Chemistry World Podcast - July 2010
00:12- Introduction
01:29- Vodka's molecular cocktail
05:04- Antibacterial silver nanoparticles grown in bacteria
08:03- Todd Sacktor from SUNY Downstate Medical Center, New York, US, explains how memories can be wiped clean away
14:38- Noodly 'cell wires' to patch up heart or spinal cord damage
16:47- Colour change test for brain chemicals
19:30- Qiagen's Steve Little tries to convince us that medicine really is getting personal
26:38- Introducing Synthia - the first synthetic cell
29:50- Nicotine hit at the flick of a switch
(00:12 - Introduction)
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Brought to you by the Royal Society of Chemistry, this is the Chemistry World Podcast.
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Interviewer - Chris Smith
This month the molecular basis of a tasty vodka if there is such a thing, antibacterial silver nano-bullets, the new electrical nicotine nano-patch and 10 years on from the publication of the Human Genome Project. Is the promise of personalized medicine about to become a reality?
Interviewee - Stephen Little
We manufacture KRAS, if you have a mutation in that gene then certain colon cancer treatments aren't going to work for you. Now, these are expensive drugs and these drugs can be 2000 or 3000 pounds a month to take. The diagnostic tests considerably less than that and certainly no more than a 1000 pounds. So, we can see that by using a worn off diagnostic to identify the 60% of the population who shouldn't be taking these drugs, we don't actually save a lot of money.
Interviewer - Chris Smith
Qiagen's Steve Little who joins us later to discuss whether pharmaco-genomics what it can deliver what it says on the tin. Hello, I am Christ Smith and also in this the July edition of the Chemistry World podcast Phil Broadwith, Nina Notman, and Anna Lewcock.
(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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Interviewer - Chris Smith
Up first this month, the stuff which has become one of the world's most popular cocktail drinks, but it is only truth in the claim that some vodkas can taste totally different to others, after all they're just ethanol and water aren't they, Anna?
Interviewee - Anna Lewcock
In theory, vodka is just ethanol and water though it's produced by fermentation and distillation and grains, potato, sugar beet, grapes, cassava and those kinds of ingredients and as any vodka drinker will tell you people tend to prefer one band over another. So, a team of researchers led by Dale Schaefer at the University of Cincinnati along with some colleagues at Moscow State University in Russia.
Interviewer - Chris Smith
You have to have the Russians in there.
Interviewee - Anna Lewcock
They tried to figure out whether there might be a molecular basis for people's preference of one vodka over another by analyzing five different vodka brands.
Interviewer - Chris Smith
And how did they do that?
Interviewee - Anna Lewcock
So the team looked at the structure and hydrogen bonding of the different brands using a range of techniques using 1H NMR, Infra Red spectra, Raman spectroscopy and they discovered that while all five brands had four essential components, so they had pure water, pure ethanol and two hydrates. They discovered that the concentration of one of those hydrates varied between the vodkas.
Interviewer - Chris Smith
You better explain what these hydrates are? What this means and what they were physically looking at?
Interviewee - Anna Lewcock
Okay, so in this case, the hydrate in question is a kind of cage complex. So, with around five water molecules surrounding one ethanol molecule. So, it was the proportion of that particular kind of hydrate that seem to vary between the different brands.
Interviewer - Chris Smith
Was it consistent, so people are saying they like a certain vodka or certain one has a certain taste, because it has more of these arrangements of molecules in it. How does that work?
Interviewee - Anna Lewcock
The only difference they could find between the brands was essentially in the proportion of this one particular hydrate and in the five brands they looked at seemed to vary between the different brands. So, as a way of trying to quantify this or measure it, the team worked out what they called a structurability parameter. So that was a kind of measure of the vodka's ability to form that hydrate structure within solution.
Interviewer - Chris Smith
Do you now think is possible there might be something else in there too though, is it, is it that when you make the vodka something else comes over with the distillers and it triggers those particular hydrate formation and they have nothing to do with the taste, should actually say the other stuff that is making that happen, they are just a side effect of it being there.
Interviewee - Anna Lewcock
It's entirely possible. I mean the researchers suggested that those trace impurities from the distillation process could somehow be influencing the hydrogen bonding and that leads to how the different hydrates are formed that kind of thing. Also, different vodka manufacturers can put in different attributes to certain extent to the flavour. But, one of the things these researchers found were, for example, the more hydrates there were the less free water molecules there were. So, if you had a vodka that had less of these hydrates and it could possibly taste somewhat watery, so people's appreciation of taste of the vodka could vary accordingly.
