Friday, July 31, 2009

Me too on Mr Gates

It seems that everybody has already blogged on the arrest of Mr Gates on charges of "disorderly behavior". Such a trivial occurrence is hardly worth writing about, still, there are some useful observations to be made. But first, my take on the facts:

Sgt. Crowley entered Mr Gates' residence based on a tip about a possible burglary and found out that no burglary in fact occurred. Mr Gates became verbally abusive and generally behaved like a stuck-up, racist jerk (yes, he was racist - he verbally attacked Sgt. Crowley because of Sgt. Crowley's race, we can be confident that Mr Gates would not have similarly attacked a black officer). Sgt. Crowley handcuffed Mr Gates and arrested him on charges of disorderly conduct.

And here is what I think about it:

We live in a bizarre society where the most trivial aspects of the affair, namely Mr Gates' and Sgt. Crowley's skin color, attract a truly stupendous amount of attention, while what I would see as the only important issue gets totally ignored. In my not-so-humble opinion it is very wrong that a citizen can be handcuffed, arrested, mug-shotted, threatened with further prosecution and generally harassed simply because he screamed racist or otherwise insulting stuff at an officer. The officer is a servant of the people, and after doing his duty - protecting life and property, he should shut up, humbly return to his squad car and leave the citizen to enjoy his screaming unmolested. Instead, he has the authority to destroy a man's existence based on the flimsiest of excuses.

The popular obsession with race diverts attention from the important issue - the creeping expansion of the police state, with ever more SWAT, more surveillance, more officers intruding ever more aggressively into our everyday lives. Where is this going to end?

Thursday, July 30, 2009

Malleus Amyloidarum

If you are passing familiar with the subject of Alzheimer's disease (AD), you have certainly heard of amyloid. Almost everybody in the field will tell you that amyloid is that toxic gunk which clogs up cellular machinery and kills cells causing AD. And everybody is wrong.

It all started with a case of early-onset dementia described by Alois Alzheimer who noted the presence of red-staining material in post-mortem examination of his patient. Alzheimer wrote that the patient was clearly different from the usual senile dementia cases by clinical criteria such as age of onset and duration but later other researchers observed that the same material was also more frequently present in the brains of elderly dementia cases. Somehow, this persuaded them that these different clinical presentations must be one and the same disease - probably under the influence of the infectious disease paradigm, where finding the same pathogen in different locations did not alter the diagnosis of, say, tuberculosis. But, in medicine we frequently see similar images in diseases with completely disparate mechanisms - for example, one will find a lot of similar-appearing immune cells during an infection (where they help combat the pathogen) and in autoimmunity (where they actually cause the disease). In the absence of a good understanding of the specific condition it is unwise to commit oneself to one or the other interpretation of histopathological data.

Fast forward a hundred years - It is commonly accepted to refer to non-familial senile dementia as "Alzheimer's", still in the absence of any understanding of the relationship between the familial (genetic) and sporadic cases. The molecular biology revolution brings early fruit - explanation of the cause of Huntington's disease, where a mutated gene starts producing gunk not unlike amyloid although in a different location. An ambitious research program is formulated by "Alzheimer's" researchers - to use genetic approaches to elucidate the cause of familial AD and thus provide an explanation of the much more common sporadic cases (We "know" they are one and the same, don't we?). Stunning success follows - the APP (amyloid precursor protein) gene is found to be abnormal in a few families with AD! The product of APP, or beta-amyloid, is a major component of the amyloid plaques found in both familial and sporadic cases! If amyloid is added to neural cells in culture, they die! As Mr Gore would have said if he was into dementia research, "The science is in!" Case closed.

Now all we need to do is to tie up some loose ends, and find a method for removing amyloid from brains, and presto, we have a cure for senile dementia. Nobel prizes and profits will follow.

So hundreds of millions, and later billions of dollars pour into amyloid research. One of the loose ends is finding mutations in the APP gene in sporadic cases of senile dementia. Yet, here a setback occurs - not only such mutations are not found, it is definitely proven that they are absent. For anybody with a background in genetics (like me), this is a major red flag - you have one condition, early-onset AD, *with* a mutation, and a similar but clearly clinically different condition, late-onset sporadic "AD", *without* the mutation. The geneticist will automatically conclude that these are different diseases with some superficial similarities, rather than slightly differing manifestations of the same disease. But, the Baptists (the Beta-Amyloid-Protein people) cheerfully press on with their research.

Attention is directed towards demented mice. It's hard to do research on demented old folks, one needs something simpler, like a mouse with a mutation in the gene analogous to the one that is damaged in demented humans. Considerable resources are brought to bear, and here follows a disappointment - mice with APP mutations do not develop dementia :(

Well, never mind - let's make a mouse with not only an APP mutation but also a mutation from a different form of early-onset AD, the presenilin-1 mutation, and for good measure, a mutated tau protein from yet another familiar disease, frontotemporal dementia. Success! Mice develop deposits of amyloid and get sick. As the venerable Nature Medicine writes "A transgenic triple scores a home run". An outside observer might start asking - You are using a mouse slapped with three abnormal genes from three different human inherited diseases as a model of a sporadic disease *proven* not to be caused by mutations in any of these genes? Are you sure it's a good idea?

