Chemistry World podcast - April 2012
0:53- A thermometer that can measure temperatures within a cell
2:55- In space, tiny diamonds are made from carbon onions
6:27- Michael Hamblin sheds light on photodynamic therapy
13:23- Usurping the functional group hierarchy
16:31- Could arsenic DNA really exist?
19:51- Volker Hessel discusses the future of flow chemistry
26:35- Using magnetic levitation to measure protein binding
29:11- Making crisps healthier
32:05- Which element links a founding father with an expedition and constipation?
Interviewer - Chris Smith
This month we're meeting head-on the toughest substance ever made and a clever way to fingerprint the formerly unfingerprintable. Hello, I am Chris Smith and with me for this month's Chemistry World are Phil Broadwith, Andrew Turley and Laura Howes.
Interviewer - Chris Smith
What do an onion, a Russian doll, a fullerene and a nanodiamond have in common? The answer is that the first two are analogies, the second two are realities and scientists have worked out using all of them, how these miniature nanodiamonds which contain trapped samples from the earliest vestiges of the universe actually came about. We'll find out shortly how it happened. Hello, I'm Chris Smith and with me for this month's Chemistry World are Philip Robinson, Andrew Turley and Patrick Walter.
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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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Interviewer - Chris Smith
And first up, a thermometer for cells. Patrick.
Interviewee - Patrick Walter
You'd like to know the temperature of a cell, try and investigate kind of what's going on in there, so certain diseases can affect certain organelles such as the mitochondria for instance, if you can look at how hot they're you might get an idea of what's going on, what the disease process is doing. So Seiichi Uchiyama at the University of Tokyo has developed a polymer that you insert into the cell and this polymer also had a fluorescent molecule, and a heat responsive portion. The polymer diffuses throughout the cell, then you're able to use fluorescence to determine what kind of temperature it is. So what happens when the temperature change? Well, the polymer begins to contract and as it contracts, it forces out the water that is bound to the polymer and as the water is forced out, this ends the quenching of the fluorescent signal that the polymer produces when light is shone on it. So what this means is the hotter it gets, the more fluorescence you see.
Interviewer - Chris Smith
How did they get around the problem then of the different concentrations of the polymer, different bits of the cells because some parts of the cell are going to be thicker, deeper than others, some are going to have an environment where the polymer tends to collect more. So, how do you make sure that you don't over read the temperature, because there's just more of the polymer there, to register a light signal?
Interviewee - Patrick Walter
So, they thought about this problem and they decided instead of working on fluorescence intensity, they'd work on lifetime. This means that the signal isn't dependent on the intensity of fluorescence. So, what happens is they look at how long the polymer fluoresces for rather than how intense that fluorescence is. This thing gives them an idea of how hot it is in certain regions. So, the nucleus for instance was a degree hotter than the cytoplasm. These are big differences, we're talking about here.
Interviewer - Chris Smith
And any kind of cell is amenable to having its temperature measured like this?
Interviewee - Patrick Walter
Yeah, any kind of cell.
Interviewer - Chris Smith
Brilliant! What an amazing discovery. Thank you very much Patrick.
Interviewer - Chris Smith
Philip, tell us about, I think this is also an amazing discovery. These nanodiamonds that have been out there in the universe in an unexplained way, now scientists think they have an explanation for where they came from.
Interviewee - Philip Robinson
Well, that's true and an unlikely explanation, you might think, if I tell you, they're made from onions. But not the onions that you'd find in your garden. These are carbon onions which are concentric fullerene structures.
Interviewer - Chris Smith
Buckeyballs.
Interviewee - Philip Robinson
Buckeyballs exactly, yeah they're sort of famous, football shaped forms of carbon. So a carbon onion has layers of these balls, so you have a Russian doll of carbon fullerenes.
Interviewer - Chris Smith
Well, first of all tell us a little about the back story behind these nanodiamonds, where were they first discovered, and why are they important. Why are scientists intrigued by them?
Interviewee - Philip Robinson
Nanodiamonds are, as the name suggests, tiny little diamonds, just a couple of nanometres in size. And they have significant astrophysical implications. People are interested in nanodiamonds because in the '80s, these nanodiamonds were discovered in meteorites and they were a significant discovery, caused quite a stir among the community at the time because this was the first time, when they were looking at these nanodiamonds, that they could say for sure that they were holding something in their hand that came from the ancient universe that existed before our solar system.
