This past Friday I was fortunate to see UCSD neurologist Mark Kritchevsky. It's hard to imagine someone more enthusiastic about medicine or research than this guy. As I decide what to specialize in, it's experiences like these that will add up to nudge me in one direction or the other.
The reason I'm posting is something that the dean of medical education at UCSD (Jess Mandel) said to Dr. Kritchevsky during the discussion that cuts straight to the heart of a) the deep problem of consciousness and b) straight to the way physicians treat and diagnose their patients. In the context of patients who present with acute anterograde amnesia (they can't form new memories, then the condition resolves itself) Dean Mandel recounted working with a neurologist whose favorite diagnosis was malingering. Every time someone came in with a strange set of symptoms, this particular neurologist thought they were faking. Dean Mandel's (unstated at the time) question was: if this is your go-to diagnosis, then why the heck would you go into neurology?
This also highlights something I recently heard from the neurologist V.S. Ramachandran (who I was fortunate to see earlier in the week as well), which is that if you see a patient and you dismiss their complaint as crazy - it's more likely that you as the physician are just not smart enough to figure out what's going on.
Sunday, September 27, 2009
Saturday, September 19, 2009
We're Living In the RNA World: Ribosomes Are the Meaning of Life
[Added later: Clearly the Nobel committee was influenced by this post.]
Our view of the world beyond our senses is necessarily influenced by the instruments we use to investigate it. There is far more protein in cells than nucleic acid; and to the naive observer, the primary sequence of an oligopeptide (with 20 possible monomer units) seems a far richer source of information than nucleic acids, with only 4. Consequently it wasn't until 1928 with Griffith's bacterial transformation experiments that people began to seriously think about nucleic acid instead of protein as the heredity chemical. The final coup came in 1953 when Watson and Crick solved the crystal structure and provided a mechanism for DNA to be the biological information carrier.
It hasn't been until the last two decades that we've begun to understand the importance and diversity of RNA in Earth's biochemistry, possibly because RNA is harder to work with than DNA. Tom Cech and Sidney Altman received the Nobel for their work in the 1980s showing that RNA has catalytic properties stemming from its extra (relative to DNA) 2' hydroxyl. Besides its crucial role in the ribosome, RNA can also catalyze its own splicing.
This last observation was critical for anyone trying to puzzle out the chemical origins of life on Earth. DNA by itself in solution is actually quite boring; it just sits there. If life began with DNA, it would have stopped there too. Crick and Orgel speculated about life's chemical origins in the 1960s, forced to the idea that there must have been either an all-protein world (from which the transition to DNA-as-heredity chemical is unclear) or an all-RNA world. They also (pessimistically) speculated that, so unlikely were these events, that perhaps replicator chemistry could diffuse more easily through space than we realize so that it only had to happen once in any given galaxy for it to spread to other stars (panspermia, first discussed by Arrhenius over half a century before; for a longer discussion on one angle on panspermia, go here). Once the work on RNA's catalytic (and autocatalytic) abilities began, the RNA-world began to seem much more feasible. As we now know, pointing to its initial favorability, RNA splicing and even the attachment of amino acids to tRNAs both proceed just fine on their own. Free nucleotides are still the universal energy currency of cells. Urey-Miller's experiments showed prebiotic processes that could produce amino acids; these studies were soon supplemented by observations that nucleobases occur spontaneously on asteroids and can have plausibly originated prebiotically.
So far this has been merely a review of the RNA world hypothesis. It's anything but proven, but it's the best story we have so far, and we even have pathogens active today that are merely self-reproducing (though host-dependent) RNAs (viroids). The idea is that once nucleic acid had been established as the dominant replicator, some interaction occurred between RNA and DNA that moved DNA upstream in the causal hierarchy; that is to say, put it chemically in charge, possibly owing to its greater stability and conservatism since it's less reactive and exists as backed-up double-stranded template and is less reactive. Like the seawater-like salt concentrations found in the cells of Earth organisms, the activity of catalytic RNAs is a biochemical fossil, along with the messenger intermediates delivering sequence information to the ribosomes, energy carriers like ATP, and cofactors like NAD.
Segregation of Fitness Factors Within Membranes
Whatever the molecular basis for Earth's first chemical replicators, if they had a diffusible element to their reproduction, they had a commonly recognized problem to solve: how to sequester advantage. That is, if there was a developing RNA world where autocatalytic RNAs had developed a set of consistent interactions to polymerize amino acids and take advantage of a more diverse chemistry, how did they keep neighboring strands from benefiting? Imagine an RNA molecule has the trick of polymerizing a nifty oligopeptide that fetches ribonucleotides just incrementally faster than any other neighboring RNA in solution, making RNA-1 increase its numbers faster than its competitors - right? Wrong. That nifty oligopeptide is going to diffuse away and is just as likely to help any other RNA in RNA-1's neighborhood. So, from RNA-1's fitness standpoint, why bother? Until there's a closed feedback loop - until that oligopeptide is for some reason more likely to associate with RNA-1 more than RNA-1's neighbors - there's no point. (Frequently overlooked in this scenario is defense - RNA-1 also wants to keep its neighbors from eating up all the free nucleotides around it, or poisoning RNA-1's phosphodiester formation process, or even hydrolyzing RNA-1 itself).
The solution, of course, was the lipid membranes that now surround all cells (but not all replicators). Membranes form a self-nonself boundary and sequester diffusible benefits while providing a defense against chemical predation. The details of how this might have begun are still up for grabs, since there would have to have been mechanisms to open the membrane from inside and to gather and react to information from outside. While admittedly all this is highly speculative just-so discussion, the central point is that it's very difficult to imagine how a well-elaborated RNA-protein interaction machinery could have developed prior to membrane encapsulation of RNAs and their associated products.
What Was the Mechanism for the Transition to the DNA World?
If we assume that cells are "about" making more nucleic acid, then DNA's stability and conservatism does in fact seem to make it a better reservoir of information. Still, RNA world speculations tend to be a little short on details on exactly how such a transition could have come about. At this point, we're talking about a reproducing RNA molecule surrounded by a membrane with some set of RNA > protein chemical rules - in modern-day terms, we have a lipid bilayer with ribosomal RNA that can reproduce. The rRNA reproduces either on its own or with the help of an RNA-RNA polymerase, like the one influenza still uses today (in fact, many eukaryotes also have endogenous RNA > RNA polymerases).
There are at least two ways we can imagine the transition occurring.
A. An intracellular transition. RNA-protein cells developed a reverse transcriptase that gradually assembled a DNA-mirror of the RNA genome of the cells. If the advantage of such a DNA-mirror was as a back-up in the event that the RNA genome is damaged, this could only have been selected for with some mechanism to convert DNA into RNA (in modern terms, transcription). Because of DNA's conservatism, cells which relied more and more on DNA would be favored, eventually leading to a cell where the only reproduction was of DNA, not RNA. One test for this model is to look for a most recent common ancestor of RNA-dependent RNA-polymerases that is older than the last common ancestor of reverse transcriptases, which is in turn older than classical DNA-dependent RNA polymerases (with reference to RNA Pol I which transcribes rRNA), which is in turn older than DNA polymerases. It should be pointed out that most eucaryotic cells code for reverse transcriptases, some of which are critical for DNA maintenance, but most of which do not obviously benefit anything but their own reproduction (selfish elements), and which comprise substantial portions of eukaryotic genomes. Selfish elements and junk DNA are thought to be absent from prokaryotic genomes due to selection pressure on fecundity.
