Author Archives: luysii

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What can dogs tell us about cancer, and (wait for it) sexually transmitted disease

What can 546 dogs tell us about cancer, and STDs (sexually transmitted diseases)?  An enormous amount ! [ Science vol 365 pp. 440 – 441, 464 3aau9923 1 –> 7 ’19 ].  You may have heard about the transmissible tumor that has reduced the Tasmanian Devil population from its appearance in ’96 by 80%.  The animals bite each other transmitting the tumor.  Only 10 – 100 cells are transferred, but death occurs within a year.  The cells survive because Tasmanian devels have low genetic diversity.

The work concerns a much older transmissible tumor (Canine Transmissible Venereal Tumor — aka CTVT) which appeared in Asia an estimated 6,000 year ago, and began dispersing worldwide 2,000 years ago.   Unlike the Tasmanian devil tumor, the tumor is usually cleared by the immune system.

The Science paper has 80+ authors from all over the world, who sequenced the protein coding part of the dog genome (the exome) to a > 100fold depth.   The exome contains 43.6 megabases.   The tumor is transmitted by sex, and the authors note that this mode of transmission nearly requires a rather indolent clinical course, as the animal must survive long enough to transmit the organism again.  This fits with syphilis, AIDs, gonorrhea.  Contrast this with anthrax, cholera, plague which spread differently and kill much faster.

So what does CTVT tell us about cancer?   Quite a bit.  First some background.  The Cancer Genome Atlas (CGA) was criticized as being a boondoggle, but it at least gave us an idea of how many mutations are present in various cancers– around 100 in colon and breast cancers.

Viewed across all dogs, the CTVT genome is riddled with somatic mutations (as compared to the genome of the dog carrying the tumor) –148,030 single nucleotide variants (3.4/1000 !) 12,177 insertion/deletions.  Of the 20,000 dog genes only 2,000 didn’t contain a mutation.   This implies that most genes in the mammalian genome aren’t needed by the cancer cells.  The CTVTs also show no signs of the high rates of chromosomal instability seen in human tumors.

The work provides evidence that cancer isn’t inherently progressive.  This gives hope that some relatively indolent human cancers (say cancer of the prostate) can be controlled.  This calls for ‘adaptive therapy’  — something that limits tumor  growth rather than trying to kill every cancer cell with curative therapy which, if it fails, essentially selects for more aggressive cancer cells.

Some 14,412 genes have 1 mutation changing the amino acid sequence (nonSynonymous) and 5,704 have protein truncating mutations.  The ratio of synonymous to non synonymous mutations is about 3 implying that the mutations which have arisen haven’t been selected for (after all the triplet code for 20 amino acids and 1 stop codon has 64 possibilities), so the average amino acid has 3 codons for it.  This is called neutral genetic drift.

They also found 5 mutated genes present in all 541 tumors — these are the driver mutations, 3 are well known, MYC, PTEN, and retinoblastoma1.

Tons to think about here.  I’ll be away for a few weeks traveling and playing music, but this work should keep you busy thinking about its implications.




Book recommendation

Tired of reading books about physics?  Want the real McCoy”?  Well written and informal?  Contains stuff whose names you know but don’t understand — Jones Polynomial, Loop Quantum Gravity, Quantum field theory, Gauge groups and transformations —  etc. etc.

Up to date?  Well no, it’s 25 years old but still very much worth a read, so very unlike molecular biology, chemistry, computer science etc. etc.

Probably you should know as much physics and math as a beginning chemistry grad student. If you studied electromagnetism through Maxwell’s equations it would be a plus.  I stopped at Coulomb’s Law, and picked up enough to understand NMR.

This will give you a sample of the way it is written

“Much odder is that we are saying the vector field v is the linear combination of . .  partial derivatives.  What we are doing might be regarded as rather sloppy, since we are identifying two different although related things: the vector  field and the operator v^i * d-/dx^i which takes a directional derivative in the direction of v.”