Interviewer - Chris Smith
What about this new breakthrough?
Interviewee - Philip Robinson
So, Nigel Marks at Curtin University in Australia, he was looking at something else entirely in fact, as is often the case in science, he is a materials chemist and he was looking at thin carbon coatings and he noticed that on the carbon coatings he was dealing with he had some imperfections there, and he realized that what was to blame were these carbon onions. So he took himself off to his computer and he ran some simulations, simulated carbon onions, impacting with a surface and he found that over the course of many many simulations, varying the conditions very slightly, in certain circumstances, when the collision happens, the onion transforms into diamond.
Interviewer - Chris Smith
So, the suggestion is then that somewhere in space, we know these fullerene carbon onions exist in space, if they're slamming into things with a right energy, which I presume they must, given the ubiquity of space.
Interviewee - Philip Robinson
Exactly.
Interviewer - Chris Smith
Then that could be the origin of the nanodiamonds, that we see floating around up there.
Interviewee - Philip Robinson
It certainly could be as Marks himself said, carbon onions are some of the most stable forms of carbon and whenever you have hot carbon vapour that cools down, they'll naturally aggregate into these spherical fullerenes, and so carbon onions would be ubiquitous in space and also the significance of this model is that it explains the age of nanodiamonds, so as these diamonds form and you have this hot carbon vapour around a star for example, as that cools down and these onions coalesce, they will capture whatever happens to the environment, around them. So far example, they'll capture noble gas isotopes that these scientists who first discovered nanodiamonds in the '80s used to infer the ancient age of these nanodiamonds.
Interviewer - Chris Smith
Incredible stuff. Very elegant but it is a theory, so is there any way that he can now take that theory and easily test it.
Interviewee - Philip Robinson
Well that is exactly what he intends to do. So, he intends now to build an instrument that will create carbon onions and collide them with surfaces to see if he can make diamond, and that for him he says is the most interesting part of his work. He'd come up with a new way to make diamond.
Interviewer - Chris Smith
But it's not so good for an engagement ring, though, could cause disappointment. Thank you Phil.
Interviewer - Chris Smith
And now let's shed some light on an aspect of medicinal chemistry that Harvard scientist, Michael Hamblin thinks has much to offer and deserves much more attention.
Interviewee - Michael Hamblin
Photodynamic therapy was discovered, would you believe 112 years ago, in 1900, when some German scientist, stained a microorganism called Paramecium, It's a single celled amoeba and they stained it with a dye accidentally left it near window, where it was exposed to sunlight. Meanwhile, another stained sample was not in the sunlight and when they came to examine them, they noticed the one that was in the sunlight, it all died and then they went on even just a year or two later to determine the presence of oxygen was needed and once they figured out the presence of oxygen was necessary, they came up with the term, photodynamic therapy. So, for the last hundred and odd years, people have studied the combination of photosensitisers, which are basically strongly coloured dyes and the production of reactive oxygen species from the oxygen which kills things, it kills bacteria and kills cancer cells and kills all sorts of undesirable cells and tissues.
Interviewer - Chris Smith
So, they must have thought, well if we've got this chemical, which goes into certain cells, but not others, we can differentially kill some cells and leave others unharmed.
Interviewee - Michael Hamblin
Yes. This came back quite a bit later, the idea of being selective with PDT. PDT is what we call photodynamic therapy. Really, in the late 1960s, they discovered that if you injected some of these dyes into the bloodstream, they had an amazing tendency to localize in tumours and initially actually the technology was proposed to be a fluorescence detection technology for tumours that you didn't know you'd got and then they realized, well they can shown the light directly on the tumour, so you have two ways of being selective.
Interviewer - Chris Smith
Apart from doing things like putting people in the light box, if they've got psoriasis, you don't really see this used very much though, do you?
