Epic Genetics

Lineage, nobility, destiny in the Shahnameh

Traditionally, people have had great respect for genetics. Traits run in families, and every culture has had its class system of assortive mating that segregated the nobility from the other classes down the line to peasants. The modern world is unusual in its insistence on equality and democracy, which arose when the old nobility system had so absurdly overreached its original justification (if indeed there was any) and put such mediocre people at the head of affairs that the whole thing naturally collapsed. Now we value diversity and, to put it in genetic terms, hybrid vigor over pure blood lines. Echos still resound at the Westminster Kennel club, but for humans, purity seems out.

As recently as in the novels of Marcel Proust, the importance of lineage is paramount, as endless pages go by of the narrator besotting himself over the faded charms of count this, baron that, or princesse whatever. The class system has had a long, lingering death in Europe. Here in the US, we are re-inventing class relations on a business model, which is a thinly veiled feudalism with lords of the manor in suits, whose most successful exemplars shine forth in all their condescension in the foundational funding announcements on NPR, not to mention running the political system by buying all that "free" speech.

But at least they don't (to my knowledge) have harems of women to flood the next generation with. Bill Gates has not (yet) devised a way to clone himself into shrink-wrapped copies with which to win the genetic race for the future.

But the rulers of old certainly did. I have been reading the Shahnameh, which is the lengthy epic of Persia, recounting the reigns of its Kings from the mythical to the Muslim conquest. The themes of linage are a constant refrain, telling how handsome, strong, wise, and just each prince and king in turn is. How beautiful and modest the women in his harem. One infant is even sent down the Tigris in a box and raised by humble peasants, only, Harry Potter-like, to instinctively take up fighting, horse riding, and other knightly pursuits in defiance of his guardian and in clear sign of his royal lineage.

It really is one of our oldest and most perennial themes- the Cindarella or foundling-prince in the rough, not only recognized eventually by merit, but documented to have royal blood all along. But obviously, the actual differences are typically vanishingly small, when education and culture are accounted for. But we focus and thrive on minor differences, defining (and "othering") tribal groups in arbitrary ways, and judging each other with the greatest subtlety in the race for status and mates. The fiercest battles are typically of brother against brother; French and German, Russian and Ukrainian, Jewish and Arab, and so on.

What did all this harem-keeping and status seeking accomplish, anyhow? Well, beauty was one object, duly attained, I think. Each nationality has its distinctive look of nobility, from Japan to England. But in terms of temperament, I think much less was accomplished, indeed negative results were attained. The most successful leaders were typically mad with ambition, so we have ended up with a lot of Shakesperean plots and palace intrigue at the head of affairs. No wonder the good king was such a rare and precious find! Power may corrupt, but assortive mating can corrupt as well, when the standards for selection are so contrary to what societies most need. And when taken to extremes of inbreeding, as in Egypt and Europe, the results have been disastrous on any level one cares to consider.

Thus the madness for lineage accomplished far more in terms of public relations than it ever did in genetics. The PR value of the Shahnameh was inestimable, training generations of Iranians in the celebrity culture of their day and thus stabilizing the feudal hierarchy / patriarchy. While the overall competition for status and success has probably been an engine for beneficial genetic selection, its manifestation at the very top of the hierarchy is another story entirely.

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Where Does it Hurt?

The mystifying cognitive biology of pain.

Pain is perhaps the bedrock of consciousness. If we want to know we are awake, we pinch ourselves. And torture is the use of inflicted, involuntary consciousness of pain against the person's higher faculties, interests, and desires. Before there was cogito ergo sum, there was morsus ergo sum. But that hasn't made pain any easier to locate and analyze as an activity of the brain and greater nervous system. There is no "pain center" in the brain, for instance.

But the brain is central to pain. Sure, we have local reflexes that respond involuntarily and unconsciously. But if pain is consciously experienced, it comes through the brain, no matter how far away in the toes it might be mapped. It is remarkable, indeed, that our brain can tell us to feel something in our toes based on signals that the toe sends from several feet away. For all our complex knowledge of the pain receptors and their circuitry on the way to the brain, the conscious experience remains mysterious.

The best approximation to date is something called a "neurologic pain signature" (NPS), which comes from neuro-imaging and consists of a variety of locations in the brain that associate specifically with the most immediate experience of pain. It is not a point, but a large network of activities and locations, all of which are often involved in other things as well. Just like consciousness in general, there is no little incubus in there, but a specific pattern of activity, that must be the experience of pain.

