Who's Driving This Wreck?

How do you find the mutations in a messy cancer sample that actually drove the cancer to exist?

Cancer is a little like a car wreck. A mechanical defect or two may cause an accident, which then causes a lot of other damage to the vehicle and to others. How does the investigator figure out what was the first thing to go wrong? In cancer cells, an accumulation of mutations is part of the mechanism by which a cell escapes normal growth controls and becomes cancerous. Unleashing a slew of mutations makes it much more likely that the cell will find (and naturally select) the two or five more mutations that allow it to transition from pre-cancerous to malignant.

But along with those causal "driver" mutations, the unleashing process usually causes hundreds or thousands of innocent "passenger" mutations, even deleterious ones that kill off some of the cancer cell descendents. Taken as a whole, the mutations are all grist for the selective mill. But for the growing practice of precision medicine, these extra mutations muddy the waters persented by the DNA sequence of a tumor sample. Modern cancer drugs are only helpful when directed against the mutant proteins that caused the cancer, and continue driving its growth.

Sure, there are a few usual suspects to round up; p53, BRCA1, 2, and others. But that is only guessing. A couple of recent papers tried to look more systematically through large sets of tumor sequences to find driver mutations, one using a popularity measure, and the other using a pathway effects measure. Unfortunately, these methods are not applied or applicable to single tumor samples, which is to say the clinical setting, but rather are academically oriented to the hunt for more genes and gene mutations to put into the hopper of possible cancer mutations that can then later be applied to clinical cases.

Simple statistics can tell you to a first approximation which mutations are more common in tumor samples than in control samples. For common mutations, like those in p53 gene, this is fine. But this method has a hard time finding uncommon cancer-causing mutations, which, though individually uncommon, are in sum a large and important class. This quest is of interest both for clinical use in compiling a complete catalog of possible driver  for prognosis and treatment, and also academically as a hunt to find new genes that have roles in causing cancer.

A recent paper takes a step towards super-charging this search by combining DNA mutation data with RNA expression data. The idea is to ask the tumor cells which pathways are particularly active or deranged from a gene expression standpoint, (and associated with cell growth and tumorigenesis), which then helps tremendously in focusing on genes that participate in those pathways as candidate tumor drivers. These would necessarily be a small fraction of the 22,000- odd genes in the whole genome.

Here is where biology starts to look a little like electrical engineering. The first step of the study is to create pathways out of the gene expression data that was drawn from their tumor samples and from other cells. Pathways are circuit diagrams of what gene regulates what other gene, in cascades of control that function everywhere in biology, especially in development, homeostasis, and environmental response, and which go haywire in cancer.

Conceptual molecular pathways that might be relevant to cancer. Misregulation of/by any gene can be detected by reading out the altered expression of targets at the bottom.

Specific example pathway, cartooning interrelations among some of the greatest hits (common driver genes mutated) in cancer biology.

An example pathway is labelled as cellular component organization, shown above. Genes like RB1, TP53, BRCA2, MYC are all well-known regulators involved in cancer. The point here is not that common cancer genes show up in such networks, but that elucidating a regulatory network should bring up all the actors in a process, including other lesser-known genes that might also play a role. Mutations in those genes are the target of this work that seeks to create a more complete catalog of known relevant genes and mutations in them that contribute to cancer. But ultimately, everything is connected with everything else, so a lot depends on how one calculates these networks. The authors seem to be relatively conservative in their scope, and cross-check their networks with those from a commercial source, Ingenuity, with which they largely agree. They also validated their final results, in terms of cancer genes and their driver mutations, using the same commercial source, rather than going into the lab to test another large batch of tumor samples, for instance, or generating transgenic mice or cell lines to evaluate the effect of each mutation.

