April 2014 – The Brain Bank North West

The Promise of Poop: Faecal transplants to treat C. difficile infection – An age old therapy moving into the light?

April 28, 2014April 28, 2014 by The Brain Bank North West

Clostridium difficile – a hospital superbug?

Clostridium difficile is a bacterium that is commonly found in the environment around us – in soil, air and water. C. difficile is also present in the gut of up to 3% of healthy adults and 66% of infants, but rarely causes any problems in healthy people. This is because it is usually kept in line by the normal bacterial population in the intestine. However, when people undergo antibiotic treatment, this can disrupt the balance of bacteria in the gut, allowing C. difficile to rapidly multiply and cause illness. C. difficile infection (CDI) can result in very mild diarrhoea, but can also result in some particularly nasty, life threatening symptoms, that in the extreme can lead to someone having their colon surgically removed.

CDI is the leading cause of infectious diarrhoea in healthcare institutions worldwide, and the problem doesn’t seem to be going away anytime soon. In fact, over the last decade CDI has become more frequent, more difficult to get rid of fully and more often actually causes death. This is thought to be due to the emergence of more aggressive C. difficile strains.

CDI is commonly treated with antibiotic therapy, but this is by no means the perfect treatment option as it is becoming increasingly associated with treatment failure and return of infection. In addition, CDI weighs a heavy financial burden on healthcare systems across the world, each case costing approximately £4000. This particular conundrum has led to a race in the development of alternative treatment therapies for the disease and has recently reignited the interest in an age old therapy: the faecal transplant.

What is a faecal transplant?

The faecal transplant has been knocking around for centuries, with its first use to treat diarrhoea being described all the way back in 4th century China. Possibly one of the reasons it hasn’t proved so popular is due to the fact that it sounds so disgusting. The faecal transplant involves the transfer of poop from a healthy individual to the gut of a patient to cure their disease. Obviously, there is only one of two routes to administer this lovely load; via a nose tube directly into the stomach (apparently rather unpleasant when the patient burps) or through colonoscopy. I think we can all agree that neither of these options seems at all appealing, but treating patients with CDI with faecal transplants does seem to work.

Indeed, clinical trials suggest that the faecal transplants are both well tolerated and very effective. In the most recent study carried out in the Netherlands, published in the New England Journal of Medicine earlier this year, it was found that that faecal transplants cured 15 out of 16 patients with recurring CDI – a 96% success rate compared to less than 30% for standard antibiotic therapy.

So, what is the science behind a faecal transplant and why does it work?

It is estimated that over 4000 bacterial species reside in the gastrointestinal tract, and amazingly, we are inherently outnumbered by the number of bacteria that live in our body. The human microbiota contains as many as 100 trillion bacteria, which is ten times greater than the number of human cells in our body. Not to worry though folks, these bacteria are friends, not foes.

In fact, it has become very apparent in recent years that friendly bacteria residing in the gut do their bit to keep us healthy. A number of diseases, including cancer, inflammatory bowel disease and arthritis, are linked with changes in the make-up of the types of gut bacteria. With respect to C. difficile infection, the disease most commonly arises in patients who have undergone antibiotic therapy, which results in the disruption of their normal intestinal microbiota. Antibiotics can wipe out the good bacteria in the gut that usually provide a protective defence against C. difficile, allowing it to flourish and cause infection.

With this in mind, a faecal transplant doesn’t seem so daft. Transferring poop from a healthy donor to the gut of a patient with CDI is thought to restore the good bacteria for them to help fight C. difficile, preventing any further disease.

Can we get past the yuck factor?

We know that the results from clinical trials suggest that the faecal transplant not only works, but is well tolerated: the two gold stars with respect to disease therapy. But the fact remains that the faecal transplant is also, quite frankly, gross. People often don’t like the thought of taking others seconds or leftovers – is this treatment taking it one step too far?

Testimonials from patients treated with the faecal transplant suggest quite the opposite; these patients have won their battle with CDI and changed their life thanks to the unusual therapy. They are all more than happy to recommend it to others.

Yes, we know that the faecal transplant is not pretty, but neither is the possibility of major surgery leaving us with a stoma bag because all other treatment has failed.

Which option would you choose?

This post, by author Hannah Simpson, was kindly donated by the Scouse Science Alliance and the original text can be found here.