B. Nucleus-as-endosymbiont. To look at cells in a non-nucleocentric way, eukaryotes have 3 membrane-bound organelles containing genomes: chloroplasts, mitochondria, and nuclei. Nuclei are unique among these three in that they export nucleic acids to interact extensively outside their own membranes. If there is latitude even in a world of highly "committed" biochemical structures (like the modern one) for the survival either RNA or DNA viruses, we can presume that there would have been room for a membrane-bound DNA viruses in the membrane-bound RNA-world. A DNA virus could infect an RNA-only cell (similar to Philip Bell's concept of "DNA virus as ancestor of all eukaryotic nuclei"). DNA viruses in the RNA world would need reverse transcriptase for their reproduction; if we also presume, in multiple infections, a viral pickup of the RNA-cells ribosomal and tRNA RNA genes, they would eventually be incorporated into the nucleus - or today, the DNA molecule. The obvious objection here is that this assumes the first DNA cell was a eukaryote. First, the model could still function without a membrane-bound DNA molecule; we just couldn't explain the membrane-segregated nucleus in terms of endosymbiosis. Second, assuming phylogenetic relationships do not conflict with this account, it can be further argued that as with selfish elements and junk DNA, ancestral cells having greater complexity than modern bacteria is not implausible; prokaryotes are a more stripped-down later version relying on greater simplicity, driven by the need for fecundity. That is to say, since the advent of DNA cells, prokaryotes have lost their internal membranes, rather than eukaryotes having gained them. Third, and most important for later points, phylogenetic relationships for the eukaryotic LUCA based on ribosomal RNA are at this stage still unclear.
Both theories fly in the face of the central dogma, but the RNA world is the best supported account of the origin of life, and details of the transition to the DNA world are sketchy. In the first, DNA is merely a backup for the (at that time) true RNA genome - a set of rRNA and possibly tRNA genes - and the DNA backup gradually usurps RNA's role. In the second, a DNA virus remains permanently in a cell and absorbs RNA genes for what would later become our rRNA genes (but coded in DNA).
Speculation about pre-DNA world biochemistry can be disorienting. Taken out of their central-dogmatic context, the definitions of genotype and phenotype become less clear - in the RNA world they overlap strongly - and there seems to be no clear causal starting point in the information cascade. Which leads to the question: is there even such a clear starting point in the modern DNA world?
Why the Centrality of DNA? Cyclic Cause and Effect
Humans are limited in our pattern recognition abilities and when we encounter a new complex phenomenon we necessarily think of it in isolable cause-and-effect narratives. Consequently, it's useful in biomedical research to think of DNA as being at the top of a causal cascade that results ultimately in the reproduction of more DNA (or in the production of protein, which results in the reproduction of more DNA). In this view, cells and whole organisms - phenotypes - are survival machines that DNA uses to make more of itself. Put concretely, the function of an apple tree isn't to make apples; it isn't even to make more apple trees. It's to make more apple tree DNA.
Of course, no DNA molecule ever reproduced itself without the help of a host of specialized proteins, and every DNA molecule in existence today is causally downstream of a set of protein-and-RNA mediated events going back billions of years (just as all of them are causally downstream from DNA). This seems trivial, but leads immediately to the question: why is DNA alone given a privileged place in that cyclic sequence of events?
There are two reasons this is so. In the first half of the twentieth century there were a number of cyclic biochemical processes elucidated, among them the urea cycle, glycolysis, and the central dogma of molecular biology. In all of these, some entity or set of entities A gives B gives C, a clear and isolable stepwise set of inputs and outputs. Second, special in the case of DNA, there is information. The carbohydrate monomers in a glycogen molecule are chemically equivalent, a chain of zero-zero-zero-zero. DNA contains a quaternary code that has no clear function apart from its information content - it has a meaning, in terms of corresponding to amino acids. Cells don't consume it for energy; cells don't build walls or tubes out of it. It's there to be read, and the only thing that determines its meaning is other DNA molecules.
Two Thought Experiments, and the Meaning of Life
Is that last statement true at all? Of course not. Without even getting into epigenetic phenomena, the on-its-own-quite-inert DNA molecule doesn't do anything that proteins (and the RNAs that made those proteins) don't let it. Without those RNAs and proteins, DNA "means" nothing. The multiple inputs upstream from DNA, and the relatively pristine outflows downstream from it, make it a convenient point in the process for us to manipulate cells. DNA only matters because of what it means, and its association with proteins that actually do the work of the cell. That fact that its conservatism allows us to trace ancestry doesn't force us to conclude that it's the point of the cell. Thought experiment: if tomorrow, physicists found some bizarre particle physics technique to trace cells based on something in the lipid membranes of lysosomes, would that mean the cell was about lysosomes?
No, you answer - unless that particle physics tag on lysosomes correlated with some property of lysosomes that interacted with the rest of the world in a consistent way, like the DNA-protein feedback loop. Then you'd have something.
Forgive the mental biology, but thought experiments allow us to think about problems without the anesthesia of the familiar masking patterns. So indulge me: imagine that the world's first biochemical string theorist is working on an exotic n-dimensional model of physics and discovers that, unique among known molecules, DNA has a prominent, nonrandom structure in the higher dimensions model. Applying this theory to phylogeny trees, it becomes clear that in those higher dimensions, some new property of DNA, its n-dimensional conformation, and not its linear sequence, are actually more conserved over time, and correlates better with protein function, than its 5' to 3' nucleotide sequence. Wouldn't that be exciting? It would become obvious that we shouldn't be so hung up on the primary sequence; we would then reasonably conclude that this higher-dimensional structure is somehow what cells are "about" and what evolution has been selecting for.
Given the title of the post, you've probably guessed where this is leading. My argument is that life on Earth is best understood in terms of an RNA World that to us seems masked by the DNA it uses as a backup. At least as much as it's about DNA, life on Earth is about ribosomes. Apple trees are one way that ribosomes can make more ribosomes, as are slime molds, great white sharks, and koalas. We can think of the function of DNA as either a) a backup of ribosomes and b) one stage in the manufacture of all the rest of the ancillary machines that ensure survival of ribosomes. How is this different from making the same argument about any other cellular element, that the point of life is proteasomes? Not only are rRNA sequences (not to mention tRNA anticodons) the most conserved nucleic acids in living things, what is conserved is the structure of the molecule, over and above its sequence. Even more specifically than ribosomes, what is being preserved and selected for and served in a giant feedback loop by the rest of the structures in the cell is this consistent set of RNA-protein interactions.
There are many possible objections to this shift in viewpoints, and among them I will address two: first, the existence of viruses, which are non-ribosome-containing replicators. Viruses are "genes that got away" but have no independent metabolism (or ability to reproduce) independently of ribosomes. In terms of this ribosome-centric hierarchy, viruses are a peripheral curiosity in the same way as prions, which are proteins that reproduce their shape (and therefore physical properties) but also cannot reproduce chemically in the absence of ribosomes; of course, in terms of biomedical relevance to human life, viruses are anything but a curiosity (but this may serve to obscure their hierarchical triviality). On the other hand, Viroids are RNA-only replicators which can, in fact, reproduce without ribosomes, using only RNA Pol II, and some are autocatalytic.
