Turning blood cells into Trojan Horses

Scientists in Italy have found a way to boost the power of MRI tracer chemicals - by hiding them inside a patient's own cells.

A major problem with contrast agents like iron oxide nanoparticles, which are designed to enhance the signals scanners can pick up from certain tissues is that the agents are rapidly diluted out or picked up and excreted from the body.  Now University of Urbino researcher Mauro Magnani and his team, writing in the Journal of Nanoscience and Nanotechnology, has found a solution.

The researchers first incubate a sample of a patient's red blood cells in a solution containing the nanoparticle-contrast agent.  Crucially the concentration of the solution is adjusted to make it more dilute than blood plasma.  This makes the cells swell up as water moves into them due to the process of osmosis.  As this happens the cell membranes become leaky allowing the iron oxide nanoparticles to enter.  When the concentration is later returned to normal the cells shrink but the nanoparticles remain trapped inside.

The blood can then be re-infused into the patient where the red cells, carrying their contrast cargo, remain in circulation for the rest of their normal lifetime, which can be up to 120 days.  This should enable doctors to make repeated measurements on patients over time, but without needing to top up the contrast.  It could prove useful in spotting signs of internal bleeding, for instance post-surgery.

The italian team have signed a deal with Phillips research to pursue the work, which has not yet been tested on humans although the contrast agent itself has and is safe.

5th Oct 2008

Marine "dead zones" could be even larger than thought

Crabs and other crustaceans in the ocean could be the first to suffocate in the increasing number of marine "dead zones" in the world, areas where there is little or no oxygen. What's more, the extent of oxygen deprivation in the oceans could be much larger than previously thought.

These are the findings of a study from Mediterranean Institute for Advanced Studies in Spain published by Raquel Vaquer-Sunyer and Carlos M. Duarte in the journal PNAS this week which looked at how well different types of bottom-dwelling marine creature can tolerate lowered levels of oxygen in the water in the laboratory.

The researchers searched through hundreds of other previously published studies of two hundred different species to investigate exactly what the threshold level of oxygen is for life in the oceans to be sustained.

What they found was that there is quite a range in the tolerance of different species to restricted oxygen. Some like the American Oyster can put up with virtually no oxygen, while others are much more sensitive - the young larvae of the rock crab will die if there is less than 8.6mg of 0₂ in every litre of water.

The problem of lowering levels of oxygen in the oceans stems mainly from a process known as eutrophication, which is triggered by nutrients - mostly agricultural fertilisers - washing off land and into coastal waters. Higher levels of nitrates and phosphates cause algal blooms, both of large seaweeds and single celled phytoplankton. When the algae die they sinks to the seabed where bacteria break them down, using up all the oxygen in the water and leading to the so-called "dead zones".

Climate change may also make the problem worse since warmer water holds less oxygen.

A study published earlier this year in the journal Science revealed that there has been an exponential increase since the 1960s in the number of "dead zones" in the world, which currently cover around 245,000 square kilometres.

That study defined dead zones based on a threshold level of around 2 mg of oxygen per litre. What this latest study now suggests is that the threshold could in fact be as high as 4.6 mg of O2 per litre, which would meant the total extent of marine dead zones could be far greater than was previously thought.

All in all, this means that we made need to think again about the health of the oceans and for water quality standards to be set accordingly to tackle the increasing extent of marine dead zones.

5th Oct 2008

Fossil AIDS virus

An international team of scientists have found new evidence pointing to 1908 as the year when HIV was born.  Writing in Nature this week, University of Arizona researcher Mike Worobey describes how he and his colleagues uncovered traces of a fossil form of HIV in tissue samples collected in Africa nearly 50 years ago.

Working with scientists in the Democratic Republic of Congo, which was historically a Belgian colony, the team gained access to a collection of old biopsy specimens and tissue samples dating from 1960.  The material had been chemically "fixed" and embedded in paraffin, which had helped to preserve it in reasonable condition.  The researchers dissolved away the wax and were able to extract genetic material from the samples, which they they then probed for signs of HIV.  In one of the extracts, which was from a lymph node biopsy, they struck gold.  The sample contained a virus frozen in time, giving the researchers a window back in time to the structure of HIV as it was in the 1960s, twenty years before the world even knew it existed.

