John Ioannidis has written a very insightful and entertaining article about the current state of the movement which calls itself "Evidence-Based Medicine".  The paper is available ahead of print at http://www.jclinepi.com/article/S0895-4356(16)00147-5/pdf.

As far as I can tell there is currently no paywall, that may change later, send me an e-mail if you are unable to access it.

Retractionwatch interviews John about the paper here: http://retractionwatch.com/2016/03/16/evidence-based-medicine-has-been-hijacked-a-confession-from-john-ioannidis/

(Full disclosure: John Ioannidis is a co-director of the Meta-Research Innovation Center at Stanford (METRICS), where I am an employee. I am posting this not in an effort to promote METRICS, but because I believe the links will be of interest to the community)

Would you notice if science died?

Science is a big deal. It would be worth knowing if it stalled, regressed, or died out, whether the body of knowledge or the techniques for generating more knowledge. You could practice by reviewing history and looking for times and places where it stumbled. In this exercise you have the advantage of hindsight, but the disadvantage of much less direct access to the raw data of the scientific practice of the time. But regardless of how it compares to the real task, this is practice. This is an opportunity to test theories and methods before committing to them. There is a limited amount of history to practice on, but it’s a lot more than the real event, the present.

Many say that they would notice if science died because engineering would grind to a halt or even regress. What does this heuristic say when applied to history? Does it match other criteria?

Many say that the Greeks were good at science and the Romans at engineering (perhaps also the Han vs the Song). This is not really compatible with the heuristic above. What options do we have to draw a coherent conclusion? Either science did not die, or engineering did not advance, or science is not so necessary for engineering; Either we are bad at judging science from history, or we are bad at judging engineering from history, or engineering is not a good heuristic for judging science. None of these are comforting for our ability to judge the future. The third is simply the rejection of the popular heuristic. The first two are the rejection of the exercise of history. But if we cannot judge history, we have no opportunity to practice. Worse, if we are unable to judge history, the present may be no easier.

One recourse is to posit that the past is difficult because of sparse information and that the future we experience ourselves will be easy to judge. But many people lived through the past; what did they think at the time? In particular, how did the Romans think they compared to the Greeks? Did they think that there was progress or regress? Did they agree with modern hindsight? They thought that the Greeks were good at science. Pop science books by Pliny and Seneca are really accounts of Greek knowledge. Similarly, Varro’s practical book of agriculture is based on dozens of Greek sources. And the Romans were proud of their engineering. Frotinus urged his readers to compared the Roman aqueducts to the idle pyramids and wonders of the Greeks. Maybe he should be discounted for his professional interest. But Pliny describes the Roman aqueducts as the most remarkable achievement in the world in the midst of account of Greek knowledge. Indeed, the modern conventional wisdom is probably simply copied from the Romans. Did the Romans endorse the third claim, that science was a prerequisite to engineering? I do not know. Perhaps the they held that it was necessary, but could be left to Greek slaves.

I think that this example should make people nervous about the heuristic about science and engineering. But people who don’t hold any such heuristic should be even more nervous.

I think I know what the answer is. I think that engineering did regress, but the Romans did not notice. They were too impressed by size, so they made bigger aqueducts, without otherwise improving on Greek techniques; and they failed to copy much other Greek technology. Perhaps the heuristic is fine, but it just passes the buck: how much can you trust your judgement of the state of engineering? On the other hand, I think that science regressed much more than engineering, so I do not think them as coupled as the heuristic suggests.

Would you notice if science died? How would you notice? Have you tried that method against history?

---

Some historical test cases: the transition from Greece to Rome; Han vs Tang vs Song; the Renaissance.

Note 1: I'm not very serious about the second part of the title, I just thought it sounds more catchy. I'm a long time lurker writing here for the first time, and it's not my intention to alienate anyone. Also, hi, nice to meet you. Please leave a comment to achieve a result of making me happy about you having left a comment. But let's get to the point.

I think you might be familiar with TED Talks. Recall the last time you watched one, and how you felt while doing it.

[BZRT BZRT sound of imagination working]

In my case, I often got the feeling like if I was learning something valuable while watching most TED Talks. The speakers are (mostly) obviously passionate and intelligent people, speaking about important matters they care about a lot. (Granted, I probably haven't watched more than a dozen TED Talks in all my life, so my sample is quite small, but I think it isn't very unrepresentative.)

But at some point, I started asking myself afterwards:

So, what have I actually learned?

Which translates in my internal dialect to:

For each major point, give a one-sentence summary and at least one example of how I could apply it.

(Note 2: don't treat this "one sentence summary" thing too strictly - of course it's only a reflex/shorthand that is useful in many situations, but not all. I like it because it's simple enough that it's installable as a subconscious trigger-action.)

And I could not state afterwards anything actually useful that I have learned from those "fascinating" videos (with at most one or two small exceptions).

This is exactly what I mean by "Education as Entertainment".

It's getting the enjoyable *feeling* of learning without any real progress.

[DUM DUM DUM sound of increasing dramatism]

And now, what if you use this concept to look at rationality materials?

For me, reading the core Eliezer's braindump (basically the content of "From AI to Zombies"), as well as braindumps (in the form of blogs) of several other people from the LW community, had definite learning value.

I take notes when I read those, and I have an accountability system in place that enables me to make sure I follow up on all the advice I give to myself, test the new ideas, and improve/drop/replace/implement as needed.

However, when I read (a significant part of) the content produced by the "modern" community-powered-LessWrong, I classify its actual learning value at around the same level as TED Talks.

Or YouTube videos with cats, only those don't give me the *impression* that I'm learning something.

THE END

Please let me know what you think.

Final Note: Please take my remarks with a grain of salt. What I write is meant to inspire thoughts in you, not to represent my best factual knowledge about the LW community.

I was asked to write up a pithy summary of the upshot of this paper. This is the best I could manage.

One of the most remarkable features of the world we live in is that we can make measurements that are consistent across space and time. By "consistent across space" I mean that you and I can look at the outcome of a measurement and agree on what that outcome was. By "consistent across time" I mean that you can make a measurement of a system at one time and then make the same measurement of that system at some later time and the results will agree.

It is tempting to think that the reason we can do these things is that there exists an objective reality that is "actually out there" in some metaphysical sense, and that our measurements are faithful reflections of that objective reality. This hypothesis works well (indeed, seems self-evidently true!) until we get to very small systems, where it seems to break down. We can still make measurements that are consistent across space and time, but as soon as we stop making measurements, then things start to behave very differently than they did before. The classical example of this is the two-slit experiment: whenever we look at a particle we only ever find it in one particular place. When we look continuously, we see the particle trace out an unambiguous and continuous trajectory. But when we don't look, the particle behaves as if it is in more than one place at once, a behavior that manifests itself as interference.

The problem of how to reconcile the seemingly incompatible behavior of physical systems depending on whether or not they are under observation has come to be called the measurement problem. The most common explanation of the measurement problem is the Copenhagen interpretation of quantum mechanics which postulates that the act of measurement changes a system via a process called wave function collapse. In the contemporary popular press you will often read about wave function collapse in conjunction with the phenomenon of quantum entanglement, which is usually referred to as "spooky action at a distance", a phrase coined by Einstein, and intended to be pejorative. For example, here's the headline and first sentence of the above piece:

More evidence to support quantum theory’s ‘spooky action at a distance’

It’s one of the strangest concepts in the already strange field of quantum physics: Measuring the condition or state of a quantum particle like an electron can instantly change the state of another electron—even if it’s light-years away." (emphasis added)

This sort of language is endemic in the popular press as well as many physics textbooks, but it is demonstrably wrong. The truth is that measurement and entanglement are actually the same physical phenomenon. What we call "measurement" is really just entanglement on a large scale. If you want to see the demonstration of the truth of this statement, read the paper or watch the video or read the original paper on which my paper and video are based. Or go back and read about Von Neumann measurements or quantum decoherence or Everett's relative state theory (often mis-labeled "many-worlds") or relational quantum mechanics or the Ithaca interpretation of quantum mechanics, all of which turn out to be saying exactly the same thing.