A second objection made frequently is that the structure of rRNA and the protein-nucleic acid that structure mediates (and the rich chemistry that sprouted around it on the young Earth) were driven by thermodynamics - that there's only one way to build the interaction surface, and only one set of 20 amino acids that could ever have been chosen. If the shape and activity of a ribosome are really just thermodynamic fate, then there's no heredity information in rRNA - no heritability information, no meaningful travel over time in the fitness landscape, and no possibility of "frozen accidents" that commit a system to climb toward local optima, any more than there is for a star or fire. Yes, fire spreads and consumes fuel, but the commitments of dumb physics force them to behave the way they do; there's no difference in the flame on a birthday candle whether you lit it from a lighter or at the edge of a burning pine forest. One way to test the question of whether ribosomes are stuck in one shape would be to run synthetic biology experiments with simple ribosome systems where you swap out the 20 legacy amino acids to search for a more robust set of monomers, with some kind of feedback to allow selection. But that would be an extremely complicated experiment. I rather think that the burden of proof is on the claimant who argues that the anticodon system we ended up with is necessarily the universally best one, and that RNA-descended aliens from Alpha Centauri would necessarily use the same set that we do.
SUMMARY
- Our understanding of molecular biology and the evolution of the cell is constrained by the useful conventions we use to study chemical processes in the cell. Despite the wide acceptance of the RNA World hypothesis, we still view life on Earth as being about DNA.
- The transition from the RNA world to the DNA world was mediated by either development of reverse transcriptase and RNA polymerase activity, or an endosymbiosis event involving a DNA virus infection and uptake by the virus of rRNA genes.
- DNA is best thought of as a back-up of a) rRNA and b) all other types of catalytic molecules (today, mostly proteins) all of whose function is to ensure the survival of rRNA.
- rRNA genes are the most conserved among living things; notably, the structure of the rRNA itself is even more conserved than the primary sequence.
- A better way of thinking about life than considering it to be about DNA is to think of it as about the propagation of ribosomes, or specifically, about propagating a specific set of protein-RNA interactions mediated by a specific type of chemical structure.
Our view of the world beyond our senses is necessarily influenced by the instruments we use to investigate it. There is far more protein in cells than nucleic acid; and to the naive observer, the primary sequence of an oligopeptide (with 20 possible monomer units) seems a far richer source of information than nucleic acids, with only 4. Consequently it wasn't until 1928 with Griffith's bacterial transformation experiments that people began to seriously think about nucleic acid instead of protein as the heredity chemical. The final coup came in 1953 when Watson and Crick solved the crystal structure and provided a mechanism for DNA to be the biological information carrier.
It hasn't been until the last two decades that we've begun to understand the importance and diversity of RNA in Earth's biochemistry, possibly because RNA is harder to work with than DNA. Tom Cech and Sidney Altman received the Nobel for their work in the 1980s showing that RNA has catalytic properties stemming from its extra (relative to DNA) 2' hydroxyl. Besides its crucial role in the ribosome, RNA can also catalyze its own splicing.
This last observation was critical for anyone trying to puzzle out the chemical origins of life on Earth. DNA by itself in solution is actually quite boring; it just sits there. If life began with DNA, it would have stopped there too. Crick and Orgel speculated about life's chemical origins in the 1960s, forced to the idea that there must have been either an all-protein world (from which the transition to DNA-as-heredity chemical is unclear) or an all-RNA world. They also (pessimistically) speculated that, so unlikely were these events, that perhaps replicator chemistry could diffuse more easily through space than we realize so that it only had to happen once in any given galaxy for it to spread to other stars (panspermia, first discussed by Arrhenius over half a century before; for a longer discussion on one angle on panspermia, go here). Once the work on RNA's catalytic (and autocatalytic) abilities began, the RNA-world began to seem much more feasible. As we now know, pointing to its initial favorability, RNA splicing and even the attachment of amino acids to tRNAs both proceed just fine on their own. Free nucleotides are still the universal energy currency of cells. Urey-Miller's experiments showed prebiotic processes that could produce amino acids; these studies were soon supplemented by observations that nucleobases occur spontaneously on asteroids and can have plausibly originated prebiotically.
So far this has been merely a review of the RNA world hypothesis. It's anything but proven, but it's the best story we have so far, and we even have pathogens active today that are merely self-reproducing (though host-dependent) RNAs (viroids). The idea is that once nucleic acid had been established as the dominant replicator, some interaction occurred between RNA and DNA that moved DNA upstream in the causal hierarchy; that is to say, put it chemically in charge, possibly owing to its greater stability and conservatism since it's less reactive and exists as backed-up double-stranded template and is less reactive. Like the seawater-like salt concentrations found in the cells of Earth organisms, the activity of catalytic RNAs is a biochemical fossil, along with the messenger intermediates delivering sequence information to the ribosomes, energy carriers like ATP, and cofactors like NAD.
Segregation of Fitness Factors Within Membranes
Whatever the molecular basis for Earth's first chemical replicators, if they had a diffusible element to their reproduction, they had a commonly recognized problem to solve: how to sequester advantage. That is, if there was a developing RNA world where autocatalytic RNAs had developed a set of consistent interactions to polymerize amino acids and take advantage of a more diverse chemistry, how did they keep neighboring strands from benefiting? Imagine an RNA molecule has the trick of polymerizing a nifty oligopeptide that fetches ribonucleotides just incrementally faster than any other neighboring RNA in solution, making RNA-1 increase its numbers faster than its competitors - right? Wrong. That nifty oligopeptide is going to diffuse away and is just as likely to help any other RNA in RNA-1's neighborhood. So, from RNA-1's fitness standpoint, why bother? Until there's a closed feedback loop - until that oligopeptide is for some reason more likely to associate with RNA-1 more than RNA-1's neighbors - there's no point. (Frequently overlooked in this scenario is defense - RNA-1 also wants to keep its neighbors from eating up all the free nucleotides around it, or poisoning RNA-1's phosphodiester formation process, or even hydrolyzing RNA-1 itself).
The solution, of course, was the lipid membranes that now surround all cells (but not all replicators). Membranes form a self-nonself boundary and sequester diffusible benefits while providing a defense against chemical predation. The details of how this might have begun are still up for grabs, since there would have to have been mechanisms to open the membrane from inside and to gather and react to information from outside. While admittedly all this is highly speculative just-so discussion, the central point is that it's very difficult to imagine how a well-elaborated RNA-protein interaction machinery could have developed prior to membrane encapsulation of RNAs and their associated products.
What Was the Mechanism for the Transition to the DNA World?
