Updates to the human germline editing saga

• News that various US based academics knew about He’s plans. The New York Times outlines that various American academics knew what He was planning, but kept silent, mostly because they didn’t know what to do about research happening in China, and/or because they thought they had dissuaded He from discontinuing. Meanwhile, STAT reports that Deem, He’s US based thesis advisor was listed as the last author of the manuscript He submitted to Nature (which declined to review it). The extent of his involvement is unclear. And the Associated Press broke the news that He had informed Nobel winning geneticist Mello about the pregnancy in April.
• The NASAM report, that I covered here, stopped short of calling for a moratorium. He seemed to think that he was not contravening it. This has lead to renewed calls for a clearer stance. Debate continues over whether a moratorium is the correct response. The New York Times editorial team issued a statement against a moratorium, and in favor of diversifying the deciders and engaging the public. “It may be impossible to prevent truly rogue actors, but it is possible to slow them down without stopping everyone else.” Jennifer Doudna opposes a moratorium, Feng Zhang supports one.
• A larger question looms about the relevant role of scientists in this debate. In an opinion piece in STAT, Are scientists’ reactions to ‘CRISPR babies’ about ethics or self-governance?, the authors make a strong case for the latter: “We believe that the alarm being sounded by the scientific community isn’t really about ethics. It’s about protecting a particular form of scientific self-governance, which the “ethics” discourse supports.” “Scientists articulated more concern about maintaining their authority to unilaterally transform human biology than a willingness to have a public debate about the ethics of whether — and under what conditions — such transformation should take place.” A Hastings Report article outlines the differences in opinion being expressed by scientists about the relevant roles of scientists and society in the future of the technology.

Controversy

• In a long piece in the New York Times Magazine on paleogenomics, takehomes here,  Gideon Lewis-Kraus points to the field’s major and recent successes, but also highlights how some archeologists fear that it traffics in “grand intellectual narratives” that history warns us against. This is an indication of culture wars between geneticists and others.

Science

• A study that doubled the number of microbial genomes available (150,000) by producing data from metagenomic studies including those covering non-Westernized countries. They grouped their ~150,000 new sequences in to 5000 “species bins”, 77% of which were novel. The new sequences dramatically increase the mappability of samples to 87%.
• A fine grained (682bp) map of where crossovers occur on chromosomes, from Decode. The CEO of Decode, and author, Dr Stefansson (source): “The classic premise of evolution is that it is powered first by random genetic change. But we see here in great detail how this process is in fact systematically regulated – by the genome itself and by the fact that recombination and de novo mutation are linked. We have identified 35 sequence variants affecting recombination rate and location, and show that de novo mutations are more than fifty times more likely at recombination sites than elsewhere in the genome. Furthermore, women contribute far more to recombination and men to de novo mutation, and it is the latter that comprise a major source of rare diseases of childhood. What we see here is that the genome is an engine for generating diversity within certain bounds. This is clearly beneficial to the success of our species but at great cost to some individuals with rare diseases, which are therefore a collective responsibility we must strive to address”
• Polygenic score for lifespan, explaining 1% of the phenotypic variance, which is 5% of the heritability. Those in the top 10% of the score can expect, on average, to live 5 years longer than those in the bottom 10%.
• GWAS for risk tolerance and risky behaviors, with genetic overlaps found between different “risky” phenotypes, and with various personality traits.

Applications

• Following the successful completion of Genomics England’s 100,000 genomes project, healthy patients will soon be able to pay for genetic tests through the NHS. The NHS has, up until this point, been free at the point of service. Fears of a ‘two tier system” are weighed against the idea that “Every genome sequenced moves us a step closer to unlocking life-saving treatments.”
• Ongoing issues with patients getting access to their own data from testing companies.
• Data sharing issues are also a hot topic in the research space, see this opinion piece that all publicly available data should be completely open access. Advances will be made each easier with improvements to tracking the ways in which data can be used in a fixed format. That is the purpose of the GA4GH’s Data Use Ontology, now open for comment.
• Identical twins tried out various ancestry kits and received somewhat different results.
• A silicon valley startup offering tumor genetic testing and personalized therapy recommendations — for dogs. The idea is that the dogs could be treated with therapies for humans, under something akin to compassionate use programs.
• An editorial in Nature calls on the WHO to integrate genomic testing of cholera to help fight outbreaks. This new-ish field is called genomic phylogeography.

Regulation

• More powers for DNA forensics. As of the beginning of January, the Rapid DNA Act comes into force. Rapid DNA machines sitting inside police stations allow police officers to obtain sequence results in 90 minutes. The Act allows for police to upload this data to CODIS, the National DNA database, and look for matches to e.g. previous crime scenes.

In other news: The preprint server for biology BioRxiv, just turned five. In 2018, about 1711 preprints were posted per month, and in October there were over 1 million downloads. A project called the Rxvist allows users to see which preprints are generating the most twitter attention. I have added this to my bookmarks, and will be using it to help inform this round-up from henceforth!

Focus on polygenic risk scores

First, let’s look at a paradigmatic example of a polygenic score publication. Inouye et al constructed a Polygenic Risk Score for CAD, gaining a hazard ratio of 4.17 for those in the top 20% compared to bottom 20% of their score. It is better as a single predictor (based on Area Under ROC curve, also known as C-statistic) than any one of smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history (it does not do as well as all of them put together). They conclude that their score “strengthens the concept of using genomic information to stratify individuals for CAD risk in general populations and demonstrates the potential for genomic screening in early life to complement conventional risk prediction.”

In reaction to articles such as this, several clear lines of criticism have emerged

1. The scores are only applicable in the ancestral population that they were developed in. Combine this with the well publicised fact that almost all studies are on Caucasian populations (reviewed here), and that the assays used are SNP chips whose genetic variants were chosen based on frequencies of variants within European populations, and several issues are immediately apparent. As an alternative to producing scores separately for each ancestral population, a suggestion that studies based on African populations would be less biased and more generalizable to other populations. It is  based on the simple fact that non-African populations have been subject to more genetic drift – i.e. change in genetic variant frequency because of small population sizes. It is also the case that there are hazards aplenty in using differences between populations to infer anything about genetics, and particularly about natural selection (see g.g. this article).
2. Hazard ratios have to be very high to be useful as screening tools. In an article that has been well circulated on twitter, “The illusion of polygenic disease risk prediction”, the authors point out that “the paradox is largely explained by the fact that odds ratios or hazard ratios typically compare risks in the tails of a single risk distribution, but these ratios ignore the proportions of individuals who will or will not develop the disease that fall in the region between the tails of the distribution”. The first author, Nicholas Wald, has been pointing this out for a long time. Note that this does not just apply to genomics, in his 1999 paper Wald takes as its case study cholesterol levels for heart disease, and shows how poor a screening test this is. (They state that no future polygenic risk score will produce a high enough relative risk — it would be good to check this, based on a score that captured the full heritability estimates for a given trait.) This argument ought not to be news. I enjoyed this slide deck by epidemiologist Cecile Janssens that traces the history of the prospect of predictive genomic tests, and some of the known pitfalls.
3. The role of the environment means that genetics is often not as useful as these scores would suggest. If the environment changes, e.g. all people stop smoking, then the polygenic scores change too. If the genetics is mediated by an independently measurable and modifiable intermediate phenotype, e.g. cholesterol levels, then it is much less useful to know the genetics. Though see the Inouye paper showing that their score is relatively independent of other known risk factors.

These skeptical voices are not preventing a full-scale rush to applications. Color announced a 100,000 person initiative to use low throughput whole genome data to provide individuals with polygenic scores.

 

Controversy

• A new documentary about James Watson shows that his views on race have not changed. The Times reports that he had a chance to salvage his reputation on race but made things worse. The relationship between genetics and race is not straightforward, as this survey of over 500 genetics professionals on their views on race demonstrated. They found that “many genetics professionals the questions of what race is and what race means remain both professionally and personally contentious.”