“Now let us define vector fields on a manifold M. .. . these will be entities whose sole ambition in life is to differentiate functions”

The book is “Gauge FIelds, Knots and Gravity” by John Baez and Javier P. Muniain.

The writing, although clear has a certain humility.  “Unfortunately understanding these new ideas depends on a through mastery of quantum field theory, general relativity, geometry, topology and algebra.  Indeed, it is almost certain that nobody is sufficiently prepared to understand these ideas fully.”

I’m going to take it with me to the amateur chamber music festival.  As usual, at least 2 math full professors will be there to help me out.  Buy it and enjoy



Clark Gesner R. I. P.

Clark Gesner Princeton ’60 was an incredibly creative individual who wrote at least 2 shows for the Princeton Triangle Club, which includes Jimmie Stewart, Josh Logan, Jose Ferrer and Brooke Shields among its alumni.  When I was there, club traveled by railroad to NYC, Albany, Cleveland, Chicago, Cincinnati etc. over Christmas vacation.  Quite an experience for a 19 year old who’d never been west of Allentown.

Despite his talent, Clark’s  musical chops weren’t that good and as a piano player in the pit band accompanying the show, I could play his stuff better than he could. We were housed in the homes of alumni for the most part, and Clark after shows would sit at the piano and play his stuff.  The girls would gather around and say “Clark, you’re going to write a broadway show some day”.  Cynical me thought they’d been watching too movies.

Well he did, writing “You’re a Good Man Charlie Brown”, and never had to work past his late 20s.

Which raises several points.  The first is that amateur musicians usually agree who is better (not so much in terms of their chops, but in terms of their ‘musicality’ a term like jazz of which Louis Armstrong said –“If you have to ask what jazz is, you’ll never know.”  This unlike composers, visual artists etc. etc.  Even chemists.  Who was the greatest chemist of the 20th century — Woodward, Pauling?  You’d get an argument.

2 years at Triangle cured me of theater.  The stage performers  never really left the stage, acting most of the time in ways that said ‘look at me, look at me’.  It became tiresome after a while.

We had real pros helping us put the shows together — Director Milt Lyon, Choreographer Peter Hamilton.  They weren’t perfect and 60 years ago Milt was always saying that ‘the unions are killing the theater’.  Milt was always in the back during performances as we traveled, leading the cheers.  Another quote –‘audiences want to clap, you just have to help them’.

There were a lot of gays in Triangle, but they were the obvious ones, florid, histrionic, effeminate.   That was the image of the gay male in the late 50s, and today’s gays owe a huge debt to the normal appearing gays who came out in that era and later.  Clark was gay and kept it well hidden, and a lot more classmates have come out subsequently.

For some, there were excellent reasons to remain in the closet.  A psychiatrist classmate from med school knew of people being thrown out of psychiatry residencies because they were gay — look at the early DMSs when homosexuality was thought to be a psychiatric disease.


The cold dead hand of the academy and classical music (US division)

For how the higher music criticism nearly strangled classical music in the US look no further than Roger Sessions —  He was the eminence grise of the Princeton music department when I was an undergraduate

Purely by luck, I decided that music was one of the few things I knew something about (having had 8 years of piano lessons through High School) so I had nothing to do with the department.  So while Roger was saying things like “I’m a specialist writing for other specialists” and “The English Department doesn’t teach typing, why should the Music Department teach performance” — this according to someone from the class of ’75, I was hitchhiking down route 1 to NYC listening to Basie at Birdland, and other jazz musicians creating a new art form (Village Vanguard etc. etc.).   I was actually able to hire Coleman Hawkins to play for a dance at our Eating Club (Princeton’s version of fraternities).

So think of some music coming out of an academic music department from that era that you want to listen to.  Bartok doesn’t count.  He was supported with grants when he got here  in 1940, but was already a very well established composer.

