Making Oblivion

I just caught Oblivion on cable -- it's visually stunning. The Skytower or glass house was shot in a very interesting way, as shown in this video. If you like modern design and architecture you'll love this.

Keep your head down, and smile

In 2005 I posted this interview of Lee Kuan Yew that appeared in Der Spiegel. It seems to me that the PRC government may not have the patience to bide its time as recommended by Lee. Once again, he appears prophetic.

SPIEGEL: The Chinese Government is promoting the peaceful rise of China. Do you believe them?

Mr. Lee: Yes, I do, with one reservation. I think they have calculated that they need 30 to 40 -- maybe 50 years of peace and quiet to catch up, to build up their system, change it from the communist system to the market system. They must avoid the mistakes made by Germany and Japan. Their competition for power, influence and resources led in the last century to two terrible wars.

SPIEGEL: What should the Chinese do differently?

Mr. Lee: They will trade, they will not demand, "This is my sphere of influence, you keep out". America goes to South America and they also go to South America. Brazil has now put aside an area as big as the state of Massachusetts to grow soya beans for China. They are going to Sudan and Venezuela for oil because the Venezuelan President doesn't like America. They are going to Iran for oil and gas. So, they are not asking for a military contest for power, but for an economic competition.

SPIEGEL: But would anybody take them really seriously without military power?

Mr. Lee: About eight years ago, I met Liu Huaqing, the man who built the Chinese Navy. Mao personally sent him to Leningrad to learn to build ships. I said to him, "The Russians made very rough, crude weapons". He replied, "You are wrong. They made first-class weapons, equal to the Americans." The Russian mistake was that they put so much into military expenditure and so little into civilian technology. So their economy collapsed. I believe the Chinese leadership have learnt: If you compete with America in armaments, you will lose. You will bankrupt yourself. So, avoid it, keep your head down, and smile, for 40 or 50 years.

SPIEGEL: What are your reservations?

Mr. Lee: I don't know whether the next generation will stay on this course. After 15 or 20 years they may feel their muscles are very powerful. We know the mind of the leaders but the mood of the people on the ground is another matter. Because there's no more communist ideology to hold the people together, the ground is now galvanised by Chinese patriotism and nationalism. Look at the anti-Japanese demonstrations. ...

For more on this topic, I recommend this talk by Lieutenant General Noboru Yamaguchi.

CHINA’S RISE, AMERICA’S PIVOT, AND JAPAN’S CHOICE: The security landscape in the Asia-Pacific region will mainly be determined in the long term by two significant actors, the People’s Republic of China and the United States. China’s rise has been and will be an extremely prominent factor; while how fast and in which direction China proceeds are open questions. The US has taken a significant step to stay involved in the region by declaring that it will rebalance towards the Asia-Pacific. For architects of Japan’s security strategy, it is crucially important, according to Lt Gen Yamaguchi, to, first, scrutinise both the negative and positive impacts of China’s rise without any bias; second, have a clear picture of the rebalancing by the US with an understanding of the roles of American allies for proper implementation of this policy; and third, develop courses of action and possible policies for Japan to better serve the region’s peace and stability.

The lecture has been made possible by the support of Japan's Ministry of Foreign Affairs.

Flying robot jellyfish

Livescience: A new teeny-tiny robot flies through the air like a jellyfish swims. The jellyfish flier is a strange sight — it looks a little bit like a Chinese lantern that's developed a hankering for the open skies — but its unique design keeps it from tipping over without the use of sensors or external controls. 

That talent could make it handy for maneuvering in small spaces, said its inventor Leif Ristroph, a postdoctoral researcher at New York University. "What's cool is you can actually build these flying things yourself," Ristroph told LiveScience. "All the components I used to make this, they cost about $15 and they're available on hobby airplane websites." 

Ristroph, whose background is in physics, studied insect flight for his doctorate. Insects are intriguing to physicists and engineers, because of their flying abilities. Contrary to what might be expected, it's harder to engineer something tiny to fly than something big, Ristroph said. ...

Cancer genomics

A great article in Esquire on the frontier of cancer genomics. It's only a matter of time before many wealthy individuals diagnosed with cancer seek out this standard of care. (I'm told that sequencing alone can lead to actionable conclusions in more than a few percent of all cases, even now.) The resulting advances will hopefully eventually reach everyone else.

Biomathematician Eric Schadt, shown above.

Esquire: ... When [Schadt] graduated high school, he joined the Air Force with the idea of subjecting himself to the rigors of Special Forces training. Instead, he blew out his shoulder on a climb, and the Air Force tried to salvage its investment by putting him through a battery of tests. He took them; when the scores came back, he was asked by stunned superiors if math had always come easily to him. Then he was sent to college and undertook the task of complete intellectual self-transformation. He received an undergraduate degree in applied mathematics and computer science at Cal Poly and his master's in pure mathematics at UC Davis. Pure math was, to him, the Special Forces of the mind—he took it because it was so hard, and he wanted to find out just how smart he was. He was pretty smart, as it turned out, but he despaired of working on problems that existed on the level of pure abstraction and had no bearing on the problems of the world. It seemed like, well, a sin. He went to UCLA to get a Ph.D. in the emerging field of biomathematics. The one problem was that the degree required a Ph.D.-level mastery of molecular biology, and the last biology course he'd taken was in high school. So he taught himself by reading textbooks. It wasn't hard. Pure math was hard. Molecular biology, after pure math, struck him as ridiculously easy.