If we assume that cells are "about" making more nucleic acid, then DNA's stability and conservatism does in fact seem to make it a better reservoir of information. Still, RNA world speculations tend to be a little short on details on exactly how such a transition could have come about. At this point, we're talking about a reproducing RNA molecule surrounded by a membrane with some set of RNA > protein chemical rules - in modern-day terms, we have a lipid bilayer with ribosomal RNA that can reproduce. The rRNA reproduces either on its own or with the help of an RNA-RNA polymerase, like the one influenza still uses today (in fact, many eukaryotes also have endogenous RNA > RNA polymerases).
There are at least two ways we can imagine the transition occurring.
A. An intracellular transition. RNA-protein cells developed a reverse transcriptase that gradually assembled a DNA-mirror of the RNA genome of the cells. If the advantage of such a DNA-mirror was as a back-up in the event that the RNA genome is damaged, this could only have been selected for with some mechanism to convert DNA into RNA (in modern terms, transcription). Because of DNA's conservatism, cells which relied more and more on DNA would be favored, eventually leading to a cell where the only reproduction was of DNA, not RNA. One test for this model is to look for a most recent common ancestor of RNA-dependent RNA-polymerases that is older than the last common ancestor of reverse transcriptases, which is in turn older than classical DNA-dependent RNA polymerases (with reference to RNA Pol I which transcribes rRNA), which is in turn older than DNA polymerases. It should be pointed out that most eucaryotic cells code for reverse transcriptases, some of which are critical for DNA maintenance, but most of which do not obviously benefit anything but their own reproduction (selfish elements), and which comprise substantial portions of eukaryotic genomes. Selfish elements and junk DNA are thought to be absent from prokaryotic genomes due to selection pressure on fecundity.
B. Nucleus-as-endosymbiont. To look at cells in a non-nucleocentric way, eukaryotes have 3 membrane-bound organelles containing genomes: chloroplasts, mitochondria, and nuclei. Nuclei are unique among these three in that they export nucleic acids to interact extensively outside their own membranes. If there is latitude even in a world of highly "committed" biochemical structures (like the modern one) for the survival either RNA or DNA viruses, we can presume that there would have been room for a membrane-bound DNA viruses in the membrane-bound RNA-world. A DNA virus could infect an RNA-only cell (similar to Philip Bell's concept of "DNA virus as ancestor of all eukaryotic nuclei"). DNA viruses in the RNA world would need reverse transcriptase for their reproduction; if we also presume, in multiple infections, a viral pickup of the RNA-cells ribosomal and tRNA RNA genes, they would eventually be incorporated into the nucleus - or today, the DNA molecule. The obvious objection here is that this assumes the first DNA cell was a eukaryote. First, the model could still function without a membrane-bound DNA molecule; we just couldn't explain the membrane-segregated nucleus in terms of endosymbiosis. Second, assuming phylogenetic relationships do not conflict with this account, it can be further argued that as with selfish elements and junk DNA, ancestral cells having greater complexity than modern bacteria is not implausible; prokaryotes are a more stripped-down later version relying on greater simplicity, driven by the need for fecundity. That is to say, since the advent of DNA cells, prokaryotes have lost their internal membranes, rather than eukaryotes having gained them. Third, and most important for later points, phylogenetic relationships for the eukaryotic LUCA based on ribosomal RNA are at this stage still unclear.
Both theories fly in the face of the central dogma, but the RNA world is the best supported account of the origin of life, and details of the transition to the DNA world are sketchy. In the first, DNA is merely a backup for the (at that time) true RNA genome - a set of rRNA and possibly tRNA genes - and the DNA backup gradually usurps RNA's role. In the second, a DNA virus remains permanently in a cell and absorbs RNA genes for what would later become our rRNA genes (but coded in DNA).
Speculation about pre-DNA world biochemistry can be disorienting. Taken out of their central-dogmatic context, the definitions of genotype and phenotype become less clear - in the RNA world they overlap strongly - and there seems to be no clear causal starting point in the information cascade. Which leads to the question: is there even such a clear starting point in the modern DNA world?
Why the Centrality of DNA? Cyclic Cause and Effect
Humans are limited in our pattern recognition abilities and when we encounter a new complex phenomenon we necessarily think of it in isolable cause-and-effect narratives. Consequently, it's useful in biomedical research to think of DNA as being at the top of a causal cascade that results ultimately in the reproduction of more DNA (or in the production of protein, which results in the reproduction of more DNA). In this view, cells and whole organisms - phenotypes - are survival machines that DNA uses to make more of itself. Put concretely, the function of an apple tree isn't to make apples; it isn't even to make more apple trees. It's to make more apple tree DNA.
Of course, no DNA molecule ever reproduced itself without the help of a host of specialized proteins, and every DNA molecule in existence today is causally downstream of a set of protein-and-RNA mediated events going back billions of years (just as all of them are causally downstream from DNA). This seems trivial, but leads immediately to the question: why is DNA alone given a privileged place in that cyclic sequence of events?
There are two reasons this is so. In the first half of the twentieth century there were a number of cyclic biochemical processes elucidated, among them the urea cycle, glycolysis, and the central dogma of molecular biology. In all of these, some entity or set of entities A gives B gives C, a clear and isolable stepwise set of inputs and outputs. Second, special in the case of DNA, there is information. The carbohydrate monomers in a glycogen molecule are chemically equivalent, a chain of zero-zero-zero-zero. DNA contains a quaternary code that has no clear function apart from its information content - it has a meaning, in terms of corresponding to amino acids. Cells don't consume it for energy; cells don't build walls or tubes out of it. It's there to be read, and the only thing that determines its meaning is other DNA molecules.
Two Thought Experiments, and the Meaning of Life
Is that last statement true at all? Of course not. Without even getting into epigenetic phenomena, the on-its-own-quite-inert DNA molecule doesn't do anything that proteins (and the RNAs that made those proteins) don't let it. Without those RNAs and proteins, DNA "means" nothing. The multiple inputs upstream from DNA, and the relatively pristine outflows downstream from it, make it a convenient point in the process for us to manipulate cells. DNA only matters because of what it means, and its association with proteins that actually do the work of the cell. That fact that its conservatism allows us to trace ancestry doesn't force us to conclude that it's the point of the cell. Thought experiment: if tomorrow, physicists found some bizarre particle physics technique to trace cells based on something in the lipid membranes of lysosomes, would that mean the cell was about lysosomes?
No, you answer - unless that particle physics tag on lysosomes correlated with some property of lysosomes that interacted with the rest of the world in a consistent way, like the DNA-protein feedback loop. Then you'd have something.
Forgive the mental biology, but thought experiments allow us to think about problems without the anesthesia of the familiar masking patterns. So indulge me: imagine that the world's first biochemical string theorist is working on an exotic n-dimensional model of physics and discovers that, unique among known molecules, DNA has a prominent, nonrandom structure in the higher dimensions model. Applying this theory to phylogeny trees, it becomes clear that in those higher dimensions, some new property of DNA, its n-dimensional conformation, and not its linear sequence, are actually more conserved over time, and correlates better with protein function, than its 5' to 3' nucleotide sequence. Wouldn't that be exciting? It would become obvious that we shouldn't be so hung up on the primary sequence; we would then reasonably conclude that this higher-dimensional structure is somehow what cells are "about" and what evolution has been selecting for.
