Wednesday, November 28, 2018

He did it: He Jiankui talk at HKU conference on gene editing

This is He's talk from a conference on gene editing, in progress now in HK. (Should start at 1h09.)

This article describes serious discussions between He and bioethicists over the last year.

CapEx required for this process is quite modest -- not beyond the capability of a medium-sized IVF clinic. The CRISPR vector was purchased, IIUC, for about $100!

The choice of CCR5 is not well motivated, from the perspective of most bioethicists: there are other ways to prevent HIV, and the edit could be regarded as an enhancement, not elimination of a disease allele.

@1h25 He claims that the parents were given the option to use unedited embryos for their pregnancy but chose to use the edited ones. (This decision was made even after being informed of the existence of a possible off-target edit in an inter-genic region. The possible off-target was not confirmed by later analysis.) If true, this has some important ethical implications. The problem becomes one of parental choice and reproductive freedom. IIUC, the father has rather strong feelings concerning HIV (being HIV positive) and the parents strongly desired HIV-resistance in their daughters. Who are we (or anyone else) to tell the parents whether to use the edited or unedited embryos?

Note it's possible I misunderstood what He said in his talk. There is a Twitter exegesis here, and a transcript here. I'm not sure I understood properly whether the intended edit was successful -- one embryo displayed mosaicism (not subsequently detected)?

Some comments I've shared with journalists and other interested parties below.
Re: Gene-editing using CRISPR, not a technical breakthrough -- it has been possible for some time. What is new is that someone had the audacity to push it to completion with human embryos. Some researchers who attended He's talk a few months ago at Cold Spring Harbor (the talk covered methodology but with no hint that real babies would be produced) found it sound but unremarkable.

In the near term most applications of CRISPR in IVF can already be accomplished simply by screening (genetic testing) against the undesirable genetic variant. No need to edit, just select one of the embryos without the variant.

With CRISPR one can potentially edit IN new genetic variants that neither parent has. This "enhancement" is much more ethically questionable, but may eventually happen. However it can only be done
with simple single-gene conditions.

Eventually we may have the technology to do multiple (hundreds?) of edits at a time, which will allow modification of polygenic traits. (Most traits are highly polygenic.) But this requires us to first identify actual causal variants (as opposed to variants used in a predictor that merely *correlate* strongly with the causal ones). This is a difficult scientific problem that may take a decade or more to solve. Predicting a complex trait is much easier than modifying it -- hence selection will dominate editing in utility for some time.

It is possible that gene editing will "normalize" selection of embryos as a less aggressive course of action!
See previous discussion Generation CRISPR?

At the same conference, George Daley, Dean of Harvard Medical School, advocates for a responsible pathway to clinical translation for gene editing.

George Church interview on what He did.

Monday, November 26, 2018

Generation CRISPR?

Very strange. This guy left his university a few years ago to concentrate on this research. Are his claims real?
Genome-edited baby claim provokes international outcry (Nature News)

The startling announcement by a Chinese scientist represents a controversial leap in the use of genome-editing.

A Chinese scientist claims that he has helped make the world's first genome-edited babies — twin girls who were born this month. The announcement has provoked shock, and some outrage, among scientists around the world.

He Jiankui, a genome-editing researcher from the Southern University of Science and Technology of China in Shenzhen, says that he implanted into a woman an embryo that had been edited to disable the genetic pathway that allows a cell to be infected with HIV.

In a video posted to YouTube, He says the girls are healthy and now at home with their parents. Genome sequencing of their DNA has shown that the editing worked, and only altered the gene they targeted, he says.

See also MIT Technology Review:
The Chinese scientist who claims he made CRISPR babies is under investigation

He, who led that effort, later released a video statement in which he said that healthy twin girls, Lulu and Nana, had been born “a few weeks ago.”

He said the girls had been conceived using IVF but that his team had added “a little protein and some information” to the fertilized eggs. That was a reference to the ingredients of CRISPR, the gene-editing technology he apparently employed to delete a gene called CCR5.

The claim set off a wave of criticism in China and abroad from experts who said the experiment created unacceptable risks for a questionable medical purpose. Feng Zhang, one of the inventors of CRISPR, called for a moratorium on its use in editing embryos for IVF procedures.