Science and Applications

• Antonio Regalado has summed up the top advances in Genetics from 2018 — seeing it all in one place is definitely impressive.
• The latest chapter on heritability, from a study of Aetna’s database of insurance claims covering about 45m individuals. Their dataset has over 56,000 pairs of twins born since 1985, and over 700,000 sibling pairs. They connect zipcodes to environmental factors of interest — SES, air pollution and weather/climate. They found that variance from these measures was much lower than from genetics and shared environment, with obesity being the phenotype with the strongest link to SES (var=0.027). Monthly cost of data was estimated at 29% heritable and 30% due to shared environment. The respective figures for co-morbidities were 43% and 24%.
• There is often concern that receiving ambiguous results can lead to increased worry for individuals. But a new study based on a sample of over 5000 women receiving HBOC genetic risk testing fond that receiving uncertain results did not increase worry among women compared to a negative result.
• The BabySeq project reports on results of exome sequencing of 159 newborns (127 healthy and 32 in the NICU). Of these 15 (9.4%) had genetic variants associated with a disease that could be managed in childhood. Genomic sequencing for newborns remains a contentious area.
• An AP poll found 70% of Americans supportive of genetic editing “to prevent an incurable or fatal disease a child otherwise would inherit, such as cystic fibrosis or Huntington’s disease”, about two thirds to “prevent a child from inheriting a non-fatal condition such as blindness, and even to reduce the risk of diseases that might develop later in life, such as cancers”, and about 70% oppose “using gene editing to alter capabilities such as intelligence or athletic talent, and to alter physical features such as eye color or height.” I can’t find any original data, just reports e.g. here.
• I thought this was an interesting story about how much of an impact the classification of a disease can make — in this case, the efforts to have schizophrenia classified as a brain disease so that it was covered by a new CDC program. Why does this matter? Mental conditions receive less funding and health insurance is often less generous. Strong echoes of dualism here.

Regulation

• Stat reports on Science with borders: A debate over genetic sequences and national rights threatens to inhibit research, reflecting the ongoing debate about the status of genetic sequences of pathogens collected in different countries.
• Australian researchers have called for a Genetic Data Protection Act in reaction to police use of genetic a) familial searching, and b) prediction of phenotypes.

Controversy

• The major news was the report of the birth of the first children genetically modified as embryos. I report on that separately here.
• The question of whether those who receive a genetic diagnosis have a duty to tell their family members is working its way through the UK courts. A man who received a genetic diagnosis of Huntington’s asked the hospital not to tell his daughter, who was pregnant at the time, because he feared she would abort the baby. The daughter has since been found to have the genetic variant associated with Huntington’s is now suing the hospital. Bioethicist Anna Middleton told the Guardian “This could really change the way we do medicine, because it is about the duty that doctors have to share genetic test results with relatives and whether the duty exists in law.”
• UCL launched an inquiry into their past ties with eugenics, including to Galton. This was motivated by a series of secretive eugenics meetings that an academic of theirs was recently involved with.

Science

• PsychENCODE, a large consortium looking at functional genomics in over 2000 developing and adult brains, has published 10 papers. To focus on one paper, they found that differences in gene expression between individuals are mostly explained by differences in fractions of cell types, and that some disorders and aging are associated with changes in these proportions. For schizophrenia, they found 321 genes associated with GWAS loci, and then did some fancy machine learning to predict phenotype from genotypes and from expression. This model did much better than a genotype polygenic score alone, and still did better when the expression data was imputed (i.e. not actually experimentally measured), “highlighting the value of having just a small amount of transcriptome data for disease prediction.”
• Large study of the genetics of ADHD finds reproducible loci. A polygenic score predicts 5.5% of the variance (for an odds ratio of 1.56). The study presents evidence that ADHD should be considered the end of a distribution: “Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.”
• A much smaller fraction of developmental disorders (DDs) are explained by recessive variation in protein-coding genes than previously thought: ~3.6% in non-consanguineous populations, compared to 31% in consanguineous populations. Compare to 50% of DDs caused by de novo mutations. This work, from Hilary Martin et al appearing in Science, is based on a burden analysis approach in over 6000 exomes from the Deciphering Developmental Disorders study. “The high proportion of unexplained patients even amongst those with affected siblings or high consanguinity suggests that future studies should investigate a wide range of modes of inheritance including oligogenic and polygenic inheritance as well as noncoding recessive variants.”
• “Just thinking you have poor endurance genes changes your body” – individuals were told a test had revealed they had one or another version of the gene CREB1, which affects how easily one tires, and were then set to run on a treadmill. Those who were told they had the version would meant they would tire more easily did indeed tire more easily. In fact, the participants had been randomized. Likewise for FTO, which can affect how full you feel, participants who were told they had the “less hungry” version of the gene reported feeling less hungry, and had higher levels of a hormone associated with feeling full. This would be a type of placebo effect for genetic information: “The results suggest that if a person just thinks they are at high risk for, say, obesity, it could change their physiology in a way that makes them more prone to the condition, Turnwald says.” (Paper here). “If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risk is warranted.”
• Calico and Ancestry.com have teamed up to show that longevity is <10% genetic. Using a single pedigree of over 400 million individuals, they were able to show that previous estimates (about 15-30%) overestimated genetic inheritance because they were confounded by non-genetic inheritance showing up via the effects of assortative mating.
• Mitochondria can be inherited from both parents in humans. The inheritance appears to be autosomal.
• We’ve known for a long time that there is a lot of undiscovered genetic diversity in African populations, and that use of the reference genome is rife with problems. Sequencing of 910 African genomes has showed just how large the problem is: at least 10% of reads failed to align to the reference genome, but were alignable to constructed pan-African contigs.
• A polygenic score for schizophrenia explained some of the variance in response to antipsychotics.
• In a severe reminder that polygenic scores cannot be used in ancestral populations not included in their construction, also using the polygenic score for schizophrenia from the Psychiatric Genetics Consortium, it was shown that the mean difference between Europeans and Africans was ten times as great as the mean difference between the European cases and controls.
• I missed this in my last round-up. At ASHG researchers in GeneRisk, from Finland, presented data on over 7000 individuals who were given cardiac risk information, some including their polygenic cardiac risk score. Those identified at higher risk, particularly if genetic, did well at making lifestyle changes.
• Mendelian Randomization is the idea that because genetics at birth is randomized and not altered by environmental confounders, considering some gene X, one can see whether gene X is subject to Loss or Gain of Function variants in the disease of interest. If it is, then Gene X is s good drug candidate – many high cost drug trials could have been avoided if MR had been performed. The technique can also be used to distinguish between correlation and causation, for example in showing that the correlation between obesity and depression is at least partially explained by obesity causing depression (depression odds ratio of 1.18 for 1 SD higher genetic risk score for high BMI). There are many improvements to the most basic MR model, see e.g. correcting for genetic correlations with shared etiology.
• As an alternative to Mendelian Randomization posted to bioarxix, BADGERS (Biobank-wide Association Discovery using GEnetic Risk Scores), designed to identify associations between a disease and hundreds to thousands genetically-predicted complex traits (using polygenic scores). Variants can be reclassified.
• A study has shown that over 30% of patients had their variants reclassified within a five year time period. “The findings of this study suggest that pediatric patients with epilepsy and previous genomic test results should have their test results reinterpreted at least every 2 years and before further genetic testing.”
• A nice review of the genetic variation relevant to immunotherapy, written by one of my former colleagues, Eric Kofman.

Applications

• Nebula Genomics will do a low-coverage whole genome sequence for free and then store it on a blockchain, if you provide some health data. This is their attempt to seed their genomic data platform, that researchers can pay to access, if the individuals permit.
• More calls for a universal DNA database for use in forensics: “if correctly implemented, a universal database would likely be more productive and less discriminatory than our current system, without compromising as much privacy.”
• A blood test for cancer (a “Liquid biopsy”) is an aggressively pursued holy grail. Scientists in Queensland think they might be onto something with a remarkably simple test that uses the fact that tumor DNA has less methylation, and hence tends to stick to metal more. Their prototype has decent accuracy and takes 10 minutes.

Regulation

• The UN’s Convention on Biological Diversity considered, and rejected, a ban on gene drives. Both those working on gene drive technology and those campaigning against it called the result a win. They state the need for informed consent, but it is not clear what this means: “who gets to decide when the African people have consented — and how unanimous a decision you need when millions of lives are on the line”
• China has cracked down on companies that have sequenced Chinese individuals and then exported the data. Adam Minter argues that this view of chinese genetic data as a national security matter is in keeping with other chinese policies on e.g. the internet. Ultimately, a lack of openness will damage science, and chinese science in particular.
• In April 2018 the FDA issued guidance on the use of databases in genomic testing. Applying that guidance, they have approved use of ClinGen’s Expert Curated Human Genetic Data as clinical evidence in approval submissions for tests. The data covers over 10,000 variants (ClinVar review status (“reviewed by expert panel”or “practice guideline”).
• LunaDNA received SEC approval to sell shares to customers, part of its business plan to incentivize individuals to share their genomic data. It currently values a whole genome at $21.

I first learnt about Lulu and Nana by watching the video that Chinese scientist He Jiankiu published explaining why he had edited embryos leading to the births of the first genetically modified babies. This is strongly recommended viewing. You can read the story, as broken by the AP, here. His claims have yet to be verified.

It was anticipated that the first International Summit on Human Gene Editing, held three years ago, would result in a consensus statement calling for a moratorium on genetically modified babies. There was no call for a moratorium. Since then, others have failed to call for a moratorium. Including the US’s National Academies report (which I covered here) which instead produced a checklist for when editing could be performed (p132), and the UK’s Nuffield Council report.

