Better Than Nanites: Custom T-cells

Rather startling developments in the use of our internal maintenance cells to target cancer or other problems.

I am a watching a very nice science fiction series, about a motley crew in space who try to be kick-ass and all, but deep down are just ... very nice people. Because they are Canadian, of course! Every show seems to steal another plot from past classics, like the Bourne Identity, Star Trek Deep Space 9, and even one featuring Zombies.

One crew member is an android, (named "Android"), but is touched with a bit of schizophrenia, a la Commander Data or Seven-of-Nine or Spock, about the virtues of humanity and being humanely idiosyncratic. She also features nanites- apparently tiny machines in her high-tech body that run around and repair things when she takes a hit for the ship.

Android to android: another android, shooting the ship's Android. Repair will now commence.

Such nanites are quite a stretch, current technology having nothing remotely similar, and Android's body being rather inhospitable to anything running around among all the wires, metal, electricity, and whatnot. Such nanites would have to have some kind of master plan for guidance, which would be pretty difficult to fit into a nano package.

Yet our own bodies do have nanites, called the cells of the immune system. This system as a whole is an organ that has no fixed location or shape, but travels around the body in the blood stream, lymph and elsewhere between cells- anywhere where damage occurs. These cells have a highly complex communication system that finds damage, detects what type, cleans out the damage, attracts other helper cells as needed, reads the local developmental and tissue patterns to help local cells do the fix correctly, and gradually turns itself off when finished.

One of the central actors of this system are helper T-cells, which intermediate between the damage signals, which come from normal tissue as well as specialized cells that roam around looking for damage, and the inflammatory and damage repair system, such as cells that create antibodies (B-cells), or that phagocytose and kill infected or damaged cells directly (CTL cells, macrophages). Some T-cells activate immune system actions, and other T-cells dampen them, and they do this over the whole time course of the damage reaction. HIV is an infection mostly of T-cells, killing them and leading to the collapse of the whole immune system.

One of the magic properties of T-cells is specificity. Like the antibody system of B-cells, T-cells use genetic/genomic trickery to generate a galaxy of specific receptors, called, as a family, the T-cell receptor, which can recognize specific molecules, such as proteins from viruses and bacteria. Each T-cell generates and shows one such variant on its surface, and thus the right individual T-cell has to go to the right place to initiate its response, part of which is rapid growth and replication into an army of T-cell clones (do that, nanite!). There is also a process, carried out mostly in the thymus, which deletes all the newly-born T-cells whose specificity is against proteins from its own body rather than against foreign entities.

Given all this, it has been interesting to learn that the immune system often acts against cancers as well. While composed of the body's own DNA and cells, cancers can express various altered proteins due to their mutations and deranged regulation, and also may express stress molecules that tip off parts of the immune system that those cells should be killed. On the other hand, cancers can also, though natural selection, cleverly express other signal molecules that turn the immune system off, thus shielding themselves from destruction. That is a serious problem, obviously.

So many researchers have been casting about for ways to get the immune system to overcome such barriers and attack cancers in a more robust way, especially in resistant cases. And after a lot of false starts, these approaches are starting to bear remarkable fruit. Some are drug-based approaches, but more direct are methods that re-engineer those cells to do what we want.

Since they are travelling cells, T-cells can be taken out of the patient. This allows new genes to be introduced, mutations made, etc., especially using the new CRISPER technologies. One approach is to add a receptor specific to the patient's cancer, such that the refreshed T-cells target it directly, and get activated by the tumor environment, and start to resolve the tumor. This approach has been quite successful, to the point that some patients undergo tumor lysis syndrome- a somewhat dangerous consequence of the tumor getting destroyed too quickly for the body to handle the resulting trash.

A recent paper elaborated this re-engineering approach to make it far more broad. Researchers introduce not only a new receptor to direct the T-cells to particular targets, but a multi-gene system to perform any additional function desired in response to targeting, such as pumping out a toxin, or a regulator / activator of nearby cells. This promises to supercharge the T-cell therapy approach, beyond the native scope of action of normal T-cells, however well-targeted.

For example, in a demonstration experiment, mice were given tumors on two sides of their bodies, one of which contained an additional genetic marker- the fluorescent protein GFP expressed on its surface. This is not a mammalian protein at all, but from an obscure bacterium, and would have no effect, if the experimenters had not also engineered a batch of that mouse's T-cells to express a combination of new genes.

One was a version of the common protein receptor Notch, which had its cell-external receptor portion replaced by a receptor for GFP, and its cell-interior portion replaced with the transcription factor Gal4. When the exterior portion of Notch proteins are activated, the internal portion gets cleaved off and typically travels to the nucleus to do its thing- activate a set of responsive genes. The other engineered gene was a Gal4-responsive gene expressing a cancer-fighting drug called Blinatumomab. This is an antibody specific to a B-cell antigen, which is appropriate since the introduced tumor is B-cell derived.

Demonstration of tumor targeting with engineered T-cells; description in the text.

The synthetic receptor is shown in green (synNotch), exposing a GFP receptor on the outside and a cleavable transcription regulator on the inside. Upon encountering the GFP-expressing tumor (green), it activates transcription of an antitumor drug (custom antibody) abbreviated BiTE, which attacks cells expressing the cell surface receptor CD19, which these tumors do. The green tumor regresses within two weeks, while the control tumor does not.

The demonstration shows that this engineered treatment can address practically any target that can be specifically distinguished from normal cells (indeed, one can imagine multiple engineered receptors being used in combination), and generate any gene product to treat it.

It also shows the increasingly expensive direction of medical care. Not only is the expressed gene product one of those recently-developed, highly expensive cancer drugs, but the T-cell extraction, reprogramming, and re-introduction has to be done on a custom basis for each patient, which is likely to be even more expensive.

• The NRA has a screw loose ... arm in arm with Wayne LaPierre!
• Guess which constitutional amendment is the most important?
• Smoking still at fault for 30% of cancer deaths ... after all this time.
• We are in deep CO2.
• Financial regulation works.
• The disorder has a name.
• And a bitter end is in sight.

