Molecules That See

Being trans is OK: retinal and the first event of vision.

Our vision is incredible. If I was not looking right now and experiencing it myself, it would be unbelievable that a biological system made up of motley molecules could accomplish the speed, acuity and color that our visual system provides. It was certainly a sticking point for creationists, who found (and perhaps still find) it incredible that nature alone can explain it, not to mention its genesis out of the mists of evolutionary time. But science has been plugging away, filling in the details of the pathway, which so far appear to arise by natural means. Where consciousness fits in has yet to be figured out, but everything else is increasingly well-accounted. 

It all starts in the eye, which has a curiously backward sheet of tissue at the back- the retina. Its nerves and blood vessels are on the surface, and after light gets through those, it hits the photoreceptor cells at the rear. These photoreceptor cells come in two types, rods (non-color sensitive) and cones (sensitive to either red, green, or blue). The photoreceptor cells have a highly polarized and complicated structure, where photosensitive pigments are bottom-most in a dense stack of membranes. Above these is a segment where the mitochondria reside, which provide power, as vision needs a lot of energy. Above these is the nucleus of the cell (the brains of the operation) and top-most is the synaptic output to the rest of the nervous system- to those nerves that network on the outside of the retina. 

A single photoreceptor cell, with the outer segment at the very back of the retina, and other elements in front.

Facing the photoreceptor membranes at the bottom of the retina is the retinal pigment epithelium, which is black with melanin. This is finally where light stops, and it also has very important functions in supporting the photoreceptor cells by buffering their ionic, metabolic, and immune environment, and phagocytosing and digesting photoreceptor membranes as they get photo-oxidized, damaged, and sloughed off. Finally, inside the photoreceptor cells are the pigment membranes, which harbor the photo-sensitive protein rhodopsin, which in turn hosts the sensing pigment, retinal. Retinal is a vitamin A-derived long-chain molecule that is bound inside rhodopsin or within other opsins which respectively confer slightly shifted color sensitivity. 

These opsins transform the tickle that retinal receives from a photon into a conformational change that they, as GPCRs (G-protein coupled receptors), transmit to G-proteins, called transducin. For each photon coming in, about 50 transducin molecules are activated. Each of activated transducin G-protein alpha subunits induce (in its target cGMP phosphodisterase) about 1000 cGMP molecules to be consumed. The local drop in cGMP concentration then closes the cGMP-gated cation channels in the photoreceptor cell membrane, which starts the electrical impulse that travels out to the synapse and nervous system. This amplification series provides the exquisite sensitivity that allows single photons to be detected by the system, along with the high density of the retinal/opsin molecules packed into the photoreceptor membranes.

Retinal, used in all photoreceptor cell types. Light causes the cis-form to kick over to the trans form, which is more stable.

The central position of retinal has long been understood, as has the key transition that a photon induces, from cis-retinal to all-trans retinal. Cis-retinal has a kink in the middle, where its double bond in the center of the fatty chain forms a "C" instead of a "W", swinging around the 3-carbon end of the chain. All-trans retinal is a sort of default state, while the cis-structure is the "cocked" state- stable but susceptible to triggering by light. Interestingly, retinal can not be reset to the cis-state while still in the opsin protein. It has to be extracted, sent off to a series of at least three different enzymes to be re-cocked. It is alarming, really, to consider the complexity of all this.

A recent paper (review) provided the first look at what actually happens to retinal at the moment of activation. This is, understandably, a very fast process, and femtosecond x-ray analysis needed to be brought in to look at it. Not only that, but as described above, once retinal flips from the dark to the light-activated state, it never reverses by itself. So every molecule or crystal used in the analysis can only be used once- no second looks are possible. The authors used a spray-crystallography system where protein crystals suspended in liquid were shot into a super-fine and fast X-ray beam, just after passing by an optical laser that activated the retinal. Computers are now helpful enough that the diffractions from these passing crystals, thrown off in all directions, can be usefully collected. In the past, crystals were painstakingly positioned on goniometers at the center of large detectors, and other issues predominated, such as how to keep such crystals cold for chemical stability. The question here was what happens in the femto- and pico-seconds after optical light absorption by retinal, ensconced in its (temporary) rhodopsin protein home.

Soon after activation, at one picosecond, retinal has squirmed around, altering many contacts with its protein. The trans (dark) conformation is shown in red, while the just-activated form is in yellow. The PSB site on the far end of the fatty chain (right) is secured against the rhodopsin host, as is the retinal ring (left side), leaving the middle of the molecule to convey most of the shape change, a bit like a bicycle pedal.

And what happens? As expected, the retinal molecule twists from cis to trans, causing the protein contacts to shift. The retinal shift happens by 200 femtoseconds, and the knock-on effects through the protein are finished by 100 picoseconds. It all makes a nanosecond seem impossibly long! As imaged above, the shape shift of retinal changes a series of contacts it has with the rhodopsin protein, inducing it to change shape as well. The two ends of the retinal molecule seem to be relatively tacked down, leaving the middle, where the shape change happens, to do most of the work. 

"One picosecond after light activation, rhodopsin has reached the red-shifted Batho-Rh intermediate. Already by this early stage of activation, the twisted retinal is freed from many of its interactions with the binding pocket while structural perturbations radiate away as a transient anisotropic breathing motion that is almost entirely decayed by 100 ps. Other subtle and transient structural rearrangements within the protein arise in important regions for GPCR activation and bear similarities to those observed by TR-SFX during photoactivation of seven-TM helix retinal-binding proteins from bacteria and archaea."

All this speed is naturally lost in the later phases, which take many milliseconds to send signals to the brain, discern movement and shape, to identify objects in the scene, and do all the other processing needed before consciousness can make any sense of it. But it is nice to know how elegant and uniform the opening scene in this drama is.

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Consciousness and the Secret Life of Plants

Could plants be conscious? What are the limits of consciousness and pain? 

Scientific American recently reviewed a book titled "Planta Sapiens". The title gives it all away, and the review was quite positive, with statements like: 

"Our senses can not grasp the rich communicative world of plants. We therefore lack language to describe the 'intelligence' of a root tip in conversation with the microbial life of the soil or the 'cognition' that emerges when chemical whispers ripple through a lacework of leaf cells."

This is provocative indeed! What if plants really do have a secret life and suffer pain with our every bite and swing of the scythe? What of our vaunted morals and ethics then?

