Tuesday, March 30, 2021

Future of CRISPR (base & prime) and epigenome editing (Interview with Prof David R. Liu)


Excellent interview with David Liu of Harvard, which gives an overview of key innovations in gene editing since the discovery of CRISPR. 

Labs all around the world are busy building new tools and libraries for gene editing, with dramatic progress since CRISPR was first discovered less than 10 years ago.

Liu is optimistic about clinical applications over the next 10 years. He does not discuss germline editing (i.e., of embryos) but one can readily imagine how these advances in technology might be applied there.

Friday, March 26, 2021

John von Neumann, 1966 Documentary


This 1966 documentary on von Neumann was produced by the Mathematical Association of America. It includes interviews with Wigner, Ulam, Halmos, Goldstine, and others. 

At ~34m Bethe (leader of the Los Alamos theory division) gives primary credit to vN for the implosion method in fission bombs. While vN's previous work on shock waves and explosive lenses is often acknowledged as important for solving the implosion problem, this is the first time I have seen him given credit for the idea itself. Seth Neddermeyer's Enrico Fermi Award citation gives him credit for "invention of the implosion technique" and the original solid core design was referred to as the "Christy gadget" after Robert Christy. As usual, history is much more complicated than the simplified narrative that becomes conventional.
Teller: He could and did talk to my three-year-old son on his own terms and I sometimes wondered whether his relations to the rest of us were a little bit similar.
A recent application of vN's Quantum Ergodic Theorem: Macroscopic Superposition States in Isolated Quantum Systems.

Cloning vN (science fiction): short story, longer (AI vs genetic engineering).

Thursday, March 25, 2021

Meritocracy x 3

Three videos: 

1. Political philosopher Daniel Bell on PRC political meritocracy. 

2. Documentary on the 2020 Gao Kao: college entrance exam taken by ~11 million kids. 

3. Semiconductor Industry Association panel on PRC push to become self-sufficient in semiconductor technology. 

Sunday, March 21, 2021

The Contribution of Cognitive and Noncognitive Skills to Intergenerational Social Mobility (McGue et al. 2020)

If you have the slightest pretension to expertise concerning social mobility, meritocracy, inequality, genetics, psychology, economics, education, history, or any related subjects, I urge you to carefully study this paper.
The Contribution of Cognitive and Noncognitive Skills to Intergenerational Social Mobility  
(Psychological Science https://doi.org/10.1177/0956797620924677)
Matt McGue, Emily A. Willoughby, Aldo Rustichini, Wendy Johnson, William G. Iacono, James J. Lee 
We investigated intergenerational educational and occupational mobility in a sample of 2,594 adult offspring and 2,530 of their parents. Participants completed assessments of general cognitive ability and five noncognitive factors related to social achievement; 88% were also genotyped, allowing computation of educational-attainment polygenic scores. Most offspring were socially mobile. Offspring who scored at least 1 standard deviation higher than their parents on both cognitive and noncognitive measures rarely moved down and frequently moved up. Polygenic scores were also associated with social mobility. Inheritance of a favorable subset of parent alleles was associated with moving up, and inheritance of an unfavorable subset was associated with moving down. Parents’ education did not moderate the association of offspring’s skill with mobility, suggesting that low-skilled offspring from advantaged homes were not protected from downward mobility. These data suggest that cognitive and noncognitive skills as well as genetic factors contribute to the reordering of social standing that takes place across generations.
From the paper:
We believe that a reasonable explanation of our findings is that the degree to which individuals are more or less skilled than their parents contributes to their upward or downward mobility. Behavioral genetic and genomic research has established the heritability of social achievements (Conley, 2016) as well as the skills thought to underlie them (Bouchard & McGue, 2003). Nonetheless, these associations may be due to passive gene–environment correlation, whereby high-achieving parents both transmit genes and provide a rearing environment that promotes their children’s social success (Scarr & McCartney, 1983). Our within-family design controlled for passive gene–environment correlation effects. Although offspring inherit all of their genes from their parents, they inherit a random subset of parental alleles because of meiotic segregation. Consequently, some offspring inherit a favorable subset of their parents’ alleles, whereas others inherit a less favorable subset. We found, as did previous researchers (Belsky et al., 2018), that the inheritance of a favorable subset of alleles was associated with an increased likelihood of upward mobility... 
...In summary, our analysis of intergenerational social mobility in a sample of 2,594 offspring from 1,321 families found that (a) most individuals were educationally and occupationally mobile, (b) mobility was predicted by offspring–parent differences in skills and genetic endowment, and (c) the relationship of offspring skills with social mobility did not vary significantly by parent social background. In an era in which there is legitimate concern over social stagnation, our findings are noteworthy in identifying the circumstances when parents’ educational and occupational success is not reproduced across generations.

