Features

Stellate cells, a type of cell in the pancreas which normally helps the body respond to damage or disease of the pancreas, can act as a double agent when it comes to cancer.

These mysterious cells become ‘partners in crime’ with pancreatic cancer cells, Oxford University researchers have shown, stimulating growth of the cancer cells and protecting them against radiotherapy.

The research, led by Professor Thomas Brunner at the Gray Institute for Radiation Oncology and Biology, suggests that developing drugs to remove specific communication lines between the pancreatic cancer cells and the stellate cells could improve patients’ response to radiotherapy in the future.

Most people diagnosed with pancreatic cancer are told that they may have less than 1 year to live. Part of the reason is that by the time someone is diagnosed, the cancer is often quite advanced. Cancer Research UK figures show that around 20 in every 100 people diagnosed with pancreatic cancer live for 1 year or more, and that only 5 out of every 100 people live for more than 5 years.

In terms of treatments, surgery is currently the only way to cure the disease – but less than 20% of all patients can be operated on, and only 5% of these patients will be alive 5 years later. Chemotherapy helps to prolong survival after an operation, and is also used when the cancer has spread elsewhere. Radiotherapy is used along with chemotherapy in patients without spread of the disease to other organs and where surgery isn’t an option.

Stellate cells – so-called because they are star shaped – normally make up around 4% of the cells in the pancreas. But upon any type of trauma (pancreatitis as well as cancer) these cells can drive an inflammatory reaction that leads to the formation of a fibrous mass. It can be up to 90% of the mass of a pancreatic tumour, for example.

‘It’s like a non-healing wound,’ says Thomas Brunner. His group has just published the first paper demonstrating the influence of the pancreatic stellate cells on how effective radiotherapy is in destroying the cancer cells. The results can be found in the journal Cancer Research.

‘We’ve tended to be so focused on the cancer that we’ve neglected what’s around,’ he adds. ‘Sherlock Holmes would not be impressed. We have forgotten there may be more to the disease in the environment surrounding the tumour.’

The group looked at the survival of pancreatic cancer cells in the lab when dosed with radiation. When the cancer cells were co-cultured with the noncancerous stellate cells, the radiation had far less effect in killing off the cancer cells.

In mouse models, tumour growth was faster with the pancreatic stellate cells present and the stellate cells provided something of a protective shield, reducing the effect of radiotherapy on the cancer.

‘It turns out that stellate cells are partners in crime with the cancer cells,’ says Professor Brunner. ‘They actively help the tumour cells and have a protective effect against radiotherapy.

‘While they normally help defend the pancreas against injury – wound healing is very critical – this response needs to stop at some point or it is harmful. In pancreatic cancer, this wound-healing response becomes active forever and that’s counterproductive in the end.’

The researchers looked at a number of signalling pathways that might be responsible for this effect by enabling the cancer cells and the stellate cells to communicate. They found that some molecules on the surface of the cells called integrins were likely to be involved.

‘Blocking the integrin signalling gets rid of any protective effect against radiotherapy,’ says Thomas Brunner. ‘By finding the mechanism behind this effect, we ultimately may be able to develop a drug to target this process and improve the outcome of radiotherapy.’

Life as a seed isn’t easy: you need to be tough enough to deter all but the most muscular-jawed predators but not so hard that you can’t germinate.

A new study published this week in Journal of the Royal Society Interface shows just how fine this evolutionary balance between protection and reproduction is.

A team, including Susan Cheyne of Oxford University’s WildCRU, analysed the properties of the seeds of the plant Mezzettia parviflora (Annonaceae) and the effort that seed predators, such as orangutans, have to put into cracking them open.

‘The intricate architecture of the Mezzettia parviflora seed allows its germination while impeding both small predators such as weevils and large ones like orangutans,’ Susan tells us.

‘Orangutans open the seed by biting into the germination bank and cracking the wooden plug, the weaker part of the seed through which the stem of the germinating seedling emerges.’

Field observations by Susan and colleagues of orangutans in Sabangau, Borneo, show that whilst orang-utans consume an average of about 120 seeds per day (up to a maximum of 1001) the jaw strength they have had to evolve to accomplish this task is formidable: the force their jaws deliver is equal to the weight of up to six people bearing down on the seed.

So is all this effort worth it? ‘The seeds contain a small amount of a lipid-rich substance which is very high in energy, so worth the effort to break not only the seed but the hard outer shell of the fruit,’ Susan explains. ‘The toughness of this fruit and seed prevents consumption by other primates, for example gibbons, who lack the jaw strength to open the seeds.’

The research is thought to be the first to show that the mechanical properties of a seed play a central role in stabilising the arms race between seeds evolving armour for protection and the predators evolving a way to open a nutritious snack.

Dr Susan Cheyne is a member of WildCRU, part of Oxford University's Department of Zoology.