... Schadt told Merck that this was a strategy doomed to fail, because disease arose not from single genes or pathways but rather out of vast networks of genes and pathways whose interactions could be understood only by supercomputers guided by abstruse algorithms. Evangelical still, though now evangelical on behalf of irreducible complexity, he asked Merck to remake itself in the image of the network model he was determined to pioneer. Merck declined and Schadt headed to Silicon Valley, to the land of data.

... In September, Mount Sinai announced that he would be head of the newly created Institute for Genomics and Multiscale Biology. A little more than a year later, Sinai announced that Schadt's operation would be renamed the Icahn Institute, just as the entire medical school would be renamed the Icahn School of Medicine at Mount Sinai. For the privilege, Carl Icahn had given Eric Schadt $150 million to claim the future of biology.

The article focuses on the treatment of Stephanie Lee's colon cancer.

Esquire: ... The first thing that needs to be understood about Stephanie's data is that there would be a lot of it. From the samples of Stephanie's blood, the gene sequencers would generate the data about the genes in her "germline"—the genes (and the gene mutations) that she inherited from her parents and that existed in every cell of her body. From the samples sliced from her colon, the sequencers would generate data about her cancer and the mutations that produced it. But the data would be raw. It would contain millions of bits of genetic information, each one a sentence in the horror story that Stephanie's cancer was telling—and all those sentences, at least initially, adding up to a bewildering Babel. The data would exist right on the edge of incoherence; then Schadt and his scientists would strive both to make sense of it and complicate it. That's their trademark, and why they need a supercomputer. The genes that Stephanie was born with would be compared with the genes that were driving Stephanie's cancer. The genes that were driving Stephanie's cancer would be compared with the vast libraries of reference data-bases that already exist on all kinds of cancers. Then they would be plotted against the "network models" that the Icahn Institute is constructing, the millions of individual data points mined for their billions and even trillions of connections.

... Schadt's scientists—his biologists and his mathematicians—were from all over the world. Many had followed Schadt from the West Coast, but before they came to America, they lived in China and India and Russia. Now they had access to near infinities of information; indeed, they would soon have access to the near infinity of information generated by the DNA of a woman in Mississippi who had been given no information at all, except the information that she was going to die. It was a point lost on no one, least of all Schadt.

... A month earlier, Cagan had started doing something that he said "had never been done before." He started creating "personalized flies" for cancer patients. He took the mutations that scientists like Schadt had revealed and loaded them into flies, essentially giving the flies the same cancer that the patient had. Then he treated them. "Why a fly? You can do this in a fly. You can capture the complexities of the tumor."

... By October 11, however, Cagan already had "one possible drug suggestion for her"—or one possible combination of drugs, since he always tests at least two at a time.

... Now the oncologists at Mount Sinai were asking Schadt and Cagan if there was something they could do in their own intractable cases. And Dr. Holcombe was asking what studies had to be done to incorporate personalized therapy into the standard of care…a standard of care derived in part from none other than little ol' Stephanie Lee. There had been the imposition of obstacles at every step of the way, and the odds against her remaining on what Schadt called "a path to fight on" had beggared even his mathematical imagination. And yet here she was. Her tumor had become, in Ross Cagan's words, "at this point in time, the most fussed-over tumor that I'm aware of." ...

Here's a peek at some of the computing infrastructure behind this kind of work.

US economic mobility data

2017 Update: the Pew report has moved; old links below are broken.

A commenter points me to the Pew Trust study on US economic mobility. I excerpt some interesting figures from the report below, but it is worth reading in full. Much of the data comes from NLSY. Note that mobility data over quintiles does not address the increasing concentration of wealth at the top: see US wealth inequality and Inside the 1%.

Americans born in middle income quintile families have roughly equal probability of ending up in any of the other quintiles. Being born in a top quintile family is far from a guarantee of persistence in the top quintile, and similarly for the bottom quintile.

White men have slightly more upward mobilility than other groups.

The outcome distribution for top quintile (family background) black men is most similar to that for median quintile white men.

Superior cognitive ability is strongly indicative of upward mobility from the lowest quintile. This is true for both blacks and whites. Individuals who are cognitively at the median in the overall population have an 80% chance of moving up and out of the bottom quintile.

Pew: Individuals with higher test scores in adolescence are more likely to move out of the bottom quintile, and test scores can explain virtually the entire black-white mobility gap. Figure 13 plots the transition rates against percentiles of the AFQT test score distribution. The upward-sloping lines indicate that, as might be expected, individuals with higher test scores are much more likely to leave the bottom income quintile. For example, for whites, moving from the first percentile of the AFQT distribution to the median roughly doubles the likelihood from 42 percent to 81 percent. The comparable increase for blacks is even more dramatic, rising from 33 percent to 78 percent. Perhaps the most stunning finding is that once one accounts for the AFQT score, the entire racial gap in mobility is eliminated for a broad portion of the distribution. At the very bottom and in the top half of the distribution a small gap remains, but it is not statistically significant. The differences in the top half of the AFQT distribution are particularly misleading because there are very few blacks in the NLSY with AFQT scores this high.

There is a tide

This novel reminds of recent dystopian movies and books such as Elysium, The Road, Never Let Me Go and Cloud Atlas. Our zeitgeist recognizes the ever accelerating gap between haves and have-nots, and these novels and films reflect that collective consciousness. The gap always existed between the rich and poor worlds, but now it exists within developed countries like the US, threatening broad swathes of the former middle class.

