Placebo; something about nothing!

I am sorry to dissent from the general chorus of both lay and scientific praise for the Horizon placebo program (Medicine's of the Mind "Power of the Placebo"). Many people seem to have found it fascinating, I'm not one of them. I thought it was all nonsense (if you are quick you can still watch it here)!

One of the disappointing things science can do is take a really simple phenomenon and make it more complex. Science should attempt to do the opposite.  So to clarify; most lay people have never (IMHO) had a problem understanding any of the following cliches:

• If something excites you (not like THAT) your heart to beats faster.
• You get a performance boost from confidence and/or positive mental attitude.
• Under-performance can result from under confidence.
• Fear can turn your stomach.
• Fear can make you go weak at the knees.
• In a fight situation, humans and other animals can suppress pain and don't really hurt until they are out of the danger zone....

There are so many of these its crazy. Placebo is just another one of these; if you truly believe you will feel better, you will feel at least a little better.

In teaching its a critical factor.  Telling students they will all do well WILL improve their performance.  And if you are my students worry not, it's no trick, I don't mind if you read this because I am absolutely sure you WILL do well.  There is nothing like confidence for optimum performance.  I have seen students in the past so nervous they couldn't even write their own name on the front of the papers.  Guess what?  They do terribly in the rest of the exam too.  Listen to my voice my students:  you WILL do well, really you will!

Now the program went to great lengths to show that there were real chemical changes in the body whilst this was happening (after people took placebo). But HELLO!! we are little more than a collection of chemicals. Everything you sense, think or do involves changes of chemicals. If you see something, glutamate is released in the eye and various neurotransmitters are released throughout the brain. If you think or imagine something, chemical changes take place in the brain. If you believe you will feel better, of course chemicals will change. If you lift your own leg... chemical changes take place in the process.
A couple of specific points about the program; the cyclists performing better and/or feeling they performed better?  Well people are absolutely hopeless at assessing their own feelings to start with (as I discussed here), and any good coach would know a bit of appropriate inspiration at the right moment will improve performance.  Why do people break so many world records at the Olympics?  This is exactly the same as the benefit of a so called "pep talk".  The the "mystery" of the placebo was further illustrated with a patient who's symptoms improved even though she was told she was going to get placebo.  All that matters is whether you feel you will feel better.  ...and typically of course the disease they chose was IBS "irritable bowl syndrome".  This is notorious for being a "there's nothing wrong with you get out of my surgery" type of disease.  Frequently people can be really ill with it too of course, and disturbingly, my guess would be that people "diagnosed" with IBS are frequently suffering from undiagnosed Crohn's or coeliac disease. Nonetheless, in many cases it the GPs way of saying, "I don't deny there is something wrong with you, but I can find anything to account for the symptoms you are reporting".  Bottom line (pun intended).. its not a great vehicle for demonstrating the magic of placebos.  

So giving people placebo, results in them thinking differently to non-placebo people and this change in thinking results in change of chemicals. To me, it is no big deal.

So why am I so evidently wound up by this? For two reasons.

(1) The idea that we are anything other than a collection of swirling chemicals and electricity is patent nonsense.  I feel there is no place for such arcane pre-science gobbledygook.  If you are surprised that chemicals change in the body when people "think positive" where have you been!? ...and if you thought that and you are even a biological scientist... Wow.

(2) Throwing your hands up in the air with amazement when someone shows that thinking changes chemicals in the brain is opening the door for woo. Why do I say that? ...because the next thing will be TV showing how people feel better after taking homeopathic remedies (aka water) and correlating this to chemical changes in the brain. Look they will say, homeopathy changes chemicals in the brain... So it was true all along. Well no it wasn't. Homeopathy is nonsense and just try and remember chemicals are constantly changing within the body. And will do so until well after we all die.

And on that cheerie note, I think I shall go and buy a high fat pizza and bring my own demise a little closer!!

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King Richard III's spine and the "ion channels", "TRPV4".

Funky ion channels in King Richard III's skeleton

I am sure that most sensible scientists, medics and vets would appreciate that ion channels are *the* most important proteins in the body? …OK all proteins are important, but none are as exciting as ion channels, which sit in the membrane of every cell and can control their functions.  …but I think it is about time to bring the word “ion channel” to the attention of archaeologists and historians through the medium of… Richard III’s skeleton.