Incidentally, even if the full set of cancer genes is known, identifying a relevant mutation, for cases like that of AURKA whose overexpression contributes to cancer, can be extremely difficult, since overexpression can be due to point mutations many thousands of bases away from the gene, in regulatory regions which are not well mapped or understood anyway. The researchers are interested, however, in simple correlation, taking many tumor samples and asking which mutations are correlated with the changes in pathway perturbation that are seen in the gene expression data. That simplifes the search somewhat.

Getting the data required for this combined analysis is not easy, yet technical advances make it possible. And the result is evidently quite powerful. The researchers claim many orders of magnitude improvement in (apparent) driver mutation detection, compared with prior algorithms, and compared with any algorithm run without pre-grouping the candidate genes by this empirical pathway-based method. Unfortunately, neither the text nor figures are very clear on this point, so I have to leave the data discussion there.

It is critically important to generate increasingly comprehensive models of cancer as part of mastering molecular biology in general. Each of our three billion DNA nucleotides is doing something, some much more than others. We have only cartoon pictures so far of a smattering of our molecular circuitry. Thankfully, nature is not coming up the new models every year, but understanding the current model of human, and the molecular accidents that befall it, is an enormous task that will keep us occupied for decades.

• Inequality, economic sclerosis, and rent.
• Rent in wage negotiations, by way of artificial austerity.
• There is no sign that the Fed should be raising rates.
• And why do bankers want higher rates anyway?
• Ben Carson ... expertise in one area does not confer authority in all. Each case has to be made on its own terms.
• The animated empire of Walt Disney.
• Does the medical market work? Not for consumers.
• Dune ... on the Afghan-Pakistani border.
• Cringely on the cyber-arms race. All is lost.

The Federal Budget Should Never Balance

Honest ... the deficits are OK. The sovereign government has a critical role in economic stabilization and prosperity.

The household analogy is a very durable one: the idea that, since taxpayers and households need to balance their budgets, that the government should as well. Politicians across the spectrum enunciate this mantra / analogy as though it were self-evident. The irony is that although liberal politicians may speak such lines with less formal conviction, it is Republican office-holders who have shown time and again over recent decades the most willingness to throw such balance out the window, in pursuit of tax cuts, with their ensuing deficits. Nothing personal, of course, just class war as usual!

The recent British debacle of liberalism kowtowing to a Tory narrative of austerity and budget-cutting is one more example of the false consciousness that is damaging particularly to liberalism, but also to everyone else who participates in modern economies. Because, in truth, the federal budget should never balance. Its imbalance is the most powerful tool we have to keep the economy stable and growing.

For households, and for dependent government entities like cities and states, the budget constraint is absolute ... there is no free money, and no use to a deficit. They may have capital accounts, with bonded debt for capital needs, like houses and roads. But every such debt has to be paid off eventually. Banks occupy a special place in this system, since they can create money, via the loans they fund. But every cent of these deposits (though not the interest ... where does that come from?) is matched by the loan note on the bank's books. Banks also have a zero-sum balance sheet.

A federal government with a sovereign, floating currency is an entirely different beast. It is the entity that creates the (high-powered) money that everyone else uses. It is not constrained by a zero-sum balance sheet. Therefore the propaganda of a federal government "running out of money" or being broke, or having to live within its means ... are all meaningless. The federal treasury (in combination with the central bank) can spend money at will on whatever it likes. The idea that it has to issue bonds to "fund" spending not matched by tax receipts (i.e. deficits) is an economic fiction. Such policies are legal fossils from another age, where money was not printed by fiat, but was backed by gold / silver. The fact of the matter is that federal spending provides the money to those who buy such bonds, and the bonds do little but replace one form of low-risk saving with another, rather than altering the buyer's behavior, affecting inflation, etc. Plus give a stream of income to the wealthy.

