Frankenplant

40% more efficient plants? Done!

What is the most common protein in the biosphere? It occurs in plants, right? Right- it is RuBisCO, the enzyme that fixes carbon dioxide from the atmosphere, is the workhorse of agriculture, and hero of the fight against global warming, should we choose to grow more plants instead of burning them down. Its full name is ribulose-1,5-bisphosphate carboxylase-oxygenase, meaning that its substrate is a five carbon sugar (ribulose) that has two phosphates attached, and the enzyme attaches a carboxyl group from CO2, but can also attach an oxygen instead (the oxygenase part). And therein lies the problem. RuBisCO is phenomenally inefficient (maybe ten reactions per second) and error-prone (using oxygen [O2] instead of CO2 roughly a quarter of the time), which is why it is made in such prodigious quantities, amounting to half the protein complement of leaves.

Plant researchers have been casting about for a long time for ways to make this core reaction more efficient. But have had no success. Indeed, an interesting paper came out a few years ago arguing that as far as this enzyme is concerned, the shape and chemical similarity between CO2 and O2 are so close that RuBisCO is perfectly optimized, exchanging speed for what specificity is possible given its substrates. It varies quite a bit in this tradeoff, depending on the specific environment, arguing that the optimization is quite dynamic over evolutionary time. One of the few innovative solutions that plants have developed is not a tweek to the enzyme, but a physiological compartment present in C4 plants (like corn), which concentrates CO2 and excludes O2, thus resolving the competitive constraint for some of their chloroplasts. Their RuBisCO enzymes are adapted to have a slightly more relaxed attitude- slightly less specific for CO2, while also almost 2-fold faster, gaining an significant advantage.

The error pathway, fixing oxygen instead of CO2, is called photorespiration, since it uses up oxygen like regular respiration, but now in a completely wasteful way. The product is phospho-glycolate instead of 3-phospho-glycerate, and the glycolate is both inhibitory to photosynthesis and difficult to dispose of. It is typically exported from the chloroplast, and bounced around between the peroxisome and mitochondrion in its way to being turned into the amino acid glycine, all at the cost of roughly twelve ATP. It is hard to believe that this waste goes on day in and day out across the biosphere, but it seems to be the case. One might note that this yet another case of the steep price of success, since RuBisCO evolved in a high CO2 environment. It was the success of the photosynthetic process that covered the earth with green and filled the atmosphere with what was to all existing life forms a poison- oxygen.

Now, a team of researchers have engineered a way around this conundrum, at least reducing the cost of glycolate recycling, if not resolving the fundamental problems of RuBisCO. They describe the import of a set of genes from other species- one from pumpkin, one from the alga Chlamydomonas, and five from the bacterium E. coli, plus a genetic suppressor of glycolate export from the chloroplast, all resulting in a far less costly recycling system for the waste product glycolate.

New pathways (red, blue) inserted into tobacco plants, plus inhibition of the glycolate transporter PLGG1. Some of the wild-type pathway for diposing of glycolate is sketched out on the right.

Firstly, glycolate export was suppressed by expressing a tiny RNA that uses the miRNA system to target and repress the gene (PLGG1) encoding the main glycolate transporter. Secondly, the researchers imported a whole metabolic system from E. coli (red part at top of diagram) that efficiently processes glycolate to glycerate, which, with a phosphorylation (one ATP) can be taken right up by the RuBisCO cycle. Lastly, they backstopped the bacterial enzymes with another pair that oxidize glycolate to glyoxylate (glycolate oxidase), and then (malate synthetase) combine two of them into malate, a normal intermediate in cellular metabolism. This was all done in tobacco plants, which, sadly, are one of the leading systems for molecular biology in plants.

Wild-type plant is on the far left, and a sample plant with all the engineered bells and whistles (AP3) is on the far right, showing noticeably more robust growth.

Combining all these technologies, they come up with plants that show biomass productivitiy 40% higher than the parent plants, as well as reducing plant stress under high light conditions. After 3 billion years of plant evolution, this is a shocking and impressive accomplishment, and can be extended to all sorts of C3 plants, like wheat and other grains (that is, non-C4 plants). Due to the number of genes involved, unintentional spread to other plants, such as weeds, is unlikely. But given the urgency of our CO2 waste problem, one wonders whether we might welcome such escapes into the wild.

• Some notes on Sweden.
• MMT is coming into the mainstream, despite kicking and screaming.
• Complete regulatory capture of the consumer financial protection bureau. Now protecting predatory lenders.
• For some countries, history is circular.
• The tribulations of absolute pitch.

