Cal Newport in Deep Work (his own word for flow work)

I'm not sure that's an accurate description for Cal Newport's Deep Work. High intensity deliberate practice that you can only do for short amounts of time per session is Deep Work in Newport's model.

How do you decide what counts as flow-work and what doesn't?

I stopped using pomodoros for flow-work, because it would break my flow state. I've found roughly 2 hour chunks work better for flow, without any particular warning to stop me if I feel like going longer. If I am in flow, I want it to keep going as long as possible, until I am fatigued, or the problem is solved.

Hi, there can be all sorts of things going wrong! Mysterious resistances, gland failures, conversion disorders, broken pituitary, broken hypothalamus, faulty deiodinase enzymes, etc. All potentially inherited or acquired. We really do seem to have no idea how this complicated system works or what it's all for, or what can cause it to go wrong.

But I would have thought that if there was widespread 'central hypothyroidism', someone would have twigged by now, since that form does show up if you do a full panel of hormone tests.

Or I would have thought that when I wrote this. By now I am in such despair about the pitiful state of medical research that I wouldn't be surprised if they'd never thought to look, so maybe it is all just perfectly obvious from blood tests and the fools have ignored it.

And the question of 'what is the optimal treatment' is bound to be tricky. I'm just trying to demonstrate that the problems exist and are widespread and thus worth looking at!

Although Skinner certainly thought 'clinical hypothyroidism' could usually be fixed by bunging enough T4 at the problem. He does mention in his book that he sometimes used T3 or NDT, but he doesn't go into details. Various other people say 'mostly T4 with a bit of extra T3', but no-one has particularly clear ideas on what works and what doesn't or why.

Thanks for the reference to Ray Peat, I hadn't heard of him before. Can you link to the best expression of his thoughts?

The reason why Barnes' paper showing that desiccated thyroid lowering cholesterol levels and seeming to prevent cardiovascular disease isn't cited is because he was basically making his patients hyperthyroid. Lower cholesterol levels occur in hyperthyroidism.

There is a doctor I know of in California who gives his patients supra-physiological levels of T3 hormone (cytomel) to increase their metabolism, to help them lose weight, and to lower their cholesterol levels. It basically suppresses the thyroid's own production of hormone. In the short term, it works. It's brilliant. But it's crazy. We have no idea what the long-term consequences are. And since I'm pretty sure he's not running a study on it, we won't.

You wouldn't need to invoke the idea of 'hormone resistance' because TSH and T4 tests normally used to diagnose hypothyroidism don't measure the active hormone - T3. T4 is just a prohormone with very little direct activity on metabolic rate.

In primates, metabolism is regulated primarily in the liver by T4->T3 conversion, so if this is inhibited for any reason it will suppress metabolism without showing up on those tests. Low calorie intake, and poor nutrition are known to cause this (e.g. Euthyroid sick syndrome). In cases of poor liver conversion, supplementing T4 can actually make symptoms worse, as it will further suppress metabolism by lowering the small amount of T3 production from the thyroid (via the TSH feedback loop).

I assume you have heard of Ray Peat? I personally had good luck applying his ideas to increase my energy levels, and my pulse, body temperature, and cold tolerance raised as well - without supplementing thyroid. His general idea is pretty simple- just look at what conditions and nutrients maximize T4->T3 conversion, and provide them (low stress, high nutrient diet).

Broda Barnes work is very interesting. It blows my mind that he published a paper in The Lancet showing that desiccated thyroid lowered cholesterol levels and seemed to prevent cardiovascular disease in his patients, and that it remains virtually un-discussed and uncited (http://www.ncbi.nlm.nih.gov/pubmed/13796871).

Much of modern medicine involves covering up symptoms with drugs proven to do this, without understanding the underlying cause of the symptom.

What, really? There certainly is a lot of that approach around, but it's not what I think of when I think of modern medicine, as opposed to more traditional forms. Can you give examples?

Most of the ones I can think of are things that have fallen to the modern turn to evidence-based practice. The poster-child one in my head is the story of H. pylori and how a better understanding of the causes of gastritis and gastric ulcers has led to better treatments than the old symptom-relieving approaches. (And I'll tell you what, although Zantac/Ranitidine is only a symptomatic reliever, it was designed to do that job based on a thorough understanding of how that symptom comes about, and it's bloody good at it, as anyone who's had it for bad heartburn or reflux can attest.)

