## 30 July, 2009

### Swine Flu Vaccine - Priorities Wrong?

In the current edition of Nature (30 July 2009) there is a short correspondence from Italian immunologists on the subject of a swine flu vaccine.

I think it conveys an important message.

In the piece entitled "Flu: vaccinate to cut risk of chimaeric virus emerging", Ilaria Capua & Giovanni Cattoli from the Istituto Zooprofilattico Sperimentale delle Venezie in Italy, make the suggestion that any decisions on priority distribution of swine flu vaccine should take into account areas at higher risk of the emergence of a reassortment virus. This is a virus containing an assortment of genes from various different viruses and can occur in geographic locations where different human and animal viruses are simultaneously present

There is a risk of generating novel influenza A viruses through reassortment of the eight genes that result in antigenic shift, which would give rise to strains to which the human population has no immunity. For example, reassortment occurred between avian and human influenza viruses to create the human pandemic viruses of 1957 and 1968

Developing countries are breeding grounds for these types of reassortment viruses due to inadequate security and safety measures. Based on this, the authors indicate that along with the vaccination of risk patients and healthcare workers, emphasis should be placed on vaccinating populations in developing countries.

Fast-tracking vaccination of humans against pandemic influenza in developing countries where zoonotic flu in poultry is endemic would help prevent reassortment between naoH1N1 or other novel pandemic influenza strains and avian influenza viruses. That would deflect the unpredictable and serious consequences of viral reassortment to humankind worldwide.

So it is vital that we think on a bigger scale here. Undoubtedly each government has prioritised the vaccination of it's own citizens (here in Ireland they are apparently buying two doses per person), however the global community needs to think outside the box and firstly prevent the emergence of reassortment viruses. This constitutes a far greater risk to the human race and must be addressed immediately.

### Show Some Support for Simon Singh!!

From Pharyngula.

(Note: this is the infamous article on chiropractic that got Simon Singh sued. It is being reposted all over the web today by multiple blogs and online magazines.)

Some practitioners claim it is a cure-all, but the research suggests chiropractic therapy has mixed results - and can even be lethal, says Simon Singh.

You might be surprised to know that the founder of chiropractic therapy, Daniel David Palmer, wrote that "99% of all diseases are caused by displaced vertebrae". In the 1860s, Palmer began to develop his theory that the spine was involved in almost every illness because the spinal cord connects the brain to the rest of the body. Therefore any misalignment could cause a problem in distant parts of the body.

In fact, Palmer's first chiropractic intervention supposedly cured a man who had been profoundly deaf for 17 years. His second treatment was equally strange, because he claimed that he treated a patient with heart trouble by correcting a displaced vertebra.

You might think that modern chiropractors restrict themselves to treating back problems, but in fact some still possess quite wacky ideas. The fundamentalists argue that they can cure anything, including helping treat children with colic, sleeping and feeding problems, frequent ear infections, asthma and prolonged crying - even though there is not a jot of evidence.

I can confidently label these assertions as utter nonsense because I have co-authored a book about alternative medicine with the world's first professor of complementary medicine, Edzard Ernst. He learned chiropractic techniques himself and used them as a doctor. This is when he began to see the need for some critical evaluation. Among other projects, he examined the evidence from 70 trials exploring the benefits of chiropractic therapy in conditions unrelated to the back. He found no evidence to suggest that chiropractors could treat any such conditions.

But what about chiropractic in the context of treating back problems? Manipulating the spine can cure some problems, but results are mixed. To be fair, conventional approaches, such as physiotherapy, also struggle to treat back problems with any consistency. Nevertheless, conventional therapy is still preferable because of the serious dangers associated with chiropractic.

In 2001, a systematic review of five studies revealed that roughly half of all chiropractic patients experience temporary adverse effects, such as pain, numbness, stiffness, dizziness and headaches. These are relatively minor effects, but the frequency is very high, and this has to be weighed against the limited benefit offered by chiropractors.

More worryingly, the hallmark technique of the chiropractor, known as high-velocity, low-amplitude thrust, carries much more significant risks. This involves pushing joints beyond their natural range of motion by applying a short, sharp force. Although this is a safe procedure for most patients, others can suffer dislocations and fractures.