The team then compared the genetics of the virus with those of another fossil sequence, uncovered several years ago in a blood sample collected in 1959.  The two viruses were significantly different from one another, arguing that HIV had potentially been circulating and evolving in the human population for much longer than thought previously.  According to Mike Worobey, "our best estimate for when HIV entered humans is 1908, but it might have been from 1884 to 1924."  Either way, what's unarguable is that these dates are slap bang in the middle of the time when the first European settlers arrived and founded large cities like Leopoldville (now Kinshasha), and the team suspect that the high population density, debaunchery and risky behaviour that tends to go on in cities was probably the catalyst that unleashed HIV on the human population.

5th Oct 2008

Mounting an Immune Attack Against Tumours

Chris - Recently researchers at the Fred Hutchinson Research Centre in Seattle have been using this approach to ‘cure’ – I’m using this word very carefully. They have successfully managed to cure a patient who had malignant melanoma. Cassian Yee is the researcher who’s been leading this work. He joins us now, hello Cassian.

Cassian - Hello, how do you do?

Chris - Very well, thank you. How does this technique to persuade the immune system to attack the tumour really work?

Cassian - We use a process known as adoptive immunotherapy. That involves collecting white blood cells. The cells that you mention can fight infection but can also fight tumour and taken from these white blood cells, a population of cells known as T cells which specifically recognise the patient’s tumour cells. In the lab we can isolate those rare T cells that can recognise and kill the melanoma cells. Melanoma cells express a target antigen. If we can expand enough of these T cells, we actually clone them as single cells, and introduce them back in the patient it’s hoped that they can travel to the melanoma site and recognise and eradicate the tumour cells.

Chris - Why don’t the T cells, if the patient’s already got them to start with and you’re just increasing the numbers, why don’t they go in there and wipe out the tumour for the patient without any help from you?

Cassian - Yeah, so that’s a very good question. For a long time people felt like perhaps these cells do exist in the body. It turns out that using specialised techniques to detect these cells they are present but in very low numbers. I think you mentioned earlier in the programme that the body sometimes suppresses the immune response against normal cells. Part of this suppressant mechanism may prevent these T cells from recognising tumours as well. Using The process of adoptive therapy we’re able to isolate these cells outside the lab and expand them without the constraints that might be present in the body that limit their expansion against the tumour cells. On top of that the tumour cells themselves have evasive mechanisms. They find ways to prevent the immune system from revving up and recognising them by releasing suppressive factors or by co-opting immune suppressor cells to prevent the immune system from recognising and expanding them. I think by removing them from that environment and putting them back in, in expanded numbers, we might be able to override some of these immune escape mechanisms.

Chris - One of the interesting things about treating cancers is that when you start to treat them, because cancers are already genetically deranged, in other words their DNA is all over the place, this means that cancers are not all the same and therefore some cells will be killed by certain therapies. Others will disguise themselves, look a bit different and they escape therapy because they evolve ways of being unresponsive to the drugs and so on. Why doesn’t that happen here? Why don’t you end up with a clone of cancer cells that aren’t recognised by these immune T cells you’re putting back in and therefore they escape and put the cancer back?

Cassian - That’s a very good question and that’s one of the major obstacles for immune therapy or any type of specific therapy. In this case we did originally do the study with one type of T cell – the CD8 T cells and found that had in some of our patients where the tumour cell was able to evade detection by suppressing expression of the antigen that was recognised by the T cell. In this case we used a different type of T cell – CD4. This T cell not only may kill the tumour cells directly by recognising this antigen but it may also recruit other immune cells that can kill in a non-specific fashion. One thing with the CD4 T cell which we’ve expanded in the lab and given back to the patient goes to the tumour site. The CD4 T cell may release other chemokines or cytokines that bring to the tumour site other immune effector cells which may kill the tumour non-specifically regardless of whether they express the antigen levels targeted in the first place or not. By bringing to bear other immune effector cells we may be able to eradicate tumour cells whether they express the antigen or not. One thing we did find in the paper in some of our patients is that when this happened the tumour cell breaks down and because the CD4 T cell is present and causes inflammatory response other antigens are brought to light and the body’s own immune response takes over and starts to direct its own T cells that we didn’t grow in the lab but were already there to expand and grow and kill other targets on the tumour cell.