Given the title of the post, you've probably guessed where this is leading. My argument is that life on Earth is best understood in terms of an RNA World that to us seems masked by the DNA it uses as a backup. At least as much as it's about DNA, life on Earth is about ribosomes. Apple trees are one way that ribosomes can make more ribosomes, as are slime molds, great white sharks, and koalas. We can think of the function of DNA as either a) a backup of ribosomes and b) one stage in the manufacture of all the rest of the ancillary machines that ensure survival of ribosomes. How is this different from making the same argument about any other cellular element, that the point of life is proteasomes? Not only are rRNA sequences (not to mention tRNA anticodons) the most conserved nucleic acids in living things, what is conserved is the structure of the molecule, over and above its sequence. Even more specifically than ribosomes, what is being preserved and selected for and served in a giant feedback loop by the rest of the structures in the cell is this consistent set of RNA-protein interactions.
There are many possible objections to this shift in viewpoints, and among them I will address two: first, the existence of viruses, which are non-ribosome-containing replicators. Viruses are "genes that got away" but have no independent metabolism (or ability to reproduce) independently of ribosomes. In terms of this ribosome-centric hierarchy, viruses are a peripheral curiosity in the same way as prions, which are proteins that reproduce their shape (and therefore physical properties) but also cannot reproduce chemically in the absence of ribosomes; of course, in terms of biomedical relevance to human life, viruses are anything but a curiosity (but this may serve to obscure their hierarchical triviality). On the other hand, Viroids are RNA-only replicators which can, in fact, reproduce without ribosomes, using only RNA Pol II, and some are autocatalytic.
A second objection made frequently is that the structure of rRNA and the protein-nucleic acid that structure mediates (and the rich chemistry that sprouted around it on the young Earth) were driven by thermodynamics - that there's only one way to build the interaction surface, and only one set of 20 amino acids that could ever have been chosen. If the shape and activity of a ribosome are really just thermodynamic fate, then there's no heredity information in rRNA - no heritability information, no meaningful travel over time in the fitness landscape, and no possibility of "frozen accidents" that commit a system to climb toward local optima, any more than there is for a star or fire. Yes, fire spreads and consumes fuel, but the commitments of dumb physics force them to behave the way they do; there's no difference in the flame on a birthday candle whether you lit it from a lighter or at the edge of a burning pine forest. One way to test the question of whether ribosomes are stuck in one shape would be to run synthetic biology experiments with simple ribosome systems where you swap out the 20 legacy amino acids to search for a more robust set of monomers, with some kind of feedback to allow selection. But that would be an extremely complicated experiment. I rather think that the burden of proof is on the claimant who argues that the anticodon system we ended up with is necessarily the universally best one, and that RNA-descended aliens from Alpha Centauri would necessarily use the same set that we do.
SUMMARY
- Our understanding of molecular biology and the evolution of the cell is constrained by the useful conventions we use to study chemical processes in the cell. Despite the wide acceptance of the RNA World hypothesis, we still view life on Earth as being about DNA.
- The transition from the RNA world to the DNA world was mediated by either development of reverse transcriptase and RNA polymerase activity, or an endosymbiosis event involving a DNA virus infection and uptake by the virus of rRNA genes.
- DNA is best thought of as a back-up of a) rRNA and b) all other types of catalytic molecules (today, mostly proteins) all of whose function is to ensure the survival of rRNA.
- rRNA genes are the most conserved among living things; notably, the structure of the rRNA itself is even more conserved than the primary sequence.
- A better way of thinking about life than considering it to be about DNA is to think of it as about the propagation of ribosomes, or specifically, about propagating a specific set of protein-RNA interactions mediated by a specific type of chemical structure.
Thursday, July 23, 2009
Cool Evolution Find: Fossil Virus
Not in stone of course, but in crocodilians' genomes. ERV covers well. Question for evolution, as she puts it: if this virus was good enough at what it did to work its way into a genome, why does it apparently have no descendants today? Two possibilities come to mind: 1) its descendants are still around, but we haven't discovered it yet (remember Nannarrup hoffmani? A whole new genus of metazoans found 7 years ago in Central Park, New York?). 2) the chance of becoming an ERV do not correlate over time with fitness.
Wednesday, July 22, 2009
Consciousness, Reduction, and Memory
A tool that I think we underutilize in the hard question of consciousness is the idea that if some entities are conscious, and some are not, then there is a boundary between the two categories. My suspicion so far is that any close examination of this boundary inevitably becomes a reductio ad absurdum, and the boundary evaporates, regardless of the examiner's initial intentions; and once the boundary has evaporated, we're left with the unintuitive non-assertion that there is no reason to think everything doesn't have some rudimentary consciousness - or the non-starter that nothing is conscious. The first assertion led Chalmers to his famous and misinterpreted statement about conscious thermostats.
You don't think thermostats are conscious? Fine. What about dogs? That's a slippery slope; as a furry, warm blooded vertebrate primate, you're subject to some pretty powerful biases about what the signposts for self-awareness are. Roger Penrose once (half-jokingly) conceded insects to the world of unconscious Turing machines, and Dan Dennett immediately challenged him: why? In other words, if dogs are conscious, why not octopi, crabs, E. coli, and the Melissa virus? Where's the line, and what is it? A 40 Hz wave? Unsatisfying, to say the least.
The point is this: if you believe that consciousness only occurs in what we on Earth call living things, then you must also believe that at one point it did not exist. Fair enough: so where and when did the first glimmer happen? It's not obviously a meaningless question to ask whether the first consciousness appeared in a trilobite scuttling about in a seabed on the piece of continental plate that is now Turkmenistan, a minute before sunrise on 28 June, 539,640,122 BCE (I think it was a Tuesday). It's tempting to dismiss point-of-origin stories like this, but the alternative is either to accept some provincial point-of-origin since the Big Bang, or accept that consciousness is a spectrum, in which case we're back to the thermostat (or to none of us being conscious). Both alternatives are counterintuitive, but modern science is littered with such choices; not surprising given how far we are out of our depth, i.e. collecting food, finding mates, and running from predators in East Africa.
So far I have not explicitly stated the materialist assumption that consciousness is related only the the matter of the entity in question, and how that matter is arranged - but there is the stickier question of within what limits that matter can vary and remain conscious. By that I mean, my brain is physically different from yours, and from a monolingual Greenlandic woman's. You could rob each of these three entities of their current level of consciousness by making physical changes to them, but all three were different to start with, so how do you know they were all conscious? Another not obviously meaningless question is to ask whether a capacity for consciousness must necessarily permeate an entire species. Why assume the conscious/non-conscious boundary follows species boundaries? Maybe on that fateful June 28 in the early Cambrian, there was just one single conscious trilobite, surrounded by zombie trilobites. And maybe some humans are conscious and some aren't.
This may seem to point the way to a reductive program, to test the boundaries of what can be conscious. We can't go looking for the boundary with a time machine to see where it all began, and of course even if we could there remains the challenge with the hard question that we have to rely on first-person accounts we get through third person reports - we can't build a consciousness meter to wave at trilobites, and they can't tell us that the sunrise was pretty. And even if they did it doesn't prove they experienced joy at seeing it; the whole problem is the inviolable subjective first-personness of it. But since we are assuming that consciousness relies on matter and arrangement (i.e. nervous systems) in a reproducible way, in a pattern that at least some humans can understand, we can still reductively investigate alterations of the material state of the basis of consciousness using human first-person accounts, in ways that don't veer off into other problems of behavior as such investigations often do. This still won't answer the hard question but it will at least show us to what things the hard question can apply.