The science behind Game of Thrones:

April 21, 2014 by The Brain Bank North West

Spoiler alert: This article refers to events up to Season 4 Episode 2 of Game of Thrones. Please do not continue reading unless you have watched up to this point! Please do not include book spoilers in the comments section.

After taking time to pick my jaw up off the floor in the wake of GOT’s Purple Wedding, this week I’ve decided to indulge my inner geek and take a look at some of the amazing real-world science which courses through the fictional land of Westeros. So sit back, relax and wonder at resurrecting reptiles, ancient beasts, amazing brain imaging and the real-world poisons that finally wiped the smirk of King Joffrey’s face.

Dragons in stasis:

Who can forget the iconic moment when Daenerys (Dany) Targaryen (mother of dragons) emerged from the flames, unscathed and cradling a small brood of adorable baby dragons. Although I can’t vouch for the scientific realism behind Dany’s apparently flame retardant skin; it seems that George R. R. Martin may have borrowed the idea of embryonic resurrection from real-life reptiles.

A number of reptiles, including turtles and chameleons, show an adaptation known as arrested embryonic development. This adaptation means that developing reptiles can remain arrested (paused) at an early stage of development, safely locked away inside their protective egg shell until environmental conditions are favourable for them to break free and explore the world. Apparently, in the case of dragons, this tends to be during periods of prolonged and intense heat. Interestingly, this form of arrested development is more common in species that lay thicker-shelled more rigid eggs – like dragons perhaps?

However, this theory falls short if you consider the apparent age of Dany’s dragon eggs – these being around 150 years old. Real life reptile eggs expressing arrested development, also known as diapause, tend to only remain dormant for a maximum period of a year – any longer and the embryo is likely to die. This is a fair way off the 150 year mark, however, if we throw invertebrates into the mix, we find reports of life emerging from eggs which have laid dormant on a museum shelf for over 120 years (specifically Tardigrade or waterbear eggs)! So, scientifically speaking, it seems Dany’s dragons are a hybrid between modern day reptiles and invertebrates with the ability to remain dormant for many years; a terrifying mesh of science fiction and science fact which will hopefully soon burn a path directly to the Iron Throne for our bad-ass dragon queen!

Dire wolves:

With wild burning eyes and powerful bone-breaking jaws the dire wolf, sigil of the ill-fated house Stark, is not only a formidable creature, but also one which does not stem purely from science-fiction. Indeed, dire wolves, also known as Canis dirus (meaning fearsome dog) are known to have roamed the Earth along with other megafauna such as giant sloths, woolly mammoths and giant beavers over 10,000 years ago.

The average dire wolf would have been roughly the same size as a grey wolf; averaging about 1.5m (4.9ft) in length, but with a significantly heavier build, weighing between 50kg (110lb) and 79kg (174lb) – making them the largest species in the genus Canis. Their teeth were also relatively large leading palaeontologists to suggest that these were used to crush bone. The animals were once common throughout North and South America; indeed, dozens of dire wolf fossils have been recovered from the La Brea Tar Pits in Los Angeles.

Was Khal Drogo really brain dead?:

Whether Dany’s feelings for Khal Drogo stemmed from true love or Stockholm syndrome, I couldn’t help but feel sad when this unexpected love story drew to an abrupt and tragic end. The enigmatic powers of blood magic appeared to leave poor Drogo in a vegetative state, but what was really going on behind his inscrutable gaze?

Modern imaging science is now revolutionising our understanding of vegetative states and is providing a window into the minds of otherwise unresponsive patients. A vegetative state is defined as when a patient is awake, but shows no signs of conscious awareness. Due to the unresponsive nature of most vegetative patients, you may be forgiven in assuming that they are actually brain dead and incapable of responding. However, recent ground-breaking work using fMRI has revealed that, in some cases, vegetative patents have an intact conscious mind and, by controlling their brain activity, can clearly provide yes or no answers to simple questions. This can be seen in the astounding video footage below where a Canadian man (Scott Routley) who, for over a decade, was believed to be in an unresponsive ‘vegetative’ state is able to ‘talk’ to scientists through an fMRI and to indicate that he is not in any pain.

[youtube http://www.youtube.com/watch?v=xFDVk6o7Gxs]

Perhaps if Vaes Dothrak had state of the art fMRI equipment this little love story may have had a happier ending?

What killed Joffrey?:

OK, so I think we can all agree that no one was particularly upset by the death of this smug teenage tyrant with more power than sense. But, following the particularly graphic and gruesome portrayal of Joff’s final moments, I question; was this death purely a work of fiction or is such an end possible with the use of real-world poisons?