Documents connected to the trial named the study’s sponsors as He along with Jinzhou Qin and said it was approved by the ethics committee of HarMoniCare Shenzhen Women and Children’s Hospital.

On Sunday, the Shenzhen City Medical Ethics Expert Board said it would begin an investigation of He’s research and released a statement saying that HarMoniCare “according to our findings … never conducted the appropriate reporting according to requirements.” The former medical director of the private hospital, Jiang Su-Qi, told Southern Capital News he had no recollection of approving He’s research while he was on its ethics committee.


The president of He’s university called an emergency gathering of researchers connected to the project. “This has nothing to do with SUST, the research wasn’t conducted at SUST,” said SUST president Chen Shiyi, according to Chinese media reports. According to the school’s biology department, the research “seriously violates ethical and academic standards and regulations.” ...

Regarding the use of CRISPR in human reproduction, here is my tweet from earlier today:

Here is what I wrote in 2014 about editing vs selection of embryos:

... the distinction between embryo selection -- the parents get a baby whose DNA originates from them, but the "best baby possible" -- and active genetic editing, which can give the child genes that neither parent had.

The movie GATTACA focuses on selection -- the director made a deliberate decision to eliminate reference to splicing or editing of genes. (Possibly because Ethan Hawke's character Vincent would have no chance competing against edited people.)

At SCI FOO, George Church seemed confident that editing would be an option in the near future. He is convinced that off-target mutations are not a problem for CRISPR. I have not yet seen this demonstrated in the literature, but of course George knows a lot more than what has been published. (Warning: I may have misunderstood his comments as there was a lot of background noise when we were talking.)

One interesting genetic variant (Lrp5?) that I learned about at the meeting, of obvious interest to future splicers and editors, apparently conveys an +8 SD increase in bone strength!

My views on all of this:
... given sufficient phenotype|genotype data, genomic prediction of traits such as cognitive ability will be possible. If, for example, 0.6 or 0.7 of total population variance is captured by the predictor, the accuracy will be roughly plus or minus half a standard deviation (e.g., a few cm of height, or 8 IQ points). The required sample size to extract a model of this accuracy is probably on the order of a million individuals. As genotyping costs continue to decline, it seems likely that we will reach this threshold within five years for easily acquired phenotypes like height (self-reported height is reasonably accurate), and perhaps within the next decade for more difficult phenotypes such as cognitive ability. At the time of this writing SNP genotyping costs are below $50 USD per individual, meaning that a single super-wealthy benefactor could independently fund a crash program for less than $100 million.

Once predictive models are available, they can be used in reproductive applications, ranging from embryo selection (choosing which IVF zygote to implant) to active genetic editing (e.g., using powerful new CRISPR techniques). In the former case, parents choosing between 10 or so zygotes could improve their expected phenotype value by a population standard deviation. For typical parents, choosing the best out of 10 might mean the difference between a child who struggles in school, versus one who is able to complete a good college degree. Zygote genotyping from single cell extraction is already technically well developed [25], so the last remaining capability required for embryo selection is complex phenotype prediction. The cost of these procedures would be less than tuition at many private kindergartens, and of course the consequences will extend over a lifetime and beyond.

The corresponding ethical issues are complex and deserve serious attention in what may be a relatively short interval before these capabilities become a reality. Each society will decide for itself where to draw the line on human genetic engineering, but we can expect a diversity of perspectives. Almost certainly, some countries will allow genetic engineering, thereby opening the door for global elites who can afford to travel for access to reproductive technology. As with most technologies, the rich and powerful will be the first beneficiaries. Eventually, though, I believe many countries will not only legalize human genetic engineering, but even make it a (voluntary) part of their national healthcare systems [26]. The alternative would be inequality of a kind never before experienced in human history.
Here is the version of the GATTACA scene that was cut. The parents are offered the choice of edited or spliced genes conferring rare mathematical or musical ability.

Saturday, November 24, 2018

Spygate in 20 minutes

Bongino (former federal agent and TV/podcast personality) gives a very clear and entertaining overview of Spygate: the illegal use of government surveillance powers against an opposition political candidate (Donald Trump). I agree with Bongino that this is the biggest political scandal in the modern era, orders of magnitude beyond Watergate. But because the story is complicated and has been largely covered up (as much as possible) by the media, few people understand what actually happened. You can get the gist of it in 20 minutes from the video. (Real content starts @6min or so.)

