What are you going to simulate?

The EU is sinking €1.2bn (and the US is proposing to spend more, $3 billion) into a colossal project to build a supercomputer simulation of the human brain. To which I say, “What the hell? We aren’t even close to building such a thing for a fruit fly brain, and you want to do that for an even more massive and poorly mapped structure? Madness!” It turns out that I’m not the only one thinking this way: European scientists are exasperated with the project.

"The main apparent goal of building the capacity to construct a larger-scale simulation of the human brain is radically premature," Peter Dayan, director of the computational neuroscience unit at UCL, told the Guardian.

"We are left with a project that can’t but fail from a scientific perspective. It is a waste of money, it will suck out funds from valuable neuroscience research, and would leave the public, who fund this work, justifiably upset," he said.

There is a place for Big Science. I’d suggest that when you’re at the preliminary exploratory stage, as we are with human brain function, it’s better to fund many small exploratory parties to map out the terrain, rather than launching a huge invasion with charts that are made out of speculation. We know a computer simulation is going to fail, because we don’t know what it’s going to simulate. So why are they doing this? Maybe it’s a question of who “they” are.

Alexandre Pouget, a signatory of the letter at Geneva University, said that while simulations were valuable, they would not be enough to explain how the brain works. "There is a danger that Europe thinks it is investing in a big neuroscience project here, but it’s not. It’s an IT project," he said. "They need to widen the scope and take advantage of the expertise we have in neuroscience. It’s not too late. We can fix it. It’s up to Europe to make the right decision."

I’ve noticed this, that a lot of gung-ho futurists and computer scientist types have this very naive vision of how the brain works — it’s just another computer. We can build those. Build a big enough computer, and it’ll be just like the brain. Nope. That’s operating on ignorance. And handing ignorant people billions of dollars to implement a glorious model of their ignorance is an exercise in futility.

Closure on the Obokata/STAP affair

I’ve been following the story of stimulus-triggered acquisition of pluripotency (STAP) cells with considerable interest, and there’s a good reason for that: from the very beginning, it contradicted how I’d always thought about cell states, and if it were true, I’d have to rethink a lot of things, which was vexing. But on the other hand, empirical results always trump mental models, so if the results held up, there was no question but that I’d have to go through that uncomfortable process of reorganizing my preconceptions. It would be OK, though, because there’d be a great prize at the end.

Well, it turns out that I don’t have to reboot my brain after all, because now that all the flailing about is over, STAP is a product of sloppiness and fakery, and is dead.

So here’s the controversy, and why I found it vexatious. We want to be able to specify cell states; in particular, we’d love to be able to take any cell from the human body, tickle it with a few specific signals, and see it throw away all of its historical constraints and become a different cell type altogether. In particular, the Holy Grail is to find the right combination of switches to cause any cell to become a pluripotent stem cell — the kind of cell we can then induce to become any other cell type we might need.

We know this can’t be impossible, and is probably even fairly simple, because we know that cells can do this already (well, to some degree; your body accomplishes this task by setting aside reserve populations of stem cells. It’s also likely that some cell types are so tightly locked in by the process of differentiation that their state is not reversible). The idea is that we just need to find the right combination of signals/genes — the right kind of key — and we can unlock the cell, and make it open to additional inductions that will allow us to manipulate it.

We have some idea of the shape of the key. Yamanaka identified four genes, Oct4, Sox2, cMyc, and Klf4, that when activated, switched cells into a pluripotent state, making induced pluripotent stem cells, or iPS cells. It works. The handicap right now is that we only have a kind of brute force method of switching those genes on, and two of them are oncogenic, so it’s as if we’ve got a rather clumsy key that opens the lock, but also damages it in unfortunate ways. The resolution to that problem, though, was learning how to finesse the genes — we need to figure out how to more delicately switch on the necessary genes by a way other than bluntly transfecting cells with copies of the genes that are always on.

Then along came Haruko Obokata, an investigator in Japan who announced that she could induce stem cells with simple, generic stress, such as by exposing them to acid or physically pushing on the cells. It was like saying she didn’t need a specific key, all you needed to do was shake the lock really hard, and it would spontaneously pop open. What, really? That just seems too simple. It would be phenomenally awesome if true, but it seemed unlikely. But then, I remember this one lab I worked in where all the publicly popular drugs, like ketamine, were kept locked in a drawer to which only the PI had a key…but the countertop wasn’t secured to the bench, so if you knew about it, you could just lift the top and get easy access. It was a backdoor to the goodies that was so stupid you couldn’t believe it existed, but it did.