To answer this question we must first consider Joff’s dying minutes:

Joff’s final moments followed from a sip of wine and a bite of pie; either of which could have been the vessel for this deadly dram. The first observable symptoms of this poisoning, manifest as a dryness in his mouth, followed by an intense coughing fit.

Gasping for breath he soon falls to the floor and vomits. Unable to stand, he lays fighting for breath and convulsing. Cersei rushes to help her son, turning him over and, in the process, revealing a grey/blue pallor to his face and lines of fresh blood coursing from his nostrils. After a final plaintive glance towards his mother (which almost convinces us he may actually be human), he rapidly dies in her arms.

From these symptoms we could conclude that whatever poison was used must have the following properties:

1) It must be fast acting.

2) It must cause respiratory distress, perhaps through pulmonary oedema (a build-up of fluid in the lungs).

3) It must cause haemorrhage, perhaps by thinning the blood, or preventing clotting.

Although there are no real-world poisons which can create this exact collection of symptoms alone, a number may induce similar effects and, in combination, may replicate George R. R. Martin’s fictional strangler.

One substance which fulfils both criteria 1 and 2 is cyanide. It only takes a small amount of cyanide to produce a toxic effect and the poison is quickly adsorbed into the body through the gut. This poison causes a burning sensation in the throat and also leads to pulmonary oedema which, more often than not, can trigger violent coughing fits. Cyanide poisoning also fits well with the observation of vomiting and a bluing of the skin. Since cyanide interferes with the body’s ability to generate energy in its cells, these cells begin to die and, as death nears, the affected person’s skin can turn blue – a clinical effect called cyanosis.

Another possible candidate toxin is Deadly nightshade. This potent poison disrupts nerve cell communication, causing convulsions, dry mouth, a sense of choking and dilation of blood vessels – turning the victims face red. However, neither cyanide or Deadly nightshade commonly lead to haemorrhaging.

Haemorrhaging may be caused by agents which prevent clotting and thin the blood, a well known example being warfarin, found in pesticides. However, the effects of warfarin are commonly not seen until several days after ingestion, meaning that this poison is too slow to be our candidate. A number of snake venoms also thin the blood, meaning that perhaps the poison used to kill Joffrey was a mixture of more than one toxin.

It is, however, also possible that the haemorrhaging seen at the purple wedding was simply caused by the violent coughing fit Joff experienced before his death.

So, the most likely candidate poison seems to be cyanide, perhaps mixed with a blood thinning venom. But, whatever the cause of death, the biggest question still remains…who put it there? With such a renowned and despised groom, anyone could be a suspect; sadly though, this is one question science can’t answer…I guess we’ll just have to wait and see!

Note: for a more in-depth discussion of Joff’s poisoning see this great article by Rachel Nuwer.

So there we have it. The fictional world of Westeros is actually awash with scientific fact. Be it ancient wolves or reptilian resurrection, science can give us valuable insights into the dramatic events of Game of Thrones. It probably cannot explain why someone might kill a whole family at a wedding though…

Post by: Sarah Fox

Is pressure to publish causing scientific fraud?

April 11, 2014 by The Brain Bank North West

A paper which was widely regarded as an exciting breakthrough has come under scrutiny, with some people suggesting that the results were false, or even fabricated. This is not the first time that a major study has been subject to accusations of fraud. Is there a reason that some scientists are willing to disregard scientific integrity in order to publish?

In January 2014, researchers at the Riken institute in Japan published a paper stating that they had found a simple way to make stem cells from adult cells. All you needed to do was wash the adult cells in acid and they would revert back to their stem cell form. The study was published in the top journal Nature and caused a ripple of excitement in the scientific community – stem cells are an extremely useful but controversial tool and finding a way to make them so easily, and without any ethical problems, was considered a game-changer.

However, doubt began to arise about these so called STAP (Stimulus-Triggered Acquisition of Pluripotency) cells as other labs were not able to reproduce the results. The lead author of the paper, Haruko Obokata, has been found guilty of misconduct after investigators at the Riken institute found that some images had been manipulated. However, this did not directly affect the result of the paper and Nature has not retracted it. Dr Obokata has apologised for the mistakes but maintains that her results are genuine. The latest twist in the tale is that an independent scientist, Kenneth Ka-Ho Lee, has managed to recreate STAP cells using a different method, although his results have yet to be verified.