He published this video on November 25th, timed just before the Second International Summit on Human Gene Editing. He referenced the NASAM report in justifying his work. (Note also that He has engaged with several bioethicists over the years.) Some, e.g. Paul Knoepfler, argue that the failure to call for a moratorium “left the door too open” for his work. The second summit also did not call for a moratorium (their consensus statement).

There has been much criticism of He, for example Oxford’s Julian Savulescu, famous for arguing that we have a moral imperative to have the best children possible, described the work as “monstrous”; Penn’s Dr Kiran Musunuru described it as “unconscionable” (link). These voices included Chinese: Qiu Renzong, bioethicist and emeritus professor at the Chinese Academy of Social Science in Beijing, stated that the work was clearly not ethical, and a fraud (link).

While most have strongly condemned He’s work, some have taken a less accusatory stance. At the summit, Dr. George Daley, dean of Harvard Medical School, characterized He’s work as a “misstep” and argues “It is time to move forward from [debates about] ethical permissibility to outline the path to clinical translation … in order to bring this technology forward.” (link). George Church states “I feel an obligation to be balanced.”, calling the criticisms of He bullying.

Should the scientific community have acted differently? David Baltimore, the convener of the Second Summit, (reported by STAT) states that “I think there has been a failure of self-regulation by the scientific community because of the lack of transparency.” Scott Gottlieb, FDA Commissioner, goes further and says that the scientific community should not have given He a platform to self promote his work. “The response from the scientific community has been far too slow and far too tepid, and the credibility of the community to self-police has already been damaged… Governments will now have to react, and that reaction may have to take consideration of the fact that the scientific community failed to convincingly assert, in this case, that certain conduct must simply be judged as over the line” (reported in BioCentury). The work would have been illegal in the US. It also likely contravened Chinese laws (link). Lawyer Glenn Cohen questions that there could be a complicit scientific community, “it seems to me that the community is acting exactly as it should when one of its members breaks the covenant” (link).

The details of the research help highlight some open ethical issues. The aim of this research was to disable the CCR5 gene, a mutation that some people (though not Han Chinese) naturally have that is protective against HIV infection. The choice seems motivated to be a CRISPR first, rather than a pressing therapeutic need. Disabling a gene is much easier than precisely tweaking a “broken” gene to be functional. The desire for fame, to have a first, was a clear motivating factor for the research: the team wrote in their submitted ethics statement “In this ever more competitive global pursuit of applications for gene editing, we hope to be a stand-out”. Potential parents were only eligible for the study if the father had HIV. Infertile women are not eligible for IVF if their partner has HIV (link). The research is thus particularly question worthy as it a) blurred the lines between research, which is supposed to recruit individuals whose main aim is to contribute to scientific knowledge, and clinical application, where direct benefit is expected, b) edited healthy embryos, rather than seeking to “fix” those who would otherwise go on to develop a serious condition, c) individuals with the introduced edit have a higher chance of infection with the West Nile virus, and a higher chance of dying from influenza; as a protective mutation, d) the edit blurs the enhancement/therapy line, e) one of the embryos was known heterozygous (and hence would not have had the protective benefits) pre-implantation; whether the prospective parents could give true informed consent has been questioned. For the very real risk of off target effects, the consent form stated that “the project team is not responsible for the risk.” The case highlights just how ambiguous language is: An item on NASAM’s checklist was that editing be done for an “unmet” medical need. As Church points out, there is no cure or vaccine for HIV. On the other hand, HIV is both preventable and treatable.

What happens next? There are decisions ahead for any editor who receives the work to review. Francis Collins, who heads the NIH, has called for a “binding international consensus”. An editorial in Nature calls for a global registry of work genetically modifying human embryos. Carl Zimmer, writing in the New York Times, draws the parallel to babies born via mitochondrial replacement therapy, and the example of how the UK has made this legal within a highly regulated environment. Throughout this debacle, two reference cases have been given. The first is to Louise Brown, the first baby born by IVF. In the years around her birth, public opinion changed from being opposed to interfering with nature in this way, to being supportive of IVF (see Table 2 here). The second is to Jesse Gelsinger, who died in 1999 after receiving an experimental gene therapy. His death seems largely creditable to hastiness around excitement of a new technology. As George Church states, it is too early to tell whether Lulu and Nana will be Louise Browns or Jesse Gelsingers. But note that, post Jesse’s death, gene therapy is once again being pursued with gusto.

Why China? While international science incentives “firsts”, this may be acutely felt in China. As Jing-Bao Nie argues, “China’s science schemes have much to do with the developing mentality that ethics is merely secondary and instrumental for cutting-edge scientific investigation and technological invention”. Additionally, Chinese society places less emphasis on the individual: As Antonio Regalado reports here, “A person who knows He said his scientific ambitions appear to be in line with prevailing social attitudes in China, including the idea that the larger communal good transcends individual ethics and even international guidelines.” Indeed, He commissioned an opinion poll that found majority support of the Chinese public for therapeutic genetic modification (this is inline with polls in the US).

I think we will see public acceptance of genetic modification of embryos, first in the therapeutic setting, and probably first in a country such as China. As we have learnt time and again from the Assisted Reproductive Technologies space, technology does change morals.

I continue to struggle to find a format for these round-ups. I am finding the division Science/Applications/Regulation useful, but there a few stories that never quite fit that pattern. I realized that these are mostly the controversial ones, and so I have carved off a section dedicated to the eyebrow raising.

Controversy

• Elizabeth Warren underwent genetic ancestry testing, in order to prove a genetic connection to her claim of Native American ancestor. Her move has been widely covered, and criticised. It throws light on the connection between genetics and identity. Here is an interesting piece comparing the relationship between genetics and cultural identity in the aboriginal populations of Australia and the US.
• Nature News reports on the The approach to predictive medicine that is taking genomics research by storm. One of the leading scientists behind polygenic scores, Peter Visscher, a geneticist at the University of Queensland, states that “I’m absolutely convinced this is going to come sooner than we think.” Myriad has begun including a polygenic score for breast cancer on its reports, in something that is rather convenient for sales, “One of the strengths of these scores is that they provide a result for everyone, says Jerry Lanchbury, Myriad’s chief scientific officer.”
• Genomic Prediction launched their Expanded Pre-implantation Genomic Testing in September. It covers many single gene disorders and uses polygenic scoring for complex disorders (Type 1 Diabetes, Type 2 Diabetes, Coronary Artery Disease, Atrial Fibrillation, Breast Cancer, Hypothyroidism, Mental Disability, Idiopathic Short Stature, Inflammatory Bowel Disease). They are working on height. The cost will be $400 per embryo (source). From the same source, the CSO, who has Type 1 Diabetes, explains that the company wants to move on to genome editing “If his own parents had that option, “they could have potentially edited out my diabetes and it would have been a cure,” he said. “I would have been here without diabetes.” The irony is, if his parents had access to their PGD product, he would probably never have been born.
• In a striking example of the misuse of genetics, an image of white supremacists chugging milk has been doing the rounds. The act goes with the message that those who can’t digest milk should “go home”. Those of caucasian ancestry, and inconveniently for the supremacists, also those of East-African ancestry, tend to have the ability to digest lactose. The report by Amy Harmon in the NYT states plainly some of the problems with addressing this: “Many geneticists at the top of their field say they do not have the ability to communicate to a general audience on such a complicated and fraught topic. Some suggest journalists might take up the task. Several declined to speak on the record for this article. And with much still unknown, some scientists worry that rebutting basic misconceptions without being able to provide definitive answers could do more harm than good. “There are often many layers of uncertainties in our findings,” said Anna Di Rienzo, a human genetics professor at the University of Chicago. “Being able to communicate that level of uncertainty to a public that often just sees things in black and white is very, very difficult.” The ASHG released a statement condemning this use of genetics, saying that concept of “racial purity” was scientifically meaningless.
• Robert Plomin’s book Blueprint, which is newly released in the UK, is already stirring controversy. One commentator notes “Yet in the end with Blueprint, there exists a risk that readers end up impressed by Plomin’s account of his science without being aware of the racial and social implications of his theory. And in the context of a resurgent right wing across the world looking for “scientific” reasons to elevate race in public policy, this seems profoundly irresponsible.”