The official line from University of Leicester (if there can be an official line) is that Ricky 3 had an idiopathic adolescent onset scoliosis.  Now the “scoliosis” bit just means “bent spine”, the “adolescent onset” bit is obvious and “idiopathic” is a posh way of saying “unknown cause”.

Therefore he had a bent spine since adolescence of unknown cause.  He also apparently had osteoarthritis.  It seems likely that a funky ion channel was at fault.  I have in mind, a particular ion channels with a gene name “TRPV4”.  In lay terms, it allows calcium to enter cells in response to movement.  Now what evidence do I have… .  eeerm…. none! That’s the great thing about blogs BUT just check-out the similarity of spine curvature with the bones of King Richard III and this well-studied literature example of a TRPV4 “channelopathy” below.

Parastremmatic dysplasia patient, with an ion channel disease

Not proof, I agree… but perhaps the many fans of Richard III should now start wearing tee-shirts with a TRPV4 channel on them… I present this suggestion below.  Have fun!!! 

Cartilage gets squished when you stand

Reprinted from Coleman et al 2012, yes with permission. It cost me $20 just to use it!
You can see the cartilage of a healthy human joint outlined in yellow (from an MRI).

I recently came across a great little paper on knee joint thickness by Coleman et al. It confirms what we may have already known or guessed.... but it does it beautifully and in a highly quantified manner. The data is from humans, but I would expect that similar would be seen with doggies! Very sophisticated experimental techniques, and modelling with some lovely beautiful pictures (!) and well controlled data.
Read the paper here Coleman et al 2012
The paper shows that there is a physical squeezing and compressing of cartilage when you stand up.  This has all kinds of ramifications to scientists who work in the area (like us!!).
The difference in thickness is quite small between day and night, but certainly significant in the knees.
Snippets of the data are that men's cartilage is much much thicker than womens'... and of course, there is a significant correlation between cartilage strain and body mass index (BMI).
...So if you want nice thick knee cartilage; be a chap, spend the day in bed*... but don't eat too much!!!

*...but seriously: it is generally accepted that moderate exercise is good for healthy joints, but excessive weight is an absolute no no......

Other blogs pertaining to osteoarthritis and exercise:
What Gives People and Animals Arthritis
Is Running Good for Your Health
Exercise and osteoarthritis

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Excuse me, but the flu is a virus

This is a VERY short blog:  I am just amazed how many people seem to not know that a cold and the flu are all viral conditions!  EVEN SCIENTISTS! So just to clarify.  There are at least (hedging my bets) three types of infection you can get: (1) Bacterial, (2) viral and (3) parasitic.   

A "cold" is a virus.

The "flu" is a virus.

"A virus" is a virus (people often say, "I don't have a cold/the flu I have a virus"!!).

Typically, but not exclusively food poisoning will be bacterial.  (And parasites  include tapeworms and fleas.)

The distinction between a virus and bacteria is pretty crucial: Antibiotics are anti-bacterial, but have no effect on viruses. Sometimes, a bad cold, with all the sneezing and wheezing and lying around indoors can leave with you with a secondary bacterial infection, but wasn't the primary cause!   In terms of how viruses and bacteria are different... well just log on to Wikipedia!

Magical Sunburn Medicines courtesy of TRPV4

28th August 2013

There was a lot of recent coverage of a paper claiming that a particular protein called "TRPV4" causes the pain of sunburn. It has been floated that this could allow us to magic up some really great sunburn relief creams and hugely increasing Q.O.L ... Quality Of Life!!

What I was hoping to do in the blog is discuss (1) why this is not such a good thing! .... (2) why I say they "claim" rather than "show", (3) what the TRPV4 protein is, and finally da da da da daaaaaaa (4) Exerimental treatments.

Why is this new discovery a bad thing?

OK chronic pain... I.e., pain which goes on for weeks, months and years is a terrible thing, and we think of this as a disease in itself. Acute pain is rather different; in some cases it is awful, but frequently it is a really effective warning that something is awry and needs to be sorted. People who lack pain sensing ability have a dreadful time, they injure themselves left right and centre and just don't know until serious harm has been done. There are animals which lack pain sensing for particular types of pain when it suits their lifestyles, but for the rest of us it's a protective mechanism to stop us injuring ourselves. So in this case, not only does the sun age your skin, but it really does, unambiguously give you cancer. The more you can tolerate being burnt, presumably the more you will allow yourself to be burnt and the more likely you are to get cancer.