I am afraid that I take a skeptical view of this kind of thing, so let's go through some of the aspects of consciousness, and ask how widespread it really is. One traditional view, from the ur-scientific types like Descartes, is that only humans have consciousness, and all other creatures, have at best a mechanism, unfeeling and mechanical, that may look like consciousness, but isn't. This, continued in a sense by B. F. Skinner in the 20th century, is a statement from ignorance. We can not fully communicate with animals, so we can not really participate in what looks like their consciousness, so let's just ignore it. This position has the added dividend of supporting our unethical treatment of animals, which was an enormous convenience, and remains the core position of capitalism generally, regarding farm animals (though its view of humans is hardly more generous).

Well, this view is totally untenable, from our experience of animals, our ability to indeed communicate with them to various degrees, to see them dreaming, not to mention from an evolutionary standpoint. Our consciousness did not arise from nothing, after all. So I think we can agree that mammals can all be included in the community of conscious fellow-beings on the planet. It is clear that the range of conscious pre-occupations can vary tremendously, but whenever we have looked at the workings of memory, attention, vision, and other components assumed to be part of or contributors to conscious awareness, they all exist in mammals, at least. 

But what about other animals like insects, jellyfish, or bacteria? Here we will need a deeper look at the principles in play. As far as we understand it, consciousness is an activity that binds various senses and models of the world into an experience. It should be distinguished from responsiveness to stimuli. A thermostat is responsive. A bacterium is responsive. That does not constitute consciousness. Bacteria are highly responsive to chemical gradients in their environment, to food sources, to the pheromones of fellow bacteria. They appear to have some amount of sensibility and will. But we can not say that they have experience in the sense of a conscious experience, even if they integrate a lot of stimuli into a holistic and sensitive approach to their environment. 

The same is true of our own cells, naturally. They also are highly responsive on an individual basis, working hard to figure out what the bloodstream is bringing them in terms of food, immune signals, pathogens, etc. Could each of our cells be conscious? I would doubt it, because their responsiveness is mechanistic, rather than being an independent as well as integrated model of their world. Simlarly, if we are under anaesthesia and a surgeon cuts off a leg, is that leg conscious? It has countless nerve cells, and sensory apparatus, but it does not represent anything about its world. It rather is built to send all these signals to a modeling system elsewhere, i.e. our brain, which is where consciousness happens, and where (conscious) pain happens as well.

So I think the bottom line is that consciousness is rather widely shared as a property of brains, thus of organisms with brains, which were devised over evolutionary time to provide the kind of integrated experience that a neural net can not supply. Jellyfish, for instance, have neural nets that feel pain, respond to food and mates, and swim exquisitely. They are highly responsive, but, I would argue, not conscious. On the other hand, insects have brains and would count as conscious, even though their level of consciousness might be very primitive. Honey bees map out their world, navigate about, select the delicacies they want from plants, and go home to a highly organized hive. They also remember experiences and learn from them.

This all makes it highly unlikely that consciousness is present in quantum phenomena, in rocks, in bacteria, or in plants. They just do not have the machinery it takes to feel something as an integrated and meaningful experience. Where exactly the line is between highly responsive and conscious is probably not sharply defined. There are brains that are exceedingly small, and neural nets that are very rich. But it is also clear that it doesn't take consciousness to experience pain or try to avoid it, (which plants, bacteria, and jellyfish all do). Where is the limit of ethical care, if our criterion shifts from consciousness to pain? Wasn't our amputated leg in pain after the operation above, and didn't we callously ignore its feelings? 

I would suggest that the limit remains that of consciousness, not that of responsiveness to pain. Pain is not problematic because of a reflex reaction. The doctor can tap our knee as often as he wants, perhaps causing pain to our tendon, but not to our consciousness. Pain is problematic because of suffering, which is a conscious construct built around memory, expectations, and models of how things "should" be. While one can easily see that a plant might have certain positive (light, air, water) and negative (herbivores, fungi) stimuli that shape its intrinsic responses to the environment, these are all reflexive, not reflective, and so do not appear (to an admittedly biased observer) to constitute suffering that rises to ethical consideration.

Journey to the Center of the Ribosome

And to the origin of the ribosome as well.

The ribosome is a relic. It is slow and inefficient, and therefore needed and made in huge amounts in all cells. It is absurdly large, with some of the most highly conserved sequences in all of life and dozens of later additions, ingloriously pasted on the outside. While those later additions are all proteins, its catalytic core is made of RNA, explaining both its age and its slowness. For it is a relic of the RNA world, and itself marks the beginning of the mechanism of protein synthesis that would provide the catalytic capacity to transcend that world. But the ribosome itself would never be superceded, only jury-rigged and augmented. While other molecules like lipids and metabolites are also crucial to biogenesis, this early phase is called the RNA world because RNA is widely thought to be the main catalytic and informational molecule.

Schematic of the ribosome, showing decoding on the small subunit, and peptide synthesis on the large subunit (top). Sausage-like tRNAs are shown lining up preparatory step (RF, also called the A site), the transferring step (P), and the exit step (E). The peptidyl transferase core is made of RNA, so all key aspects of this machine are run by RNA.

So where did the ribosome begin? Its core function is to line up an RNA message that carries the genetic code, to which other RNAs dock, by sequence recognition. These special (transfer RNAs, or tRNAs) have amino acids stuck on their other ends, which then likewise line up and get linked together, forming the nascent protein. It is pretty clear that, while the genetic code now has three nucleotides per unit (codon), enabling 64 possibilities and in fact coding for 20 amino acids, it began with only two, offering 16 possible amino acids. About half of current amino acids are now coded by "degenerate" codons, where the last letter doesn't make any difference- all four (say, GGU, GGC, GGA, GGG, for glycine) code for the same amino acid. 

A more detailed structure of the ribosome, with RNA shown in thin orange helixes, and proteins shown in teal and green ribbons. The tRNAs are shown in gray (E), orange (P) and purple (A).

From a great deal of other work, it has been shown to be possible (though whether likely, or inevitable, is another matter) for RNAs to assemble in pre-biotic chemical conditions, and to laboriously operate on each other with catalytic effect, both in polymerization and degradation. Indeed, our mRNA splicing apparatus remains, like the ribosome, based on an RNA catalytic core. And this work suggests that RNAs of some length, like maybe under 100 nucleotides (nt) are plausible, while longer ones would be less plausible. There is some debate about whether in later epochs, the RNA world could have hosted very long RNAs, thereby making up in length and complexity what it generally lacked in conformational precision and chemical versatility. So the question arises- how much is really needed to get to the protein synthesis stage of biogenesis? How might several RNAs have come together to collaborate in this dance of protein synthesis, and what were the minimal requirements? 