Leonard Lopate Show: Chang-Rae Lee talks about his new novel, On Such a Full Sea, set in a future, when a long-declining America is strictly stratified by class. Abandoned urban neighborhoods have become high-walled, self-contained labor colonies. The members of the labor class work to provide quality produce and fish to elite villages. In this world lives Fan, a female fish-tank diver, who leaves her home in the B-Mor settlement (once known as Baltimore), when the man she loves mysteriously disappears.

Interestingly, the wealthy dwellers of the Charters allow the top 1 percent of children from the labor colonies to ascend in class. The main character Fan's brother was adopted by a Charter family, and she seeks him out for help. The genomic angle manifests in the disappearance of Fan's love, who is dispatched (for study?) because of a rare mutation that makes him resistant to the still-deadly "C-diseases" (cancer?).

An excerpt from the book.

... When our ancestors were first brought here—the archival vids and pix show them rolling in on fleets of shiny silver company buses—the air was to them fresh and clear, just like in the image of the roofless row house, and when they stepped out, they must have been entranced by the scant briny notes of the harbor waters, breathing them in deep. And think of how startled they might have been by the strange brand of tidiness in this place (once known as Baltimore) and other abandoned cities that settlers were sent to in other eastern and midwestern states, this preservation by dint of absence, such that after they gathered their luggage from the curb and were shuttled by carts to the houses assigned to them, our and your and Fan's forebears among them, their gasps were not of trepidation or disappointment but of gratitude and relief.

Indeed, it's difficult for us to understand how genuinely grateful they were; we glance around B-Mor now and it's impossible to imagine how our people could have felt that way (how time and safety and a filled belly rapidly evolve us!), to be presented with so depleted a cityscape and still have a heart-surge of excitement. The legendary Wen Shurbao, who would be our first and only mayor, reportedly exhorted his brethren by invoking the classic proverb: "Our generation will plant the trees. The next will enjoy the shade."

Surely there were the discontented among those originals, but which of them could deny the promise of this place? Here was an entire community, ready for revitalization. Yes, the houses were basically shells, but in fact many still had roofs and walls and sturdy stairs; yes, few had any boilers, but the majority had salvageable wiring and plumbing; yes, the floors had to be scraped and sanded and refinished, every cabinet and counter scrubbed and disinfected of the leavings of birds and vermin and insects, and yet what activity offers more immediate, honest gratification than shining up a seemingly ruined surface back to the distinctive grain of its essence?

... We should concede that unlike the experience of most immigrants, there was very little to encounter by way of an indigenous population. There were smatterings of them, to be sure, pockets of residents on the outskirts of what is now the heart of B-Mor, these descendants of nineteenth-century African slaves and twentieth-century laborers from Central America and even bands of twenty-first-century urban-nostalgics, all of whom settled the intimate grid of these blocks and thrived for a time and, for reasons that history can confidently trace and identify but never quite seem to solve, inexorably declined and finally disappeared. Our predecessors had the unique advantage of being husbanded by one of the federated companies, rather than the revolving cast of governmental bodies that overreached in their efforts or were disastrously neglectful, all of them downright clueless. The originals were brought in en masse for a strict purpose but with their work- and family-centric culture intact, such that they would not only endure and eventually profit the seed investors but also prosper in a manner that would be perpetually regenerative.

... Perhaps it was the same with our originals, though in a different circumstance. They went about their first labors, renovating the row houses in the same way, it turns out, that certain antique American communities used to do, the foreman or forewoman of each block marshaling all its residents to converge on one address and revamp, say, the bathrooms or kitchen, the museum clips just like a science class vid of hundreds of ants tugging a sourball-sized rock. You can picture it now. They'd go from one house to the next, right on down the block, this mobile, instantly adaptive assembly line, each person assigned a function, with the children passing beach pails of dust and rubble in a brigade, the elderly offering sips of cool chrysanthemum tea from canteens, even the unwell propped up in chairs close by or even inside the site, so that they might lend moral support or learn by watching. ...

Julius Caesar, Act 4, Scene 3,

BRUTUS
Under your pardon. You must note beside,
That we have tried the utmost of our friends,
Our legions are brim-full, our cause is ripe.
The enemy increaseth every day.
We, at the height, are ready to decline.
There is a tide in the affairs of men,
Which, taken at the flood, leads on to fortune;
Omitted, all the voyage of their life
Is bound in shallows and in miseries.
On such a full sea are we now afloat,
And we must take the current when it serves
Or lose our ventures.

Meritocrats

An essay by the late historian Tony Judt, composed as he slowly died of motor neuron disease.

Meritocrats

I came up to King’s College, Cambridge, in 1966...

My King’s was the very incarnation of meritocratic postwar Britain. Most of us got where we were by doing well in exams and, to a striking extent, we pursued occupations that reflected our early talents and interests. The cohort of Kingsmen who came up in 1966 stand out in their choice of careers: more than any group before or since, we opted for education, public service, the higher reaches of journalism, the arts, and the unprofitable end of the liberal professions.

It is thus altogether appropriate that the most promising economist of our generation—Mervyn King—should have ended up as the governor of the Bank of England, rather than an investment banker or hedge funder. Before our time, talented Kingsmen doubtless followed similar paths. But a glance at the obituaries of an older generation reveals just how many of them returned to the family business or to the traditional professions of their fathers and grandfathers.

As for those who came after, it is depressing to record how quickly and in what numbers the graduates of the 1970s and since resorted to the world of private banking, commerce, and the more remunerative reaches of the law. Perhaps one should not blame them; in our time, jobs were still plentiful and we could bask in the waning rays of postwar prosperity. All the same, it’s very clear that our elective affinities lay elsewhere.