Dr Obokata and her team are not the only people to have published in a high-level journal to then be suspected of fraud. The most infamous example is ex-Dr Andrew Wakefield, whose study into a link between the triple MMR vaccine and autism was published in the Lancet and widely publicised in the media. Subsequently, a thorough investigation discovered huge amounts of misconduct and fraud. Another example from the field of stem cell research is the South Korean researcher Hwang Woo-Suk, who published a series of high profile articles in Science suggesting that he had achieved human cloning; it later turned out that these results had been falsified.

But this blog post is not about whether the STAP cell result was genuine or not; that is up to the investigators and other stem cell biologists. The question I’m asking here is – how and why does scientific fraud occur in the first place?

Pressure to publish well

When the validity of a scientific article comes into doubt, it is often retracted by the journal (the website Retraction Watch monitors this). Journals are ascribed an “impact factor”, giving an idea of how influential the journal is in scientific circles. Those with the highest impact factors include Nature, Science and Cell. These high-impact journals have amongst the highest rates of retraction. This indicates that the more prestigious the journal, the more likely it is that people may fake their results to get published in them.

Why would people fake results to get published in a better journal? The answer is simple and unsurprising: money. The more papers you publish in high-impact journals, the more publicity you get and the more likely you are to be able to secure grants to continue your investigations.

Researchers at the beginning of their careers, like Dr Obokata, may feel under pressure to perform almost-miracles to get their results published in a high-impact journal. The pressure may come from their immediate boss, or the institution, or the fact that other researchers are working on the same thing – publishing breakthrough results first is always the key to getting into high-impact journals. In some cases, this may lead to the fabrication of good results in order to try and relieve some this pressure.

Just plain old greed

There are some researchers, Andrew Wakefield and Hwang Woo-Suk amongst them, who wilfully commit fraud for monetary gain – not just through increased grants but from private companies. Wakefield was developing his own single vaccine for measles, and so had a vested monetary interest in discrediting the triple MMR vaccine. Woo-Suk embezzled a lot of the money given to him to carry out this research.

It should be pointed out that scientists such as this are extremely rare. Ethics and good lab practice are taught and enforced throughout degrees and at PhD level. The majority of scientists realise that faking results would ultimately lead nowhere.

An honest mistake

One of the reasons that the warning flags went up about the STAP cells is that other labs could not reproduce the results as described in the paper. Reproducibility is the cornerstone of a good scientific finding – it is only considered to be a genuine result if independent labs can recreate it. However, there are many differences between labs – techniques, reagents and work ethic are variable. This means that it may actually be quite difficult to exactly recreate someone else’s work. Therefore it may be that a difference in techniques or practices is causing these problems, rather than direct fraud. If this is the case, it does not mean that the result is fraudulent, but maybe that it is not as far-reaching or ground-breaking as first thought.

A lot of scientific “fraud” or retracted papers could possibly be attributed to the researchers accidentally misinterpreting results or unwittingly doing something during the protocol which has affected the result. Scientists are people too and mistakes are made; some are just more high profile than others.

This point comes back around to the pressure to publish. With the need to get good results out quickly, it’s possible that these mistakes happen because the researchers are rushing to get their results out to the good journals.

A problem with the peer-review process?

Articles published in high-impact journals have to go through a process called peer review, where study results are scrutinised by other top scientists in the field. This is supposed to filter out the questionable results, so that only good science gets published. However, peer reviewers can only study the presented results; it is not always possible to detect a fraudulent result this way. The benefits versus problems with peer review are outside of the scope of this article and have been discussed at length elsewhere, but the fact that the peer reviewers can be fooled by fraudulent results may contribute to the reason that some scientists risk it.

Scientific fraud is still relatively rare but does exist. So far it is unclear what the best way is to combat it, because publication in high-impact, peer-reviewed journals remains the best way to get results out to the scientific community. Possibly more transparency between different labs would help – then results can be tried for reproducibility prior to initial publication.

Whatever the answer, this example and others alike represent a problem that must be addressed. Apart from the obvious impact on the scientific community, the public’s belief in scientists and scientific research is strengthening all the time; stories like the STAP cell report are damaging this fragile trust. Steps must be taken to prevent researchers sacrificing scientific ethics and integrity under the pressure to publish well and for monetary gain.

Post by: Louise Walker