Precision Embryo Genotyping and CRISPR Chromosome Deletions (Genomic Prediction)

This recent Cell paper received a lot of attention as it suggests that CRISPR editing can result in chromosome loss. It was cited in the recent National Academies report Heritable Human Genome Editing (2020) as an example of unexpected consequences / side-effects from CRISPR.

Allele-Specific Chromosome Removal after Cas9 Cleavage in Human Embryos 

https://doi.org/10.1016/j.cell.2020.10.025  

Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos. 

BioRxiv preprint 

My Genomic Prediction colleagues Jia Xu, Diego Marin, and Nathan Treff are co-authors of the paper. GP's precision embryo genotyping capabilities were necessary to determine that a paternal chromosome is sometimes deleted in the embryo due to CRISPR. In GP's standard embryo testing process both parents are genotyped as well as the embryo. The parental genotypes are used to error correct the embryo genotype: DNA amplification starting from just a few biopsied cells introduces noise, but it can be removed. GP can determine whether specific alleles from a parent are present in the embryo. Detection of the deletion of an entire chunk of chromosome would be fairly straightforward.

WIRED: In Embryos, Crispr Can Cut Out Whole Chromosomes—That's Bad

Othram helps solve cold case: killer of Siobhan McGuinness (age 5) identified after 46 years

Othram, a DNA forensics company I co-founded, has helped to solve another cold case. 

Montana Girl, 5, Was Abducted Near Home and Found Dead in Drain — and Killer ID'd 46 Years Later 

For 46 years, the family of Siobhan McGuinness waited to find out who killed the spunky 5-year-old back in 1974 

On a frigid February afternoon in 1974, Siobhan McGuinness was walking the short distance home from a friend’s house in Missoula, Montana, when she vanished. Two days later, the 5-year-old’s body was found in a snow-covered drain culvert near the exit for Turah on I-90, just outside the city limits. She had been sexually assaulted. She also sustained trauma to her head and stab wounds to her chest, according to the FBI. 

Detectives at the time searched tirelessly for the little girl’s killer, but came up empty. The case went cold for decades. 

On Monday, authorities announced that after 46 years, the Missoula County Sheriff’s Office Cold Case Squad, detectives from the Missoula Police Department and others had finally identified the man who took the life of the spunky child who was always smiling. Richard William Davis was 32 when he was traveling through the area at the time of Siobhan’s murder, Missoula Police Chief Jason White said at a press conference on Monday. ... 

Using DNA left behind at the crime scene, specialists at private technology company Othram Inc. were able to create a genealogical profile of the suspect, which led them to Davis, the company says in a press release.

See Othram: the future of DNA forensics

The existing FBI standard (CODIS) for DNA identification uses only 20 markers (STRs -- previously only 13 loci were used!). By contrast, genome wide sequencing can reliably call millions of genetic variants. 

For the first time, the cost curves for these two methods have crossed: modern sequencing costs no more than extracting CODIS markers using the now ~30 year old technology. 

What can you do with millions of genetic markers? 

1. Determine relatedness of two individuals with high precision. This allows detectives to immediately identify a relative (ranging from distant cousin to sibling or parent) of the source of the DNA sample, simply by scanning through large DNA databases. ...

If you have contacts in law enforcement, please alert them to the potential of this new technology.

David Goldman (Spengler): China's Plan to Sino-Form the World

The latest from the always entertaining David Goldman, who writes (wrote?) the Spengler column at Asia Times.

 

See 2018 post David Goldman: Will China overtake the U.S. as the world's leading superpower? 

In the lecture below, Goldman summarizes the main themes of his new book You Will Be Assimilated: China’s Plan to Sino-Form the World.

 

In this next interview (on the China-Iran deal of summer 2020) Goldman drops his guard a bit and waxes poetic with anti-Chinese rhetoric, as he discusses Israel, Iran, and China.

He refers to the Chinese (speaking broadly) as philo-semitic, but then jokes that this means anti-semites who like jews! In light of that remark I wonder how one should characterize Goldman's views on China and the Chinese: philo-sinic or just plain anti-Chinese?

Composite Polygenic Risk Score predicts longevity

The paper below (senior author at Johns Hopkins University) builds a composite polygenic risk score for mortality (longevity). Outliers (top vs bottom 5%) differ by about 5 years in life expectancy. 

I expect longevity prediction to improve considerably with more and better data to analyze. See also Live Long and Prosper: Genetic Architecture of Complex Traits and Disease Risk Predictors:

We found that genetic risks are largely uncorrelated for different conditions. This suggests that there can exist individuals with, e.g., low risk simultaneously in each of multiple conditions, for essentially any combination of conditions. There is no trade-off required between different disease risks ... One could speculate that a lucky individual with exceptionally low risk across multiple conditions might have an unusually long life expectancy.

If I read the graph below correctly, in their late 70s a positive outlier (male) has ~90% chance of surviving (not sure of timescale, might be next few years? See comments), whereas for a negative outlier the odds are only ~75%.

Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality 

Allison Meisner, Prosenjit Kundu, Yan Dora Zhang, Lauren V. Lan, Sungwon Kim, Disha Ghandwani, Parichoy Pal Choudhury, Sonja I. Berndt, Neal D. Freedman, Montserrat Garcia-Closas, Nilanjan Chatterjee 

doi: https://doi.org/10.1101/2020.03.13.20035527 

The American Journal of Human Genetics doi: 10.1016/j.ajhg.2020.07.002 

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry. The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.

Replications of Height Genomic Prediction: Harvard, Stanford, 23andMe

These are two replications of our 2017 height prediction results (also recently validated using sibling data) that I neglected to blog about previously.