... I served for a while as a very junior member on the College Fellowship Electors with Williams, John Dunn, Sydney Brenner (the Nobel Prize winner in medicine), Sir Frank Kermode, Geoffrey Lloyd (the historian of ancient science), and Sir Martin Rees (the Astronomer Royal). I have never lost the sense that this was learning: wit, range, and above all the ability (as Forster put it in another context) to connect. 

My greatest debt, though I did not fully appreciate it at the time, was to Dunn, then a very young college Research Fellow, now a distinguished professor emeritus. It was John who—in the course of one extended conversation on the political thought of John Locke—broke through my well-armored adolescent Marxism and first introduced me to the challenges of intellectual history. He managed this by the simple device of listening very intently to everything I said, taking it with extraordinary seriousness on its own terms, and then picking it gently and firmly apart in a way that I could both accept and respect.

That is teaching. It is also a certain sort of liberalism: the kind that engages in good faith with dissenting (or simply mistaken) opinions across a broad political spectrum. No doubt such tolerant intellectual breadth was not confined to King’s. But listening to friends and contemporaries describe their experiences elsewhere, I sometimes wonder. Lecturers in other establishments often sounded disengaged and busy, or else professionally self-absorbed in the manner of American academic departments at their least impressive.

... For forty years, British education has been subjected to a catastrophic sequence of “reforms” aimed at curbing its elitist inheritance and institutionalizing “equality.” The havoc wrought in higher education was well summarized by Anthony Grafton in this magazine, but the worst damage has been at the secondary level. Intent upon destroying the selective state schools that afforded my generation a first-rate education at public expense, politicians have foisted upon the state sector a system of enforced downward uniformity.

... Universities are elitist: they are about selecting the most able cohort of a generation and educating them to their ability—breaking open the elite and making it consistently anew. Equality of opportunity and equality of outcome are not the same thing. A society divided by wealth and inheritance cannot redress this injustice by camouflaging it in educational institutions—by denying distinctions of ability or by restricting selective opportunity—while favoring a steadily widening income gap in the name of the free market. This is mere cant and hypocrisy. ...

See also Defining Merit and Les Grandes Ecoles Chinoises.

There and back again

A day at the beach.

Obligatory selfie.

The kids caught two lizards in the backyard -- "Larry" and "Barry" :-)

Rose Bowl victory for MSU.

The scene at Detroit airport  :-(

I have a lot more photos but the wife has decreed that family photos are not to appear online.

PS I would have preferred to stay at home and work but other forces prevailed.

The Gene Factory (New Yorker)

LETTER FROM SHENZHEN: THE GENE FACTORY

A Chinese firm’s bid to crack hunger, illness, evolution—and the genetics of human intelligence.

BY MICHAEL SPECTER

A well-balanced article about BGI in the New Yorker.

I am misquoted about our current ability to predict height from genomic information, despite an hour on the phone with the Harvard-educated fact checker. There is also some confusion in that paragraph concerning the correlation between height and IQ and its relevance to the broader discussion  :-(

Chris Chang has the wise, last words in the article :-)  Click for larger version.

Research rankings

Some notes for my own use on research rankings by discipline for Michigan State University. The ranges are 95% confidence intervals using the R-rank (including, among other things, publications, citations, grants and awards) from the 2010 NRC evaluation (see, e.g., here). Rank ordered by, e.g., central value of R range, most of the departments below come out in the top 20-30 in the US. More data: S rankings in various fields.

Physics                                     17-41
Chemistry                                 21-59
Computer Science                    12-32
Math                                         11-43
EE/CE                                      47-87
Biochem/MoBio                      54-96
Neuroscience                            72-89
Plant Biology                            6-32

In the NSF HERD (total R&D expenditures) data MSU is ranked 36th in the US, with 2012 expenditures just over $500 million. If research hospital numbers are excluded (MSU has historically had a teaching medical school, although this is changing), the MSU rank would be quite a bit higher.

Peace on Earth, Good Will to Men 2013

For years, when asked what I wanted for Christmas, I've been replying: peace on earth, good will toward men :-)

No one ever seems to recognize that this comes from the bible, Luke 2.14 to be precise!

Linus said it best in A Charlie Brown Christmas:

And there were in the same country shepherds abiding in the field, keeping watch over their flock by night.

And, lo, the angel of the Lord came upon them, and the glory of the Lord shone round about them: and they were sore afraid.

And the angel said unto them, Fear not: for, behold, I bring you good tidings of great joy, which shall be to all people.

For unto you is born this day in the city of David a Saviour, which is Christ the Lord.

And this shall be a sign unto you; Ye shall find the babe wrapped in swaddling clothes, lying in a manger.

And suddenly there was with the angel a multitude of the heavenly host praising God, and saying,

Glory to God in the highest, and on earth peace, good will toward men.

Merry Christmas!



Here's a longer excerpt from A Charlie Brown Christmas.

Back in the day

Two old photos I discovered at my mom's house. These would be from 1986 (the graduation photo) and probably a year or two after that for the other one (taken in our garage in Iowa during Xmas break, check out the penny loafers!).

Here's an old Wham! video from the same era :-) Eighties forever!

The dawn of genetic engineering?

Some CRISPR links. This technology is for real. See earlier post CRISPR. Watch realtime action here. GeCKO knockout in human cells.

Zhang and Church raise $43M for new venture Editas.

Application to Cystic Fibrosis in human stem cells , Cataracts in mouse.

The Scientist: It was less than a year ago that scientists first applied CRISPR, a genome-editing technique, to human cells. In short order, the technique has taken off like wildfire. And now, two papers appearing in Cell Stem Cell today (December 5) show that CRISPR can be used to rewrite genetic defects to effectively cure diseases in mice and human stem cells.