For more on these points, see the previous post –

So jazz, rock, country and western musics will take care of themselves.  They exist independently of what is written about them.  There still is a problem for people like me.  I’m not creative enough to make my own music, but classical music being written down allows me to explore and experience the great musical minds of Bach, Mozart etc. etc.  I want more stuff written by today’s people that my friends and I can play.  The difference between listening to music and playing it, is the difference between you know what and sex.

Some thoughts on music

I’m leaving for what one of my friend’s grandsons calls “Band Camp for Adults”. Mercifully we usually all agree to allow the world to spin on its axis without our help, meaning we talk only about music leaving politics behind (thank God).

I’ve agreed to play the Brahms horn trio with an excellent violinist and an equally excellent french horn player.  It’s scary. Brahms must have had enormous hands, asking you to play an octave with your right hand while trilling with the fifth finger.  He must also have had a huge technique, asking you to jump about playing octaves with your left hand.  Adding to the anxiety, is that the other two have performed the piece despite the fact that we’re amateurs.  They want to perform it as well, something that gives me the yips (they’re both very good).

I asked one of last year’s coaches to note whether the hard headed scientific types (mathematicians, physicists, computer programmers) play any differently than the touchy feely types (who are scared of ‘chemicals’ etc. etc.) both invariantly present in about equal numbers among amateur chamber musicians.  I don’t think so, but we’ll see what she says.  Probably she forgot, chamber musicians having to be extremely precise  when they play, leading them to be sloppy about most other things.  We’ll see.

There are excellent faculty concerts most nights and hopefully they won’t have much ‘eat your spinach’ contemporary work on the program.  You all know what it is, contemporary music with no rhythm, melody or structure and usually hideous sound, that you are supposed to sit through because it’s good for you.  A few years ago, there was a concert with no intermission where they literally locked the doors and played an awful Elliot Carter string quartet.  It wasn’t announced on the program so we couldn’t bail.

Which brings me to another point.  People who say they like all music, really like none of it.  To really like music there must be music that you hate.  I hate Shastakovich (which is tough as a cellist I play with has cats named Shasti and Kovich), my cousin hates Ravel.

Which brings me to another point — how musical criticism has brought classical music low (see the bit about Adorno later).  Classic composers if they want to be played and heard have to bow to current elite critical opinion.  Fortunately this seems to be ending.  There are several people composing in the area whose music has melody, rhythm, structure, tonality and is good to listen to.

One is Zeke Hecker — — whose wife is an excellent violist that I played one of the Faure piano quartets with.  He’s written lots of stuff in classical form (symphonies etc. etc. ) which is musicly interesting.

Another is Scott Slapin — — and we recently went to a concert where he wrote some very interesting music for 4 violas.  He has a sense of humor and since he lives in South Hadley Massachusetts, he wrote a 12 minute piece for 4 violas called the South Hadley Mass.

Now to the dark side — an article in the New Yorker described how a critic, Theordor Adorno, singlehandedly nearly destroyed the magnificent German musical tradition —

Here’s a quote from the article — “Implicit in his assault on mass culture is the belief that any work of art that attracts large numbers of people has no value.”  So the music he champions certainly doesn’t attract hordes.

Here’s more.  “In 1949, it worked: “The Philosophy of New Music” wowed the confused young minds who were seeking new certitudes, new laws, new gods. Adorno, together with his comrade-in-arms Boulez, probably succeeded in frightening more than a few composers of the neoclassical type into thinking that their music was not just bad but criminal. It is instructive to look at the names of works that were played at Darmstadt from 1946 on. In the first few years, you see titles such as Sonatine, Suite for Piano, Chamber Symphony, Scherzo, and Concerto in E Flat. After 1949, the year of the “Philosophy,” neoclassical titles dwindle and are replaced by phrases fit for a “Star Trek” episode: “Music in Two Dimensions,” “Schipot,” “Polyphonie X,” “Syntaxis,” “Anepigraphe.” There was a fad for abstractions in the plural: “Perspectives,” “Structures,” “Quantities,” “Configurations,” “Interpolations.” Audiences enjoyed “Spectogram,” “Seismogramme,” “Audiogramme,” and “Sphenogramme.”