Interviewer - Chris Smith
I wonder if this means that in future then we're going to start seeing people manipulating the vodka in order to achieve more and more fewer of these hydrate structures to adjust the taste and when perhaps that might then transfer on to other spirits as well.
Interviewee - Anna Lewcock
It's possible, I mean those research has been carried out so that the people can barely tell that if they used to drink 30% vodka and 40% vodka. So, these tiny molecular variations possibly people's palates aren't sophisticated enough to be able to detect but you never know they might find out whether it is more important than that.
Interviewer - Chris Smith
That's good to me, Anna thank you very much.
Interviewer - Chris Smith
Phil, let's stay with the science of the very small but this is not quite so small as bacteria and they are playing around with silver.
Interviewee - Phil Broadwith
Yes Chris, well then one of the strategies has been used to try and protect us from bacteria in terms of our fridges or plastics whatever is to load them up with silver +ions but what Mitchel Doktycz and a group from Illinois have shown is that if you grow a particular kind of bacteria in a solution of silver nitrate it can take that silver on board reduce it to silver metal and make silver nano crystals.
Interviewer - Chris Smith
So, these bacteria are presumably resistant to the toxic effect of silver, because, like you say, people of, ever since the ancient Egyptians have been using silver to kill bacteria because it is recognized it is toxic so why are these bugs not dying then.
Interviewee - Phil Broadwith
I'm not sure that's entirely clear but this particular strain does seem to have developed resistance I think they probably bred them specifically for it.
Interviewer - Chris Smith
What are they called?
Interviewee - Phil Broadwith
Shewanella oneidensis.
Interviewer - Chris Smith
So how have they deployed these bacteria then?
Interviewee - Phil Broadwith
Well, there's two strands to this. One is the fact that silver nano particles are themselves antibacterial. So, when the team took the nanocrystals from the Shewanella oneidensis they found that if they gave those nano crystals to other bacteria such as bacillus subtilis or E. coli they kill those bacteria and they were more effective at killing those bacteria than chemically produced silver nanoparticles, so colloidal silver which is just a bare nano particle or silver nano particles with oleate which is a sort of long chain fatty acid on the surface.
Interviewer - Chris Smith
That's very interesting. That said then, there's something about the silver which has been added to it or adjust something on the surface perhaps which is making it have that enhanced toxicity. So, presumably if you work out what that is if you got a way of making silver much more antibacterial.
Interviewee - Phil Broadwith
Absolutely Chris. Well, what the group did then was look at the surface of these nanoparticles and they found an as yet unidentified subject. But, they do say that it looks like a protein that gives us as you say the possibility to tune the toxicity we can tune it to be very toxic to bacteria that hopefully less toxic to humans. The other advantage of these nanoparticles is that they are very small and very uniform in size which is very difficult to do with chemical means as well. So, from that point of view it's a really win-win situation.
Interviewer - Chris Smith
So would the strategy be then to grow these bacteria in some kind of big fermenter feeding them silver make these nanoparticles extract them and then sort of functionalized state they are in and use them as some kind of antibacterial preparation.
Interviewee - Phil Broadwith
Yeah, that's absolutely one of the things that these guys are saying. The implications of this is that you can't just look at nanoparticles and say we will classify them by size that it takes their toxicity they are saying very much more, it's to do with what's on the surface of those nanoparticles that has a much bigger effect.
Interviewer - Chris Smith
So all that glitters isn't necessarily gold? Silver is pretty important too, especially it seems when it comes to nanoparticles. Thank you Phil.
Interviewer - Chris Smith
All of us can probably recall an event we rather not remember but what if you could chemically wipe out the memory that you prefer to forget. Well that could be about to happen. Todd Sacktor.
Interviewee - Todd Sacktor
What scientists have postulated for a century really is a memories are stored by changes in the strains of the connections between neurons which are called synapses. So they were thought you to get stronger in a persistent fashion or weaker and this combination of strengthening and weakening that was due to the change that happened during the experience that will then permanently alter the network of connections of neurons that are storing information in the brain. Though scientists didn't know how was that there was this persistent change in synaptic strain and what we discovered was that there was one specific molecule, actually an enzyme that was persistently strengthening synaptic connections between neurons. And because of an enzyme that meant that we could actually inhibit the enzyme with the drug and that is this drug ZIP called zeta inhibitory peptide to test the hypothesis that this molecule which is called PKMzeta protein kinase Mzeta was the storage mechanism for memory or within this we basically trained animals such that they could have a memory in their brains for days, weeks and even months and then we gave this drug ZIP in to the area of the brain where we thought that the memory would be stored, and then the memories were within an hour to erase.