1. Senior author Liang is in Epidemiology and Biostatistics at Harvard.

Efficient cross-trait penalized regression increases prediction accuracy in large cohorts using secondary phenotypes 

Wonil Chung, Jun Chen, Constance Turman, Sara Lindstrom, Zhaozhong Zhu, Po-Ru Loh, Peter Kraft and Liming Liang 

Nature Communications volume 10, Article number: 569 (2019) 

We introduce cross-trait penalized regression (CTPR), a powerful and practical approach for multi-trait polygenic risk prediction in large cohorts. Specifically, we propose a novel cross-trait penalty function with the Lasso and the minimax concave penalty (MCP) to incorporate the shared genetic effects across multiple traits for large-sample GWAS data. Our approach extracts information from the secondary traits that is beneficial for predicting the primary trait based on individual-level genotypes and/or summary statistics. Our novel implementation of a parallel computing algorithm makes it feasible to apply our method to biobank-scale GWAS data. We illustrate our method using large-scale GWAS data (~1M SNPs) from the UK Biobank (N = 456,837). We show that our multi-trait method outperforms the recently proposed multi-trait analysis of GWAS (MTAG) for predictive performance. The prediction accuracy for height by the aid of BMI improves from R2 = 35.8% (MTAG) to 42.5% (MCP + CTPR) or 42.8% (Lasso + CTPR) with UK Biobank data.

2. This is a 2019 Stanford paper. Tibshirani and Hastie are famous researchers in statistics and machine learning. Figure is from their paper.

A Fast and Flexible Algorithm for Solving the Lasso in Large-scale and Ultrahigh-dimensional Problems 

Junyang Qian, Wenfei Du, Yosuke Tanigawa, Matthew Aguirre, Robert Tibshirani, Manuel A. Rivas, Trevor Hastie 

1Department of Statistics, Stanford University 2Department of Biomedical Data Science, Stanford University 

Since its first proposal in statistics (Tibshirani, 1996), the lasso has been an effective method for simultaneous variable selection and estimation. A number of packages have been developed to solve the lasso efficiently. However as large datasets become more prevalent, many algorithms are constrained by efficiency or memory bounds. In this paper, we propose a meta algorithm batch screening iterative lasso (BASIL) that can take advantage of any existing lasso solver and build a scalable lasso solution for large datasets. We also introduce snpnet, an R package that implements the proposed algorithm on top of glmnet (Friedman et al., 2010a) for large-scale single nucleotide polymorphism (SNP) datasets that are widely studied in genetics. We demonstrate results on a large genotype-phenotype dataset from the UK Biobank, where we achieve state-of-the-art heritability estimation on quantitative and qualitative traits including height, body mass index, asthma and high cholesterol.

The very first validation I heard about was soon after we posted our paper (2018 IIRC): I visited 23andMe to give a talk about genomic prediction and one of the PhD researchers there said that they had reproduced our results, presumably using their own data. At a meeting later in the day, one of the VPs from the business side who had missed my talk in the morning was shocked when I mentioned few cm accuracy for height. He turned to one of the 23andMe scientists in the room and exclaimed 

I thought WE were the best in the world at this stuff!?

Down the Rabbit Hole: Mark Lane, the Zapruder film, and the JFK Conspiracy

Putting these here for future reference. From comments:

At minimum the evidence is strong for a CIA JFK coverup -- see last video, for example. It doesn't mean they did it, ofc. Johnson pressured Warren to lead the commission with the argument that if the public became convinced the Soviets/Cubans were behind it WW3 would result. This could have affected CIA actions post-Dallas as well. But I suspect something more sinister on the part of certain elements of CIA, and there is tons of evidence to that effect leaking out over the years. 

I enjoy listening to Mark Lane speak even if he turns out to be incorrect in some or many of his allegations. I think he destroys Buckley in their debate: Lane the Rationalist and Buckley a good example of motivated or biased reasoning. 

I've followed Spygate for 4 years now, with the media covering it up and FBI/CIA refusing to produce documents, Barr probably acting to protect the institutions, FISA court obviously corrupt, etc. The JFK matter has a very familiar feel to it. [ Should add the Epstein matter, which unfolded in plain sight over 20y, as another example. ]

Mark Lane, at the peak of his powers, discusses the Warren Commission report with William F. Buckley (1966):

   

 Mark Lane, near the end of his life:

    

Astonishing 2014 claims about the Zapruder film in CIA hands in the days after Dallas: the creation of two different briefing boards, one seen by CIA director John McCone, the other given to the Warren Commission. The interview is remarkable.

 

Horne and Brugioni strike me as very credible. CIA NPIC's main activity was interpreting U2 spy plane photographs, and had some of the most advanced photographic technology of the era. They were a logical choice to have a first look at the Zapruder film, but Brugioni did not learn until decades later that the CIA modified the film (removing certain frames, esp. near #313 which shows Kennedy's head exploding) and only gave a full briefing to McCone while witholding information from the Warren Commission. 

While serving as chief analyst of military records at the Assassination Records Review Board in 1997, Douglas Horne discovered that the Zapruder Film was examined by the CIA's National Photographic Interpretation Center two days after the assassination of President Kennedy. 

In this film, Horne interviews legendary NPIC photo interpreter Dino Brugioni, who speaks for the first time about another NPIC examination of the film the day after the assassination. Brugioni didn't know about the second examination and believes the Zapruder Film in the archives today is not the film he saw the day after the assassination.

Bonus: Interview with son of E. Howard Hunt (CIA, convicted Watergate Plumber), including audio of Hunt's confession. Note link to Cord Meyer, also see Mary Meyer 1964 execution in Georgetown...