“What’s significant about this is it’s taking CRISPR to that next step of what it can be used for, and in this case, it’s correcting mutations that cause disease,” said Charles Gersbach, a genomics researcher at Duke University, who was not involved in either study.

CRISPR stands for clustered regularly interspaced short palindromic repeats. These RNA sequences serve an immune function in archaea and bacteria, but in the last year or so, scientists have seized upon them to rewrite genes. The RNA sequence serves as a guide to target a DNA sequence in, say, a zygote or a stem cell. The guide sequence leads an enzyme, Cas9, to the DNA of interest. Cas9 can cut the double strand, nick it, or even knock down gene expression. After Cas9 injures the DNA, repair systems fix the sequence—or new sequences can be inserted.

In one of the new papers, a team from China used CRISPR/Cas9 to replace a single base pair mutation that causes cataracts in mice. The researchers, led by Jinsong Li at the Shanghai Institute for Biological Sciences, designed a guide RNA that led Cas9 to the mutant allele where it induced a cleavage of the DNA. Then using either the other wild-type allele or oligos given to the zygotes repair mechanisms corrected the sequence of the broken allele.

Li said that about 33 percent of the mutant zygotes that were injected with CRISPR/Cas9 grew up to be cataract-free mice. In an e-mail to The Scientist, Li said the efficiency of the technique was low, “and, for clinical purpose, the efficiency should reach 100 percent.”

Still, this was the first time CRISPR had been used to cure a disease in a whole animal, an advance that Jennifer Doudna, a leader in CRISPR technology at the University of California, Berkeley, said was encouraging. Both studies “show the potential for using the technology to correct disease-causing mutations, and that’s what very exciting here,” she said.

Hans Clevers, a stem cell researcher at the Hubrecht Institute in Utrecht, The Netherlands, led the other study, which used CRISPR/Cas9 to correct a defect associated with cystic fibrosis in human stem cells. The team’s target was the gene for an ion channel, cystic fibrosis transmembrane conductor receptor (CFTR). A deletion in CFTR causes the protein to misfold in cystic fibrosis patients.

Using cultured intestinal stem cells developed from cell samples from two children with cystic fibrosis, Clevers’s team was able to correct the defect using CRISPR along with a donor plasmid containing the reparative sequence to be inserted. The researchers then grew the cells into intestinal “organoids,” or miniature guts, and showed that they functioned normally. In this case, about half of clonal organoids underwent the proper genetic correction, Clevers said.

For both studies, the researchers did not have to make significant modifications to existing CRISPR protocols. Clevers said in an e-mail to The Scientist that, compared with other gene editing techniques, CRISPR was straightforward. “We tried TALENs [transcription activator-like effector nucleases] and Zinc finger approaches. CRISPR is exquisitely fast and simple,” Clevers said. Li agreed. “I think CRISPR/Cas9 system may be the easiest strategy to cure genetic disease than any other available gene-editing techniques,” he said.

One limitation of CRISPR is that the approach can create off-target effects—alterations to sites other than the target DNA. In both studies, off-target effects were relatively rare, said Gersbach. “While reducing off-target effects is a priority, it’s unrealistic to think you’d be able to get rid of all off-target effects,” he told The Scientist.

While the approach is far from ready for prime time, the results of both these studies show promise for future clinical potential. “I think each time an advance like this is made, people are more sure that this is a technique that is likely to be useful in treating humans,” said Doudna.

One in a thousand

Good evening. The organizers have seen fit to place me on the schedule between you and dinner. So I will be mercifully brief.

As Terry mentioned, we had the awesome task of reviewing 150 promotion files last year. The word "awesome" can mean many things. Here it means humbling. It was humbling to review the impressive files of the full professor candidates. Our university is fortunate to have such tremendously accomplished faculty.

Terry, the Provost, and I upheld the highest standards in full professor promotion cases. Each and every person being honored here tonight has made important contributions to scholarship and learning, and is an invaluable member of our university community.

A final remark before we eat our rubber chickens. It is often said that we are entering or have entered the age of the knowledge economy -- that a person's contributions will be from their knowledge, intelligence, and creativity. But when an attorney prepares a case it is for her client. When a Google engineer develops a new algorithm, it is for Google -- for money. Fewer than one in a thousand individuals in our society have the privilege, the freedom, to pursue their own ideas and creations. The vast majority of such people are at research universities. A smaller number are at think tanks or national labs, but most are professors like yourselves. It is you who will make the future better than the past; who will bring new wonders into existence. Your work may be largely invisible to our fellow citizens, but the future owes its greatness to you. My sincere congratulations.

Neanderthals dumb?

This figure is from the Supplement (p.62) of a recent Nature paper describing a 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; see earlier post Structural genomic variants (CNVs) affect cognition.

From the Supplement (p.62):

Of particular interest is the modern human-specific duplication on 16p11.2 which encompasses the BOLA2 gene. This locus is the breakpoint of the 16p11.2 micro-deletion, which results in developmental delay, intellectual disability, and autism5,6. We genotyped the BOLA2 gene in 675 diverse human individuals sequenced to low coverage as part of the 1000 Genome Project Phase I7 to assess the population distribution of copy numbers in homo-sapiens (Figure S8.3). While both the Altai Neandertal and Denisova individual exhibit the ancestral diploid copy number as seen in all the non-human great apes, only a single human individual exhibits this diploid copy number state.