But obviously, there is a constraint on federal spending and money creation. That is the overall level of economic growth and monetary inflation. Since the government is free to create money, it assumes the risk of fostering inflation and the responsibility to manage monetary growth to keep pace with the various forms of economic growth: population growth, productivity growth, and trade deficits, if any. Additionally, economics has found that modest inflation, on the order of 2%, is beneficial to encourage productive investment over inert savings (such as gold). Add all these categories of monetary growth together, and you get a virtually constant need for federal deficits. This is why, as a matter of fact, we in the US do have perpetual deficits, why making the federal budget go into surplus creates highly unstable economic conditions, and why politicians seeking to balance the federal budget are charlatans.

Taxation is part of this scheme as well, of course. While deficits may be required in perpetuity, they are not typically enough on their own to fund the whole government. Additionally, the central role of the fiat currency has to be established at the outset. Taxation fills both roles, creating a need for the "legal tender for all debts, public and private" which is demanded by the government for taxes, and which it uses to commandeer a large share of the private economy, above and beyond the annual growth it funds with new money.

So much for normal economic times and methods. It is in crisis when the powers of the federal monetary system become most important and evident. Where in the old gold standard days, a government could do nothing during the frequent business collapses, busts, depressions, etc., a modern federal government can spend exactly as much as is needed to make up for the evaporation of bank credit and the money that bank credit represents. The government can resolve deflation in a matter of a few pen strokes. Properly handled, there is no need for economic slowdown or unemployment at all, since the full gap of private credit-based money (which characterizes a depression) can be made up as needed by federal spending of new money.

Note, however, that such a gap can not be made up by the central bank alone. As currently constituted, central banks can lower short-term interest rates and can lower long-term rates by way of "quantitative easing", but they can not inject money directly into the economy. If banks do not want to lend, or borrowers do not want to borrow, no interest rate is going to induce them to do so. And they will be particularly shy of lending after having just lost their shirts in a credit-destroying debacle. Thus it is critical for the rest of the government to not sit on its hands, but spend as needed to cover the monetary shortfall created by declining economic conditions, or a credit crisis in the private banking system.

Of course, it isn't all spending and free money. When boom times come, (as measured by very low unemployment and rising inflation), the federal government needs to have the discipline to take away the punch bowl, using its tools of fiscal retrenchment, taxation, and higher interest rates to restrict inflation. Past governments have shown some laxity in this department, as is tempting and unfortunate. We spent the seventies perplexed by the connection between high government spending and inflation, before Paul Volker pulled the plug with a high interest rate-induced recession. But the fact is that the current atmosphere permeating central banking and conservative politics is far too scared of inflation, fighting a war that was won decades ago. The focus on austerity and budget constraints is not really about inflation anymore, but about keeping workers powerless and underpaid in a perpetually under-performing and under-employing economy.

Tom Tomorrow, on markets.

• For more on MMT & Keynesian economics, see a blog by Bill Mitchell.
• Brad Delong on Fed structure, mandate, and policy.
• Surowiecky on Stieglitz and inequality. 
• Krugman/Thoma on Keynesian policy.
• Robert Schiller on the idiocy of conservative economics: "But adhering to an approach that overlooks these factors is akin to doing away with fire departments, on the grounds that without them people would be more careful – and so there would then be no fires."
• Why do governments love banks so much?
• The bureaucrats knew a thing or two about Vietnam.
• What lack of competition and regulation is costing us in internet service.
• Buying the feudal political system you want ...
•  ... Leads to weakness in the Western (and antipodean) political class.
• The curse of year-around plenty in the tropics.
• Is complexity in scientific data opening the door to obfuscation and worse?
• Economic graph of the week ... median income:

If You Prick Us, Do We Not Bleed?

Reflections on competitiveness, othering and empathy.

Our sympathies radiate outward from the self in ever-widening, and attenuating, circles to family, friends, neighbors, city, nation, species, genus, order, phylum, etc. The pain of some carries great meaning and demands empathy, while others we eat for food or trample underfoot without a second thought. A recent podcast about the livestock industry described the deplorable treatment of animals raised and slaughtered for food, which seemingly is intrinsic to the industrialized methods requisite to the modern way of, and scale of, life.

