Cholesterol, Pauli Ohukainen & Authority

No. Just that it’s always the totality and magnitude of all risk factors over a lifetime that ultimately determines when CVD hits

So it’s multifactorial? Sure. But you see, saying that explains everything and anything. Or, nothing…A good theory unifies these disparate factors. That’s what we failed to do in medicine so far. And risk factors are just that, statistical associations. A theory does away with those statistical artefacts that are mere associations and identifies only those relevant, causal elements. The 2 hypotheses that feed into one another, the Diet-heart hypothesis (fat => cholesterol => bad) and Cholesterol-CVD hypothesis (cholesterol blocks arteries) have both been falsified. First off, there are multiple associations which falsify the both theories: midle-aged women have lower all-cause mortality the higher the cholesterol, Japanese cohorts don’t see increased risk of death or CVD with higher LDLc or TC, the supposed French Paradoxes etc..It’s important to note that you don’t need to weigh the number of associations supporting & not supporting your hypothesis; (assuming the associational study is well done – granted, a big ‘if’) all that is needed is a single association that doesn’t fit your hypothesis and that is enough to have it thrown out. All the other favorable ones be damned!

Although LDL’s causality is inferred from many independent lines of evidence, it may not always predict a clinical event.

This is where peopole in medicine and nutrition need to wake up: IF YOUR THEORY FAILS IN ITS PREDICTIONS, ITS A SHITTY THEORY. We need to realize that the fields of medicine & nutrition are the alcoholics of the science world: the first step for solving a problem is realizing & admitting we have one. Mainstream advice for weight loss, diabetes, CVD, cancer, alzheimers etc. SUCKS! Why? No good working theory. Neither about what causes these diseases or what revereses them. We fail to admit we cannot predict, to any useful degree, who will get it & why. We rather brandish the Multifactorial Flag – a useless truism & tautology mostly – so that we can hide & excuse our ignorance, pretending there is no general lack of scientific acumen amongst researchers.


So how ’bout dem receptor kinetics? Part of the ‘great work’ or ‘misapplied findings’?

What about receptor kinetics? What are you expecting the Michaelis-Menten constant (Km), in and of itself, to tell you about the causal process of CVD? You can do all the molecular biological work you want, but that will not replace animal & human models with controlled variables and well donce associational studies falsfiying predictions (or anything you might see in in vitro for that matter). I study molecular biology and can honestly say that Brown & Goldstein’s work to elucidate the FH gene is impressive and exemplar of good science for aspiring researchers. Credit where credit is due. But this isn’t politics, so there are no ‘carry over credits’ for the other claims they make using their original discovery. On day 1 of a genetics course, you understand that although there is ‘the gene for X’, this is in NO WAY A GUARANTEE that only X is affected by the gene encoding it. The nuclear DNA library is a vanishingly small fraction of the story of how phenotype emerges from genotype. The way laymen & the majority of doctors I know, really do not understand genetics. I would count myelf in that group until about 2010. Furthermore, my understanding of epigenetics has completely changed in the past 4 months after reading Mark Ptashne’s work. In fact, many *geneticists* talk a lot of nonsense about epigenetics (as I did previously). No one needs to take the word of Nobel Laureates. That’s the beauty of it all, we can and should scrutinize their ideas. The findings of Brown & Goldstein do not support Cholesterol-CVD hypothesis; rather interestingly, it open up a door to the pivotal role cholesterol plays in the maintaing epithelial integrity and how this affects its interactions with solutes in the blood. Cholesterol IS important in CVD, but not as an inherently negative agent.


3 thoughts on “Cholesterol, Pauli Ohukainen & Authority

  1. Pauli Ohukainen says:

    Thanks Raphi for your comments! Normally I wouldn’t respond to a blog post (not because I wouldn’t want to but due to time constraints) but since you made me the “star” of your post, I feel obliged.

    My background is in molecular biology, too. I can totally understand where you’re coming from with your approach to scientific theories. I just hope you give the researchers in the field the benefit of the doubt that they might actually know more than you do.

    For example, when I got into the field of basic biomedical research, I’ve had to learn a great deal. It turns out that medical theories are not similarly subject to the most ‘naive falsificationism’ that other sciences (like biochemistry) might be. Medical science is messy and theories have to be constructed from multiple levels of evidence to make a coherent case. Often times ones that have had plausible backgrounds have failed and better ones have risen in their stead.

    I believe my views represent those of a global community of atherosclerosis researchers. There are thousands of people out there who have dedicated their careers to the basic science of atherosclerosis. While it’s certainly possible that you know things better than they do but I find that improbable. I know there’s nothing I can say that’ll change your mind but I’d appreciate you acknowledging at least that the people in the field might actually have a case.

    Now, a few quick responses to your points:

    1. You misrepresent my view. I don’t claim that LDL explains everything (and therefore nothing). My view is that out of all risk factors, it seems to be the biological ‘sine qua non’ of atherosclerosis. This can be challenged by e.g. studies where atherosclerosis can be induced to animals that have zero LDL in their blood. Then I would admit the theory is in trouble. We know from human studies that you can get atherosclerosis without smoking, diabetes or elevated blood pressure. I just think that the evidence from PCSK9 lof-mutation carriers supports the fact that with a low lifetime LDL the risk of heart disease is virtually abolished (-90%) despite all risk factors. If there’s another mutation that lowers LDL significantly since birth and no effect on heart disease, I would again have to admit that the theory is in trouble.

    2. You didn’t quite catch my point. While LDL particles are required for plaque to initiate and grow, that doesn’t mean that the same particles are the best predictors of its progression. It’s not a passive disease but rather an active one. I do think LDL is a decent (apoB even better) marker and an ok target for intervention but I hope in the future we can do better. The ultimate cause of death in CHD is rupture of a plaque. I hope that we can find better predictors of that rupture. Looking at LDL may not predict that particular event and this is completely consistent with the complex theory of disease. Please don’t look for the naive falsifications.

    3. With receptor kinetics, I was referring to B&G’s work on determining what the physiological optimum of LDL for human beings could be. That’s what we were discussing on Twitter and I said B&G found it to be 25-60mg/dl. This is extrapolated from a concentration where the saturation and subsequent recycling of LDL receptors is most effective. Above that, the cells don’t handle LDL that well. I believe it to be a strong case for some kind of (fairly low) LDL concentration being there. This can be challenged by showing that e.g the more LDL there is, receptor kinetics is unaffected or even improved. If the receptors get saturated, doesn’t that already say that too much can be a problem?

    Anyway, I’d certainly love to talk about this more but I just don’t have the time right now. I’m sure we’ll bump to each other on Twitter on another occasion and maybe then I’ll have more. For now, I thank you for the challenging thoughts and a thorough blogpost. Please don’t think we’re stupid – I’m sure we’re all trying to look for the truth and we certainly know more every day 🙂


  2. Craig says:

    This seems like a relevant quote and a potent assertion, via Nick Lane (vital life)

    ‘Peter Medawar described a hypothesis as an imaginative leap into the unknown. Once the leap is taken, a hypothesis becomes an attempt to tell a story that is understandable in human terms. To be science, the hypothesis must make predictions that are testable. There’s no greater insult in science than to say that an argument is ‘not even wrong’, that it is invulnerable to disproof.’

    You can wriggle and squirm about the details of your scientific fishing expedition until the cows come home but if the core hypothesis doesn’t hold up you simply have a collection of ideas that may or may not be useful in some other context.

    Liked by 1 person

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