Rolling Stone article (2007).

James Jesus Angleton -- "A Wilderness of Mirrors"

Note Added in response to a question in the comments:

I suggest you invest an hour or two in 

1. Brugioni interview: establishes that a conspiracy at the highest level of CIA to alter the film evidence was in place within ~24h of the shooting. Hard to explain unless there was very strong motivation already... bureaucracies usually can't react that fast when *surprised* by events. 

2. Interview with Hunt's son, concerning his deathbed confession of being aware of (and playing a minor role in) the assassination conspiracy. Hunt is a well-known CIA figure who was involved in lots of covert ops including Watergate. You don't have to accept this as fully credible of course, but you can't say that conspiracy didn't happen because otherwise information would have leaked out. It may very well have leaked out! But few pay attention because of the groupthink against "conspiracy theory" (this term was literally invented and promulgated by CIA to discourage public attention to what it was doing during the Cold War).   

I would say I am very confident of an active cover up post assasination, less confident of a CIA role in the killing. 

Other facts that have leaked out (now confirmed by official documents and the official CIA historian) include the fact that CIA was very closely monitoring Oswald starting in 1959 and that his file was closely held by none other than CIA prince of darkness James Jesus Angleton. Now look into the unsolved killing of Angleton's friend Mary Meyer (who was having an affair with JFK when he was shot) in 1964 and you are off to the races... Their common friend Ben Bradlee (WaPo editor of Watergate fame) wrote in his memoirs of catching Angleton, having broken into Meyer's house, with her diary... 

BTW, over the years it was wrongly reported that RFK did NOT believe in a conspiracy against his brother. The evidence is pretty convincing now that he always believed in a conspiracy but didn't admit it in public.

Election 2020: quant analysis of new party registrations vs actual votes

I think we should ascribe very high uncertainty to polling results in this election, for a number of reasons including the shy Trump voter effect as well as the sampling corrections applied which depend heavily on assumptions about likely turnout. 

Graphs below are from a JP Morgan quant analysis of changes in number of registered voters by party and state, and the correlation with actual votes in subsequent election. Of course it is possible that negative covid impact has largely counteracted the effect discussed below (which is an integrated effect over the last 4 years) -- i.e., Trump was in a strong position at the beginning of 2020 but has declined since then. 

This is an unusual election for a number of reasons so it's quite hard to call the outcome. There's also a good chance the results on election night will be heavily contested.

The author of this analysis is Marko Kolanovic, Global Head of Macro Quantitative and Derivatives Strategy at J.P. Morgan. He graduated from New York University with a PhD in theoretical high-energy physics.

Anyone with high conviction about the election is welcome to post their analysis in the comments.

US and China: A New Cold War (video interview with Lanxin Xiang)

 

This is an excellent discussion of the US-China geopolitical situation with Professor Lanxin Xiang. Xiang was trained at SAIS (JHU PhD), and currently holds an academic position in Geneva while directing a research institute in Shanghai.

He has a uniquely deep understanding of both Western and Chinese perspectives on globalization, economic development, US-China competition. 

Interestingly, he recently translated Skidelsky's biography of Keynes.

Two related articles in Asia Times by the Brazilian journalist Pepe Escobar:

Shedding light on the limits of Chinese power 

Confucius and Marx will never marry in China

Bonus: Bill Owens interview. See comments about Huawei at ~50m.

 

Wikipedia: William A. Owens (born May 8, 1940) is a retired admiral of the United States Navy and who served as Vice Chairman of the Joint Chiefs of Staff from 1994 to 1996.[1][2] Since leaving the military in 1996, he served as an executive or as a member of the board of directors of various companies, including Nortel Networks Corporation.

Othram Helps Solve 1974 Cold Case: Carla Walker Murder

Othram, a DNA forensics company I co-founded, has solved another cold case. 

Carla Walker of Fort Worth TX was tortured, raped, and murdered in 1974. Finally the killer has been identified and arrested.

This was an open and high profile case just a few months ago. See this April 2020 episode of The DNA of Murder (Oxygen channel), hosted by Paul Holes, the detective who caught the Golden State Killer.

Who Killed Carla Walker? In 1974, 17-year-old Carla Walker’s reported abduction out of the arms of her boyfriend sent a Texas town on a massive manhunt. She was discovered murdered in a culvert three days later. Paul Holes interviews the only witness, Carla’s boyfriend. 

Walker and her boyfriend, Western Hills High School football quarterback Rodney McCoy, attended a Valentine’s dance on Feb. 16, 1974. After the dance, they met up with friends and then stopped by a Fort Worth bowling alley. 

McCoy has always maintained that a man approached the couple while they were sitting inside his car at the bowling alley parking lot and pointed a gun at him. He was beaten unconscious, and when he awoke, he found his cheerleader girlfriend missing.

 

See Othram: the future of DNA forensics

The existing FBI standard (CODIS) for DNA identification uses only 20 markers (STRs -- previously only 13 loci were used!). By contrast, genome wide sequencing can reliably call millions of genetic variants. 

For the first time, the cost curves for these two methods have crossed: modern sequencing costs no more than extracting CODIS markers using the now ~30 year old technology. 

What can you do with millions of genetic markers? 

1. Determine relatedness of two individuals with high precision. This allows detectives to immediately identify a relative (ranging from distant cousin to sibling or parent) of the source of the DNA sample, simply by scanning through large DNA databases. ...

If you have contacts in law enforcement, please alert them to the potential of this new technology.