It may be our home but just how special is the Milk Way?

That’s the question a team including Oxford University scientists have been looking to answer using simulations of our galaxy and our neighbours, the Magellanic Clouds.

Their findings, reported in a paper in The Astrophysical Journal could help in the hunt for dark matter. I asked one of the paper’s authors, Phil Marshall of Oxford University’s Department of Physics, about Universal assumptions, starless galaxies, and telltale gamma rays…

OxSciBlog: What made cosmologists assume that the Milky Way is an 'ordinary' galaxy?
Phil Marshall: Basically, we had to start somewhere! The cosmological principle states that we do not live in a special place in the Universe, one that has a special viewpoint. Asserting this principle allows us to make many wide-ranging inferences about the Universe, even though we can only observe it from one location (Earth). But it's important to test our assumptions, so we asked whether the galaxy we live in was, in fact, special - at least in one respect.

OSB: How can the Magellanic Clouds reveal if the Milky Way is special?
PM: A galaxy's neighbours - its ‘satellite galaxies’ - are one of its observable features. We wondered if having these two very nearby neighbours, the Magellanic Clouds, made the Milky Way special.

So we looked in the Sloan Digital Sky Survey [SDSS] sky survey at thousands of galaxies that have the same brightness as the Milky Way, and asked how many of them have two nearby neighbours like our Magellanic Clouds. It turns out that only about 4% of them do - so the Milky Way is a little unusual, but not very unusual. It's a one-in-twenty-five galaxy, rather than one in a million.

OSB: How did you use simulations to see how the Milky Way relates to its neighbours?
PM: We did the same thing in a simulated sky survey, counting neighbouring objects around Milky Way-like objects. If the simulated Milky Way galaxies don't have as many satellites as the SDSS galaxies, then the simulation needs more work.

We used a simulation called ‘Bolshoi’ that followed the formation of about 100,000 galaxies, and picked out the ones that were about as bright as the Milky Way. This is tricky to do actually, because the simulated galaxies don't have any simulated stars in them! They are just dark matter ‘halos’ - blobs of dark matter that would contain gas and stars in real life. The simulation doesn't include stars and gas, because it's too difficult to simulate them. Dark matter structures are easier to model - for them, it's only gravity you have to understand, and not the complicated physics and chemistry of how stars are made.

What we do is match the simulated dark matter halos to the real SDSS galaxies, one by one, most massive halo to most luminous galaxy and so on. You end up with a model Universe full of dark matter halos with bright galaxies ‘painted on’ - and it turns out this painted Universe looks very similar to the real one indeed. Then we can select all the model galaxies that are as bright as the Milky Way, and count their neighbours.

OSB: What can you infer about how 'odd' our home galaxy is?
PM: We found that, just like in the real Universe, Magellanic Clouds occur in about 5% of Milky Way galaxies. So the simulation matches the SDSS sky survey very well, right down to the smallest galaxies it contains, the Magellanic Cloud-like satellites.

Actually we can say quite a lot about our home galaxy without doing all the matching I just described: If we just look in the simulation for halos that have 2 subhalos that are the same mass as the Magellanic Clouds, and that are at the same distance from their host galaxy as our Magellanic Clouds are from us, and that are moving at the same speeds as our Magellanic Clouds are, we can collect a group of model halos that really resemble our own halo very closely.

We call these halos ‘analogs’, and they show us some possibilities for what our own dark matter halo is like. For example, they weigh about a trillion solar masses each, so we can say that this is probably what our halo weighs. Likewise, looking at the formation histories of each our analogs, we can infer that our Magellanic Clouds probably arrived quite recently (within the last billion years), and they probably arrived together.

OSB: How might such simulations help in the hunt for dark matter?
PM: Understanding the distribution of dark matter in our own galaxy is very important, especially when searching for the very faint glow expected if dark matter turns into something else.

The idea is that dark matter particles in our galaxy could, very occasionally, collide with each other, and ‘annihilate’, in a very faint flash of gamma rays. These flashes may be so faint that knowing where the dark matter is likely to be, ahead of time, from its gravity, would really help in interpreting the gamma rays that telescopes, like Fermi, detect.

Dr Phil Marshall is based at Oxford University’s Department of Physics

Saturn skydive illustration

Image: OU

Daredevils regularly bail out at high altitude to skydive through Earth’s atmosphere but what would it be like to skydive on Saturn?

Would you jump in summer into an atmosphere shrouded in a yellow-ochre haze, aim for winter when the planet is tinged blue, or maybe leap into the shadow of those famous rings?

These thoughts were prompted by new research from an international team led by Oxford University scientists into a powerful storm on Saturn first spotted in December 2010. 

‘What we see when we look at Saturn in visible light is the top of the cloud decks – that’s near the top of the troposphere or ‘weather zone’ – made up of ammonia clouds and other hazy materials,’ Leigh Fletcher of Oxford University’s Department of Physics, who led the work, tells us.