Chris - What’s the risk, having said what you said, that you might end up with inappropriate attack? In other words if you look at certain diseases like thyroid disease or rheumatoid arthritis and certain types of diabetes that’s where the immune system is inappropriately attacking healthy tissue. If you’re priming the immune system like that and getting this spill-over to other bits of the immune system what’s the danger – or is there a danger that you might get an auto-immune disease and instead of just attacking tumours these cells then start attacking something else you don’t want them to hit?

Cassian - That’s a very good question. In part that might be limited by the local effect with the initial homing or trafficking of the T cells that we gave to the patients end up expanding. That’s a local inflammatory process where we’ve targeted the tumour specifically and it may set off an inflammatory environment that causes an immune reaction to occur. That’s not to say that some of these cells can’t travel to other sites and cause some auto-immunity. In fact we have seen some auto-immunity in patients where some of the target antigens on the cells are also expressed on normal cells. In the case of melanoma some of these targets are pigmented proteins so whatever is responsible for the colouration on your skin. When we start killing the tumour cells some of the T cells may also end up killing normal pigmented skin cells and we see a whitening, a lightening colour on normal skin. That type of autoimmunity is not too toxic. It’s still relatively safe in terms of patient discomfort. When we see this we also recognise that if patients have a high likelihood of responding as well to the immunotherapy. What’s happening in the normal cells is also happening to the tumours. There is some auto-immunity but we think a lot of it is concentrated where the initial inflammatory reaction occurs.

Chris - Finally Cassian, you’ve done this with malignant melanoma. That’s an important problem because the numbers have gone up in this country at least 100% in the last ten years. Every Western country has seen lots of malignant melanoma but we’re also seeing lots of other cancers, particularly things like lung cancer. Will the same approach that you’ve taken also apply to other types of tumours?

Cassian - Yes. We’ve taken melanomas as sort of a model tumour because a lot of the target antigens are known for it. We know that there are T cells are generated that will recognise those target antigens. It turns out there are also antigens that are shared with lung cancer, breast cancer and prostate cancer however a lot of those studies are in very early stages while people work out what the differences are in the conditions and what the timing of immune-therapy is for treating other types of cancer.

October 2008

Beetles use antibiotics to protect their food

Beetles use an antibiotic new to science to protect their fungal food stores from attack by other fungal invaders.  That's according to a new study published this week in the journal Science by a team of researchers led by Jarrod Scott from the University of Wisconsin Madison.

Southern pine beetles are a major pest in the southern United States where they infest pine trees and cause millions of pounds of damage.  The adult beetles dig tunnels under the bark of pine trees, and infest them with a particular strain of fungi, called Entomocorticium, which they carry in a special pouch called a mycanjium.  The beetles then harvest the fungus to feed to their growing larvae.

It was already known that the Entomocorticium fungus the beetles carefully farm can be outcompeted by another fungus called Ophiostoma, which disrupts the development of young beetles because they don't have enough food.  What Scott and his team have discovered is that the beetles play host to two types of bacteria that produce antibiotics which keeps the invading fungus at bay, but which leave the beneficial food fungus alone.

Using a scanning electron microscope they scrutinised the beetles and their homes and it was noticed that the tunnels dug by the beetles in the pine bark were filled with a type of bacteria called actino-bacteria that no-one had noticed before.  The researchers  also found the bacteria inside the mycanjium pouches of the adult beetles, where they carry the food fungi.  They tested the effects of the bacteria and showed that the invading fungus is 20 times more susceptible to it than the food fungus.

This is the first time that beetle has been shown to seek out the help of not just the food fungus but also the bacteria to protect it.  Back in 2006, leaf cutter ants were discovered to do something very similar, using home-made antibiotics to protect the colonies of fungus that grow on leaf clippings inside their nests.  Future research targeting the bacteria and antibiotics used by the Southern Pine Beetles could provide a brand new way of dealing with the pest beetle and others like it.