Obama's Greatest Error

Syria can be laid at his doorstep.

I have generally given Barack Obama very good marks. He has been a steady hand in the middle of political crazy the defies historical comparison. A compassionate and intelligent leader at home and abroad, while faced with endless vitriol whose source lies uncomfortably deep in the body politic, somewhere. His method has been the classic boxer's rope-a-dope, feinting when the Republicans punch, letting them hang themselves with fatuous House bills and hateful rhetoric from organs like FOX news and the editorial page of the Wall Street Journal.

The idea is that the more the Republicans show their true colors, the more the real players in the game, the observant American people, will wake up and recognize who is serving their true interests. But it hasn't worked out that way, really. The right wing-o-sphere has been so hermetic, so well-funded and so well-gerrymandered that it has not had to face the music of its own madness. Not until now. The advent of Donald Trump has brought the full mariachi out of the basement and into plain view, and it hasn't been pretty, on either the policy or the personal levels. Yet Trump will still carry some states, which, after all we have seen and heard, is unfathomable and disgusting.

But Obama's policy is tinged with weakness. He is playing a long game, dependent on his own imperviousness to scandal and superior sanity. He is not attacking his opponents directly. This is laudible and perhaps effective in domestic policy, but has its limits in international policy. Waiting for international opinion to catch up with bad actors like ISIS or Russia is waiting for Godot, especially when that opinion often sways to strength rather than to goodness.

This has all come to a head in the case of Syria. While Obama has been pursuing low-level campaigns on many military fronts, against Al Qaeda, the Taliban, ISIS, Libya, Pakistan, Iran, etc., he is unwilling to go to greater lengths where it seems most pressing: Syria.

Syria has been a multi-dimensional cataclysm, brought on by a collision between hope and entrenched, ruthless power, sectarianism, millenarian Islam, and other currents. Obama originally spoke eloquently about freedom for the next generation in the Islamic world, about the horror of the Syrian reaction, and his wish for the reign of Assad to end. But what of it? He has had plenty of reasons to not get involved. The example of Iraq, for one. The example of Libya, for another. Our interventions seem to always go wrong, especially in the Islamic world where our intellectual understanding and moral capital is so low. Iraq has been especially disastrous, going from abhorrent stability to US-sponsored anarchy, and now to Shia-led sectarianism, incompetence and corruption. What's a decent and powerful country to do?

The lesson is, as usual, that every case is different, and while being cognizant of our weaknesses and of the bitter lessons of history, we should also not lose hope of influencing world events for the better. In Syria, there was, and remains, a compelling case for a no-fly zone to prevent the bad actors who have air power- Assad and Russia- from maintaining their bombing campaigns on civilians and rebels. Doing so now would be extremely difficult, with Russia already in the air. But doing so at the start, when Assad was alone and dumping chemical weapons of various sorts on rebel areas, would have been far more possible, in practical and political respects.

We could have directly forestalled tens of thousands of casualties, swung the balance of the war significantly, and most importantly, kept Russia out of it, all while maintaining our campaign against ISIS to whatever extent we wished. I think there was at the time a clear humanitarian as well as strategic rationale that should have swayed Obama to take such action. The drawback, as we saw in Libya, is that even if successful against Assad and/or ISIS, we had little or no influence over the ultimate outcome, which could just as well have empowered some other ISIS variant or Iranian client as well as whatever democratic opposition might exist. That would have been an opportunity to shape events politically, making the case internationally for some reasonable coalition of Syrian parties. But we haven't wanted to do that work either.

The Arab spring was a gift. Like the Ukrainian, Russian, and most other color revolutions, it ended in tears mostly due to overwhelming cultural inertia and the entrenched power, both military and cultural, of the traditional autocrats. But we didn't help much either, with our mixed signals and dithering. The tragedy of Bengazi was not that we lost an ambassador and other personnel in horrific circumstances, but that we had so few resources there in the first place for the nation-building effort. For that is what Libya so clearly needed. Such things as a model for governance, disarmament of the various militias, basic bureaucracy, technology and utility management, etc. There is a long list where we and the Europeans could have been far more involved and helpful in the transition from anarchy to organization. granted, our credentials based on our occupation of Iraq were not sterling. But have we learned absolutely nothing, either?

The Egyptian case is likewise very painful, and shows Obama in a particularly poor light. Here, as later with Assad, he pronounced Mubarak to be illigitimate, but unlike the case of Assad, someone believed him, and the Egyptians took it as a green light to remove Mubarak from power. So far so good. But did we follow up to help broker relations between the military, which has long been far too strong in Egyptian society, and the new Muslim Brotherhood government? Did we help guide the new Morsi government in its constitutional predicaments? No. Cultural inertia, particularly of the military and bureaucracy, was the main problem here, as well as a total political disconnect between Morsi and the rest of the country. The US kept its hands off, listened to the nay-sayers from the Israeli right, and the result was that Egypt under its new military regime is in even worse shape than it was under Mubarak- more repressive and in greater economic distress ... even if it is now more pro-Israel than ever.

These cases are hard to second-guess, because our influence was truly small, partly due to our principled stand of non-interference, and partly due to our political capital in the Muslim world being so low. The Obama administration's continued, if grudging, support for Israel and its military occupation of Palestine is perhaps the leading reason for this, and another failure to lead the world to a better future. We should be cutting aid, not increasing it. And this lack of leadership had a direct connection to our bad relations Egypt in general and Egypt in the period of the revolution in particular.

So there is a pattern of doing just enough to keep the status quo going, attempting modest positive change, and not entangling ourselves in new quagmires. Which has its good points, certainly. But look at Russia. Russia is not in a quagmire in Syria. Quite the opposite. They are in it to win, and have brought the Assad regime back from the dead with a relentless and ruthless military compaign. Russia is gaining international power by applying its power strategically, supporting its friends in an effective fashion. And now the Phillippines wants to be their friend too. Power gains more power, if it is intelligently used, while leading from behind eventually turns into not leading at all.

