Chemistry World Podcast - October 2008

00:10 --   Introduction

02:09 --   A failed anxiety drug could provide a novel treatment for cancer

04:29 --   A biosensor made from proteins could speed drug development 

06:43 --   Fred Vom Saal from the endocrine disrupters group at the University of Missouri-Columbia explains the clinical concern over a chemical commonly found in plastics - bisphenol A   

12:58 --   How to break the bonds of global warming

15:55 --   How plants manipulate their pollinators with chemicals

18:14 --   Medicinal chemist Robert Fecik from the University of Minnesota takes us through the latest research in the quest to find new superbug-beating antibiotics

24:44 --   Lab on a chip could improve IVF by identifying healthy embryos before implantation

27:15 --   How to play pinball with atoms

29:57 --   What seasonal fruit is associated with the atom? And do you know the answer to our Nobel-themed chemistry conundrum?

(Promo)

Brought to you by the Royal Society of Chemistry, this is the Chemistry World Podcast.

(End Promo)

(00:10 --   Introduction)

Interviewer - Chris Smith

Hello! Welcome to October edition of Chemistry World Podcast with Victoria Gill, Richard Van Noorden, and Ananyo Bhattacharya.   I'm Chris Smith.   Coming up, how a drug that was originally intended to tackle anxiety has now found a new lease of life, combating cancer.

Interviewee - Victoria Gill

What this does give the researchers is, sort of, a new paradigm for cancer drug design, so they have a small molecule that they know a lot about, they've, sort of, toxicity tested it and they've got it to early stage clinical trials, so they could use that to design new cancer drugs that interact specifically with this messenger.

Interviewer - Chris Smith

You can hear how it works shortly, also on the way bisphenol  A, it's in tin cans and plastic bottles and that means it's probably also in us, but is it dangerous?

Interviewee - Fredrick S. Vom Saal

What we know from animal research is if you take young animals and you feed them that amount of bisphenol A, you have brain damage, reproductive damage, immune damage, liver damage; you damage virtually every system in the body.

Interviewer - Chris Smith

Well that's Fred Vom Saal who'll be explaining why should not boil your baby bottles later in the program.   We also get the answer to another organic nuisance.

Interviewee - Richard Van Noorden

This is some very nifty chemistry.   A catalyst and a reagent combination together used to breakdown the famously strong very inert carbon-fluorine bond at room temperature.   Fluorocarbons are persistent organic pollutants.   They do build up in penguins, if they are gases they do buildup in the atmosphere and they are potent greenhouse gases.

Interviewer - Chris Smith

Plus if you cast your mind back to last month's autumnal chemical conundrum... 

Interviewee - Richard Van Noorden

If you lived a 100 years ago, which seasonal British fruit would you associate with the atom.   So if you've sent in a fruity suggestion then you could be one of this month's winners.   The answer is on the way.  

(Advertisement)

The Chemistry World podcast is brought to you by the Royal Society of Chemistry.   Look us up online at chemistryworld dot org

(End Advertisement)

02:09 --    A failed anxiety drug could provide a novel treatment for cancer)

Interviewer - Chris Smith

First this week, scientists have found Victoria, that a drug originally intended to knock anxiety on the head actually does a much better job of blocking the overgrowth of cancer cells and in an entirely novel way.

Interviewee - Victoria Gill

Yeah exactly, a failed drug it would seem at this clinical level that they thought had effects on anxiety and now it turns out that it could be used to treat cancer in a brand new way that hasn't been seen before.   So this is work that comes out of the University of Helsinki, Paavo Kinnunen and his group and the drug is already being tested at sort of, very early clinical stages and it's called siramesine.   It acts at the cellular level on a specific receptor on the cell membrane and that was what they were hoping and would have the effect against anxiety.   It's a particular receptor on neurons.   But at the clinical level, it just didn't seem to work.

Interviewer - Chris Smith

So how did they then decide to apply it to cancer?

Interviewee - Victoria Gill

As you know with testing a drug from very early stages of discovery right through to approval, it costs lot of money, so if you find that your drug fails at a very early stage, you might want to look into another effect that it might have.   So looking at it in cell cultures they found that it has an anticancer effect.   It seems to prevent cancer cells from proliferating or, sort of, reproducing themselves.

Interviewer - Chris Smith

Do they know how?

Interviewee - Victoria Gill

Yes they do and it's a brand new way that hasn't been seen before.   It interacts with a second messenger molecule, a phospholipid on the cell membrane and this phospholipid is a second messenger to stimulate a biochemical pathway that causes the tumour cells to proliferate and it binds and interacts with this phospholipid which is called phosphatidic acid and prevents this second messenger from being used, so the cancer cells can't reproduce.