 

Science

• The UK biobank has released its data on 500,000 individuals. Each individual is genotyped, and will have their health outcomes collected prospectively. MRI data for 100,000 of the individuals should be available by 2020. “UK Biobank is an open-access resource that encourages researchers from around the world, including those from the academic, charity, public and commercial sectors, to access the data for any health-related research that is in the public interest.”
• Successful in utero gene-editing of mice. The researchers introduced to the mice what is probably the most famous “good news” gene variant, a loss of function in PCSK9, which lead to lower LDL-C and coronary heart disease incidence.
• Chinese scientists report on the birth of mice with two mums (“bi-maternal”) and with two dads (“bi-paternal”). Some of the bi-materna pups survived to adulthood and were fertile. Some of the bi-paternal mice survived birth, but died shortly afterwards. The researchers had to deal with the fact that a lot of the genome is imprinted in a sex specific fashion.
• Unpublished results were presented at ASHG on ~37,000 exomes of those with Autism Spectrum Disorder. They identify ~100 genes related to the condition, but a surprise was that a large proportion were more closely associated to intellectual disability or developmental delay.
• From ASHG: Preliminary results of 30,000 trios (patient and parents) of patients with developmental delay has found genetic causes in about a quarter of participants, linking 302 genes to the condition.
• In further results reported ahead of publication at ASHG, in a dataset of ~490,000 people researchers identified 4 variants (2 just in males) that are associated with having had same-sex partners, a trait that is about ~40% heritable. “We found that variants predisposing to non-heterosexual behavior are, among heterosexuals, positively associated with having more self-reported lifetime sexual partners and, in heterosexual males, with being judged more to be physically attractive. This is consistent with the hypothesis that genetic variants predisposing to non-heterosexual behavior confer a mating advantage to heterosexual carriers.”
• Continuing the story of the widely covered Educational Achievement polygenic score which I covered in my last post

• Economic researchers applied the score in combination with economic data (working paper). The results? As one of the authors reported to the Post, “If you don’t have the family resources, even the bright kids — the kids who are naturally gifted — are going to have to face uphill battles.”
• A twin study based on UK individuals on the genetics of university success produced heritability estimates for: entrance exam achievement (57%), the choice to study at university (51%), the quality of university attended (57%) and achievement at university (46%). (Numbers are the proportion of variance in the trait explained by inherited factors). The Educational Achievement polygenic score, which captures 11-13% of variance in number of years of education, captured 4%, 5%, 2%, 7% of this variation respectively.

• This was a piece I started to read not expecting a connection to genomics: the story of the placebo effect, and attempts to unpick its biochemistry. Researchers formed a hypothesis that variation that affected the levels of COMT, an enzyme that helps determine levels of dopamine and its relatives. They have indeed found evidence of this. The suggestion is that somehow the caring involved in a patient-physician interaction stimulates the same biochemical pathway that many drugs use. This suggests that the blinded placebo trial may be inappropriate: “the placebo effect is not just some constant to be subtracted from the drug effect but an intrinsic part of a complex interaction among genes, drugs and mind.” And of course “The [pharma]industry would be delighted if it were able to identify placebo responders — say, by their genome — and exclude them from clinical trials.” Thinking beyond trials to the administration of medicine, “Should medical rituals be doled out according to genotype, with warmth and caring withheld in order to clear the way for the drugs?”
• I had previously missed this: a European initiative to overcome data silos and privacy concerns to assemble a million genomes by 2022.
• A new study from Calico and Ancestry.com estimates the heritability of lifespan to be under 10%. It was previously believed to be higher, but they think that this was inflated due to the effects of assortative mating.
• The largest ever genetic study from China of over 140,000 Chinese individuals has been reported. It was based on blood processed for Non-invasive prenatal testing of pregnant women.
• The Garvan Institute in Australia has sequenced the genomes of 4000 healthy elderly individuals. I remember when 4000 sounded enormous…
• In more new datasets, about 2000 genomes of individuals from rural Uganda, and genotype results from thousands of other across Africa. This is beginning to help us unpick the early starts of human population structure.
• Gout was previously thought to be associated with diet. But a new study of ~17,000 individuals finds that the effects of diet are very minimal, whereas genetics plays a large role, explaining ~24% of the variance.
• A new version of CRISPR, CRISPR-GO can alter the genome’s organization.

 

Applications

• In a major consolidation in the sequencing space, Illumina is buying PacBio, allowing the market leader access to long read technology.
• An analysis of variant classification changes in Myriad’s reports over the last ten years found that 25% of reports had variants of uncertain significance that had since been re-classified. A full 90% of these variants were reclassified as likely benign/benign. In its coverage of this, the NYT stresses that most labs do not have a good process in place for what to do when a variant is re-classified.
• Should tests for Fragile-X and SMA be added to the newborn screening panel? A pilot is under way in North Carolina.
• 23andMe’s FDA approval for displaying health related genetic information grow further, now extending to some pharmacogneomic variants. Key to the approval was data submitted to show user comprehension.
• A study that shows that “about 60% of the searches for individuals of European descent will result in a third-cousin or closer match, which theoretically allows their identification using demographic identifiers”. The search was based on data in te MyHeritage database, which has about 1.28 million users at the time. The first author of that paper, Yaniv Erlich, has been tweeting to keep track of cold cases solved via familial DNA searching. Count as of Nov 3 is 22.
• A pilot study of expanded carrier screening of over 10,000 people in China, funded by BGI. The authors conclude “Our data demonstrate the feasibility of ECS, and provide evidence that ECS is a promising alternative to traditional one-condition screening strategies.” Compare to this call for the implementation of this testing throughout China, where the first authors are from the Research Institute for Birth Defect Prevention and Control.
• It’s easy to bash precision medicine, but there are some success stories. Here’s a story of a N-of-1 drug for a girl with Batten disease, which is fatal. The drug is an antisense oligonucleotide, the same class of drugs as nusinersen/Spinraza for spinal muscular atrophy (SMA)
• The BabySeq and MedSeq projects, with both sequence genomes of healthy individuals, reported at ASHG that they had found “unanticipated risk variants” in 16 of 110 adults (14.5%) and 18 of 159 infants (11.3%). Upon follow up, some of these were found to indeed have the diseases indicated. These numbers were higher than they were expected.

 

Regulation

• A bill to recognise certified genetic counsellors as health providers has been introduced to the US house of representatives. If passed, counselling services could be covered by Medicare..
• In Australia, life insurers will no longer require the disclosure of adverse genetic testing results.
• A comparison of data sharing regulations in seven countries. Part of the Global Alliance for Global Health, the work was seen as a prerequisite to build upon: “The future of genomic data sharing depends on a creative yet responsible interpretation of existing legal norms in order to ensure that we truly respect the human right of everyone to benefit from scientific progress and its applications,” said Knoppers.
• A meta-analyses of studies investigating people’s fears of genetic privacy found over 50 studies, found “The picture of genetic privacy that emerges from this systematic literature review is complex and riddled with gaps.” I found this conversation with Jen King, director of consumer privacy at the Center for Internet and Society at Stanford Law School, referencing results that people tend not to think of their genetic data as any more personal than their google searches. This motivates contributing data to research, but individuals can think differently again when they are walked through potential implications — e.g. that drug companies can sell any drugs produced at whatever price the market will bear.
• A loophole involving the collection of DNA from minors has been closed with a bill in California. What most interested me about this is the close involvement of the Electronic Frontier Foundation, which makes sense as DNA data is increasingly another tool of surveillance.

Another major gap from me as my travels have continued…

A major theme that emerges for me over the past few months is on non-medical uses of genetics, made possible by 1) Continued growth of Direct to Consumer (DTC) testing, 2) large scale studies of non-health traits, and 3) increased acceptance of polygenic risk scores, whereby an aggregate score for a given trait is made from small contributions from many genetic markers. This is something we need to talk about.

1) Millions of DTC tests have been sold in the US (over 12 million, according to one estimate from February). A poll found that “Some 17 percent of Americans already have undergone at least one kind of DNA test, and 52 percent of the remainder say they’d like to.”

2) In the last few months, there have been large scale studies of neuroticism, intelligence, social mobility, and on social traits including loneliness. A lot of research into such “social” traits is performed under a health mandate, as many such traits correlate with health outcomes.

3) Polygenic risk scores can be much better at identifying those at risk of serious conditions. That’s the conclusion of a paper and the basis for a new tool that will ingest e.g. 23andMe data and give you a score. From the paper: “The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively.” These successes, combined with the type of studies I listed above, lead to, for example, educational achievement and cognitive performance polygenic risk scores, explaining 11-13% of variance, 7-10% of variance respectively. Such scores have already make it into DTC tests, for example educational achievement markers are available from Helix.

Needless to say, such scores have the potential for large social implications. The educational achievement study has appeared all over the press, but I have found good critique of possible implications scant. This piece is an exception, one example:

“There’s as much to be learned about the nature of our educational system as about the nature of the individual in this data,” said Mary Helen Immordino-Yang, professor of education, psychology, and neuroscience at the University of Southern California. Specifically, if certain genetic variants are associated with better educational outcomes, then there might be something about the structure of our educational system that’s favoring people with these variants. For example, if the variants were involved in language comprehension, that could tell educators that current teaching methods aren’t working for students who process language differently. That means they should be designing new interventions to accommodate that variation, Belsky said.”

