Aggressive Flies and Carbon-Hungry MOFs

In this week's NewsFlash, we find out how to capture carbon in Metal Organic Frameworks, or MOFs, discuss progress in treating Cystic Fibrosis, explore aggressive fruitfies...
07 December 2009
Presented by Ben Valsler


In this week's NewsFlash, we find out how to capture carbon in Metal Organic Frameworks, or MOFs, discuss progress in treating Cystic Fibrosis, explore aggressive fruitfies and a potential new treatment for hepatitis C.

In this episode

Smokestacks from a wartime production plant, World War II.

New way to lock up carbon dioxide

Scientists may have found a much more cost-effective way to extract the CO2 from exhaust gases.

Smokestacks from a wartime production plant, World War II.With Copenhagen just around the corner the attention of the world is firmly fixed on the question of cleaning up our emissions.  But efficient ways to selectively scrub CO2 from the waste gas streams leaving power-stations or other heavy industries have proved hard to find.

The best contenders to date have involved dissolving the gas in solutions of amines, but this is problematic because to re-release the gas from the amine - to store or sequester it - consumes large amounts of energy, making the process inviable in energy terms.

But now a new molecular structure may have come to the rescue, the MOF or metal organic framework.  These are large molecular structures resembling chemical cages linked together in a repetitive sequence.  But what's special about these cages is that the 'bars' consist of organic molecules that plug into metal atoms at the vertices and this combination gives these structures very exciting chemical properties including the ability to selectively lock away certain gases inside the cages but simultaneously reject others.  This means that they can behave like molecular sieves and California Nanosystems Institute scientist David Britt and his colleagues have developed a MOF that is very good at selectively grabbing CO2.

Writing in PNAS, the team present a molecule called Mg-MOF-74, which contains magnesium atoms linked to the organic material DOT, short for 2,5-dioidoterephthalate.  Exposed to a mixture of gases that includes a low concentration of CO2, this MOF selectively sequesters the carbon dioxide by linking it to the magnesium atoms inside the molecular cages; the other gas molecules meanwhile, slip through unimpeded.  Fully charged the MOF can soak up close to 9% of its weight in CO2; better still is can re-release the CO2 just with gentle warming to only 80 degrees C, liberating the gas and regenerating the MOF.

This say the scientists meakes these molecules excellent candidates as CO2 capture media; they also offer the advantage over existing methods of being non-toxic and non-corrosive, which are unpleasant features of the amine solutions currently being trialled.

Progress in cystic fibrosis

Researchers in California have discovered a way to partially repair damaged lung cells from patients with cystic fibrosis, an inherited disease that affects more than 70,000 people around the world. The results are published in the journal Nature Chemical Biology this week, led by Professor William Balch and his team at the Scripps Research Institute.

An example of a breathing treatment for a younger Cystic fibrosis patient.It all centres on protein processing - when proteins are made in our cells, they are folded up into the correct shape. But if there's a fault in the protein, or in the folding process, then the protein doesn't work properly and it gets broken down again. 

In cystic fibrosis, the disease is caused by faults in the gene that makes a protein called CFTR, which normally sits on the surface of cells and helps to shuttle salts across the cell membrane. Around nine out of ten people with the disease have a faulty version of the CFTR known as DF508 CFTR. The resulting protein is the wrong shape, and gets broken down in the cell's endoplasmic reticulum - the molecular factory where proteins are made.

The researchers figured that if they could stop the DF508 version of the protein being degraded, then it might work at least a bit, and help to relieve some of the symptoms of cystic fibrosis - and that's just what they've managed to do.

The scientists used a drug called suberoylanilide hydroxamic acid, or SAHA for short, which blocks enzymes called histone deacetylases. These normally work to affect the proteins that package DNA in the nucleus of the cell, helping to switch genes on and off, but they also have other effects on the processing of proteins.

They tested the drug on lung cells taken from cystic fibrosis patients with the DF508 fault,  and found that SAHA treatment restored the level of CFTR activity to 28 per cent of that found in normal lung cells.

That may not sound like a lot, but it could make a real difference. For example, patients with less severe cystic fibrosis, with around 15 to 30 per cent levels of CFTR activity, can lead a much more normal lifestyle, compared with people carrying a more severe fault like DF508.  So being able to restore 28 per cent of lung cell function could really be significant.

