CRISPR gene editing progressing to germ line genetic editing and the application for intelligence enhancement

Harvard’s Luhan Yang described a human germline genetic editing experiment. Researchers hoped to obtain, from a hospital in New York, the ovaries of a woman undergoing surgery for ovarian cancer, caused by a mutation in a gene called BRCA1. Working with another Harvard laboratory, that of antiaging specialist David Sinclair, they would extract immature egg cells that could be coaxed to grow and divide in the laboratory. Yang would use CRISPR in these cells to correct the DNA of the BRCA1 gene. The objective would be to create a viable egg without the genetic error that caused the woman’s cancer.

Regardless of the fate of that particular experiment, human germ line engineering has become a burgeoning research concept. At least one other center in Boston is working on it, as are scientists in China, in the U.K., and at a biotechnology company called OvaScience, based in Cambridge, Massachusetts, that boasts some of the world’s leading fertility doctors on its advisory board.

The objective of these groups is to demonstrate that it’s possible to produce children free of specific genes that cause inherited disease. If it’s possible to correct the DNA in a woman’s egg, or a man’s sperm, those cells could be used in an in vitro fertilization (IVF) clinic to produce an embryo and then a child. It might also be possible to directly edit the DNA of an early-stage IVF embryo using CRISPR. Several people interviewed by MIT Technology Review said that such experiments had already been carried out in China and that results describing edited embryos were pending publication. These people didn’t wish to comment publicly because the papers are under review.

Guoping Feng, a neurobiologist at MIT’s McGovern Institute for Brain Research, where a colony of marmoset monkeys is being established with the aim of using CRISPR to create accurate models of human brain diseases. To create the models, Feng will edit the DNA of embryos and then transfer them into female marmosets to produce live monkeys. One gene Feng hopes to alter is SHANK3. The gene is involved in how neurons communicate and, when it’s damaged in children, is known to cause autism.

Nature Scientific Reports – Asymmetric parental genome engineering by Cas9 during mouse meiotic exit

Mammalian genomes can be edited by injecting pronuclear embryos with Cas9 cRNA and guide RNA (gRNA) but it is unknown whether editing can also occur during the onset of embryonic development, prior to pronuclear embryogenesis. We here report Cas9-mediated editing during sperm-induced meiotic exit and the initiation of development. Injection of unfertilized, mouse metaphase II (mII) oocytes with Cas9 cRNA, gRNA and sperm enabled efficient editing of transgenic and native alleles. Pre-loading oocytes with Cas9 increased sensitivity to gRNA ~100-fold. Paternal allelic editing occurred as an early event: single embryo genome analysis revealed editing within 3 h of sperm injection, coinciding with sperm chromatin decondensation during the gamete-to-embryo transition but prior to pronucleus formation. Maternal alleles underwent editing after the first round of DNA replication, resulting in mosaicism. Asymmetric editing of maternal and paternal alleles suggests a novel strategy for discriminatory targeting of parental genomes.

Pre-implantation genetic diagnosis (PGD) enables people with an inheritable condition in their family to avoid passing it on to their children. It involves checking the genes and/or chromosomes of embryos created through IVF. PGD can currently be used to test for virtually any genetic condition where a specific gene is known to cause that condition. It is currently approved to screen for over 250 genetic conditions.

Progress to Understanding Genetics of Intelligence and the likelihood of Tiger mom adoption of gene editing and embryo selection

Molecular Psychiatry – Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32.

The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

Stephen Hsu posted on the main genetic findings on intelligence. Stephen Hsu has written extensively on the genetic basis on intelligence and the near future of embryo selection. Stephen advises BGI the main genomics company of China.

There was a review of five years of genome-wide association studies in 2011.

Scientists looking for the genes underlying intelligence are in for a slog. One of the largest, most rigorous genetic studies of human cognition1 has turned up inconclusive findings, and experts concede that they will probably need to scour the genomes of more than 1 million people to confidently identify even a small genetic influence on intelligence and other behavioural traits. The results were published in the Journal Nature.

In a 2013 study comparing the genomes of more than 126,000 people, the group identified three gene variants associated with with how many years of schooling a person had gone through or whether they had attended university. But the effect of these variants was small — each variant correlated with roughly one additional month of schooling in people who had it compared with people who did not.

In another study of 106,000 people, researchers picked out 69 gene variants most strongly linked to education level. To establish a more direct link with IQ, they cross-checked this list with genetic variants in a second sample of 24,000 people who also had taken tests of cognitive ability. Three gene variants were found to be associated with both educational attainment and higher IQ scores.

The three variants the researchers identified were each responsible for an average of 0.3 points on an IQ test. (About two-thirds of the population score between 85 and 115.) That means that a person with two copies of each variant would score 1.8 points higher on an intelligence test than a person with none of them.

To put those figures in perspective, those variants have about one-twentieth the influence on intelligence as do gene variants linked to other complex traits such as height, says Daniel Benjamin, a social scientist at Cornell University in Ithaca, New York, who co-led the study.

Benjamin says that studies of more than 1 million people will be needed to find enough common gene variants to explain 15% of the variation across people in IQ scores, educational attainment and other behavioral traits.

Selecting for intelligence or genetically engineering for intelligence will require larger studies to identify the genes and more genes will need to be altered to achieve the enhancement

I gave a talk at Transhuman Visions early in 2014.