Genomic Prediction and Embryo Selection (video panel discussion)

 

This is a recent panel discussion on genomic prediction, and applications in IVF and health systems (e.g., early screening of high risk individuals for breast cancer, heart disease). 

Jamie Metzl and Simon Fishel are my co-panelists. Metzl is the author of the best seller Hacking Darwin: Genetic Engineering and the Future of Humanity. Fishel was part of the team that produced the first IVF baby in 1978, and has been a leader in IVF research ever since. 

Today millions of babies are produced through IVF. In most developed countries roughly 3-5 percent of all births are through IVF, and in Denmark the fraction is about 10 percent! But when the technology was first introduced with the birth of Louise Brown in 1978, the pioneering scientists had to overcome significant resistance. There may be an alternate universe in which IVF was not allowed to develop, and those millions of children were never born.

Wikipedia: ...During these controversial early years of IVF, Fishel and his colleagues received extensive opposition from critics both outside of and within the medical and scientific communities, including a civil writ for murder.[16] Fishel has since stated that "the whole establishment was outraged" by their early work and that people thought that he was "potentially a mad scientist".[17]

I predict that within 5 years the use of polygenic risk scores will become common in some health systems and in IVF. Reasonable people will wonder why the technology was ever controversial at all, just as in the case of IVF.

Previous discussion: Sibling Validation of Polygenic Risk Scores and Complex Trait Prediction (Nature Scientific Reports)

Feynman on AI

Thanks to a reader for sending the video to me. The first clip is of Feynman discussing AI, taken from the longer 1985 lecture in the second video.

There is not much to disagree with in his remarks on AI. He was remarkably well calibrated and would not have been very surprised by what has happened in the following 35 years, except that he did not anticipate (at least, does not explicitly predict) the success that neural nets and deep learning would have for the problem that he describes several times as "pattern recognition" (face recognition, fingerprint recognition, gait recognition). Feynman was well aware of early work on neural nets, through his colleague John Hopfield.  [1] [2] [3]

I was at Caltech in 1985 and this is Feynman as I remember him. To me, still a teen ager, he seemed ancient. But his mind was marvelously active! As you can see from the talk he was following the fields of AI and computation rather closely. 

Of course, he and other Manhattan project physicists were present at the creation. They had to use crude early contraptions for mechanical calculation in bomb design computations. Thus, the habit of reducing a complex problem (whether in physics or machine learning) to primitive operations was second nature. Already for kids of my generation it was not second nature -- we grew up with early "home computers" like the Apple II and Commodore, so there was a black box magic aspect already to programming in high level languages. Machine language was useful for speeding up video games, but not everyone learned it. The problem is even worse today: children first encounter computers as phones or tablets that already seem like magic. The highly advanced nature of these devices discourages them from trying to grasp the underlying first principles.  

If I am not mistaken the t-shirt he is wearing is from the startup Thinking Machines, which built early parallel supercomputers.

Just three years later he was gone. The finely tuned neural connections in his brain -- which allowed him to reason with such acuity and communicate with such clarity still in 1985 -- were lost forever.

Foreign Observers of US Empire

Four recommended discussions, with perspectives largely absent from US media and establishment sources. 

1. US, Russia, China, Iran: Geopolitics and Realpolitik, discussed by a former UK diplomat, a professor at Tehran University, and a Brazilian journalist who covers Eurasia, living in Thailand.

   

2. Carl Zha, Caltech alumnus and China watcher. TikTok, WeChat, Huawei, semiconductors. The insidious role of US intelligence agencies in the tech war. Part 2.

      

3. Columbia economic historian Adam Tooze: World Order, Then And Now, ChinaTalk Podcast. Among other topics: State Capitalism, or National Socialism? Why Carl Schmitt is widely studied among Chinese intellectuals. The US won the cold war in Europe, but perhaps not in Asia...  More Tooze

4. The New Great Game: Bruno Maçães and diplomat, writer and former National Security Adviser Shivshankar Menon discuss Asia’s search for a constructive new equilibrium in the wake of growing tensions between China and its neighbours.

 

Bonus! Energy, Geopolitics, And The New Map: A Book Talk With Daniel Yergin.

 

Manhattan Institute: 

The shale revolution brought about not only an American competitive advantage in the global oil and gas market, but also an entirely new geopolitical dynamic. Energy is the bedrock of every industrial economy, and even minor shifts in production and prices have had resounding impacts on international diplomacy. 

Today, the global energy landscape differs drastically from a decade ago. The U.S. now leads the world in oil production thanks to fracking, and the world is reacting. But even as Russia pivots to China, and Middle Eastern producers try to recalibrate, every oil-producing country faces the same questions about the future of energy: Will renewable energy reign? And how will international relationships fare with this new map? These issues will become even more controversial during the presidential campaigns.

See also Remarks on the Decline of American Empire for earlier discussion of the impact of fracking on geopolitics.

When Machine Learning Met Genetic Engineering | CogX 2019 (video)

 

I recently came across this video on YouTube. 

Hard to believe it's been over a year since the conference. 2020 versions of these meetings were all killed by the pandemic.

Post from June 2019: London: CogX, Founders Forum, Healthtech

I'm in London again to give the talk below and attend some meetings, including Founders Forum and their Healthtech event the day before.

CogX: The Festival of AI and Emerging Technology
King's Cross, London, N1C 4BH

When Machine Learning Met Genetic Engineering

3:30 pm Tuesday June 11 Cutting Edge stage

Speakers

Stephen Hsu
Senior Vice-President for Research and Innovation
Michigan State University

Helen O’Neill
Lecturer in Reproductive and Molecular Genetics
UCL

Martin Varsavsky
Executive Chairman
Prelude Fertility

Azeem Azhar (moderator)
Founder
Exponential View

Regent's Canal, Camden Town near King's Cross.