The scientists also found that SAHA works best at relatively low doses, which is important if it's to be taken forward for clinical trials. The other good thing about the drug is that it has already been used in clinical trials for treating cancer, but in higher doses over a short period of time.

More research and tests need to be done to find out if it's suitable for giving in lower doses over a lifetime, which would be the case for treating people with cystic fibrosis. But these early results are certainly promising. And Balch thinks that a similar approach might also work for other conditions such as type II diabetes, arthritis, osteoporosis, and Alzheimer's disease.


Mobile phones off the hook as cause of brain cancer?

A large study of brain cancer cases has failed to find any increase in line with mobile phone use.

try15Writing in the Journal of the National Cancer Institute, Danish Cancer Society scientist Isabelle Deltour and her colleagues looked at 60,000 patients with brain cancers diagnosed between 1974 and 2003 from a population of more than 16 million.  The researchers found that the incidence of gliomas and meningiomas among adults was stable over this time and, critically, there was no change reflecting the sudden surge in mobile phone use that occurred in the mid 1990s.

The authors acknowledge that the time between mobile phone exposure and the development of a brain tumour could be greater than the 5-10 year lead-time investigated in the study, and they also point out that, if such an effect does exist, it may also be be too small to be observed here.  But, more reassuringly, it could also confirm that there is no increased risk of brain cancer conferred by mobile phone use.

As we have no way of knowing which it is, for the meantime at least, we'll just need to hang on to find out...

This image shows a 0.1 x 0.03 inch (2.5 x 0.8 mm) small Drosophila melanogaster fly.

Come and have a go if you think you're hard enough

Researchers from Caltech, the California Institute of Technology, have made a step forward in understanding how aggression may be hardwired into the genes, at least for fruit flies.

Drosophila melanogaster flyThis is research from Professor David Anderson and his colleagues, writing in the journal Nature this week. They've found a chemical pheromone that controls aggression in flies, and have also pinpointed the nerve cells in their antennae that detect the pheromones and send signals to the brain, telling it to kick off.

We've known for a while that insects can respond aggressively to certain chemicals, or pheromones, when they're presented with artificial versions of them. But we don't know how much they use these  pheromones normally to control their aggression. To prove it, the scientists had to track down the exact receptors in insect nerve cells that receive the pheromone signals - something that could only be done using fruit flies, as scientists have done a lot of research into their nervous system.

The researchers discovered that a chemical called 11-cis-vaccenylacetate, or cVA for short, can make pairs of male flies get aggressive, rearing up on their hind legs and hitting each other with their forelegs. And when they put pairs of male flies near a mesh cage containing other males that were releasing the chemical, they also became aggressive.  But when the researchers silenced the nerve cells that respond to cVA, the flies no longer showed the aggressive behaviour.

Male fruit flies gather on food, because it gives them opportunities to mate with passing female flies. Normally they all get along OK, but if there are too many male flies, then this might interfere with feeding and mating.

The researchers took male flies that had been genetically manipulated to have hyper-sensitive nerve cells that detect cVA. They found that when these flies gathered on food, they fought each other until there was just one victor left. But when they tested unmodified flies, they just gathered together happily.

The researchers thinks that when the population of male flies gets high enough, the levels of cVA that they produce rises. This makes the flies aggressive and they fight, driving away some of them. As the flies fly off, the concentration of cVA drops again, and the flies calm down - and this cycle keeps repeating.

At the moment, these experiments have just been done in the lab, but the team thinks that it should be possible to reproduce them in the wild. And it would be very interesting to find out if the same kind of thing is at work in humans. Researchers have found aggressive pheromones in mice, so it's possible that we may also have them.

The Liver, from Grays Anatomy

13:20 - Hitting Hepatitis C

Henrik Øren discusses a potential new drug to stop Hepatitis C in its tracks...

Hitting Hepatitis C
Henrik Øren, Santaris Pharma

Chris - Also in the news this week, in the journal Science, there's a paper which highlights a potential new treatment for hepatitis C.  This new paper describes a molecule which will target hepatitis C by attacking a microRNA, a short piece of genetic material, which liver cells make and which seems to be absolutely critical for the virus to be able to replicate or grow.  One of the people who's helped to make this possible is Dr. Henrik Øren from Santaris Pharma.  He's with us now.  Hello, Henrik.