How did such an idiot gain such power?  It’s worth reading the whole article in the link (although it’s pretty depressing)

Well there is a human urge to listen, play and create music and it’s coming back. To hell with the higher musical criticism.

Schizophrenia research, the good news and the bad news

If you are an identical twin whose twin is schizophrenic, your chances of getting schizophrenia is 40%, if you are just a fraternal twin your chance is 15%, amazingly much higher than the 1% chance the rest of us  have, because that’s the incidence in the general population. For what schizophrenia is really like see the old post after the *** at the end

So to find out what causes schizophrenia, study the genes of schizophrenics and compare them to those without it.     [ Neuron vol. 103 pp. 203 – 216 ’19 ] First off —  the Psychiatric Genomics Consortium (PGC) has identified well over 100 (genomic loci) loci with a significant genome-wide association with risk for schizophrenia.  This means that unlike cystic fibrosis (where over 1,700 disease associated mutations have been found in the causative gene),and despite the genetics schizophrenia is not going to be due to one gene.

The good news is that serious money and attention to the genomes of schizophrenics is being paid.The paper reports the latest results from the horribly named BrainSeq.  This is a precompetitive initiative launched by the Liber Institute for Brain Development (LIBD) with heavy big pharma involvement (Eli Lilly, Johnson and Johnson, Hoffman-LaRoche, AstraZenica).    The LIBD has over 1,900 human  postmortem neuropsychiatric disease and control samples.   They are mapping all sorts of genetic information (DNA sequences, RNA sequencing, DNA epigenetics (cytosine methylation) etc. etc.)

The bad news is what this research is telling us.  The paper looked in differences in messenger RNA (mRNA) levels in two areas of the brain in 286 schizophrenics and 265 normal controls.  mRNA levels are a marker for gene expression, levels of the proteins coded for by the mRNA would be better, but is presently beyond our technology (when you are looking at the whole genome, as they were).

Well, out of our 20,000 or so protein coding genes, they found 48 differently expressed (by schizophrenics compared to normals) in one area (the hippocampus) and 245 in another (the dorsolateral prefrontal cortex).  That’s not a big deal, the two areas of the brain have rather different neurons and organization.

The bad news is there was almost no overlap between the 48 and the 245.  So although schizophrenics express their genome differently than normals, the expression varies in brain areas.  It would be great if there was some overlap, so then the genes differentiating schizophrenics from normal could be intensively studied.

The work also casts a shadow over a lot of earlier work, in which gene expression in schizophrenic brain was studied either in one area (or in ground up whole brain), and the results were assumed to be applicable to the brain as a whole.  They aren’t.  Back to the drawing board.


What is schizophrenia really like ?

The recent tragic death of John Nash and his wife warrants reposting the following written 11 October 2009

“I feel that writing to you there I am writing to the source of a ray of light from within a pit of semi-darkness. It is a strange place where you live, where administration is heaped upon administration, and all tremble with fear or abhorrence (in spite of pious phrases) at symptoms of actual non-local thinking. Up the river, slightly better, but still very strange in a certain area with which we are both familiar. And yet, to see this strangeness, the viewer must be strange.”

“I observed the local Romans show a considerable interest in getting into telephone booths and talking on the telephone and one of their favorite words was pronto. So it’s like ping-pong, pinging back again the bell pinged to me.”

Could you paraphrase this? Neither can I, and when, as a neurologist I had occasion to see schizophrenics, the only way to capture their speech was to transcribe it verbatim. It can’t be paraphrased, because it makes no sense, even though it’s reasonably gramatical.