Which is: the reason that measurements are consistent across space and time is not because these measurements are a faithful reflection of an underlying objective reality. The reason that measurements are consistent across space and time is because this is what quantum mechanics predicts when you consider only parts of the wave function and ignore other parts.

Specifically, it is possible to write down a mathematical description of a particle and two observers as a quantum mechanical system. If you ignore the particle (this is a formal mathematical operation called a partial trace of an operator matrix ) what you are left with is a description of the observers. And if you then apply information theoretical operations to that, what pops out is that the two observers are in classically correlated states. The exact same thing happens for observations made of the same particle at two different times.

The upshot is that nothing special happens during a measurement. Measurements are not instantaneous (though they are very fast ) and they are in principle reversible, though not in practice.

The final consequence of this, the one that grates most heavily on the intuition, is that your existence as a classical entity is an illusion. Because measurements are not a faithful reflection of an underlying objective reality, your own self-perception (which is a kind of measurement) is not a faithful reflection of an underlying objective reality either. You are not, in point of metaphysical fact, made of atoms. Atoms are a very (very!) good approximation to the truth, but they are not the truth. At the deepest level, you are a slice of the quantum wave function that behaves, to a very high degree of approximation, as if it were a classical system but is not in fact a classical system. You are in a very real sense living in the Matrix, except that the Matrix you are living in is running on a quantum computer, and so you -- the very close approximation to a classical entity that is reading these words -- can never "escape" the way Neo did.

As a corollary to this, time travel is impossible, because in point of metaphysical fact there is no time. Your perception of time is caused by the accumulation of entanglements in your slice of the wave function, resulting in the creation of information that you (and the rest of your classically-correlated slice of the wave function) "remember". It is those memories that define the past, you could even say create the past. Going "back to the past" is not merely impossible it is logically incoherent, no different from trying to construct a four-sided triangle. (And if you don't buy that argument, here's a more prosaic one: having a physical entity suddenly vanish from one time and reappear at a different time would violate conservation of energy.)

Summary:

• Chronic Fatigue and Fibromyalgia look very like Hypothyroidism.
• Thyroid Patients aren't happy with either the diagnosis or treatment of Hypothyroidism.
• It is possible that lots of FMS/CFS cases are 'something wrong with the thyroid system that doesn't show up on laboratory hormone level tests'.
• It's possible that it's not too difficult to fix these CFS/FMS cases with thyroid hormones.
• I believe that there may have been a stupendous cock-up that's hurt millions.
• Less Wrong should be interested, because it could be a real example of how bad inference can cause the sciences to come to false conclusions, as well as a good practice problem for the things we really care about.

 

---

Edit:

 

I found a possible answer here:
http://lesswrong.com/lw/nbm/thyroid_hormones_chronic_fatigue_and_fibromyalgia/
I do not believe it, because I do not understand it, but contemplation of it seems to be enlightening. In particular, the problem is much broader than I originally thought.

A summary of the argument in the first two posts, together with links to lots of evidence in the literature:

http://lesswrong.com/r/discussion/lw/nef/the_thyroid_madness_core_argument_evidence/

And this is pretty much proof, I think:

http://lesswrong.com/lw/nhs/the_thyroid_madness_two_apparently_contradictory/

At this point, I think I'm as confident as I can be without some sort of formal trial (so 25% maybe?)

But certainly, if you're suffering from Chronic Fatigue Syndrome/Fibromyalgia/Major Depression/Irritable Bowel Syndrome, or any of the many similar disorders which just seem to be different names for 'hypothyroidism with normal TSH', I reckon this is worth trying!

I have done, and it worked for me. For about four months now...

 

---

 

Original Post:

 

I believe that I've come across a genuine puzzle, and I wonder if you can help me solve it. This problem is complicated, and subtle, and has confounded and defeated good people for forty years. And yet there are huge and obvious clues. No-one seems to have conducted the simple experiments which the clues suggest, even though many clever people have thought hard about it, and the answer to the problem would be very valuable. And so I wonder what it is that I am missing.

 

I am going to tell a story which rather extravagantly privileges a hypothesis that I have concocted from many different sources, but a large part of it is from the work of the late Doctor John C Lowe, an American chiropractor who claimed that he could cure Fibromyalgia.

 

I myself am drowning in confirmation bias to the point where I doubt my own sanity. Every time I look for evidence to disconfirm my hypothesis, I find only new reasons to believe. But I am utterly unqualified to judge. Three months ago I didn't know what an amino acid was. And so I appeal to wiser heads for help.

 

Crocker's Rules on this. I suspect that I am being the most spectacular fool, but I can't see why, and I'd like to know.

 

Setting the Scene

 

Chronic Fatigue Syndrome, Myalgic Encephalitis, and Fibromyalgia are 'new diseases'. There is considerable dispute as to whether they even exist, and if so how to diagnose them. They all seem to have a large number of possible symptoms, and in any given case, these symptoms may or may not occur with varying severity.

 

As far as I can tell, if someone claims that they're 'Tired All The Time', then a competent doctor will first of all check that they're getting enough sleep and are not unduly stressed, then rule out all of the known diseases that cause fatigue (there are a very lot!), and finally diagnose one of the three 'by exclusion', which means that there doesn't appear to be anything wrong, except that you're ill.

 

If widespread pain is one of the symptoms, it's Fibromyalgia Syndrome (FMS). If there's no pain, then it's CFS or ME. These may or may not be the same thing, but Myalgic Encephalitis is preferred by patients because it's greek and so sounds like a disease. Unfortunately Myalgic Encephalitis means 'hurty muscles brain inflammation', and if one had hurty muscles, it would be Fibromyalgia, and if one had brain inflammation, it would be something else entirely.

 

Despite the widespread belief that these are 'somatoform' diseases (all in the mind), the severity of them ranges from relatively mild (tired all the time, can't think straight), to devastating (wheelchair bound, can't leave the house, can't open one eye because the pain is too great).

 

All three seem to have come spontaneously into existence in the 1970s, and yet searches for the responsible infective agent have proved fruitless. Neither have palliative measures been discovered, apart from the tried and true method of telling the sufferers that it's all in their heads.

 

The only treatments that have proved effective are Cognitive Behavioural Therapy / Graded Exercise. A Cochrane Review reckoned that they do around 15% over placebo in producing a measurable alleviation of symptoms. I'm not very impressed. CBT/GE sound a lot like 'sports coaching', and I'm pretty sure that if we thought of 'Not Being Very Good at Rowing' as a somatoform disorder, then I could produce an improvement over placebo in a measurable outcome in ten percent of my victims without too much trouble.

 

But any book on CFS will tell you that the disease was well known to the Victorians, under the name of neurasthenia. The hypothesis that God lifted the curse of neurasthenia from the people of the Earth as a reward for their courage during the wars of the early twentieth century, while well supported by the clinical evidence, has a low prior probability.

 

We face therefore something of a mystery, and in the traditional manner of my people, a mystery requires a Just-So Story:

 

How It Was In The Beginning

 

In the dark days of Victoria, the brilliant physician William Miller Ord noticed large numbers of mainly female patients suffering from late-onset cretinism.

 

These patients, exhausted, tired, stupid, sad, cold, fat and emotional, declined steeply, and invariably died.

 

As any man of decent curiosity would, Dr Ord cut their corpses apart, and in the midst of the carnage noticed that the thyroid, a small butterfly-shaped gland in the throat, was wasted and shrunken.

 

One imagines that he may have thought to himself: "What has killed them may cure them."

 

After a few false starts and a brilliant shot in the dark by the brave George Redmayne Murray, Dr Ord secured a supply of animal thyroid glands (cheaply available at any butcher, sautée with nutmeg and basil) and fed them to his remaining patients, who were presumably by this time too weak to resist.

 

They recovered miraculously, and completely.

 

I'm not sure why Dr Ord isn't better known, since this appears to have been the first time in recorded history that something a doctor did had a positive effect.