Ice Cream is True

Many philosophers seem to think that what we like and want may also be true. Critique of "On Truth", by Simon Blackburn

Hardly any academic field is subject to such divergent opinions as philosophy. While most people ignore philosophy and especially what philosophers say, with complete indifference, if not mockery, philosophers see themselves as grappling with the most enormous questions that lie at the very heart of our society and humanity. They are the ones asking the deepest questions of what is good, what is true, what is meaning, and what is being. Why, oh why are they marooned in ivory towers writing tedious monographs that no one reads or cares about? Specialization is particularly pernicious in this field, transforming what might be a pleasant conversational raconteur and dorm room bullshitter into an academic mired in most arcane and pointless hairsplitting, in emulation of fields of actual research, employed solely because university students must, after all, have philosophy courses.

Still, hope springs eternal that the mental firepower so evident in the written work of these fields could come down off the mountain and briefly enlighten the masses about what is true. Such is the project of Simon Blackburn, eminent atheist philosopher retired from Cambridge and other institutions. His book is modeled on that great work of Harry Frankfurt, On Bullshit. Bullshit happens when the speaker doesn't care about truth at all, whether for it (truth) , or against it (lying). Our current president puts out a lot of bullshit, but mostly he is a pathological liar with a genius for coming up with the most mendacious and divisive lie in any situation. That is why speaking with Muller was deemed by everyone around him to be a "perjury trap". Going further, the new politics we inhabit seems to have left rational discourse behind. The right decries political correctness, which cruelly enforces reason and decency. The solution is to create an emotional discourse full of tribal identifiers but otherwise senseless, making of our politics a simple blue/green contest, ending up, ironically enough, in identity politics.

Blackburn also takes some political shots, which, since he is British, aim mostly at the egregious lying prevalent in the pro-Brexit campaign. But the book is largely a survey / critique of philosophical attitudes towards truth. The starting point, naturally, is the correspondence theory of truth. While called a theory, is it more a definition- that truth consists of mental models that correspond with reality. Heliocentrism is more true than geocentrism, Thucidides is more true than Herodotus, NPR news is more true than FOX news. Blackburn takes those outré philosophers (postmodernists particularly) to task for disputing such basic conceptions.

"At the end of the twentieth century the intellectual fashion known as postmodernism took an ironical stance towards science, regarding it in an anthropological spirit as simply the ideology of a particular tribe of self-selecting people calling themselves physicists, chemists, engineers, and biologists. The standpoint seemed to many to be a sophisticated response to science's claims to authority. It was tough-minded and knowing, and its proponents could flatter themselves as having seen through and exploded spurious claims to authority, as relativists and skeptics typically do. It was all very exciting- until one saw the same sophisticates using iPhones and GPS devices, relying detergents and paints and aeroplanes, vaccinating their children, and doing all the other things that the progress of science has enabled us to do. And then its glamour disappears, and instead it looks more than a little bonkers."

But there have been other, less dismissive approaches to defining truth- the coherence theory and pragmatism. Both take a step back from the correspondence definition, in light of our practical difficulties in knowing when we have gotten to that glorious state of correspondence. Coherence substitutes an agreement among authorities, such as a convergence among physicists of the late 1800's that everything of importance had already been found, and it was only left to work out the details. Global warming supplies another example- if 99% of relevant experts assign it to human causes, then perhaps it is, for all practical purposes, true. Pragmatism takes a similarly indirect approach relying on practical effects for validation of a truth. If planes fly, then much of the aeronautical theory underlying them is likely, again, to be true. I think it is useful to class coherence and pragamatism as methods of ascertaining or approximating truth, not as definitions. The point of truth remains getting us in sync with reality. If we were gods, then no pragmatism or coherence among authorities of lines of evidence would be needed- we would just know what the truth is, but it would still be a matter of correspondence between reality and our sovereign mind.

From there, things really start going downhill. Blackburn makes a diversion into deflationism, which claims that the correspondence theory is not so much a theory as a tautology, therefore meaningless. The problem here is a reliance on absurd linguistics. The word truth is generally not needed in truth claims, like "grass is green", as opposed to "the thought that grass is green corresponds with the facts", or "it is true that grass is green". It should be obvious that in the first phrase, the word "is" does a lot of work, setting out the truth claim quite clearly. It is hardly meaningless, or not a truth claim, thus it is little surprise that adding extra "truthy" qualifiers hardly add anything.