DOCTOR DOCTOR, I KEEP TRYING TO GIVE MYSELF SKIN CANCER, BUT SUNBURN KEEPS DRIVING ME IN DOORS... WHAT CAN I DO ABOUT IT?

As for pain relief; in theory morphine like drugs and local anaesthetics would already stop the pain if that was all you wished to do. Morphine is considered too dangerous, and local anaesthetics, basically inappropriate. Obviously you should speak to your pharmacist of GP about treatment, but generally they'll say moisturising creams will feel nice and some ibuprofen-like drugs or paracetamol (acetaminophen) may help... a bit.

Why did I say "claim", rather than "show"?

I really hate "scientists have shown" on the news. What they should say is Dr Fred blogs and colleagues have shown... Or possibly "a new research a paper shows". Frequently, these days the truth would be "a University Public Relations press release says"..... Anyway in this case it was a research paper that the information was published. The Journal is called the Proceedings if the National Academy of Sciences (PNAS).

Well it is no suprise that TRPV4 would be involved, it is found all over the body and important for all sorts of things, but there is always scope for skepticism with this type of report. It was published in the journal PNAS, which has an excellent reputation although it has an unusual procedure for selection and review of scientific papers. Some people have raised objections to this. Secondly, there is a tendency for people to always find the particular protein they work on to be the lynchpin of whatever system they happen to work on ;-)

In fact my own colleagues and I were looking at a different protein that seemed important. They don't have to be mutually exlusive though. There are probably many proteins which are involved in sunburn pain.

TRPV4 is likely to be involved however, because it is a protein which is important to sensing much of the normal mechanical (touch) stimulation of the skin. In sunburn we have an oversensitivity to touch, therefore, it stands to reason that if you loose the ability to sense touch, you will also loose the sunburn induced oversensitivity!

What is the TRPV4 protein?

This is top dead centre my area of research. I'd like to step back and remind people that we are, as animals, mostly chemicals and electricity. Now I am sure many people know this, but if you don't its going to sound like sci-fi, but it really is known quite well. All nerves that either transmit senses like touch, pain or pleasure are effectively electric wires. Electric current flows through them like wires running between a switch and a light. The voltage is about a thousandth that of a domestic light, or a hundredth of a modern torch. TRPV4 is a type of protein called an "ion channel" which acts to generate this voltage... An ion channel has two parts conceptually, a battery and a switch. In th case of TRPV4, the sunburn throws the switch thus stimulating the nerve cells which conduct the pain to the brain. In fact this "ion channel" can be activated by all sorts of other things too... Including pressure and some drugs/chemicals. The problem with it, a drug target though, is it really is found so widely throughout the body... Side effects could be a real problem.

Some experimente to see if its true?

I think not! There are a number of chemicals known which inhibit the action of TPRV4 already. Therefore they should prevent the pain of sunburn. It would be irresponsible of me to list them here, but they are no doubt, findable with some Googling. Presumably they would reduce the pain of sunburn. Most of these compounds are expensive and pretty deadly. TRPV4 is found all over the body, so you'd not just loose the sunburn, your kidney would not work properly, your joints would be affected, you'd feel numbness and loose control of your blood pressure. So direct application to the skin? Unfortunately, they tend either to not penetrate the skin, or they do absorb nicely, but they give you cancer :-(

Personally, waiting it out or using paracetamol seems a better idea to me.

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Blame your mum!

There are a lot of things we know you can do in an attempt to fight off the ravages of time:

Don't smoke

Keep fit

Don't be obese

Eat healthily

Don't fight alligators

Don't let yourself get sunburned

...but that said, a new paper published this week in Nature shows that at least some of your ageing is not your fault, but your mum's! Feel better?

Now the science bit... Everyone knows that we inherit loads of features about ourselves from our DNA. This is of course kept safely inside our cells' control centres (nucleus).... However, each of the cells in our body also contains mitochondria. These are the tiny structures which produce the energy necessary to keep cells working. However, it's increasingly become known that they also have their own supply of DNA. It was quite surprising when that was discovered, but we are now quite certain this is the case. Amazingly, you don't inherit your mitochondria from both parents.... you inherit them only from your mum.