Worse still, manipulation of the neck can damage the vertebral arteries, which supply blood to the brain. So-called vertebral dissection can ultimately cut off the blood supply, which in turn can lead to a stroke and even death. Because there is usually a delay between the vertebral dissection and the blockage of blood to the brain, the link between chiropractic and strokes went unnoticed for many years. Recently, however, it has been possible to identify cases where spinal manipulation has certainly been the cause of vertebral dissection.

Laurie Mathiason was a 20-year-old Canadian waitress who visited a chiropractor 21 times between 1997 and 1998 to relieve her low-back pain. On her penultimate visit she complained of stiffness in her neck. That evening she began dropping plates at the restaurant, so she returned to the chiropractor. As the chiropractor manipulated her neck, Mathiason began to cry, her eyes started to roll, she foamed at the mouth and her body began to convulse. She was rushed to hospital, slipped into a coma and died three days later. At the inquest, the coroner declared: "Laurie died of a ruptured vertebral artery, which occurred in association with a chiropractic manipulation of the neck."

This case is not unique. In Canada alone there have been several other women who have died after receiving chiropractic therapy, and Edzard Ernst has identified about 700 cases of serious complications among the medical literature. This should be a major concern for health officials, particularly as under-reporting will mean that the actual number of cases is much higher.

If spinal manipulation were a drug with such serious adverse effects and so little demonstrable benefit, then it would almost certainly have been taken off the market.

Simon Singh is a science writer in London and the co-author, with Edzard Ernst, of Trick or Treatment? Alternative Medicine on Trial. This is an edited version of an article published in The Guardian for which Singh is being personally sued for libel by the British Chiropractic Association.

## 27 July, 2009

### Thunderf00t vs Comfort

Here is the long awaited debate/discussion between YouTube heavyweight Thunderf00t (red t-shirt) and creationist Ray Comfort (blue shirt).

Round 1: Thunderf00t definitely had the better of the first part, mainly because he's doing all the talking. Thunderf00t 1-0 Ray

Round 2: Here I think Ray does a bit better. Not because he makes any good points, but because Thunderf00t gets bogged down on the painter-painting analogy without really making his point succinctly. This makes him look slightly unsure of what he's saying, although I doubt that's the case. When the conversation turns to morality, Thunder00t seems more assured in what he's saying. Still very little from Ray. Thunderf00t 2-0 Ray

Round 3: OK Ray starts to talk a bit more here. Unfortunately, Thunderf00t shows his inexperience of this form of debate and misses a lot of opportunities to pin him down. When the discussion goes back to morality Ray does the typical creationist thing and uses the extreme example of a child being raped. Thunderf00t's response is not the angle I would have taken. I think Ray gains in confidence here. Thunderf00t 2-1 Ray

Round 4: A long winded but good point made by Thunderf00t here about anthropomorhpism and Todd, although I'm not sure that Ray appreciates what is being said. That is actually a running theme now, Thunderf00t is very slow and methodical in his approach whilst Ray mainly uses one liners backed up with bible quotes. Due to this, I can already see this discussion going nowhere. Thunderf00t 3-1 Ray

Round 5: I think Ray scored a few points here with his morality questions, again going for extreme case like rape and paedophilia. However, Thunderf00t finished strong by turning the same line of questioning back on Ray. Ray's refusal to answer the question is an obvious act of denial. He knows he is sticking his head in the sand. Still, a point each here. Thunderf00t 4-2 Ray

Round 6: The discussion goes onto abortion here which is slightly off topic, but Ray does admit that he doesn't know if a cell is 'life', which casts doubt on his anti-abortion stance. Thunderf00t brings it back to God vs Todd and forces Ray to concede that the only difference is that God is described in the bible. Thunderf00t is about to jump all over this when the camerman suggests a break. Typical. Thunderf00t 5-2 Ray

Round 7: Ray is struggling with evolution here and Thunderf00t should of hammered home this point - that Ray publicly denounces something he clearly doesn't understand. He can't even grasp the difference between genetic incompatability and infertility. Sheesh! Thunderf00t 6-2 Ray

Round 8: More on morality here but little headway made here by either participant. A bit of bible talk too. No score. Thunderf00t 6-2 Ray

Round 9 and 9a: Ray is in his element when discussing the bible so he easily brushes Thunderf00t aside here. Thunderf00t should stick to science until he has read the bible thoroughly. Thunderf00t 6-3 Ray

So I declare Thunderf00t the 'winner' by a score of 6 to 3. To take my boxing analogy futher I would say he won on points as he never delivered the knockout blow. He had Ray on the ropes a few times but backed off instead of going for the kill.