 

Dr Ord's syndrome was named Ord's Thyroiditis, and it is now known to be an autoimmune disease where the patient's own antibodies attack and destroy the thyroid gland. In Ord's thyroiditis, there is no goiter.

 

A similar disease, where the thyroid swells to form a disfiguring deformity of the neck (goiter), was described by Hakaru Hashimoto in 1912 (who rather charmingly published in German), and as part of the war reparations of 1946 it was decided to confuse the two diseases under the single name of Hashimoto's Thyroiditis. Apart from the goiter, both conditions share a characteristic set of symptoms, and were easily treated with animal thyroid gland, with no complications.

 

Many years before, in 1835, a fourth physician, Robert James Graves, had described a different syndrome, now known as Graves' Disease, which has as its characteristic symptoms irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhoea, and weight loss. Unfortunately Dr Graves could not think how to cure his eponymous horror, and so the disease is still named after him.

 

The Horror Spreads

 

Victorian medicine being what it was, we can assume that animal glands were sprayed over and into any wealthy person unwise enough to be remotely ill in the vicinity of a doctor. I seem to remember a number of jokes about "monkey glands" in PG Wodehouse, and indeed a man might be tempted to assume that chimpanzee parts would be a good substitute for humans. Supply issues seem to have limited monkey glands to a few millionaires worried about impotence, and it may be that the corresponding procedure inflicted on their wives has come down to us as Hormone Replacement Therapy.

 

Certainly anyone looking a bit cold, tired, fat, stupid, sad or emotional is going to have been eating thyroids. We can assume that in a certain number of cases, this was just the thing, and I think it may also be safe to assume that a fair number of people who had nothing wrong with them at all died as a result of treatment, although the fact that animal thyroid is still part of the human food chain suggests it can't be that dangerous.

 

I mean seriously, these people use high pressure hoses to recover the last scraps of meat from the floors of slaughterhouses, they're not going to carefully remove all the nasty gristly throat-bits before they make ready meals, are they?

 

The Armour Sausage company, owner of extensive meat-packing facilities in Chicago, Illinois, and thus in possession of a large number of pig thyroids which, if not quite surplus to requirements, at the very least faced a market sluggish to non-existent as foodstuffs, brilliantly decided to sell them in freeze-dried form as a cure for whatever ails you.

 

 

Some Sort of Sanity Emerges, in a Decade not Noted for its Sanity

 

Around the time of the second world war, doctors became interested in whether their treatments actually helped, and an effort was made to determine what was going on with thyroids and the constellation of sadness that I will henceforth call 'hypometabolism', which is the set of symptoms associated with Ord's thyroiditis. Jumping the gun a little, I shall also define 'hypermetabolism' as the set of symptoms associated with Graves' disease.

 

The thyroid gland appeared to be some sort of metabolic regulator, in some ways analogous to a thermostat. In hypometabolism, every system of the body is running slow, and so it produces a vast range of bad effects, affecting almost every organ. Different sufferers can have very different symptoms, and so diagnosis is very difficult.

 

Dr Broda Barnes decided that the key symptom of hypometabolism was a low core body temperature. By careful experiment he established that in patients with no symptoms of hypometabolism the average temperature of the armpit on waking was 98 degrees Fahrenheit (or 36.6 Celsius). He believed that temperature variation of +/- 0.2 degrees Fahrenheit was unusual enough to merit diagnosis. He also seems to have believed, in the manner of the proverbial man with a hammer, that all human ailments without exception were caused by hypometabolism, and to have given freeze-dried thyroid to almost everyone he came into contact with, to see if it helped. A true scientist. Doctor Barnes became convinced that fully 40% of the population of America suffered from hypometabolism, and recommended Armour's Freeze Dried Pig Thyroid to cure America's ills.

 

In a brilliant stroke, Freeze Dried Pig's Thyroid was renamed 'Natural Desiccated Thyroid', which almost sounds like the sort of thing you might take in sound mind. I love marketing. It's so clever.

 

America being infested with religious lunatics, and Chicago being infested with nasty useless gristly bits of cow's throat, led almost inevitably to a second form of 'Natural Desiccated Thyroid' on the market.

 

Dr Barnes' hypometabolism test never seems to have caught on. There are several ways your temperature can go outside his 'normal' range, including fever (too hot), starvation (too cold), alcohol (too hot), sleeping under too many duvets (too hot), sleeping under too few duvets (too cold). Also mercury thermometers are a complete pain in the neck, and take ten minutes to get a sensible reading, which is a long time to lie around in bed carefully doing nothing so that you don't inadvertently raise your body temperature. To make the situation even worse, while men's temperature is reasonably constant, the body temperature of healthy young women goes up and down like the Assyrian Empire.

 

Several other tests were proposed. One of the most interesting is the speed of the Achilles Tendon Reflex, which is apparently super-fast in hypermetabolism, and either weirdly slow or has a freaky pause in it if you're running a bit cold. Drawbacks of this test include 'It's completely subjective, give me something with numbers in it', and 'I don't seem to have one, where am I supposed to tap the hammer-thing again?'.

 

By this time, neurasthenia was no longer a thing. In the same way that spiritualism was no longer a thing, and the British Empire was no longer a thing.

 

As far as we know, Chronic Fatigue Syndrome was not a thing either, and neither was Fibromyalgia (which is just Chronic Fatigue Syndrome but it hurts), nor Myalgic Encephalitis. There was something called 'Myalgic Neurasthenia' in 1934, but it seems to have been a painful infectious disease and they thought it was polio.

 

 

Finally, Science

 

It turned out that the purpose of the thyroid gland is to make hormones which control the metabolism. It takes in the amino acid tyrosine, and it takes in iodine. It releases Thyroglobulin, mono-iodo-tyrosine (MIT), di-iodo-tyrosine (DIT), thyroxine (T4) and triiodothyronine (T3) into the blood. The chemistry is interesting but too complicated to explain in a just-so story.

 

I believe that we currently think that thyroglobulin, MIT and DIT are simply by-products of the process that makes T3 and T4.

 

T3 is the hormone. It seems to control the rate of metabolism in all cells. T4 has something of the same effect, but is much less active, and called a 'prohormone'. Its main purpose seems to be to be deiodinated to make more T3. This happens outside the thyroid gland, in the other parts of the body ('peripheral conversion'). I believe mainly in the liver, but to some extent in all cells.

 

Our forefathers knew about thyroxine (T4, or thyronine-with-four-iodines-attached), and triiodothyronine (T3, or thyronine-with-three-iodines-attached)

 

It seems to me that just from the names, thyroxine was the first one to be discovered. But I'm not sure about that. You try finding a history-of-endocrinology website. At any rate they seem to have known about T4 and T3 fairly early on.

 

The mystery of Graves', Ord's and Hashimoto's thyroid diseases was explained.

 

Ord's and Hashimoto's are diseases where the thryoid gland under-produces (hypothyroidism). The metabolism of all cells slows down. As might be expected, this causes a huge number of effects, which seem to manifest differently in different sufferers.

 

Graves' disease is caused by the thyroid gland over-producing (hyperthyroidism). The metabolism of all cells speeds up. Again, there are a lot of possible symptoms.

 

All three are thought to be autoimmune diseases. Some people think that they may be different manifestations of the same disease. They are all fairly common.

 

Desiccated thryoid cures hypothyroidism because the ground-up thyroids contain T4 and T3, as well as lots of thyroglobulin, MIT and DIT, and they are absorbed by the stomach. They get into the blood and speed up the metabolism of all cells. By titrating the dose carefully you can restore roughly the correct levels of the thyroid hormones in all tissues, and the patient gets better. (Titration is where you change something carefully until you get it right)

 

The theory has considerable explanatory power. It explains cretinism, which is caused either by a genetic disease, or by iodine deficiency in childhood. If you grow up in an iodine deficient area, then your growth is stunted, your brain doesn't develop properly, and your thyroid gland may become hugely enlarged. Presumably because the brain is desperately trying to get it to produce more thyroid hormones, and it responds by swelling.