From there, the discussion descends into aesthetics, morality, and religion. Blackburn seems to have a hard time making sense of these fields, virtually giving up critique, and laying out lots of philosophical history and attitudes, which end up putting quite a bit of value on truth talk in these fields. For example, if we all agree that killing babies is bad, then it is true that killing babies is bad. Or, if ice cream is good, then it is true as well. There is a lengthy discussion of the formation of tastes, such that experts with deep knowledge of some art form can educate others to have more refined tastes, which all seems to form an argument for the truth of the tastes and the authority of the experts.

"But if we have been careful and imaginative and profited from the best opinion of others in the common pursuit, we can be reasonably confident that we have done justice to the topic [of some case of artistic evaluation]. We can advance our opinions, which also means we can judge them, perhaps provisionally and in cognisance of our own fallibility, as true."

But here I have to differ fundamentally. Philosophy deals with what is true and what is good. These are not the same things. Just because everyone agrees on something being good ... does not make it true. The criterion is radically different, being our judgement of goodness for human existence, whether for us personally, or for larger social structures such as our family, country or global society. Even if that judgement is putatively objective, such as population growth in response to "good"  policies or virtues, the value of that criterion remains subjective, as it is we who value population growth and flourishing, not perhaps the other animals who may die as a result. So one might claim it to be true that something is good, given expert justification or widespread agreement, but calling things true because they are good, or very good, in some aesthetic, moral, or other subjective sense, is bad philosophy as well as bad language. Whether Blackburn really intends this claim is unclear due to the murky nature of the discussion, unfortunately. At any rate, it is the age-old gambit of religions, to cast what they wish and like as truth. For philosophy to confusedly retain this atavism in its approach to morality and other goods would be deeply mistaken.

• Lawyers and truth.
• Facebook is evil.

UBI: Creeping Communism or Libertarian Liberation?

Review of "Give People Money", advocating for Universal Basic Income, by Annie Lowrey. Subititled "How a universal basic income would end poverty, revolutionize work, and remake the world".

This is a good book if one wants to read a litany of complaints about late capitalism- inequality, crummy work, appalling poverty in the midst of plenty, gender inequality and unpaid work, misdirected foreign aid. One might indeed say that never have so many reasons been adduced for a policy with which they are so tenuously connected. To put the argument briefly, if we were to give everyone in the US a monthly income of, say, $1,000, no questions asked, it would by definition end poverty, set an effective minimum wage of roughly $6.25 (full time), and cost about $3.8 trillion, roughly doubling the federal budget.

What are the various problems that the UBI is thought to address? First is of course poverty. While $6.25 is even below the current minimum wage, it is enough for a bare existence. Lowrey cites several experiments in poor third world countries that show that this kind of income is generally put to good use- much better use than aid that comes in the form of second-hand clothes, bed nets, shoes, or any of the other myriad do-good schemes that first world donors cook up. But there is a crucial difference- these experiments are conducted among a functional population generally at par for their society, whose only problem is that they, as are everyone else around them, poor, relative to more developed economies, whose goods and technologies are available for a price.

The poverty-stricken in the US are, by contrast and almost definition, dysfunctional, with health problems, drug problems, intellectual problems, and other issues that money alone is unlikely to fix, and may well make worse. San Francisco has had, for example, a long-term program to switch from money to in-kind and supportive care. If the problem is merely lack of money, then yes, cash assistance is an ideal solution. But UBI is, for this problem, a nuclear bomb, spewing money to everyone regardless of need, and possibly to the detriment of those in the most need of more structured help. There are better policies, as there are for virtually every problem that UBI putatively addresses.

Day laborers wait for work. Would UBI help?

Another problem dwelt on in the book is crummy jobs and inequality in its many dimensions, from a slipping middle class to persistent gender and racial discrimination and lack of wealth accumulation. Needless to say, the pittance represented by UBI is going to address none of these issues. The best that might be said is that it gives something, which is more than nothing, to those out of the workforce who are caring for children, the elderly, on a love-instead-of-money basis. And since the poor are disproportionately female and minority, they would also benefit the most from UBI, at least in subjective / relative terms. But again, it is a pittance, and since everyone gets the UBI, it does a poor job addressing inequality, particularly if its funding comes from a regressive source like a carbon tax, though better if it comes from an income or financial transaction tax. It does not even raise the minimum wage, given its extremely low level.