‘This top layer of cloud is a bit like the skin of an apple, it stops us seeing the body and ‘core’ of the planet underneath.’ What lies beneath is a mystery, but Saturn sometimes shows its true colours in spectacular fashion.

Seeing (infra)red
As the team report in this week’s Science, for the first time scientists have been able to study a major storm on Saturn using both observations from an orbiting spacecraft (NASA's Cassini) and ground-based telescope (ESO's VLT) at thermal infrared wavelengths.

These wavelengths are longer than the visible light we normally see reflected from Saturn’s clouds and enable researchers to figure out the temperatures, winds and composition of the atmosphere, helping them to build up a picture of its weather in 3D.

So the first question when imagining a Saturn skydive is: where do you start?

Like the Earth, Saturn’s upper atmosphere – its stratosphere – is relatively stable. This stratosphere extends way above the troposphere and the visible cloud deck, radiating energy generated within the planet out into space. 

But whilst Earth’s stratosphere starts around 10km above the surface of our planet (a few kilometres above the clouds) on Saturn the stratosphere extends hundreds of kilometres above the clouds.

Saturn’s stratosphere should be a ‘weather-free’ zone, relatively unaffected by the turmoil of storm clouds churning deep below, ‘but this turns out to be completely wrong’ Leigh explains.

Instead, the new observations spotted ‘beacons’ in the stratosphere that, at 15-20 degrees Kelvin hotter than their surroundings (120-140 Kelvin), stand out like the beacons of a lighthouse. In fact, the spectacular effects of Saturn’s giant storm were being felt in the stratosphere almost 300km above the visible clouds, ‘that’s almost as far as the International Space Station orbits above the surface of the Earth’ Leigh adds.

‘It’s as if the storms in the troposphere are giving the normally stable stratosphere a punch – hitting it and causing the hotspots we’ve been able to pick up in infrared.’

Light the beacons
These beacons are thought to be created when ‘air’ (87% hydrogen, 12% helium, 1% other trace gases) wells up and then descends; becoming compressed and heating up like the air in a bicycle pump. It’s the emission from the other 1%, gases such as methane, ethane, and acetylene, which makes the beacons visible.

Our skydiver would have to plummet some 300kms from the stratospheric beacons to reach the troposphere where convection rules and energy is turned into powerful air currents. Here, at the topmost layer of the clouds, the bright white areas we see in visible light are plumes of fresh material as yet untainted by Saturn ‘smog’.

But of course, this being Saturn, these aren’t ordinary storm clouds: instead they are clouds mostly made up of crystals of ammonia ice and other exotic materials.

‘It’s as if, by injecting these plumes of fresh material up into the troposphere, the planet is doing a gigantic experiment for us; injecting a visible tracer that we are then able to use to track Saturn’s jet streams as they travel from east to west around the planet,’ Leigh tells us.

These top layers of clouds that ‘cloak’ the planet - shielding the lower reaches of the atmosphere from view - vary in colour from the pristine, bright and new, to old, dark clumps that have accumulated ‘dirt’ or contaminate as they circulate in the turbulent currents of the giant storm.

Yet the journey of our intrepid skydiver is nowhere near over even now she’s reached the top of the visible clouds. She would have to plunge even deeper, into cloud decks normally hidden from telescopes and orbiting spacecraft, to find the source of the powerful storms and beacons observed by the team.

‘The storms don’t begin in the troposphere with these ammonia clouds, we think that they start around 200-300km below the top of the troposphere, possibly within clouds of water hidden deep within Saturn’s atmosphere,’ explains Leigh.

Stormy weather
Here, over 500km below the beacons in Saturn’s stratosphere, is where bad weather is brewed. An injection of energy into this cloud deck can form giant bubbles or plumes which rise upwards. These drag with them material that will eventually form the visible tropospheric clouds, and it’s the response to this powerful convection that is likely to be generating those hot beacons which show up in infrared in Saturn’s stratosphere.

If our skydiver has made it this far, she’s reached the part of the atmosphere scientists would really like to study – one possible source of the incredible phenomena seen on giant planets.

These latest observations are just the beginning of the story of Saturn’s stormy weather. Since the work reported in Science the team have been continuing to monitor the behaviour of the beacons and hope that they can reveal much more about the planet’s atmosphere.

Leigh comments: ‘We’ve taken what people think of as a serene and beautiful astronomical object and moved it into the messy and volatile realm of meteorology. It’s a nice thought when you look up at a blue sky on Earth filled with fluffy clouds of water vapour that the same physics of weather is driving vast storms on another, very different, planet.’