Could it be that cells similarly had a stupid weakness that could be so easily exploited? The short answer is no; read the whole article by David Cyranoski.

But the paper1 that set out the fundamental technique was soon shot full of holes. There was plagiarized text in the article. Figures showed signs of manipulation, and some images were identical or nearly identical to those used later in the same paper and elsewhere to represent different experiments. More damning were genetic analyses that strongly suggested the cells were not what they were purported to be. And although deriving STAP cells was advertised as simple and straightforward, no one has yet been able to repeat the experiment.

Within the space of six months, Obokata was found guilty of misconduct by her institution; well-respected scientists, including RIKEN head Ryoji Noyori, bowed their heads in apology; and both papers were retracted. In the end, the evidence for STAP cells seemed so flimsy that observers began to ask where were the extra precautions and the ‘extraordinary proof’ that had been promised post-Hwang.

It sure would have been nice to have a simple technique for generating stem cells, but I have to confess to being a bit relieved. There’s the vindication of prior thinking and the value of incrementally improving our stem cell protocols, of course, but also, I’d personally rather that it weren’t trivial to switch my cells to a de-differentiated pluripotent state — that’s a recipe for easy cancer generation, too. It is somehow reassuring to think that evolution has shaped multi-cellular organisms to be somewhat resistant to spontaneously going all stem-celly under stress.

The difference between astronomers and biologists

The debate about intelligent, extra-terrestrial aliens goes on, with the usual divide: astronomers insisting that the galaxy must be swarming with alien intelligences, which is popular with the media, and the biologists saying no, it’s not likely, there are probably swarms of single-celled organisms, but big multicellular intelligences like ours are probably rare. And the media ignores us, because that answer simply is not sufficiently sensational.

But we will fight back! Here’s an interesting review of the alien argument. There is actually a historical and conceptual reason why astronomers think the way they do.

In response [to a paper arguing that SETI was a waste of time], Sagan co-wrote a paper with William Newman “The Solipsist Approach to Extraterrestrial Intelligence” which right from the title attacks Tipler for believing Earth to be unique. Sagan is of course citing the Copernican Principle, which roughly states the Earth is NOT the center of the heavens. The Copernican Principle is the modern foundation for Astronomy, Cosmology and Relativistic Physics. Sagan thought anyone claiming the Earth to be special must be doing bad science. Here’s a typical quote: Despite the utter mediocrity of our position in space and time, it is occasionally asserted, with no sense of irony, that our intelligence and technology are unparalleled in the history of the cosmos. It seems to us more likely that this is merely the latest in the long series of anthropocentric and self-congratulatory pronouncements on scientific issues that dates back to well before the time of Claudius Ptolemy.

It’s all about our perception of the rules. Astronomers see a universe with uniform laws that set up similar patterns everywhere: stars, rocks, gas. Life is lumped in with rocks as a phenomenon that just pops up everywhere, and with their limited idea of biology, just see all life as life like ours. Biologists also see universal laws, but we know from our experience that those laws generate endless diversity — there are millions of species on this planet, and each one is unique.

Now unlike Astronomy, the discipline of Biology takes a highly favorable view of uniqueness. Evolution constantly discovers quirky and highly contingent historical paths. Biology takes it for granted that everybody is a special snowflake. In fact the third sentence of Tipler’s 1980 paper calls this out:

The contemporary advocates for the existence of such [extraterrestrial intelligent] beings seem to be primarily astronomers and physicists, such as Sagan (2), Drake (3), and Morrison (4), while most leading experts in evolutionary biology, such as Dobzhansky (5), Simpson (6) Francois (7), Ayala et al. (8) and Mayr (9) contend that the Earth is probably unique in harbouring intelligence, at least amongst the planets of our Galaxy.