See also Game Over: Genomic Prediction of Social Mobility (PNAS July 9, 2018: 201801238). Both papers provide out of sample validation of polygenic predictors for cognitive ability, specifically of the relationship to intergenerational social mobility.

Thursday, March 18, 2021

Council on Foreign Relations: The Rise and Fall of Great Powers? America, China, and the Global Order


Insights from Ray Dalio and Paul Kennedy (The Rise and Fall of the Great Powers, 1987) on the balance of power and future global order. I was in graduate school when Kennedy's book was first published and I still have the hardcover first edition somewhere. Dalio and Kennedy have both carefully studied historical examples and present, in my opinion, a realistic view of what is happening. Kennedy mentions the PRC naval build up as a very explicit, material comparison of strength, whereas Dalio focuses on financial and economic matters. Elizabeth Economy provides some interesting comments on internal Chinese politics, but I am unsure how much insight any US analysts can have into the fine details of this.

The Naval War College Review article mentioned by Paul Kennedy is: 

Related: PRC ASBM Test in South China Sea and links therein.

Panelists discuss the rise and fall of great powers and the competing grand strategies of the United States and China. 
Ray Dalio Founder, Co-chairman, and Co-chief Investment Officer, Bridgewater Associates, LP; Author, The Changing World Order: Why Nations Succeed and Fail 
CFR Member Elizabeth C. Economy Senior Fellow for China Studies, Council on Foreign Relations; Senior Fellow, Hoover Institution, Stanford University; Author, The Third Revolution: Xi Jinping and the New Chinese State; @LizEconomy 
Paul M. Kennedy J. Richardson Dilworth Professor of History and Director of International Security Studies, Yale University; Author, The Rise and Fall of the Great Powers

Bonus! Short WSJ piece on digital RMB rollout. SWIFT beware...


Wednesday, March 10, 2021

Academic Freedom Alliance

We live in an era of preference falsification. 

Vocal, dishonest, irrational activists have cowed all but the most courageous of the few remaining serious thinkers, even at our greatest universities. 