• Left, against a no-fly zone.
• Britain can do infrastructure... why can't we?
• Stiglitz on Trump- the economic pain is real, even if the candidate isn't.
• Some notes on Bernie.
• Some notes on Republicans.
• Hillary is doing OK.
• Despite the relentless right-ward frame of the last debate.
• Where are our forests going?
• Economics vs morality.
• Economic comparisons of well-being.
• Skills? The real skill is having luck.
• Hope for the world, on piano.
• A woman in science.
• Reflections on Afghanistan. A land called hope, but a neighbor called Pakistan.

The Odd Stripes

In the early fly embryo, a gene called odd-paired (opa), is essential for the transition from 7 to 14 segments.

Scientific data is sometimes boring, but other times quite aesthetic, even stunning. Astronomy can be a matter of graphs and spectra, but it can also be revelatory images from distant galaxies, or from weirdly amazing planets and moons in our own solar system. Fly embryology and genetics is one of the more conceptually, technically, and also aesthetically advanced areas of biology, leading the way in the understanding as well as visualization of early animal development.

Segmentation is a body plan principle shared by all chordates, most insects, and some worms. It provides a convenient blend of modularity that allows for repetition of a basic plan to organize cells into an extended, worm-like body, while also allowing variation and specialization in each segment, to the point that organisms like us end up not seeming segmented at all as adults. It may have evolved independently in those three lineages, though also shares some strategies and molecular details, so the full evolutionary story is not quite settled.

General plan and progression of fly embryogenesis, from rough location determination to finer and more precise specification. During this time what starts as a large mass of egg cytoplasm turns into a synctium of positioned, divided nuclei, which then lead to cell formation around the inner surface, and the beginning of tissue formation.

In each phylum, there is a progressive front-to-back and gross-to-fine scale process that is a little like an image coming into focus. A cascade of transcriptional regulation and related molecular events first decide which end of the fertilized egg is front. Then, as cell proliferation proceeds, this cascade subdivides the embryo into about seven zones, (in the fruit fly), and lastly divides those zones into fourteen parasegments, which eventually lead to formation of the ultimate physical segments, with their particular cells and organs, whether common or specialized.

A recent paper focused on one gene that participates in this process: the odd-paired gene of fruit flies. When this gene is missing, embryos don't form the 14 parasegments, but only the seven larger bands. Development is arrested, fatally. Yet odd-paired is expressed all over the body. It does not have the kind of localized segmental or parasegmenal expression that was expected, and is found for the other "pair-rule" genes, at least until quite a bit later on. How does that work?

Incidentally, the odd-paired gene is the homolog (or rough equivalent by sequence, and presumably, function) of a significant gene of humans, GLI1, which is found mutated in cancers, especially glioblastoma. It is typical for master regulators of early development, when cell proliferation is very high and differentiation is low, to be involved in cancer if they are activated through some kind of error at a later time, helping to re-create that embryonic condition in an uncontrolled form.

"Through gene regulation, the GLI1 family of proteins regulates a number of important cellular processes, such as, neural development, cell proliferation, oncogenesis, survival, epithelial-mesenchymal transition (EMT), migration, invasion and metastasis."

Detection of gene expression (mRNA) of selected pair rule genes in early embryos. Red is the odd-skipped gene, green is even-skipped, purple is runt, and turquoise is the paired gene. The time period in this panel (t4) is a slightly earlier stage of development vs the panel below (t6). The patten of seven stripes for each gene, offset slightly to its particular sub-location in the nascent double-segment, is very clear.

Under the influence of odd-paired, (wild-type case), the stripes from above have doubled after about 1.3 hours vs the panel above. 

The cascade of segmentation refinement is mostly a matter of gene expression. Transcription regulators are expressed in various places along the body axis, and their combination, overlapping in some places, absent in others, dictates (through their binding to enhancers at DNA of target genes, thus activating them) a refined pattern for the next step, which consists mostly of another set of transcription regulators. The "gap" genes each regulate portions of the ~seven broad bands of expression, and their combinations activate the next set of "pair-rule" genes that are typically expressed in the same seven bands, which over time (involving mutual back and forth regulation) resolve to and help form fourteen parasegments, each of which comprise the front half of one future physical segment, and the back half of another. Lastly, a set of "segment-polarity" genes are activated in one-cell wide stripes to specify one or the other side of each of these fourteen parasegments, preparatory to the more complex work of specifying the details of cell types, and tissues that are to reside there.

Expression of odd-paired (green) is all over the trunk, while another gene, odd-skipped, is nicely restricted to nascent double-segment zones. The phases refer to time points of embryogenesis, indicating that odd-paired comes on rather suddenly during this process.

The locations of gene expression can be visualized by constucting DNA molecules complementary to the expected mRNA from the respective pair rule or other genes. That DNA is labelled with a tag that can later be reacted to produce the intense fluorescent signals seen in the figures. This DNA (probe) is physically diffused into the chemically stabilized/fixed embryos under warm conditions so that it selectively hybridizes to the target mRNA, thus showing where it is located.

It is the endogenous refining transition of the "pair-rule" genes from seven to fourteen zones of expression that interested these researchers. They reason that perhaps the appearance of the odd-paired mutant, which misses features of each odd-numbered segment, indicating that it participates in specifying the parasegments, arises not from its own location of expression, but from its critically timed regulation of the other pair rule genes. It is known to come on right when this focusing event takes place, and binds to and regulates several of the pair-rule genes, as well as cooperates with them in their mutual regulation.

Embryos mutant for odd-paired (opa) compared to the normal wild-type (wt) case. Opa5 is a partial mutant, opa8 is more severe. The neat stripes in the wild-type are progressively deranged, and lack doubling during this later embryonic phase, gastrulation.

Unfortunately, the data of this paper consists entirely of anatomical expression patterns, rather than the enhancer structure and activation data they would need to support the final model, which was essentially replicated by another lab around the same time (and amplifies existing work). The model is that odd-paired cooperates selectively, and in a strictly timed fashion with the other pair-rule genes to regulate pair-rule as well as genes in the next level down, the segment polarity genes, to accomplish the positional refinement and particularly the band doubling that is absent when odd-paired is absent. The phenomenology, as seen in the expression visualizations, is very striking, and reflects circuitry at the level of gene regulation that, while painstaking to analyze, would give definitive answers about exactly what each of the actors in this process does.