The pseudo-dimeric core of the peptidyl transferase center, pulled out of the larger ribosome structure. This tiny structure is what the current workers attempted to use to simulate very early forms of protein synthesis.

The site within the ribosome where the single amino acids are linked together (polymerized) is called the peptidyl transferase center. Given properly tRNA-linked acyl-amino acids, it takes only proper steric encouragement, not extra inputs of energy such as ATP, to create the peptide bond. It turns out that the peptidyl transferase center of the ribosome can be thought of as a dimer of two ~ 60 nt long RNAs. Structures of that center show this as the extremely conserved, somewhat kinked helical dimer within all current ribosomes. But can such tiny RNAs do the job? Or do they absolutely require the kind of superstructure in which they are currently embedded? 

A recent paper shows that they can do the job by themselves, if very inefficiently.

"The actual reaction occurs within a semi-symmetrical molecular pocket that hosts the A- and P-tRNAs, situated within the peptidyl transferase center (PTC), which provides the sites for the two CCA-tRNA ends. This semi-symmetrical entity provides the framework for optimal positioning of the ribosomal substrates in a favored stereochemistry for peptide bond formation and it confines the void required for the motions associated with protein elongation. The amazingly high conservation of this semi-symmetrical site structure, which seems to be preserved throughout the entire living kingdom, indicates that it is resistant to evolution. Hence, suggesting that it could have existed as a self-folded active entity in the pre-biotic world. Therefore, called by us the protoribosome, i. e. the ancestor of the contemporary ribosome."

Ingredient 1: the mini-rRNA sequence and presumed base-pairing.

Ingredient 2: the mini-tRNA sequence and base-pairing.

The hard part was showing that this is true, which is what two groups have done, one in Japan, one in Israel. They have demonstrated slight amounts of protein synthesis using these tiny RNA molecules, in addition to other RNAs standing in for the code and the tRNAs. This was extremely difficult to do, grinding through the careers of several graduate students and post-docs. The ingredients are as follows: one putative / mini ribosomal RNA of about 71 nt, which forms the dimer of the putative peptide transferase core, and a putative transfer RNA of about 35 nt, which was pre-supplied with an attached amino acid (alanine). Given only those two inputs, they found in the reaction products the dipeptide alanyl-alanine, indicating that one step of synthesis had occurred. The template was a tag of GGU that had been added to the mini-ribosomal RNA, to match the ACCA tail of the mini-tRNA. 

So this is a highly unnatural setting, without a true template, and with pre-charged mini-tRNA molecules, and with just-detectable efficacy. But the principle is significant- not only can RNA of relatively simple sorts that we can envision occurring in the RNA world synthesize, cleave, and alter other RNAs, but they can also get to the nascent stage of protein synthesis, one of the bigger hurdles on the way to life as we know it.

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The Eye is the Window to the Brain

Alpha oscillations of the brain prefigure the saccades by which our eyes move as we read.

Reading is a complicated activity. We scan symbols on a page, focusing on some in turn, while scanning along for the next one. Data goes to the brain not in full images, but in the complex coding of differences from moment to moment. Simultaneously, various levels of processing in the brain decode the dark and light spots, the letter forms, the word chunks, the phrases, and on up to the ideas being conveyed.

While our brain is not rigidly clocked like a computer, (where each step of computation happens in sync with the master clock), it does have dynamic oscillations at several different frequencies and ranging over variable regions and coalitions of neurons that organize its processing. And the eye is really a part of that same central nervous system- an outpost that conveys so much sensitive information, both in and out.

We take in visual scenes by jerks, or saccades, using our peripheral vision to orient generally and detect noteworthy portions, then bringing our high-acuity fovea to focus on them. The eye moves about four times per second, a span that is used to process the current scene and to plan where to shift next. Alpha oscillations (about 10 per second) in the brain, which are inhibitory, are known to (anti-) correlate with motor control of the saccade period. The processing of the visual sensory system resets its oscillations with each shift in scene, so is keyed to saccades in a receiving sense. Since vision only happens in the rest/focal periods between saccades, it is helpful, conceptually, to coordinate the two processes so that the visual processing system is maximally receptive (via its oscillatory phase) at the same time that the eye comes to rest after a saccade and sends it a new scene. Conversely, the visual sensory system would presumably tell the motor system when it was done processing the last unit, to gate a shift to the next scene.

A recent paper extended this work to ask how brain oscillations relate to the specific visual task of reading, including texts that are more or less difficult to comprehend. They used the non-invasive method of magnetic encephalography to visualize electrical activity within the brains of people reading. The duration of saccades were very uniform, (and short), while the times spent paused on each focal point (word) varied slightly with how difficult the word was to parse. It is worth noting that no evidence supports the lexical processing of words out of the peripheral vision- this only happens from foveal/focused images.

Subjects spent more time focused on rare/difficult words than on easy words, during a free reading exercise (C). On the other hand, the duration of saccades to such words was unchanged (D).

In the author's main finding, alpha oscillations were correlated as the person shifted from word to word, pausing to view each one. These oscillations tracked the pausing more closely when shifting towards more difficult words, rather than to simple words. And these peaks of phase locking happened anatomically in the Brodmann area 7, which is a motor area that mediates between the visual system and motor control of the eye. Presumably this results from communication from the visual processing area to the visual motor area, just next door. They also found that the phase locking was strongest for the start of saccades, not their end, when the scene comes back into focus. This may simply be a timing issue, since there are lags at all points in the visual processing system, and since the saccade duration is relatively fixed, this interval may be appropriate to keep the motor and sensory areas in effective synchronization.

Alpha oscillation locks to some degree with initiation of saccades, and does so more strongly when heading to difficult words, rather than to easy words. Figure B shows the difference in alpha power between the easy and difficult word target. How can this be? 

So while higher frequency (gamma) oscillations participate in sensory processing of vision, this lower alpha frequency is dominant in the area that controls eye movement, in keeping with muscle control mechanisms more generally. But it does raise the question of why they found a signal (phase locking for the initiation of a saccade) for the difficulty of the upcoming word, before it was actually lexically processed. The peripheral visual system is evidently making some rough guess, perhaps by size or some other property, of the difficulty of words, prior to fully decoding them, and it will be interesting to learn where this analysis is done.