Interviewer - Chris Smith

I can see that they are really useful, but one worry is, if all cells use this mechanism, will it not have terrible side effects.

Interviewee - Victoria Gill

Potentially and that's always a problem with quite harsh, sort of, cytotoxic, cell killing cancer drugs, but what this does gives the researchers is, sort of, a new paradigm for cancer drug design, so they have a small molecule that they know a lot about.   They've, sort of, toxicity tested it and they've got it to early stage clinical trials, so they could use that to design new cancer drugs that interact specifically with this messenger and they can, sort of, design out the side effects.

Interviewer - Chris Smith

Thanks Vic.   So that's very exciting.   Let's hope that that makes its way into the clinic soon.

(04:29 --   A biosensor made from proteins could speed drug development)

Interviewer - Chris Smith

And talking of people discovering new drugs Ananyo this is very exciting, it looks like there's a new way for people to determine whether or not the thing that they think is targeting certain structures on cells that's working or not.

Interviewee - Ananyo Bhattacharya

Yeah that's right Chris, it's an invention of researchers in France that come up with a biosensor that can tell you if your drug is binding to the right, sort of, target on a cell.   That could be tremendously useful for the pharmaceutical industry because it would allow them to screen large numbers of drugs very directly and quickly.   And what they did to come up with this is that they got a protein called G-protein coupled receptor.   It's a very common target for many many drugs, I think about 30% of all drugs bind to this receptor.   And they coupled that to another protein called an ion channel and this ion channel regulates the flow of ions in and out of cells and what they did with a clever piece of genetics engineering itself, they linked the two so that when a drug bounds the G-protein coupled receptor it target on the ion channel opened it up and the ions flowed and you got an electric current which they could then measure.  

Interviewer - Chris Smith

So you can work out exactly how active the drug is at the cell surfaces.   So you've effectively got an objective reader out here.

Interviewee - Ananyo Bhattacharya

Yeah, it's all very direct and very very sensitive.   I mean at the moment what the pharmaceutical industry does is they have various indirect methods like the use radioactive tags or fluorescent tags on their compound and they see whether it's binding roughly to the protein that they are interested in; or what they do is the monitor a cell and see if it's producing the sort of biochemical changes in the cell that they would expect, but this sensor is, you know, it could offer a much more direct way of saying if that drugs is working.

Interviewer - Chris Smith

Is this something which could be used tomorrow or is this really just proof of principle and it's going to be ages before we can really see drugs being produced because of this.

Interviewee - Ananyo Bhattacharya

I suspect it's more of the latter.   I think there's a way to go, for example, one of the questions raised by a scientists we talked to was that but what happens if your drug is triggering the ion channel and how do you know you going to have to try and differentiate between that and the G-protein coupled receptor.

Interviewer - Chris Smith

So good news for the pharmaceutical sector.   Thank you Ananyo.  

(06:43 --   Fred Vom Saal from the endocrine disrupters group at the University of Missouri-Columbia explains the clinical concern over a chemical commonly found in plastics - bisphenol A)

Interviewer - Chris Smith

Something that all new parents take very seriously is food hygiene.   Most people obsessively sterilize their baby's bottles, often by nuking them in the microwave for 10 minutes or soaking them in boiling water; any one of them.   But now some scientists are saying that the baby might be better of taking its chances with the bacteria rather than the Bisphenol A that is leaking out of the plastic.   Here's Fred Vom Saal.

Interviewee - Fredrick S. Vom Saal

Bisphenol A is a chemical that's used to make hard, clear, reusable plastic products that are used as food containers, sport water bottles, baby bottles, microwavable safe containers for food, also to line food and beverage cans and it is used in many many other applications.   There are 7 billion pounds of this manufactured and put into products a year, but our main concern is it's used as a food contact item, where we think the greatest human exposure is coming from and based on data from Europe and Asia and the United States virtually everyone has detectable levels of Bisphenol A in his or her body and that of course is a very serious concern.

Interviewer - Chris Smith

Why is it so ubiquitously used in the ways you have just described?