 

Once upon a time, this swelling (goitre) was called 'Derbyshire Neck'. I grew up near Derbyshire, and I remember an old rhyme: "Derbyshire born, Derbyshire bred, strong in the arm, and weak in the head". I always thought it was just an insult. Maybe not. Cretinism was also popular in the Alps, and there is a story of an English traveller in Switzerland of whom it was remarked that he would have been quite handsome if only he had had a goitre. So it must have been very common there.

 

But at this point I am *extremely suspicious*. The thyroid/metabolic regulation system is ancient (universal in vertebrates, I believe), crucial to life, and it really shouldn't just go wrong. We should suspect either an infectious cause, or a recent environmental influence which we haven't had time to adjust to, an evolved defence against an infectious disease, or just possibly, a recently evolved but as yet imperfect defence against a less recent environmental change.

 

(Cretinism in particular is very strange. Presumably animals in iodine-deficient areas aren't cretinous, and yet they should be. Perhaps a change to a farming from a hunter-gatherer lifestyle has increased our dependency on iodine from crops, which crops have sucked what little iodine occurs naturally out of the soil?)

 

It's also not entirely clear to me what the thyroid system is *for*. If there's just a particular rate that cells are supposed to run at, then why do they need a control signal to tell them that? I could believe that it was a literal thermostat, designed to keep the body temperature constant at the best speed for the various biological reactions, but it's universal in *vertebrates*. There are plenty of vertebrates which don't keep a constant temperature.

 

 

The Fall of Desiccated Thyroid

 

There turned out to be some problems with Natural Desiccated Thyroid (NDT).

 

Firstly, there were many competing brands and types, and even if you stuck to one brand the quality control wasn't great, so the dose you'd be taking would have been a bit variable.

 

Secondly, it's fucking pig's thyroid from an abattoir. It could have all sorts of nasty things in it. Also, ick.

 

Thirdly, it turned out that pigs made quite a lot more T3 in their thyroids than humans do. It also seems that T3 is better absorbed by the gut than T4 is, so someone taking NDT to compensate for their own underproduction will have too much of the active hormone compared to the prohormone. That may not be good news.

 

With the discovery of 'peripheral conversion', and the possibility of cheap clean synthesis, it was decided that modern scientific thyroid treatment would henceforth be by synthetic T4 (thyroxine) alone. The body would make its own T3 from the T4 supply.

 

Alarm bells should be ringing at this point. Apart from the above points, I'm not aware of any great reason for the switch from NDT to thyroxine in the treatment of hypothyroidism, but it seems to have been pretty much universal, and it seems to have worked.

 

Aware of the lack of T3, doctors compensated by giving people more T4 than was in their pig-thyroid doses. And there don't seem to have been any complaints.

 

Over the years, NDT seems to have become a crazy fringe treatment despite there not being any evidence against it. It's still a legal prescription drug, but in America it's only prescribed by eccentrics. In England a doctor prescribing it would be, at the very least, summoned to explain himself before the GMC.

 

However, since it was (a) sold over the counter for so many years, and (b) part of the food chain, it is still perfectly legal to sell as a food supplement in both countries, as long as you don't make any medical claims for it. And the internet being what it is, the prescription-only synthetic hormones T3 and T4 are easily obtained without a prescription. These are extremely powerful hormones which have an effect on metabolism. If 'body-builders' and sports cheats aren't consuming all three in vast quantities, I am a Dutchman.

 

The Clinical Diagnosis of Hypothyroidism

 

We pass now to the beginning of the 1970s.

 

Hypothyroidism is ferociously difficult to diagnose. People complain of 'Tired All The Time' well, ... all the time, and it has literally hundreds of causes.

 

And it must be diagnosed correctly! If you miss a case of hypothyroidism, your patient is likely to collapse and possibly die at some point in the medium-term future. If you diagnose hypothyroidism where it isn't, you'll start giving the poor bugger powerful hormones which he doesn't need and *cause* hypermetabolism.

 

The last word in 'diagnosis by symptoms' was the absolutely excellent paper:

Statistical Methods Applied To The Diagnosis Of Hypothyroidism

by W. Z. Billewicz, R. S. Chapman, J. Crooks, M. E. Day, J. Gossage, Sir Edward Wayne, and J. A. Young

Connoisseurs will note the clever and careful application of 'machine learning' techniques, before there were machines to learn!

 

One important thing to note is that this is a way of separating hypothyroid cases from other cases of tiredness at the point where people have been referred by their GP to a specialist at a hospital on suspicion of hypothyroidism. That changes the statistics remarkably. This is *not* a way of diagnosing hypothyroidism in the general population. But if someone's been to their GP (general practitioner, the doctor that a British person likely makes first contact with) and their GP has suspected their thryoid function might be inadequate, this test should probably still work.

 

For instance, they consider Physical Tiredness, Mental Lethargy, Slow Cerebration, Dry Hair, and Muscle Pain, the classic symptoms of hypothyroidism, present in most cases, to be indications *against* the disease.

 

That's because if you didn't have these things, you likely wouldn't have got that far. So in the population they're seeing (of people whose doctor suspects they might be hypothyroid), they're not of great value either way, but their presence is likely the reason why the person's GP has referred them even though they've really got iron-deficiency anaemia or one of the other causes of fatigue.

 

In their population, the strongest indicators are 'Ankle Jerk' and 'Slow Movements', subtle hypothyroid symptoms which aren't likely to be present in people who are fatigued for other reasons.

 

But this absolutely isn't a test you should use for population screening! In the general population, the classic symptoms are strong indicators of hypothyroidism.

 

Probability Theory is weird, huh?

 

Luckily, there were lab tests for hypothyroidism too, but they were expensive, complicated, annoying and difficult to interpret. Billewicz et al used them to calibrate their test, and recommend them for the difficult cases where their test doesn't give a clear answer.

 

And of course, the final test is to give them thyroid treatment and see whether they get better. If you're not sure, go slow, watch very carefully and look for hyper symptoms.

 

Overconfidence is definitely the way to go. If you don't diagnose it and it is, that's catastrophe. If it isn't, but you diagnose it anyway, then as long as you're paying attention the hyper symptoms are easy enough to spot, and you can pull back with little harm done.

 

A Better Way

 

It should be obvious from the above that the diagnosis of hypothyroidism by symptoms is absolutely fraught with complexity, and very easy to get wrong, and if you get it wrong the bad way, it's a disaster. Doctors were absolutely screaming for a decisive way to test for hypothyroidism.

 

Unfortunately, testing directly for the levels of thyroid hormones is very difficult, and the tests of the 1960s weren't accurate enough to be used for diagnosis.

 

The answer came from an understanding of how the thyroid regulatory system works, and the development of an accurate blood test for a crucial signalling hormone.

 

Three structures control the level of thyroid hormones in the blood.

 

The thyroid gland produces the hormones and secretes them into the blood.

 

Its activity is controlled by the hormone thyrotropin, or Thyroid Signalling Hormone (TSH). Lots of TSH works the thyroid hard. In the absence of TSH the thyroid relaxes but doesn't switch off entirely. However the basal level of thyroid activity in the absence of TSH is far too low.

 

TSH is controlled by the pituitary gland, a tiny structure attached to the brain.

 

The pituitary itself is controlled, via Thyroid Releasing Hormone (TRH), by the hypothalamus, which is part of the brain.

 

This was thought to be a classic example of a feedback control system.

 

hypothalamus->pituitary->thyroid

 

It turns out that the level of thyrotropin TSH in the blood is exquisitely sensitive to the levels of thyroid hormones in the blood.

 

Administer thyroid hormone to a patient and their TSH level will rapidly adjust downwards by an easily detectable amount.

 

So:

 

In hypothyroidism, where the thyroid has failed, the body will be desperately trying to produce more thyroid hormones, and the TSH level will be extremely high.

 

In Graves' Disease, this theory says, where the thyroid has grown too large, and the metabolism is running damagingly fast, the body will be, like a central bank trying to stimulate growth in a deflationary economy by reducing interest rates, 'pushing on a piece of string'. TSH will be undetectable.