"In the even parasegment, our data support a combinatorial model wherein Ftz [fushi terazu] activates en [engrailed] expression and odd [odd-skipped] restricts this activation to the anterior-most Ftz-expressing cells. An essential facet of this model is that Opa [odd-paired] must repress odd transcription in a specific cell, the anterior-most Ftz-expressing cell, to allow induction of en by Ftz. The Run [runt] pair-rule protein is a candidate for a cofactor with which Opa may cooperate to specifically repress odd." (from Benedyk, et al.)

While the data relies on molecular biology for the visualization and modeling, it carries on a grand tradition of anatomy and genetics as well, in its beautiful micrographs and focus on the physical structure of the later organism, which at the points pictured here is quite invisible, only incipient in the molecular patterning that is going on incognito, as it were.

• Our political sewer: FOX and friends.
• The Catholic conservative issue.
• Afghanistan, still going badly.
• Bill Mitchell on the Federal debt.
• Skills are important, but demand, macroeconomic management, and general economic justice are perhaps more important.
• Bill Clinton's shameful bombing in Sudan.

Does No One Understand the National Debt?

In the debates, we could have heard adults talking about finances. But instead we heard infants yelling incoherently.

Here is a full exchange from the vice presidential debate:

QUIJANO: According to the nonpartisan Committee for a Responsible Federal Budget, neither of your economic plans will reduce the growing $19 trillion gross national debt. In fact, your plans would add even more to it. 

Both of you were governors who balanced state budgets. Are you concerned that adding more to the debt could be disastrous for the country. Governor Pence? 

PENCE: I think the fact that -- that under this past administration was of which Hillary Clinton was a part, we've almost doubled the national debt is atrocious. I mean, I'm very proud of the fact that -- I come from a state that works. The state of Indiana has balanced budgets. We cut taxes, we've made record investments in education and in infrastructure, and I still finish my term with $2 billion in the bank. 

That's a little bit different than when Senator Kaine was governor here in Virginia. He actually -- he actually tried to raise taxes by about $4 billion. He left his state about $2 billion in the hole. In the state of Indiana, we've cut unemployment in half; unemployment doubled when he was governor. 

PENCE: But I think he's a very fitting running mate for Hillary Clinton, because in the wake of a season where American families are struggling in this economy under the weight of higher taxes and Obamacare and the war on coal and the stifling avalanche of regulation coming out of this administration, Hillary Clinton and Tim Kaine want more of the same. It really is remarkable that they actually are advocating a trillion dollars in tax increases, which I get that. You tried to raise taxes here in Virginia and were unsuccessful. 

But a trillion dollars in tax increases, more regulation, more of the same war on coal, and more of Obamacare that now even former President Bill Clinton calls Obamacare a crazy plan. But Hillary Clinton and Tim Kaine want to build on Obamacare. They want to expand it into a single-payer program. And for all the world, Hillary Clinton just thinks Obamacare is a good start. 

Look, Donald Trump and I have a plan to get this economy moving again just the way that it worked in the 1980s, just the way it worked in the 1960s, and that is by lowering taxes across the board for working families, small businesses and family farms, ending the war on coal that is hurting jobs and hurting this economy even here in Virginia, repealing Obamacare lock, stock, and barrel, and repealing all of the executive orders that Barack Obama has signed that are stifling economic growth in this economy. 

We can get America moving again. Put on top of that the kind of trade deals that'll put the American worker first, and you've got a prescription for real growth. And when you get the economy growing, Elaine, that's when you can deal with the national debt. When we get back to 3.5 percent to 4 percent growth with Donald Trump's plan will do, then we're going to have the resources to meet our nation's needs at home and abroad, and we're going to have the ability to bring down the national debt. 

QUIJANO: Senator Kaine? 

KAINE: Elaine, on the economy, there's a fundamental choice for the American electorate. Do you want a "you're hired" president in Hillary Clinton or do you want a "you're fired" president in Donald Trump? I think that's not such a hard choice. 

Hillary and I have a plan that's on the table that's a "you're hired" plan. Five components. First thing we do is we invest in manufacturing, infrastructure, and research in the clean energy jobs of tomorrow. Second thing is we invest in our workforce, from pre-K education to great teachers to debt-free college and tuition-free college for families that make less than $125,000 a year. 

Third, we promote fairness by raising the minimum wage, so you can't work full-time and be under the poverty level, and by paying women equal pay for equal work. 

Fourth, we promote small business growth, just as we've done in Virginia, to make it easier to start and grow small businesses. Hillary and I each grew up in small-business families. My dad, who ran an iron working and welding shop, is here tonight. 

And, fifth, we have a tax plan that targets tax relief to middle- class individuals and small businesses and asks those at the very top who've benefited as we've come out of recession to pay more. 

KAINE: The Trump plan is a different plan. It's a "you're fired" plan. And there's two key elements to it. First, Donald Trump said wages are too high. And both Donald Trump and Mike Pence think we ought to eliminate the federal minimum wage. 

Mike Pence, when he was in Congress, voted against raising the minimum wage above $5.15. And he has been a one-man bulwark against minimum wage increases in Indiana. 

The second component of the plan is massive tax breaks for the very top, trillions of dollars of tax breaks for people just like Donald Trump. The problem with this, Elaine, is that's exactly what we did 10 years ago and it put the economy into the deepest recession -- the deepest recession since the 1930s. 

Independent analysts say the Clinton plan would grow the economy by 10.5 million jobs. The Trump plan would cost 3.5 million jobs. And Donald Trump -- why would he do this? Because his tax plan basically helps him. And if he ever met his promise and he gave his tax returns to the American public like he said he would, we would see just how much his economic plan is really a Trump-first plan.

One can see that the question is heavily weighted, and Pence laps it right up, going the moderator one better by calling the national debt "atrocious". Then he spins a total fantasy about how trillions on tax breaks for the wealthy will bring it down.

