The Physiological Society Benevolent (Financial Hardship) Fund

This not a blog... just a plug for the Physiological Society's hardship fund called the Benevolent Fund (or BenFund for short).  If you have an extreme financial crisis and work or study in a Physiology type of discipline, it might be worth checking it out.  I am now the Chair.
The link is here

Teaching Old Drugs New Tricks

My blog on drugs to treat ageing dogs: Copied from the University Liverpool Website: 

“Rapamycin is an old immunosuppressant drug that is now being re-investigated for its so-called ‘anti-ageing’ properties, not only for us but also, as reported recently in all the newspapers, for our canine companions (see Nature report on University of Washington in Seattle study).

So I ask myself; will a pill to increase lifespan really help us and will it help our dogs?

On the face of it, stopping the ravages of time seems a good idea. There are, as a consequence, lots of putative anti-ageing compounds under investigation at the moment. “Anti-oxidants”, curcumin (the chief component of the spice turmeric), green tea extracts, and my personal favourite resveratrol (found in red wine) are all under investigation, but my excitement is in our increasing understanding of how and why we grow old, rather than any marginal longevity gain with some “nutraceutical” or another.

Mechanisms of deterioration

The objective should surely be to increase our understanding of the mechanisms of deterioration rather than to just pump ourselves (and now our pets) with herbal remedies or other chemicals and play “Last Man Standing”.

A question that many ask is; is it even a good idea for us to interfere with such a fundamentally natural process as human ageing?  My answer is ‘yes’, obviously, because whilst there are occasional scare stories suggesting people will live for 1000 years and the planet will be completely coated by humanity several layers thick… most people researching ageing are actually researching disordersassociated with ageing such as frailty, osteoarthritis, Alzheimer’s Disease, for example.

The aim is to deliver a better quality of life rather than some miserable immortality.

Trialling these drugs in dogs first is a sensible idea though. They are reasonably safe, although nothing is entirely without risk and mechanisms of ageing are similar between animal species, but are essentially sped up in mice and canines.The study should therefore return data far quicker than it would come back from a human study and it negates the need for some laboratory animal experiments.

”Most people researching ageing are actually researching disordersassociated with ageing such as frailty, osteoarthritis and Alzheimer’s, for example. The aim is to deliver a better quality of life rather than some miserable immortality”

Generally, with notable exceptions, animal life is proportional to size, with tiny mammals surviving only a couple of years and us larger animals lasting for decades.  With dogs themselves, it’s generally the other way around though.

The 1999 multi-breed study by the Animal Health Trust found that, again with exceptions, smaller dogs tend to significantly outlast larger breeds.  In fact the short-life expectancy of many breeds is shocking to many people.

The Kennel Club is inching in the right direction, but one might hypothesise this is largely under continuing pressure from the paradigm shifting BBC docuxposé “Pedigree Dogs Exposed” aired in 2008.

For us dog fanciers, dogs contribute so much to society already; from companionship to finding people in avalanches or earthquake building collapses.  From assisting people with disabilities to protecting us at airports by sniffing out people with explosives and other bad guys.

Most recently, it has become evident that dogs can help with human health too. Dogs can most assuredly detect certain diseases with their exquisite sense of smell and, ironically, they encourage exercise and activity in people; activity being the anti-ageing therapy with the very strongest evidence base of all!

A small increase

So now, they are helping us to develop drugs to increase our own longevity and for this, their reward will be, potentially, a small increase in their own life spans.

Let’s not kid ourselves this will be some sort of advance for canine health though.  In mouse studies, really large doses of rapamycin increased longevity by about 9% for male mice.  Perhaps we can hope for an increase of 5% or more in dogs?

To us humans, a 5% increase could be a really big deal, a few years of (hopefully) happy healthy life. …but to dogs? Well consider the poor old Irish Wolfhound.  Median life expectancy 6.2 years. Increasing this by 5% equates to just a few months.

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!!! 

Bad Pharma and Negative Data

Negative clinical data.

This is a topic getting a lot of airplay and a lot of words! Here are a lot more (sorry). There is a huge issue with clinical trials failing to report the failure of a drug. There are also a number of quack remedies which have been tested frequently and usually deliver negative results that are never published. If ever, by the effect of pure chance, they do appear provide some marginal benefit, this is shouted from the rooftops. So how how are your sports team doing? There are two ways you could assess that, you could say they are 100% winners. To get this value you simply report the results where they won. However, a fairer assessment would be to report all the results and then you would see that if it were baseball, most likely, they loose half the time and win half the time. More-or-less. The withholding of negative clinical trials data is thus wicked, but I think outside of the people who do it, it is already universally condemned! This was discussed at great length by Ben Goldacre in his book Bad Pharma. It is indeed an excellent book and very important. Although I feel I can make four criticisms since I am pretty certain he would never follow me on Twitter!!! ...

"Reps may do bad things I suppose, unlike me. I do good things, but I just do them badly!"

(1) Bad Pharma was painfully long and I was quite frankly on my knees by the time I approached the end. (2) Ben is really horrid about drug reps. Ben seems to think they are evil, but I have known people go into drug repping and from my experience they were just ordinary people searching for a job. They may not love their job like the rest of us do, but they have to do it because it is their livelihood! I would blame the system that allows Vets and Medics to be ill equipped to handle the high pressure sales and gobbledygook "science talk". I feel sorry for drug reps trying to sell their wares to hospitals/GPs/Vets. (3) There were not many laughs in there, given how long the book is! (4) I don't think he quite gets the situation with negative preclinical data. So here's my bit on that.

"The Bad Pharma book by Ben Goldacre highlighted problems with negative data, but it treated clinical sciences and basic research just the same."

Negative Preclinical Data

It is not the same. I know the Journal Editors (I also Edit!), will all say negative data is perfectly acceptable, but the reality is; it is just not as hot.

"List all the Nobel Prize Winners you can think of that got the Prize by showing that their own theory was untrue"

Firstly, even I accept that negative data is less exciting; we knock about ideas in my lab... we wonder if this works like that. We do an experiment and we find.... it doesn't. No one can really pretend that is going to be a widely exciting read for others. RBJ had this great idea: His group spent months testing it and turn out to be wrong. Sure if there is some huge piece of dogma you can debunk you could probably publish this IF you also included an alternative positive set of data. Not true? OK lets have a competition, you list all the Nobel Prize winners who got their Nobel Prizes for the failure to discover something? OK I'll even allow you to throw in the discovery that something they thought might work.. doesn't work. Meanwhile, I will start to list Prize winners who were elected on the basis of positive data. Its all nonsense. A hypothesis constructed, tested and verified (positive data) is nearly always going to be easier to publish in a mainstream journal than "we tried this... it didn't work".

Am I complaining? Not about the fact that negative scientific data is tricky to publish, it has always been like that. My gripe is that (a) Ben and others seem to think this is in someway scientific corruption. (b) Editors need to have the courage to say, generally positive PRE-clinical data is more interesting and publishable than negative. I can have 10 new theories before breakfast, when tested, most of them will prove untrue I am sure, we can't fill the literature with disproving of all our own theories!

"None of us want to spend our days reading about how Jo Blogs tested his own private theory and found it to be untrue!"

The last point, wouldn't it be useful to have access to negative data to stop scientists around the world keep trying the same things and getting the same negative results? Oh yes indeed. Little journals or peer-review repositories which specialise in negative data are the way to go. They exist already, so lets just use them (if you are a scientist) and stop confusing the shocking hiding of negative clinical data, with the quite legitimate low profile publishing of negative data and broken hypotheses.

There feel better now.

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