Interviewee - Fredrick S. Vom Saal

Actually it does not need to be.   All of the products that are made with Bisphenol A in countries like Japan particularly all of them have been replaced, particularly the food contact items.   It's not used to line cans anymore.   This is a chemical that became used extensively at a time that people did not understand that it is structurally very similar to the oestrogen drug diethylstilbestrol and has the same activity of the natural oestrogen produced in a person's body.   So we have referred to this as an endocrine disrupting chemical and it acts like a sex hormone when it breaks out of the polymer that forms this hard, clear, odourless, tasteless material.   The problem is that it is quite unstable when heated and people are told that they can take baby bottles for instance and stick them in boiling water.   Well there are plenty of data out there now that when you do that you break apart the Bisphenol A molecules out of this polycarbonate plastic and the baby is then drinking Bisphenol A along with its baby formula.

Interviewer - Chris Smith

On a normal day-to-day basis, what sort of dose are we getting?

Interviewee - Fredrick S. Vom Saal

Well there is consensus for baby's drinking baby formula out of baby bottles.   They are getting somewhere between 2 and 14 mcg/kg/day.   What we know from animal research is if you take young baby animals and you feed them that amount of Bisphenol A you have brain damage, reproductive damage, immune damage, liver damage; you damage virtually every system in the body and among other things those animals become obese; they go into early puberty, so you have metabolic derangement as well.   So this is a chemical that particularly in early life causes a tremendous an amount of harm.

Interviewer - Chris Smith

And if you look at the health risks and published clinical data on people who have been exposed, is the clinical data bearing out what's you're saying?

Interviewee - Fredrick S. Vom Saal

So last week in the Journal of the American Medial Association, David Melzer's group in England published a study based on the United States National Health Survey showing that the higher your levels of Bisphenol A the more likely you were to show elevated insulin levels, elevated glucose levels, insulin resistance, liver damage and cardiovascular disease including the higher probability of dying of a heart attack.

Interviewer - Chris Smith

What about the alternatives, because if you're saying that at least people have an alternative and Bisphenol A is not used, what will they use instead and what's the evidence that that's any safer?

Interviewee - Fredrick S. Vom Saal

There are other kinds of polymers that are made from chemicals like polyethersulphone, which is sulphone molecules linked together that are highly resistant to breaking down under heat or acidic or basic conditions such as heating up in a can of tomato sauce where you get this massive amounts of Bisphenol A being found, so if you have a stable material that is not going to leech out into the food, it is going to be inherently safer even though it may be as a molecule potentially as dangerous as Bisphenol A if you are not exposed to it, it doesn't pose a danger.

Interviewer - Chris Smith

Well that's certainly food for thought.   That was Fred Vom Saal from the University of Missouri talking about the effects of Bisphenol A that's leaking out of the things that we use to store food in and if you like to follow up on the article that Fred mentioned, it is in the 17th of September 2008 edition of the Journal of the American Medical Association.

(Music)

Interviewer - Chris Smith

This is the Chemistry World podcast with me Chris Smith still to come how plants trick pollinators so they don't just stay there welcome, two new ways to battle drug-resistant bacteria and IVF on a chip.  

(12:58 --   How to break the bonds of global warming)

Interviewer - Chris Smith

First though Richard scientists have found a way to breakdown persistent organic pollutants including the notorious carbon-fluorine bond.

Interviewee - Richard Van Noorden

Exactly this is some very nifty chemistry.   A catalyst and a reagent combination together used to breakdown the famously strong, very inert carbon-fluorine bond at room temperature.   It's from Oleg Ozerov's group at Brandeis University in Massachusetts and fluorocarbons are persistent organic pollutants.   They do build up in penguins; if they are gases they do build up in the atmosphere and they are potent greenhouse gases.

Interviewer - Chris Smith

Why do they build up?

Interviewee - Richard Van Noorden

Well it's very very hard to breakdown that carbon fluorine bond, very inert.   So they just hang around for thousands of years and there's no natural process by which they could either be broken up into smaller pieces.

Interviewer - Chris Smith

And what does this team done to try and solve the problem?

Interviewee - Richard Van Noorden

This team had earlier shown that if you have got a very strong Lewis acid, a cation that pulled electrons away from the carbon-fluorine bond, you could get that bond to break but unfortunately that was very short lived and when it break a few and then that was it.  

Interviewer - Chris Smith

It was also not very practical on a global scale given these things were accumulating in the atmosphere and in the sea to do that is it?

Interviewee - Richard Van Noorden

Well the idea here would actually be to try and store what you've got and break it down in a reactor.   They haven't yet got to the stage of deciding what to do about the things that have already built up.   But for this chemistry they had already shown that an acid can break down the carbon-fluorine bond; it didn't hand around long.   Here they have got another strong solo cation, it's actually a silylium surrounded by three other groups which is a cation and there is a balancing counter ion, a carborane which doesn't really get in the way much, so the cation is free to pull away the fluorine from the carbon-fluorine bond not easily with the positively charged carbon and they have got another reagent coming in triethylsilane which is a positively charged silicon but you have got hydrogen on the end making it a molecule and that hydrogen is taken by what was your carbon-fluorine bond you end up with the hydrocarbon, a carbon hydrogen bond that's much right for the environment.   Now your catalysts will then turn over, your reagents being used up and you will end up with fluorine sort of being bonded with carbon being bonded with the silicon and the researchers say that that has a less of an impact on the atmosphere.  