It turns out that this mitochondrial DNA confers some of the differences between ageing rate in people.

Ergo.... Some of your propensity to ageing is inherited directly from your mum!

 

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"On no we are not changing the nuclear DNA"... just the mitochondrial.

On BBC radio news today we were treated to the exciting news that mitochondrial DNA transplants were going to be legal in the UK.  This would, if successfully achieved cure inherited mitochondrial metabolic diseases at a swoop.  

BUT

This horrible pill (?) had to be sweetened with all those statement that this would not be changing "who we are" because it would not touch our DNA.  

Well, lots of things change who we are.  Getting cancer and dying changes who are you, getting cancer and surviving also changes who you are.  It changes who your family is too. All sorts of things change who you are.  All sorts of things change the DNA.

For most diseases we really don't know enough about how the genes go wrong (but frequently we know that they do).  Even if we do... correcting that DNA is coming, but will be tricky. 

But should we change the nuclear DNA if we could??

Hell Yes!

The Taste of Cheese: ... visual illusions, acupuncture and medical research!!?

The BBC were running a story all yesterday about how cheese and yoghurt taste different when eaten in different ways, like from a metal versus plastic spoon?  Did you hear it?  http://bit.ly/CheeseSense Their science editors made a mistake, because they thought it was a science is silly story.  That's is pretty much mostly what the BBC science editors like.

So why is it not silly?  Because it is a simple example of a phenomenon so hugely important that it hampers diagnoses, makes creation of new medicines difficult and fuels "woo" science and medicine.  People believe they can trust their own senses, but they simply cannot.

So lets have a visual example; this page shows a number of small videos where it is very difficult to spot obvious differences between the two images: http://bit.ly/VisualIllusions.

So as our resident experimental psychologists and neuroscientists will tell you: "you cannot trust your eyes".  

Does this relate to cheese taste?  YES.  You can't trust your eyes, and you can't trust your tongue either. The cheese obviously tastes the same (in that it is chemically identical), but you think it tastes different because of the context.  We humans are easily confused.  An aside: I guess this proves the Cher song "it's in his kiss" to be totally wrong.

Yuk, may be I shouldn't have gone there.

OK now medicine, "woo medicine" in particular.  Pain is just the same.  The owner of any particular pain is really bad at knowing the intensity of their own pain.  It is a fundamental problem.  Now there are several things going on here:

(1) It is difficult to describe or quantify pain.  Scoring, as you do to your clinician on their 1-10 scale is difficult.  We all know this, but it is different to the topic of this blog.

(2) There are definite built in body processes which dampen down pain in the same way as strong pain killers such as morphine.  These tend to be based around chemicals called "endorphins".  ...they can be activated, by stress and all sorts of things that are not fully understood.  Furthermore, the awful truth about "chronic pain" (sometimes people have long term pain without clear physical cause) is that there seem to be "un-endorphin" mechanisms we know little about (we are tying believe me!!).  This is still different though.

(3) Even excluding (1) and (2) we can't judge our own pain!  so have you had an aspirin for  headache and someone ask you if it's better? you reply something stupid like "I think so"?  Well I do!!!  ...but is not just me.  I was in great pain myself once and given morphine on a drip.  I remember saying to my nurse... "I think that seems to be working".  Obviously  3o mins later it was blindingly obvious the pain was relieved, but EXACTLY when it went off was always a bit vague to me.  So here we now have the nub of the problem... if you give someone a painkiller that is mildly effective it is very difficult for people to really know whether it has "worked" or not.  Put pressure on them, by clearly investing a lot of time and effort in trying to help them and they will say "yes its a little better" even if they really don't know.  Its human nature.  So there are ways we get around this.  We use placebos.  Just give them nothing disguised as something and see if they can tell the difference?  Frequently people "say" they feel better after they actually had nothing.  This is sometimes called the "placebo" effect and it is a scientificy way to say they said they thought they were better, but they were mistaken. It's a sensory illusion! People including scientists and clinicians frequently try to investigate a so called placebo effect, but this is nonsense.  The phenomenon is simply that there is a tendency for people to believe a pain has improved when really it hasn't. Now this is the same as the cheese*!! 
 You simply cannot trust your own senses.  So if you have a new pill you wish to test, you compare it to a placebo. If it doesn't beat the placebo you through it away. "Simples!"

