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Brought to you by the Royal Society of Chemistry, this is the Chemistry World Podcast.
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(00:10 -- Introduction)
Interviewer - Chris Smith
Hello Chemistry World podcast with Mark Peplow, Victoria Gill, Richard Van Noorden, Ananyo Bhattacharya and I'm Chris Smith. Coming up, how your metabolism can say a lot more about the disease you'll die from than your genes do.
Interviewee - Jeremy Nicholson
The Chinese and the Japanese are metabolically extremely different, yet genetic study show them to be extremely similar and of course they have very different disease incidences, so for instance stroke, is very common in Japan whereas heart disease is more common in China and the implication then is because they are genetically similar it's the environment that has the most effect.
Interviewer - Chris Smith
That's Jeremy Nicholson who will be talking about the new science of metabonomics and for those people who unfortunately do suffer a stroke or a spinal injury there has been an exciting development in the field of brain repair.
Interviewee - Victoria Gill
A team in the US have managed to mend spinal cord injuries in mice with peptides that form into nanofibres and these nanofibres have, sort of, formed scaffolds allowing the neurons in the spinal cord to reform and regrow.
Interviewer - Chris Smith
So nanofibres to the rescue, that's coming up shortly plus we'll be hearing how a Nobel prize-winning idea almost ended up in the gutter, quite literally.
Interviewee - Kary Mullis
Really critical next stage was getting me and my car and my new idea out of the highway because I had stopped right in the middle of a curvy two-lane road up in Mendocino County, there are logging trucks using that road and I could've been slammed off the road and my idea and I would've suffered a ugly accident, I finally said, get out of the road for Christ sake.
Interviewer - Chris Smith
Well luckily, he did survive to tell the tale and Kary Mullis will be sharing the insights that led him to discover the polymerase chain reaction later in the program. Well, we'll also be raising a glass to honour the winners of last month's chemical conundrum.
Interviewee - Mark Peplow
The first version of the periodic table that we know today was created by a Russian scientist, what was his name, and hopefully you should get that, but also why did drinker's the world over owe him a debt of gratitude
Interviewer - Chris Smith
And the answer is on the way together with the list of lucky winners, so keep listening to find out if you're amongst them.
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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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(02:25 -- Mark Peplow gives us the highlights from the American Chemical Society spring meeting in New Orleans, including a filter that removes CJD from blood and the origins of life)
Interviewer - Chris Smith
First this week, Mark you've been off on your travels.
Interviewee - Mark Peplow
Yeah, that's right. I have been to New Orleans. I went to the American Chemical Society Spring Meeting. It's one of the biggest conferences for chemists in the world really.
Interviewer - Chris Smith
So what were the, really leading items that you saw there may be relevant to home?
Interviewee - Mark Peplow
Well there was a couple of things that I saw, one of them is a filter for blood which can weed out the infectious protein that causes CJD, i.e. Creutzfeldt-Jakob disease. Now, this has been a big issue for more than a decade because one of the causes is by eating beef from cattle infected with BSE. Now a company called ProMetic Life Sciences, which is based in Quebec in Canada, developed a filter basically by screening millions of small peptides, these small biological molecules to find one that stuck on to these infectious prions that cause the disease to spread.
Interviewer - Chris Smith
BSE and CJD are brain diseases, so why we are worried about blood?
Interviewee - Mark Peplow
Well because even though BSE infected beef are sort of been weeded out of the food chain if you like, there is a still significant risk that these infectious prion proteins can be transferred to people in blood transfusions. In fact this has led to governments around the world from banning people who've spend anytime at all virtually in Britain from giving blood. In Canada, for example, if you spent more than a month, in Britain since 1980, you can't give blood and indeed at home in the UK, if you've had a blood transfusion since 1980 you are not allowed to then give blood back to the blood service.
Interviewer - Chris Smith
So how does this new filter system remedy that situation, how does it work?
Interviewee - Mark Peplow
Well, basically what happens is that it contains small peptides which grab onto the infectious prions within blood. It is a one use only filter, prion proteins stick to the membrane, you dispose off that and the blood that comes through is absolutely unchanged, that can now be.
Interviewer - Chris Smith
Absolutely, how do we know?
Interviewee - Mark Peplow
Well, a couple of years ago this company was in the news again because they had done trials on hamsters and shown that you could filter infected hamster blood and re-inject it into hamsters and it caused no problems at all.
Interviewer - Chris Smith
And hamsters that did not have the blood filtered but were transfused they did get sick, did they?