CogX speakers reception, Sunday evening:

HealthTech

Commanding heights of global capital:

Sunset, Camden locks:

Schrodinger's Cat and the Normaliens

Yesterday I had cause to look something up related to macroscopic superposition states ("Schrodinger cat states") in Serge Haroche's book Exploring the Quantum. Curiosity led me to Haroche's 2012 Nobel Lecture and autobiography, which I found fascinating. 

One wonders how long an elitist, highly meritocratic and undeniably productive system like the French Grandes Ecoles can continue to function in the current political climate. Quel dommage.

... I was fascinated by astronomy and by calculus, the notion of derivatives and simple differential equations which describe so directly and so well the laws of dynamics obeyed by moving bodies. This was the time of the first artificial satellites, the sputniks which orbited the earth and launched the American-Soviet race to the moon. 

I marveled at the fact that I was able, with the elementary calculus I knew, to compute the escape velocity of rockets, the periods of satellites on their orbits and the gravitational field at the surface of all the planets … I understood then that nature obeys mathematical laws, a fact that did not cease to astonish me. I knew, from that time on, that I wanted to be a scientist. For that, I embarked in the strenuous and demanding “classes préparatoires” of the famed Lycée Louis-Le-Grand, one of the preparatory schools which train the best French students for the contest examinations leading to the “Grandes Ecoles.” They are the engineering and academic schools, which since the French Revolution, have formed the scientific elite of France. These were two years of intensive study where I learned a lot of math and of classical physics. I eventually was admitted in 1963 to the Ecole Polytechnique (ranking first in the national examination, to the great pride of my parents) and at the Ecole Normale Supérieure (ENS). I chose to enter the latter because, at that time, it offered a much better opportunity to embark in a scientist career. 

The years as a student at ENS (1963–1967) have left me wonderful memories, contrasting sharply with the strenuous training of the preparatory school. Here, in the middle of the Latin Quarter, I was free to organize my time as I wished, to meet and discuss with students working in all kinds of fields in science or humanities and to enjoy all the distractions and cultural activities Paris has to offer. And I was paid for that, since the “Normaliens” as the ENS students are called, are considered civil servants and receive a generous stipend! These were my formative years as a scientist. Coming so to speak from the physics of the 19th century which was taught in the classes préparatoires, I was immediately thrown into modern physics and the quantum world by the classes of exceptional teachers. Alfred Kastler gave us a lyrical description of the dance of atomic kinetic moments, and gave atoms and photons a near poetic existence. Jean Brossel brought us back to Earth by describing the great experiments thanks to which quantum concepts were established, instilling in us the austere passion for precision. And Claude Cohen-Tannoudji revealed the theory’s formalism to us with extraordinary depth and clarity. I still remember three books I read avidly at the time: Quantum Mechanics by Albert Messiah, where I truly understood the depth and beauty of the quantum theory; Principlesof Nuclear Magnetism by Anatole Abragam, who introduced me to the subtle world of atomic magnetic moments; and Feynman’s Lectures on Physics, which was a revelation.

See also 

Where Nobel winners get their start (Nature) 

Brainpower Matters: The French H-Bomb 

The Normaliens

One hundred thousand brains 

Quantum GDP

Orwell: 1944, 1984, and Today

George Orwell 1944 Letter foreshadows 1984, and today:

... Already history has in a sense ceased to exist, i.e. there is no such thing as a history of our own times which could be universally accepted, and the exact sciences are endangered as soon as military necessity ceases to keep people up to the mark. Hitler can say that the Jews started the war, and if he survives that will become official history. He can’t say that two and two are five, because for the purposes of, say, ballistics they have to make four. But if the sort of world that I am afraid of arrives, a world of two or three great superstates which are unable to conquer one another, two and two could become five if the fuhrer wished it. That, so far as I can see, is the direction in which we are actually moving ... 

... intellectuals are more totalitarian in outlook than the common people. On the whole the English intelligentsia have opposed Hitler, but only at the price of accepting Stalin. Most of them are perfectly ready for dictatorial methods, secret police, systematic falsification of history etc. so long as they feel that it is on ‘our’ side.

I am sure any reader can provide examples of the following from the "news" or academia or even from a national lab:

there is no such thing as a history of our own times which could be universally accepted  

the exact sciences are endangered  

two and two could become five

dictatorial methods ... systematic falsification of history etc. so long as they feel that it is on ‘our’ side.

Of course, there is nothing new under the sun. It takes only a generation for costly lessons to be entirely forgotten...

Wikipedia: Trofim Denisovich Lysenko ...Soviet agronomist and biologist. Lysenko was a strong proponent of soft inheritance and rejected Mendelian genetics in favor of pseudoscientific ideas termed Lysenkoism.[1][2] In 1940, Lysenko became director of the Institute of Genetics within the USSR's Academy of Sciences, and he used his political influence and power to suppress dissenting opinions and discredit, marginalize, and imprison his critics, elevating his anti-Mendelian theories to state-sanctioned doctrine. 

Soviet scientists who refused to renounce genetics were dismissed from their posts and left destitute. Hundreds if not thousands of others were imprisoned. Several were sentenced to death as enemies of the state, including the botanist Nikolai Vavilov. Scientific dissent from Lysenko's theories of environmentally acquired inheritance was formally outlawed in the Soviet Union in 1948. As a result of Lysenkoism and forced collectivization, 15-30 million Soviet and Chinese citizens starved to death in the Holodomor and the Great Chinese Famine. ...