To put it slightly differently, the "I" is never an objectified being, but intrinsically a subject defined by feelings and thoughts, rather than by physical nature. Descartes defined being by this subjectivity, not by objective & physical reality. We have souls, but do others? Do animals? The farther one gets from the self, the less possible it is to feel for the other, the less intersubjective one tends to be. As a child it is jarring to realize that our bones can be broken, elbows scraped, and that our bodies are seen as objects by the medical profession, among others. Is the subjectivity of the "I" an illusion, or is the objectivity of the body?

But even within our own species, we clearly have ways to limit empathy, demonizing others by whatever social construct as opponent groups, nations, races, and as less than human. One shudders to think of the cruelties that were once routine, like children torturing cats, heretics burned at the stake, prisoners drawn and quartered, etc. The catalog is astonishing and disturbing. ISIS seems to be continuing in traditional fashion, though we certainly did our bit during the reign of George W. Bush.

Sure, we are programmed genetically (morally) to feel for our brethren and hate our foes. The science of human empathy has advanced markedly of late, and finds many ways by which we are genetically programmed to feel for those close to us. Yet others, including animals, have feelings just as we do. Their subjective existence is no different from ours in kind or value. Our programming against universal empathy is thus illogical, and arises purely from the competitive necessity by which we must at some point summon the ruthlessness to dispossess others of what they have so that we can prosper in their place. Sometimes by taking their land, sometimes by eating them.

This is the mystifying aspect of our love of competition, such as sports. Granted, sports might be better than war, but the valorization of such anti-social aspects of ourselves, where winning is everything, and legions of losers must suffer defeat so that one champion can be crowned ... it seems morally suspect, at least. If one looks askance at Donald Tump's demonization of Mexican immigrants, one can hardly in the next moment cheer on one's team to crush its opponents, one's country to win its wars, and one's family to succeed in its dreams of professional and reproductive dominance over other people. Competitiveness is all of a piece, and is a moral disaster.

What does competitiveness get us beyond our narrow interests? By way of natural selection, it gets us more successful populations where the weak are culled out and the most ruthless, strong, and clever survive to create yet more successful progeny. And is that the world we want to build, as humanity reaches gargantuan proportions of population and success on Earth? Our success vis-à-vis the rest of the biosphere is painfully evident. We have no competitors but each other. What does success against each other then mean, other than pain and waste?

In the economic system we have devised for ourselves to share out scarce resources, competition is supposed to generate innovation and efficiency. But typically, real innovation comes more from individual inspiration and from government funded research, with the business system merely implementing and applying what others have found, bringing it to a market scale. That is not unimportant work, and the basic market mechanisms that distribute goods are indeed very effective. But it is a principle that can be taken way too far, invading our human values and common cultural projects.

That is the subtext of our cultural moment grappling with inequality, conservatism, and a GOP that has escaped earthly bounds into an ideology of extreme competitiveness that dare not speak its full name. The 1% are, by capitalist definition, the most successful of the species. By conservative, competitive principles, they (exemplified by Donald Trump and Mitt Romney) have the duty and right to shape the social system to perpetuate their own kind at the expense of the lesser competitors among us (technically, losers). Yet there is a democracy to think about, so lip service is paid to propsperity for all, possibly through tax cuts for the rich, possibly through cutting social spending on the poor. But such hypocrisies may not even be needed as the culture becomes inured to a new feudalism, with its ever-hardening social hierarchy.

What is the answer, other than the cultivation of unifying cultural themes, and the critique of divisive, competitive, and unfeeling ones? As the black lives matter movement has brought to consciousness, there are very deep levels of social construction and competition in our society that need ongoing critique and inner work. I think that as part of the work of expanding our field of empathy among fellow humans and other beings, it is useful to see ourselves as an other as well.