Interviewer - Chris Smith
So, this memory is permanently missing, in other words, could you take lifetime experience memories and you just wipe them away with this molecule.
Interviewee - Todd Sacktor
That's right; it's permanent as we can test.
Interviewer - Chris Smith
So what do you think it's doing, how is it doing that?
Interviewee - Todd Sacktor
Well, it's working on this molecule PKMzeta, it's an inhibitor of the enzymes. So the question is how is the enzyme maintaining the memory. So what the enzyme is doing is in that synapse of one side, the neuron is releasing neurotransmitter. On the other side of the neuron, it's called the postsynaptic side; it's receiving that information through, what's called receptors that are on the membrane of the synapse. Now the PKMzeta is being made on that postsynaptic side and what it's doing is its enzymatic activity is continuously trafficking more of the receptors, twice the normal number of receptors into the synapse. So, the strength of the synaptic connection if PKMzeta is in that connection is twice as strong as normal. So, when you add that within minutes, the number of receptors goes back down to what it was before the memory was stored, so that the memory is gone. In addition, the ZIP effect also seems to allow the PKMzeta itself to diffuse away from the synapse and once the PKMzeta is gone from the synapse, we think that's really the erasing part of the memory.
Interviewer - Chris Smith
So, is there way in which we could exploit this effect clinically because there are of course a number of disorders that are directly caused by people having memories that are too good. I'm thinking of things like posttraumatic stress disorder where people get hooked on to certain stimuli, which then yield various things like panic attacks, and anxiety syndromes. Could we wipe out selective memories with this?
Interviewee - Todd Sacktor
Well, right now, we don't know how to wipe out the selective memory using drugs like ZIP, because you're basically going to be erasing probably the person's lifetime's worth of memory, in that brain area, where you've ejected the ZIP. Now, for posttraumatic stress disorder, one might imagine, you could inject that drug in the fear area of the brain, which is called the amygdala and that would erase all the person's previous fears.
Interviewer - Chris Smith
Which sounds like it could be quite useful then?
Interviewee - Todd Sacktor
Well, in a sense it's probably way too powerful because there's a probably lot of important memories for fear that you wouldn't want to erase whether they have posttraumatic stress disorder or not. The clinical usefulness of the ZIP might actually be in something little bit different, which is there's preliminary evidence that the ZIP if you put it into another area of the brain, where drug addiction memories are that the addictive aspect of memories gets erased. So that actually might be somewhat more in the realm of possibility. And then there's also another neurological disorder called Central Neuropathic Pain, in which a memory for pain gets set up very often in the spinal cord and that seems to be again this very same process of memory, but it's not for a conscious memory, it's for the sort of unconscious experience of pain and this is a devastating disorder because there's really no treatment and these people does have continual pain through their lives. That actually might be treatable, ironically because we could put the ZIP far away from the brain and keep a person's memories intact, or hopefully erasing the sort of aberrant memory of pain that gets set up.
Interviewer - Chris Smith
Todd Sacktor. He's a neurologist, neuroscientist from the State University of New York in Brooklyn.
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Interviewer - Chris Smith
You're listening Chemistry World with me Chris Smith. Still to come, the electrical nicotine nanopatch, and can we really tailor medicine to a person's genetic makeup.
Interviewer - Chris Smith
But first, how scientists have found a way to weave cells into wires, Phil!
Interviewee - Phil Broadwith
Okay Chris, well this is some work that's been done by Sam Stupp at Northwestern University in Illinois in the States. They've got sort of polymer that's made from protein at one end and a long chain hydrocarbon at the other end and these kind of proteins are known to associate into fibrils. But, what they found is that if you heat them up, you get a kind of a liquid crystal vase that you can then drag out into long macroscopic noodle like fibres. They also found that if they mix up cells with that liquid crystal phase and draw it out, the cells first of all, survive the process and they secondly can then proliferate. They tried it out with some heart muscle cells. They pulled out these fibres, left them for a few days and the heart cells grew within the structure, so you then have a kind of a noodle of heart cells supported by this polymer and because they're heart muscle cells, they spontaneously generate electricity and they had pulses of electricity going up the whole length of the fibber.
Interviewer - Chris Smith
Oh, I guess, if you make the material and you have cells mixed in at the same time, the cells survive the process and get incorporated into this thing that you draw out and they then can continue to proliferate and grow and connect up and the electrical behaviour can be propagated along the length.