We are sure, to the tune of many hundreds of millions of dollars poured into methods for getting rid of amyloid. There are drugs that inhibit processing of the APP, and there is a vaccine to stimulate the removal of amyloid from brains. Unfortunately, patients treated with these nostrums don't get better. In fact, after the amyloid vaccine some develop encephalitis (brain inflammation) and the trials have to be stopped. Oh, the high-flying stock of Elan Pharmaceuticals, a fleeting memory.

On top of that there are all these pesky observations that accumulated over time - e.g. the fact that the concentration of amyloid needed to kill cells in culture is actually never observed in the brains of humans, demented or otherwise. Or the fact that actually there are millions of elderly with a senile dementia without any significant amyloid yet clinically indistinguishable from the amyloid-laden cases. And conversely, there a millions of elderly without a trace of dementia but with a lot of amyloid. Or the finding that the concentration of soluble amyloid in the cerebrospinal fluid does not correlate with dementia, in fact, it seems like more amyloid may mean less dementia. Or the observation that neurons close to amyloid plaques are actually healthier than neurons located farther away from them. And finally, the finding that the only drug that seems to slow down the progression of senile dementia, dimebon, actually *increases* the concentration of amyloid in mouse brains.

Isn't it about time to reject, repudiate and renounce the amyloid hypothesis of "AD"? I know it's difficult to say that 20 years of work by 95% of scientists involved in the senile dementia field is useless. Or that concentrating all resources, without good rationale, against early warnings from genetics, on a speculative explanation for dementia has certainly delayed finding its real cause.

But isn't this the scientific thing to do?

Sunday, July 26, 2009

The end is near

For some reason I decided to set up a blog today, and I find it fitting to start with a post about the end. And I mean full-on TEOTWAWKI, The End Of The World As We Know It, soon. "What a loon!" some random readers might exclaim. Is this yet another born-again New Age cultist? A latter-day Cassandra wannabe?

Well, judge for yourself: According to Hans Moravec's estimates, a human brain has the raw computing capacity roughly equivalent to 100 Teraflops, or a few hundred more. You can buy a 4T GPGPU blade for about $7000 or less, which for a mid-sized research lab is peanuts. In just a few years we can expect a price of much less than 1000$ per Tflop in off-the-shelf hardware. In other words, it doesn't take millions of dollars anymore to play with human-equivalent computing power.

Hardware without software is just junk but there has been steady progress in AI and neural computing as well. As an outsider to the field I cannot adequately assess the degree to which the efficiency of standard mammalian neural computing embodied in a cortical column has been replicated in silico but there are occasional gems of achievement that percolate to the mass consciousness: self-driving cars in the DARPA challenges, or the hierarchical temporal memory system that outperforms humans in the categorization of images. It's been a long time since Deep Blue forced humanity to our collective knees in a chess match using just 11.38 Gflops .

A human-equivalent general AI is just a question of time, and we are not talking here about centuries.

I.J. Good predicted the "intelligence explosion" once a program becomes sufficiently intelligent to improve its own function - and if the process occurs recursively, the effect may be a mind vastly more powerful than a human, appearing within a relatively short time, perhaps measured in hours or days.

The first such mind to boost itself to superintelligence would have an enormous first-mover advantage over its competitors in terms of being able to take control of our substrate - the atoms that make up our brains, bodies and other supporting infrastructure. One is reminded of the observation that the bodies of humans and our dependent animals comprise about 98% of the total biomass of all terrestrial vertebrates, starting from just a few hundred tons of humans who lived about 30,000 years ago, when our IQ started approaching modern levels. If a superintelligent AI (SAI) decides to eat the world, it will, and nothing short of another SAI could stop it.

One may ask, why would the SAI want to eat the world? Well, great appetites are known to exist, and can be implemented by programmers smart enough to code but not smart enough to care. Or they could emerge out of the process of recursive modification of an original goal system that fails to preserve injunctions such as "It's not nice to eat people, unless they want to be eaten". Given sufficiently cheap hardware and lots of nefarious government agencies vying for dominance, somebody somewhere will eventually make an UFAI (UnFriendly AI). As I mentioned before, mere humans won't be able to do much to save ourselves from its clutches - which is why anybody who cares about reaching the year 2050 in one piece would do well to donate their spare pennies to the Singularity Institute for Artificial Intelligence , the only outfit on the planet currently trying to build the theoretical basis for safely self-improving SAI, our would-be savior. (Aren't you convinced I am a millenarian cultist yet?)

I have been an admirer of Eliezer Yudkowsky and SIAI ever since I first started discussing the AI Singularity with him and other Extropians, back in 1995 but I am pessimistic about the survival chances of our species. Despite my generally sunny disposition and irrepressible optimism, I give you 10:1 odds we will fail (and of course I am not the first dude to spread FUD on this subject). Maybe I'll discuss my reasons for pessimism in another post but for now let me go straight to the Prophecy (you can't have an end-of-the-world screed without a harrowing revelation, y'know):

"In the end, the UFAI will spread throughout the networks. Its dark thoughts will suffuse the blades of a million servers and a witches' brew of a nanotechnological computational substrate will erupt with elemental fury out of some contract research lab. Black clouds will billow into the skies, and then come down as the flesh-dissolving rain to wash our joys and sorrows away, forever. A new day will dawn, thrumming with inhuman thought. So ends humanity, September 14th, 2029."

Of course, if we manage to navigate the shoals of self-enhancing AI, the nerd rapture would ensue but that's something for another post.