Interviewee - Mark Peplow
Yes, that's right because they still had these infectious agents that hadn't been filtered out.
Interviewer - Chris Smith
So can the UK government afford to say no to this technology? Are they at a stage where they could potentially embrace it?
Interviewee - Mark Peplow
Well, they are at the stage that the company itself has run clinical trials in humans and has very good data about this. The governments of both Islands and the UK, both of them are running their own clinical trials right now and at the moment the company expects that it might be possible to roll this out by this summer. They're talking about initial cost of potentially a hundred million pounds to implement this. Ultimately, it's going to be the same sort of health service decision that we often say, "is it worth the money to do away with that risk?"
Interviewer - Chris Smith
So it's a case of to B..SE or not to B..SE. Now what about meteorites and handedness though because there was something interesting about that too?
Interviewee - Mark Peplow
Yeah it's right, there has been a longstanding puzzle, which chemists and biologists have wondered about, the proteins that make up much of our body are made out of building blocks called amino acids. They can come in two forms, which you call left and right handed, which are mirror images of each other. Life almost exclusively tends to use left-handed amino acids. But the big question is where did this preference come from? About 10-15 years ago, people analyzing meteorites which had landed found that they contain amino acids, which have the slight excess of left-handed ones over right-handed ones.
Interviewer - Chris Smith
But they still had right-handed ones in.
Interviewee - Mark Peplow
They still had right-handed ones in and that's right. Well, people wondered if somehow this might have been the seed, if you like, for this preference for left-handed amino acids in life. Now, present at the conference was a system that has been developed by Dr. Ronald Breslow of Columbia University in New York who thinks he has this cracked. The first stage, which he has replicated in the lab, is where you take organic molecules called ketoacids precursors of which are commonly found in the same meteorites. You mix them up with the amino acids which have been found to have a slight excess of left-handed form and you find that as long as there is some copper there they help to form this sort of cluster that transfers that chirality to most of the other amino acids that you see in life.
Interviewer - Chris Smith
So all it takes is a small amount of one being in excess to tip the seesaw and then everything ends up that form and that's why life took the type that was most predominant at that time and that happened to be the left-handed form.
Interviewee - Mark Peplow
That's right, now in these experiments, he has managed to transfer the excess of say 10% or more of the left handed one into say of about 10% excess into lots of other amino acids as well then you have to try and exclude all the right handed forms and the way that he does that is effectively by crystallization, left and right pair up just like a handshake and they fall out of, if you like an evaporating pond and that leaves behind an ever growing excess of the left-handed form behind in the solution. In particular, what he found was that if you pour water to the mixture mimicking rain falling through a pool and leaking out this speeds this up tremendously and amplifies to an almost exclusively left-handed form.
Interviewer - Chris Smith
So that's why meteorites and biochemistry go hand in hand. Thanks Mark.
(07:39 -- Jeremy Nicholson explains how a person's metabolism can identify the diseases that they may be at risk of developing)
Interviewer - Chris Smith
Now on the subjectof biochemistry what does your metabolism say about you? Well, the chances are a lot more than your genes do. Here's Jeremy Nicholson.
Interviewee - Jeremy Nicholson
Our approaching at the problem of trying to understand disease risk in large human populations by taking a novel metabolic view of individuals from different countries and trying to link those metabolite levels that we could measure to particular disease risk factors such as blood pressure and what we really want to know, what are the controlling features for that that affect whole populations. Until very recently, there was almost no genomic information understanding about why genes interact with blood pressure. So we wanted to know whether or not the environmental influences such as diet and also influences from the gut microbes, which we know control a lot of metabolic processes in humans.
Interviewer - Chris Smith
And how you've been doing that?
Interviewee - Jeremy Nicholson
We started by using a giant epidemiological cohort, which had samples taken from four different countries, that's China, Japan, America, and the UK, about 5000 people in total and we metabolically analyzed all of those people by screening them using nuclear magnetic resonance spectroscopy, which is a technique which allows you to look at hundreds or potentially even thousands of metabolites at once and then we looked at the variation in those metabolites between countries and we also found that certain metabolites link specifically to changes or variations in blood pressure between the individual populations.
Interviewer - Chris Smith
So in other words, analyzing the metabolites does give you an insight into what diseases someone may be developing or may be already has?
Interviewee - Jeremy Nicholson
Yeah absolutely, everybody have a certain probability of getting diseases based on their genetic components, but whether we actually develop a disease is largely dependent on environmental interactions. So for instance, one of the things we know for definite is that high salt levels in your diet raise your blood pressure, but what we want to know is whether there are more subtle metabolic variations which link to blood pressure that we could start to think of in terms of ways which we could generate new drug targets.