Interviewee - Michael Hamblin
No as much as we'd like to see it used, which seems to be, yeah, it's been like a comedy of errors, a lot of the companies that were set up to commercialize this technology made major mistakes, even silly elementary mistakes, got too greedy, and went bankrupt because nobody says that PDT doesn't work or it's not worth doing. The big question is how can a company make money out of doing PDT? One of the bottlenecks about PDT is it's a drug device combinations. You've got to have the photosensitizing drug and you got to have the light source and typically medical device companies, are not the same companies as pharmaceutical companies and drug device combinations have always had a tricky road to regulatory approval and commercialization. I think another possible bottleneck is until you've seen PDT work, a lot of people don't really believe it can be that good. You know, you've got a harmless, nontoxic dye, you've got some harmless red light and you put them together and you do like amazing things like turn great big tumours black and they just sort of crumble up and fall off and they're gone and I mean I've seen that happen.
Interviewer - Chris Smith
One of the things, which I think people are sceptical about, is the access problem because if I have a lesion on my hand or in my mouth and I can show you that, it's pretty obvious, where you've got to direct the light and also the photosensitizing agent, but what about if I have disease, which is deep seated somewhere, inaccessible inside my body or even a tumour that has metastasized all over the body, is there any easy way to get the light in there or is that a problem that scientists are still grappling with?
Interviewee - Michael Hamblin
PDT is used to treat cancer deep in the body for instance, tumours in the liver, prostate tumours, brain tumours, many tumours deep inside the body are treated with photodynamic therapy and what they generally do is insert fibre optics through the guiding needles then they thread the fibre optic through the needle, so the light is delivered exactly in the right place, deep inside the body. Another attractive thing about doing PDT for cancer is PDT is one of the few cancer treatments that is known to activate the immune system. So, if you have a disseminated cancer, in other words, one that is spread from its original point of origin to metastasize in the lungs or the brain, or the liver, which is a very common problem and is why people die of cancer, then it is possible that you can destroy the primary tumour with PDT, but at the same time, sensitize the immune system to track down and destroy all these little metastatic deposits that are all over the body and PDT is one of the few cancer treatments that can do this, so you know, if you'd use ionizing radiation or chemotherapy, they may destroy your primary tumour, but they kind of depress your immune system and allow all these metastatic tumours to get away basically.
Interviewer - Chris Smith
So if I could pretend I was Bill Gates for a moment and I could whip out my cheque book and say Michael I will write to you a very big cheque. You can spend it on anything you like to bring this industry forward, what do you want that money spent on?
Interviewee - Michael Hamblin
I think the most exciting application of PDT is the one I just touched on which is the possibility of activating the immune system to track down metastatic cancer, I mean if you could come up with a treatment for metastatic cancer, it could save untold millions of lives, as they say people that die of cancer generally die because their cancer is metastasized. Now it's quite clear that at the moment this is not obvious how to do this, because most people who get PDT do not magically have an anti-tumour immune response but some do, a few do and the thing is to understand exactly what distinguishes the patients that do have an anti-tumour immune response and then when you understand that how can you combine PDT with some kind of immune stimulant that will allow it to happen on a much wider proportion of patients.
Interviewer - Chris Smith
So, if you're listening Mr. Gates, which I am sure you do, Michael would like some investment. That was Harvard photodynamic scientist Michael Hamblin.
Interviewer - Chris Smith
A major frustration for chemists is getting the right bits of molecules to react the right times, leaving other bits of molecules untouched until they are needed. Doing this often involves adding chemical shields which are called protecting groups but this increases the number of steps needed to make things sometimes to the point where there is almost nothing left to purify at the end of the process. But now a new catalyst has been created that can reverse the usual reactivity series of one class, a very important compound and this could totally change things around, Andrew.
Interviewee - Andrew Turley
Okay, so this is a very important group of chemicals called carbonyl functional groups that are characterized by a carbon attached to oxygen with a double bond in between and the various variations of this aldehydes, ketones, esters, this all carbonyls where the carbon is attached to other groups.
Interviewer - Chris Smith
And they differ in how reactive they are, don't they? So some of those things will react more vigorously or more keen to take part in some reactions and others.
Interviewee - Andrew Turley
Yes that's correct, they react if only according to either the sterics of the situations, so it's got bulky atoms attached to them, then certain things can access the reactive centres and also some of the electronic effects and in particular for reduction reactions, aldehydes are much more reactive than ketones and esters and what this group has done led by Istv?n Mark? at the Catholic University of Louvain in Belgium is to reverse the order that you would expect, they were able to get ketones and esters to react in preference to the aldehydes.
Interviewer - Chris Smith
Well, how are they doing that?