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An Origin Story for Spider Venom

Phylogenetic analysis shows that the major component of spider venom derives from one ancient ancestor.

One reason why biologists are so fully committed to the Darwinian account of natural selection and evolution is that it keeps explaining and organizing what we see. Despite the almost incredible diversity and complexity of life, every close look keeps confirming what Darwin sensed and outlined so long ago. In the modern era, biology has gone through the "Modern Synthesis", bringing genetics, molecular biology, and evolutionary theory into alignment with mutually supporting data and theories. For example, it was Linus Pauling and colleagues (after they lost the race to determine the structure of DNA) who proposed that the composition of proteins (hemoglobin, in their case) could be used to estimate evolutionary relationships, both among those molecules, and among their host species.

Naturally, these methods have become vastly more powerful, to the point that most phylogenetic analyses of the relationship between species (including the definition of what species are, vs subspecies, hybrids, etc.) are led these days by DNA analysis, which provides the richest possible trove of differentiating characters- a vast spectrum from universally conserved to highly (and forensically) varying. And, naturally, it also constitutes a record of the mutational steps that make up the evolutionary process. The correlation of such analyses with other traditionally used diagnostic characters, and with the paleontological record, is a huge area of productive science, which leads, again and again, to new revelations about life's history.

One sample structure of a DRP- the disulfide rich protein that makes up most of spider venoms.

 The disulfide bond (between two cysteines) is shown in red. There is usually another disulfide helping to hold the two halves of the molecule together as well. The rest of the molecule is (evolutionarily, and structurally) free to change shape and character, in order to carry out its neuron-channel blocking or other toxic function.

One small example was published recently, in a study of spider venoms. Spiders arose, from current estimates, about 375 million years ago, and comprise the second most prevalent form of animal life, second only to their cousins, the insects. They generally have a hunting lifestyle, using venom to immobilize their prey, after capture and before digestion. These venoms are highly complex brews that can have over a hundred distinct molecules, including potassium, acids, tissue- and membrane-digesting enzymes, nucleosides, pore-forming peptides, and neurotoxins. At over three-fourths of the venom, the protein-based neurotoxins are the most interesting and best studied of the venom components, and a spider typically deploys dozens of types in its venom. They are also called cysteine-rich peptides or disulfide-rich peptides (DRPs) due to their composition. The fact that spiders tend to each have a large variety of these DRPs in their collection argues that a lot of gene duplication and diversification has occured.

A general phylogenetic tree of spiders (left). On the right are the signal peptides of a variety of venoms from some of these species. The identity of many of these signal sequences, which are not present in the final active protein, is a sign that these venom genes were recently duplicated.

So where do they come from? Sequences of the peptides themselves are of limited assistance, being small, (averaging ~60 amino acids), and under extensive selection to diversify. But they are processed from larger proteins (pro-proteins) and genes that show better conservation, providing the present authors more material for their evolutionary studies. The figure above, for example, shows, on the far right, the signal peptides from families of these DRP genes from single species. Signal peptides are the small leading section of a translated protein that directs it to be secreted rather than being kept inside the cell. Right after the protein is processed to the right place, this signal is clipped off and thus is not part of the mature venom protein. These signal peptides tend to be far more conserved than the mature venom protein, despite that fact that they have little to do- just send the protein to the right place, which can be accomplished by all sorts of sequences. But this is a sign that the venoms are under positive evolutionary pressure- to be more effective, to extend the range of possible victims, and to overcome whatever resistance the victims might evolve against them. 

Indeed, these authors show specifically that strong positive selection is at work, which is one more insight that molecular data can provide. (First, by comparing the rates of protein-coding positions that are neutral via the genetic code (synonymous) vs those that make the protein sequence change (non-synonymous), and second by the pattern and tempo of evolution of venom sequences compared with the mass of neutral sequences of the species.

"Given their significant sequence divergence since their deep-rooted evolutionary origin, the entire protein-coding gene, including the signal and propeptide regions, has accumulated significant differences. Consistent with this hypothesis, the majority of positively selected sites (~96%) identified in spider venom DRP toxins (all sites in Araneomorphae, and all but two sites in Mygalomorphae) were restricted to the mature peptide region, whereas the signal and propeptide regions harboured a minor proportion of these sites (1% and 3%, respectively)."

 

Phylogenetic tree (left), connecting up venom genes from across the spider phylogeny. On right, some of the venom sequences are shown just by their cysteine (C) locations, which form the basic structural scaffold of these proteins (top figure).

The more general phyogenetic analysis from all their sequences tells these authors that all the venom DRP genes, from all spider species, came from one origin. One easy way to see this is in the image above on the right, where just the cysteine scaffold of these proteins from around the phylogeny are lined up, showing that this scaffold is very highly conserved, regardless of the rest of the sequence. This finding (which confirms prior work) is surprising, since venoms of other animals, like snakes, tend to incorporate a motley bunch of active enzymes and components, sourced from a variety of ancestral sources. So to see spiders sticking so tenaciously to this fundamental structure and template for the major component of their venom is impressive- clearly it is a very effective molecule. The authors point out the cone snails, another notorious venom-maker, originated much more recently, (about 45 million years ago), and shows the same pattern of using one ancestral form to evolve a diversified blizzard of venom components, which have been of significant interest to medical science.

• Example: a spider swings a bolas to snare a moth.

New World Order, or Old World Order?

As we gaze into the future, are we looking at a new Cold War?

The international landscape is taking on a tone of deja vu these days, as we return to Kremlinology and proxy wars. It feels like a new Cold war is upon us. The familiar lineup of Russia and China, with various other formerly communist states, are aligned against "the West" writ large: the US with core European countries, plus also those European post-Soviet states that turned in revulsion against their former captor. Only Belarus was left behind as a pawn of Russia. Iran is perhaps the one large country that was previously part of the US coalition and has decisively switched to the other side, though several countries like Turkey, Indonesia, and Pakistan are non-aligned or hostile.