 

In 1964, physicist Andrei Sakharov spoke out against Lysenko in the General Assembly of the Academy of Sciences of the USSR: "He is responsible for the shameful backwardness of Soviet biology and of genetics in particular, for the dissemination of pseudo-scientific views, for adventurism, for the degradation of learning, and for the defamation, firing, arrest, even death, of many genuine scientists."

Adam Tooze: American Power in the Long 20th Century

  

London Review of Books (LRB) lecture:

The history of American power, as it is commonly written, is a weighty subject, a matter of military and economic heft, of ‘throw-weight’, of resource mobilisation and material culture, of ‘boots on the ground’. In his lecture, Adam Tooze examines an alternative, counterintuitive vision of America, as a power defying gravity. This image gives us a less materialistic, more fantastical and more unstable vision of America’s role in the world.

The Q&A at 1h03min is probably the best (at least most concise) part of the talk. I don't find the Geithner anecdote quite as important / symbolic as Tooze does. Geithner is expressing the point that financial markets and economies are heavily affected by animal spirits, investor confidence, etc. Geithner understands well how much the power of central banks depends on purely psychological multiplier effects.

From a YouTube comment, this outline:

1:10 - Tim Geithner; U.S. Treasury: America had been “defying gravity" 

5:50 - U.S. was the “gravity” of world 

11:07 - U.S. is now also subject to the “gravity” of world 

13:28 - 100 years of 9 historic U.S. events; Overview 

14:44 - Adam Tooze; Historian “Ordering rather than Order, and the Disordering effects of efforts at Ordering.” 

16:28 - Start at the beginning of 1800’s 

17:12 - 1898 U.S. Imperialist power 

17:50 - 1916 U.S. Globalist power 

18:47 - Woodrow Wilson; U.S. President 

22:46 - 1920s Republican domestic priority of Financial Austerity and Tax cuts. 

25:59 - Great American Financial shocks/panics; 1857, 1873, 1893, 1896, 1907, 1920, 1929 26:49 - 1920s Great Depression 

27:18 - 1930s U.S. Hyper militaristic power 

31:51 - World War 2; One World, One War (1942) 

33:48 - Post World War 2, Bretton Woods economic conference. 

36:24 - Marshall Plan not the same as Bretton Woods... 

41:10 - Cold War: Asia 

43:30 - U.S. President Nixon abandons the Gold peg in 1971. Which results in inflation in G7 countries and Switzerland. 

44:10 - Keynesian era 50s to 60s. Start of Neoliberalism or the Paul Volcker shock 1979. 

45:07 - Cold War: Europe 1980s, Reagan & Gorbachev 

47:13 - Concluding phase of the talk 

1:01:56 - Challenges in 2019 and going forward; China and Climate Change 

1:03:20 - Q&A

Also recommended: Tooze on US-China geopolitical competition (August 6 2020 Sinica podcast). This discussion focuses more on the present and future than the past and may be of more interest to readers.

This conversation with Tyler Cowen is excellent, with more focus on Europe.

This is part 3 of a discussion at the Paris School of Economics. Thomas Piketty is on the panel and his remarks are in part 2, following Tooze's presentation in part 1. I recommend part 3 as the most interesting. Topics covered include MMT, inequality, central banks, current sources of systemic risk. Note this discussion took place before the Covid19 pandemic. Tooze mentions individual hedge fund compensation in the hundreds of millions or billions of dollars. Typically in such cases a big chunk of this compensation is really returns from the individual's own net worth which is co-invested with the fund. So it's not directly comparable to other forms of compensation, such as salary or bonus.

PRC ASBM Test in South China Sea

 

This is an interesting discussion of PRC Anti-Ship Ballistic Missiles (ASBM), including the DF21, DF26, and DF17 systems. You can set the captions to English if necessary. 

In response to US activity in the South China Sea and elsewhere, PRC recently conducted a test of DF21 and DF26 in the open ocean. Reportedly, a US "Cobra Ball" RC135S missile intelligence aircraft was present to monitor the activity. 

The YouTube video discusses PRC ASBM capabilities, including 

1. Infrared and radar final targeting

2. Maneuver capability

3. Capability of the missile to receive (ground based) over-the-horizon radar and satellite information while in flight. 

These are the frequent subject of speculation in Western sources: "There is a long kill chain and we are not sure whether it is operational..." etc.

Assuming that PRC ASBM have these capabilities, which seems quite plausible to me, this test was presumably a demonstration for the US, to make sure that our military appreciates the PLARF ability to hit a moving target (e.g., US aircraft carrier) at sea. Once this mutual understanding is in place, FONOPs in the South China Sea become mere theatrics for the dim witted.

See related posts

The Future of the U.S. Aircraft Carrier: Fearsome Warship or Expensive Target? (Heritage panel; video) 

On the military balance of power in the Western Pacific (South China Sea, ASBM, etc.)

Machine intelligence threatens overpriced aircraft carriers (first principles analysis of final targeting problem)

A2AD fait accompli? (Yaogan satellite surveillance of the western Pacific)

The Inheritors and The Grisly Folk: H.G. Wells and William Golding on Neanderthals

Some time ago I posted about The Grisly Folk by H.G. Wells, an essay on Neanderthals and their encounters with modern humans. See also The Neanderthal Problem, about the potential resurrection of early hominids via genomic technology, and the associated ethical problems. 