Interviewee - Andrew Turley
Well, what you would normally do in this situation is that you would add a protecting group, it puts the aldehyde in a little bubble on its own that effectively removes it from the environment but you have got to put that protecting group on, you then got to do the reaction and then you got to take the protecting group off. So it's another step where you can lose some of your stuff that you want at the end.
Interviewer - Chris Smith
So, what's different here then?
Interviewee - Andrew Turley
So, they found a catalyst that will do this for you in one go and what it does is sort of seeks out the aldehyde group and gets all bundled up with it, (15.41) start, so the reaction can take place on the other group, so it's a very simple and very efficient way of doing it.
Interviewer - Chris Smith
Do they know how it's working then?
Interviewee - Andrew Turley
No not at this stage, they've shown it's working and often as it's not really necessary if you can find something to do what you wanted to do in the right way, then it can come much later actually working on the mechanics of it.
Interviewer - Chris Smith
Is it a class generalisable thing, have they proved this with all aldehydes?
Interviewee - Andrew Turley
They've tried with a lot of different aldehydes and ketones and what's quite nice about this particular experiment is that they have done it with molecules that have got both groups on the same stretch of kind of string of carbons as at one end you've got the aldehyde and the other end you've got the ester and it preferentially reacts with the ester group.
Interviewer - Chris Smith
Fantastic thank you very much.
Interviewer - Chris Smith
Let's move now on to arsenic. I remember this story coming out last year Patrick when we were told with much fanfare that scientists have uncovered bacteria which could substitute arsenic for phosphorous in things like their DNA and this was suggested that there could be other forms of life which are not necessarily dependent upon phosphorous around. It met with some contention though afterwards, didn't it?
Interviewee - Patrick Walter
Yeah it certainly did, so when it was unveiled this announcement, there was a lot of excitement, first people thought they might have discovered ET finally but it turned out to be a bit less huge but it was still an interesting discovery nonetheless because it cracked open the door to life that didn't just use the standard element that we know, carbon, hydrogen, oxygen, nitrogen, phosphorous, sulfur, adding one more arsenic. So, this might mean that throughout the universe there could be other life forms that are using different elements. So silicon is often been talked about but now maybe arsenic was another one.
Interviewer - Chris Smith
There were quite a few negative sentiments expressed that people said they did not believe that the arsenic was really being incorporated, they were saying "yes you can show that it gets into the cells but you can't show what it is doing biochemically in those cells".
Interviewee - Patrick Walter
Exactly, there were some complaints about the paper from various different people and it is still very contentious and there's still a lot of work going on into it but one of the criticisms was that any replacement of the phosphorous with arsenic to make an arsenate is the backbone of the DNA molecule that it would be very unstable that it would be the subject of attack, it would be hydrolyzed and it would be quickly broken down but now Jiande Gu from the Chinese Academy of Sciences and Jerzy Leszczynski from Jackson State University in the US have had a bit of a tinker with the computational model coming at it from another direction.
Interviewer - Chris Smith
And what's that?
Interviewee - Patrick Walter
They looked at the models people have been working on to make these claims that arsenate wouldn't be stable and they came to some conclusion it wasn't really a great model so one of the models people have been using to make these claims with arsenate was dimethyl arsenate and they decided that this wasn't really a good kind of match for arsenate containing DNA. So what they did was they looked at dinucleoside arsenate. This is much more similar to DNA because it's got a base and it's got a sugar and then it's got that arsenate of course that everyone is interested in. The base stacking and inter-strand hydrogen bonding in their model suggested that arsenate would be more stable because it would raise the activation energy for these hydrolysis reactions that would destroy this arsenate containing DNA.
Interviewer - Chris Smith
So arsenic is back on the drawing board, Thank you Patrick.
Jingle
Interviewer - Chris Smith
You're listening to Chemistry World with me Chris Smith. Still to come, how to make crisps healthier and retracing a journey made hundreds of years ago across America by following a trail of constipation medicine. And talking of tubes now listen to a man who is revolutionizing chemistry using microfluidics, Volker Hessel
Interviewee - Volker Hessel
I work in the field of micro reaction technology and people also call it flow chemistry and this means to make reactions which are classically made in a pot like we do cooking sill and makes these reactions now in slower like very small pipings, it's very exciting because we're changing completely chemistry. Formerly chemistry was made from times and days, certainly in times of hours, now we do chemistry in minutes even seconds or sometimes milliseconds and thousands times faster. We do chemistry at temperatures which are 200 times higher, we do it under higher pressure, 50 bar, 100 bar. So we do chemistry really in a very different way and this is enabled by a new kind of apparatus which is called microreactor. Small reactor that small dimensions can be as small as a human hair; can be a bit bigger below a millimetre and these are artificial microfabricated devices which enables this new kind of chemistry.
