Wednesday, 16 December 2015

Patsies and unintended consequences

As I've said many times before on my travels through the www, I have a double dose of the e4 version of Apolipoprotein E. 

Settle, this isn't all about me. 

Just most of it.

Ahem...If you spend any amount of time looking into the wonderful world of ApoE, and who doesn't, you quickly realise that e4 is the equivalent of a pirate treasure map that has been shared among all the bio-labs around the world. There are quite a few missing pieces and obstructive blood stains on the map, but what is so enticing, and the reason why it’s so feverishly studied, is the mind-blowingly enormous ship-load of treasure that awaits the lab that can piece together the mechanism for e4’s apparent increased risk of Alzheimer’s Disease (AD) and develop a drug that will rectify it. 

Bugger the likely side effects or unintended consequences or the possibility that the problem might not be with e4, but with a modern society’s inherent toxic environment and shitty nutrition.

The problem I have with the majority of this noble and altruistic research is the mindset that a lot of the lab coats have, that comes through quite clear in the language they use. I spend a fair amount of my almost non-existent free time searching for informative and insightful research on ApoE, and unfortunately, despite the enormous amounts of money spent, a lot of it is neither insightful nor particularly useful.

Smart but blinkered lab rats can be so boring.
 
buy a retired human e4 breeder for a measly $US400
The impetus for this post was the latest in a long line of potential solutions to my imperfectness – the suggestion that gene editing could delete my kind from future human offspring. Using something called CRISPR, apparently mums and dads suffering from e4-induced self-pity could guarantee that their babies are born with the e3 or e2 versions, effectively reducing their kids' risk of uncomfortable and condescending conversations with doctors.

I get the impression this sort of gene manipulation isn't new, but it seems the techniques are getting more accurate and sophisticated. 

Some background - the apolipoprotein E gene is located on the long arm of chromosome 19 and codes for …ha ha, just kidding. If you want to know what ApoE is, I have some mildly informative stuff here, but very basically, it is a protein that, among many other known and unknown roles, tells your lipoprotein particles where to go and when. 

Lipoprotein particles, despite the low density version’s reputation as being the 5th horseman of the apocalypse, are actually very useful things that deliver nutrients to your cells, and without which, you would be very dead. The importance of ApoE cannot, therefore, be understated, despite idiotic claims to the contrary.

“Defective gene” is a term I've come across more than once when scientists refer to e4. These people are on a quest to ‘fix’ this gene and save us poor sufferers from inevitable neuron extinction. While that’s very nice of them, I don’t really want someone messing around with the genes I was given unless they can first prove that I am indeed defective. Even then, I think I’ll take my chances rather than risk some unforeseen cascade of genetic consequences that might see me dead or dribbling incoherently before my allotted time has expired.

It might sound a bit odd to be offended by someone calling your genes ‘defective’. I'm certainly not a believer that everything happens for a reason and that an unseen deity has a logical plan for all the little kiddies that he gives brain tumours to. Some genes turn out shitty, I get that, and while I definitely agree that the genetic soup that is a human embryo can go a little sour every now and then, I'm not convinced that e4 is an obvious lemon.

For starters, very few people know what their ApoE profile is and, because of all the scaremongering, a lot of people do not want to know. Which means there could be an enormous amount of old ‘defective’ people walking around with healthy brains and hearts that don’t know they need fixing. 

I know that sounds na├»ve and ignorant, but very old e4 homozygotes exist. If e4 is such a brain death sentence – how is that possible? Sure, that particular person may have been a freak anomaly, with a secret stash of leprechaun magic mushrooms, and while I look fairly normal and don’t have any symptoms (yet), I acknowledge I may not be such a special case and there is a chance my brain is accumulating enormous amounts of amyloid beta as I type this.

E4 is hypothesised to be the ‘ancestral gene’, with e3 and e2 evolving in the last 10-20,000 years. You could play guessing games for ages, trying to come up with the most likely explanation as to why that might be, but inevitably you’d have to answer why, if the e4 is so faulty, haven’t owners of it simply gone the way of the Tasmanian Tiger? Evolution doesn't typically waste its time and energy on genetic losers. 

E4 is not a guarantee that you will develop AD, that much is clear. So deleting it, without knowing for sure that Mrs Evolution isn't keeping it around for a number of very good reasons, thankyouverymuch, seems a tad premature.

There is a striking resemblance, to me at least, between e4 and LDL particles in that pharmaceutical companies are doing their very best to design drugs that either prohibit the body’s natural production of them or make them behave in, what they feel is, a more friendly manner.

I find that logic fascinating. 

Damn the downstream effects or prohibition of any other natural substances that the body wishes to make in the same process – their firm belief is that taking out a potential suspect will prevent countless early deaths. 

The possibility that the suspect is merely a patsy for Mr Big never enters their thoughts. By focussing on just one player in a multifaceted process, I believe the research is manifestly obtuse. Whether blinded by the pirate treasure or simple narrow-mindedness, the quest for pharmaceutical or genetic solutions to problems that may not actually be problems, has the potential for enormous ramifications. The pharmaceutical industry and the regulatory authorities are not known for their patience – PCSK9 inhibitors are just one recent and outrageous example.

We all have our biases. Mine may be rooted in my life's quest not to follow a lot of my e4 brethren into dementia, but my gut is telling me we have high levels of plasma cholesterol for a reason and that the modern diet, heavily weighted toward foods that appeared roughly (maybe) the same time that e3 and e2 turned up, is simply not suited to us. 

Time reveals all but in the interim I can't ignore my instincts until the evidence tells me that I'm clearly wrong. 

Enough seriousness. Time to spread some peanut butter:



4 comments:

  1. Interesting reading Chips. I completely agree about the weird assumptions the various researchers make about genetic outcomes and their assumption of the primacy of those outcomes.


    I've just been reading 'Tripping over the Truth' which is the story of the failure of 100,000,000$s of research funding spent on the (nuclear) genetic theories of cancer to arrive at a useful endpoint, vs the metabolic/mitochondrial outlook promulgated by Thomas Seyfried et al which seems to be becoming useful rather quickly. Bundle all that together with the various whacko dietitians who still abound, the sugar apologists etc. and it makes you wonder. If you need to wonder. They seem like a blue-green algae infestation in a river; feeds on crap, toxic, and hard to get rid of.


    Season's greetings!
    C.

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    1. Same to you, C.

      Thanks for the book tip, will look it up.

      I read 1984 recently, the first time since high school. What a trip.

      Cheers.

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  2. Hi Chips -
    follow @billbarendse on twitter, he posts about ApoE4 every day at the moment, revealing stuff.

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    1. Thanks, George. My stubborn refusal to acknowledge Twitter is becoming much less tenable lately. I'll take a look.

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