We can't quite cut out brain tissue and ask people whether they're conscious (the idea is to restore the previous state, when you know they were conscious as near as that can be known by a third-party). But what we can do, and have done is study cognitively abnormal humans who can communicate their experience. These break down into 1) people with some disorder, either through trauma or congenital condition and 2) people who change their brain chemistry either from some activity (meditation, extreme exertion) or consume mind-altering compounds. With #1, people usually remain in the same state. With #2, these occasions occur under very uncontrolled conditions and we have very limited options ethically - "go run a hundred miles then meditate for a month and tell me what it's like" - and scientifically - there are only so much agonists for receptor X and the brain doesn't cooperate in the way they're distributed.
If we have anything to say about it hopefully the numbers of people in category #1 will drop. If as time passes our ability to reversibly under- or over-stimulate parts of the brain increases, as I hope it will, then I hope future neuroscientists will be able to pick from a suite of compounds that block specific tissues in the brain (not just receptors) from interacting with the rest. Of course, this program might not be able to tell the difference between basic requirements of consciousness, and the provincial arrangements of our own brains - or primate, or mammalian, or vertebrate brains. (Note: I am not advocating kidnapping of and experimenting on aliens, though if you have one, call me). It seems to me the two components of consciousness in our normal cognition that would be of immediate interest and are relatively isolable in anatomical terms are memory (sensory, short- and long-term) and goal-orientated behavior, specifically with regard to pain and pleasure.
Regarding reductive investigations of memory: is it possible to remove consciousness in a way that is reportable later? In other words, say you find a molecule that shuts off only the here-and-now experience, but not anything else, including memory. While the subject is under the influence, she's same as she ever was, lucid, talking, responding - a classic philosophical zombie. You give the wash-out. She reports that she now remembers the conversation, remembers what happened while she was "under", but somehow didn't experience them at the time. Can this even be meaningful?
Science fiction thought experiments of memory implants come to mind: in the movie Blade Runner, androids that live only four years are given childhood memories so they don't realize they're androids; did they experience those childhoods? The reverse situation - that is, experience, but no memory, known as anterograde amnesia - is the subject of the movie Memento (category #1, abnormal human), and does occur in the real world, but there are also abundant real-world examples in category #2, as anyone who consumes alcohol can learn. A personal account illustrates this. At a friend's birthday party I overindulged. Among the many escapades that evening which charmed and delighted my fellow party-goers was the following groan I emitted while sitting in the hot tub: "Oh god, I'm going to be sick...what's the point of blacking out if you have to experience it anyway." At which point they wisely shooed me from the tub, and my prophecy was realized.
I tell this story not to concern you more for my liver than my brain, but because the interesting part is that I don't remember it. I did black out - I know this only from (effectively) third-hand accounts. Thanks to my ethanol-clogged NMDA receptors, I have no memory at all of that event (or many others that evening). Did I experience nausea? Where did the experience "go"? What evidence do I have that at that moment I was not a zombie, even to myself? One solution is that I'm silly to worry about where the experience goes - that at least in human brains, experience requires only sensory memory (in us, a second or so), or that it requires sensory and short-term memory (in us, five to ten minutes). But is there a drug even in principle like the one in the experiment above that could have saved me from the experience of nausea but preserved the memory? That's not an entirely dispassionate question, becuase I would make that trade in a second.
The second area of investigation - goal-seeking behavior - raises questions about whether it is meaningful to talk about consciousness in the absence of pain or pleasure. I'm not talking about full-body analgesia; I'm talking about not experiencing psychological discomfort in response to thoughts about seeing their kids at the end of the day or worrying about your mortgage. Granted, that's a little more involved than questions about memory.
I think a continuing focus on specific parts of the brain in a reductive search for absolute boundaries of consciousness - if indeed there are any - is wise for more than just theoretical reasons. Any research program that ignores its sources of financial support is one that won't move along very quickly. The hard problem of consciousness, while I consider it the central question of philosophy and science, is not one that promises any immediate application that can return effort invested in it. I'm obviously sympathetic to philosophy and science for its own sake, or I wouldn't be writing this out of personal passion. But we all want to see progress on this question, and being able to sell the research based on applications to Alzheimers, ADHD, and schizophrenia would go a long way to obtaining support and public awareness. Technology that we don't yet have that will require money to develop - or, technology that we do have that requires money to obtain and use. And in the end, I can't think of a better outcome anyway than that this research could end up helping human beings suffering with cognitive disorders.
You don't think thermostats are conscious? Fine. What about dogs? That's a slippery slope; as a furry, warm blooded vertebrate primate, you're subject to some pretty powerful biases about what the signposts for self-awareness are. Roger Penrose once (half-jokingly) conceded insects to the world of unconscious Turing machines, and Dan Dennett immediately challenged him: why? In other words, if dogs are conscious, why not octopi, crabs, E. coli, and the Melissa virus? Where's the line, and what is it? A 40 Hz wave? Unsatisfying, to say the least.
The point is this: if you believe that consciousness only occurs in what we on Earth call living things, then you must also believe that at one point it did not exist. Fair enough: so where and when did the first glimmer happen? It's not obviously a meaningless question to ask whether the first consciousness appeared in a trilobite scuttling about in a seabed on the piece of continental plate that is now Turkmenistan, a minute before sunrise on 28 June, 539,640,122 BCE (I think it was a Tuesday). It's tempting to dismiss point-of-origin stories like this, but the alternative is either to accept some provincial point-of-origin since the Big Bang, or accept that consciousness is a spectrum, in which case we're back to the thermostat (or to none of us being conscious). Both alternatives are counterintuitive, but modern science is littered with such choices; not surprising given how far we are out of our depth, i.e. collecting food, finding mates, and running from predators in East Africa.
So far I have not explicitly stated the materialist assumption that consciousness is related only the the matter of the entity in question, and how that matter is arranged - but there is the stickier question of within what limits that matter can vary and remain conscious. By that I mean, my brain is physically different from yours, and from a monolingual Greenlandic woman's. You could rob each of these three entities of their current level of consciousness by making physical changes to them, but all three were different to start with, so how do you know they were all conscious? Another not obviously meaningless question is to ask whether a capacity for consciousness must necessarily permeate an entire species. Why assume the conscious/non-conscious boundary follows species boundaries? Maybe on that fateful June 28 in the early Cambrian, there was just one single conscious trilobite, surrounded by zombie trilobites. And maybe some humans are conscious and some aren't.
This may seem to point the way to a reductive program, to test the boundaries of what can be conscious. We can't go looking for the boundary with a time machine to see where it all began, and of course even if we could there remains the challenge with the hard question that we have to rely on first-person accounts we get through third person reports - we can't build a consciousness meter to wave at trilobites, and they can't tell us that the sunrise was pretty. And even if they did it doesn't prove they experienced joy at seeing it; the whole problem is the inviolable subjective first-personness of it. But since we are assuming that consciousness relies on matter and arrangement (i.e. nervous systems) in a reproducible way, in a pattern that at least some humans can understand, we can still reductively investigate alterations of the material state of the basis of consciousness using human first-person accounts, in ways that don't veer off into other problems of behavior as such investigations often do. This still won't answer the hard question but it will at least show us to what things the hard question can apply.