My recollection from the earlier (less precise) Neanderthal sequences is that the number of bp differences between them and us is few per thousand. Whereas, for modern humans it's 1 per thousand with an additional +/-15% variation due to ethnicity. So, I think it's fair to say that they are qualitatively much more different from us than we (moderns) are from each other. See also The genetics of humanness.

My colleague James Lee (I note he is too modest to list his Harvard Law degree on his faculty page!) describes the current era in genomics as an "age of wonder" :-)  We can anticipate tremendous discoveries in the next decade.

Structural genomic variants (CNVs) affect cognition

CNVs (structural genomic variants) associated with increased autism and schizo risk are found to depress cognitive function in carriers who do not present for either condition. There are also effects on physical brain structure.

This is the future of neuroscience: read out the genome and look for the direct effect on phenotype. Assuming the results hold up, we can conclude that these mutations cause abnormal cognitive function in humans. We are just at the beginning of this line of research: mutations of smaller effect size will require larger samples to detect, but they almost certainly exist.

Note this is deCODE and Kari Stefansson -- they have access to all health records and genotypes in Iceland. See also deCODE, de novo mutations, and autism risk.

CNVs conferring risk of autism or schizophrenia affect cognition in controls (Nature)

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

This figure shows impairment in population SDs for different groups. V IQ and P IQ are Verbal and Performance IQ (Wechsler), IIUC.

From the Supplement -- check out the p values ;-)

My guess is that most intelligence alleles have negative effect. That is, the majority of genetic variation in cognitive ability is determined by the number and type of somewhat deleterious mutations we all carry around. (There are probably also minor alleles of positive effect, but fewer of them.) Note the CNVs in this article, while having a significantly (1 SD) negative effect on IQ, do not prevent reproduction (fecundity is reduced, but not to zero), so clearly mutations of large effect can linger for some generations. Mutations of smaller effect might even be neutral due to pleiotropy, etc.

Her: Singularity as romantic comedy

Can't quite decide whether this is a dystopian or utopian future  :-)

New Yorker ...Spike Jonze’s movie, which was shot in Los Angeles and Shanghai, is set in a near but dateless future, where the rough edges of existence have been rubbed away. The colors of clothes and furnishings, though citrus-bright, are diluted by the pastel softness of the lighting, so that nothing hurts the eye. People ride in smoothly humming trains, not belching cars. And Theodore’s cell phone reminds you of those slender vintage cases for cigarettes and visiting cards; if the ghost of Steve Jobs is watching, he will glow a covetous green.

This little flat box, plus an earpiece that Theodore plugs in whenever he wakes up or can’t sleep, is his portal. It links him to OS1, “the first artificially intelligent operating system,” which is newly installed on his computer. More than that, “it’s a consciousness,” with a voice of your choice, and a rapidly evolving personality, which grows not like a baby, or a library, but like an unstoppable alien spore. Theodore’s version is called Samantha, and practically her first request is: “You mind if I look through your hard drive?” She tidies his e-mails, reads a book in two-hundredths of a second, fixes him up on a date, and, when that goes badly, has sex with him—aural sex, so to speak, but Theodore will take what he can get. No surprise, really, given that the role of Samantha is spoken by Scarlett Johansson.

... And it is romantic: Theodore and Samantha click together as twin souls, not caring that one soul is no more than a digital swarm. Sad, kooky, and daunting in equal measure, “Her” is the right film at the right time. It brings to full bloom what was only hinted at in the polite exchanges between the astronaut and hal, in “2001: A Space Odyssey,” and, toward the end, as Samantha joins forces with like minds in cyberspace, it offers a seductive, nonviolent answer to Skynet, the system in the “Terminator” films that attacked its mortal masters. We are easy prey, not least when we fall in love.

Yuri Slezkine: The Jewish Century

Yuri Slezkine of UC Berkeley, author of The Jewish Century (reviewed in The Nation).

@7 min "I was unprincipled enough to put down Russian in all my official paperwork because, obviously, it made it much easier to get into college." [ Slezkine is half Jewish; his father is Russian. See They take students like you there and I'm not Asian. ]

@29:30 The evolution of anti-semitism in the Soviet Union. From an overrepresentation of Jews in the early Soviet leadership, to (post-WWII and -Stalin) an era of quotas and overt discrimination, and an increasing identification of the Soviet state with Russian nationality.

From the introduction to The Jewish Century:

The Modern Age is the Jewish Age, and the twentieth century, in particular, is the Jewish Century. Modernization is about everyone becoming urban, mobile, literate, articulate, intellectually intricate, physically fastidious, and occupationally flexible. It is about learning how to cultivate people and symbols, not fields or herds. It is about pursuing wealth for the sake of learning, learning for the sake of wealth, and both wealth and learning for their own sake. It is about transforming peasants and princes into merchants and priests, replacing inherited privilege with acquired prestige, and dismantling social estates for the benefit of individuals, nuclear families, and book-reading tribes (nations). Modernization, in other words, is about everyone becoming Jewish.

Some peasants and princes have done better than others, but no one is better at being Jewish than the Jews themselves. In the age of capital, they are the most creative entrepreneurs; in the age of alienation, they are the most experienced exiles; and in the age of expertise, they are the most proficient professionals. Some of the oldest Jewish specialties-commerce, law, medicine, textual interpretation, and cultural mediation-have become the most fundamental (and the most Jewish) of all modern pursuits. It is by being exemplary ancients that the Jews have become model moderns. ...

Lévi-Strauss in Tokyo

Claude Lévi-Strauss has been called the father of modern (social) anthropology. He lived to be 100 years old, passing in 2009. I recommend his Tristes Tropiques, a memoir of time in the jungles of Brazil (full text in English). The lectures in the book below were delivered in Tokyo in 1986.