The Grisly Folk: ... Many and obstinate were the duels and battles these two sorts of men fought for this world in that bleak age of the windy steppes, thirty or forty thousand years ago. The two races were intolerable to each other. They both wanted the eaves and the banks by the rivers where the big flints were got. They fought over the dead mammoths that had been bogged in the marshes, and over the reindeer stags that had been killed in the rutting season. When a human tribe found signs of the grisly folk near their cave and squatting place, they had perforce to track them down and kill them; their own safety and the safety of their little ones was only to be secured by that killing. The Neandertalers thought the little children of men fair game and pleasant eating. ...

William Golding was inspired by Wells to write The Inheritors (his second book, after Lord of the Flies), which is rendered mostly (until the end, at which point the perspective is reversed) from the Neanderthal point of view. Both Wells and Golding assume that Neanderthals were not as cognitively capable as modern humans, but Golding's primitives are peaceful quasi-vegetarians, quite unlike the Grisly Folk of Wells.

The Inheritors 

Golding considered this his finest novel and it is a beautifully realised tale about the last days of the Neanderthal people and our fear of the ‘other’ and the unfamiliar. The action is revealed through the eyes of the Neanderthals whose peaceful world is threatened by the emergence of Homo sapiens. 

The struggle between the simple Neanderthals and the malevolent modern humans ends in helpless despair ... 

From the book jacket: "When the spring came the people - what was left of them - moved back by the old paths from the sea. But this year strange things were happening, terrifying things that had never happened before. Inexplicable sounds and smells; new, unimaginable creatures half glimpsed through the leaves. What the people didn't, and perhaps never would, know, was that the day of their people was already over."

See this episode of the podcast Backlisted for an excellent discussion of the book. 

I am particularly interested in how Golding captures the perspective of pre-humans with limited cognitive abilities. He conveys the strangeness and incomprehensibility of modern humans as perceived by Neanderthals. In this sense, the book is a type of Science Fiction: it describes a first encounter with Aliens of superior capability.

We are approaching the day when modern humans will encounter a new and quasi-alien intelligence: it may be AI, or it may be genetically enhanced versions of ourselves.

On a scientific note, can someone provide an update to this 2013 work: "... high quality genome sequence obtained from the toe of a female Neanderthal who lived in the Altai mountains in Siberia. Interestingly, copy number variation at 16p11.2 is one of the structural variants identified in a recent deCODE study as related to IQ depression"? Here is an interesting follow up paper: Nature 2016 Aug 11; 536(7615): 205–209.

   

Audiobook:

 

Othram helps identify murder victim from ~20 cells equivalent DNA sample

Othram, a DNA forensics company I co-founded, continues to solve cold cases around the world. 

Murder victim Rodney Peter Johnson was identified from a sample of only 0.2 nanograms of DNA (equivalent of 20 cells). Mr. Johnson had last been seen in 1987, when he was 25 years old. His body was discovered in 1994 by a fisherman in Lake Stickney, near Everett WA. It was badly decomposed and could not be identified.

The Johnson family has waited decades for closure. Press conference video.

See Othram: the future of DNA forensics

The existing FBI standard (CODIS) for DNA identification uses only 20 markers (STRs -- previously only 13 loci were used!). By contrast, genome wide sequencing can reliably call millions of genetic variants. 

For the first time, the cost curves for these two methods have crossed: modern sequencing costs no more than extracting CODIS markers using the now ~30 year old technology. 

What can you do with millions of genetic markers? 

1. Determine relatedness of two individuals with high precision. This allows detectives to immediately identify a relative (ranging from distant cousin to sibling or parent) of the source of the DNA sample, simply by scanning through large DNA databases. ...

If you have contacts in law enforcement, please alert them to the potential of this new technology.

Cheap Document Camera

I built this using a $35 1080p web camera and a $20 LED lamp I already had in my office. 

I've tested on Google Meet and Zoom, it allows me to display equations and quick sketches to collaborators and students. There are much fancier purpose-built document cameras with similar functionality, but these are mostly sold out on Amazon, due to the increase in remote work and online teaching. The particular web cam I am using (see link above) has a manual focus, in case the software auto-focus is unsatisfactory.

Both Google Meet and Zoom allow to switch from the default internal camera on my laptop to the external web cam (a simple toggle in Settings). The web cam is auto-detected on both Mac OS and Chrome -- I did not have to install any drivers.

The plastic clip I used to attach the web cam to the lamp is from the kitchen (Bed Bath and Beyond). Tape would also work as the web cam is very light.

Here is the rig in action, using Google Meet. I write on the pad and my colleague can see it very clearly.

U.S.-China Decoupling: Separating Myth From Reality (Georgetown panel)

 

This is a good panel on US-China decoupling, from June 2020. I especially recommend the discussion between 1h and 1h30m.

Regarding semiconductors: How fast will SMIC close the gap with TSMC? It's now a huge priority. 

Chip design in China advanced much faster than most US observers expected in the past few years, and I think semiconductor fabrication will also advance quickly in the future. Fabs are huge, complex infrastructure investments, which they tend to do well. (According to Goodrich, 60 fabs under construction right now in China.) I also expect them to be good at fine-tuning the production process, pulling in engineering talent from Taiwan and S. Korea as necessary. The most difficult technology hurdle will be the advanced lithography machines that still depend on US and European intellectual property. 

Georgetown US-China Dialogue 2020 

Wang Tao is a managing director and head of Asia Economic Research at UBS investment bank in Hong Kong. She covers macroeconomic and policy issues in Asia and China. 

Jörg Wuttke is the chief representative in China of BASF, a large German chemical company. He is also the president of the European Union Chamber of Commerce in China. 