Kaine on the other hand does not address the question at all.

What was so unfortunate about this whole exchange is that it failed to give Americans an adult discussion about what the debt is, and its role in the government and the economy. And moderator Quijano led the way into this infantilism, though she is far from alone in sharing this tired, conventional wisdom.

Firstly, the federal system and debt are nothing like state debts or household debts. States do not issue currency and do not print money. Like the various Euro countries, states are bound by an income/outgo ledger. They have to fund their budgets from taxes, or if the federal government is generous, grants and other aid from above.

The Federal government uses taxes as well, but it has the additional job of running the whole economic system, including the currency. The national debt is in truth an economic management tool, whereby growth is accommodated and inflation managed by creating money to spend more than it receives in taxes. Yes, there is, and should be, a perpetual deficit so that economic growth can be met with the issuance of new money. Who gets that new money? The federal government does, to spend into the economy. Treasury bonds represent a legalistic (and in actuality unnecessary) tool to avoid issuance of more currency (which is also a debt/liability of the federal government) using the issuance of a longer-term debt that rewards rich people for saving, presumably with less inflationary impact than currency, but in practice with little different impact at all.

We have been brought up to think that the Fed manages the money supply. But it only controls interest rates, and even there can not get very far ahead of or behind the market. Interest rates have a profound impact on the money creation by banks. Yes, private banks create money too. Every new loan is a creation of new money, and every payment you make on a loan disappears into a monetary black hole. Banks can create money/loans on the strength of their capitalization, and on their regulatory authorization from the government, and lastly on their estimation of market conditions and the worthiness of particular borrowers.

But this new money is very unstable, as we learned in the last financial panic. Private loans can be called in, bank capital can vaporize, borrowers can skip town, and glitzy real estate developers can go bankrupt ... multiple times! Thus we need someone else and some other mechanism to keep the monetary system stable, and that is the federal government in its spending and money creation capacity, which is shared between the Fed and the Treasury.

The federal debt represents that part of the national liability pool that is stable, and is managed in part with an eye towards economic growth and inflation. If inflation and growth are both low, as they are now, the proper federal policy is to spend more money while taking in less tax. Which in turn implies growing the federal debt. The textbook case was in the depths of the banking meltdown, when congress reluctantly approved almost a billion dollars of extra spending and debt. That was far from enough, but certainly helped stabilize the monetary system and economy.

As Alexander Hamilton first said (or did he sing it?) "A national debt, if it is not excessive, will be to us a blessing". This was in the context of the new federal government taking on the various war debts of the former colonies, now states, in both a political sense and in a financial sense, that a well-managed debt is (as England had shown) a tremendous benefit to the national state and economy.

Secondly, the debt is not something that anyone has to "pay off". The calculations that state it in terms of each citizen's personal share are wildly off the mark. We may in sum have a cultural debt to our predecessors for creating that much wealth (the obverse of debt) that is now circulating through the hands of bondholders, other investors, our infrastructure, etc., but it is not a weight hanging over anyone's head. Even if interest rates were to rise, so would inflation and GDP, making the effective debt and its debt service little different. Bondholders like their bonds, roll them over perpetually, and would dislike being paid off in cash.

The real danger of excessive spending by the federal government is inflation. If federal spending (enabled by borrowing/printing in excess of taxation) rises too much, that excess money drives prices up, in a process that may be pleasant and politically easy at the beginning, but becomes very onerous to unwind later on. So there is certainly a point to keeping a lid on inflation, via Federal Reserve independence, etc. But of late, we have been too focussed on fighting the last war (that of the 70's inflation) and not enough on the current one of restoring growth and fighting deflation in the US (see also Japan on how diffucult this fight can be).

What is so ironic about all this is that during our painful recession, it has been the Republicans in congress who have been most vociferous in fighting more spending and debt (at least when a Democratic president is in office; otherwise, debt and spending go up dramatically). They are the ones who have put the brakes on macroeconomic management and growth, all in an effort to pin the resulting poor economic performance on Barack Obama. Well, we have eeked out a little growth anyhow, and Obama easily gained a second term, with a protoge ready to be shoed in to boot, so their destructive efforts have not, thankfully, been sufficiently effective politically, though they have been extremely damaging economically and socially.

And effectively, both parties have the same macroeconomic policy on the debt- expand it. Republicans do so by reducing taxes for their friends, and Democrats do so by spending, also often to help their friends. So all the bluster about how terrible the debt is turns out to be a back-door way to screw with the other party's ability to carry out its priorities, ending up in gridlock. We really can do better by having an adult discussion about finances, while judging those other priorities directly.

So to hear this debate moderator going on about the debt, which she, and the whole media, and the candidates themselves, so thoroughly (or willfully) misunderstand, is sad and disappointing, not to mention flagrantly biased. We need higher debt right now, and specifically we deperately need more spending on our infrastructure to get the economy back on track and pointed to the future. That would be far more productive than complaining about trade deals, or the manufacturing jobs that are long-gone, not to mention the immigration crisis that happened over a decade ago.

• "Inflation targeting has become the poisoned chalice of macroeconomic policy"
• Perhaps 2008 was all about a failure to regulate banks.
• Pence- a worthy running mate.
• The Taliban overruns another district in Afghanistan.
• What people need is work.
• Rent: everyone worships the market, but everyone works as hard as possible to get out from under its rule.
• Some more psychoanalysis of Trump.
• And lying analysis.
• Annals of Republican cowardice.

Capitalism is Not a Moral System; Corporations Are Not Moral Entities

Enthusiasm for capitalism sometimes edges into moralism. Why?

I was raised on Forbes, Friedman, and Rukeyser- each one a tireless cheerleader for the moral and practical rightness of capitalism. Back in the cold war days, with Reds breathing down our necks, this was understandable, though if the Communists had such a terrible, unworkable system, why be so worried about it? And how did our marquee accomplishment of landing people on the moon with a massive public / bureaucratic / military program justify a capitalist system? There were clearly other agendas going on, which typically did not come up in the discussion.