Anthropology Confronts the Problems of the Modern World

(p. 98-99) And who knows whether aggressive or contemplative dispositions, technical ingenuity, and so on, are not partly linked to genetic factors? None of these traits, as we apprehend them at the cultural level, can be clearly linked to a genetic foundation, but we cannot rule out a priori the distant effects of intermediate links. If such effects are real, it would be true to say that every culture selects genetic abilities that, by retroaction, influence the culture and reinforce its orientation.

Go train jiujitsu!

Some beautiful jiujitsu from ADCC 2013.




Estima v. Galvao superfight:




I hadn't been on the mat in a long time, but over Thanksgiving I had a chance to show some things to my nephew. Almost ten years of training -- not all of it is gone yet :-)

Is science self-correcting?

More fun from our man Ioannidis. See earlier posts Medical science? , NIH discovers reproducibility and Bounded cognition.

A toy model of the dynamics of scientific research, with probability distributions for accuracy of experimental results, mechanisms for updating of beliefs by individual scientists, crowd behavior, bounded cognition, etc. can easily exhibit parameter regions where progress is limited (one could even find equilibria in which most beliefs held by individual scientists are false!). Obviously the complexity of the systems under study and the quality of human capital in a particular field are important determinants of the rate of progress and its character.

In physics it is said that successful new theories swallow their predecessors whole. That is, even revolutionary new theories (e.g., special relativity or quantum mechanics) reduce to their predecessors in the previously studied circumstances (e.g., low velocity, macroscopic objects). Swallowing whole is a sign of proper function -- it means the previous generation of scientists was competent: what they believed to be true was (at least approximately) true. Their models were accurate in some limit and could continue to be used when appropriate (e.g., Newtonian mechanics).

In some fields (not to name names!) we don't see this phenomenon. Rather, we see new paradigms which wholly contradict earlier strongly held beliefs that were predominant in the field* -- there was no range of circumstances in which the earlier beliefs were correct. We might even see oscillations of mutually contradictory, widely accepted paradigms over decades.

It takes a serious interest in the history of science (and some brainpower) to determine which of the two regimes above describes a particular area of research. I believe we have good examples of both types in the academy.

* This means the earlier (or later!) generation of scientists in that field was incompetent. One or more of the following must have been true: their experimental observations were shoddy, they derived overly strong beliefs from weak data, they allowed overly strong priors to determine their beliefs.

Why Science Is Not Necessarily Self-Correcting 

(DOI: 10.1177/1745691612464056)

John P. A. Ioannidis
Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, and Department of Statistics, Stanford University School of Humanities and Sciences

The ability to self-correct is considered a hallmark of science. However, self-correction does not always happen to scientific evidence by default. The trajectory of scientific credibility can fluctuate over time, both for defined scientific fields and for science at-large. History suggests that major catastrophes in scientific credibility are unfortunately possible and the argument that “it is obvious that progress is made” is weak. Careful evaluation of the current status of credibility of various scientific fields is important in order to understand any credibility deficits and how one could obtain and establish more trustworthy results. Efficient and unbiased replication mechanisms are essential for maintaining high levels of scientific credibility. Depending on the types of results obtained in the discovery and replication phases, there are different paradigms of research: optimal, self-correcting, false nonreplication, and perpetuated fallacy. In the absence of replication efforts, one is left with unconfirmed (genuine) discoveries and unchallenged fallacies. In several fields of investigation, including many areas of psychological science, perpetuated and unchallenged fallacies may comprise the majority of the circulating evidence. I catalogue a number of impediments to self-correction that have been empirically studied in psychological science. Finally, I discuss some proposed solutions to promote sound replication practices enhancing the credibility of scientific results as well as some potential disadvantages of each of them. Any deviation from the principle that seeking the truth has priority over any other goals may be seriously damaging to the self-correcting functions of science

Corrupt practices

OK for Harvard but not for JP. Legacy and "strategic" admits still a big chunk of each entering class. Foreign Corrupt Practices Act.

NYTimes: Federal authorities have obtained confidential documents that shed new light on JPMorgan Chase’s decision to hire the children of China’s ruling elite, securing emails that show how the bank linked one prominent hire to “existing and potential business opportunities” from a Chinese government-run company.

The documents, which also include spreadsheets that list the bank’s “track record” for converting hires into business deals, offer the most detailed account yet of JPMorgan’s “Sons and Daughters” hiring program, which has been at the center of a federal bribery investigation for months. The spreadsheets and emails — recently submitted by JPMorgan to authorities — illuminate how the bank created the program to prevent questionable hiring practices but ultimately viewed it as a gateway to doing business with state-owned companies in China, which commonly issue stock with the help of Wall Street banks.

NIH discovers reproducibility

When someone first described to me the evidence-based medicine movement, I responded (shocked): "Is that like science-based science? What were they doing before?"

Nature News: In biomedical science, at least one thing is apparently reproducible: a steady stream of studies that show the irreproducibility of many important experiments.

In a 2011 internal survey, pharmaceutical firm Bayer HealthCare of Leverkusen, Germany, was unable to validate the relevant preclinical research for almost two-thirds of 67 in-house projects. Then, in 2012, scientists at Amgen, a drug company based in Thousand Oaks, California, reported their failure to replicate 89% of the findings from 53 landmark cancer papers. And in a study published in May, more than half of the respondents to a survey at the MD Anderson Cancer Center in Houston, Texas, reported failing at least once in attempts at reproducing published data (see 'Make believe').

