seems that it's all down to a quantum effect, called quantum tunneling.

Interviewer - Azi Khatiri

So, what exactly is quan