The most successful approach, in my opinion, was the God vs Todd discussion. Ray was forced to admit that the only difference between the two was that God is described in a book. Thunderf00t should have jumped on this but sadly he didn't, mainly down to the intervention of the camerman. He should have continued by saying that he could theoretically write a book about Todd through Todd's revelation, thus demolishing Ray's argument.

Also, Thunderf00t didn't capitalise on Ray's blatant misunderstanding of speciation and evolution. I would have liked to see him call out Ray on his errors instead of just correcting him politely.

All in all, it was a good effort, and interesting, but Ray's followers won't be convinced by Thunderf00t's approach, as he was very slow and methodical. I doubt whether anyone has changed their opinion based on this.

Thunderf00t's reflections:

## 23 July, 2009

### The Impact of Immunology on Human Welfare

As part of our daily lives we are constantly exposed to an extensive array of pathogens, such as bacteria, viruses and parasites. These microscopic invaders tirelessly attempt to gain entry into the cells, tissues and organs of our bodies – and yet despite this relentless barrage of germs, symptomatic disease is relatively uncommon. Key to this defence is the immune system. Over the years the combined efforts of immunologists, in understanding how the immune system functions, have impacted significantly on human welfare.

Vaccination, for example, is commonplace today; we can safely immunise both children and adults against a variety of viruses. For this, we owe a debt of gratitude to early immunologists, such as Edward Jenner and Louis Pasteur, who pioneered the development of vaccines, consequently leading to the eradication of smallpox. Whilst the number of lives that have been saved through vaccination is surely beyond comprehension, the annual influenza vaccine alone is estimated to be 70-90% effective at preventing hospitalisations from influenza complications according to the US Centers for Disease Control and Prevention.

Increased understanding of the causes of organ rejection was another significant impact of immunological research on human life, as it paved the way for successful transplantation medicine thus prolonging the lives of countless otherwise condemned patients. Specifically, the realisation that cell, tissue or organ rejection is due to a host versus graft immune response proved critical.

On a broader scale, the generation of monoclonal antibodies (MAbs), usually produced by immune cells to detect pathogens, has assisted researchers to study protein function, impacting on a diverse range of biological sciences. MAb techniques are still widely used today and their contribution to biological research, not to mention their extensive use in medical intervention, cannot be underestimated.

However, despite the continuing success stories, one area of research in need of a significant breakthrough is autoimmunity. This topic covers a number of disorders in which the body fails to discriminate ‘self’ from ‘non-self’ and consequently attacks host cells in the absence of pathogenic signals. Whilst a lot of progress has been made in several autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus, the underlying mechanisms causing these diseases are still unknown. As such, treatment invariably involves symptomatic relief rather than preventing disease pathogenesis.

One of the major problems in preventing autoimmunity is the inevitable unwanted side effects of potential treatments. Current strategies involve dampening the immune response in affected individuals, which treats the symptoms of autoimmunity but also leaves the patient severely immunocompromised and at risk of infection. This conundrum leads to a patient also being prescribed antibiotics and antivirals, along with their side-effects, to counteract the diminished immunity. Researchers are currently trying to bypass this problem by specifically targeting immune cells involved in autoimmune disorders, namely activated Th1 and Th17 cells, whilst sparing other uninvolved immune cells, allowing patients to maintain an adequate defence against infection. Further work is required, but it seems there may be light at the end of the autoimmune tunnel.

## 22 July, 2009

### Highlights from Nature (Jul 16th 09)

-The Schistosoma japonicum genome reveals features of host–parasite interplay

-The genome of the blood fluke Schistosoma mansoni

-The active form of DNA polymerase V is UmuD′2C–RecA–ATP

-Contamination of the asteroid belt by primordial trans-Neptunian objects

-Manipulation of photons at the surface of three-dimension
al photonic crystals

-Photoconductance and inverse photoconductance in films of functionalized metal nanoparticles

-Evidence for middle Eocene Arctic sea ice from diatoms a
nd ice-rafted debris

-Migration of the subtropical front as a modulator of glacial climate

-Global patterns of speciation and diversity

-Evolution of a malaria resistance gene in wild primates

-Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

-A conserved ubiquitination pathway determines longevity in response to diet restriction

-A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning

-The AP-1 transcription factor Batf controls TH17 differentiation

-Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus

I've briefly commented on the highlighted studies below the fold

--------------------------------------------------------------------

The study on Global patterns of speciation and diversity by de Aguiar
et al employs a computational model to measure speciation.