When I think of modern medicine, I think of things like Rituximab, which is a monoclonal antibody designed with a very sophisticated understanding of how the body's immune system works - it targets B cells specifically, and has revolutionised drug treatment for diseases like non-Hodgkin's lymphomas where you want to get rid of B cells. So much so that for some of those lymphomas, we don't have very robust 5 year survival data, because the improvement over traditional chemotherapy alone is so large that the old survival data is no use (we know people will live much longer than that), and Rituximab hasn't been widely used for long enough to get new data. In the last 25 years our understanding of cancer has gone from "it's mutations in the genes, probably these ones" to vast databases of which specific mutations at which specific locations on which specific genes are associated with which specific cancer symptoms, and how those are correlated with prognosis and treatment. And as a result cancer survival rates have improved markedly. We don't have "A Cure For Cancer", and we now know we never will, any more than we can have "A Cure For Infection", but we do have a good enough understanding of how it happens to get much better at reducing its impact.

Even modern medical disasters like Vioxx are hardly a result of a lack of understanding the underlying cause, but more us learning more about other complexities of human biology. Admittedly we don't yet fully understand how pain works, but we do know enough to know that targeting COX-2 exclusively (rather than COX-1 as well, which looks after your gut lining) would be safer for your gut. This is understanding down at the molecular level. It turns out in large scale studies that they are safer for your gut, but of course they're not very safe for your heart, so we've stopped using them. And actually doing the full-scale research on modern rationally-designed drugs like Vioxx suggests that similar old drugs (that we never bothered to test) have the same effect on hearts.

I have been attempting to do this with biology and medicine, seriously for about 5 years now. Not by actually repeating experiments, but in trying to understand the original evidence, and see if I agree that it was interpreted correctly. Of course this is nearly impossible as biology is too broad and complex for one person to understand all of the details.

It's a confusing mess, but I think I am still learning a lot. Even if I come to agree with most of the mainstream ideas, I'd like to think I'd then understand them more deeply, in a way that is more functionally useful.

For much of medicine, there really isn't any biological basis or evidence to review. Much of modern medicine involves covering up symptoms with drugs proven to do this, without understanding the underlying cause of the symptom.

I'm gonna split up this reply, since I think part of it is important enough to be seen more and will go into a higher-level reply to the post itself. I will also preface this by saying that my primary areas of expertise are in energy metabolism (mostly glycolysis) and the cell division cycle, along with all the basic enzymology you need to know to do molecular biology.

As for ATP thermodynamics, I looked deeper into Ling's writings before replying and was more and more distressed by what I saw. They literally cannot correctly do thermodynamics and biochemistry that I learned in my senior year of high school. The end result of several extremely basic math and conceptual errors in their justification for their theories is that their calculated value for the free energy available from cellular metabolism to pump sodium and potassium across the membrane is approximately 1/12 the true value! Given that this is approximately the figure they give for the factor of insufficiency of cellular metabolism to provide enough energy to run the pumps (they give a factor of 15-30 [without stating the error bars] ), and that I have other reasons to distrust almost everything this person has ever done, it is safe to say that Ling's objection to the sodium/potassium pump on thermodynamic grounds is quite simply unjustified.

I will be walking through this in more detail in my other top-level reply along with other reasons that you shouldn't accept their work at face value.

I will only say more about the thermodynamics of the sodium potassium pump by pointing to a paper that I found after a few moments of google scholar searching indicating that hepatocytes under oxygen starvation conditions not dissimilar to those described in Ling's experiments put about 75% of their cellular energy into maintaining the ion gradient, but that under normal circumstances they use a much more reasonable less than one quarter. This is not an unexplored area of research and insinuating that there is some sort of controversy here is simply false.

I will summarize the research on membrane formation and calcium-mediated membrane vesicle fusion before linking to a paper that you can see figures of without a paywall.