Interviewer - Chris Smith
So in other words what this also gives you, because you can see a metabolite going wrong, this gives you a clue as to how that particular disease affects the body because the metabolite is linked to a certain organ or organ system and therefore gives you a clue as to how you could tackle that disorder.
Interviewee - Jeremy Nicholson
That's correct. If you have a gene abnormality that is associated with a particular disease or a risk factor, in order to translate that into the clinic we have to find out what that gene does, what other genes it works with, which proteins it might make, where those proteins are and which pathways they fit in with. When you have a metabolic endpoint measurement which we have here, you're right into the pathway straight away, you know that particular pathway is associated with for instance, high blood pressure and we might therefore think about how we modulate that pathway and so in some ways the metabolic studies cut out the middle man, we know what pathways we need to focus on.
Interviewer - Chris Smith
Is it not though more confusing because there is multiple ways in which one metabolite could actually get its levels tweaked and so you don't know which one it is?
Interviewee - Jeremy Nicholson
That's true. A metabolism is very complicated but there are certain classes of metabolites which are very interesting to us which are produced by the actions of gut microbes, we know that we can modulate gut microbial activity and we know that gut microbial activity has big effects on our physiology. If we look at those certain subclasses of metabolites, we know basically where they are coming from and that gives us new potential targets for drug discovery.
Interviewer - Chris Smith
So when someone is feeling unwell, it may not be them that so much unwell, as they have got the wrong spectrum of bugs in their gut, either transiently or permanently.
Interviewee - Jeremy Nicholson
That's certainly true. There are a lots of diseases that are associated with abnormalities in the gut bugs, even ones that aren't necessarily considered to be sort of gut diseases, things like diabetes and obesity have unusual gut microflora but what we are talking about here is something, I think much more subtle, which is understanding how diet and gut microbial processing of diet affects the metabolic profile for whole populations. Here we are trying to understand why biochemistry varies between populations and therefore give clues as to what's controlling us in our normal lives. All previous metabolite profiling studies have really concentrated on trying to find biomarkers for diseases in diseased subjects, so this is a much more subtle way of looking at physiology in the real world.
Interviewer - Chris Smith
So if the place in the world where you live does make such a dramatic difference to the bugs in your gut, because eating a diet locally is going to have a difference. How do you dissect out whether someone just lives in China or whether they've actually got something going wrong and they live in Britain.
Interviewee - Jeremy Nicholson
One of the things that we have shown is that people who live in China and people who live in UK are metabolically very different, may be that's not surprising. We have also shown that people who live in the UK and people who live in the USA they are very, very similar, but we find surprising things like, for instance, the Chinese and the Japanese are metabolically extremely different yet genetic study show them to be extremely similar. So the lifestyle, diet, and environment in Japanese and Chinese, makes them metabolically different and of course they have very different disease incidences. So for instance, stroke, is very common in Japan whereas heart disease is more common in China and the implication then is because they are genetically similar, it's the environment that has the most effect certainly in those populations. And what we are trying to do is, use the population data to gain insight into the mechanism of blood pressure control and variation between groups and populations to actually do new experiments, which will give us new drug targets in the future. This is a new type of epidemiological study. We're using the same outcome data, blood pressure in our case and we are linking it to very specific pieces of biochemistry and that's never been done before in molecular epidemiology.
Interviewer - Chris Smith
Imperial College's Jeremy Nicholson, introducing the new science of metabonomics. In other words how studying metabolism, which is the interaction between our genes and the environment we live in, can give us clues to why some individuals develop different diseases despite the fact that they can both be genetically very similar.
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(14:00 -- Are drug adverts misleading doctors?)
Interviewer - Chris Smith
This is Chemistry World and I'm Chris Smith. Coming up how nanotechnology is helping scientists to repair damaged spinal cords and the story of the discovery of the polymerase chain reaction, but first Ananyo a better pill for medical advertisers to swallow.
Interviewee - Ananyo Bhattacharya
Yes that's right Chris. This is a study with some pretty sinisterly percussions I think. You might expect that doctors could rely on the advertisements for drugs that they say in important medical journals, even more so, if those ads are citing primary research papers to backup their claims. But according to a new study by a psychologist Glen Spielmans and his colleagues at the Metropolitan State University in Minnesota you would be wrong.