What is a neurologist doing seeing schizophrenics? That’s for shrinks isn’t it? Sometimes in the early stages, the symptoms suggest something neurological. Epilepsy for example. One lady with funny spells was sent to me with her husband. Family history is important in just about all neurological disorders, particularly epilepsy. I asked if anyone in her family had epilepsy. She thought her nephew might have it. Her husband looked puzzled and asked her why. She said she thought so because they had the same birthday.

It’s time for a little history. The board which certifies neurologists, is called the American Board of Psychiatry and Neurology. This is not an accident as the two fields are joined at the hip. Freud himself started out as a neurologist, wrote papers on cerebral palsy, and studied with a great neurologist of the time, Charcot at la Salpetriere in Paris. 6 months of my 3 year residency were spent in Psychiatry, just as psychiatrists spend time learning neurology (and are tested on it when they take their Boards).

Once a month, a psychiatrist friend and I would go to lunch, discussing cases that were neither psychiatric nor neurologic but a mixture of both. We never lacked for new material.

Mental illness is scary as hell. Society deals with it the same way that kids deal with their fears, by romanticizing it, making it somehow more human and less horrible in the process. My kids were always talking about good monsters and bad monsters when they were little. Look at Sesame street. There are some fairly horrible looking characters on it which turn out actually to be pretty nice. Adults have books like “One flew over the Cuckoo’s nest” etc. etc.

The first quote above is from a letter John Nash wrote to Norbert Weiner in 1959. All this, and much much more, can be found in “A Beatiful Mind” by Sylvia Nasar. It is absolutely the best description of schizophrenia I’ve ever come across. No, I haven’t seen the movie, but there’s no way it can be more accurate than the book.

Unfortunately, the book is about a mathematician, which immediately turns off 95% of the populace. But that is exactly its strength. Nash became ill much later than most schizophrenics — around 30 when he had already done great work. So people saved what he wrote, and could describe what went on decades later. Even better, the mathematicians had no theoretical axe to grind (Freudian or otherwise). So there’s no ego, id, superego or penis envy in the book, just page after page of description from well over 100 people interviewed for the book, who just talked about what they saw. The description of Nash at his sickest covers 120 pages or so in the middle of the book. It’s extremely depressing reading, but you’ll never find a better description of what schizophrenia is actually like — e.g. (p. 242) She recalled that “he kept shifting from station to station. We thought he was just being pesky. But he thought that they were broadcasting messages to him. The things he did were mad, but we didn’t really know it.”

Because of his previous mathematical achievments, people saved what he wrote — the second quote above being from a letter written in 1971 and kept by the recipient for decades, the first quote from a letter written in 12 years before that.

There are a few heartening aspects of the book. His wife Alicia is a true saint, and stood by him and tried to help as best she could. The mathematicians also come off very well, in their attempts to shelter him and to get him treatment (they even took up a collection for this at one point).

I was also very pleased to see rather sympathetic portraits of the docs who took care of him. No 20/20 hindsight is to be found. They are described as doing the best for him that they could given the limited knowledge (and therapies) of the time. This is the way medicine has been and always will be practiced — we never really know enough about the diseases we’re treating, and the therapies are almost never optimal. We just try to do our best with what we know and what we have.

I actually ran into Nash shortly after the book came out. The Princeton University Store had a fabulous collection of math books back then — several hundred at least, most of them over $50, so it was a great place to browse, which I did whenever I was in the area. Afterwards, I stopped in a coffee shop in Nassau Square and there he was, carrying a large disheveled bunch of papers with what appeared to be scribbling on them. I couldn’t bring myself to speak to him. He had the eyes of a hunted animal.