Such reflection is critical. Contrast this with the authors of a paper titled “The stability of educational achievement across school years is largely explained by genetic factors”,  state the motivations and consequences of their work are that “we could use DNA tests at birth to identify children at genetic risk for developing reading problems, and give them early intervention.”

Separately, additional potential downsides of the DTC genomics movement have been in the news. I highlight three:

• What happens when DTC tests reveal unexpected family secrets? The Atlantic has a piece on a facebook group, with over 1000 members, that allows individuals affected to vent emotions and plan next steps. Meanwhile in the UK, the fertility regulator has called for genetic testing companies to better highlight chances of uncovering family secrets, additionally saying that anonymity for sperm/egg donors is a thing of the past.
• In the light of Ancestry.com and Spotify teaming up to offer playlists based on your results, a critique of how genetic ancestry testing, who focus on the fact your DNA reveals something meaningful about you. This runs from “conflating DNA and cultural identity” (routing for a World Cup team based on results) to “game programs set up to address past injustices” (using results to prove Native American or African ancestry), to reifying race as a meaningful category (citing a study that showed reading about these tests increased beliefs in racial differences).
• A report on four cases of families who act on information obtained from raw data provided by DTC tests. In these cases, none of the SNPs reported turned out to be present. Another story of a discordant 23andMe and Ancestry result over a very worrying variant.

I think it is worth highlighting what we have learnt about consumer preferences

• The Associated Press reports a poll of 1109 adults it performed on questions related to genetic testing (also refed above on number of people interested in genetic testing). On whether people would want to know if DNA showed they had a genetic variant associated with an incurable disease. 60% said Yes, for under 30s the number was 78%. Most (but not all) would tell family members). The poll also asked about the use of DNA by the Feds — “Half of people think genetic data should be used to help solve crimes only with the consent of the person tested, a third think it’s OK without that consent — and 13 percent don’t think law enforcement should use it at all.”
• A Pew poll found majority support for gene editing for babies for health reasons. Men and more supportive; religious people are less supportive. If the intervention relies on testing embryos, most are opposed.
• A U of Michigan study on patient attitudes to their biobank samples being commercialized. “67 percent of participants agreed that clear notification of potential commercialization of biospecimens is warranted, but only 23 percent were comfortable with such use. Sixty-two percent believed that profits should be used only to support future research, and 41 percent supported sharing profits with the public.”
• STAT reports on consumer adoption of genetics in China. Those in the space refer to a particular emphasis on a Chinese fascination of how genetics affects identity and destiny, and, for the generations born under the one child policy, with finding family. Routine newborn genome sequencing is on the cards within the next five years (Veritas already has a product in pilot out there). Because there isn’t an entrenched medical genetics profession, there will be less paternalism about results.

It strikes me that the academic literature is all about efforts to ensure that people’s informed choices are respected. A lot of this type of work, which looks at what those choices are likely to be, happens outside the academic mainstream. This is an observation I intend to check.

Applications

• A Federal official said that DNA tests were being used to reunify families. Jeff Sessions says on this clip from Washington Watch that many of the children may not be biologically related to the adults that bring them to the border. Ethical issues abound.
• The UK’s Genomic Medicine Service will launch on October 1. All new cancer patients will have their tumors genetically sequenced.
• An interesting story about how the existence of an ICD code to cover a condition can have a direct impact on patients’ lives — these codes are what is searched in databases, and what a lot of insurance is tied to.
• 23andMe and GSK have entered into an exclusive drug development partnership, and GSK have bought a $300m stake. They hope to use 23andMe’s database to locate better drug targets. Note that at about 5m customers, that is ~$60 per current customer. In possibly related news, 23andMe have blocked access to deidentified raw genetic data by commercial third parties through its API.
• A firm is inviting you to upload your genetic info to help you plan for your financial future.
• Many DTC companies will adopt new privacy guidelines. These include companies getting explicit consent from customers before sharing with third parties. Though the title of this piece captures it: Deleting Your Online DNA Data Is Brutally Difficult.
• Australia has a government run, opt out electronic health record, which will be able to store genetic information. Some fear for privacy.
• The first CRISPR based gene therapy trial backed by a US company has started. It will recruit beta thalassemia patients in Germany.
• George Church has his say on how we benefit from having our genomes sequenced. He introduces a new start-up he has co-founded, Nebula, which will use blockchain technology to address “issues of transparency and control” in “delegating data access and recording of transactions”. He states: “The Nebula team and approach I personally trust because of emphasis on ethical issues.”
• A NYTimes Op-Ed that successes of precision medicine and vastly outnumbered by failures. At the ASCO conference, the four precision therapy trials presented with results were all failures, and yet there was no news reporting.
• Federal money to develop a system intended to recognize emerging bio threats based on DNA orders placed, to e.g. spot if someone was trying to re-create an extinct virus.

Regulation

• A Federal Court maintained the status quo over IP for CRISPR in eukaryotic cells, maintaining the patents of the Broad Institute, a blow to Berkeley.
• An extension to the European Convention on Human Rights and Biomedicine covering genetic tests come into force on July 1, ten years after it was written. It covers “Article 3 – Primacy of the human being: The interests and welfare of the human being concerned by genetic tests covered by this Protocol shall prevail over the sole interest of society or science, ” and bans genetic discrimination. It outlines the procedures involved if a person is not able to give consent, and clarifies that the information from a test should be made available to the person.
• The NASEM have recommended that researchers should attempt to give back data to research participants, including those not very medically significant.
• A four year effort has culminated in a recommendation not to sequence all newborns, published by the Hastings Center in the context of a whole issue dedicated to investigating the ethics of the issue. Meanwhile, the four year BabySeq project reports a low uptake in the study by parents of newborns — only 10% were interested in an enrollment session, of whom 67% signed up.
• The UK based Nuffield Council on bioethics issued a report saying that human germline editing is not in and off itself ethically problematic, if it is in the best interests of the child and does not exacerbate social inequalities.
• Projects that utilize “Ethics dumping” will no longer receive EU funding — this is the practice where research that would be unethical in one country is performed in another with laxer standards.
• The UN has been meeting about how to regulate the genetic riches of the oceans. Genetic prospectors have filed 13,000 patents, half owned by one chemical manufacturer.
• Genetic editing will be treated as a form of genetic modification in Europe — with large implications for agriculture. Japan may be about to take the opposite route.
• Gene therapy trials have traditionally requires an additional layer of oversight, provided by the Recombinant DNA Advisory Committee (RAC). But that special treatment will no longer needed. Gottlieb and NIH Director Francis Collins wrote “there is no longer sufficient evidence to claim that the risks of gene therapy are entirely unique and unpredictable—or that the field still requires special oversight that falls outside our existing framework for ensuring safety.”
• The UK opposition party has called for a ban on using Non-Invasive prenatal screening for determining sex.
• In the 1970s, scientists converged on a “14 day rule”: embryos could be studied up to 14 days post fertilization, which is when the “first inklings” of a nervous system first appear, and the point at which the embryo can no longer split. At that time, it wasn’t possible to keep embryos alive in cell culture beyond a few days. Now, scientists are just about at the 14 day limit. To push beyond this limit, some researchers have used “synthetic embryo like structures” made from stem-cells. This piece covers the advances.