Our imaginary skydiver has taken us on a wild ride deep into the heart of this gas giant but she’s still only scratched the surface. Saturn’s deep churning atmosphere extends another 58,000km to the core – that’s 3.5 times the diameter of the Earth. Assuming she survived the incredible heat, pressure, and poisonous fumes she’d still be faced by one final problem: how do you land on a planet that has no solid surface?

 Dr Leigh Fletcher is based at Oxford University’s Department of Physics.

‘When Suzanne Ludgate of the Medicines and Healthcare products Regulatory Agency (MHRA), the government regulator of medical devices in the UK, says she was "appalled at how many devices are brought to market with a lack of appropriate clinical data," you know there must be a problem.’

So Dr Carl Heneghan, director of the Centre for Evidence-Based Medicine at the University of Oxford, begins a blog post on The Guardian site.

The term 'medical device' covers a huge range of products that have a medical use and are not medicines. The MHRA notes that this includes anything from walking sticks and hip replacements to glucose monitors, blood pressure machines and pregnancy testing kits. Every day in the UK, millions of people safely use medical devices.

But it is the regulation of these devices that Carl and colleagues at Oxford are concerned with. They have just completed an analysis of product recalls in the UK as part of a joint investigation by the BMJ medical journal and Channel 4’s documentary series Dispatches into medical device regulation. Carl’s post explains the main findings:

‘For the past 6 months, my group at the Centre for Evidence-Based Medicine at the University of Oxford has been looking at how many devices are recalled in the UK each year and what evidence supports their clinical use ... Device recalls are rising dramatically, from 62 in 2006 to 757 in 2010: a 1,220% increase. And yet, when we asked manufacturers for clinical data related to the recalls, we were stonewalled. Of 192 manufactures we contacted, only 53% (101/192) replied, and only four (2%) provided any clinical data.’

In Europe, he writes, high-risk devices only have to establish safety and performance and do not have to prove they make a difference to patients. Carl contrasts this situation with that in the US, where approvals are undertaken by the FDA, and information held is readily available.

Carl calls for the current system of medical device regulation to be tightened so that it requires evidence of improvements in clinical outcomes for patients.

Carl is not alone in this opinion. The BMJ has published a series of commentaries from leading academics as part of its assessment of the issue, from Nick Freemantle, Stefan James, Alan Fraser, John Skinner, and C Di Mario.

The BMJ’s press release says its investigation [see articles here and here] with Dispatches raises ‘serious concerns about the regulation of medical devices and ask how well these high-risk devices are tested before they come onto the market.’ It continues:

‘[BMJ and Dispatches] explore a European approval process negotiated by private companies behind closed doors and reveal a worrying lack of public information about the number of devices being used and their potential risks. They also discuss links between surgeons paid to design devices and the companies promoting them. The investigations findings are clear. The current system is not fit for purpose and we urgently need better regulation to protect patients.’

The Channel 4 Dispatches programme was broadcast last night at 8pm.

The BMJ/Dispatches investigation also saw coverage in the Daily Mail, Independent and online in the Daily Telegraph.

Separately, in an article in the European Heart Journal, heart specialists have called for an overhaul of the system for regulating medical devices such as heart valves and diagnostic imaging equipment, Andrew Jack notes in the Financial Times.

Jack’s article in the FT also offers a comparison of the current approaches to medical device regulation in the US and in Europe:

‘[The British Medical Journal has] published a series of articles highlighting weaknesses in the EU regulatory system for medical devices at a time of growing debate on reforms on both sides of the Atlantic ... European medical device trade bodies have also called for reforms to clarify existing regulatory standards and embraced with counterparts in North America, Australia and Japan through a Global Harmonization Task Force. However, they have also cautioned that excessive regulation risked damaging the medical device sector and could delay access to patients. They pointed to the US, where medical devices are introduced more slowly than in the EU as a result of tighter regulation, while, they claimed, not improving safety.’

Jack points to examples where UK regulators were the first to identify problems, and conversely where devices were rejected in the US but accepted then subsequently withdrawn or discontinued in the EU.

An MHRA spokesperson responded to the BMJ/Dispatches investigation, saying:

‘Medical devices bring widespread health benefits for patients and the public but no product is risk-free. We ensure that the benefits always outweigh the risks. Our priority is to ensure that patients have acceptably safe medical devices. We monitor all adverse incident reports and take prompt action to address any safety or performance concerns.'

The regulators note that manufacturers of all devices are required to have clinical data to support their performance claims for the device. In most cases, and in particular for higher risk devices, this information will come from a specific clinical trial on the device itself. However clinical data may also come from a literature review of the clinical information on equivalent devices. Where a manufacturer plans to carry out a clinical trial in the UK, agreement must be obtained from the MHRA. 

The spokesperson adds: ‘What must be borne in mind is the balancing act of generating clinical data pre-market and the benefit to patients of innovative products reaching the market place.’ 

Where this balance should lie is the question that concerns all of these parties.