A recent paper and review about our ability to manipulate our pain experience through distraction, placebo effects, and other high-level cognitive mechanisms outlined these issues. The paper basically divides the pain system into two parts- a basic reception part that gets signals from the body, (and corresponds to the NPS mentioned above), and a cognitive part that happens when those signals hit yet other parts of the brain, especially in the frontal system. This latter part, which can be engaged successfully to dampen a subject's pain experience, upon appropriate instruction, had big effects on the subjective experience of pain, but no effect on the activity of the NPS, as observed in brain scans.

"This means that whatever information is used in the NPS decoding, it doesn't simply represent the subjective experience of pain. Instead, the authors found that the influence of modulation is reflected in different brain regions—notably the nucleus accumbens and ventromedial prefrontal cortex (in brief, greater activity reflects less pain)."

"Thus, our NAc-vmPFC [frontal area] pathway findings may reflect evaluative processes that play an important role in the construction of pain experience and in shaping long-term motivated behaviors and outcomes."

Diagram from the paper, showing the subjective pain ratings (left, bottom) compared to the neurologic pain signature by brain scanning (right, bottom). Subjective ratings were modestly affected by conscious training. Part A shows the overall schematic, that the NPS, a brain core network, doesn't budge when one tries to consciously either dampen to increase the pain, while certain locations in the frontal areas (blue) are more active when trying to dampen the subjective pain experience.

So subjective pain is something else again, not really the NPS alone, though clearly derived from it somehow. Are these small frontal areas that light up caused by the effort involved in modulating the pain, or are they more directly associated with the subjective pain itself? Likely the former. The brain is full of mechanisms to shut out distracting stimuli, since only a small portion of all the sensory modes and data coming in ever make it to consciousness. The frontal areas are frequently a big part of this filtering and habituating process. Thus the NPS may still constitute pain consciousness, whose access or presentation is regulated, much as vision or hearing is regulated, by other parts of the brain in a (slightly) top-down way.

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Molecular Medicine

Down the rabbit hole: what medicine will be like in the future.

The primitive nature of current medicine is usually hidden behind white lab coats and alien machinery. But typically, the knowledge of what is wrong with you is sorely lacking. Cancer treatment consists of shots in the dark, killing all growing cells with horrible poisons that in most cases still do not resolve metastisis and only add a few months of sickened life. More broadly, all sorts of syndromes from diabetes to cronic fatigue, depression, and autoimmune processes, to name a few, have very murky causes and again only trial and error treatments that palliate more than cure. The dizzying round-about of nutrition and diet advice is a symptom of this pervasive ignorance.

One might see the progression as going from big to small: from the wilds of intuition, with its often cosmic / astrological concepts, to scientific anatomy, to the advent of microbiology and cellular biology. The next step is molecular, where the real foundations of biology lie. Whether we have truly mastered the microbiological level is open to question, of course, with the recent measles and ebola outbreaks, the continued scandal of hospital-acquired infections, and our thoughtless use of antibiotics in animals.

What would a better world look like? First, we would know what we are seeing and doing, not just sort of, in a we-gave-it-a-name kind of way, but in a mechanistic, engineering sense. Second, we would have technology to truly address the many defects that can arise out of our systems, at those causal points, rather than farther down the line. Wouldn't it be better to re-instruct cancer cells to become normal again, rather than killing them and all their more or less distant relations? The second goal is far more difficult than the first, but depends entirely on the first being fulfilled.

Molecular medicine (some call it "precision medicine") will be the way to address these issues, and has four elements. First, everyone's genome will be sequenced as a matter of course and be a core part of the personal medical record. Then, wayward growths, infections, fluids, and other samples will be not just subject to the ever more advanced lab tests for metabolic and histologic evaluation, (second element), but will also be sequenced and compared with that genome reference sequence (third element) to nail down molecular alterations that lie at the root of many diseases.

But what would these sequences tell us? However advanced and cheap the sequencing technology, it does no good without knowledge behind it- the biological models of which gene does what, what pathway causes which disease, which mutation causes what effect. That is the fourth and most important element. The war on cancer was only a down-payment on this knowledge, funding the profusion of molecular biology scholarship and technique that has blossomed since the discovery of the structure of DNA in 1953. Unlike the two sequencing elements, which have discernable end-points in terms of creating complete, inexpensive sequences from our DNA samples, this third is essentially open-ended and ever-developing. It may take another hundred years to work out in a full engineering sense this (alien) technology that is human biology.