We simulated the evolution of a population whose members, at the beginning, are uniformly distributed in space and have identical genomes. The population evolves under the combined influences of sexual reproduction, mutations and dispersal. During reproduction, potential mates are identified from among those in a spatial region around an individual (specified by a spatial mating distance, S) whose genomes are sufficiently similar to that of the individual (specified by a genetic mating distance, G). This is a minimal form of sexual selection, essential (necessary but not sufficient) for speciation, called assortative mating (postzygotic genetic incompatibilities may have a role but are not essential). A mate is chosen from this set at random. Reproduction with crossover and mutation occurs. An offspring is then dispersed within a region around the originating and expiring parent. Genetic variation grows over time, due to mutation and recombination. We identify a species as a group of organisms reproductively separated from all others by the genetic restriction on mating and connected among themselves by the same condition...

Here is a figure showing the speciation of a 2000-strong homogeneous population into several distinct 'species' (colours) without any geographical boundaries:

What is interesting about this result is that it correlates well with what is known to occur in nature, as explained here:

Examples of such patterns are the constant rate of speciation observed in the fossil record; the higher diversity of freshwater ray-finned fishes than of their marine counterparts; the species–area relationships of birds, flowering plants and tropical-forest trees; and the relative species abundance of birds and forest trees.

This is clearly just one step in the marathon that is understanding biodiversity, but it's informative, nicely presented and has lots of pretty colours!

---------------------------------------------------------------

Next, the study by Schraml et al entitled The AP-1 transcription factor Batf controls TH17 differentiation investigates the role of Batf in TH17 cell maturation and hence how this transcription factor contributes to autoimmunity, my specific area of interest.

I've desribed the role of TH17 cells in autoimmunity in an earlier post. They are a subset of T helper cells, the others being TH1 and TH2 cells, which direct the immune response following pathogenic assault. However, overactivation or a lack of appropriate suppression of this response can result in autoimmunity as these cells will drive the response towards host cells in the absence of pathogens.

In this paper, the authors have generated Batf-/- mice in order to study the effects of Batf on their experimental model, namely experimental autoimmune encephalomyelitis (EAE), an autoimmune disease in mice. They found that Batf-/- mice produced less IL-17 than wildtype mice (figure below, b), suggesting that Batf is involved in TH17 cell development. The same mice showed normal IL2, IFN- and IL10 levels, indicative of normal TH1 cell function.

Interestingly, the Batf-/- mice were resistent to EAE, as shown in the figure below (a, open triangles). This result adds further evidence to the role of TH17 cells in autoimmunity, and points to Batf as a critical transcription factor regulating its pathogenesis. To further prove this point, the authors gave the Batf-/- mice functional naive T cells (CD4+) from wildtype mice and this resulted in the mice becoming susceptible once again to EAE (c, open triangles).

This adds to the TH17 story which is becoming a very hot area in immunology. If we can understand what is driving the differentiation of these cells, we will theoretically be able to suppress this to combat autoimmunity.

## 09 July, 2009

### Father Ted Was Fiction, Right...?

Most days I'm proud to be Irish.

Some days I'm not...

It has been 14 years since her last major apparition in Ireland, but the Virgin Mary is back and this time in the lowly form of a tree stump in Limerick...

This time more than 2,000 people have signed a petition to prevent the stump’s removal, while hundreds of worshippers have been gathering to recite decades of the rosary and to light candles. Nightly prayer vigils are being held.

At least there's one sensible person down in Limerick though:

Asked what he saw in the stump Mr Reddin replied: ”I see it as the grain of a tree myself.”

## 06 July, 2009

### Fermat's Last Theorem

I'm no mathematician. However there is something that has always intrigued me about the purity of mathematical proof. That is why I tend to read a lot of popular science books on maths. An excellent example is Simon Singh's book detailing the events behind the proof to Fermat's Last Theorem.

We all know Pythagorus' Theorem, it was drilled into us at school:

$a^2 + b^2 = c^2\!\,$

This equation is true when c is the hypoteneuse of a triangle and a and b are the other two sides. It's a straightforward enough mathematical concept and has been proved many times in completely different ways. Indeed, as a child, I was taught a number of the more easily understandable methods.