In my look at near term transhumanism, I see older Tiger Moms as being the driver of early adoption of genetic intelligence enhancement and the lifting of the One child policy in China.

China’s One child policy is being lifted just as embryo selection based upon intelligence for invitro fertilized (IVF) babies becomes possible and we are on the cusp of genetic engineering. Women in China who are now older were banned from having babies but now will be allowed to have children. Many will not be able to conceive naturally and will use IVF. I see IVF going from 400,000 per year worldwide to 2-8 million per year over the next 10 years. IVF babies are more easily embryo selected and accessible for genetic modification. This would provide an economic boost to China in 20-30 years and the beginnings of a significant societal shift.

* Older women use IVF more than younger women.
* Societal shifts that cause more older women to use IVF to have children means more opportunity for embryo selection and genetic intelligence enhancement.
* Countries that permit embyro selection and genetic intelligence enhancement provide the opportunity for IVF to be used for enhancement
* Medical tourism to permissive countries is another means for older women to use IVF in combination with embryo selection or genetic enhancement.

In my talk I first summarized enhancement of human capabilities via products that we can buy. (Smartphones, Google Glass, Apple Siri, IBM Watson, forklifts, cars etc…) As those things get better, anyone can adopt them by buying the latest versions.

Steroids do enhance performance. They work. About 10 million people use them and it is primarily because of vanity. However, we do not live in the wild west or have to compete as Gladiators in Rome. The more powerful people in the world are the billionaires. In the real world the equivalent of Montgomery Burns from the Simpsons has more power than the equivalent of Captain America. Burns can hire his own police force or mercenaries. It is his lawyers and lobbyists who do his work.

100 years ago it was vaccines that began altering the physical attributes of people in a meaningful way. It extended lifespans and improved health. Health improvement boosted productivity and GDP.

I make the case that studies show that more intelligence leads to better lives for people. They go to jail less. Their jobs are better and they divorce less.

Each one-point increase in a country’s average IQ, the per capita GDP was $229 higher. It made an even bigger difference if the smartest 5 percent of the population got smarter; for every additional IQ point in that group, a country’s per capita GDP was $468 higher. This is according to Are the Wealthiest Countries the Smartest Countries? (Heiner Rindermann, of the Chemnitz University of Technology, Psychological Science )

However, we can see the damage when intelligence is lower across large national populations.

48% of children in India are stunted. Diseases can leave brain damage when they do not kill. This reduces IQ points by 11-20 on average across the country. This makes India more poor.

Embryo Selection

* In Vitro Fertilization (IVF) currently is used for 400,000 babies each year.
* A new “Alka Seltzer method” for controlling PH reduces costs from $10K-20K in developed world to about $1K
* Developing world was $2-4K and can be $200
* Comprehensive Chromosome Screening (about $6000) can boost successful IVF by 10-20%

–> Lower costs for IVF means more adoption and widespread basic genetic screening via chromosome screening will already be used for high IVF success rate

* China lifting one child ban
* This will mean annual birthrates will go from about 16 million ==> 25.5 million
* 23-42 normal child bearing age
* IVF at older ages up to 50-55 now at about 5-15% but improving
* More older women in China will use IVF
* China is not culturally against enhancing children (a lot of tiger moms and cultural differences)
* Lower cost and more effective IVF with standard chromosome screening, easy step to gene screening
* Maybe 4 million IVF/year with gene screening

Children tend to fall within a spread of 13 IQ points above and below the average IQ of their parents.
Positive outlier at around 2 or 3 percent where child is two standard deviations above parents
Pick the smartest genome from a batch of, say, 20 embryos (but it could 50 or more embryos) to get 20-30 IQ points higher
We are technologically close to non-destructive sequencing of human gametes and zygotes by sequencing 10-20 cells.

Genetic Engineering for Intelligence

BGI (Beijing Genomics institute has a large intelligence study of thousands of geniuses
Various studies finding genes with up to 0.5% impact on intelligence
Intelligence is 40-80% inheritable
There are likely hundreds to a thousand thousands to tens of thousands of genes that genetically determine intelligence
This is twenty times more complex than height. According to Steve Hsu’s estimates (based on actual data) most humans have (order of magnitude) 1000 rare (-) alleles for height. So about 20,000 rare alleles for intelligence.

One standard deviation above average has (very roughly) 30 fewer (-) variants.
No negative alleles might be 30 SD above average! Such a person has yet to exist in human history…
Each standard deviation (SD) up or down are defined as 15 IQ points greater or less,
95 percent of the population scores an IQ between 70 and 130, which is within two standard deviations of the mean.
30 SD above average would be and IQ of 550.

Maybe IQ 550 is Impossible or Meaningless

550 IQ would be like a 13 foot tall person
Physiology limits practical height
What are intelligence limits ?
Brain structure
Average human height is 70 inches and 3 inch SD (standard deviation)
8 feet 1 inch – 97 inches this is 9 Standard Deviations over average
235 IQ is the equivalent in intelligence of a 8 foot 1 inch person

Geniuses and Society

5% of population with 30 points higher intelligence might be about $14000 more GDP per capita
5% of population with 120 points higher intelligence might be about $56000 more GDP per capita
What would a society with tens of millions of Edisons, Einsteins, Steve Jobs and Elon Musks be like ?
Could we get beyond them in capability?

5% of population significantly intelligence enhanced would be possible if IVF takes off and embryo selection and genetic engineering with it over the next 10-20 years.

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