The more convincing, and libertarian, argument for a UBI is its simplicity and possible role in replacing other poverty programs. Aid like food stamps, housing assistance, and work training are all rather paternalistic and ridden with absurd paperwork, dehumanizing conditions, and arcane regulations. While some of these burdens come from simple bureaucratic evolution, most come from intentional policy built up to discourage people from becoming poor by penalizing and controlling them in various ways, resulting usually from right-wing and Southern racist politics. Replacing much of this with cash is very attractive, even if much of the new income will be wasted or if its amount fails to cover actual needs like housing in expensive areas. However, as mentioned above, many of the poor are dysfunctional, and got to where they are due precisely to their inability to handle money. To make cash assistance work, the responsible sheep would need to be separated from the goats who will end up on the street even with a UBI. This would inevitably bring back the caseworkers, rules, and other periphernalia of the welfare state.

The next level of the libertarian argument is that robots are going to take all our jobs, to which UBI is a solution. It pains me to have to say this, but this makes little sense. First, automation has been with us since the invention of the spear. Lowrey herself quotes Bill Gates: "What the world wants is to take this opportunity to make all the goods and services we have today, and free up labor let us do a better job of reaching out to the elderly, having smaller class sizes, helping kids with special needs. You know, all of those are things where human empathy and understanding are still very, very unique. And we still deal with an immense shortage of people to help out there." Clumsily put, but you get the idea- taking care of each other is the core of what we as people want to do, and should be doing. Making widgets is only one baroque byway on the true path of our life's work. Lowrey closes by mentioning the Star Trek economy- where no one needs money, all fundamantal needs are fulfilled, yet there are still jobs and ambition- a competition for status directly, not via the accumulation of money, but through the medium of work and service.

But this is probably not what libertarians have in mind. Their idea is more that the eggheads and Hank Reardons of Silicon Valley can keep on working their interesting, highly paid jobs, and not worry about stepping over homeless people, or being responsible employers in the new app-disintermediated gig economy, or facing the pitchforks of a vast and growing proletariat, all by feeding them crumbs of UBI. It is hardly an attractive future. On the other hand, one can view UBI as the first phase of future communism, where everyone shares in a basic level of decency, regardless of contribution. The UBI might be programmed to increase with time, in proportion to economic productivity or technological displacement. I can not regard this as an attractive future either, really, given the fundmantal importance of work in our personal and communal lives, and the impossibility of seeing an end to work, or having some principle to tell us what the best level of UBI should really be. Having ever-growing numbers of parasites living off the fat of the robots is reminiscent of ancient Rome, where maybe one fifth of the city population was on the dole, supported by the vast resources of the empire and armies of slaves. While this system was durable, lasting over five centuries, it does not look to me like one worthy of emulation.

Lastly, there are the children. Lowrey does not go into in detail since its ramifications may be so perverse, but supposing that UBI is granted from birth, the accumulation of children would likewise accumulate a sizeable income. Such an excessively pro-child policy would encourage more children among those most poor and most dependent on UBI, a social and plantery disaster.

---

What is an alternative to all this? A job guarantee has many positive characteristics, which I have mentioned previously.

• It gives money to those in need, not to everyone.
• It provides a decent standard of living, not a pittance, perhaps $25,000 per year, plus benefits.
• It automatically sets a substantial floor for wages, working conditions, and benefits for the private economy.
• It is automatically and strongly counter-cyclical, increasing when the private economy goes into recession.
• It naturally replaces much of the current poverty infrastructure.
• It provides services, insofar as the job holders are doing something productive.
• One could imagine a central job board, used internally by government projects and prospective employees, but also by private employers to make better offers to those employed in the program.

I would envision the job guarantee system as offering a full range of government-run work, from NASA engineering to street sweeping. Employees could be fired at will, demoted from better jobs to worse jobs, (or promoted), as their talents, behavior, and willingness to move merit. If they crash out of the simplest jobs, like litter pickup and invasive plant clearing, they could be offered a basic income for no work (at the UBI level of $12,000 per year- plus health insurance, which would be universal anyway). The conditions would be that they stay out of jail, off the streets, and out of drug and mental facilities. If they crash out of that, they would be faced with more paternalistic options of case worker intervention, food vouchers, group home living, having their finances handled by a trustee, etc. At this level, work requirements would not exist anymore, or lifetime caps, etc.

One of the most positive aspects of communism was its guarantee of work. The work may not have been efficient, but it gave everyone a place in society, and a paycheck, and benefits. It is one of the few aspects of communism worth emulating, if it can be made to work alongside a higher-paying, innovative, and well-regulated private economy.

Combining a job guarantee, cash benefits, and more controlled programs, a spectrum of appropriate options would be available at all levels of society to lift everyone out of poverty, to intervene where needed, to provide maximal freedom, and to use public money efficiently. Whether job guarantee holders actually accomplish anything is secondary- the major benefits occur regardless. Yet as noted above, there is a great, indeed infinite need, for work. For example, child care up to school age, and elder care (given some certification of disability and need for care) could qualify for one job guarantee position, regardless of the status of other people in the household. This would help families cope with services that are so important to society at large.