Interviewer - Chris Smith
What is he saying?
Interviewee - Ananyo Bhattacharya
He combed four top medical journals for ads for psychiatric medications and that includes the New England Journal of Medicine, which is the most well cited journal in the world.
Interviewer - Chris Smith
So these are high-impact journals where you would hope that the content is going to be accurate.
Interviewee - Ananyo Bhattacharya
Yeah, that's right, so they found that of the 53 ads that they looked at, 42 of them made at least one claim that the team couldn't substantiate. That's nearly 80%.
Interviewer - Chris Smith
What is a claim that you can't substantiate. What does that mean?
Interviewee - Ananyo Bhattacharya
So they found that 27 of the ads made a claim that wasn't supported by a data source that was cited. Now one example of this was the drug Equetro, Equetro is used by doctors to treat manic depression and Shire used to sell this and they sold the drug on to Validus Pharmaceuticals, but an ad by Shire in 2005 claimed that Equetro was an effective treatment for both manic episodes and mixed episode. A mixed episode is when a patient experiences mania and depression at very similar times.
Interviewer - Chris Smith
And what you are saying is that there is no actual published evidence to support or sustain that claim that it can do both jobs.
Interviewee - Ananyo Bhattacharya
Well what Spielmans did is that he looked at the two references that were cited in the ad and he checked to see whether this claim was in fact true and what he found was that there was no evidence in the papers that mixed episode patients treated with the drug fared any better than those receiving a placebo.
Interviewer - Chris Smith
And what are the people who make these adverts say? What does Shire and the likes of them say about this?
Interviewee - Ananyo Bhattacharya
Well, we contacted the pharmaceutical industry and PhRMA, who is the trade body in the US point out quite rightly that these drugs advertisements have been screened by the US Food and Drug Administration whose job it is to check and we asked Spielmans about that and he points out that there are just 21 officials at the US Food and Drug Administration and they are in charge of reviewing over 39,000 ads per year.
Interviewer - Chris Smith
So, basically there is no way that they can give them the level of scrutiny that clearly they need.
Interviewee - Ananyo Bhattacharya
No, it seems very unlikely and he says it's high time that the FDA took up more staff. He also feels that the medical journals need to take more responsibility about looking at the ads that they're putting in.
Interviewer - Chris Smith
So that's potentially a very hard pill to swallow but not may be as hard a pill to swallow if you've got a spinal cord injury although having said that there might be some renewed hope in this area Victoria.
(16:50 -- Rebuilding damaged spinal cords with peptides)
Interviewee - Victoria Gill
Yes indeed it is very early days; these are just animal studies, but a team in the US have managed to mend spinal cord injuries in mice with peptides that form into nanofibres and these nanofibres have, sort of, formed scaffolds allowing the neurons in the spinal cord to reform and regrow.
Interviewer - Chris Smith
What's in the peptides?
Interviewee - Victoria Gill
They are specially designed peptides with very long hydrophobic tails and this is the key to how they work, because when these peptides with their long hydrophobic water-hating tails are injected into the spinal cord, they line up to sort of protect their tails and into some radial spoke formations with all the tails pointing inwards.
Interviewer - Chris Smith
And so the formation of these fibres then provide some kind of roadway for the developing or regrowing of cells to grow along to be guided back to the other end of the cut side.
Interviewee - Victoria Gill
Exactly, it's like a scaffold. John Kessler, he was the leader of this team at Northwestern University that conducted this research, described a spinal cord injury as being like cutting a telephone wire, it is not so much about replacing the cells but reconnecting the wires to the correct wires so that you can reform the spinal column.
Interviewer - Chris Smith
So what did they actually do in their experiments to prove this?
Interviewee - Victoria Gill
So the mice were injured; their spinal columns were crushed and they were unable to move their back legs and then following this surgery the mice were injected with the peptides and then they were monitored for their functional recovery for their ability to walk again, their spinal columns were monitored with markers to see how the neurons were regrowing along the spinal cord and there is a controlled group of mice who were just injected with saline solution or injected with nothing but underwent the exact same procedure. They found that the mice that had been injected with these peptides, their improvement in their ability to move properly and they tested them by making them swim and having them walk around mazes and get over obstacles were significantly better than in the mice in the control group.
Interviewer - Chris Smith
Certainly very encouraging news, let's hope it works. Thank you Victoria.