Membrane lipids and the contents of membrane-bound compartments move around between compartments via vesicles. Proteins are extruded into the interior of the endoplasmic reticulum compartment before being packaged through a series of other membrane-bound organelles before being secreted, and all the membrane-lipid-building enzymes are for the most part embedded in the ER membrane so the lipids have to get from there to all the other membranes somehow. This turns out to be done via extremely tiny submicroscopic vesicles. They are rather smaller than the wavelength of light because they are pinched off their parent membranes by molecular machines consisting of single-digit numbers of protein molecules and thus are invisible to a light microscope but you can see them with an electron microscope and in some places, like the growing tips of fungal threads, they are densely packed enough that they make the cytoplasm milky.

These vesicles are attached to their destination membranes by a complex of proteins called SNARES which require calcium to work. V-SNARES on the vesicles bind to T-SNARES on the destination membranes and as the complex forms they warp the membranes and cause them to fuse. I've seen very interesting molecular simulations from the Folding@Home project of this process, which if I recall correctly indicated that as the membranes get warped and pushed together by the binding together of the SNARES, the hydration shells of the hydrophilic head groups of the lipids clash and produce interesting ordered structures that suddenly exclude all solvent from between the two membranes, causing the membranes to rapidly fuse.

Calcium is ordinarily excluded from the cytoplasm almost entirely, being sequestered into the ER compartment and the extracellular fluid. As a result SNARE function is normally very slow, except near the surface of membranes that bear calcium channels. In neurons, calcium rushes in for a miniscule fraction of a second after the neuron fires and this is what mediates the fusion of neurotransmitter-carrying vesicles to the presynaptic membrane allowing the signal to be passed to another neuron.

Cells DO get rips and tears in their membranes but often manage to repair them before losing undue cell contents. The main research on how this happens was done in starfish and echinoderm egg cells and embryos because they are cheap ways of getting lots of cytoplasm. A representative paper can be seen here: “Large Plasma Membrane Disruptions Are Rapidly Resealed by Ca 2+ dependent Vesicle–Vesicle Fusion Events”.

Figure 1: something like an eigth of the membrane of a starfish egg is torn off and while there is an initial puff of cytoplasm that squirts out, a new membrane forms behind it and retains the cell contents within seconds.

Figure 2: same thing but in an egg that had been injected with a substance that only glows in the presence of calcium ions. Upon membrane tearing the calcium RUSHES in rapidly, and the area of very high concentration is where the new membrane forms. The remaining calcium that makes it past the new barrier then diffuses throughout the rest of the cell rather than being excluded from some kind of water matrix.

Figure 5: injecting fluorescent dye without calcium into a starfish egg lets the dye immediately diffuse throughout the cell, while injecting it with calcium ions causes a vesicle to form around the dye containing it and preventing it from getting into the cytosol.

Figure 7: the cytoplasm around a vesicle formed like in figure 5 is full of membrane vesicles of odd shapes and sizes.

Figure 9: starfish egg cytoplasm dripped out of a needle into non-calcium-containing media loses a fluorescent dye in it to the media, while when dripped into calcium-containing media it forms a membrane and holds it in.

Figure 10: cytoplasm centrifuged so that it no longer contains membrane-bound vesicles is unable to form a barrier in response to calcium while the centrifuged down membranous organelles and vesicles are able to.

Figure 11: a diagram of the proposed mechanism.

It appears that when the horrifically abnormally high levels of calcium that appear when a membrane is cut hit the small membrane vesicles present in the cytoplasm, they rapidly indiscriminately fuse until they manage to create a new membrane barrier from themselves and any other membranes they touch that holds the cytoplasm in and restores ion sequestration. Other papers both before and after this saw the resealing of membranes in normal body cells but were unable to closely examine it, the large egg cells made it possible to do all these interesting manipulations.

This immediately suggests an explanation for Ling's experiment in which they sliced frog muscle cells in half and put the cut ends in an ion solution (“Ringer's solution”) which they measured the ion flux in and out of and saw it was normal. I note that Ringer's solution contains large amounts of calcium. They claim that they checked via electron microscopy that the cytoplasm did not reseal, but the insides of muscle fibers are horrifically dense complicated places and there's no guarantee that it resealed RIGHT at the cut site – it could have resealed microns or even millimeters away.

I think this post illustrates the kind of thinking that made me hate molecular biology. I started studying bioinformatics with the plan of afterwards making a master in neuroinformatics and do congitive enhancement. I used to believe.

