A New Role for Vitamin D ?

Everyone seems convinced that vitamin C has wonderful preventative and curative powers for viral illnesses like colds and 'flu despite the fact that there is very little evidence to support the belief. Evidence is starting to build though, that vitamin D might be much more significant in the maintenance of health.

There are two main ways to top up your vitamin D supplies. One is to expose you skin to sunlight and the other is to eat animal fats - in particular oily fish.  

It has been long been recognised as the substance that prevents rickets - a deficiency disease in babies and young children in which bones are inadequately calcified. The leg bones bend under the child's weight, the skull can be as thin as a ping-pong ball and the whole skeleton is deformed.

We now know that there are receptors for vitamin D on the surface of cells all over the body, including immune cells and not just in bone cells. Receptors are like mail boxes - you don't have them, unless you are expecting some mail. There is particular research interest in the way this vitamin interacts with tuberculosis (TB).

TB is a bacterial disease that has evolved a unique relationship the immune system. Many people infected with the TB bacterium remain healthy. The immune system often manages to contain pockets of infection as harmless nodules so that the disease is “latent”. As long as the immune system can successfully maintain this state of siege the TB cannot spread and inflict further damage. It is well know that those with an HIV-damaged immune system are susceptible.

Before the advent of antibiotics, TB was very difficult to treat but sunshine therapy was one of the methods that seemed to be helpful in pushing the disease back into latency. There is a complex interplay between immune cells and TB bacteria and there is a strong suspicion that one of the things that helps the immune system to maintain its ability to contain the disease is to have an adequate supply of vitamin D in the body. Research recently published seems to show that giving patients supplements of vitamin D (alongside their antibiotics) significantly speeds recovery.

There are other clinical trials taking place into the links between vitamin D and a range of diseases. This is one of the most interesting lines of current research, in terms of things individuals might be able to do to support the function of their own immune systems.

A variety of TB that is resistant to all available drug treatments is no longer a spectre but a reality. Several cases have been identified in India. Once this starts spreading across the globe, and spread it inevitably will, TB will become an incurable killer as it was in the 19^th and early 20^th centuries. Anything we can discover that will help people resist this disease will be important to individual and public health.

Queen Mary, University of London. "High doses of vitamin D help tuberculosis patients recover more quickly." ScienceDaily, 3 Sep. 2012. Web. 24 Sep. 2012. http://www.sciencedaily.com/releases/2012/09/120903154008.htm

Stem Cell Transplants to Cure AIDS?

I am always concerned when the press run stories of cures. The science may well be interesting but I feel compassion for those who have hopes raised.

There was much publicity recently about the man who was "cured of HIV" by a stem cell transplant. He was unfortunate enough to have leukaemia. And he was HIV positive. In the process of treating his leukaemia in 2007, with a procedure known as a stem cell transplant, it appears that the AIDS virus was cleared from his immune system and he remains healthy. It is possible though that HIV still lurks in his brain, beyond the reach of his immune cells.

So does this news offer hope for those who have to take a daily cocktail of antivirals to keep their HIV infection in check?

The stem cells that make up the red bone marrow produce the full range of "white blood cells" that, in turn, make up the immune system. Leukaemia is a disease of the bone marrow - one type of stem cell turns cancerous and the mix of immune cells is thrown wildly off balance, with fatal consequences. Stem cell transplants have superceded "bone marrow transplants". These days the stem cells can be harvested from the donor's blood using a process similar to a single session of dialysis.

If normal chemotherapy fails to cure a case of leukaemia, the only solution is to use stronger drugs to kill off the bone marrow. Then the patient is given a transplant of healthy stem cells from a donor. This rebuilds the immune system with cells that are genetically matched to the donor.