Interviewer - Chris Smith

So what's the resulting product?

Interviewee - Richard Van Noorden

Silicon surrounded by hydrocarbons with a fluorine atom attached to it.   Previously you had fluorine attached to carbon

Interviewer - Chris Smith

And they say this is better for the environment; it's a lesser degree greenhouse gas than the carbon-fluorine bond we had there before.

Interviewee - Richard Van Noorden

Yes they do.

Interviewer - Chris Smith

What's about environmental safety to animals, to humans, that kind of thing?

Interviewee - Richard Van Noorden

Well the idea would not be to let this stuff leak out into the environment, it may indeed turn out to be toxic, but the idea there, that's clever chemistry, you can break down this bond, is what really that which excites them, now they haven't tried this is on a kilogram scale.   We are just talking catalyst lab scale good turnover, but it's just extremely amazing that at room temperature you can actually break down this strong bond.

Interviewer - Chris Smith

I guess we just have to wait and see what the long term future holds for that particular bit of chemistry.   Thanks Richard.  

(15:55 --   How plants manipulate their pollinators with chemicals)

Interviewer - Chris Smith

Now Victoria, back on to something which is very much an issue that has been going on for thousands of years and that's pollination of plants and scientists have got to the bottom of how plants manage to sort out the weed from the chaff if you like.

Interviewee - Victoria Gill

Indeed, I mean, it seems that they use a, kind of, clever bit of chemistry to trick their pollinators.   This is work that comes out of the Max Planck Institute of Chemical Ecology in Jena and Ian Baldwin and his team have discovered that plants use a very finely tuned mixture of attractants and repellent chemicals to sort of tease pollinators into pollinate them and take their nectar.

Interviewer - Chris Smith

So, on the one hand they are attracting them or giving them something nice and at the same time repelling them.

Interviewee - Victoria Gill

Yes, and then using a sort of toxic chemical to repel them to make them go away before they have taken all the nectar and so that other pollinators will have a chance to pollinate plants.   That way they get to reproduce more successfully.

Interviewer - Chris Smith

Okay, so in other words if you had something that was entirely attractive, a nice juicy flower full of nectar, then greedy insects might be tempted to just spend all day on one flower.

Interviewee - Victoria Gill

Yes.

Interviewer - Chris Smith

And that would not fulfil any of the obligations of being a pollinator.

Interviewee - Victoria Gill

Exactly!

Interviewer - Chris Smith

Because they would not carry any pollen.

Interviewee - Victoria Gill

And that flower wouldn't be able to, sort of, spread its seeds and reproduce successfully as other plants.

Interviewer - Chris Smith

So what did they do to prove this was what the plants were doing?

Interviewee - Victoria Gill

So they have been studying these particular tobacco plants for a long time now and they have discovered that there are two chemicals that are the most important attractant and repellent chemicals.   Benzyl acetone is their most important attractant and nicotine is the most important repellent and they used fake flowers with these particular chemicals on to show that these attracted and repelled pollinators, bees and humming birds.   So using RNA interference which is a method of, sort of, silencing a particular gene that makes a chemical for example, they have silenced the genes that make benzyl acetone the attractant and the nicotine, the repellent.   And so they have generated plants that produce either just repellents or just attractants or a balanced mixture of the two.   And they have videoed these plants to see how much they are visited by pollinators and what they have found is that the plants have to have this very delicate balance of the two chemicals in order to be visited by as many pollinators as possible.

Interviewer - Chris Smith

Sneaky plants.   You do have to wonder though whether the pollinators are actually hooked on the nicotine and that's why they keep coming back.   Thank you Victoria.  

(18:14 --   Medicinal chemist Robert Fecik from the University of Minnesota takes us through the latest research in the quest to find new superbug-beating antibiotics)

Interviewer - Chris Smith

And now to the question of antibiotic resistance and the race to develop new drugs to combat bacteria that are becoming increasingly more difficult to deal with.   Thankfully, now scientists have got two new targets to aim at.   Here's Robert Fecik.  