 

The original TSH test was developed in 1965, by the startlingly clever method of radio-immuno-assay.

 

[For reasons that aren't clear to me, rather than being expressed in grams/litre, or mols/litre, the TSH test is expressed in 'international units/liter'. But I don't think that that's important]

 

A small number of people in whom there was no suspicion of thyroid disease were assessed, and the 'normal range' of TSH was calculated.

 

Again, 'endocrinology history' resources are not easy to find, but the first test was not terribly sensitive, and I think originally hyperthyroidism was thought to result in a complete absence of TSH, and that the highest value considered normal was about 4 (milli-international-units/liter).

 

This apparently pretty much solved the problem of diagnosing thyroid disorders.

 

Forgetfulness

 

It's no longer necessary to diagnose hypo- and hyper-thyroidism by symptoms. It was error prone anyway, and the question is easily decided by a cheap and simple test.

 

Natural Desiccated Thyroid is one with Nineveh and Tyre.

 

No doctor trained since the 1980s knows much about hypothyroid symptoms.

 

Medical textbooks mention them only in passing, as an unweighted list of classic symptoms. You couldn't use that for diagnosis of this famously difficult disease.

 

If you suspect hypothyroidism, you order a TSH test. If the value of TSH is very low, that's hyperthyroidism. If the value is very high then that's hypothyroidism. Otherwise you're 'euthyroid' (greek again, good-thyroid), and your symptoms are caused by some other problem.

 

The treatment for hyperthyroidism is to damage the thyroid gland. There are various ways. This often results in hypothyroidism. *For reasons that are not terribly well understood*.

 

The treatment for hypothyroidism is to give the patient sufficient thyroxine (T4) to cause TSH levels to come back into their normal range.

 

The conditions hyperthyroidism and hypothyroidism are now *defined* by TSH levels.

 

Hypothyroidism, in particular, a fairly common disease, is considered to be such a solved problem that it's usually treated by the GP, without involving any kind of specialist.

 

 

Present Day

 

It was found that the traditional amount of thyroxine (T4) administered to cure hypothyroid patients, was in fact too high. The amount of T4 that had always been used to replace the hormones that had once been produced by a thyroid gland now dead, destroyed, or surgically removed appeared now to be too much. That amount causes suppression of TSH to below its normal range. The brain, theory says, is asking for the level to be reduced.

 

The amount of T4 administered in such cases (there are many) has been reduced by a factor of around two, to the level where it produces 'normal' TSH levels in the blood. Treatment is now titrated to produce the normal levels of TSH.

 

TSH tests have improved enormously since their introduction, and are on their third or fourth generation. The accuracy of measurement is very good indeed.

 

It's now possible to detect the tiny remaining levels of TSH in overtly hyperthyroid patients, so hyperthyroidism is also now defined by the TSH test.

 

In England, the normal range is 0.35 to 5.5. This is considered to be the definition of 'euthyroidism'. If your levels are normal, you're fine.

 

If you have hypothyroid symptoms but a normal TSH level, then your symptoms are caused by something else. Look for Anaemia, look for Lyme Disease. There are hundreds of other possible causes. Once you rule out all the other causes, then it's the mysterious CFS/FMS/ME, for which there is no cause and no treatment.

 

If your doctor is very good, very careful and very paranoid, he might order tests of the levels of T4 and T3 directly. But actually the direct T4 and T3 tests, although much more accurate than they were in the 1960s, are quite badly standardised, and there's considerable controversy about what they actually measure. Different assay techniques can produce quite different readings. They're expensive. It's fairly common, and on the face of it perfectly reasonable, for a lab to refuse to conduct the T3 and T4 tests if the TSH level is normal.

 

It's been discovered that quite small increases in TSH actually predict hypothyroidism. Minute changes in thyroid hormone levels, which don't produce symptoms, cause detectable changes in the TSH levels. Normal, but slightly high values of TSH, especially in combination with the presence of thyroid related antibodies (there are several types), indicate a slight risk of one day developing hypothyroidism.

 

There's quite a lot of controversy about what the normal range for TSH actually is. Many doctors consider that the optimal range is 1-2, and target that range when administering thyroxine. Many think that just getting the value in the normal range is good enough. None of this is properly understood, to understate the case rather dramatically.

 

There are new categories, 'sub-clinical hypothyroidism' and 'sub-clinical hyperthyroidism', which are defined by abnormal TSH tests in the absence of symptoms. There is considerable controversy over whether it is a good idea to treat these, in order to prevent subtle hormonal imbalances which may cause difficult-to-detect long term problems.

 

Everyone is a little concerned about accidentally over-treating people, (remember that hyperthyroidism is now defined by TSH<0.35).

 

Hyperthyroidism has long been associated with Atrial Fibrillation (a heart problem), and Osteoporosis, both very nasty things. A large population study in Denmark recently revealed that there is a greater incidence of Atrial Fibrillation in sub-clinical hyperthyroidism, and that hypothyroidism actually has a 'protective effect' against Atrial Fibrillation.

 

It's known that TSH has a circadian rhythm, higher in the early morning, lower at night. This makes the test rather noisy, as your TSH level can be doubled or halved depending on what time of day you have the blood drawn.

 

But the big problems of the 1960s and 1970s are completely solved. We are just tidying up the details.

 

Doubt

 

Many hypothyroid patients complain that they suffer from 'Tired All The Time', and have some of the classic hypothyroid symptoms, even though their TSH levels have been carefully adjusted to be in the normal range.

 

I've no idea how many, but opinions range from 'the great majority of patients are perfectly happy' to 'around half of hypothyroid sufferers have hypothyroid symptoms even though they're being treated'.

 

The internet is black with people complaining about it, and there are many books and alternative medicine practitioners trying to cure them, or possibly trying to extract as much money as possible from people in desperate need of relief from an unpleasant, debilitating and inexplicable malaise.

 

THE PLURAL OF ANECDOTE IS DATA.

 

Not good data, to be sure. But if ten people mention to you in passing that the sun is shining, you are a damned fool if you think you know nothing about the weather.

 

It's known that TSH ranges aren't 'normally distributed' (in the sense of Gauss/the bell curve distribution) in the healthy population.

 

If you log-transform them, they do look a bit more normal.

 

The American Academy of Clinical Biochemists, in 2003, decided to settle the question once and for all. They carefully screened out anyone with even the slightest sign that there might be anything wrong with their thyroid at all, and measured their TSH very accurately.

 

In their report, they said (this is a direct quote):

 

In the future, it is likely that the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L because >95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.

 

Many other studies disagree, and propose wider ranges for normal TSH.

 

But if the AACB report were taken seriously, it would lead to diagnosis of hypothyroidism in vast numbers of people who are perfectly healthy! In fact the levels of noise in the test would put people whose thyroid systems are perfectly normal in danger of being diagnosed and inappropriately treated.

 

For fairly obvious reasons, biochemists have been extremely, and quite properly, reluctant to take the report of their own professional body seriously. And yet it is hard to see where the AACB have gone wrong in their report.

 

Neurasthenia is back.

 

A little after the time of the introduction of the TSH test, new forms of 'Tired All The Time' were discovered.

 

As I said, CFS and ME are just two names for the same thing. Fibromyalgia Syndrome (FMS) is much worse, since it is CFS with constant pain, for which there is no known cause and from which there is no relief. Most drugs make it worse.

 

But if you combine the three things (CFS/ME/FMS), then you get a single disease, which has a large number of very non-specific symptoms.

 

These symptoms are the classic symptoms of 'hypometabolism'. Any doctor who has a patient who has CFS/ME/FMS and hasn't tested their thyroid function is *de facto* incompetent. I think the vast majority of medical people would agree with this statement.

 

And yet, when you test the TSH levels in CFS/ME/FMS sufferers, they are perfectly normal.

 

All three/two/one are appalling, crippling, terrible syndromes which ruin people's lives. They are fairly common. You almost certainly know one or two sufferers. The suffering is made worse by the fact that most people believe that they're psychosomatic, which is a polite word for 'imaginary'.