Antioxidants — the dark side

There was (and probably still is) quite a vogue for antioxidants.  They were supposed to counteract aging, vascular disease, and prevent cancer.  So much so that 25 years ago, they were given in a trial to prevent lung cancer.  It didn’t work.  Here are the gory details

[ New England J. Med. vol. 330 pp. 1029 – 1035 ’94 ] The Alpha-Tocopherol, Beta-Carotene Trial (ATBC trial)  randomized double blind placebo controlled of daily supplementation with alpha-tocopherol (a form of vitamin E), beta carotene or both to see if it reduced the incidence of lung cancer was done in 29000 Finnish male smokers ages 50 – 69 (when most of the damage had been done).  They received either alpha tocopherol 50 mg/day, beta carotene 20 mg/day or both.   There was a high incidence of lung cancer (876/29000) during the 5 – 8 year period of followup.  Alpha tocopherol didn’t decrease the incidence of lung cancer, and there was a higher incidence among the men receiving beta carotene (by 18%).    Alpha tocopherol had no benefit on mortality (although there were more deaths from hemorrhagic stroke among the men receiving the supplement).   Total mortality was 8% higher among the participants on beta carotene (more deaths from lung cancer and ischemic heart disease).  It is unlikely that the dose was too low, since it was much higher than the estimated intake thought to be protective in the uncontrolled dietaryt studies.   The trial organizers were so baffled by the results that they even wondered whether the beta-carotene pills used in the study had become contaminated with some known carcinogen during the manufacturing process.  However, tests have ruled out that possibility.

Needless to say investigators in other beta carotene clinical trials (the Women’s Health Study, the Carotene and Retinoid Efficacy Trial) are upset.  [ Science vol. 264 pp. 501 – 502 ’94 ]  “In our heart of hearts, we don’t believe [ beta carotene is ] toxic”  says one researcher.

This is not science.

On to the present [ Cell vol. 178 pp. 265 – 267, 316 – 329, 330 – 345 ’19 ] in which the following appears “Recent evidence ‘suggests’ that antioxidants can also promote tumor formation”

The work concerns an animal model of nonsmallcell lung cancer (NSCLC).  I’m always wary of animal models, as they have been so useless in pointing to a useful therapy for stroke.  But the model is worth studying as it provides a mechanism by which antioxidants promote metastases of the primary tumor.  It is also worth studying because it shows the fiendish complexity of cellular biochemistry and physiology.

The only way you can appreciate complexity is by being buried in details. So let’s begin.  The actual details aren’t that important, just the number and the intricacy of them.

30% of humans with NSCLC have mutations in two genes (NFEL2L2, KEAP1).  The mutation in NFEL2L2 produces mutated NRF2 (a transcriptional activator of the antioxidant response gene set). The mutation doesn’t inactivate NRF2, but leaves it in a hyperactivated state.  KEAP1 normally inactivates NRF2, but not the mutated forms found in NSCLC.

One gene turned on by activated NRF2 is HO1 (heme oxidase).  During oxidative stress heme is released from heme containing resulting elevated intracellular heme lever resulting in the creation of free radicals which are inherently oxidative.  HO1 destroys heme. So this is one mechanisms of NRF2’s antioxidative activity.

Heme isn’t all bad, as it destabilizes BACH1 (not the composer)which is a prometastatic transcription factor.  Antioxidants (N-acetyl-cysteine, tocopherol [ vitamin E to you ] reduce heme levels stabilizing BACH1 (hence promoting metastasis).  Genes activated by BACH1 include glycolytic enzymes (hexokinase2, GAPDH).  So what?  Cancer cells use a lot of glycolytic enzymes even when oxygen is available — this is called aerobic glycolysis.  This is the Warburg effect.

I’m sure there’s far more to discover, but this should be enough to convince you that things are pretty complicated inside us.

The wages of inbreeding

Saguenay Lac St. Jean is a beautiful region of Quebec. It’s fairly isolated. Once you get to the top of the lake there is no way that you can drive farther north (no road).  We spent part of our 25th anniversary there.  The population bears a heavy load of genetic disease (through no fault of their own).