Darwin took the first great leap in this direction, taking humans down from a metaphysical singularity and back into the family of life. To realize that we are apes, that we are no more feeling than other organisms that fight tenaciously to live in their own way, and that, considering our own workings as organisms, we have so very little insight that we have no personal idea how our organs work, how our very mind works, that we are strangers in a strange land. Programmed, yes, to feel that our feelings take precedence over all else and all others, but maybe capable of feeling a commonality of mystery and empathy as well.

• Jeb! and the disaster that is mainstream Republicanism.
• The ultimate form of capitalist debt and peonage ... human capital contracts. Why not sell your first-born at birth to the corporations and be done with it?
• Saudis educating children...
• Political polarization is another bad consequence of economic inequality, since money and democracy want different things.
• Australia's internet speed is even worse than ours ... another failure of conservatism.
• A better bus system might be better than chimerical trains.
• Bill Black on DOJ, closing the barn door seven years after the horses left.
• An agenda to address economic inequality. Missing are a financial transaction tax and wealth taxes, such as Piketty's annual wealth tax, or a much higher estate tax.
• Housing shortages increase inequality and feed the rentier class.
• Saving appearances in the Wall Street Journal: "Bush Wants Fewer Tax Breaks for Wealthy Than Most in GOP."

Orthologs and Homologs and Ohnologs, Oh My!

Long ago, vertebrate genomes underwent genome duplication, which unleashed great evolutionary opportunities.

Among the most ignorant arguments ever foisted on a gullible public by anti-evolutionary Creationists was that information can not increase in living systems by natural means. Put in its sophistical garb, with a intimation of high-power mathematics and quantum theory, it was hard to resist the idea that this PhD from the finest schools really knew what he was talking about. But, obviously not, since information is interchangeable with energy, as we do every day with our keyboards, and as life forms spend their time doing internally as well.

The clearest refutation of this appalling hypothesis is the phenomenon of gene duplication, when by some accident of replication or recombination, stretches of DNA can double, and an organism ends up with two genes where only one was before. As time goes on, the extra copy may disappear, recombining back out of existence, but on the other hand it may share functions with its brother (or homolog) and gain variations in its regulation or expressed sequence that lead to some new function and thus a selective reason to remain in the genome.

DNA duplications are simply accidents, no more mysterious or transgressive than the existence of DNA in the first place. And they can happen at any scale, from single nucleotides up to whole genomes. In fact, the duplication of whole genomes has been tremendously important in evolution and has been recorded in the histories and genomes of many lineages. A recent paper delved into two rounds of genome duplication that happened to the early vertebrate lineage, whose traces are peppered throughout the genomes of ourselves as well as all other vertebrates.

Incidentally, plants have experienced lots of gene duplication events, even triplications. This is the main reason why many plants have more genes than we do, despite not (apparently) being more significantly more complex.

Genome duplications and triplications in the history of angiosperms.

When a gene duplicates, a race begins between the forces of recombination, which tend to splice it back out due to the pair's identical sequences, and the forces of evolution (i.e. natural selection) which, if some kind of diversification happens, or some other rationale for keeping the extra copy, keeps it around. The rationale may simply be higher production of the same product from two, rather than one, gene. But over time, the reasons tend to get more interesting, with each gene diverging, and thus specializing, in the regulation of its own expression, or the activity of its expressed protein. Once both copies have specialized for different functions, the race is done and the gene is there to stay.

Since evolutionary biology is all about relatives and lineages, a complicated terminology has developed for describing related gene sequences, which are so very useful in finding interesting genes and deducing their function. Two genes with similar sequences are called homologs, which also means that the two sequences are related by descent. There are many families of genes, some with hundreds of members in a single species which are related in such a way, a testament to the profuseness and usefulness of gene duplication over the history of life.

If a gene is related 1:1 to a homolog in another species, such that they are fulfilling a similar role and came from the common ancestor by lineal descent, they are called orthologs. While many orthologs are relatively easy to recognize, the ability of genes to keep duplicating and diversifying in some lineages but not others can sometimes make it difficult to decide on orthologous relationships. Indeed, homologous family members present in one species are called paralogs, and whether each paralog has its separate ortholog in another species, or whether only one of them is the true ortholog and the rest are later sproutlings depends on the precise lineage history, which one has to figure out by lining up the relevant genes from several different species.