• Bitcoin is absurd and wasteful.
• Could gerrymandering get even worse?
• Fixing refrigeration is the top climate change solution.
• Reich on paying the rich to "fund" the government. (Which is quite unnecessary.)
• A recession is on the way.
• Collusion.
• The real crisis is climate change. And a fascist president.

Not a crisis

Not a crisis

To Re-engineer a Bacterium

Computational modeling of E. coli regulatory circuitry suggests that some bloat has crept in over the years.

Are we at the point of redesigning life? So far, studies of biology have relied on observation, and on mutations, generally for the worse. We have also tinkered around the edges by introducing new modular functions to some species, most notoriously pesticide and herbicide resistance in crop plants, and antibiotic resistance in bacteria. But what about redesigning whole organisms? A paper from a few years back (2012) took a stab at redesigning the genome of the model bacterium, E. coli, for simplicity. The quest was pretty elementary- ask whether the genes of the organism could be re-organized to function as well as the wild-type genome, but in fewer operons, with simpler regulation. Operons are sets of protein-coding genes lined up like a multi-car train, all induced transcriptionally by one promoter at the upstream end. The more similar functions one can stuff into one operon, the simpler the overall regulatory system can be. On the other hand, the joined genes are harnessed together in mRNA/transcription terms, so any regulatory flexibility that might be useful at that level is lost.

A schematic operon, with a promoter and other regulatory sites, which drive transcription of a set of coding genes, which are transcribed into one mRNA message, which is then translated into a series of distinct proteins. What is gained from chaining many related genes into one operon?

It was, admittedly, a rather academic exercise, with limited criteria for "normal function" of the genome: that its genome should produce all the products of the wild-type organism under ~100 different environmenal conditions. And it was all computational, done by iterative, computer-based evolution but never translated into a lab test of actual organisms (though synthesizing a bacterial genome based on this data is probably quite practical at this point). What they did have was a set of differential equations expressing key regulatory activities of a normal cell, concerning its metabolism, environmental inducers, transcriptional regulators, and genome targets. This is not a full cell simulation, leaving out protein translational controls, degradation, cellular structure and other modes of regulation, but still covers a lot of territory.

Process of computational refinement of the target genome, making random variations, then assaying for modularity and transcriptional output, and then iterating again, many times. Top graph shows regulatory modularity, which increased almost monotonously due to the design of the genome manipulations. Bottom graph is the (computed/simulated) similarity of the transcriptional output vs the original genome, which takes a big hit at first, before climbing back to the original state.

They performed thousands of computerized steps of shuffling regulatory sites and genes around the imaginary genome, testing the result each time for its similarity to the wild-type case in terms of output, and for its modularity/simplicity. As one can see in the graph above, (bottom), the output was quite unlike the standard (wild-type) for a long time during this simulation, before regaining an approximation of the wild-type pattern later on. Clearly the first order of business was simplification, with accuracy of output secondary. The final results are impressive, given the limitations, reducing the total number of operon clusters to about 1/4 of the original.

Example loci from the work. After genome re-organization, several operons have many more genes (black arrows, text notes).

An example is given above. The arc operon is turned on in anerobic (low oxygen) conditions, and encodes factors that repress aerobic loci, such as those involved in oxidative phosphorylation- the use of oxygen to generate ATP efficiently. In the rewired cell, this promoter encodes not one, but 11 other genes as well, probably gaining time and parallel control for a lot of other functions that could benefit from coordinate regulation. But what is galS doing there? This is a key regulator that turns on galactose import, a function completely unconnected with anaerobic conditions. This is one instance (which the authors bring up themselves) where, due to the limited selective pressure these experimenters put on their models, they came up with an intuitively poor result. But overall, they document that, as expected, the functions of genes now coalesced into single operons are overwhelmingly similar as well.

This work, while abstract, and unlikely to have resulted in a bacterium as fit in the wild as its founding strain, is a very small example of computational cell and molecular modeling which has, like artificial intelligence, been the next big thing in biology for decades, but is becoming more powerful and may actually contribute something to biology and medicine in the coming decades.

• An analogous simplification experiment in yeast cells.
• A good diet is lots of activity.
• The Fed is wrong.
• It is hard for a fool not to look foolish.
• How European banks (and the Euro) fostered the financial crisis: “Six European banks were pumping out “private label MBS” from their “US … affiliates””.
• Libraries are civic institutions full of wonder.
• Just how dead is the Republican party?