The reason is historical. Only 8,000 people emigrated from France to Quebec between 1608 and 1763. After the English victory that year  only 1,000 emigrated in the next 90 years.  In 1992, the population of the Saguenay  region was around 300,000 and Quebec itself 2,000,000.

This means that once the population began expanding with relatively little outside input, recessive genes began to meet each other, as in a large population there are so many more ways to make this happen than in a small one.

To keep the the nonBiologists reading this aboard, here is what recessive means. Our genome has 46 chromosomes.  We all have two sex chromosomes (either X and Y or X and X).  The other 44 chromosomes come in pairs.  This gives you two copies of each gene.  The classic recessive gene is that for sickle cell anemia.  If just one of the pair has the Sickle trait you are OK, if both have it, you have sickle cell anemia (which you definitely don’t want to have).  Actually if you live in Africa it is better if you have one gene with the trait as it makes you more resistant to Malaria.  This is why the trait became so common in Africans.  It’s natural selection in action (and in a human population to boot).  Just one good sickle gene (not carrying the trait) is enough to mask the effects of the bad gene, so the carrier is normal.   This is why sickle cell trait is called a recessive gene.

Here is one example.  The incidence of a muscle disease (myotonic dystrophy) worldwide is 2 – 14/100,000.  In the Saguenay region it is 189/100,000.

Even 20 years ago, the carrier frequency of many genetic disorders up there was quite high [ Proc. Natl. Acad. Sci. vol. 95 pp. 15140 – 15144 ’98 ]

Spastic ataxia 1/21

Type I tyrosinemia 1/22

Sensorimotor polyneuropathy 1/23

Pseudovitamin D deficient rickets 1/26

Cytochrome C oxidase deficiency 1/26

Cystinosis 1/39

Histidase 1/32

Lipoprotein lipase 1/43

Pyruvic kinase 1/64

Then again, there are all sorts of genetic diseases found only in this region.

Similar conditions may apply to the ancestors of today’s native Americans — for details see the previous post —  Incredible as it may sound, the rape and pillage of the conquistadores may have actually been good from a genetic point of view.  Similar considerations may apply to any pair of populations meeting each other for the first time.  Hard stuff indeed, but you can’t repeal biology.

So, from a genetic point of view, it’s good if you reproduce with someone from a different group.  It’s why I’m glad to have a Chinese daughter in law, 2 grand-nephews whose father is Hindu, and a Russian woman about to marry our nephew.



The initial native Americans were quite inbred

From Science vol. 365 pp. 138, eaat 5447 pp.  1 —> 9 ’19  12 July ‘19

“Genetic studies of contemporary Indigenous people and ancient individuals from Asia and the Americas reveal an outline of the ancestry of the first humans to settle the Americas, providing age estimates for the timing of population contact, divergence, and migration. Studies of contemporary mitochondrial DNA (mtDNA) and Y-chromosome DNA lineages gave the first genetic insights into Indigenous American population history (6). These studies demonstrated that the ancestors of all contemporary Indigenous people had descended from only five maternal lineages (haplogroups A, B, C, D, and X) and two paternal lineages (haplogroups C and Q). These lineages also showed that the founding population came from Asia and experienced a severe genetic bottleneck, in which a small number of people with limited genetic diversity gave rise to all Indigenous people who occupied the continent before European arrival.”

Interesting that the authors of the papers discussed below didn’t know this (or weren’t telling) when I wrote them last December asking if there was limited genetic diversity in the ancestors of today’s native Americans (or Indians as they called themselves when we lived in Montana in the 70s and 80s).


Usually when I eMail the author(s) of a paper or a math book with a question or a comment I get a quick response.  My cynical wife says thing this is because mathematicians don’t have much to do.  Not so in this case. Hence the hopefully attention getting title of this post.