The basic case goes back to Hayek and the Austrians- a temperamental antipathy to egalitariansm, the French revolutionary spirit, and particularly to government doing anything significant, because that will land us in bondage to the bureaucrat, who is by definition corrupt. The Russian system, then and (ironically) now, exemplifies this bondage- the process by which the government's control of the economy and media fosters an amplification of political power into despotism and the creeping disenfranchisement of everyone else- workers and owners alike.

On the other hand, slavery and capitalism are hardly antithetical. In the US, slaves were the single most valuable form of property in the pre-civil war South, greater even than land. They were sold and bought like so many bales of cotton and listed, separated, and passed down in estates. They were tortured, mutilated, chased down, and terrorized, all in the service of successful business. They were the soul, one might say, of that system of capitalism which was fervently defended by people who cherished freedom above all things, such that in the Civil War one-quarter of all military eligible men in the South died.

So while capitalism may be a practical system, it is not inherently a moral system. Like Darwinian natural selection, it may build wonderful things, but it is a blind, pitiless and quite amoral mechanism for doing so. Both systems harness greed, competition, and destruction to weed out the weak and enrich the rich. And their blindness means that they may take vastly more time, and induce vastly more suffering, than required to get there. Indeed, even if one brings sanguine thoughts and upright morals to the business world, it will grind them down, for Gresham's dynamic makes sure that, to meet the competition, you stoop to their level and their methods. Nice guys finish last.

Capitalism is thus in principle and in practice, amoral, and efforts to associate it with apple pie and the flag are pure (class-ist) propaganda. Confusion certainly arises from the fact that corporations are made up of people, who are themselves good and moral, so the whole must have some moral character, right? Unfortunately, the whole in this case is less than the sum of its parts. If the system itself is amoral, then the morality of its components is of little avail. And the leadership of the system tends to go to the least moral, most psychopathic types of people, since they are best suited(!) to that system.

Critiques from the anti-corporate left include the Occupy movement, Bernie Sanders, and basic empirical observation of what is going on around us, now and in the past. The left makes its business to poke holes in the narrative of friendly, moral community-upholding companies. Which in turn spend zillions of dollars portraying their moral rectitude in white-washing, green-washing happy-people advertisements. We need to take a more mature approach to this whole relationship.

One problem is assuming that companies are or even can be moral and decent corporate citizens. That is a simple category error. It is certainly nice if a company behaves decently, but the reigning corporate philosophy and legal / fiduciary duty is to increase shareholder value, whether that and the means of getting there is moral or not. And to obey the law, or at least not get caught. Or if caught, to corrupt the justice system and the political system to the extent that it doesn't matter. And so forth. Some business models foster better behavior than others, but even in the most customer friendly, repeated-interaction, transparent kind of business, there is room for assymetric information and reward for immorality.

The point is the we should not rely on corporations to be moral beings, at least under current systems of governance. We need our other institutions to be the moral actors in the system. If global warming is screwing up the future of the entire biosphere, the solution is not to moan about how evil fossil fuel companies are, but to legally circumscribe them to serve the public purposes, such as raising carbon taxes, regulating their direct impacts, and raising investment and incentives for clean energy.

The fossil fuel industry is corrupting the very system that has the role of holding it to account- the political system, which is our expression of our moral and other long-term interests. Surely that is evil, but again, addressing it is a matter of organization and politics, not of trying to convince Exxon to change its stripes from the predatory organization and purpose that it embodies.

The fossil fuel industry is additionally corrupting the very media that we rely on for information and organization in the effort to mount moral political changes that would regulate its activities and reshape our energy system. Surely that is evil, but again, no change happens without conflict with the incumbant, conservative (if wildly non-conserving) powers who like things just as they are.

The upshot of all these digressions is that the access that corporations have to our public affairs is a relic of a past where we assumed (or were brainwashed to think) that they were civic entities with a public spirited morality. That is not the case, and we need to act accordingly to separate them rigorously. They have interests, surely. But they are not public interests. They have legal personhood. But no moral personhood, and thus no proper role in our collective moral deliberations, or media in the form of a blanket constitutional right of expression.

But here we are with our popularly elected legislators and executive officials sucking at the corporate teat. As though that were where the money was. All the while, the government prints money in the billions, but can't seem to stage an informative election, or make election days into holidays, or publically fund the central exercise of democracy.

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Trees Look Serene, But Operate Under Very High Pressure

Xylem, phloem, turgor ... what the heck is going on in tall plants so they can drink from dizzying heights?

Atmospheric pressure is 76 cm of mercury, or 10.3 meters of water, or 0.1 MPa. That means that even a vacuum can't pull water up higher than 10 meters from the earth's surface. Yet Redwoods grow to 115 meters. How does that happen? There are two problems- where does the pulling force come from, and even with the requisite force, how can anything conduct water to far greater heights than a vacuum on bulk water would allow?

The answer to the second issue is capillary action. Plants have a circulatory system somewhat analogous to ours, with two parts going in opposite directions connected by tiny selective membranes. But there is no heart- no pump. Fluid is moved around by high pressure differentials, driven by osmotic differentials, strong cellular architecture, and active molecular transport at the sub-microscopic level.

One part (phloem, maybe analogous to arteries) is for the sugars produced by the leaves, called sap. The second is xylem, (maybe analogous to veins), conducting water and minerals up from the roots. Xylem is a dead, porous tissue inside the cambium. Using tiny, hydrophilic vessels allows water tension to "hold it all together", while the negative pressure at the top of a plant pulls continuously upwards. How much pressure is needed at the top of a plant? Well, about 19 atmospheres of negative pressure for a hundred-meter tall tree, or ~2MPa. (Compared to this, our blood pressure is negligible, at 0.015 MPa.) The xylem is carefully constructed to prevent bubbles from forming, and from spreading if they do form, helping the natural cohesion of water (which causes the phenomena of capillary action and surface tension) to keep the water column intact under such intense pressures.

Xylem, full of small conducting pores, and carefully isolated within the plant to sustain high negative pressures. The pores  also stand ready to break the spread of air, if any is introduced.