5th Oct 2008

News from the NCRI Conference

Kat - I’m here at the NCRI conference, that’s the National Cancer Research Institute which is an organisation which brings together all the funders of cancer research here in the UK. That’s people like the government, charities all sorts of organisations that are funding cancer research.  The conference is really a fantastic opportunity to showcase what’s going on in the world of cancer research. We’ve got everyone from people doing the really fundamental lab research. We had a talk this afternoon from Professor Tony Kouzarides from Cambridge University who’s looking right at the sort of molecular post-it notes that are put on our DNA that are important in cancer. Right now we’re sat above the lecture theatre and there’s someone talking about the importance of dying with dignity when people come to the end of their journey with cancer. There’s going to be everything from the very basic research through to the much more quality of life, patient care areas.

Chris - What’s the problem with the UK allegedly not doing so well with the cancer stakes compared with the rest of Europe?

Kat - Exactly. The first lecture today was from Professor Michel Coleman from the London School of Hygiene and Tropical Medicine. He’s one of the world’s leading epidemiologists. That’s someone who studies the statistics and the populations to do with cancer and he was pointing out there have been a lot of studies. These Eurocare studies that have shown that Britain pretty much is one of the sick men in Europe. In terms of football league tables we’re drifting towards the relegation zone. This is happening for a number of reasons. For a start the Eurocare studies are using relatively old data. In fact, here in the UK around the year 2000, 2002 we brought in a cancer plan. We are turning around what we’re doing but it has shown that the UK has been falling behind. It’s not actually what people think. It’s not about access to drugs. It’s actually really to do with early detection. That was one of the most interesting results hat he showed. When you look at five year survival rates across Europe (this is the standard bench mark that people use for how many people survive that long). If you take out from those statistics all the people who die from cancer within a year, that’s people who die from very late/very advanced tumours, if you take those people out of the equation Britain comes back in line with the European average. This tells us that in fact in Britain our major problem is diagnosing cancer early.

Chris - Why is that?

Kat - There’s a number of reasons. It’s obviously a problem with just educating people. We need to get more information out there about what the symptoms of cancer are and that people should not just get the stiff upper lip and think it’ll probably go away if I ignore it. Go to the doctor. There’s also an issue with educating the GPs as well to spot when someone presenting with certain symptoms may have cancer. You’d think well cancer is a relatively common disease but actually GPs may only see six to ten patients a year who actually do have cancer in a list of 2-3000 patients. It’s not really that common for each GP so we need to do more in education for GPs and the public. Also more in things like CT scanning, MRI scanning to try and get cancer detected as early as possible.

Chris - Also in the news this week is a story about how computers can help to read mammograms which might help to bring out the prediction and detection rates.

Kat - Exactly and this ties in to the whole early detection thing. In the Uk we have a fantastic system of breast screening run by the NHS and it does save thousands of lives. It invites all women in their fifties from fifty to seventy to go for a mammogram every three years. Every mammogram is read by two doctors; two radiologists look at it, look for any dodgy spots and decide whether to call the woman back or not. Now what these researchers, led by Professor Fiona Gilbert at the University of Aberdeen, have shown is that you can use one doctor and a computer-aided detection system. How this works is the computer system scans through the mammogram, spots anything that it thinks looks suspicious and then the doctor looks at it and goes, ‘ Yep, that looks dodgy...no, that’s just an area of fluff or whatever.’ Then you only need to have one doctor’s time per mammogram. Basically you’re holding the workload for doctors. This is really important because in some areas of the country we’re seeing screening – the interval of screening is meant to be 3 years – but we’re seeing it drift out to three and a half, four years. There simply aren’t the resources. This could be a really great way to get more women screened and to help ease the pressure on screening services.

Chris - Which would be very good for affecting that diagnosis detection problem.

October 2008

Steam Powered Can Crusher

How to use the power of the atmosphere to crush your drinks cans for you...

What you need

What to Do

What may Happen

The can collapses very soon after it hits the cold water