But the familiar names and grudges belie vast changes in the landscape. The principal shift is that the Soviet economic system, and the communist economic systems more widely, is no longer the albatross it once was. Virtually every country has ditched communism (or, more precisely, top-down planning), discovered capitalism, and put it to work resolving fundamental economic problems and built modern economies, more or less. North Korea may be the only exception, (and perhaps Cuba), showing its entreprenurial spirit in the sphere of international crime, but otherwise hewing doggedly to a fully planned economy. China is foremost in this new authoritarian movement, having mastered a hybrid system of one-party politics and multi-party economics. This new model, (perhaps pioneered ultimately by Singapore), is a far more concerning and long-term threat than communism ever was. Straight communism was brutally impractical, and demanded correspondingly brutal methods of implementation. As it turned out, it was only attractive to the most extreme authoritarians, such as Lenin, Stalin, Mao, and Ho Chi Minh, and their starry-eyed believers. 

Prevalence of government types, world-wide. There has been a noticeable regression over the last decade or two.

But the new model is much more widely applicable and attractive. Even we in the US had a narrow escape during the last administration, and half the country remains in thrall to its lure. If power is one's goal, autocracy, or "managed democracy", is far more attractive than a truly competitive democracy. While in the 20th century many authoritarian states transitioned to democracy, this century has shown a different trend, as countries like Hungary, India, Venezuela, and Russia head away from more or less functional democracy. 

The Ukraine war has obviously broken all this open, manifesting Vladimir Putin's seething resentment that yet one more former Soviet "Republic" and Imperial satrapy resisted all his efforts at corruption and cooptation, and through force of popular will dared to aligned itself with the West. Every country has to choose a position, and those positions were recently enunciated in the recent UN assembly vote against the aggressor. China has exposed itself as fatally hypocritical to its former mantras of non-interference, peaceful coexistence, and national self-determination. Support of its fellow authoritarian, in war that so closely mirrors the one it contemplates against Taiwan, takes precedence over any lip-service to principle or peace. The Western coalition of democracies fell naturally into line as well, in reaction to the horror that was unfolding, which everyone thought the experiences of the last century would have made impossible. Not so! The new authoritarian model has an ancillary and deeply related property, which is revived imperialist ambitions, just as it did back in World War 2, and earlier.

An interesting question is where India lands in this new alignment. It would seem a pretty simple proposition for India to condem the appalling and cruel invasion (couched in the clearest imperial and anti-democratic ambitions). India itself has been nibbled at by the bellicose ambitions of both Pakistan and China. But no. India abstained from the UN vote, along with China. India is propping up Russia by buying its discounted oil, and is otherwise mum, hearking back to its non-aligned status during the cold war. This is not helpful, as the world's largest country by population, and largest putative democracy. But India itself has been heading into an authoritarian, in its case Hindutva, direction, and clearly is torn regarding its allegiances, whether to true democracy, or to managed democracy, and its long-time quasi-friend, Russia. While it doubtless seeks to avoid the looming world where it ends up on the opposite side from an alliance between China, Russia, and possibly Pakistan and Iran, (which also abstained), that world is coming regardless. India flirted with alliance with the US over the last two decades, but this recent stance would seem to doom that relationship, or make it a non-reciprocal one. That India's stand is unprincipled goes without saying. Whether it will be tactically effective is another matter. Unlike smaller countries, India does not rely on rules in the international arena, but rather on power. Failure to support others in the face of unjustified and brutal invasion and spiteful bombardment of civilians saps international solidarity, impairs India's international reputation, and weakens its own future claims to sympathy when the wolf is at its own door. But its relationship with Russia may be valuable enough to repay those costs.

It should be obvious that, as a collective action problem, the way to avoid war is for all other countries to band together to forstall, condemn, reverse, and punish belligerent invasions like that started by Russia. Allowing Russia to get away with a half-a-loaf negotiated takeover would only invite future attempts by it or other aggressors. Punishment, when concentrated on the perpetrators, (not necessarily their national and captive populations), is critical to deterrence.

So it was heartening that most countries were not so cynical and saw the general danger well enough to have supported the UN resolution, toothless as it was. The question overall is whether international relations progress to a new world order, or regress to an old one. Since World War 2, Europe has enjoyed substantial and deepening peace, with an especially peaceful re-integration of Germany, re-establishment of the Baltic nations, Poland, and most nations of Eastern Europe. Yugoslavia was the only region that fell into warfare, and continues in an uneasy constellation of truces, mostly enforced by the dream of joining the peaceful and prosperous European community. While the breakup of the Soviet Union was caused by, and furthered, long-standing nationalist sentiments, those sentiments were kept in check by guardrails of the "new", or liberal international order, which prizes peace and tranquility, under the policing of NATO combined arms, with those of the US at the forefront. Of course Russia had its role as well in managing the post-beakup nationalisms, for instance in Chechnya and Georgia, and it was not interested in any liberal order. But the assault on Ukraine is an entirely new line that has been crossed.

The old world order is one that foreign policy "realists" relish. The old spheres of influence, and balances of power warm the hearts of Metternichian traditionalists, savoring the way it has always been. There, guile and propaganda, selective alliances and stealth were the order of the day, throwing small countries to the dogs while the big countries do what they wish, each pursuing imperial dreams. They claim that this is just the way things are, there is no alternative, and any hopey-changey ambitions for a better international system amount to just another League of Nations or toothless UN. 

One can grant that the international scene is not, yet, bound by a legal system or effective police powers. The US has tried to be the policeman, and done a generally well-intentioned, but poor job of it. We run a vast network of military bases that has stretched over the globe, and exert soft power of many kinds. This has given room for countless small nations to pursue their dreams, subject to, but not crushed, by great power spheres and pressures. Taiwan grew into a flourishing independent democracy, Poland shook off centuries of partitions and subjugation. People power rose up in the Phillipines, in Ukraine, and in the Middle East. Africa has had a fitful time, but generally has been able to at least breathe free of explicit colonial oppression. US policy over the last few decades has been a race to establish a civil international order that is entrenched enough to survive our own demise as a superpower. Even the Iraq war was, at least in spirit, intended to break the patterns of authoritarianism that plague the Middle East, and implant a new, prosperous democracy. But bringing a new and happy dispensation on a plate of hellfire did not work out so well. Indeed, the implanted Western democracy of Israel shows more signs of aligning with the local political patterns than of changing them. 

So, change is hard, as is management of international relations in the absence of rules and police. The realists would say that other nations, both major competitors and spoilers, always line up against the powerful nation of the moment, due to natural competitiveness. But the Ukraine war should be, if any international event can be, the most glaring example of the boundary line between possible systems, and possible futures.