Interviewee - Robert Fecik

Well the issue addressed by the two papers is the lack of new antibacterial drug targets.   It's been widely recognized that there has been a lack of new antibiotics in the drug industry pipeline.   Part of the problem has been a dearth of new drug targets that could be exploited for antibacterial drugs and so in these two papers the authors have set out to try to establish or validate a certain drug targets that could be exploited for antibacterial therapy.

Interviewer - Chris Smith

So briefly how does these two new targets that they have uncovered work, what approaches do they take, which are different to those antimicrobials that we already have to throw to patients at the moment.

Interviewee - Robert Fecik

In the first paper this was published by scientists at Prolysis.   They have identified a protein called FtSZ, sometimes it is referred to as FitSZ, this is a protein that is critical for cell division in bacteria and so this is very vital for them to grow and this protein, FtSZ attracted a lot of attention because it turns out that this is the homologous in bacteria to Tubulin in mammals and Tubulin is a well known anti-cancer drug target.   This is a target of drugs such as Taxol, Vinblastine, Vincristine and so the idea is that if this Tubulin protein is effective to stop cancerous cells growing then the homologous protein in bacteria should also be an effective antibiotic treatment to stop bacteria from growing.

Interviewer - Chris Smith

How do the bacteria use the protein?

Interviewee - Robert Fecik

This FtSZ protein forms what is called the Z-rings and the protein polymerizes to form a ring on the inside of the bacterial cell wall as it is undergoing cell division and the presence of this ring then helps to recruit other proteins to this ring site that enables the process of cell division to occur.

Interviewer - Chris Smith

All right so this is how bacteria quite literally split in two when they undergo binary fission and one bacterium becomes two.

Interviewee - Robert Fecik

Correct.

Interviewer - Chris Smith

So how does this agent actually affect that protein and therefore stop the bacteria dividing?

Interviewee - Robert Fecik

So the compound reported in this study has a code named PC190723.   This compound actually prevents the FtSZ protein from polymerizing, so you can think of it as an agent that blocks the formation of this Z-ring.   This essentially shuts down the key event that needs to take place for bacteria to divide and grow.

Interviewer - Chris Smith

So we know that this new agent works and it can stop the bacteria from dividing presumably or is this just has been done in vitro.

Interviewee - Robert Fecik

In the current study, the authors have taken this one stop beyond in vitro work that others have demonstrated and have now taken this into an in vivo mouse model of bacterial infection and for instance they have found that upon single injection over a 7-day time period that this compound that inhibits FtSZ polymerization cures mice of a lethal infection.

Interviewer - Chris Smith

And is this target found in all kinds of bacteria or are there certain subtypes of bacteria and therefore it's not going to be panacea for everything, and it will only cure a some certain infection for certain types of bacteria.

Interviewee - Robert Fecik

So FtSZ is almost entirely conserved amongst all bacteria and so presumably this could be a very broad-spectrum type of antibiotic, however, one interesting thing that has been found by a number of groups is that compounds that inhibit FtSZ polymerization are generally more effective against gram-positive organisms and so the most clinically significant of these are multi-drug resistant Staph aureus or MRSA infections and so this tends to lead to some hope that perhaps in agents such as this could be a targeted type of antibacterial infection that could be reserved for multi-drug resistant infections, particularly gram-positive ones.

Interviewer - Chris Smith

Unless Fecik, we certainly need some.   So that's one of the publications.   There was a second paper, this was the group in Japan and they have been looking at a slightly different target.

Interviewee - Robert Fecik

Yes and so the group in Japan Tohru Dairi, they have been looking at a protein called menaquinone and this is a protein that plays a critical role in bacterial respiration and so bacteria need proper functioning of this to survive.   However, they found that there are certain strains of H. pylori or this is the bacteria which commonly causes stomach ulcers that they use an alternate pathway and so they actually produce a different type of protein critical for bacterial respiration and so this suggests again getting back to the theme of selective antibacterial agents or targeted antibacterial agents that interfering with this pathway that has only so far been found in H. pylori that this could be a selective antibiotic agent useful for the treatment of stomach ulcers.

Interviewer - Chris Smith

So another promising target, but how long do you think it would take before this one and the previous agent that we talked about will actually find their way into patients?

Interviewee - Robert Fecik

It will likely be a number of years before any agents from these studies could be translated into clinical useful therapies.   Establishing in vivo animal efficacy data is one of the essential early steps and so there is much work to be done here for instance we know nothing up long term toxicity of these agents, potential side effects and other types of infections that these compounds could be potentially useful in and so it would likely be 3 to 5 years potentially till a new agent at this stage could enter human clinical trials.

Inter