Science

• Chinese scientists report on base editing of a Marfan syndrome variant in viable human embryos. Base editing is a form of gene editing that does not introduce a double stranded break, and hence should be less prone to error. This is another first for China in this space. 18 of 18 embryos had the desired variant edited, and 2 of 18 had additional off target effects.
• Link between Alzheimers and the herpes virus — based on RNA sequencing from brains
• CRISPR can cause large scale structural variants that may be pathogenic. The news sent companies using the technology stocks’ down.
• Successful gene editing of mice’s brains using a non-viral delivery of CRISPR. The phenotype, repetitive behaviors, reduced in mice models of autism.
• Gene drives in mammals reported for the first time — the inheritance of a specific genetic variant went from 50% to 73% in female embryos only, suggesting the controversial tech has a long way to go. (Note that gene drive research in mosquitos is being actively pursued.)
• A case of uniparental diploidy, where most of an 11 year old’s cells only have DNA from her father. She has not yet presented malignancy, though all of the other ~20 such cases worldwide have presented malignancy early in life.
• An accessible introduction to “Inborn errors of immunity” — where genetics, rather than unspecified bad luck, can lead to someone succumbing to an infection. Knowledge of the underlying genetics can lead to successful therapeutic approaches.
• ExPecto, a tool to predict the effect on gene expression of any genetic variant.
• A tool to predict how many SNPs, and hence what sample sizes, are likely to be involved in various traits.
• Knowledge of how genetics influences behavior can lead to “free will doubt”, with potential implications for how individuals view justice. In general, free will doubt decreases support for justice based on retribution, towards justice based on consequentialism. A study shows that, while this is true for violent crime, for “low affect” crime, free will doubt actually decreases support for either type of justice.
• Evidence that whole genome or exome testing outperforms the current standard of care (chromosomal microarray) for children born with suspected genetic disease.
• The genome can gather mutations as we go through life (a phenomena well known as the cause of cancer). A study (and a nice write-up) shows that early life experiences can end up written in your DNA — some genetic mutations in brain cells depend on the amount of maternal care baby mice received.
• Genes responsible for antibiotic resistance have been located in the air of all major cities tested, with San Francisco topping the list.
• Variable penetrance significantly complicates the picture linking genetics to disease — this is the phenomenon by which the same genetic variant can have a very different effect in different individuals. A new study shows that the variable penetrance of rare coding variants can often be explained by the common regulatory variants for the coding regions in question. (This write-up is more accessible.)
• Your DNA, Your Say, an international online survey about attitudes to genomic data sharing using videos to educate has recruited 20,000+ participants in at least 14 languages.
• The genes that are most studied can be predicted based on a handful of factors indicating how easy they were to study decades ago, rather than on factors which best indicate which are likely to be the most disease relevant. They suggest funding changes are needed to counter this preference for conformity.

And finally, a nice piece from science historian Oren Harman on use of the term “gene” — historically and in the future. And another lovely piece about how some of the genes got their names, including the background to “Pray for Elves”, which I learnt originates with someone I used to work with, Prof Mark Yandell.

Close to society

• The Golden State Killer left DNA behind at many of his crime scenes from 1974-86. The DNA did not lead to any suspect until April of this year, when an officer uploaded the killer’s genetic profile to an open source genetic database designed to help people find relatives. They got a partial hit to a family member, and used this to identify a suspect subsequently found to be a match to the killer. The same technique has been used for other cases. I will write much more extensively about this case separately.
• A good investigational piece, using data from a new database, that shows that pharma contributions to patient advocacy groups dwarf their spend on lobbying.
• The All of Us program has officially launched (formerly the Precision Medicine Initiative). The project aims to enroll 1 million US residents, and anyone over the age of 18 can sign up. The first interview question Scientific American asked the program’s director Eric Dishman was about the golden state killer case, the response was that law forbids one federal agency sharing data from the program with another, even if subpoenaed. A moving story from WIRED about some of the individuals behind the diversity programs for the project.
• Dubai Health Authority (DHA) is planning to map the genomes of all of its residents. It aims to “issue reports that support research, forecast future disorders and epidemics, and plan preventive measures.”
• In the wake of the separation of families by US border control, 23andMe offered its tests to hep reunite the families. Many were swift to point out that genetics in the hands of US border control is a scary prospect.
• The biohacker scene has been in the spotlight thanks in particular to the combination of some headline grabbing antics (e.g. live self injection with gene therapies) and prominent voices raising concern (see e.g. here). The recent death of one of the leading activists, Aaron Traywick, has given the nascent field pause for reflection.
• African scientists have formalized a voluntary framework aimed to prevent foreign researchers from using African genetic data without involving African scientists (“helicopter science”).
• In a startling combination of buzz words, there is a plan to publish the cannabis genome to a blockchain, as a challenge to the conventional scientific publishing market. The idea is that this model will give a permanent, transparent record of a scientific advance, preventing corporations from laying claim to certain advances.
• The EarthBioGenome project (EBP), which aims to sequence the ~1.5 million known eukaryotic species in the next 10 years, is facing up to some of its challenges, including finding funding for the endeavor, which has an estimated price tag of ~$5b.

Close(r) to the clinic

• Liquid biopsy — a major early player is withdrawing, and ASCO/CAP have said that they don’t see a role for the tests outside of clinical trials.
• Geisinger’s whole exome efforts are moving beyond research. Long at the forefront og genomic medicine, they are piloting a clinical whole exome, with a view to sequence every one of its patients at birth. 
• It has long been argued whether knowing information about genetic risk actually improves health outcomes by altering behavior. A new study using risk score for cardiac health risks did find changes in behavior.
• Taking the precision medicine approach to arthritis
• A prospective study of a polygenic risk score, this one for Atrial Fibrillation, showed reasonable prognostic abilities.
• Proof of concept for nanopore sequencing for Pre-implatation Genetic Screening – quicker, and potentially cheaper.
• Researchers have shows that they can use circulating placental DNA in the mother’s blood to predict the due date of the baby as reliably (and hopefully cheaper) as first trimester ultrasounds, and can also discriminate those at risk of a pre-term birth.
• Color genomics in spearheading the route of self-insured employers, who offer tests as benefits, to bring genomics to a wider audience, as a way to make a case for population based breast cancer risk screening. 

New science

• The interstitium, a fascinating story of how a quirk of technology lead to us overlooking what is now classified as our largest organ. 
• More on the somatic genome: we all have pieces of circular DNA, formed from breakpoints. 
• In a new chapter for how nurture can shape nature, the not so static genome: How attentive a mother is to her babes correlates with how many copies of the jumping gene L1 the babies have.
• In another contribution to the nature-nurture debate, genetic risk for schizophrenia is modulated by the placental environment – schizophrenia patients who had these early life complications (ELCs) had higher polygenic risk scores, and the genetic scores better predicted schizophrenia presence in individuals with ELCs. The genes involved are expressed in the placenta during complicated pregnancies, signalling a placenta under stress.
• A large study (265,218 patients and 784,643 controls) found that whereas the underlying genetic risk for each neurological disorder tends to be distinct, there is a lot of overlap for psychiatric conditions, adding evidence that “current clinical boundaries do not reflect distinct underlying pathogenic processes” for psychiatric conditions.
• Transposons make up half the mammalian genome, and have long been thought to be functionally inert. A study shows that one transposon is necessary for normal embryo development. 
• A role for pericentromic Satellite DNA, part of the non-coding DNA previously without a known function, has been shown to be vital in holding the genome together in the nucleus, through a protein called D1 that binds to it and helps hold chromosomes together.
• A good news genetic variant protects against liver disease.
• And more work that highlights the role of rare variants, from a study that uses a large cohort of de-identified EHR data and genetic data to identify patients who have symptoms associated with rare genetic diseases, to try and identify those who may have an identified genetic condition, and then looking for common underlying genetics of those identified. 
• Advances in DNA computing.

Genetic modification

• The FDA put the brakes on the first US based CRISPR clinical trial, for unspecified reasons.
• “Genome surgery is coming”, says the team that reports the first successful results of find-and-replace CRISPRing of a heterozygous mutation causing in a retinal disease. The challenge in these autosomal conditions is to just target the faulty version.
• CRISPRing cells can activate the cell’s DNA repair mechanism pathways, specifically that involving p53. This can cause a selective advantage for cells that have a compromised p53 pathway, i.e. CRISPR can lead to a selective advantage for cancerous cells. The conclusion “p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9”.
• The US Department of agriculture announced that it will not regulate genetically edited plants, on the basis that they could have been produced by classical breeding techniques.
• The Association for Responsible Research and Innovation in Genome Editing (ARRIGE) has been formed
• The scientists that published the widely cited study that CRISPRing cells led to many off target effects have been unable to replicate their results.
• Epigenetic version of CRISPR shown to work in vitro. 

Spotlight on genetics and intelligence

Spotlight on genetics and race

• A “blackhole of accountability” regarding research participants. A privately funded, off shore, unregulated trial of a herpes vaccine has highlighted the lack of protections for research subjects in the US. Federal agencies are underfunded and have shown themselves to be unwilling to engage in even the most egregious cases. Bioethicist Arthur Caplan asks. “How is the government going to manage subjects, researchers and investors who don’t like regulations?”
• A perspective from Laura Hercher on ”the ghettoization of genetic disease” – that non-invasive prenatal screening will mean reduced prevalence of conditions such as Downs, but only in specific communities, as communities have very different cultural attitudes and access to abortion and to disability. We need a “genetics community that fights for all vulnerable individuals with as much vigor as it fights for reproductive rights.”
• An argument for the importance of ethnic diversity in genomic datasets, from the point of view of access to genetic testing in the first place. And a genetic counsellors report that the saying “De algo nos vamos a morir” — “We’re all going to die of something is common from the hispanic population, and is an attitude that affects take up of genetic testing.
• Pre-marital testing for some genetic diseases has been mandatory in Saudi Arabia for a decade, but it has not deterred all couples, and is only limited to a handful of disorders. There is a renewed push in the country to screen more widely. About 40% of Saudis marry their close relatives, a practice that leaves them very vulnerable to recessive disease.
• The right-to-try legislation, which passed in the Senate, has stalled in the House. Proponents argue that patients have the right to try any drugs that have been tested in humans. Opponents argue that the bill would undermine patient safety.
• Whether or not genetic editing counts as genetic modification is heating up as a legal question, for example within the EU over plants.
• A systematic review of how personalized/precision medicine is presented in the press finds that coverage is overwhelmingly optimistic, thus contributing to science hyping.
• The World Anti Doping Association discussed making it mandatory for athletes to have whole genome sequencing, in an effort to boost their chances of detecting genetic modification for performance enhancement (“gene doping”)
• An interesting historical summary of the attitude of African Americans to eugenics in the 20th century argues that there was initially some enthusiasm for the prospect of racial improvement, but that disproportionate targeting of African Americans for eugenic legislation (such as forced sterilizations) changed this tide.