Interviewee - Phil Broadwith
Yes, Chris that's absolutely right. So, the idea is that this would be used for tissue engineering, in regenerating tissues where directionality is very important. So, things like nerves, spinal cord, heart, where you need conduction, that kind of thing.
Interviewer - Chris Smith
And is this biocompatible? Could we actually do this in the body or have they not got as far as to actually doing tests on say animals yet?
Interviewee - Phil Broadwith
Essentially, the polymer is made of protein and fatty acids. So, there shouldn't be any particular reason why it wouldn't be biocompatible although they haven't really shown that definitely.
Interviewer - Chris Smith
And apart from the electrical properties, is there anything else that would come in handy from doing this?
Interviewee - Phil Broadwith
There's no reason why you couldn't grow any other kind of cell, any other kind of stem cells or cells within the structure. So there's all sorts of things that you could use it for.
Interviewer - Chris Smith
Intriguing stuff. I would have to watch what happens with that. Thanks very much Phil.
Interviewer - Chris Smith
So Nina, now tell us about this because sticking with Phil mentioned brain cells and nerve cells and things. There's a way of detecting where the brain is utilizing glucose and it's a step forward in what we had before.
Interviewee - Nina Notman
Yeah, so this is a simplified way of looking at glucose levels in different areas of the brain. So, this method is based on gold nanoparticles and it's a simple colour change test. So, it's visible to naked eye and the current method that they're often looking at they have problems with interference from other electrically active species that might not be glucose you're detecting for example. But in their system because they're using an enzyme, which is specific for glucose, their system is very selective.
Interviewer - Chris Smith
So, talk us through a step by step. So, you want to know which bits of the brain are using x amounts of glucose. How do you do it?
Interviewee - Nina Notman
So, you take samples from the and in this case, the rat's brain and you put it into solution. The basic system they're using is a gold nanoparticles and when that's dispersed in the solution, it turned red. If they then add salt to this, the nanoparticles would aggregate and form a blue to purple solution,. But, if there's single strand DNA in that that protects the nanoparticles from sticking together so there's no colour change. The complex and more complex system that they're using, they also add glucose oxidase and iron to this mixture that triggers a cascade of reactions when glucose is in the solution.
Interviewer - Chris Smith
So, go on then, the glucose oxidase presumably attacks the glucose and oxidizes it, what's the next?
Interviewee - Nina Notman
Yeah, they indeed oxidize it to hydrogen peroxide. The iron then causes the hydrogen peroxide to form hydroxyl radical and the radicals cleave for single stranded DNA, it's obviously they for nanoparticles, they are not going to protect it, so if salt is added, the aggravation occurs and you can see the colour change.
Interviewer - Chris Smith
And the amount of colour change is presumably proportional to how much glucose was or wasn't there to start with.
Interviewee - Nina Notman
Yeah indeed. So you can see initially just from the colour change, but if you want to get concentration more precisely, you can give the IR spectroscopy to do that.
Interviewer - Chris Smith
Can you use this to do a sort of real time monitor? So if you had a little tube going into a certain bit of the brain, and you instilled some fluid to wash out a sample from that bit of brain, say continuously, so you have fluid coming in, you take some fluid back out and you analyze that, can that give you sort of a tracing or a graph to work out how that bit of brain is responding and reacting to say whatever an animal is doing?
Interviewee - Nina Notman
Yeah, definitely you can do that and they're hoping that if you're doing that they'll be able to help with things like not really just understanding the brain better but also with disease diagnosis.
Interviewer - Chris Smith
Thanks Nina. When the Human Genome Project announced the completion of the first draft sequence about 10 years ago, one of the things it promised to usher in was pharmacogenomics or personalized medicine, but what does this actually mean and will it ever happen? Stephen Little is the Vice President responsible for healthcare at Qiagen.
Interviewee - Stephen Little
Personalized medicine, it's a really quite a very simple concept. It's the idea of using a diagnostic test to identify which patients may best benefit from the medicine, and the reason it's necessary is due to the simple fact that not all medicines benefits all patients that take them; if they did, there wouldn't be any need for personalized medicine. But, given that drugs only work in a proportion, the people who take them, for example, cancer drugs can work in as low as 25% of patients who take them. There is a real need to identify those patients who will benefit and hence they'll get a drug which suits them and when you identify the patients who won't benefit, they can either be spared the side effects or more likely identify drug that would work for them.
Interviewer - Chris Smith
I suppose it is a bit strange that the way we have run healthcare up until now whereby it's the pharmacological equivalent of me walking into a shoe shop and saying, I need a pair of shoes and without even measuring my feet, someone just take the first thing off the shelf, gives it to me and say these fit most people.