Dan Wang is a Beijing-based technology analyst at Gavekal Dragonomics, an economic research firm. His focus is on China's technology progress—especially on semiconductors—as well as the unfolding tech war related to the Committee on Foreign Investment in the United States, export controls, and Huawei. 

Jimmy Goodrich is vice president for global policy at the Semiconductor Industry Association (SIA). In this role, he leads SIA’s global policy team and its research and analysis of foreign semiconductor policies and capabilities. Jimmy is also the executive committee chair of the United States Information Technology Office (USITO) in Beijing, representing SIA in his capacity.

Related: China's eRMB, a blockchain based digital currency linked 1-1 to the yuan, seems to be flying under the radar. In my opinion this has huge possibilities -- in the future, anyone with the app (an eRMB account) can transact in RMB whether they are in Germany or Iran. This development is an inevitable consequence of the US weaponizing SWIFT...  

Ray Dalio Warns of U.S.-China ‘Capital War’ That Would Hit Dollar (Bloomberg)

 

Sibling Validation of Polygenic Risk Scores and Complex Trait Prediction (Nature Scientific Reports)

This is the published version of our paper which uses tens of thousands of siblings to validate polygenic trait and risk prediction. We show that the predictors can differentiate between siblings (which one has heart disease? is taller?), despite similarity in childhood environments and genotype. The predictors work almost as well in pairwise sibling comparisons as in comparisons between randomly selected strangers. 

There are now many validations of polygenic prediction in the scientific literature, conducted using groups of people born on different continents and in different decades than the original populations used in training. With the new sibling results our confidence is extremely high that the predictors are capturing causal genetic effects, and that complex trait prediction from DNA alone is a reality.

Sibling Validation of Polygenic Risk Scores and Complex Trait Prediction 

nature.com/articles/s41598-020-69927-7

Louis Lello, Timothy Raben, Stephen D. H. Hsu

I posted about the bioRxiv preprint version back in March:

We test a variety of polygenic predictors using tens of thousands of genetic siblings for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in within-family designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (less than 84th percentile) and 1 sibling with high PRS score (top few percentiles), the predictors identify the affected sibling about 70-90 percent of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. For height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.

From the paper:

If a girl grows up to be taller than her sister, with whom she spent the first 18 years of her life, it seems likely at least some of the height difference is due to genetic differences. How much of phenotype difference can we predict from DNA alone? If one of the sisters develops breast cancer later in life, how much of the risk was due to genetic variants that she does not share with her asymptomatic sister? These are fundamental questions in human biology, which we address (at least to some extent) in this paper.

... We emphasize that predictors trained on even larger datasets will likely have significantly stronger performance than the ones analyzed here [13, 14]. As we elaborated in earlier work, where many of these predictors were first investigated, their main practical utility at the moment is in the identification of outliers who may be at exceptionally high (or low) risk for a specific disease condition. The results here confirm that high risk score outliers are indeed at elevated risk, even compared to their (normal range score) siblings.

The sibling results presented in this paper, together with the many out of sample validations of polygenic scores that continue to appear in the literature, suggest that genomic prediction in humans is a robust and important advance that will lead to improvements in translational medicine as well as deep insights into human genetics.

Discrete Hilbert Space, the Born Rule, and Quantum Gravity

This is a new paper which I only recently found the time to write up, although I have been thinking about the ideas off and on for some time.

It extends ideas first discussed in two papers with A. Zee and R. Buniy: Is Hilbert space discrete? and Discreteness and the origin of probability in quantum mechanics.

Slides from a related talk at Caltech IQIM.

The new paper connects discrete Hilbert space to specific models of quantum gravity, such as simplicial or lattice quantum gravity.

Discrete Hilbert Space, the Born Rule, and Quantum Gravity
https://arxiv.org/abs/2007.12938

Quantum gravitational effects suggest a minimal length, or spacetime interval, of order the Planck length. This in turn suggests that Hilbert space itself may be discrete rather than continuous. One implication is that quantum states with norm below some very small threshold do not exist. The exclusion of what Everett referred to as maverick branches is necessary for the emergence of the Born Rule in no collapse quantum mechanics. We discuss this in the context of quantum gravity, showing that discrete models (such as simplicial or lattice quantum gravity) indeed suggest a discrete Hilbert space with minimum norm. These considerations are related to the ultimate level of fine-graining found in decoherent histories (of spacetime geometry plus matter fields) produced by quantum gravity.

From the Discussion:

No collapse (or many worlds) versions of quantum mechanics are often characterized as extravagant, because of the many branches of the wavefunction. However it is also extravagant to postulate that spacetime or Hilbert space are infinitely continuous. Continuous Hilbert space requires that for any two choices of orientation of a qubit spin (see Figure 1), no matter how close together, there are an infinite number of physically distinct states between them, with intermediate orientation. Instead, there may only be a finite (but very large) number of distinct orientations allowed, suggesting a minimum norm in Hilbert space. No experiment can probe absolute continuity, and indeed there seem to be fundamental limits on such experiments, arising from quantum gravity itself.

We illustrated a direct connection between discrete spacetime (the simplex length a) and discrete Hilbert space (minimum non-zero distance in Hilbert space produced by time evolution), in a specific class of quantum gravity models based on Feynman path integrals. It may be the case that maximally fine-grained decoherent histories generated within quantum gravity have discrete geometries and exist in a discrete Hilbert space. Consequently histories with sufficiently small norm are never generated, thereby solving Everett's problem with maverick branches. In the remaining branches, deviations from Born Rule probabilities are almost entirely hidden from semi-classical observers. ...

See also

The Quantum Simulation Hypothesis: Do we live in a quantum multiverse simulation?

Feynman and Everett

Gork revisited