Now...replace the number 2 in the above equation with n>2 (that is any number greater than 2) and replace the equals sign with a 'does not equal' sign. This is known as Fermat's Last Theorem and can be summarised as:

If an integer n is greater than 2, then the equation an + bn = cn has no solutions in non-zero integers a, b, and c.

In principle, this makes the equation no more difficult to understand. Essentially, you can split a square number into a sum of two lower square numbers, but you can't do the same for cube number or higher powers. Easy enough.

Should be simple enough to prove right?

Wrong.

A man called Pierre de Fermat claimed to have a proof in 1637, although bizarrely he didn't record it as he didn't have enough space in the margin of his copy of Arithmetica:

To resolve a cube into the sum of two cubes, a fourth power into two fourth powers, or in general any power higher than the second into two of the same kind, is impossible; of which fact I have found a remarkable proof. The margin is too small to contain it.

There is no doubt that Fermat was a brilliant mathematician in his own right and provided many proofs which were later verified. Thus, the proof he provided that became known as Fermat's Last Theorem was so called as it was the last of Fermat's asserted theorems to remain unproven. This gave it an air of romanticism which attracted many people, all hoping to be the one to finally crack it, but the proof proved elusive.

In the following centuries many people attempted to prove the theorem (technically it was a conjecture, not a theorem) but were unable to do so. Instead they succeeded in proving that there were no solutions for specific integers; Euler provided proof for n=3, Fermat himself for n=4, and so on.

A big step towards a proof came in the 1980s with the realisation that a seemingly unrelated mathematical conjecture, called the Taniyama–Shimura–Weil conjecture, when applied to certain elliptic curves actually implies Fermat's Last Theorem. This is where Andrew Wiles comes in. He had been fascinated by the theorem since childhood and had secretly been attempting his own proof for some time. When he heard about the link with the Taniyama–Shimura–Weil conjecture, he gave up his other commitments and worked on this association for several years in the attic of his house.

I don't want to give away any more of the story as the details can be read in the Simon Singh book Fermat's Last Theorem, also titled as Fermat's Enigma (I recommend it highly), but to summarise, in 1993 Wiles eventually succeeded in proving the theorem, thus fulfilling a life-long dream, although the story didn't end there as there were a few twists and turns after that.

However, the intriguing thing is that in order to prove the theorem, Wiles had to develop several novel mathematical techniques that would be considered as '20th century mathematics' and were thus unavailable to Fermat back in 1637. So the question still remains as to whether Fermat did actually have a proof. It's seems impossible, due to the sophisticated new techniques needed, but it cannot be categorically denied, fueling the intrigue.

Wiki:
Fermat's alleged "marvellous proof"...would have had to be fairly elementary, given the state of the mathematical knowledge at the time, and so could not have been the same as Wiles's. And in fact, most mathematicians and science historians doubt that Fermat had a valid proof of his theorem for all exponents n, as it seems unlikely there is an elementary proof.

## 01 July, 2009

### Public Acceptance of Evolution

A poll on public knowledge and acceptance of evolution across several countries can be found on the Guardian website.

The British Council has asked, with the help of Ipsos MORI, over ten thousand adults across ten countries from China to the USA, just what they think of evolution.

The results show that the majority of adults surveyed have heard of Charles Darwin and know at least a little about his theory of evolution. But they also show that there are significant minorities of people who either want nothing to do with evolution - and think it should either not be taught in schools or alongside creationism.

Here are the results:

## BELIEFS IN EVOLUTION

All figures in %.

Countries
Heard of Darwin
Agree the scientific evidence for evolution exists
Think evolution should NOT be taught, only other theories
Argentina 86 44 6
China 90 55 19
Egypt 38 8 8
Great Britain 91 51 6
India 62 38 13
Mexico 91 52 9
Russia 93 39 13
South Africa 27 8 12
Spain 72 39 7
USA 84 33 9

Nothing new here really. There are a few interesting results though. The Chinese population has the highest acceptance of evidence for the theory of evolution (55%) and one of the highest scores for public knowledge of Darwin (90%), yet 19% of Chinese people think evolution should not be taught, as opposed to say Egypt or South Africa where only 8% and 12% are against teaching evolution respectively, even though 92% of Eygptians and South Africans do not agree that the evidence supports it.

Assuming there are no mistakes in how the data was presented, that seems a bit strange. What's going on in China...?