As Bongino states, the factual claims in his talk can all be sourced from reporting by "mainstream" news outlets such as CNN, NYTimes, WSJ, or from government documents such as the declassified (2017) FISC report on abuses of surveillance powers. But you will not find them all in one place as you do in the video (or on my blog).

See Deep State Update (May 2018):
It's been clear for well over a year now that the Obama DOJ-FBI-CIA used massive surveillance powers (FISA warrant, and before that, national security letters and illegal contractor access to intelligence data) against the Trump campaign. In addition to SIGINT (signals intelligence, such as email or phone intercepts), we now know that HUMINT (spies, informants) was also used.

Until recently one could still be called a conspiracy theorist by the clueless for stating the facts in the paragraph above. But a few days ago the NYTimes and WaPo finally gave up (in an effort to shape the narrative in advance of DOJ Inspector General report(s) and other document releases that are imminent) and admitted that all of these things actually happened. The justification advanced by the lying press is that this was all motivated by fear of Russian interference -- there was no partisan political motivation for the Obama administration to investigate the opposition party during a presidential election.

If the Times and Post were dead wrong a year ago, what makes you think they are correct now?

Thursday, November 22, 2018

Contingency, History, and the Atomic Bomb: Alexander Sachs

[ Financier Alexander Sachs, Look Magazine, March 14, 1950. Article: How FDR Planned to use the A-Bomb ]

Last month I received an astonishing email, partly excerpted below.

By way of introduction, my grandfather, General Groves, led the Manhattan Project. I’m now working on a documentary series about the making of the bomb.

I first came across Robert Jungk’s account of the Sachs-FDR meetings not in Jungk's book, but in your “Contingency, History, and the Atomic Bomb” posting online. Thank you.

It’s an important episode that appears in almost none of the histories, Rhodes’ Making of the Atomic Bomb included. And it’s relevant: anyone who has had to pitch a complicated idea or project knows that getting the initial approval and funding can be more challenging than completing the work proposed.

I’ve since found quite a bit of material pertaining to the story. I thought you might find it interesting.


I imagine some graduate history, science, or economics student could turn this into a PhD thesis. (Why did FDR always have time for Sachs? I see some hints that Sachs may have been ahead of his time in macroeconomics.) Or – Szilard and Wigner’s efforts to get the matter in front of FDR could be a management case study.

Anyway, thank you for posting the story. The full version will definitely make it into my production.

Dick Groves
From Contingency, History, and the Atomic Bomb (excerpt from Jungk):
How Alexander Sachs, acting on behalf of Szilard and Einstein, narrowly convinced FDR to initiate the atomic bomb project. History sometimes hangs on a fragile thread: had the project been delayed a year, atomic weapons might not have been used in WWII. Had the project completed a year earlier, the bombs might have been used against Germany.

See also A Brief History of the Future, as told to the Masters of the Universe.
... It was nearly ten weeks before Alexander Sachs at last found an opportunity, on October 11, 1939, to hand President Roosevelt, in person, the letter composed by [Leo] Szilard and signed by [Albert] Einstein at the beginning of August [1939]. In order to ensure that the President should thoroughly appreciate the contents of the document and not lay it aside with a heap of other papers awaiting attention, Sachs read to him, in addition to the message and an appended memorandum by Szilard, a further much more comprehensive statement by himself. The effect of these communications was by no means so overpowering as Sachs had expected. Roosevelt, wearied by the prolonged effort of listening to his visitor, made an attempt to disengage himself from the whole affair. ...

Sachs, however, was able, as he took his leave, to extort from the President the consolation of an invitation to breakfast the following morning. "That night I didn't sleep a wink," Sachs remembers.


[ The next morning, at the White House ]

After Sachs finished speaking the President remained silent for several minutes. Then he wrote something on a scrap of paper and handed it to the servant who had been waiting at table. The latter soon returned with a parcel which, at Roosevelt's order, he began slowly to unwrap. It contained a bottle of old French brandy of Napoleon's time, which the Roosevelt family had possessed for many years. The President, still maintaining a significant silence, told the man to fill two glasses. Then he raised his own, nodded to Sachs and drank to him.