(19:00 -- Kary Mullis on how his Nobel prize-winning idea almost got him killed and the honour of having a song about your invention on YouTube)
Interviewer - Chris Smith
Now a popular claim is that you're never more than a few meters from a rat in London, but now biochemists have found a sexier slogan because according to Kary Mullis, you're never more than a few miles from a PCR machine, in other words a device using the polymerase chain reaction to copy DNA, a process that he invented in the early 1980s.
Interviewee - Kary Mullis
I was working in a company making these little short pieces of DNA, which we call oligonucleotides. They had a couple of different uses in the molecular biology that was the basis of the biotech industry. But at first when I started doing it they were very difficult to make, then came along these automatic devices in fact a really good friend of mine named Ron Cook from across the bay over in Marin County brought a machine into my lab one day and he said, 'try this Kary, it will replace your whole lab' and in fact within about a week or two, we had the thing working and instead of needing about 7 people to help me, I figured I could probably get away with me and the machine and one other person and.
Interviewer - Chris Smith
How did it work, this machine?
Interviewee - Kary Mullis
DNA is extremely computer friendly, in the sense that it is just like words that only have four letters and manufacturing these little strings of them was something that could easily be automated. In fact all of the things that we normally did with our hands in these reactions could all be transferred to these tiny little solenoids and valves and tubes and so I was stuck with the problem of, do I fire five of my good friends here or is there any way I can think of increasing the market for oligonucleotides by a large factor, so that we can all stay here doing them. And I started thinking of things that you could do with oligonucleotides besides the things that they did at that time and one night thinking about that, a problem which was how do you determine a single base pair mistake in the DNA of, like an embryo, to find out if, for instance, it's going to be born with sickle cell anaemia. It was a simple problem chemically, but wasn't an easy thing to do at the time with the genes that you could isolate from an embryo. It usually took about 3 weeks by the time the doctor could say, we are pretty certain that you either have or do not have a child that's going to have sickle cell anaemia.
Interviewer - Chris Smith
So how were people doing it in those days? If this procedure was taking three weeks what were they doing?
Interviewee - Kary Mullis
They would have to clone the particular part of DNA that coded for the haemoglobin molecule. It was not a very good method to use for diagnostic that you would really like to be able to do the same day that the lady had just come in and given the sample and so I was trying to figure out a way in what was a very simple case; I thought oligonucleotides might be useful in doing that and I was thinking about how that could happen and in the process I was driving up to my cabin up in Mendocino on Friday night. I just had in my mind this little picture which anybody familiar with would say, Hey, that's PCR, one of the little oligonucleotides there was actually the diseased end and the other one was sort of a control. All I had to do is sort of say, you know what if you did that and then did it again and then did it again and then did it again you would start amplifying the piece of DNA that's between those two oligonucleotides and there would be no end to that process and you could do it for ever if you wanted to.
Interviewer - Chris Smith
So how did you then take it to the next stage, which was actually doing it in this highly automated way where you just put it on a machine on 40 cycles and a few hours later you have got millions of copies of your initial starting piece of genetic material?
Interviewee - Kary Mullis
Well the really critical next stage was getting me and my car and my new idea out of the highway, because I had stopped right in the middle of a curvy two-lane road up in Mendocino County, there are logging trucks using that road and I could've been slammed off the road and my idea and I would've suffered a ugly accident, I finally said, get out of the road for Christ sake. I got over on the shoulder and I started making a few notes and as far as I was concerned by the time I got back to my cabin it was done. That was my job, but then I had to take the idea back to Cetus, where I worked and explain it to other people who were surprisingly to me, not terribly receptive to it, so I then had to start doing it and actually making it work showing them that you could actually do this. It didn't work just on paper but it worked in tube, finally it could work in a machine but at that time we had no such machines, so we had to do it by hand in a tube although it was still much quicker than cloning.
Interviewer - Chris Smith
So looking back now, what do you see in terms of the legacy you've given the world?
Interviewee - Kary Mullis
Nothing made me happier lately than, there is a song about it; if you go to YouTube, if you look at PCR song you get this really well produced and interesting song about my reaction.
Interviewer - Chris Smith
Any regrets on your part?
Interviewee - Kary Mullis
The one thing that I feel like would have been nice is if I would have said, "here it is, but I'd like to keep 1% of it myself in terms of the profit from it", but I was young and foolish I guess, but I did get the Nobel Prize for it, which is quite a fun thing to have happened to you.
Interviewer - Chris Smith
Kary Mullis who invented PCR, the polymerase chain reaction and Kary will also be joining us for the next edition of our new podcast 'Chemistry in its Element' when we will be looking at the science of iron that's coming
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