Just as interesting, however, is the phloem system, which generates high positive pressures and is integral to the whole circulatory regime. Phloem is living tissue- just outside the cambium (in trees) and specialized to conduct sugar fluid to sites that need it, like fruits and roots, all over the plant. The xylem and phloem systems are selectively interconnected. The key "capillary" point in the leaves where xylem fluid is drawn towards the phloem fluid, due to the osmotic pressure from a low-solute (xylem) to a high solute (sugary phloem) fluid, forms the pressure differential that makes the whole system work, by what is called the Münch hypothesis.

It has taken decades to test this hypothesis, since it was proposed almost a century ago, for technical reasons- the second you cut into a plant to look at its phloem, the pressure drops in that region. A recent paper (review) used fluorescence tracers and microneedle probes as new methods to observe pressures and flow rates in living, whole plants- the morning glory vine.

Phloem, while largely empty space, has a complex internal surface, including walls (and companion cells) which contain the selective ionic barriers that keep sugars in while letting water and minerals from the xylem fluid enter, at least in locations like the leaves where that is useful. They also have open pores (sieve plate pores) between successive cells (called sieve tubes) that allow flow, but can quickly restrict it in case of injury. Sieve tubes even have their own type of plastid, whose function is entirely unknown.

Phloem sieve tube plates, aligned with a plant and locations from which they were sampled. The lower plates are more tilted to allow more flow. Their pores are also larger, though that is not so apparent here.

The morning glory vine was used for obvious reasons. It is highly accessible, easy to grow, grows to great heights, is easily manipulated, and has a thin stem that is easily dissected. In its stem, it has phloem both inside and outside of a xylem zone, which reinforces the idea that the xylem needs to be carefully protected from the atmosphere.

A stem section taken at four meters height. Phloem- dashed arrows, xylem- yellow and green arrows.

The researchers calculated the sap viscosity, its flow rate, and the phloem volume and cell structural characteristics, to come up with the pressures and other parameters required to achieve it. They also used micro-pressure guage needles and fluorescent dyes in the sap to attempt direct measurements on the phloem channels. Results where that the sap had a sugar concentration of 18%, and about 0.2MPa are needed per meter to drive sap flow. Over a seven meter plant, which was what they were studying at first, this amounts to about +1.4 MPa overall at the leaves, to drive fluid movement to the roots, which was indeed observed overall.

Next, they grew the plants to 17 meters high, removed the lower leaves to simplify the analysis, and measured again. The phloem pressure at the top was +2.2 MPa, which is high, but not enough by their prior analysis to get the fluid all the way to the roots. So they took a second look at the anatomy, and found that the plant had instituted structural changes to ease sap flow. The lower you are on the plant, the larger the pores between successive phloem cells, the larger and more tilted the pore plates themselves, and the higher the sap conductivity, up to six-fold. They conclude that the phloem system is pressure-driven, with the pressure carefully raised, along with other physiological parameters, to adapt to longer lengths of transport.

This leads to a unified picture of plant fluid transport, where very high pressures, both positive and negative, and clever anatomy, allow the transport of both key fluids- the water from the roots, and the precious photosythesized food from the leaves. Osmotic pressure is key at both ends, since not only does the high sugar content of the phloem sap drive root water towards it and supply its pressurization, but in the roots, a modest level of sugar and/or other concentrated ions drives water from the surrounding soils into the root, the pressure of which varies in different plants.

• Another evil lobby & product, in the grand tradition of guns, tobacco and oil: sugar.
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The Desktop is Dead

Stick computers like the Chromebit are part of our future- tiny, portable, cheap.

As someone who consults frequently on personal computer issues, it was interesting to hear about a new form factor- the stick computer. The leading example is the Chromebit. Chrome books are better known- petite laptops that give you a Google Chrome browser that is a portal to the whole web, including a series of web apps and soon, android apps as well. The Chromecast product is also better known, as a tiny computer that lets you channel WiFi streams into your TV, using a phone as a remote controller.

The Chromebit is a bit of each, with a small size of the Chromecast, a bargain basement price of $85, and the computer capabilities of a Chrome computer. Like the Chromecast, it plugs into an HDMI port on any TV or monitor. But it turns that screen into a computer, given that web apps such as mail, docs, and storage now allow one to work entirely online, including cloud printing. Storage is negligible, so everything has to go to Google drive or some similar online service. Likewise, connectivity is minimal, with one USB 2.0 port- enough for connecting a camera in a pinch, or a keyboard or mouse, though these should be bluetooth. Naturally, you have to be online to do anything with this device.

Intel and Android also offer stick computers. At $150, the Intel stick is a fully stocked Windows 10 computer, though with only 32G of storage. Android sticks do not offer full computer capability, being restricted to apps, like a tablet, but these capabilities obviously run quite a gamut, from skype to web browsing, voice control, and millions of other programs.

For a person on a tight budget, these computers are an impressive way to get online with minimal expense, and one can use an existing TV to save even more. A full system would run something like...

$85 - computer
$15 - bluetooth mouse
$30 - bluetooth keyboard
$70 - cloud-compatible printer (optional)
$100- monitor with HDMI (or use existing TV)
=====
$300

This is impressive from a budget perspective, but it also indicates something about the future. One can imagine a world where our phones act as the computers behind everthing we do, which we can plug into dumb screens wherever we want, turing them into secure, full computers. Whether the applications also reside in the cloud as Google is working towards, reducing reliance on any local computing power, is uncertain. This depends only on slightly faster network connections than most of us have today to make fully animated clients driven almost entirely from distant sources. How much we can trust those corporate, centralized sources in an always-connected ecosystem to serve us faithfully is, naturally, another question.

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Meanwhile, while we are on tech issues, to power all these bluetooth devices, rechargeable batteries are the sustainable and cost-effective solution. Charging such batteries can be tricky. It pays to use a smart charger that operates not just on a timer as most chargers do, but by sensing the status of the battery.

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• Recidivism from Guantanamo.

Association, Attention, and Gamma Waves

Associative memory gets broken down by frequency band and location.