...but how can you set up a placebo for acupuncture?  or gels you smear on your need to help osteoarthritis  ....or faith healers etc?  You just can't.  ...and therefore if you are trying to look for smallish improvements in peoples health and sense of well-being there is no point asking the person concerned.  Just like the cheese and the visual illusions, people are too easily confused by the context.

You cannot trust your own senses (or anyone else's).

*There is also the "pressure" aspect, ever asked directions and someone replies in a funny accent?... you will ask them to repeat it once, maybe twice, but embarrassment would prevent you from asking for 100 repeats even if you still didn't get it.  Students do it all the time.  Their mouths say "yes I understand" their eyes say "I have no idea what you are talking about".  The difference here is obviously people know they don't know, but are embarrassed to say...

Antibiotic Resistance

Yes, it's true. There is a danger of widespread catastrophic failure of antibiotics in the future, as stated on our radios this morning by Sally Davies. I think it is sometime off however, but here's what antibiotic resistance is all about, why it happens and what can be done to prevent it.

What does antibiotic resistance mean?

There is a feeling that "natural" things are good and "synthetic" things bad. This is why the processed food story is so appealing. Sorry, but this is simply not true. Bugs ("pathogens", bacteria, virus and fungal infections) are all totally natural and they are out to get us. Also, many natural plant extracts and animal "secretions" are poisonous without any known medicinal use. Antibiotics on the other hand are our allies. They generally derive from a natural substance, but they are then chemically synthesised in a lab. They attack bacteria in one or more of a range of possible different ways. Some attack the bacterium's cell wall (it's skin if you like) and others stop them reproducing etc etc. But they evolve. And they evolve really fast. Or the adapt and any rate like the Borg in StarTrek. When they adapt, they can withstand the attack by the antibiotics and you have to switch to a different antibiotic to get'em!

Why does it happen?
Well there are two levels to this question. "Biologically" what happens and "therapeutically" what happens. Biologically first. As I said above, it's like a kind of evolution. The genetics of bacteria change really fast and so the unfit bacteria perish and the strong ones survive. So "unfit" means unfit to fight that particular antibiotic. Get a dish of bacteria and they are constantly mutating subtly. Some mutations make them stronger, others make them weaker. This just happens. there is not much we can do about it. Then add your antibiotic to the dish: Most of the bacteria will be killed, but a few will survive, that's inevitable. BUT, here's the rub... the ones which survive will obviously be the ones who have a genetic mutation which makes them slightly better at resisting the antibiotic. Now take those survivors away, grow them up and hit them again with the same antibiotic: What would you expect? ...well the antibiotic will kill many of them, but now those strong survivors have multiplied and a large proportion of them will now survive. Take these survivors, do the same again and you have a superbug! Congratulations! ...you've moved closer to the end of mankind :-/
So medically/therapeutically how does it happen: You don't use a dish you use a person. You give a person with an infection an antibiotic and enough will be killed to make the person feel better..... but there may be a few bacterial survivors. These spread on to the next person and the experiment above is recreated in a real person rather than a dish and you are creating superbugs. Simple as that.

What can be done about it?
Well sure, invent new classes of antibiotics which work in entirely different ways to the current ones. Thanks Sally! But that is the hard way. The easier ways are these:
(1) Don't ask for antibiotics unless you really need them! (Clinicians should not give them to you even if you ask unless it really is necessary). There are frequently alternatives. Usually infections passes. If its a cold or flu antibiotics won't work anyway, because they are viral. Antibiotics only work on bacteria. You always think they work, because by the time you get the clinician to give you the drug you are just starting to get better anyway (yes even though you don't feel any better yet).
(2) Don't give them to animals to increase farming yield. Use better animal husbandry instead. If you cram your chicken (for example) into ridiculously tight spaces so infections spread by wildfire and then load them up with antibiotics "just in case".... you are not just being cruel to the chicken you are going to end up killing people. Yes you are!!!
(3) Finish your course of antibiotics if you do get them. People frequently get a course of antibiotics and stop taking them when they feel better. Its innocent enough, but this is a huge problem, It massively increases the chances of strong bugs surviving and going on to spawn a new generation of superbugs. If you read down this far and want one message its this, please please please, a thousand times please finish your meds!!!!