• A California rep has introduced a Federal bill designed to promote precision medicine, called the Advancing Access to Precision Medicine Act. The Act has been referred to the House Committee on Energy and Commerce.
• Three of the top five articles of 2017 on Genomeweb concerned regulatory decisions, including FDA guidance around development of companion diagnostics in precision medicine, a Supreme Court decision regarding a decision concerning a forensic DNA kit, and FDA approval for a multi-gene, multi-drug companion diagnostic.
• Last year CMS announced its coverage position for somatic genetic tests, which is basically to pay for FDA approved assays, which some have argued goes too far and others not far enough. Some commercial payors have indicated that they will likely follow suit.
• A study of physician knowledge of and attitude to genetics reveals basic barriers, such as lack of knowledge of how to refer to a genetic counsellor.

• Genetic privacy hit the news again, with Senate Minority Leader Chuck Schumer called on the Federal Trade Commission to launch an investigation into the way DTC genetic testing companies handle customer data. He doesn’t think that companies should be able to sell individuals’ genetic data without their knowledge. The data can be subpoenaed in court, stolen, bundled and sold.
• The first case of theft of the genetic information in DNA is in progress. It differs from previous cases in its focus on information rather than sample, and privacy rather than economic gain. So far, legal precedent is that you don’t own your DNA — which runs counter to the belief that many people have.
• A commentary that outlines the tension between HIPAA’s requirement that individuals have access to their own data with FDA and CMS, who often regulate to limit access on the basis of safety concerns.
• The UK Personal Genomics Project are putting together an “open consent”, based on the idea that whoever has had their genome sequenced is the final owner of the data

• Launch of Pheramor, a Dating App that incorporates DNA analysis of pheromone variability to help suggest potential dates. Based on science such as the sweaty T-shirt study, showing that we tend to be attracted to people with different HLA types than us, it is almost certainly an example of a little science being used to attempt something in a lucrative market.
• 23andMe have launched a weight loss study, designed to be both interventional and remote, timed for the New Year. They hope to involve 100,000 people. I signed up, and have been disappointed that all I have received from them with some minimal information about what foods to try and eat less of. They hope to gather data that will allow them to make tailored weight loss plans for their customers, and also to prove a model for running trials that could prove lucrative.
• A new kid on the block for consumer genomics, Pillar Health, has launched. they aim to differentiate themselves by being longitudinal, and through focusing on environmental causes of health differences.
• Start-up Prescient has developed a test that it claims helps identify, on the basis of a gene panel test, those most likely to become addicted to opiods, and who hence should be offered alternative pain medication.
• Lynparza, a PARP inhibitor has been approved for use in women with metastatic breast cancer who have a BRCA mutation. An FDA spokesperson: “This approval demonstrates the current paradigm of developing drugs that target the underlying genetic causes of a cancer, often across cancer types. 
• Couples can have carrier screening to determine what recessive diseases a child of theirs has a chance of having. HumanCode, for $259, uses the same techniques to look at the sunnier side of what a future child might look like, for example, whether they are likely to have a sweet tooth. Queue worries about labelling children, in this case before they are even conceived.
• The Earth BioGenome Project and the Earth Bank of Codes have announced a partnership as part of the mission to sequence all 1.5 million vertebrate species and make their genomes available to those developing solutions to preserve biodiversity and promote sustainability.
• Towards the holy grail in cancer diagnostics — an early detection test. A multi-institution effort called CancerSEEK based on cell-free DNA reports ~70% sensitivity and ~99% specificity.
• The anticipated delivery date of 500,000 whole exomes by the UK BioBank initiative is 2020.
• Invitae plans now offers its ~130 “proactive cancer and cardiovascular screen” gene panel test for healthy individuals for $250. Based on their pilot data, ~15% of individuals received positive results.
• An update from ClinVar, the public repo of variant classifications, most from clinical labs: there are now classifications on ~376,000 variants, covered by 582,000 submissions from ~900 submitters. Medically relevant discordance of classification is ~2%.

• Gene Chain from EncrypGen
• Luna DNA, who have snagged a top exec from Illumina
• Nebula Genomics, a George Church project
• Zenome

• Researchers report in Science that children can be influenced by the alleles that they DON’T inherit from their parents (30% as much as a transmitted allele), through that allele’s influence on the environment. This comes from deCODE, and adds to the complexity of the nature-nurture debate. Commentary here and here.
• An investigation of over 5000 American adolescents reveals that friends are more genetically similar to each other than non-friends. The authors term the phenomenon “Social-genetic interaction” and hypothesize that it is due to shared social forces.
• Its never been clear how alcohol causes long term damage; new evidence suggests that alcohol can damage DNA, including of blood stem cells.
• For its 20th birthday, the journal Genetics in Medicine reviews the field of public health genomics.
• Advances in nudging the micromiobe, through interfering with the metabolism of bacteria that are most abnormal in IBD.
• Two papers (here and here) in Science identify which tumors are most likely to respond to immunotherapy — those with inactivating mutations in proteins involved in chromatin remodellin
• A large fraction of people will likely have immune systems that attack Cas9, the main protein involved in CRISPR treatements. It is not surprising that many people have antibodies against Cas9, as it is a protein from a common bacteria. It is likely this finding won’t prove too much of an issue, as other versions of CRISPR use different proteins.
• Sleep deprivation affects us in various ways, but for individuals with a particular DRD2 variant, their cognitive flexibility is less impaired (steps towards the Beggars in Spain scenario, whereby we work out the genetics behind needing sleep and some are born “sleepless”…?)
• NPR focus on one individuals story to illustrate one of the main issues with targeted therapies: great responses are often short-lived.
• Polygenic underpinnings of Alzheimers and Parkinsons beginning to be uncovered.
• A GWAS of ~160,000 Japanese individuals across 58 quantitative traits, uncovering several hundred new links, that may have been missed by other studies because of the ethnic make-up of participants. 
• Basket trials, which try targeted therapies on cancer types other than those they are currently indicated for, are finding mixed results: these drugs do sometimes work in other cancers, but not all the time.
• Stephen Kingsmore has set a world record for the fastest “solving” of a genetic case using whole genome sequencing, taking 19.5 hours, and using the software of my previous employer, Fabric Genomics.

A look at the arguments for restrictive regulation of biotechnology as presented in Francis Fukuyama’s 2002 book “Our Posthuman Future: Consequences of the Biotechnology Revolution”

In the face of technology that has great potential for saving lives, it is not that fashionable to argue for more regulation. Nor is it particularly clear who would make that case. In Our Posthuman Future: Consequences of the Biotechnology Revolution, American political scientist Francis Fukuyama does just that.

Although Fukuyama rose to fame through proclaiming the End of History through the winning out of liberal democracy, he revisits this position in Our Posthuman Future: there can be no end of history without an end of technological advancement, and biotechnology in particular puts liberal democracy at risk. Published in 2002, the form of the argument is as relevant now as it was then.

The argument turns on the importance of human nature to what we hold dear, and hence that we have much to lose from technology that alters human nature.

First, what is human nature? His definition is that it is “the sum of the behavior and characteristics that are typical of the human species, arising from genetic rather than environmental factors.” The relative roles of nature and nurture have been fought over through the centuries. All we need for the rest of the argument is that it is malleable (by culture, environment, learning), but not infinitely so. He further makes the case that the spread of human emotions is a critical component piece of human nature.

Although the book is framed as one argument, I think there are two fairly separate cases put forward. These require untangling.