 

And the people suffering are mainly middle-aged women. Middle-aged women are easy to ignore. Especially stupid middle-aged women who are worried about being overweight and obviously faking their symptoms in order to get drugs which are popularly believed to induce weight loss. It's clearly their hormones. Or they're trying to scrounge up welfare benefits. Or they're trying to claim insurance. Even though there's nothing wrong with them and you've checked so carefully for everything that it could possibly be.

 

But it's not all middle aged women. These diseases affect men, and the young. Sometimes they affect little children. Exhaustion, stupidity, constant pain. Endless other problems as your body rots away. Lifelong. No remission and no cure.

 

And I have Doubts of my Own

 

And I can't believe that careful, numerate Billewicz and his co-authors would have made this mistake, but I can't find where the doctors of the 1970s checked for the sensitivity of the TSH test.

 

Specificity, yes. They tested a lot of people who hadn't got any sign of hypothyroidism for TSH levels. If you're well, then your TSH level will be in a narrow range, which may be 0-6, or it may be 1-2. Opinions are weirdly divided on this point in a hard to explain way.

 

But Sensitivity? Where's the bit where they checked for the other arm of the conditional?

 

The bit where they show that no-one who's suffering from hypometabolism, and who gets well when you give them Desiccated Thyroid, had, on first contact, TSH levels outside the normal range.

 

If you're trying to prove A <=> B, you can't just prove A => B and call it a day. You couldn't get that past an A-level maths student. And certainly anyone with a science degree wouldn't make that error. Surely? I mean you shouldn't be able to get that past anyone who can reason their way out of a paper bag.

 

I'm going to say this a third time, because I think it's important and maybe it's not obvious to everyone.

 

If you're trying to prove that two things are the same thing, then proving that the first one is always the second one is not good enough.

 

IF YOU KNOW THAT THE KING OF FRANCE IS ALWAYS FRENCH, YOU DO *NOT* KNOW THAT ANYONE WHO IS FRENCH IS KING OF FRANCE.

 

It's possible, of course, that I've missed this bit. As I say, 'History of Endocrinology' is not one of those popular, fashionable subjects that you can easily find out about.

 

I wonder if they just assumed that the thyroid system was a thermostat. The analogy is still common today.

 

But it doesn't look like a thermostat to me. The thyroid system with its vast numbers of hormones and transforming enzymes is insanely, incomprehensibly complicated. And very poorly understood. And evolutionarily ancient. It looks as though originally it was the system that coordinated metamorphosis. Or maybe it signalled when resources were high enough to undergo metamorphosis. But whatever it did originally in our most ancient ancestors, it looks as though the blind watchmaker has layered hack after hack after hack on top of it on the way to us.

 

Only the thyroid originally, controlling major changes in body plan in tiny creatures that metamorphose.

 

Of course, humans metamorphose too, but it's all in the womb, and who measures thyroid levels in the unborn when they still look like tiny fish?

 

And of course, humans undergo very rapid growth and change after we are born. Especially in the brain. Baby horses can walk seconds after they're born. Baby humans take months to learn to crawl. I wonder if that's got anything to do with cretinism.

 

And I'm told that baby humans have very high hormone levels. I wonder why they need to be so hot? If it's a thermostat, I mean.

 

But then on top of the thyroid, the pituitary. I wonder what that adds to the system? If the thyroid's just a thermostat, or just a device for keeping T4 levels constant, why can't it just do the sensing itself?

 

What evolutionary process created the pituitary control over the thyroid? Is that the thermostat bit?

 

And then the hypothalamus, controlling the pituitary. Why? Why would the brain need to set the temperature when the ideal temperature of metabolic reactions is always 37C in every animal? That's the temperature everything's designed for. Why would you dial it up or down, to a place where the chemical reactions that you are don't work properly?

 

I can think of reasons why. Perhaps you're hibernating. Many of our ancestors must have hibernated. Maybe it's a good idea to slow the metabolism sometimes. Perhaps to conserve your fat supplies. Your stored food.

 

Perhaps it's a good idea to slow the metabolism in times of famine?

 

Perhaps the whole calories in/calories out thing is wrong, and people whose energy expenditure goes over their calorie intake have slow metabolisms, slowly sacrificing every bodily function including immune defence in order to avoid starvation.

 

I wonder at the willpower that could keep an animal sane in that state. While its body does everything it can to keep its precious fat reserves high so that it can get through the famine.

 

And then I remember about Anorexia Nervosa, where young women who want to lose weight starve themselves to the point where they no longer feel hungry at all. Another mysterious psychological disease that's just put down to crazy females. We really need some female doctors.

 

And I remember about Seth Robert's Shangri-La Diet, that I tried, to see if it worked, some years ago, just because it was so weird, where by eating strange things, like tasteless oil and raw sugar, you can make your appetite disappear, and lose weight. It seemed to work pretty well, to my surprise. Seth came up with it while thinking about rats. And apparently it works on rats too. I wonder why it hasn't caught on.

 

It seems, my female friends tell me, that a lot of diets work well for a bit, but then after a few weeks the effect just stops. If we think of a particular diet as a meme, this would seem to be its infectious period, where the host enthusiastically spreads the idea.

 

And I wonder about the role of the thyronine de-iodinating enzymes, and the whole fantastically complicated process of stripping the iodines and the amino acid bits from thyroxine in various patterns that no-one understands, and what could be going on there if the thyroid system were just a simple thermostat.

 

And I wonder about reports I am reading where elite athletes are finding themselves suffering from hypothyroidism in numbers far too large to be credible, if it wasn't, say, a physical response to calorie intake less than calorie output.

 

I've been looking ever so hard to find out why the TSH test, or any of the various available thyroid blood tests are a good way to assess the function of this fantastically complicated and very poorly understood system.

 

But every time I look, I just come up with more reasons to believe that they don't tell you very much at all.

 

 

The Mystery

 

Can anyone convince me that the converse arm has been carefully checked?

 

That everyone who's suffering from hypometabolism, and who gets well when you give them Desiccated Thyroid, has, before you fix them, TSH levels outside the normal range.

 

In other words, that we haven't just thrown, though carelessness, a long standing, perfectly safe, well tested treatment, for a horrible disabling disease that often causes excruciating pain, that the Victorians knew how to cure, and that the people of the 1950s and 60s routinely cured, away.

Most discussion of uploading talks of uploading from the inside out: simply, a biological person undergoes a disruptive procedure which digitises their mind. The digital mind then continues the person’s timeline as a digital existence, with all that entails.

 

The thing that stands out here is the disruptive nature of the process from biological to digital being. It is not only a huge step to undergo such a transformation, but few things in reality operate in such binary terms. More commonly, things happen gradually.

 

Being an entrepreneur and also having a keen interest in the future, I both respect audacious visions, and study how they come to be realised. Very rarely does progress come from someone investing a bunch of resources in a black-box process that ends in a world-changing breakthrough. Much more commonly, massive innovations are realised through a process of iteration and exploration, fueled by a need that motivates people to solve thousands of problems, big and small. Massive trends interact with other innovations to open up opportunities that when exploited cause a further acceleration of innovation. Every successful startup and technology, from Facebook to Tesla and from mobile phones to modern medicine can be understood in these terms.

 

With this lens in mind, how might uploading be realised? This is one potential timeline, barring AI explosion or existential catastrophy.

 

It is perhaps useful to explore the notion of “above/below the API”. A slew of companies have formed, often called “Uber for X” or “AirBnB for Y”, solving needs we have, through a computer system, such as a laptop or a mobile phone app. The app might issue a call to a server via an API, and that server may delegate the task to some other system, often powered by other humans. The original issuer of the command then gets their need covered, minimising direct contact with other humans, the traditional way of having our needs covered. It is crucial to understand that API-mediated interactions win because they are superior to their traditional alternative. Once they were possible, it was only natural for them to proliferate. As an example, compare the experience of taking a taxi with using Uber.