All this came to mind when reading a recent paper on the properties of one human mutation. A gene called HOXB13 is about 4,000 nucleotides long and encodes a protein that is 277 amino acids long. If you knock out its function completely, the organism is dead ... the protein is essential for early development. (Mice were used to find this out, thankfully.) But less severe defects, like, say, the mutation of deoxycytidine (C) 407 to deoxyguanosine (G), which causes the encoded protein to change at position 84 from glycine (G) to glutamate (E), have far more subtle effects, which require population studies, statistics, and much else to figure out.

Such studies say that the mutation raises the holder's chances of developing cancer, about five-fold in the case of prostate cancer. The authors give a chart of some of the other cancers that have been studied:

Effect of the position 84 mutation of HOXB13 on various cancers. The frequency in column 4, which is the rate of finding this mutation in those who have cancer, can be compared to a general population frequency of this mutation of about 0.45% The higher frequencies generate Odds ratios > 1 which denote a positive association between the mutation and the cancer, and the p-value estimates from the sample sizes how significant this odds ratio, or correlation, is (lower is better). For prostate cancer, not listed, the odds ration is about 4.5, with very well-attested significance.

The odds ratio is perhaps the most easily interpretable statistic, being the odds of some effect, given the hypothesized cause. It is a simple ratio of the rate of the effect in the "with" population over the "without" population. A value of 1 means that there is no connection, and higher values mean that there is a positive correlation. Here, the odds ratio of 3.3 for kidney cancer claims that having the mutation raises the odds of this cancer. For prostate cancer, the odds ratio is 4.51. The P-value is a helpful associated statistic, which tells you how much confidence to place in the odds ratio, since a small population in the study, for instance, may create a very skewed odds ratio, with little significance. The lower the P-value, the greater the significance. So when we get down to oral cancer and leukemia, the association with this mutation is negligable in all respects.

The mutation is very rare, occurring about 0.3% in European populations, and most prevalent in Northwestern European / Russian populations. The rarity is doubtless because of its bad effects, killing its bearers at significantly higher rates than the norm. But it may have other, conceivably beneficial effects- so much is not known. This gene is part of the extremely interesting HOX group that are transcription activators that help the body interpret where its parts are, and activate organ growth during development. This one is strongly turned on in the embryonic tail and urogenital system, including the prostate.

Expression locations of HOXB13 in the embryonic mouse.  UGS = urogenital system. HG =  hindgut.

So, why isn't there a definitive effect? Why are only risks increased, and all these statistics deployed? What could we do to gain a more accurate prognosis? It is likely that if the other three billion nucleotides in our genomes are put through a similar analysis, covering each of their four possible alleles(!), we could gain much better predictive value for each person's genome as a whole. The present statistics were gathered over a population that is essentially random with respect to every position other than this single one, and it may well be that this cancer-promoting effect arises from the interaction between several more or less rare mutations, or at least from biological settings that are more specific than just a random sample, either in genetic terms or other environmental respects. Drug development and treatment is heading in this direction, focusing on specific genotypes that have the most to gain from a particular drug, even if in a totally random population with the disease at issue, that drug may have little discernible positive effect.

But additionally, knowledge doesn't obviate stochasticity / randomness, which is unavoidable in biology as it is in any other complex process. Cancers arise from environmental insults, chemical accidents, and behaviors as much as from innate genetics. In future medicine, the presence and effects of our living conditions would be visible by way of thorough biological testing, taking the typical blood or urine test to a new level of insight to assess what the immune system has seen, for instance, whether nascent cancers have released a few cells, or what subtle imbalances the metabolic system is dealing with; even what you had to eat for lunch.

Once, say, a cancer is detected, (in a very early stage, given a far more sensitive fluid and tissue testing system), the knowledge that a patient has mutations like the one above would inform treatment, which could be assembled from a shelf full of gene-specific medicines that shut off or turn on each encoded protein respectively, as the data indicate, or even create novel activities. We may someday even be able to re-program the DNA of our cells, directly correcting this and the dozens of other mutations that will have conspired to form that particular cancer.

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Men, Booze, and Cigarettes: The Autobiography of Lauren Bacall

One of the great memoirs, about the loves and wisdom of a dramatic life.

You wouldn't expect an outstanding memoir from a Hollywood starlet who took the nation by storm (giving it "the look"), snatched Humphrey Bogart from his third wife, and went on to an outstanding, if patchy, career in film and theater. But there it is. Bacall (originally Betty Bacal) was raised in very modest circumstances, in a solid New York (Bronx) Jewish familiy, but with the significant void of a father who left (was thrown out, really) very early in her life, between five and eight years old. Just old enough to remember him, but not old enough to understand why. She spent much of her life looking for father figures, with mixed success.