Next he remarked: "Alex, what you are after is to see that the Nazis don't blow us up?"


It was only then that Roosevelt called in his attaché, [Brigadier] General [Edwin] "Pa" Watson, and addressed him—pointing to the documents Sachs had brought—in words which have since become famous:

"Pa, this requires action!
Sachs was a trusted but largely anonymous advisor to Roosevelt. He advised Roosevelt through the Great Depression and foresaw the rise of Hitler and the military threat from Germany. From the profile in Look Magazine:
... only one word describes him: genius. A story about how he helped President Roosevelt to understand the atomic energy problem in 1939 throws light on why Dr. Sachs is so described. ...

... Schooled at Columbia and Harvard, he never left the school of self-education.

Dr. Alexander Sachs' career has been in economics, with a special emphasis on the mathematics of statistics. But the range of his intellectual interests embraces religion, science, history, and politics. ...

Tuesday, November 20, 2018

Super-smart designer babies (Guardian UK)

The title (likely chosen by an editor at The Guardian) is a bit disturbing. But the article itself is clear and insightful.
Super-smart designer babies could be on offer soon. But is that ethical?

... The company [ Genomic Prediction ] says it is only offering such testing to spot embryos with an IQ low enough to be classed as a disability, and won’t conduct analyses for high IQ.

... The development must be set, too, against what is already possible and permitted in IVF embryo screening. The procedure called pre-implantation genetic diagnosis (PGD) involves extracting cells from embryos at a very early stage and “reading” their genomes before choosing which to implant. It has been enabled by rapid advances in genome-sequencing technology, making the process fast and relatively cheap.

... before we get too indignant about the horrors of designer babies, bear in mind that already we permit, even in the UK, prenatal screening for Down’s syndrome, a disability that produces low to moderate intellectual disability. It’s not easy to make a moral or philosophical case that the screening offered by Genomic Prediction for low IQ is any different. There may be more uncertainty but, given not all IVF embryos will be implanted anyway, can we object to tipping the scales? And how can we condone efforts to improve your child’s intelligence after birth but not before?

The questions are complicated. How to balance individual rights against what is good for society as a whole? When does avoidance of disease and disability shade into enhancement? Should society be more receptive to disability rather than seeing it as something to be eradicated? When does choice become tyranny?

In the UK we are extraordinarily lucky to have the HFEA [Human Fertilisation and Embryology Authority], which frames binding regulation after careful deliberation and acts as a brake so the technology does not outrun the debate. “Embryo selection needs robust regulation that society can be confident in,” says Ewan Birney, director of the European Bioinformatics Institute in Cambridge. Leaving a matter such as this to unregulated market forces is dangerous.
The writer is Philip Ball, a longtime editor at Nature and PhD in Physics.

The US does not have an HFEA. Here is what the Genomic Prediction FAQ says:
There is a formal bioethics position on this general subject, recently updated in 2018, written by the Ethics Committee of the American Society for Reproductive Medicine.

A key phrase from the paper:

PGD for adult-onset conditions is ethically justified when the condition is serious and no safe, effective interventions are available. It is ethically allowed for conditions of lesser severity or penetrance. The Committee strongly recommends that an experienced genetic counselor play a major role in counseling patients considering such procedures.

The recent burst of news coverage of Genomic Prediction was triggered by articles in The Economist and New Scientist. My earlier comments are reproduced below:
This Economist article on Genomic Prediction has been in waiting for weeks, to appear in The World in 2019 special issue. I spent a couple hours briefing their science team on what is coming in AI and genomics -- I would guess there will be more coverage of polygenic scores and health care in the future.

See also this New Scientist article on GP.

2019 may be the Year of the Designer Baby, if journos are to be believed ;-) Of course, this is sensationalism. It is more accurate to say that 2019 will see the first deployment of advanced genetic tests which can be used to screen against complex disease and health risks. Already today ~1 million IVF embryos per year are screened worldwide using less sophisticated genetic tests for single gene disease mutations and chromosomal abnormality.

The Economist:
In 2019, ... [ GP clients ] will have an opportunity to give their offspring a greater chance of living a long and healthy life.