 

And so computer systems are inserted between human-to-human interactions. This post is composed on a computer, through which I will publish it in a digital location, where it might be seen by others. If I am to hear their response to it, it will also be mediated by APIs. Whenever a successful new API is launched, fortunes are made and lost. An entire industry, venture capital, exists to fund efforts to bring new APIs into existence, each new API making life easier for its users than what came before, and adding additional API layers.

 

As APIs flood interpersonal space, humans gain superpowers. Presence is less and less important, and a person anywhere in the connected world can communicate and effect change anywhere else. And with APIs comes control of personal space and time. Personal safety increases both by decreasing random physical contact and by always being connected to others who can send help if something goes wrong. The demand for connectivity and computation is driving networking everywhere, and the cost of hardware to fall through the floor.

 

Given the trends that are in motion, what’s next? Well, if computer-mediated experience is increasing, it might grow to the point where every interaction a human has with the world around them will be mediated by computers. If this sounds absurd, think of noise-cancelling headphones. Many of us now use them not to listen to music, but to block the sound from our environment. Or consider augmented reality. If the visual field, the data pipeline of the brain, can be used to provide critical, or entertaining, context about the physical environment, who would want to forego it? Consider biofeedback: if it’s easy to know at all times what is happening within our bodies and prevent things from going wrong, who wouldn’t want to? It’s not a question of whether these needs exist, but of when technology will be able to cover them.

 

Once most interaction is API-mediated, the digital world switches from opt-in to opt-out. It’s not a matter of turning the laptop on, but of turning it off for a while, perhaps to enjoy a walk in nature, or for a repair. But wouldn’t you want to bring your augmented reality goggles that can tell you the story of each tree, and ensure you’re not exposed to any pathogens as you wander in the biological jungle? As new generations grow up in a computer-mediated world, fewer and fewer excursions into the offline will happen. Technology, after all, is what was invented after you were born. Few of us consider hunting and gathering our food or living in caves to be a romantic return to the past. When we take a step backward, perhaps to signal virtue, like foregoing vaccination or buying locally grown food, we make sure our move will not deprive us of the benefits of the modern world.

 

Somewhere around the time when APIs close the loop around us or even before then, the human body will begin to be modified. Artificial limbs that are either plainly superior to their biological counterparts, or better adapted to that world will make sense, and brain-computer interfaces (whether direct or via the existing senses) will become ever more permanent. As our bodies are replaced with mechanical parts, the brain will come next. Perhaps certain simple parts will be easy to replace with more durable, better performing ones. Intelligence enhancement will finally be possible by adding processing power natural selection alone could never have evolved. Gradually, step by small step, the last critical biological components will be removed, as a final cutting of the cord with the physical world.

 

Humans will have digitised themselves, not by inventing a machine that takes flesh as input and outputs ones and zeroes, not by cyberpunk pioneers jumping into an empty digital world to populate it. We will have done it by making incremental choices, each one a sound rational decision that was in hindsight inevitable, incorporating inventions that made sense, and in the end it will be unclear when the critical step was made. We will have uploaded ourselves simply in the course of everyday life.

This text has many, many hyperlinks, it is useful to at least glance at frontpage of the linked material to get it. It is an expression of me thinking so it has many community jargon terms. Thank Oliver Habryka, Daniel Kokotajlo and James Norris for comments. No, really, check the front page of the hyperlinks. 

• Why I Grew Skeptical of Transhumanism
• Why I Grew Skeptical of Immortalism
• Why I Grew Skeptical of Effective Altruism
• Only Game in Town

 

Wonderland’s rabbit said it best: The hurrier I go, the behinder I get.

 

We approach 2016, and the more I see light, the more I see brilliance popping everywhere, the Effective Altruism movement growing, TEDs and Elons spreading the word, the more we switch our heroes in the right direction, the behinder I get. But why? - you say.

Clarity, precision, I am tempted to reply. I have left the intellectual suburbs of Brazil, straight into the strongest hub of production of things that matter, The Bay Area, via Oxford’s FHI office, I now split my time between UC Berkeley, and the CFAR/MIRI office. In the process, I have navigated an ocean of information, read hundreds of books, papers, saw thousands of classes, became proficient in a handful of languages and a handful of intellectual disciplines. I’ve visited the Olympus and I met our living demigods in person as well.

Against the overwhelming forces of an extremely upbeat personality surfing a hyper base-level happiness, these three forces: approaching the center, learning voraciously, and meeting the so-called heroes, have brought me to the current state of pessimism.

I was a transhumanist, an immortalist, and an effective altruist.

 

Why I Grew Skeptical of Transhumanism

The transhumanist in me is skeptical of technological development fast enough for improving the human condition to be worth it now, he sees most technologies as fancy toys that don’t get us there. Our technologies can’t and won’t for a while lead our minds to peaks anywhere near the peaks we found by simply introducing weirdly shaped molecules into our brains. The strangeness of Salvia, the beauty of LSD, the love of MDMA are orders and orders of magnitude beyond what we know how to change from an engineering perspective. We can induce a rainbow, but we don’t even have the concept of force yet. Our knowledge about the brain, given our goals about the brain, is at the level of knowledge of physics of someone who found out that spraying water on a sunny day causes the rainbow. It’s not even physics yet.

Believe me, I have read thousands of pages of papers in the most advanced topics in cognitive neuroscience, my advisor spent his entire career, from Harvard to Tenure, doing neuroscience, and was the first person to implant neurons that actually healed a brain to the point of recovering functionality by using non-human neurons. As Marvin Minsky, who invented the multi-agent computational theory of mind, told me: I don’t recommend entering a field where every four years all knowledge is obsolete, they just don’t know it yet.

 

Why I Grew Skeptical of Immortalism

The immortalist in me is skeptical because he understands the complexity of biology from conversations with the centimillionaires and with the chief scientists of anti-aging research facilities worldwide, he met the bio-startup founders and gets that the structure of incentives does not look good for bio-startups anyway, so although he was once very excited about the prospect of defeating the mechanisms of ageing, back when less than 300 thousand dollars were directly invested in it, he is now, with billions pledged against ageing, confident that the problem is substantially harder to surmount than the number of man-hours left to be invested in the problem, at least during my lifetime, or before the Intelligence Explosion.

Believe me, I was the first cryonicist among the 200 million people striding my country, won a prize for anti-ageing research at the bright young age of 17, and hang out on a regular basis with all the people in this world who want to beat death that still share in our privilege of living, just in case some new insight comes that changes the tides, but none has come in the last ten years, as our friend Aubrey will be keen to tell you in detail.

 

Why I Grew Skeptical of Effective Altruism

The Effective Altruist is skeptical too, although less so, I’m still founding an EA research institute, keeping a loving eye on the one I left behind, living with EAs, working at EA offices and mostly broadcasting ideas and researching with EAs. Here are some problems with EA which make me skeptical after being shook around by the three forces:

1. The Status Games: Signalling, countersignalling, going one more meta-level up, outsmarting your opponent, seeing others as opponents, my cause is the only true cause, zero-sum mating scarcity, pretending that poly eliminates mating scarcity, founders X joiners, researchers X executives, us institutions versus them institutions, cheap individuals versus expensive institutional salaries, it's gore all the way up and down.

2. Reasoning by Analogy: Few EAs are able to and doing their due intellectual diligence. I don’t blame them, the space of Crucial Considerations is not only very large, but extremely uncomfortable to look at, who wants to know our species has not even found the stepping stones to make sure that what matters is preserved and guaranteed at the end of the day? It is a hefty ordeal. Nevertheless, it is problematic that fewer than 20 EAs (one in 300?) are actually reasoning from first principles, thinking all things through from the very beginning. Most of us are looking away from at least some philosophical assumption or technological prediction. Most of us are cooks and not yet chefs. Some of us have not even waken up yet.

3. Babies with a Detonator: Most EAs still carry their transitional objects around, clinging desperately to an idea or a person they think more guaranteed to be true, be it hardcore patternism about philosophy of mind, global aggregative utilitarianism, veganism, or the expectation of immortality.

4. The Size of the Problem: No matter if you are fighting suffering, Nature, Chronos (death), Azathoth (evolutionary forces) or Moloch (deranged emergent structures of incentives), the size of the problem is just tremendous. One completely ordinary reason to not want to face the problem, or to be in denial, is the problem’s enormity.