Interviewee - Stephen Little
Well, I guess that's true though, you know, there always has been a lot of trial and error. I mean, for example, if you have high blood pressure, you might take 4 or 5 different medicines before you find one that really suits you, but for some thing like blood pressure to use that example that's not too bad because it isn't going to kill you in the next 3 or 4 week and you've got time to get yourselves sorted out. But for other conditions, which are much more acute over time is more pressing and oncology is the obvious example. It obviously makes sense to get things right first time as best as you can, but I think there are some reasons why this idea which has been along for long time hasn't been practiced so much in the past and is being practiced more now. And I think the main way is probably dealt with technology. With things we can do now, we have a better understanding of human genetics, we have a better understanding of disease processes and we have a better understanding of how drugs work and that allows us to develop these assays which will identify which patients will benefit. But, of course it's no good just having technical solution, if it doesn't also work at a commercial level.
Interviewer - Chris Smith
You've raised a really point there Steve, which is of course the question of finance, especially now in the strained financial circumstances in which we all find ourselves. Is this eminently fundable, because we've got to the point where every single person on this planet is genetically different and therefore they could potentially all need their own repertoire of personalized treatments, can we deliver that?
Interviewee - Stephen Little
Well, not only they're eminently fundable, but it actually saves money. One of the phrases we use is better healthcare for less money, what's not to like. To give you an example, we manufacture KRAS test. KRAS is a gene that's mutated in colon cancer. It turns out if you have mutation in that gene, then certain colon cancer treatments aren't going to work for you. So there's no point in taking them. Now these are expensive drugs. These drugs can be 2 or 3 thousand pounds a month to take. The diagnostic tests are considerably less than that and certainly not more than a thousand pounds and probably less than that. So you can see that by using a worn off diagnostic to identify the 50% of population who shouldn't be taking these drugs, we don't actually save a lot of money. And one calculation I saw recently said that just with that one example of KRAS for one classic drug, in the USA to help provide it has saved 350 million dollars. So, I think to answer to your question can we afford it, I think we should turn that around and say can we afford not to do it is actually really good partly for money in this type of medicine.
Interviewer - Chris Smith
But you have picked on rare drugs that are currently used in a minority of patients that are really expensive. What about the example you gave early with blood pressure. Common condition, lots of possible agents on the market, how does the equation balance out then?
Interviewee - Stephen Little
Well it's a lot tougher because the technical issues are so difficult; but someone got to do the research and the development and also the clinical studies to demonstrate that this test whatever it is, is going to identify which is the best hypertension medicine. There was a problem here, because most of the hypertension medicines that we take have gone generic by now and so drug committee will really be excited about doing that. So I think this is a real place where publicly funded research can have a big impact because you're right for the new drugs and for the expensive drugs, the drug industry and the diagnostic industry would take care of that part by themselves but for common drugs and drugs which have come off patent the commercial imperative is there, that's a great place to invest public health finance to identify tests which once they're applied will again save money.
Interviewer - Chris Smith
Have we got the technology platforms that are necessary to do those sorts of tests and to identify the markers and the genetic sequences that are associated with better or worse outcomes with different drugs and therapies?
Interviewee - Stephen Little
Yes, I think we have and I think after change you know 10 years ago it was possible to run a genome scan, it was expensive it was difficult, you could only do it in a very specialized centre. That's all changed now. Complete sequence analysis for genome is still difficult but it is by no means out of the question. It's quite feasible now to justify those sorts of analyses to find biomarkers for a common conditions or rare conditions. So, the technology is there to allow screening for biomarkers in the first place, furthermore the technology to deliver those assays whatever they are into the marketplace, routine diagnostic stuff there was well. The bit that's missing is the bit in the middle. It's not discovering markers that are tricky; it's demonstrating with great confidence that these markers actually work in a clinical setting, because sometimes the clinical trials which have to be done to show that these tests work can be substantial.
Interviewer - Chris Smith
Now you're coming at this from the perspective of a company which has got a massive international presence now, Qiagen, one of the biggest biotech companies. You're obviously clear in where you see this going and how you see this fitting into the marketplace. What are the politicians and people like NICE, the National Institute for Clinical Excellence as it was known what do they say about it?
Interviewee - Steve Little
Well I think NICE has been very slow to pick up on the use of diagnostics to target drugs. So, it looks to me, it is exactly the sort of thing that they should be looking at. I am pleased to say over the last
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