I hope the creation of the Academic Freedom Alliance will provide a much needed corrective to the dishonest reign of terror in place today.
Chronicle: When I spoke to the Princeton University legal scholar and political philosopher Robert P. George in August, he offered a vivid zoological metaphor to describe what happens when outrage mobs attack academics. When hunted by lions, herds of zebras “fly off in a million directions, and the targeted member is easily taken down and destroyed and eaten.” A herd of elephants, by contrast, will “circle around the vulnerable elephant.” 
... What had begun as a group of 20 Princeton professors organized to defend academic freedom at one college was rapidly scaling up its ambitions and capacity: It would become a nationwide organization. George had already hired an executive director and secured millions in funding. 
... Today, that organization, the Academic Freedom Alliance, formally issued a manifesto declaring that “an attack on academic freedom anywhere is an attack on academic freedom everywhere,” and committing its nearly 200 members to providing aid and support in defense of “freedom of thought and expression in their work as researchers and writers or in their lives as citizens,” “freedom to design courses and conduct classes using reasonable pedagogical judgment,” and “freedom from ideological tests, affirmations, and oaths.” 
... All members of the alliance have an automatic right for requests for legal aid to be considered, but the organization is also open to considering the cases of faculty nonmembers, university staff, or even students on a case-by-case basis. The alliance’s legal-advisory committee includes well-known lawyers such as Floyd Abrams and the prolific U.S. Supreme Court litigator Lisa S. Blatt. 
When I spoke to him in February, as the date of AFA’s public announcement drew closer, George expressed surprise and satisfaction at the success the organization had found in signing up liberals and progressives. “If anything we’ve gone too far — we’re imbalanced over to the left side of the agenda,” he noted wryly. “That’s because our yield was a little higher than we expected it to be when we got in touch with folks.” 
The yield was higher, as George would learn, quoting one such progressive member, because progressives in academe often feel themselves to be even more closely monitored for ideological orthodoxy by students and activist colleagues than their conservative peers. “‘You conservative guys, people like you and Adrian Vermeule, you think you’re vulnerable. You’re not nearly as vulnerable as we liberals are,’” George quoted this member as saying. “They are absolutely terrified, and they know they can never keep up with the wokeness. What’s OK today is over the line tomorrow, and nobody gave you the memo.” 
George went on to note that some of the progressives he spoke with were indeed too frightened of the very censorious atmosphere that the alliance proposes to challenge to be willing to affiliate with it, at least at the outset. 
... Nadine Strossen, a New York Law School law professor and former president of the ACLU, emphasized the problem of self-censorship that she saw the alliance as counteracting. “When somebody is attacked by a university official or, for lack of a better term, a Twitter mob, there are constant reports from all individuals targeted that they receive so many private communications and emails saying ‘I support you and agree with you, but I just can’t say it publicly.’” 
She hopes that the combined reputations of the organization’s members will provide a permission structure allowing other faculty members to stand up for their private convictions in public. While a lawsuit can vindicate someone’s constitutional or contractual rights, Strossen noted, only a change in the cultural atmosphere around these issues — a preference for open debate and free exchange over stigmatization and punishment as the default way to negotiate controversy in academe — could resolve the overall problem. 
The Princeton University political historian Keith E. Whittington, who is chairman of the alliance’s academic committee, echoed Strossen’s point. The recruitment effort, he said, aimed to gather “people who would be respectable and hopefully influential to college administrators — such that if a group like that came to them and said ‘Look, you’re behaving badly here on these academic-freedom principles,’ this is a group that they might pay attention to.” 
“Administrators feel very buffeted by political pressures, often only from one side,” Whittington told me. “They hear from all the people who are demanding action, and the easiest, lowest-cost thing to do in those circumstances is to go with the flow and throw the prof under the bus. So we do hope that we can help balance that equation a little bit, make it a little more costly for administrators.” ...
Perhaps amusingly, I am one of the progressive founding members of AFA. At least, I have for most of my life been politically to the left of Robby George and many of the original Princeton 20 that started the project. 

When I left the position of Senior Vice-President for Research and Innovation at MSU last summer, I wrote
6. Many professors and non-academics who supported me were afraid to sign our petition -- they did not want to be subject to mob attack. We received many communications expressing this sentiment. 
7. The victory of the twitter mob will likely have a chilling effect on academic freedom on campus.

For another vivid example of the atmosphere on US university campuses, see Struggles at Yale.  

Obama on political correctness:
... I’ve heard some college campuses where they don’t want to have a guest speaker who is too conservative or they don’t want to read a book if it has language that is offensive to African-Americans or somehow sends a demeaning signal towards women. I gotta tell you, I don’t agree with that either. I don’t agree that you, when you become students at colleges, have to be coddled and protected from different points of view. I think you should be able to — anybody who comes to speak to you and you disagree with, you should have an argument with ‘em. But you shouldn’t silence them by saying, "You can’t come because I'm too sensitive to hear what you have to say." That’s not the way we learn ...

Monday, March 08, 2021

Psychology Is: interview with Nick Fortino


This is a recent interview. Enjoy!
In episode 14 of the Psychology Is podcast, we have the special opportunity to talk to Dr. Steve Hsu, a physicist, professor at MSU, and founder of Genomic Prediction. We discuss the newest innovations related to genetic testing and editing, including Genomic Prediction and CRISPR. We also discuss what these innovations may make possible (for better or worse), and how we can proceed carefully as we learn to harness this new power.
For more, see this recent review article.

Inside AI/ML: Mark Saroufim


Great discussion and insider views of AI/ML research. 
Academics think of themselves as trailblazers, explorers — seekers of the truth. 
Any fundamental discovery involves a significant degree of risk. If an idea is guaranteed to work then it moves from the realm of research to engineering. Unfortunately, this also means that most research careers will invariably be failures at least if failures are measured via “objective” metrics like citations. 
Today we discuss the recent article from Mark Saroufim called Machine Learning: the great stagnation. We discuss the rise of gentleman scientists, fake rigor, incentives in ML, SOTA-chasing, "graduate student descent", distribution of talent in ML and how to learn effectively.
Topics include: OpenAI, GPT-3, RL: Dota & Starcraft, conference papers, incentives and incremental research, Is there an ML stagnation? Is theory useful? Is ML entirely empirical these days? How to suceed as a researcher, Why everyone is forced to become their own media company, and much more.