And as quoted in Mark A. Sheirdan’s book, we have eminent Evolutionary Biologist Theodosius Dobzhansky (“Nothing in Biology Makes Sense Except in the Light of Evolution“) joining the fray:

In his article Dobzhanksy turned Sagan’s argument on its head. Dobzhansky cited the fact that of the more than two million species living on Earth only one had evolved language, extragenetically transmitted culture, and awareness of self and death, as proof that it is “fatuous” to hold “the opinion that if life exists anywhere else it must eventually give rise to rational beings.”

And here’s a nice, short table to summarize the differences.

intellife2

I have to add that it is probably another of those universal laws that Darwinian replicators will expand to fill an empty ecosystem, but that there are many ways to do that. It’s also a rule that the replicators are exploiting short term advantages to supplant competitors — there is no teleological imperative that says Strategy X is a good one, because while it slows our species down for the next billion years, there’s a chance we might build spaceships two billion years from now. Spaceship building is never going to be a selectively advantageous feature — it’s only going to emerge as a spandrel, which might lead to a species that can occupy a novel niche. And that means that spaceship builders are only going to arise as a product of chance, which will mean they’re going to be very rare.

On the other hand, a species that does successfully exploit space as an ecosystem is going to have a phenomenally fascinating future history of radiating forms. Think of the first space colonizers as equivalent to the first cells that evolved a metabolism that allowed them to exist outside the coddled, energy-rich environment of a deep-sea vent. It’s only the first step in a long evolutionary process that’s going to produce endless forms most beautiful…and also unexpected variations. It’s silly to expect that the successful, thriving interstellar life forms will be bipeds adapted to life on a planetary surface, living in large metal shells as autonomous agents crewing a spaceship. The real thing would be alien, and probably terrifyingly incomprehensible.

My zombie story

The zombie plague was a dud. When the first cases emerged, scattered around the globe, everyone knew exactly how to put them down: destroy the brain. The world had been so saturated with zombie comic books, zombie TV shows, zombie novels, and zombie movies in the greatest, if unplanned, public health information program ever, that the responses to the outbreaks was always swift and thorough. In fact, most civilian casualties were caused not by the zombies themselves, but by the way everyone had been conditioned by the media to respond to lumbering, moaning, disheveled humanoid forms with instant and brutal violence.

The death of a few homeless or mentally ill people, or others who just weren’t perky morning people, was considered a small price to pay for the ruthless efficiency with which the zombie problem was eradicated. There was talk of giving George Romero a Nobel peace prize; Time Magazine ran an issue with “Heroic Humanity” featured on the cover; the public acquired a cocky attitude and brain-smashing weapons of destruction became the hot new fashion accessory. The horror of the worst catastrophe we could imagine, the emergence of an evil twin of our species, corrupt and mindlessly destructive, had been met and dismissed with arrogant ease.

An important lesson was not learned. Zombies were our mirror image, big animals that were short-sighted and heedlessly destructive, and we had easily wiped them out…because big animals are delicate, fragile things with a limited population size, requiring immense amounts of cooperation to survive. Our pride was undeserved. We had discovered how easy it was to kill small groups of bipedal primates. Nature laughed at our trivial accomplishment.

The same plague had been burning through rat populations. Every city, every small town garbage dump, every ship, had been boiling with upheaval in the darkness as the zombie rats spread the infection everywhere. The rats were numerous, and it took three months for the disease to consume them…and then the undead rodents slithered upwards, looking for a new food source. They were ubiquitous and silent and sneaky, and found ways into bedrooms at night, where the smug humans lay with shotguns and pistols and hammers for demolishing large-skulled stupid targets, their doors safely (they thought) barred against 70 kilogram intruders. The little, mindless zombie rats scurried forward, and gnawed.

Homo sapiens was extinct within a year.

(I had this idea for a great and accurate zombie novel that would reveal the true message of the zombie fad — come on, look at yourselves, it’s all about rapacious humans with no restraint — and would also make me millions of dollars. I got up this morning all excited and rushed to start writing it, and then I discovered that I could tell the whole story in five paragraphs. Oops. Is there much of a market for one-page novels? With a totally depressing conclusion?)

So that’s what chemistry is good for…

Stinky stuff! This fits perfectly with my biased preconceptions. So here are two examples of chemistry used to analyze things you’d normally run away from.