Do you have your own madelaine? A place, song, taste, or feel that transports you into the past? That is associative memory, retrieving a more complete set of experiences based on a relatively simple, (if uncannily specific) cue. It may seem effortless, but under the hood, a great deal is obviously going on. Memory is associated with the hippocampus structure deep within the brain. Missing that structure blocks formation of new memories or retrieval memories by association. (Though some older memories may still be available- it is not clear yet whether memories are stored exclusively in the hippocampus, or are only staged there for eventual transfer to other parts of the cortex for long-term storage.)

"Specifically, dense recurrent connections among CA3 pyramidal cells [in the hippocampus] are thought to allow, after a single exposure, for auto-associative reinstatement of a previous learning pattern upon receiving a retrieval cue. Consistent with a role for pattern completion, selective knock-out of the CA3 NMDA receptor was shown to result in impaired memory on a Morris water maze when only partial environmental cues were available, i.e. when performance presumably relied more strongly on successful pattern completion."

A recent paper makes use of direct recording in the brains of surgical patients to observe neural activity and rhythyms as they learn and recall events. Given enough analysis, one can "fingerprint" particular experiences, and see that they are represented similarly when they first occur, and again when they are remembered. The acuity of being able to put electrodes directly into the hippocampus is far higher than the non-invasive methods of fMRI.

The test was to present patients with words and pictures to make an association. Then later, the word alone was presented and the patient asked to remember the full scene. Or a control word with no association was presented. The latter was called item recognition, which involves others types of recall, while the former was called associative recognition.

Correlation between the first presentation and the recall event, in activity from the hippocampus electrodes. For associative recall, (vs item recall) the correlation is clearly higher and more complex. The AR surrogate data comes from the average of the original readings during the presentation of the AR stimulus/scenes, rather than their recall, as an additional control similar to the item recall.

It is clear that associative recall generates a richer experience and richer readings from the hippocampus. That is not news, really. What was interesting was that the researchers had access to far more activity detail and could especially look at the rhythmic effects of this recall.

A dramatic increase in gamma waves as recall happens. Concurrently, alpha waves decline.

That is basically it for this rather short paper. They make the key points that recall involves re-representation of the original stimulus, in some form that is detected by these electrode readings, though far from being understood or decoded by them. And secondly that this recall is accompanied, on this very local basis, by a big increase in gamma wave activity and a decrease in alpha wave activity. This all agrees with the developing paradigm, which is that alpha wave patterns correlate with default / resting brain activity, while gamma waves happen during attention and intense thought. Gamma waves are not carriers of information the way radio waves are, but seem to represent the coordination of select areas of the brain as they form ad-hoc coalitions to attend to some thing- the spotlight of attention, and of consciousness.

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• And ends up sabotaging our infrastructure and lives, if there's a profit.
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• But who is really paying attention?
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Living on the Spectrum

Of sexuality, and other existential dimensions.

It is common now to refer to people diagnosed with autism as being "on the spectrum". The disorder is unusual for the number of genes whose mutation can contribute to it, estimated at about 100 to 400. Thus it is easy to see why affected people turn up with a wide spectrum of phenotypes, and indeed why that spectrum extends well into the "normal" range- people who may be only slightly odd, but never formally diagnosed.

But we live on many other spectra of talent, capability, being. Indeed everything about us is variable. Height, color, sociability, musical ability, extraversion, intelligence are common examples. A recent story in the New Yorker profiled a London police unit of specialists who recognize faces. It turns out that people occupy a wide spectrum of facial recognition talent, from those who can not recognize themselves in a mirror, to those who never forget a face, no matter how briefly glimpsed. It is a capability that is so private and obscure that people typically do not realize what the normal range is and where they fall in its spectrum. So it is only with the burgeoning video surveillance carried out in Britain that high levels of this talent became belatedly recognized as relatively common as well as useful.

One of the most interesting spectra is that of gender. The Olympics reminded us (among many other forms of diversity) that diversity among humans extends to a spectrum of gender. Indeed, one's biological gender, and the gender one feels oneself to be, and the gender one is sexually attracted to, each seem to lie on spectra that, while usually correlated with the "normal" axes and occupying a bimodal distribution, can range spectacularly, and independently, to far reaches.

This is particularly interesting in light of the tight and binary social construction that has traditionally been put on gender. Why is that? Why enforce uniformity where there is variability? An interesting book about the philosophy of the Matrix series of films poses a similar question, in the context of Zion, which tries to be a gender-neutral society, as opposed to the Matrix, which is conventionally normed. Can we escape binary thinking? Should we?

I can think of three general hypotheses. First is pure patriarchy and power. The clear delineation of gender, as also happens in white/black racism with the one-drop rule, eliminates ambiguity when power is being divided up, with all power going to one group, and not the other. Oppression is much harder to institutionalize (and tribalize) without simple rules about who is in, and who is out. Setting the "normal" standard for each class is also a form of social power, as everyone in junior high school learns. When power and attractiveness are properties by definition of the "typical" and "normal", the social system maintains itself in a consistent, conservative way.

A second reason is simply our way of thinking. We are habitually reductionistic, thinking in cartoons and schematics. Cars are reduced to metaphorical "wheels", men and women are objectified mutually to their most basic aspects and organs. With a natural bimodal distribution of gender, it is natural to schematize them as two clear classes, declare those as "normal" and then be made uncomfortable by deviation from that simple mental model. Perhaps, conceptually, humans do not "do" diversity terribly well, since our understanding of the world depends so strongly on our capacity to make "sense", i.e. rules and schemata, out of the welter of reality.

Thirdly, one might turn to deeper psychology, seeing that our models for existence come from complex, unconscious archetypes. The mother/female and father/male archetypes are probably the most powerful we have. Whole religions have been founded on each, with the father especially blowing up to cosmic, infinite, and omnipotent proportions. Conversely, the Catholic church has a difficult time controlling the growth of the mother archetype in the person of the Madonna, which in some regions such as Mexico can even put Jesus in the shade.

So we have to fight on numerious psychological fronts to deal with reality in an honest way, especially to interact with the reality and psychology of others fairly.

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