There are many risks and difficulties. While waiting for the transplant to start working, the patient's immune system dwindles to almost nothing for a few weeks, leaving them highly vulnerable to infection. Any pre-existing infections would run riot - so that probably excludes anyone suffering from AIDS. The other problem is finding a suitable donor. We have all heard of people who need a bone marrow transplant but cannot find a suitably matched donor. The problem is the huge variety of possible tissue types. The tissue types of patient and donor need to be very similar if they transplant is to work. Rejection can bring life-threatening complications. So a stem cell transplant is a risky, expensive, treatment-of-last-resort, that is only used in a minority of cases of leukaemia.

 In this remarkable case the patient was able to receive a transplant from another unusual person - someone who had a natural immunity to HIV. These people are extremely rare. So it was not necessarily the transplant that cleared the virus - it might have been the particular genetic makeup of the donated cells.

 So to use this as a treatment for HIV you would need a reasonably healthy patient who has not succumbed to any AIDS-related infections and a matched donor, with a very special, very rare immune system.  

This was not an experiment. An imaginative doctor identifying an opportunity and tried something new. It could well turn out to be a one-off case, thought provoking for scientists, but for the time being (sadly) a million miles away from being a realistic prospect as a treatment for HIV. A cure for HIV may someday be found, but it will result from painstaking research and not from stem cell transplants as we know them today.

Another Tiny Piece in the Cancer Jigsaw

Most cancers kill by spreading to other organs. Breast cancer, for instance, if it stayed at the original site, would cause a nasty ulcer, but this would not cause death. Surgery could cure every case. The problem comes when it seeds secondaries in places like the lungs or liver, co-opts the blood supply and eventually prevents an essential organ from doing its job. Result - another cancer death. Not surprising then that one branch of cancer research is trying to find out how this process takes place. How do those marauding cells break away and travel to far-flung parts of the body?

Surgery, radiotherapy and chemotherapy are a bit like tackling an overgrown garden - you can slash the weeds down, burn them off or spray them with weedkiller. Trouble is that you might also destroy attractive plants and helpful creatures in the process. These combined methods have saved many lives, including mine, but we all know that they are far from ideal and can cause a fair bit of collateral damage to healthy tissues.

So research these days delves into the most detailed, molecular level. Until you know the exact molecular interactions, you can't devise a treatment that could halt the progress of cancer in a focussed way, with limited side effects.  

A team in Germany has just made progress in this area. They have discovered that some cancer cells use an immune system chemical to break through artery walls and gain access to the body's high-speed transport system - the blood.

There are many of these immune chemicals, known as chemokines or cytokines. Together they form a complex communication system that allows our millions of immune cells to communicate with the other cells in the body. When the immune system sets up an area of inflammation, some of these chemicals act on the walls of blood vessels, opening up gaps and allowing immune cells to move out of the blood and attack bacteria in the surrounding tissues. Normally blood vessels will allow simple molecules to pass through them, but not relatively huge objects like cells. During inflammation however, some of the body's largest cells can travel out of the blood system and into the tissues.

It seems that some cancer cells use this mechanism in reverse, using a specific immune chemical, opening up holes in nearby blood vessels and creating a route into the blood.

Painstaking research like this opens up the possibility of blocking the action of such chemicals and so outwitting more and more cancers.

Wolf et al. Endothelial CCR2 Signaling Induced by Colon Carcinoma Cells Enables Extravasation via the JAK2-Stat5 and p38MAPK Pathway. Cancer Cell, 2012; 22 (1): 

Could flu be stopped in its tracks?

During a 'flu epidemic vaccination helps. It reduces the pool of susceptible individuals and reduces infection rates in groups most likely to need hospital treatment. The big limitation is that it does not work very quickly. It takes the adaptive division of the immune system a week or two to respond to the vaccine and by that time someone could have contracted flu and become seriously ill. So it would be very handy if there were some means of protecting those who have been exposed to the disease - family members, carers, patients in hospital wards and residents in residential settings spring to mind. Not to mention people with weakened immune systems who may be vulnerable to both 'flu and secondary infections.