You basically think that there something called intelligence with has a clear definition which you don't have to establish. Then you say that evolution tried to maximize that intelligence and think that the thing that contrains intelligence obviously falls in your domain of molecular biology and has to be ATP.

A while ago I tried to get a performance metric for my brain functioning and did it through a bunch of reaction tests. At the beginning I called it intelligence. I talk with a psychology phd and he told me if I wanted to speak to an academic audience I shouldn't use the word intelligence but rather speak about cognitive performance.

Ten million years ago our ancestors made decisions very differently than todays humans do. Today's humans use very different heustrics to make decisions and there no good reason to assume that we spent a lot of time from an evolutionary perspective to optimize our brains to make decisions based on those heuristics.

Those heuristics allowed us to build tools and then everything went very fast and today we have brains that do a lot of amazing tasks for which they are not optimized. We outcompeted Neandertalers that have bigger brains than us.

What practical evidence do I have that this is the case? Take memory. On example from my physiology lecture was someone who nearly gets hit by a car while traveling to work. That produces information storage. Even a year latter when the person has consciously forgotten the event the amygdala will still fire when the person gets in the same physical location and blood pulse will rise.

On the other hand if I hear a name of another person once, I will often forget the name a year latter. Our brains are not optimized for storing that information. Wanting to store the information does nothing at all but it would be very useful if we had something like a switch to mark information that should be remembered and other information that's irrelevant.

In physiology lecture we learned that the brain always uses the same amount of energy regardles if we are "mentally active" or relax. On the other hand the intestines use different amounts of energy when they are actively and do hard work and if they are not. Really everything expect the brain uses a different amount of energy when it's in hard work modus.

The funny thing about using therodynamics in the title of the post is that you just might use the term entropy at the wrong level of abstraction. Having a constant well defined stream of information brings entropy in a informational system. Given that the brain regulates to constant energy consumption, constant amount of glucose input might be more important than it's quantity for intelligence.

But let's go back to hard mental work. At the beginning I couldn't believe that the brain uses the same amount of energy. It's a consensus belief if you look at biology stackexchange.

One of the core reason why I didn't believe was mnemonics. Memorizing a deck of card in half an hour was for me a very challenging mental activity. It made me breath faster. It was kind of obvious that my brain needed more energy for doing hard mental work and I therefore breathed faster. But my physiology professor wasn't convinced. He told me that things aren't as straightforward.

My problem was that doing mnemonics triggered a stress response. That stress response was completely unnecessary. The brain doesn't need more energy. On the other hand the stress does reduce cogntiive function and made practicing mnemonics really uncomfortable. At the time I didn't know enough about emotions to tackle the problem at it's core, remove the unncessary stress response and focus on learning mnemonics. In the end I let it go, because memorizing decks of cards isn't really a useful lifeskill anyway.

The same goes for other delibrate practice of mental skills. Humans can't simply do delibrate practice for 8 hours per day, because a bunch of emotional crap triggers and cost resources.

3 million years ago monkey's wouldn't want to practice memorizing decks of cards for 3 hours in a row or proving math theorems for hours on end. Our emotional system is not made for that.

It's rather made for preparing for running after the animal that we are hunting when we use our mental prowness to read it's tracks.

Humans are also doing other strange things when it comes to emotions. Nearly every animal has sex at times of the year when it makes sense to have sex. In the mating session. We humans don't interact with our emotions that way. We have simply sex all the time, because having sex is fun. Just like our vitamin C production, something broke about making smart mating choices. Evolution is chaos. All that mental stuff distracts us from reacting to our emotions in a way that we do substantially different things in May then in September. The price of having heuristics that are useful for tool making was worth it.

Too many people are still Darwinists in the sense that believe all evolution is about natural selection. They don't understand the huge effects of genetic drift and other ways that process break down and really aren't optimized.

The pickup community who thinks that it's natural that a male always wants sex has got it very wrong. Most species don't behave that way. It's more of an accident. Things aren't working as they should, because man suddenly started to use his brain differently than most other species.

If we want to succeed with cognitive enhancement, the solutions won't be at the molecular biology level or seen in fMRI images. We need to understand a lot about how humans process information that's not on those levels. The important bottlenecks are not on that level.