Henrik -   Hi.

Chris -   Welcome to The Naked Scientists.

Henrik -   Thank you.

Chris -   So please tell us first of all, what is the problem with hepatitis C, actually treating it at the moment with existing therapy?

The Liver - from GrayHenrik -   Well, at this time, there's probably about a couple of hundred million hepatitis C sufferers worldwide and the standard care is a combination of interferon and ribavirin which is effective in only about 50% of patients and associated with significant adverse effects.

Chris -   So what you're saying is that we can't do much about hepatitis C at this stage, so we have a strong need for better therapies.

Henrik -   There's absolutely a very strong need for new therapies.

Chris -   And what have you done?

Henrik -   So what we've done is we've taken a non-traditional approach.  Rather than trying to attack the virus directly, we're attacking it indirectly by sequestering a host factor that the virus uses for its replication.  It turns out that when we do it, we get a drug that is very potent in the chimpanzee model, which is the only other species (other than humans) that can contract HCV, so it packs a combination of very good potency and good safety, and a unique barrier to resistance.

Chris -   So first of all, tell us, what is the new drug and how does it work?

Henrik -   It works by binding to and sequestering an endogenous microRNA called microRNA-122 that is specifically expressed in the liver and which the virus uses for its replicative cycle.  And sequestering this basically removes it from the virus and hence stops the virus replicating.

Chris -   Why should the virus rely on a human cellular factor, this microRNA to grow at all?  Why does it need that?

Henrik -   Well, viruses depend on a lot of host factors.  They do not encode all of the functions they need to complete their life cycles.  So, when they enter cells, they do co-opt a lot of different host factors to complete that.

Chris -   And your new agent, how does it work?  What does it do to that microRNA in the liver cells to make it so that the cells will no longer allow the hepatitis C to grow there?

Henrik -   Well, the microRNA in the infected liver cell basically binds to two sites in the 5' end of the HCV genome.  And although the mechanism by which this binding facilitates replication is not entirely known in details at this point, it is known to be a direct binding event between the microRNA and the HCV genome.

Chris -   So in some way, that microRNA encourages the virus.  It then enables the virus to copy its genetic material.

Henrik -   Yes.  So, what our drug does is it binds competitively to the microRNA and sequesters it in a form that it can no longer bind to the HCV genome.

Chris -   Where else in the body would your cells make microRNA-122, this particular linchpin, and does your drug therefore have the potential to inactivate a key component of cells in other bits of the body and therefore, cause side effects?

Henrik -   All present data shows us that microRNA-122 is a liver-specific microRNA and it's normal function is involved in the biosynthesis and metabolism of lipids and cholesterol.  So, what we observed as the only other effect so far in extensive toxin pharmacology studies when we inhibit the microRNA-122 is the expected reduction in plasma levels of cholesterol.

Chris -   And so, when you inhibit this particular microRNA in the liver with your drug, what happens to the hepatitis C infected chimpanzees you were trying it on?

Henrik -   So we injected them once weekly every 12 weeks and during the whole dosage periods, we saw a steady decrease of virus titres, both in plasma and in the liver.  And at the end of dosing, this effect lasted a couple of months post-dosing, consistent with the fairly long half-life of the drug.  So, over a period of 5 months where we kept the microRNA fully suppressed in these chimps, they was a steady decline and very strong response on the virus that did not bounce back at any point in time.  I think this combination of a good response in the virus and the safe treatment, combined with the apparent complete absence of a viral breakthrough through this extended period of time, that's the combination that really creates excitement in the community.

Chris -   And the next step is presumably now to try this in humans?

Henrik -   Yes.  We've so far conducted the first study in healthy volunteers.  It's a single-dose study, single ascending dose study.  We're currently conducting a multiple ascending dose study to define the dose and the dosing schedules and we'll hopefully move to patients in the near future.  We haven't quite worked out the design and where those studies are going to be conducted, but we will setup a patient information centre on our homepage where patients interested in this new drug can get the relevant information.

Chris -   And you can get more relevant information in the journal Science this week and the drug that Henrik was talking about is SPC3649.  That was Dr. Henrik Øren who is from Santaris Pharma.


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