The other limitation is that flu vaccines are currently strain-specific. When swine flu started to spread in 2009 it took months before an effective vaccine was in full production. Too late to nip the pandemic in the bud. Too late to prevent some quarter of a million deaths, worldwide. These numbers are far higher than original estimates according to a recent analysis published in The Lancet Infectious Diseases last month

Exciting then, that an American research team have identified a protein that, when administered to mice that had just been deliberately infected with 'flu virus, seems to have a significantly protective effect. It works by stimulating the innate division of the immune system into action - something that is slow to happen in normal 'flu infection. Furthermore this protein is already approved for use in humans, as an immune-stimulating adjuvant in vaccines. This means that translating the research into human trials will be easier than if it was an untried substance. One of the benefits might be that it is generic, rather than strain-specific, which could be a real life saver next time a new pandemic strain emerges.

This would be an unusual treatment - something that truly "boosts" part of the immune system - as opposed to a wide range of ineffective vitamins, potions and herbs.

Sam D. Sanderson, Marilyn L. Thoman, Kornelia Kis, Elizabeth L. Virts, Edgar B. Herrera, Stephanie Widmann, Homero Sepulveda, Joy A. Phillips. Innate Immune Induction and Influenza Protection Elicited by a Response-Selective Agonist of Human C5a. PLoS ONE, 2012; 7 (7): 

Yeast is Yeast

For anyone struggling to imagine the liveliness and power of their gut bacteria, I suggest a small experiment.

Take a large glass, half fill with warm water and sprinkle in a couple of teaspoons of dried yeast. Maybe it's been packaged for years, forgotten in the back of your fridge, but this will still work. Add a teaspoonful of sugar and retire to a warm place to stir and then to observe. It will take you a minute or so to ensure that this desiccated product is fully dissolved in water. As you stir, vast numbers of microscopic yeast cells are resurrecting themselves from suspended animation and springing into life. Now be still and watch. A faint froth is forming, then it becomes a foam and within ten minutes a thick creamy "head" made of bubbles has appeared. Peer into the murky khaki-coloured liquid and you will see the tiny bubbles streaming upwards as the yeast cells break down sucrose, garner energy and release carbon dioxide. Before your eyes is evidence that microscopic life, given a bit of the right kind of food, will burst into life, carry out complex biochemical processes, replicate itself and in the process produce quantities of gas. From a standing, chilly, dehydrated start.

Stand back and admire these simple life forms in action. Small these cells may be, but when they swing into action they are surely impressive. Fortunately our bowels are not full of bakers yeast, but the organisms that do dwell there live similar lives - hunkered down at times and then burgeoning when the right kind of food molecules come their way.

As I used these miraculous microorganisms to make my pizza dough rise I felt slightly apologetic towards them. All that enthusiasm, only to end up in my hot oven. But still, they acted as inspiration for this short blog. And the pizza looks good.

Immunology and Cancer

Ten years ago the author of a keynote speech on the science of immunology remarked: "The paradox of today's immunology is that tremendous progress in basic science has been matched by only a few clinical applications." At the time, he noted, a journal paper in immunology was being published every 15 minutes but little of this knowledge was translated into useful treatments for patients.

The task of trying to understand what is happening in the immune system reminds me of the Walrus and the Carpenter who wondered whether the shore could be cleared of sand: "if seven maids with seven mops swept for half a year". You could envisage those poor maids, sweeping diligently, only to discover layer beneath layer of sand. So it has been in the biological sciences with layer after layer of complexity being revealed, the deeper the scientists dig. Ten years ago only ten of the immune-based drugs known as monoclonal antibodies were in use. The list has grown rapidly since then and many of them being used to treat various forms of cancer. It has taken an astounding amount of pure research to enable these immune-based treatments to prolong lives. Herceptin is the best known example.