One can liken the old order to a city with gangs or mafia families. The gangs are always in flux, growing, shrinking, and competing. Long times may go by with relatively stable constellations, but then all hell breaks loose and the warfare is in brutal earnest. The new international order is, in contrast, more like a modern city, with representative government, laws, and a police force. Its violence confined to small-time spoilers, criminals and malcontents. Large scale warfare is unknown. Who wouldn't want the second over the first? Well, that takes solidarity- that nations do not only look out for themselves for the moment, but take a long view of the system and their long-term interests, and band together globally to make that future happen.

Perhaps the US is uniquely able to pursue this vision of international relations due to (in addition to its wealth) its makeup as a polyglot nation, its long experience with self-government at all levels, its fascination with the Western and the Police procedural as its reigning entertainment forms, and its modest remove from the European wars of imperialism and domination. We were motive forces behind both the UN and the League of Nations. Whatever the cause, the logic remains that international peace relies entirely on the collective will hold it as an ideal, and then to enforce it. This future does take some imagination, which realists seem to be lacking. But international standards have advanced significantly. Slavery used to also be just the way things were in a naturally competitive world. Poison gas used to be a standard weapon of war. We can change the landscape of international competition.

With a modicum of international solidarity and policing, the international community can put an end to imperialistic wars of aggression. And that movement starts now, in Ukraine, by beating back Russia and all the lies, cruelty, and stupid condescension that it stands for.

• History for the Ukraine conflict. Russia's policy was always predicated on keeping Ukraine down.
• Scenarios for the Ukraine conflict.
• Democracy could work better.
• Or it could work a lot better.

Drought Causes Cultural Breakdown

What happened to the Hittites, and the late Bronze Age?

Climate change is already causing wars and migration, misery on a vast scale. The global South takes the heat, while the global North keeps making it, pumping out the CO2. Can we adapt, or is the human population going to decrease, either gently or not so gently, as conditions deteriorate? The answer is not at all clear. The adaptation measures taken by the rich world involve highly contentious politics, and uncertain technology that, at best, requires a great deal more resource extraction. The poor, on the other hand, are left to either try developing (if they can maintain good political and economic governance) to join the rich in their extractive ways, (China, India), or migrate en masse to rich countries (Africa, Central America). All this is going to get worse, not better, since we are still at peak CO2 emissions and only beginning the process of global heating.

Our emissions of CO2 are still going up, not down. Therefore climate change will be getting worse, faster. Conflict is one likely outcome.

Well, migrations and dislocation have happened before. Over the last millennium, it was cold temperatures, not hot, that have correlated with conflict. Epic migrations occurred in the declining days of the Roman Empire, when the Huns drove a domino series of migrations of Germanic tribes that fought their way throughout Europe. What prompted the Huns out of the Asian steppe is unknown, however. Jared Diamond wrote of several other cultures that met their end after exhausing their resources and technologies. A recent paper added one more such case- the Hittites of late Bronze Age.

The Hittites were a big deal in their time (1700 to 1200 BCE, very roughly), running what is now Eastern and Southern Turkey, and occasionally Syria and points South. They were an early offshoot of the Indo-European migrations, and had a convulsive (though not very well understood) history of rises and falls, mostly due to their political dynamics. At the height of Hittite power, they fought Egypt directy at the battle of Kadesh, (1274 BCE), which occured just a little north of current-day Lebanon. This was the complex frontier between Assyria / Babylon, the Hittites, and Egypt. Egyptian history is full of expeditions- military, economic, and diplomatic- through the Levant.

The Hittites were artists as well as warriors.

The Hittites were also one of several communities around the Mediterranean that shared in the late Bronze Age collapse. This is the epic time that saw the Greek siege of Troy, (~1200 BCE), and the "Sea People's" invasion of Egypt. Its causes and details remain a long-standing historical mystery. But its scale was vast. Greece entered its dark age that lasted from 1200 to the 800's BCE. North Africa, the Balkans, Turkey, Levant, and the Caucaus all declined. Assyria and Egypt were weakened, but did not collapse. The latest paper uses tree-ring data from junipers from around the former Hittite capital in what is now central Turkey to more precisely date a severe drought that may have caused this collapse. Drought is just the kind of cause that would have been wide-spread enough and foundational enough to destroy the regional economies and prompt migrations and wars. Wars.. there are always wars, but no single war would have caused the collapse of cultures on such a wide scale, including a weakening of Egypt. Plagues are also not a great candidate, since they do not harm a society's resource base, but only its population. Such population reductions typically benefit the survivors, who rebuild in short order.

Moisture levels inferred from tree ring data, with lower values dryer. There are three consecutive catastrophic years dated to 1198-1196 BCE in this region, which is around the ancient Hittite capital. The ensuing decade was also unusually dry and likely poor for agriculture. The 20% and 6.25% levels of drought are by comparison to wider sampling, including modern data.

The drought these authors identified and located with precision was extraordinary. They note that, using modern data for indexing, the 20% level (representing about 30 cm of annual rain) is the minimum viable threshold for growing wheat. The 6.25% level is far below that and represents widespread crop failure. They developed two types of data from the tree rings, drawn from 18 individual trees whose rings spanned about a thousand years across the second millenium BCE. First is the size of the rings themselves, whose data are shown above. Second is the carbon 13 isotope ratio, which is a separate index of dryness, based on the isotopic discrimination that plants exercise over CO2 respiration under different climatic conditions. 

The same tree rings that provided the inferences above from their geometry (width) also here provided carbon 13 isotope data that lead to a similar conclusion, though with much less precision. High proportions of C13 indicate drier climate, here continuous around 1200 BCE.

The paper shows three consecutive years at the 6.25% level of rainfall, starting at 1198 BC. The ensuing decade was also harshly dry. All this correlates with cuneiform texts found in the Levant that were letters from the Hittites, bemoaning their drought and begging for assistance. But everyone in the region was in a similar position. The Hittite culture never recovered. 