I refer to the following papers [ Cell vol. 175 pp. 1173 – 1174, 1185 – 1197 ’18 ]  Nature vol. 563 pp. 303 – 304 ’18,Science vol. 362 pp. 1128 eaav2621  1 –> 11 ’18 ] I’ve sent a bunch letters to the authors and have heard nothing back in a week.

So what is all this about?  It’s about population bottlenecks and founder effects in the ancestors of what are now called ‘native Americans’ — although while living in Montana from ’72 – ’87, if you called an Indian, a Native American, you would have received some strange looks.

I am not a population geneticist, so I wonder just how many people made it over the Bering land bridge during the last ice age, and just how genetically diverse they were.  Northern Siberia today is a rather forbidding place, and I doubt that hordes of genetically different people lived here.  I’m not sure how long the land bridge was open and how many people crossed it.

So modern native Americans may be quite genetically homogeneous.  How to tell?  This is where the papers come in.  They sequenced genomes from a variety of locations in the western hemisphere, all dying over a thousand years ago (before the Europeans came and interbred with them).  It seems that they have around 100 such genomes.

I wrote to ask how similar these genomes are.  No response.  Is it because the answer might be politically incorrect?

I don’t think the question is idiotic.  Possibly we don’t have enough genomes to make a sensible statement, but if they’re all really close (however defined) we could say something.

Anybody out there have any thoughts (or even better)  knowledge about these matters?

Happy 4th of July to the world’s second worst economist — Larry Summers

Any scientist who made such massively incorrect explanations and predictions would be laughed out of town. Not so, one of the ‘smartest guys in the room’ and former Harvard President Larry Summers.

Here’s Larry in December 2013 coming up with ‘secular stagnation’ to explain why the recovery from recession was one of the weakest and slowest on record and why this was the way things would be, and we’d better get used to it.

Here’s the link —

Here’s a direct quote from the beginning of the article

” Is it possible that the US and other major global economies might not return to full employment and strong growth without the help of unconventional policy support? I raised that notion – the old idea of “secular stagnation” – recently in a talk hosted by the International Monetary Fund.

My concern rests on a number of considerations. First, even though financial repair had largely taken place four years ago, recovery has only kept up with population growth and normal productivity growth in the US, and has been worse elsewhere in the industrial world.

Second, manifestly unsustainable bubbles and loosening of credit standards during the middle of the past decade, along with very easy money, were sufficient to drive only moderate economic growth.

Third, short-term interest rates are severely constrained by the zero lower bound: real rates may not be able to fall far enough to spur enough investment to lead to full employment.

Fourth, in such situations falling wages and prices or lower-than-expected are likely to worsen performance by encouraging consumers and investors to delay spending, and to redistribute income and wealth from high-spending debtors to low-spending creditors.”

There’s more but (mercifully) this is enough to give you the gist.

Then we have Larry from May 2017 — here’s the link

What history tells us about Trump’s budget fantasy

Here’s Larry talking about the Trump claim of 3% economic growth “The Trump economic team has not engaged in serious analysis or been in dialogue with those who are capable of it so they have had nothing to say in defense of their forecast except extravagant claims for their policies. Taking their supply-side perspective, do they really believe that through tax cuts and deregulation they are going to accomplish more than Ronald Reagan, who after all reduced the top tax rate from 70 to 28 percent? Between 1981 and 1988, GDP per adult grew by an average of 2.5 percent, distinctly slower than what they are forecasting. Even this figure reflects a substantial cyclical tail wind from the decline in unemployment from 7.6 percent to 5.5 percent (which from Okun’s law implies adding about half a percent to GDP growth) — something unavailable in the present context.”

Now follow the following link to the actual numbers —

At the time Larry was writing in 2nd quarter of 2017, economic growth that quarter would hit 3% right under his nose.

Of the 8 quarters from then through the 1st quarter of 2019 (2nd quarter results not in yet), economic growth was 3% or greater in half, and always over 2.5 in the other half.

OK back to the science in subsequent posts.

For the world’s worst economist  — see