The growing problem is threatening the reputation of the US National Institutes of Health (NIH) based in Bethesda, Maryland, which funds many of the studies in question. Senior NIH officials are now considering adding requirements to grant applications to make experimental validations routine for certain types of science, such as the foundational work that leads to costly clinical trials. ...

A comment from a researcher quoted in the article notes

... a broader need to shift biomedical research from categorical statements and simple schematics to quantifiable hypotheses backed up by modeling and computation, open access to data (itself requiring new approaches and infrastructure) and better application of probability theory and statistics.

See also Medical science? (are most research findings false?) and Bounded cognition.

PLINK 1.90 alpha

WDIST is now PLINK 1.9 alpha. WDIST (= "weighted distance" calculator) was originally written to compute pairwise genomic distances. The mighty Chris Chang then amazingly re-implemented all of PLINK with significant improvements (see below).

PLINK 1.9 even has support for LASSO (i.e., L1 penalized optimization, a particular method for Compressed Sensing).

This is a comprehensive update to Shaun Purcell's popular PLINK command-line program, developed by Christopher Chang with support from the NIH-NIDDK's Laboratory of Biological Modeling and others. (What's new?) (Credits.)

It isn't finished yet (hence the 'alpha' designation), but it's getting there. We are working with Dr. Purcell to launch a large-scale beta test in the near future. ...

Unprecedented speed 

Thanks to heavy use of bitwise operators, sequential memory access patterns, multithreading, and higher-level algorithmic improvements, PLINK 1.9 is much, much faster than PLINK 1.07 and other popular software. Several of the most demanding jobs, including identity-by-state matrix computation, distance-based clustering, LD-based pruning, and association analysis max(T) permutation tests, now complete hundreds or even thousands of times as quickly, and even the most trivial operations tend to be 5-10x faster due to I/O improvements.

We hasten to add that the vast majority of ideas contributing to PLINK 1.9's performance were developed elsewhere; in several cases, we have simply ported little-known but outstanding implementations without significant further revision (even while possibly uglifying them beyond recognition; sorry about that, Roman...). See the credits page for a partial list of people to thank. On a related note, if you are aware of an implementation of a PLINK command which is substantially better what we currently do, let us know; we'll be happy to switch to their algorithm and give them credit in our documentation and papers.

Nearly unlimited scale 

The main genomic data matrix no longer has to fit in RAM, so bleeding-edge datasets containing tens of thousands of individuals with exome- or whole-genome sequence calls at millions of sites can be processed on ordinary desktops (and this processing will usually complete in a reasonable amount of time). In addition, several key individual x individual and variant x variant matrix computations (including the GRM mentioned below) can be cleanly split across computing clusters (or serially handled in manageable chunks by a single computer).

Command-line interface improvements
We've standardized how the command-line parser works, migrated from the original 'everything is a flag' design toward a more organized flags + modifiers approach (while retaining backwards compatibility), and added a thorough command-line help facility.

Additional functions
In 2009, GCTA didn't exist. Today, there is an important and growing ecosystem of tools supporting the use of genetic relationship matrices in mixed model association analysis and other calculations; our contributions are a fast, multithreaded, memory-efficient --make-grm-gz/--make-grm-bin implementation which runs on OS X and Windows as well as Linux, and a closer-to-optimal --rel-cutoff pruner.

There are other additions here and there, such as cluster-based filters which might make a few population geneticists' lives easier, and a coordinate-descent LASSO. New functions are not a top priority for now (reaching 95%+ backward compatibility, and supporting dosage/phased/triallelic data, are more important...), but we're willing to take time off from just working on the program core if you ask nicely.

Height prediction from common DNA variants

Still early days but it's clear where this is heading. Note the design using an outlier (case) and normal (control) group.

See also Five years of GWAS discovery and Recent human evolution: European height.

Common DNA variants predict tall stature in Europeans
DOI 10.1007/s00439-013-1394-0 (Journal: Human Genetics)

Abstract Genomic prediction of the extreme forms of adult body height or stature is of practical relevance in several areas such as pediatric endocrinology and forensic investigations. Here, we examine 770 extremely tall cases and 9,591 normal height controls in a population-based Dutch European sample to evaluate the capability of known height-associated DNA variants in predicting tall stature. Among the 180 normal height-associated single nucleotide polymorphisms (SNPs) previously reported by the Genetic Investigation of ANthropocentric Traits (GIANT) genome-wide association study on normal stature, in our data 166 (92.2 %) showed directionally consistent effects and 75 (41.7 %) showed nominally significant association with tall stature, indicating that the 180 GIANT SNPs are informative for tall stature in our Dutch sample. A prediction analysis based on the weighted allele sums method demonstrated a substantially improved potential for predicting tall stature (AUC = 0.75; 95 % CI 0.72–0.79) compared to a previous attempt using 54 height-associated SNPs (AUC = 0.65). The achieved accuracy is approaching practical relevance such as in pediatrics and forensics. Furthermore, a reanalysis of all SNPs at the 180 GIANT loci in our data identified novel secondary association signals for extreme tall stature at TGFB2 (P = 1.8 × 10−13) and PCSK5 (P = 7.8 × 10−11) suggesting the existence of allelic heterogeneity and underlining the importance of fine analysis of already discovered loci. Extrapolating from our results suggests that the genomic prediction of at least the extreme forms of common complex traits in humans including common diseases are likely to be informative if large numbers of trait-associated common DNA variants are available. [ Italics mine ]

AUC = Area Under Curve for the ROC curve defined as in the figure below. An ideal predictor has AUC = 1.