So drought is now a leading hypothesis for the ultimate cause of the late Bronze Age collapse around many parts of the Mediterranean, with Greece and Anatolia particularly affected. While it is reasonable to imagine that such conditions would lead to desperation, migration, and war, there is no direct link yet. The nature and origin of the Sea Peoples who attacked Egypt remain unknown, for instance. The reasons for the seige of Troy are lost to myth. The Illiad never mentions drought, nor would Troy have been in a much better position than Mycenaean Greece, climatically speaking. But the consequences of geopolitical shifts in alignment can be unpredictable, as we continue to experience today. It is exciting (as well as sobering) to get a glimpse into this cloudy history- into a vast swath of human experience that built great cultures and suffered epic defeats.

• The planet can just go to hell.
• And so can our political system and media.
• The next Mein Kampf.
• Maybe governments should really do things themselves.

Everything is Alive, but the Gods are all Dead

Barbara Ehrenreich's memoir and theological ruminations in "Living with a Wild God".

It turns out that everyone is a seeker. Somewhere there must be something or someone to tell us the meaning of life- something we don't have to manufacture with our own hands, but rather can go into a store and buy. Atheists are just as much seekers as anyone else, only they never find anything worth buying. The late writer Barbara Ehrenreich was such an atheist, as well as a remarkable writer and intellectual who wrote a memoir of her formation. Unusually and fruitfully, it focuses on those intense early and teen years when we are reaching out with both hands to seize the world- a world that is maddeningly just beyond our grasp, full of secrets and codes it takes a lifetime and more to understand. Religion is the ultimate hidden secret, the greatest mystery which has been solved in countless ways, each of them conflicting and confounding.

Ehrenreich's tale is more memoir than theology, taking us on a tour through a dysfunctional childhood with alcoholic parents and tough love. A story of growth, striking out into the world, and sad coming-to-terms with the parents who each die tragically. But it also turns on a pattern of mystical experiences that she keeps having, throughout her adult life, which she ultimately diagnoses as dissociative states where she zones out and has a sort of psychedelic communion with the world.

"Something peeled off the visible world, taking with it all meaning, inference, association, labels, and words. I was looking at a tree, and if anyone had asked, that's what I would have said I was doing, but the word "tree" was gone, along with all the notions of tree-ness that had accumulated in the last dozen years or so since I had acquired language. Was it a place that was suddenly revealed to me? Or was it a substance- the indivisible, elemental material out of which the entire known and agreed-upon world arises as a fantastic elaboration? I don't know, because this substance, this residue, was stolidly, imperturbably mute. The interesting thing, some might say alarming, was that when you take away all the human attributions- the words, the names of species, the wisps of remembered tree-related poetry, the fables of photosynthesis and capillary action- that when you take all this this away, there is still something left."

This is not very hard to understand as a neurological phenomenon of some kind of transient disconnection of just the kind of brain areas she mentions- those that do all the labeling, name-calling, and boxing-in. In schizophrenia, it runs to the pathological, but in Ehrenreich's case, she does not regard it as pathological at all, as it is always quite brief. But obviously, the emotional impact and weirdness of the experience- that is something else altogether, and something that humans have been inducing with drugs, and puzzling over, forever. 

Source

As a memoir, the book is very engaging. As a theological quest, however, it doesn't work as well, because the mystical experience is, as noted above, resolutely meaningless. It neither compels Ehrenreich to take up Christianity, as after a Pauline conversion, nor any other faith or belief system. It offers a peek behind the curtain, but, stripped of meaning as this view is, Ehrenreich is perhaps too skeptical or bereft of imagination to give it another, whether of her own or one available from the conventional array of sects and religions. So while the experiences are doubtless mystical, one can not call them religious, let alone god-given, because Ehrenreich hasn't interpreted them that away. This hearkens back to the writings of William James, who declined to assign general significance to mystical experiences, while freely admitting their momentous and convincing nature to those who experienced them.

Only in one brief section (which had clearly been originally destined for an entirely different book) does she offer a more interesting and insightful analysis. There, Ehrenreich notes that the history of religion can be understood as a progressive bloodbath of deicide. At first, everything is alive and sacred, to an animist mind. Every leaf and grain of sand holds wonders. Every stream and cloud is divine. This is probably our natural state, which a great deal of culture has been required to stamp out of us. Next is a hunting kind of religion, where deities are concentrated in the economic objects (and social patterns) of the tribe- the prey animals, the great plants that are eaten, and perhaps the more striking natural phenomena and powerful beasts. But by the time of paganism, the pantheon is cut down still more and tamed into a domestic household, with its soap-opera dramas and an increasingly tight focus on the major gods- the head of the family, as it were. 

Monotheism comes next, doing away with all the dedicated gods of the ocean, of medicine, of amor and war, etc., cutting the cast down to one. One, which is inflated to absurd proportions with all-goodness, all-power, all-knowledge, etc. A final and terrifying authoritarianism, probably patterned on the primitive royal state. This is the phase when the natural world is left in the lurch, as an undeified and unprotected zone where human economic greed can run rampant, safe in the belief that the one god is focused entirely on man's doings, whether for good or for ill, not on that of any other creature or feature of the natural world. A phase when even animals, who are so patently conscious, can, through the narcissism of primitive science and egoistic religion, be deemed mere mechanisms without feeling. This process doesn't even touch on the intercultural deicide committed by colonialism and conquest.

This in turn invites the last deicide- that by rational people who toss aside this now-cartoonish super-god, and return to a simpler reverence for the world as we naturally respond to it, without carting in a lot of social power-and-drama baggage. It is the cultural phase we are in right now, but the transition is painfully slow, uneven, and drawn-out. For Ehrenreich, there are plenty of signs- in the non-linear chemical phenomena of her undergraduate research, in the liveliness of quantum physics even into the non-empty vacuum, in the animals who populate our world and are perhaps the alien consciousnesses that we should be seeking in place of the hunt through outer space, and in our natural delight in, and dreams about, nature at large. So she ends the book as atheist as ever, but hinting that perhaps the liveliness of the universe around us holds some message that we are not the only thinking and sentient beings.

"Ah, you say, this is all in your mind. And you are right to be skeptical; I expect no less. It is in my mind, which I have acknowledged from the beginning is a less than perfect instrument. but this is what appears to be the purpose of my mind, and no doubt yours as well, its designed function beyond all the mundane calculations: to condense all the chaos and mystery of the world into a palpable Other or Others, not necessarily because we love it, and certainly not out of any intention to "worship" it. But because ultimately we may have no choice in the matter. I have the impression, growing out of the experiences chronicled here, that it may be seeking us out." 