Interviewer - Chris Smith
Why should shrinking things down in this way make the chemistry much more diverse, much easier and so much better along the lines of the way you have said, how does it help doing this?
Interviewee - Volker Hessel
Yeah, if we go down in dimensions we have very essential engineering processes to become much more faster and much more efficient. For example, this is mixing, a common experience if we do mixing on a large scale it takes longer it takes seconds or minute, take a coffee cup and you mix milk into coffee you stir and stir quite a while, if you have really a homogeneous texture of the colour. Micro mixers are much different, they are very small in dimensions can go down to 20 micrometers which is a fourth of a human hair and then the diffusion of the molecules on their own become very fast so that mixing is accomplished in milliseconds and even more since they are small we also have small volumes so even if you use the most hazardous and the most explosive substances that can be handled quite safely in this microreactors. It can go to quite extreme conditions meaning high temperatures, meaning high pressures without any danger, actually we can use this condition and this part actually of my research which is called processing which means, a small tiny apparatus opens chemistry to a processing range which was formerly not of use at all and obviously having new products open new markets.
Interviewer - Chris Smith
So, why is it given the huge tangible benefits that you have outlined that this sort of way of doing chemistry has only just got on, it must be down to technical challenge, so what sorts of problems have had to be overcome in order to make this happen?
Interviewee - Volker Hessel
This is driven by two issues one reason is the market and other reason is technical development. With the market we currently see a major shift of chemical plants outside of Europe and we have an increased impact of sustainability issues on the commissioning of new plants, so its costs and sustainability which are different very different than it was maybe 20 years ago. So this is actually the market pull, there was also technology push which came from actually the computer development from all the microfabrication area which was very strongly pushed in the 80s after the first computers emerged and the development actually started with small microchannel heat exchangers for computers and once this was technologically possible to fabricate those devices it was very soon the idea driven by the market pull also to use this device also for chemistry and for biology actually initially and this combined focus made the emerge of microreactor possible which actually happened In 94, so it took almost 15 years until this was sufficiently realized.
Interviewer - Chris Smith
And can you actually make meaningful amounts of products, because it was one consequence of shrinking things to the smallest scale, is that you also shrink the amount of product, so can you make industrial quantities of things like the big old fashioned round bottom flasks would have done but in this microsynthetic way.
Interviewee - Volker Hessel
Yeah, originally the whole development was very much technologically driven which also means we worked with really small actually too small dimensions just to show how nicely we are able to structure materials. This very small reactor indeed had very small volumes and could produce only very tiny amount, meanwhile we've done two things, one is to bring the general diameter to a reasonable needed demand. This can be 200 micrometers but this can be also larger it's so called milli or meso technology so we increased the channel size as it's already on its own things quite a substantial increase in throughputto the effect of 10 or 100 and then in addition my idea on this novel processing which means high temperature reaction and by increase in temperature but also in pressure and also in concentrations you can gain another factor of 100 to thousand, so summing up this two factors you easily come to an increased path micro channel of 10000 and then you have reasonably productivity as a matter of fact most of applications and production are based around this one micro reactor which has several micro channels.
Interviewer - Chris Smith
Volker Hessel, he's based at Eindhoven University in the Netherlands.
Interviewer - Chris Smith
Magnetic levitation now and a way to do cheaper quicker diagnostics, Phil.
Interviewee - Philip Robinson
Magnetic levitation yeah that's right and in this case using magnetic levitation to determine protein binding, let's take straight back there and look at protein binding that's an important process because it can tell us for example if protein disease marker is present in a sample then it tells us that there is a disease. So in order to detect that you commonly perform an assay in which you have a small molecule for example that will bind to that protein of interest and when that binding event happens you'll then have some other event that tells you it's taking place. For example, you might have a fluorescent molecule that fluoresces when that binding event takes place...
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