Bacall writes with incredible immediacy. Her heart is right there on the page, as she is smitten with movie stars in her childhood, has a gushing personal encounter with the surprisingly kind Betty White, and pursues acting relentlessly in her teens. But money is very tight, and she has to do modelling on the side. The big break comes with a cover in Harper's Bazaar, under the genius Diana Vreeland.

This cover led to several offers from far-off Hollywood, and just like that, Bacall was on the train and in the expert hands of Howard Hawkes. He was understandably pleased with what he saw, and cast Bacall in her first film, To Have and Have Not. Not only did Bacall turn out to have the looks, she also had the voice, the humor, and the acting skill to rise to the occasion (singing would always be a problem, though). While Bacall was in quite a different place when she wrote all this in the mid-seventies, she is obviously reliving this special time with acute memory and a unique dramatic sense, as she was smitten by co-star Humphrey Bogart who was, yes, old enough to be her father.

It turns out to be one of the love affairs of the century. Bogart was not just a character, but truly had character. They treated each other with great respect, and she describes a largely idylic life. He was a bit of a drinker when they met, having been beaten down by several bad marriages, especially his third, but drinks less as time goes on, now having children and his all-important sailboat to live for. Bacall's highest praise, in retrospect after future failures in love, was that she was married to a mature man. Unlike all the others.

But like all biography, the story of Humphrey Bogart ends tragically in his mid-fifties, from cancer clearly brought on by drinking and smoking. Within a year he wastes away to practically nothing, and Bacall writes so movingly of his illness and death that it is heartbreaking to read. All else, certainly her career, took a back seat to her personal life, and her Hollywood career never fully recovered. She was anxious to get back to work after Bogie's death, but the industry, the town, seemed uninterested, perhaps pigeonholing her as the wife, rather than the actor she was also. While it was frustrating for her to be out of work for long stretches, (eventually she made a new life on Broadway), it is a great loss to the rest of us to not see more of her on film.

Bacall did a good deal of falling apart and rebounding after Bogie died. She ran around with Frank Sinatra for a while, until he pathetically backed out of a marriage proposal- truly one of the "rat pack". Then, esconced on Broadway, Bacall met and fell in love with Jason Robards. This time, she succeeded in dragging him to the altar, but lived to regret it as his drinking kept right on going. She remarks that the only thing she could count on was that he would be at the theater he was appearing at a half hour before show time. Bacall, who prided herself on her motivation, character, and life sense, found herself treated shabbily, utterly unmoored, with up to six children to take care of at times.

It took six years, but she finally threw him out and embraced a single life, with occasional film roles, but mostly working on Broadway. Katherine Hepburn was a great friend, and indeed a mentor in how to live singly, and how to brush off the constant stream of negativity from critics, missed roles, the press. Bacall worked extremely hard on Broadway, even in musicals, and won a Tony eventually. But the time lost to bad men, and the adoption of a single life, clearly caused rankling regret, after her idyl with the king, which is to say her time of having it all- a great marriage, children, stardom, and a great social life, with Humphrey Bogart.

The theme of father figures is one of the more interesting in this story. Bacall denies seeing any physical (vocal, name ... ) resemblance between Bogart and Robards(!) At least Robards was her age. Anyway, she pays explicit homage at one point to the most influential & positive male figures in her life- her uncle Charlie Weinstein, Bogart, and Adelai Stevenson, whom she campaigned for, flirted with, and who all but offered himself as a partner after Bogie's death. She clearly valued, even hungered for, this influence, which puts her in contrast to the current trend of gender neutrality and anti-patriarchial agitation.

But the father figure is among the deepest archetypes, one we have worshipped forever, name: "God". I think it is fair to say that we all seek father figures through life- as mentors, leaders, power-brokers and status confer-ers, stabilizers. While the patriarchial complex has amplified this archetype out of all proportion, it is biologically programmed and not to be denied. But who can possibly fulfill the role? Very few. And the first ingredient is ... training with another father figure. So the cultural round keeps going, generally in very flawed and even destructive and tragic ways, but so very valuable when it does go right. Many of the ancient epics and fairy tales put a strong black / white frame around this- the good king, ruling a happy land, contrasted with the bad king, beset with bad luck, misery, defeat. Not only the lives of great women, but of whole cultures, hang on the quality of this training, acting, and being.

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