Thus the book ends, and I find it a rather poor ending. It feels ripped from an X-Files episode, highly suggestive and playing into all the Deepak and similar mystical tropes of cosmic consciousness. That is, if this passage really means much at all. Anyhow, the rest of the trip is well worth it, and it is appropriate to return to the issue of the mystical experience, which is here handled with such judicious care and restraint. Where imagination could have run rampant, the cooly scientific view (Ehrenreich had a doctorate in biology) is that the experiences she had, while fascinating and possibly book-proposal-worthy, did not force a religious interpretation. This is radically unlike the treatment of such matters in countless other hands, needless to say. Perhaps our normal consciousness should not be automatically valued less than more rare and esoteric states, just because it is common, or because it is even-tempered.

• God would like us to use "they".
• If you are interested in early Christianity, Gnosticism is a good place to start.
• Green is still an uphill battle.

A Gene is Born

Yes, genes do develop out of nothing.

The "intelligent" design movement has long made a fetish of information. As science has found, life relies on encoded information for its genetic inheritance and the reliable expression of its physical manifestations. The ID proposition is, quite simply, that all this information could not have developed out of a mindless process, but only through "design" by a conscious being. Evidently, Darwinian natural selection still sticks on some people's craw. Michael Behe even developed a pseudo-mathematical theory about how, yes, genes could be copied mindlessly, but new genes could never be conjured out of nothing, due to ... information.

My understanding of information science equates information to loss of entropy, and expresses a minimal cost of the energy needed to create, compute or transmit information- that is, the Shannon limits. A quite different concept comes from physics, in the form of information conservation in places like black holes. This form of information is really the implicit information of the wave functions and states of physical matter, not anything encoded or transmitted in the sense of biology or communication. Physical state information may be indestructable (and un-create-able) on this principle, but coded information is an entirely different matter.

In a parody of scientific discussion, intelligent design proponents are hosted by the once-respectable Hoover Institution for a discussion about, well, god.

So the fecundity that life shows in creating new genes out of existing genes, (duplications), and even making whole-chromosome or whole-genome duplications, has long been a problem for creationists. Energetically, it is easy to explain as a mere side-effect of having plenty of energy to work with, combined with error-prone methods of replication. But creationistically, god must come into play somewhere, right? Perhaps it comes into play in the creation of really new genes, like those that arise from nothing, such as at the origin of life?

A recent paper discussed genes in humans that have over our recent evolutionary history arisen from essentially nothing. It drew on prior work in yeast that elegantly laid out a spectrum or life cycle of genes, from birth to death. It turns out that there is an active literature on the birth of genes, which shows that, just like duplication processes, it is entirely natural for genes to develop out of humble, junky precursors. And no information theory needs to be wheeled in to show that this is possible.

Yeast provides the tools to study novel genes in some detail, with rich genetics and lots of sequenced relatives, near and far. Here is portrayed a general life cycle of a gene, from birth out of non-gene DNA sequences (left) into the key step of translation, and on to a subject of normal natural selection ("Exposed") for some function. But if that function decays or is replaced, the gene may also die, by mutation, becoming a pseudogene, and eventually just some more genomic junk.

The death of genes is quite well understood. The databases are full of "pseudogenes" that are very similar to active genes, but are disabled for some reason, such as a truncation somewhere or loss of reading frame due to a point mutation or splicing mutation. Their annotation status is dynamic, as they are sometimes later found to be active after all, under obscure conditions or to some low level. Our genomes are also full of transposons and retroviruses that have died in this fashion, by mutation.

Duplications are also well-understood, some of which have over evolutionary time given rise to huge families of related proteins, such as kinases, odorant receptors, or zinc-finger transcription factors. But the hunt for genes that have developed out of non-gene materials is a relatively new area, due to its technical difficulty. Genome annotators were originally content to pay attention to genes that coded for a hundred amino acids or more, and ignore everything else. That became untenable when a huge variety of non-coding RNAs came on the scene. Also, occasional cases of very small genes that encoded proteins came up from work that found them by their functional effects.

As genome annotation progressed, it became apparent that, while a huge proportion of genes are conserved between species, (or members of families of related proteins), other genes had no relatives at all, and would never provide information by this highly convenient route of computer analysis. They are orphans, and must have either been so heavily mutated since divergence that their relationships have become unrecognizable, or have arisen recently (that is, since their evolutionary divergence from related species that are used for sequence comparison) from novel sources that provide no clue about their function. Finer analysis of ever more closely related species is often informative in these cases.

The recent paper on human novel genes makes the finer point that splicing and export from the nucleus constitute the major threshold between junk genes and "real" genes. Once an RNA gets out of the nucleus, any reading frame it may have will be translated and exposed to selection. So the acquisition of splicing signals is a key step, in their argument, to get a randomly expressed bit of RNA over the threshold.

A recent paper provided a remarkable example of novel gene origination. It uncovered a series of 74 human genes that are not shared with macaque, (which they took as their reference), have a clear path of origin from non-coding precursors, and some of which have significant biological effects on human development. They point to a gradual process whereby promiscuous transcription from the genome gave rise by chance to RNAs that acquired splice sites, which piped them into the nuclear export machinery and out to the cytoplasm. Once there, they could be translated, over whatever small coding region they might possess, after which selection could operate on their small protein products. A few appear to have gained enough function to encourage expansion of the coding region, resulting in growth of the gene and entrenchment as part of the developmental program.

Brain "organoids" grown from genetically manipulated human stem cells. On left is the control, in middle is where ENSG00000205704 was deleted, and on the right is where ENSG00000205704 is over-expressed. The result is very striking, as an evolutionarily momentous effect of a tiny and novel gene.

One gene, "ENSG00000205704" is shown as an example. Where in macaque, the genomic region corresponding to this gene encodes at best a non-coding RNA that is not exported from the nucleus, in humans it encodes a spliced and exported mRNA that encodes a protein of 107 amino acids. In humans it is also highly expressed in the brain, and when the researchers deleted it in embryonic stem cells and used those cells to grow "organoids", or clumps of brain-like tissue, the growth was significantly reduced by the knockout, and increased by the over-expression of this gene. What this gene does is completely unknown. Its sequence, not being related to anything else in human or other species, gives no clue. But it is a classic example of gene that arose from nothing to have what looks like a significant effect on human evolution. Does that somehow violate physics or math? Nothing could be farther from the truth.

• Will nuclear power get there?
• What the heck happened to Amazon shopping?