5. The Complexity of The Solution: Let me spell this out, the nature of the solution is not simple in the least. It’s possible that we luck out and it turns out the Orthogonality Thesis and the Doomsday Argument and Mind Crime are just philosophical curiosities that have no practical bearing in our earthly engineering efforts, that the AGI or Emulation will by default fall into an attractor basin which implements some form of MaxiPok with details that it only grasps after CEV or the Crypto, and we will be Ok. It is possible, and it is more likely than that our efforts will end up being the decisive factor. We need to focus our actions in the branches where they matter though.

6. The Nature of the Solution: So let’s sit down side by side and stare at the void together for a bit. The nature of the solution is getting a group of apes who just invented the internet from everywhere around the world, and get them to coordinate an effort that fills in the entire box of Crucial Considerations yet unknown - this is the goal of Convergence Analysis, by the way - find every single last one of them to the point where the box is filled, then, once we have all the Crucial Considerations available, develop, faster than anyone else trying, a translation scheme that translates our values to a machine or emulation, in a physically sound and technically robust way (that’s if we don’t find a Crucial Consideration otherwise which, say, steers our course towards Mars). Then we need to develop the engineering prerequisites to implement a thinking being smarter than all our scientists together who can reflect philosophically better than the last two thousand years of effort while becoming the most powerful entity in the universe’s history, that will fall into the right attractor basin within mindspace. That’s if Superintelligences are even possible technically. Add to that we or it have to guess correctly all the philosophical problems that are A)Relevant B)Unsolvable within physics (if any) or by computers, all of this has to happen while the most powerful corporations, States, armies and individuals attempt to seize control of the smart systems themselves. without being curtailed by the hindrance counter incentive of not destroying the world either because they don’t realize it, or because the first mover advantage seems worth the risk, or because they are about to die anyway so there’s not much to lose.

7. How Large an Uncertainty: Our uncertainties loom large. We have some technical but not much philosophical understanding of suffering, and our technical understanding is insufficient to confidently assign moral status to other entities, specially if they diverge in more dimensions than brain size and architecture. We’ve barely scratched the surface of technical understanding on happiness increase, and philosophical understanding is also in its first steps.

8. Macrostrategy is Hard: A Chess Grandmaster usually takes many years to acquire sufficient strategic skill to command the title. It takes a deep and profound understanding of unfolding structures to grasp how to beam a message or a change into the future. We are attempting to beam a complete value lock-in in the right basin, which is proportionally harder.

9. Probabilistic Reasoning = Reasoning by Analogy: We need a community that at once understands probability theory, doesn’t play reference class tennis, and doesn’t lose motivation by considering the base rates of other people trying to do something, because the other people were cooks, not chefs, and also because sometimes you actually need to try a one in ten thousand chance. But people are too proud of their command of Bayes to let go of the easy chance of showing off their ability to find mathematically sound reasons not to try.

10. Excessive Trust in Institutions: Very often people go through a simplifying set of assumptions that collapses a brilliant idea into an awful donation, when they reason:
    I have concluded that cause X is the most relevant
    Institution A is an EA organization fighting for cause X
    Therefore I donate to institution A to fight for cause X.
    To begin with, this is very expensive compared to donating to any of the three P’s: projects, people or prizes. Furthermore, the crucial points to fund institutions are when they are about to die, just starting, or building a type of momentum that has a narrow window of opportunity where the derivative gains are particularly large or you have private information about their current value. To agree with you about a cause being important is far from sufficient to assess the expected value of your donation.

11. Delusional Optimism: Everyone who like past-me moves in with delusional optimism will always have a blind spot in the feature of reality about which they are in denial. It is not a problem to have some individuals with a blind spot, as long as the rate doesn’t surpass some group sanity threshold, yet, on an individual level, it is often the case that those who can gaze into the void a little longer than the rest end up being the ones who accomplish things. Staring into the void makes people show up.

12. Convergence of opinions may strengthen separation within EA:  Thus far, the longer someone is an EA for, the more likely they are to transition to an opinion in the subsequent boxes in this flowchart from whichever box they are at at the time. There are still people in all the opinion boxes, but the trend has been to move in that flow. Institutions however have a harder time escaping being locked into a specific opinion. As FHI moves deeper into AI, and GWWC into poverty, 80k into career selection etc… they become more congealed. People’s opinions are still changing, and some of the money follows, but institutions are crystallizing into some opinions, and in the future they might prevent transition between opinion clusters and free mobility of individuals, like national frontiers already do. Once institutions, which in theory are commanded by people who agree with institutional values, notice that their rate of loss towards the EA movement is higher than their rate of gain, they will have incentives to prevent the flow of talent, ideas and resources that has so far been a hallmark of Effective Altruism and why many of us find it impressive, it’s being an intensional movement. Any part that congeals or becomes extensional will drift off behind, and this may create unsurmountable separation between groups that want to claim ‘EA’ for themselves.

 

Only Game in Town

 

The reasons above have transformed a pathological optimist into a wary skeptical about our future, and the value of our plans to get there. And yet, I don’t see other option than to continue the battle. I wake up in the morning and consider my alternatives: Hedonism, well, that is fun for a while, and I could try a quantitative approach to guarantee maximal happiness over the course of the 300 000 hours I have left. But all things considered, anyone reading this is already too close to the epicenter of something that can become extremely important and change the world to have the affordance to wander off indeterminately. I look at my high base-happiness and don’t feel justified in maximizing it up to the point of no marginal return, there clearly is value elsewhere than here (points inwards), clearly the self of which I am made has strong altruistic urges anyway, so at least above a threshold of happiness, has reason to purchase the extremely good deals in expected value happiness of others that seem to be on the market. Other alternatives? Existentialism? Well, yes, we always have a fundamental choice and I feel the thrownness into this world as much as any Kierkegaard does. Power? When we read Nietzsche it gives that fantasy impression that power is really interesting and worth fighting for, but at the end of the day we still live in a universe where the wealthy are often reduced to having to spend their power in pathetic signalling games and zero sum disputes or coercing minds to act against their will. Nihilism and Moral Fictionalism, like Existentialism all collapse into having a choice, and if I have a choice my choice is always going to be the choice to, most of the time, care, try and do.

Ideally, I am still a transhumanist and an immortalist. But in practice, I have abandoned those noble ideals, and pragmatically only continue to be an EA.

It is the only game in town.

Eight months ago, I announced that the Less Wrong Study Hall, a virtual coworking space where people do pomodoros together, has moved to Complice. Complice is a software system I made to help people achieve their goals. About 20% of rationalists who've tried it have started using it full-time, which by my math gives signing up positive expected value. Anyway...

What follows is a brief history of the LWSH's development thus far. If you just wanna try it, click here: complice.co/room/lesswrong

By embedding the original tinychat window within a larger page, I let users see what the pomodoro timer was up to as soon as they joined, and the page also doesn't let breaks run overtime because the timer just keeps ticking. Also, users could now show a persistent status of what they're working on.

Cross-posted from my blog here.

One of the greatest successes of mankind over the last few centuries has been the enormous amount of wealth that has been created. Once upon a time virtually everyone lived in grinding poverty; now, thanks to the forces of science, capitalism and total factor productivity, we produce enough to support a much larger population at a much higher standard of living.

EAs being a highly intellectual lot, our preferred form of ritual celebration is charts. The ordained chart for celebrating this triumph of our people is the Declining Share of People Living in Extreme Poverty Chart.

(Source)

However, as a heretic, I think this chart is a mistake. What is so great about reducing the share? We could achieve that by killing all the poor people, but that would not be a good thing! Life is good, and poverty is not death; it is simply better for it to be rich.

As such, I think this is a much better chart. Here we show the world population. Those in extreme poverty are in purple – not red, for their existence is not bad. Those who the wheels of progress have lifted into wealth unbeknownst to our ancestors, on the other hand, are depicted in blue, rising triumphantly.

Long may their rise continue.