We can't quite cut out brain tissue and ask people whether they're conscious (the idea is to restore the previous state, when you know they were conscious as near as that can be known by a third-party). But what we can do, and have done is study cognitively abnormal humans who can communicate their experience. These break down into 1) people with some disorder, either through trauma or congenital condition and 2) people who change their brain chemistry either from some activity (meditation, extreme exertion) or consume mind-altering compounds. With #1, people usually remain in the same state. With #2, these occasions occur under very uncontrolled conditions and we have very limited options ethically - "go run a hundred miles then meditate for a month and tell me what it's like" - and scientifically - there are only so much agonists for receptor X and the brain doesn't cooperate in the way they're distributed.
If we have anything to say about it hopefully the numbers of people in category #1 will drop. If as time passes our ability to reversibly under- or over-stimulate parts of the brain increases, as I hope it will, then I hope future neuroscientists will be able to pick from a suite of compounds that block specific tissues in the brain (not just receptors) from interacting with the rest. Of course, this program might not be able to tell the difference between basic requirements of consciousness, and the provincial arrangements of our own brains - or primate, or mammalian, or vertebrate brains. (Note: I am not advocating kidnapping of and experimenting on aliens, though if you have one, call me). It seems to me the two components of consciousness in our normal cognition that would be of immediate interest and are relatively isolable in anatomical terms are memory (sensory, short- and long-term) and goal-orientated behavior, specifically with regard to pain and pleasure.
Regarding reductive investigations of memory: is it possible to remove consciousness in a way that is reportable later? In other words, say you find a molecule that shuts off only the here-and-now experience, but not anything else, including memory. While the subject is under the influence, she's same as she ever was, lucid, talking, responding - a classic philosophical zombie. You give the wash-out. She reports that she now remembers the conversation, remembers what happened while she was "under", but somehow didn't experience them at the time. Can this even be meaningful?
Science fiction thought experiments of memory implants come to mind: in the movie Blade Runner, androids that live only four years are given childhood memories so they don't realize they're androids; did they experience those childhoods? The reverse situation - that is, experience, but no memory, known as anterograde amnesia - is the subject of the movie Memento (category #1, abnormal human), and does occur in the real world, but there are also abundant real-world examples in category #2, as anyone who consumes alcohol can learn. A personal account illustrates this. At a friend's birthday party I overindulged. Among the many escapades that evening which charmed and delighted my fellow party-goers was the following groan I emitted while sitting in the hot tub: "Oh god, I'm going to be sick...what's the point of blacking out if you have to experience it anyway." At which point they wisely shooed me from the tub, and my prophecy was realized.
I tell this story not to concern you more for my liver than my brain, but because the interesting part is that I don't remember it. I did black out - I know this only from (effectively) third-hand accounts. Thanks to my ethanol-clogged NMDA receptors, I have no memory at all of that event (or many others that evening). Did I experience nausea? Where did the experience "go"? What evidence do I have that at that moment I was not a zombie, even to myself? One solution is that I'm silly to worry about where the experience goes - that at least in human brains, experience requires only sensory memory (in us, a second or so), or that it requires sensory and short-term memory (in us, five to ten minutes). But is there a drug even in principle like the one in the experiment above that could have saved me from the experience of nausea but preserved the memory? That's not an entirely dispassionate question, becuase I would make that trade in a second.
The second area of investigation - goal-seeking behavior - raises questions about whether it is meaningful to talk about consciousness in the absence of pain or pleasure. I'm not talking about full-body analgesia; I'm talking about not experiencing psychological discomfort in response to thoughts about seeing their kids at the end of the day or worrying about your mortgage. Granted, that's a little more involved than questions about memory.
I think a continuing focus on specific parts of the brain in a reductive search for absolute boundaries of consciousness - if indeed there are any - is wise for more than just theoretical reasons. Any research program that ignores its sources of financial support is one that won't move along very quickly. The hard problem of consciousness, while I consider it the central question of philosophy and science, is not one that promises any immediate application that can return effort invested in it. I'm obviously sympathetic to philosophy and science for its own sake, or I wouldn't be writing this out of personal passion. But we all want to see progress on this question, and being able to sell the research based on applications to Alzheimers, ADHD, and schizophrenia would go a long way to obtaining support and public awareness. Technology that we don't yet have that will require money to develop - or, technology that we do have that requires money to obtain and use. And in the end, I can't think of a better outcome anyway than that this research could end up helping human beings suffering with cognitive disorders.
Monday, July 20, 2009
Monkeys Can Respond to Grammar-Like Patterns in Sound
Article here. Essentially, tamarin monkeys showed a capacity for recognizing a pattern of phonemes, and then recognizing when a novel pattern appeared (if an affix was used in the wrong place).
Primates can frequently recognize language-like stimuli when exposed to them, but whether they can be trained to generate them is another question. (And we know they don't generate them spontaneously.) It seems to me there are two take-homes here. First, that many primates (including those not even that closely-related to us) have the hardware for linguistic pattern recognition. This raises the question of whether other linguistic substrates delivered over a time sequence could evince similar responses: chains of images for example. It would be interesting to compare human and non-human primates in these experiments (with sound and non-sound grammar).
The second, and to me more interesting, point to investigate is to what degree non-human primates can associate the patterned-sounds they're hearing with semantic content. No, it wasn't a concern at all in this experiment, but it's crucial to the development of language. While Endress et all conducted this experiment with particular reference to grammar acquisition, a model of vocabulary acquisition in human children uses much the same pattern-recognition skill: children learn words by looking for sequence rules, and take notice when they're violated. A chid learning English for the first time has no way to know that "word boundary" is two words, and where the dividing line is, until they figure out that English words don't often start with "db"; in fact words don't even have that sound combination so much (and of course they hear the words separately). The tamarins were doing some form of this.
What the tamarins can't do that childre can - or at least no one's shown that tamarins can do it, and I don't think anyone expects it - is that once they've parsed out the elements and learned the order they usually occur in, they can build a network and assign each element to an object or attribute they see in the real world. I wouldn't be blown away if a tamarin learns to be "surprised" (as in this experiment) by an "o" coming at the beginning of a word, as opposed to at the end. What the tamarins won't ever learn is that the -o ending means that the word in question is an object that is receiving action, as opposed to performing it. Yet somehow every normal Japanese child learns exactly this by age 5, and lots of other such content-sound relations as well.
Animals clearly can associate a few sets of sounds with concrete, specific content. Anyone who has ever had to spell out "W-A-L-K" to a fellow human in front of a dog knows this. But the extent of language perception in non-human animals is an interesting question because it gives us a chance to do some comparative biology with reference to the following questions. How how many of these sets of sounds can the dog (or the tamarin) learn? How generalizable is the ability - i.e., given the internal states of the animal as they reflect the outside world, how broad or distinct are the categories that can be covered by a single signifier - your dog understands tree, but does it understand redwood? Plant? How complex a relationship between signifiers can the animal construct, e.g., can the animal tell a difference between walk, walked, and don't walk? And to what degree are these things related - that is, do human children get a mnemonic benefit from pinning the sounds they learn into a richer network of semantic content? Pinning down these differences to the activity of physical structures in our brains will go a long way to understanding how we acquire and process language.