The oldest traces of human poop have been dug out of a cave in Spain — and it’s Neandertal poop. It’s about 50,000 years old, and it’s been reduced to a compressed, thin smear of organic compounds, so I guess it isn’t actually so stinky anymore, but there was enough of it to analyze chromatographically. In case you’ve wondered your whole life about what Neandertal poop would look like, here you go.

Microphotographs of a slightly burned coprolite of putative human origin identified in El Salt Stratigraphic Unit X (sample SALT-08-13). The images under plane polarized light show the pale brown color and massive structure of the coprolite, as well as the common presence of inclusions, which are possibly parasitic nematode eggs or spores.

Microphotographs of a slightly burned coprolite of putative human origin identified in El Salt Stratigraphic Unit X (sample SALT-08-13). The images under plane polarized light show the pale brown color and massive structure of the coprolite, as well as the common presence of inclusions, which are possibly parasitic nematode eggs or spores.

Dead for 50 millennia, and what we know about this dead person is that they took a massive dump that was full of parasites. TMI.

I thought the paper was preliminary and rather general — they don’t or can’t make very specific conclusions, but then, I imagine they were excited to be the first to get any discussion of Neandertal feces into the scientific literature. We do know a couple of things: Neandertals ate both their meat and their vegetables, and they had gut bacteria with similar physiological properties to our own.

Taken together, these data suggest that the Neanderthals from El Salt consumed both meat and vegetables, in agreement with recent hypotheses based on indirect evidence. Future studies in Middle Palaeolithic sites using the faecal biomarker approach will help clarify the nature, role and proportion of the plant component in the Neanderthal diet, and allow us to assess whether our results reflect occasional consumption or can be representative of their staple diet. Also, this data represents the oldest positive identification of human faecal matter, in a molecular level, using organic geochemical methods.

Besides having corroborated our method and obtained the first evidence of an omnivorous Neanderthal diet from faeces, our results also have implications regarding digestive systems and gut microbiota evolution. Approaching the evolution of the human digestive system is difficult because there is no fossil record indicating soft tissue preservation. Our results show that Neanderthals, like anatomically modern humans, have a high rate of conversion of cholesterol to coprostanol due to the presence of bacteria capable of doing so in their guts. Further research will allow us explore this issue in the context of human evolution.

I said I had two unpleasant examples of useful chemistry, and here’s the second: using the characteristic odors of different stages of decay to quantify the time of death.

An international research team used two-dimensional gas chromatography time-of-flight mass spectrometry to characterise the odours that create this smell of death:  volatile organic compounds (VOCs).  By measuring the VOCs released from pig carcasses the team identified a cocktail of several different families of molecules, including carboxylic acids, aromatics, sulfurs, alcohols, nitro compounds, as well as aldehydes and ketones. The combination and quantities of these VOCs change as a function of time as a cadaver goes through different stages of decomposition.

I think I’m getting a sense of the difference between chemistry and biology. I prefer the bodily fluids in my subjects to be fresh, preferably spurting; chemists seem to favor observing the degradation and volatilization of fluids from dead things. Chemists may offer their repudiations of my sentiments in the comments.

Time to kill all the kittens

I think that’s the only reasonable response. We’ve been conditioned to think that animals are all furry and big-eyed and most importantly, cute, and every animal that isn’t must be reclassified as vermin. We’re going to need a radical readjustment of the public; every time you send someone a LOLcat, a thousand annelids and a million arthropods die in despair.

At least, that’s how I feel on the news that the Smithsonian is closing their Invertebrate Zoo. There are some fucked-up priorities here.

The Smithsonian says the Invertebrate Exhibit costs $1 million a year to operate, and that necessary upgrades to the facility will cost another $5 million. "We have several other fundraising priorities which preclude us from launching a… campaign for the invertebrates to stay in their existing space," reads a statement on the Zoo’s Facebook page.

The National Zoo’s annual budget runs about $20 million, with its friends group kicking in another $4 to $8 million a year. Which basically means the Zoo has decided it can’t afford to allocate five percent of its annual budget to educate the public about 97 percent of the animal species in the world.

“Priorities”. What defines their priorities? An accurate presentation of the science, or pandering to brains high on fluff? I suggest we start feeding the Red Pandas to the octopuses until those priorities get readjusted.