"Expert" opinion seems to have evolved as follows:

1. Of course babies can't be "designed" because genes don't really affect anything -- we're all products of our environment!

2. Gulp, even if genes do affect things it's much too complicated to ever figure out!

3. Anyone who wants to use this technology (hmm... it works) needs to tread carefully, and to seriously consider the ethical issues.

Only point 3 is actually correct, although there are still plenty of people who believe 1 and 2 :-(

Wednesday, November 14, 2018

London / DeepMind photos

I've been very lucky with the London weather on this trip -- in the 50s and sunny.

These were taken from the roof terrace of the Google building that houses DeepMind:

These are from the nearby area: St. Pancras, Granary Square, in King's Cross.

More photos from the area.

Photos below from The Economist (also rooftop views of London, but not as posh as GOOG) and BBC visits.

This Economist article on Genomic Prediction has been in waiting for weeks, to appear in The World in 2019 special issue. I spent a couple hours briefing their science team on what is coming in AI and genomics -- I would guess there will be more coverage of polygenic scores and health care in the future.

See also this New Scientist article on GP.

2019 may be the Year of the Designer Baby, if journos are to be believed ;-)  Of course, this is sensationalism. It is more accurate to say that 2019 will see the first deployment of advanced genetic tests which can be used to screen against complex disease and health risks. Already today ~1 million IVF embryos per year are screened worldwide using less sophisticated genetic tests for single gene disease mutations and chromosomal abnormality.

The Economist:
In 2019, ... those with the cash to do so will have an opportunity to give their offspring a greater chance of living a long and healthy life.

"Expert" opinion seems to have evolved as follows:
1. Of course babies can't be "designed" because genes don't really affect anything -- we're all products of our environment!

2. Gulp, even if genes do affect things it's much too complicated to ever figure out!

3. Anyone who wants to use this technology (hmm... it works) needs to tread carefully, and to seriously consider the ethical issues.

Only point 3 is actually correct, although there are still plenty of people who believe 1 and 2   :-(
BBC wanted me for their Radio 4 Today show. I went in and recorded some clips, but the broadcast may be delayed due to all the Brexit excitement -- Theresa May has finally revealed the proposed EU-UK agreement her administration negotiated. Angry Brexiteer Tory MPs may vote her out. I had a ringside seat to all this thanks to my friend Dominic Cummings!

Friday, November 09, 2018

DeepMind Talk: Genomic Prediction of Complex Traits and Disease Risks via Machine Learning

I'll be at DeepMind in London next week to give the talk below. Quite a thrill for me given how much I've admired their AI breakthroughs in recent years. Perhaps AlphaGo can lead to AlphaGenome :-)

Hope the weather holds up!
Title: Genomic Prediction of Complex Traits and Disease Risks via Machine Learning

Abstract: After a brief review (suitable for non-specialists) of computational genomics and complex traits, I describe recent progress in this area. Using methods from Compressed Sensing (L1-penalized regression; Donoho-Tanner phase transition with noise) and the UK BioBank dataset of 500k SNP genotypes, we construct genomic predictors for several complex traits. Our height predictor captures nearly all of the predicted SNP heritability for this trait -- actual heights of most individuals in validation tests are within a few cm of predicted heights. I also discuss application of these methods to cognitive ability and polygenic disease risk: sparsity estimates (of the number of causal loci), combined with phase transition scaling analysis, allow estimates of the amount of data required to construct good predictors. We can now identify risk outliers for conditions such as heart disease, diabetes, breast cancer, hypothyroidism, etc. using inexpensive genotyping. Finally, I discuss how these advances will affect human reproduction (embryo selection for In Vitro Fertilization (IVF); gene editing) in the coming decade.

Bio: Stephen Hsu is VP for Research and Professor of Theoretical Physics at Michigan State University. He is also a researcher in computational genomics and founder of several Silicon Valley startups, ranging from information security to biotech. Educated at Caltech and Berkeley, he was a Harvard Junior Fellow and held faculty positions at Yale and the University of Oregon before joining MSU.

Action Photos!

Wednesday, November 07, 2018

Validation of simultaneous preimplantation genetic testing (PGT) for aneuploidy, monogenic, and polygenic disorders (Dr. Nathan Treff, Genomic Prediction, Inc.)