Primates can frequently recognize language-like stimuli when exposed to them, but whether they can be trained to generate them is another question. (And we know they don't generate them spontaneously.) It seems to me there are two take-homes here. First, that many primates (including those not even that closely-related to us) have the hardware for linguistic pattern recognition. This raises the question of whether other linguistic substrates delivered over a time sequence could evince similar responses: chains of images for example. It would be interesting to compare human and non-human primates in these experiments (with sound and non-sound grammar).
The second, and to me more interesting, point to investigate is to what degree non-human primates can associate the patterned-sounds they're hearing with semantic content. No, it wasn't a concern at all in this experiment, but it's crucial to the development of language. While Endress et all conducted this experiment with particular reference to grammar acquisition, a model of vocabulary acquisition in human children uses much the same pattern-recognition skill: children learn words by looking for sequence rules, and take notice when they're violated. A chid learning English for the first time has no way to know that "word boundary" is two words, and where the dividing line is, until they figure out that English words don't often start with "db"; in fact words don't even have that sound combination so much (and of course they hear the words separately). The tamarins were doing some form of this.
What the tamarins can't do that childre can - or at least no one's shown that tamarins can do it, and I don't think anyone expects it - is that once they've parsed out the elements and learned the order they usually occur in, they can build a network and assign each element to an object or attribute they see in the real world. I wouldn't be blown away if a tamarin learns to be "surprised" (as in this experiment) by an "o" coming at the beginning of a word, as opposed to at the end. What the tamarins won't ever learn is that the -o ending means that the word in question is an object that is receiving action, as opposed to performing it. Yet somehow every normal Japanese child learns exactly this by age 5, and lots of other such content-sound relations as well.
Animals clearly can associate a few sets of sounds with concrete, specific content. Anyone who has ever had to spell out "W-A-L-K" to a fellow human in front of a dog knows this. But the extent of language perception in non-human animals is an interesting question because it gives us a chance to do some comparative biology with reference to the following questions. How how many of these sets of sounds can the dog (or the tamarin) learn? How generalizable is the ability - i.e., given the internal states of the animal as they reflect the outside world, how broad or distinct are the categories that can be covered by a single signifier - your dog understands tree, but does it understand redwood? Plant? How complex a relationship between signifiers can the animal construct, e.g., can the animal tell a difference between walk, walked, and don't walk? And to what degree are these things related - that is, do human children get a mnemonic benefit from pinning the sounds they learn into a richer network of semantic content? Pinning down these differences to the activity of physical structures in our brains will go a long way to understanding how we acquire and process language.
Bias Bias
So we're biased against seeing our biases: while it's nice to have experimental verification, this should not be surprising, else our biases would be subject to examination and we could get rid of them.
A frequent subtext of bias studies goes is this: "Look how distorted our perspective of the world is. It's good that we study these tendencies so that maybe we can diminish or eliminate them, and people would have a less distorted view of reality." It would be useful to ask what would humans be like without these biases. How would individuals behave differently? What would society look like? Aren't some of these biases fairly obvious beneficial self-deception strategies that evolved as a result of conspecific competition; would cutting them out of some humans (but not all) actually result in individuals handicapped in the survival and reproduction game, and wouldn't similar strategies redevelop over time? Most importantly, without our biases would we be happier? Is it meaningful to talk about waving a magic wand and re-wiring the brain to eliminate these biases, or are they so deep-wired as to require much more profound commensurate changes to retain a functioning central nervous system?
A frequent subtext of bias studies goes is this: "Look how distorted our perspective of the world is. It's good that we study these tendencies so that maybe we can diminish or eliminate them, and people would have a less distorted view of reality." It would be useful to ask what would humans be like without these biases. How would individuals behave differently? What would society look like? Aren't some of these biases fairly obvious beneficial self-deception strategies that evolved as a result of conspecific competition; would cutting them out of some humans (but not all) actually result in individuals handicapped in the survival and reproduction game, and wouldn't similar strategies redevelop over time? Most importantly, without our biases would we be happier? Is it meaningful to talk about waving a magic wand and re-wiring the brain to eliminate these biases, or are they so deep-wired as to require much more profound commensurate changes to retain a functioning central nervous system?
Sunday, July 19, 2009
What Do Serial Killers and Suicidal Rats Have in Common?
Serial murder is such an astonishingly maladaptive behavior that I've often speculated whether we're not seeing a) a gene that, when heterozygous, is adaptive, but when homozygous, can lead to this behavior, or b) a toxoplasma gondii-like infection.
Toxoplasma gondii is the pathogen that makes the rodents it infects behave (basically) suicidally around predators, like cats; the cat eats the rat, the organism survives in the cat's gut, and when the cat defecates, it spreads more Toxoplasma. (I first read about this organism and the incredibly specific behavior an infection engenders in the work of Daniel Dennett, who is a big fan of this organism as a metaphor for other replicators.) Now it turns out that humans infected with Toxoplasma are also more likely to behave dangerously, judging by car accident rates. (Hat tip to Marginal Revolution).
Humans engage in many apparently maladaptive behaviors (serial murder among them) and this story gives us no reason to conclude that serial murder is the result of an infection, but it does show that even in humans, complex behaviors can be affected by an organism in ways similar to the other host species we've studied. Behaviors like serial killing are so inexplicable that hypotheses about their origins should include infection as a possible etiology.
I grant the full-on speculative nature of this post, and even if serial killers are infected with a T. gondii-like pathogen, then it remains to be explained a) whether the infection-induced behavior would have been the same in our hunter-gatherer ancestors (how can you be a serial killer in a band of 25 people?) and b) how exactly the behavior would improve transmission, which is clear in the case of rats and cats.
Toxoplasma gondii is the pathogen that makes the rodents it infects behave (basically) suicidally around predators, like cats; the cat eats the rat, the organism survives in the cat's gut, and when the cat defecates, it spreads more Toxoplasma. (I first read about this organism and the incredibly specific behavior an infection engenders in the work of Daniel Dennett, who is a big fan of this organism as a metaphor for other replicators.) Now it turns out that humans infected with Toxoplasma are also more likely to behave dangerously, judging by car accident rates. (Hat tip to Marginal Revolution).
Humans engage in many apparently maladaptive behaviors (serial murder among them) and this story gives us no reason to conclude that serial murder is the result of an infection, but it does show that even in humans, complex behaviors can be affected by an organism in ways similar to the other host species we've studied. Behaviors like serial killing are so inexplicable that hypotheses about their origins should include infection as a possible etiology.
I grant the full-on speculative nature of this post, and even if serial killers are infected with a T. gondii-like pathogen, then it remains to be explained a) whether the infection-induced behavior would have been the same in our hunter-gatherer ancestors (how can you be a serial killer in a band of 25 people?) and b) how exactly the behavior would improve transmission, which is clear in the case of rats and cats.
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