In the world of cancer drug development there are a two main strategies. The traditional one is to try out various chemical compounds until you find one that kills cancer cells without killing, or permanently damaging the patient. The more recent and much more sophisticated method is to pinpoint a particular cancer gene or molecular pathway, and then devise a molecule that will block the gene or disrupt the pathway. Unlike the generic weedkiller approach of chemotherapy the new drugs are very specific. They may have dangerous side effects but they are unlikely to be the ones that traditionally accompany chemotherapy: hair falling out and immune system being seriously impaired.

Some of the underpinning research is done by immunologists who are slowly starting to understand the puzzling interactions between cancers and the immune system. We have known for a long time that some immune cells can destroy cancer cells and in recent years there is increasing understanding about why they might fail to do so and how, sometimes, immune cells are deceived into promoting the spread of cancer. But the processes have to be unpicked, one molecule at a time if they are to be used by medicine.

Research published in this month's New England Journal of Medicine reveals some encouraging results for another antibody-based drug. The interesting thing about this one is that it operates directly on one of the molecular interactions between the immune system and cancer. It does not, as Science Daily implies in its headline "boost" the immune system. Instead it prevents the cancer from using one of the possible ways of defending itself against an immune attack.

The new drug was tested on 296 patients who were suffering from some of the more lethal kinds of cancer - melanoma, lung cancer and so on, who had already had other forms of treatment. The results showed that "approximately one in four to one in five patients" responded in an encouraging way. These results are exciting, given the nature of their diseases. Immunology did indeed make slow beginnings in terms of practical applications, but at last it is starting to produce benefits for patients.

  

Antonio Coutinho Immunology at the crossroads EMBO Rep. 2002 November; 3(11): 1008–1011.

Suzanne L. Topalian et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. New England Journal of Medicine, 2012 DOI

http://en.wikipedia.org/wiki/List_of_monoclonal_antibodies

http://www.sciencedaily.com/releases/2012/06/120602134835.htm

FAECAL TRANSPLANTS – WEIRD OR WONDERFUL?

One of the more bizarre new medical treatments currently under investigation is a transplant of gut bacteria. This sounds, on the face of it, pretty weird. Even weirder when you talk of faecal transplants. Faeces are smelly things we want to get rid of, aren’t they? Why would anyone want a transplant of someone else’s?

There are some scientists who believe that gut bacteria (that live, mainly, in the colon) are so important that they should be viewed as an additional body organ. Others might argue that it is possible to live your life without a colon (after cancer surgery for instance) so that neither the contents nor the colon are essential.

Some people find themselves wretchedly ill if their normal gut bacteria are killed off. Imagine, if you will, a dense tropical forest with many species of plant, all flourishing away in leafy harmony. Then someone sprays the forest with strong herbicides, killing off every leaf and shoot. This allows an aggressive weed to invade and flourish. This is the effect that can occur in the colon after treatment with broad-spectrum antibiotics. The original infection elsewhere in the body may be cured, but the patient cannot return to health because they are suffering the miseries of diarrhoea. At its most serious, this diarrhoea is caused by Clostridium difficile, which can cause death in weak patients.

Probiotics may be protective but they are not a cure. If the normal gut bacteria have all been killed, yoghurt bacteria are no replacement.  What the colon needs is a blend of dozens of harmless species of gut flora.

The idea of a gut bacteria transplant is a fairly new one. The process is to take a faecal sample from another person, mix it with water to produce an enema, and administer it to the patient. Relatives may be used as donors, because they are most likely to share the bacterial blend that the patient's immune system normally lives with.

In early studies with small groups of patients the results are encouraging.

In a systematic review of small trials, involving 124 patients, (83%) improved immediately after the first FT procedure, and some patients stayed diarrhoea free for several months or years. There is still a need to conduct controlled trials to compare faecal transplant with the standard treatment.

Although the idea may seem a little weird, it would indeed be wonderful if this kind of treatment did prove effective in curing this distressing and dangerous condition.

Aliment Pharmacol Ther. 2012 Apr;35(8):865-75.

Guo et al