Dr. Nathan Treff, co-founder of Genomic Prediction, at the 2018 American Society of Reproductive Medicine meeting. His talk introduces Expanded Pre-Implantation Genomic Testing (EPⓖT):
EPⓖT allows the routine, inexpensive evaluation of hundreds of thousands of genetic variants, implementing a novel combination of embryo genotyping methods not previously combined into a reproductive genetics application.

Universal coverage of common single-gene disorders, such as Cystic Fibrosis, Thalassemia, BRCA, Sickle Cell Anemia, and Gaucher Disease.

Complex disorders whose risk can be predicted include:
Type 1 Diabetes, Type 2 Diabetes, Coronary Artery Disease, Atrial Fibrillation, Breast Cancer, Hypothyroidism, Mental Disability, Idiopathic Short Stature, Inflammatory Bowel Disease
At the American Society of Human Genetics (ASHG) meeting last month in San Diego, several people recognized me and came over to marvel at Genomic Prediction.
"Look at all these people walking around, with no idea what is happening right now...  You guys are Creating the Future!"

From Comments:
John C. • 11 hours ago
What could be the use of predicting atrial fibrillation, coronary artery disease and Type 2 diabetes risk be? Tell people to not gain weight as they age?

Bobdisqus • 3 hours ago
Well as someone who had an ablation for AFIB, two stents in my RCA, and a family history that includes a brother with first heart attack at 38, and my father at 43 I would say the value is immense. Beyond that the extended family on both sides is rife with such. The number of men in my ancestry that made it past 70 is tiny. My children now have the option with a couple of rounds of egg harvesting which is well advised for my brood of daughters anyway given the human fertility curve and their plans for education to filter the worst of this scourge from our line going forward. Their sons can then anticipate fine old ages into their 90s much like the people of their Mother's line.

Tuesday, November 06, 2018

1 In 4 Biostatisticians Surveyed Say They Were Asked To Commit Scientific Fraud

In the survey reported below, about 1 in 4 biostatisticians were asked to commit scientific fraud. I don't know whether this bad behavior was more prevalent in industry as opposed to academia, but I am not surprised by the results.

I do not accept the claim that researchers in data-driven areas can be ignorant of statistics. It is common practice to outsource statistical analysis to people like the "consulting biostatisticians" surveyed below. But scientists who do not understand statistics will not be effective in planning future research, nor in understanding the implications of results in their own field. See the candidate gene and missing heritability nonsense the field of genetics has been subject to for the last decade.

I cannot count the number of times, in talking to a scientist with limited quantitative background, that I have performed -- to their amazement -- a quick back of the envelope analysis of a statistical design or new results. This kind of quick estimate is essential to understand whether the results in question should be trusted, or whether a prospective experiment is worth doing. The fact that they cannot understand my simple calculation means that they literally do not understand how inference in their own field should be performed.
Researcher Requests for Inappropriate Analysis and Reporting: A U.S. Survey of Consulting Biostatisticians

(Annals of Internal Medicine 554-558. Published: 16-Oct-2018. DOI: 10.7326/M18-1230)

Of 522 consulting biostatisticians contacted, 390 provided sufficient responses: a completion rate of 74.7%. The 4 most frequently reported inappropriate requests rated as “most severe” by at least 20% of the respondents were, in order of frequency, removing or altering some data records to better support the research hypothesis; interpreting the statistical findings on the basis of expectation, not actual results; not reporting the presence of key missing data that might bias the results; and ignoring violations of assumptions that would change results from positive to negative. These requests were reported most often by younger biostatisticians.
This kind of behavior is consistent with the generally low rate of replication for results in biomedical science, even those published in top journals:
What is medicine’s 5 sigma? (Editorial in the Lancet)... much of the [BIOMEDICAL] scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, [BIOMEDICAL] science has taken a turn towards darkness. As one participant put it, “poor methods get results”. The Academy of Medical Sciences, Medical Research Council, and Biotechnology and Biological Sciences Research Council have now put their reputational weight behind an investigation into these questionable research practices. The apparent endemicity of bad research behaviour is alarming. In their quest for telling a compelling story, scientists too often sculpt data to fit their preferred theory of the world. ...
More background on the ongoing replication crisis in certain fields of science. See also Bounded Cognition.

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