Lastly, the current paper studies homologs which descend not from single gene duplications, but from whole genome duplications, and are called Ohnologs, in honor of Susumo Ohno, who first proposed their existence. In some respects, whole genome duplications happen relatively easily. A cell just forgets the chromosome division process during mitosis, and voila- a duplicated genome. There are no dosage effects of one gene present at unusual amounts, since all are duplicated equally. There are problems mating with other organisms, however, as the chromosomes no longer match. But if parthengenesis is an option, even that issue can be overcome and a new species is founded into the bargain.

Whatever the short-term difficulties, the long-term implications of a successful genome duplication event are momentous. The new species has extra genes coming out of its ears, which lend themselves to countless opportunities for specialization and diversification. To new features that would not have been possible through the painstakingly slow accumulation of alterations in one gene. The current paper documents in the greatest detail yet the back-to-back duplication events that happened at the base of the vertebrate lineage, about 600 million years ago. The authors labor to detect as many of the remaining genes as possible, despite the ravages of time through which genes get shuffled, lost, reduplicated, garbled, etc.

They use whole genomes from several species, both inside and outside vertebrates, to look for traces of related duplicates or quadruplicates. The main piece of evidence is synteny, which is the similar ordered location of genes along the genome, comparing two species, or in the case of ohnologs, homologous genes within one species. The problem is that smaller gene duplication events can show very similar signatures to ancient whole-genome duplications that were later shuffled around by recombination. So the authors need to use a collection of species that are broad enough to place the hypothesized duplication back in time at the putative vertebrate duplication events. At the highest stringency of analysis, they come up with 1381 ohnolog sets, i.e. two or more genes traceable to a single originating gene. At lower stringency, they find up to 2642 sets, comprising almost 8,000 genes. This is over a quarter of the human genome complement, so is not bad work for events that were so long ago. It is remarkable to see so many duplicate genes preserved at a detectable level.

A pre-eminent example of such gene duplication is the Hox genes, which control broad tissue identity, especially by segment, of the body plan. The diagram below shows a classic case of ohnolog inheritance, where, using alignments of the relevant genome regions of several species, four versions of the Hox cluster are present in humans where only one is present in flies and in the chordate (but not vertebrate) lancelet. Individual copies of the Hox genes were lost in the vertebrate lineage, presumably before their diversification had established new and essential functions, but most stuck around in some form. The diversification of Hox genes allowed greater body plan complexity, as extra copies contribute to identity of novel tissues all over the body, such as limbs, digits, and parts of the head, going substantially beyond the strictly segmental identity system used in flies.

Genes controlling segmental identity in the body plan of animal species, the Hox genes, show clear evidence of the ancient genome duplications that happened at the base of the vertebrate lineage. Though some of the Hox genes were subsequently lost, the rest comprise sets of Ohnologs.

• Bonus paper on the ancient genome duplication in yeast.
• The Fed is getting ready to make a mistake.
• Rank Christianity... the sacred liberty to cram my religion down your throat.
• Annals of the class war.. who wins from QE? Mostly the financial sector, which wouldn't be the case if we had used fiscal policy instead. And more on public debt.
• The Stepford mistress-bots.
• Excess global savings is the new normal, and doesn't mix well with a free capital and investment market.
• Wag the dog.. markets have very long time horizons, which can whipsaw current valuations.
• Socialism and worker power.. scaring capitalists straight.
• Charity is closely related to feudalism. Governments do it better and fairer.
• Annals of denial.. ISIS and its brand of Islam.
• The garbage patch is worse than ever.
• How MMT differs from Keynes.
• Image of the week.. it's full of stars! A Hubble field of numerous lensed galaxy images.