If you don't want to watch the video, read these (by Mark Saroufim) instead:

Machine Learning: The Great Stagnation 

Friday, March 05, 2021

Genetic correlation of social outcomes between relatives (Fisher 1918) tested using lineage of 400k English individuals

Greg Clark (UC Davis and London School of Economics) deserves enormous credit for producing a large multi-generational dataset which is relevant to some of the most fundamental issues in social science: inequality, economic development, social policy, wealth formation, meritocracy, and recent human evolution. If you have even a casual interest in the dynamics of human society you should study these results carefully...

See previous discussion on this blog. 

Clark recently posted this preprint on his web page. A book covering similar topics is forthcoming.
For Whom the Bell Curve Tolls: A Lineage of 400,000 English Individuals 1750-2020 shows Genetics Determines most Social Outcomes 
Gregory Clark, University of California, Davis and LSE (March 1, 2021) 
Economics, Sociology, and Anthropology are dominated by the belief that social outcomes depend mainly on parental investment and community socialization. Using a lineage of 402,000 English people 1750-2020 we test whether such mechanisms better predict outcomes than a simple additive genetics model. The genetics model predicts better in all cases except for the transmission of wealth. The high persistence of status over multiple generations, however, would require in a genetic mechanism strong genetic assortative in mating. This has been until recently believed impossible. There is however, also strong evidence consistent with just such sorting, all the way from 1837 to 2020. Thus the outcomes here are actually the product of an interesting genetics-culture combination.
The correlational results in the table below were originally deduced by Fisher under the assumption of additive genetic inheritance: h2 is heritability, m is assortativity by genotype, r assortativity by phenotype. (Assortative mating describes the tendency of husband and wife to resemble each other more than randomly chosen M-F pairs in the general population.)
Fisher, R. A. 1918. “The Correlation between Relatives on the Supposition of Mendelian Inheritance.” Transactions of the Royal Society of Edinburgh, 52: 399-433
Thanks to Clark the predictions of Fisher's models, applied to social outcomes, can now be compared directly to data through many generations and across many branches of English family trees. (Figures below from the paper.)

The additive model fits the data well, but requires high heritabilities h2 and a high level m of assortative mating. Most analysts, including myself, thought that the required values of m were implausibly large. However, using modern genomic datasets one can estimate the level of assortative mating by simply looking at the genotypes of married couples. 

From the paper:
(p.26) a recent study from the UK Biobank, which has a collection of genotypes of individuals together with measures of their social characteristics, supports the idea that there is strong genetic assortment in mating. Robinson et al. (2017) look at the phenotype and genotype correlations for a variety of traits – height, BMI, blood pressure, years of education - using data from the biobank. For most traits they find as expected that the genotype correlation between the parties is less than the phenotype correlation. But there is one notable exception. For years of education, the phenotype correlation across spouses is 0.41 (0.011 SE). However, the correlation across the same couples for the genetic predictor of educational attainment is significantly higher at 0.654 (0.014 SE) (Robinson et al., 2017, 4). Thus couples in marriage in recent years in England were sorting on the genotype as opposed to the phenotype when it comes to educational status. 
It is not mysterious how this happens. The phenotype measure here is just the number of years of education. But when couples interact they will have a much more refined sense of what the intellectual abilities of their partner are: what is their general knowledge, ability to reason about the world, and general intellectual ability. Somehow in the process of matching modern couples in England are combining based on the weighted sum of a set of variations at several hundred locations on the genome, to the point where their correlation on this measure is 0.65.
Correction: Height, Educational Attainment (EA), and cognitive ability predictors are controlled by many thousands of genetic loci, not hundreds! 

This is a 2018 talk by Clark which covers most of what is in the paper.

For out of sample validation of the Educational Attainment (EA) polygenic score, see Game Over: Genomic Prediction of Social Mobility.


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