The first is that political equality is based on human equality, which is based on our shared human nature:

1. Biotechnology can modify human nature
2. Human nature is the basis for our human rights
3. Therefore, use of biotechnology risks undermining our human rights, which is the basis for our morality

Premise (2) is not currently popular. Instead, the doctrine that human rights come from Man Himself holds the day. Fukuyama argues that a) those that hold this position do actually appeal to human nature, just in a sneaky fashion, and b) they are forced to be cultural relativists. A shared appeal to what we all have in common, our human nature, allows for drawing a “bright red line” within which all humans are equal. A lot of the political progress we have made is expanding this circle of who deserves political rights, from a privileged set of men to all humans. The “nature of nature” has helped in this regard: many attempts to justify the red line as excluding some but not others were shown to be prejudices that didn’t stand up to the facts. Moral order comes from nature, with no appeals to culture necessary. If we alter human nature, we risk introducing the type of  political hierarchy that we’ve fought long and hard to get rid of.

The example that most clearly fits (1) is the possibility of genetic engineering producing the genetic “haves” and “have nots”. Indeed, I think something as extreme as this would be necessary for this argument, as the aspects of human nature that are doing the work for political equality are so basic, that we would need considerable change to adjust where the bright red line is drawn. Before we face such a shift, we will face inequalities that, although they do not change our human essence, nonetheless will further alter opportunities between the haves and have nots.

Can only humans display “human nature”? While I am sympathetic to an appeal to human nature as the basis for rights, I prefer an appeal to this as a functional category, rather than something that adheres to a physical human. We can agree that those who have the traits that we consider to be core to the human essence – rationality, the capacity for moral choice, the spread of emotions – are indeed worthy of rights, while still thinking that something other than a human could share in having those properties. On this account, Spock would fall within the bright red line.

The second line of argument also appeals to the importance of human nature. It concerns the threats of utilitarianism:

1. Much of biotechnology is very utilitarian in its approach, i.e. it aims to minimize suffering
2. A utilitarian approach downplays the importance of “the full emotional gamut” of human nature and hence the human condition, for example, the role that suffering plays in building human character
3. Biotechnology is likely to be applied broadly
4. Therefore, biotechnology risks destroying that which makes us human

To demonstrate the likely broad reach of biotechnology (C), Fukuyama points to the increasing medicalization of the human condition, for example the prescription of Ritalin not just to those at the far extreme of the spectrum of hyperactivity. We show a desire to medicalize. This is the move to “Don’t blame me! I’m wired wrong!” in the future laid out by Tom Wolfe in his essay “Sorry, But Your Soul Just Died”.

Whereas the biotechnology in question in the first line of argument was genetic engineering, in this second line of argument, it is drugs and the prospect of “cosmetic pharmacology” that looms large. And the use of drugs to alter ourselves in a day-to-day, non-therapeutic way, is even less science fiction than it was in 2002, with use of Adderall (another stimulant for treatment of ADHD) as a cognitive enhancer reported to be widespread. I have on occasion had it offered to me by well-meaning folk who knew I had a hard day’s work ahead.

While cosmetic pharmacology is surely here to stay, to what extent is this likely to lead to a pleasure-maximizing, pain-minimizing (and hence diminished) version of humanity? Would we all take the Soma of Brave New World? If it existed, should we regulate its use?

Fukuyama’s answer to this, and other technologies that have the potential to alter human nature, is a resounding Yes. He is fed up with the defeatist attitude that is always wheeled out: restrictive regulation will push the development of these technologies overseas. We do have examples of regulation that is broadly successful at the international scale, from nuclear power to human experimentation. Unlike nuclear power, where it was obvious to all at the outset that here was a technology that needed strong international regulation, biotechnology will advance through battling one disease at a time. By the time we realize what is at stake, we may have lost it.

It has been a very eventful few weeks, especially on the regulatory front. Meanwhile, I have been writing another article with Sarah on the regulation of genetically modified animals, watch this space.

• Spark Therapeutics Luxurna has become the first FDA approved gene therapy that targets a specific gene. It stops the progression of a rare retinal disease.
• First gene-editing in the human body, an individual with the metabolic disease Hunter Syndrome has been injected with a treatment based on Zinc Finger Nucleases and a “correct” copy of the enzyme that his body lacks. 
• For the first time, levels of the protein that causes Huntington’s disease have been lowered, using an antisense drug now licensed by Roche. The drug selectively binds to mRNA made from the mutated HTT gene.
• Mice have successfully been genetically edited to be cured from an inherited form of deafness. The technique is based on CRISPR.
• Biohacker Josiah Zayner made headlines by self-administering CRISPR designed to inhibit myostatin. US law allows for researchers to experiment on themselves. Meanwhile a patient injected himself with an unproven gene therapy. Two companies have said that they will continue to market their DIY CRISPR kits, despite FDA warnings.
• A new version of CRISPR that selectively alters gene expression levels (rather than cleaving DNA). The paper introducing the technique includes encouraging results on mouse models of Muscular Dystrophy and kidney disease. 
• Start-up Inscripta want to democratize gene-editing by making the CRISPR-enzymes freely available. While Cas9 is the enzyme at the core of the IP battle between Berkeley and the Broad, they have made their enzyme, MAD7, publicly available.
• George Church makes the case for a data-driven approach to human germline editing in the NEJM. To the standard slippery slope arguments he retorts: “we often regulate practices on the basis of ethical costs and benefits at specified points along a continuum — for example, speed limits, blood alcohol levels, and age limits. We already embrace many enhancements inherited over multiple generations — generally without consulting future grandchildren — for example, education, homes, and extinction of pathogens through the use of vaccinations.” 
• Craig Venter, he of genome sequencing fame, argues that we should be putting our efforts into continued genomic sequencing and analysis, and that clinical genome editing is not yet ready for primetime. 

• Moderna has started its trial of personalized cancer vaccines.
• The Economist reviews the fledgling enterprises aimed at altering the microbiome to promote health. Seres therapeutics have launched a clinical trial to test their microbe medicine alongside a PD-1 drug.
• Genetic links between lymphoma and auto-immune disease.
• Specific HLA genotypes can lead to better patient outcome on immunotherapies.
• A highly conserved long, non-coding RNA called THOR has been found to be oncogenic.
• A blog post that steams through our historical understanding of cancer, and consequent treatment approaches, which relegates targeted therapies to the history books, and points to atavistic models, in which cancer cells are regarded as having reverted to single-cell organism behaviors, as the current paradigm.

• The first genetic variant protective against aging has been discovered by analysis of an Amish population. Two copies of the variant in SERPINE1 lead to a rare bleeding disorder; one copy leads to longer telomeres and an increased live-span averaging 10%.
• Based on analysis of flies that had been selected based on whether they were extreme short or long sleepers, many candidate loci that can help explain the differences between how long we each need to sleep have been uncovered. These overlap heavily with the usual suspect genes — i.e. genes involved in major pathways: “The involvement of highly pleiotropic pathway genes suggests that sleep duration in natural populations can be influenced by a wide variety of biological processes, which may be why the purpose of sleep has been so elusive.” There was no difference in lifespan between naturally shorter- and longer- sleeping flies.
• Genetic sequencing of a  family who are insensitive to pain has led to the pinpointing of a mutation that researchers hope will eventually help our understanding of chronic pain. 
• The Personal Genome Project, a George Church brainchild whose members contribute their genomic and phenotypic data to the research community, has expanded to China, where it will be the country’s first open science initiative. Says Church,  “I have ridiculously high hopes.”
• An update from Regeneron, who have sequenced >100,000 exomes to date and are headed to a 400-500,000 exomes a year. Their strategy is to partner with groups who have large cohorts of patients with phenotypic data attached, most notably Geisinger Health System and the UK BioBank. They then look for the genetic outliers for ideas of drugs to develop.
• Some heart-warming stories of “extreme parenting”, i.e. the fight that some parents take-up when faced with a diagnosis of an extremely rare condition for a child.
• Three dozen genomes of supercenterians (age >110) have been made publicly available. Supercenterians, unlike centerians, tend to live healthy lives up until the end. This NYT article goes into the tribulations of collecting the samples.
• Genetic variation in the GPCR family of genes (G-protein-coupled receptors), which are targets of about a third of FDA approved therapies, are thought likely to alter drug response in about 3% of individuals.
• A write-up of a conversation at the AMP conference on the legal challenges of variant classification reporting.
• A sketch based on DNA of a suspect in a murder case lead to his arrest and confession.
• An overview of the evidence that there were multiple points at which humans left Africa to populate the rest of the world.
• UK biobank data has been used to demonstrate ways in which humans are still evolving.

• Bacteriophages – viruses that affect bacteria – were formerly believed not to interact with eukaryotic cells, but have now been shown to be absorbed into human cells in the gut, prompting talk of the human phageome, and hypotheses about its role in human health and disease.
• Scientists have added two new functional letters to the genetic code, claiming “The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions.”
• The introduction of a new tool, trim-away, for targeting and destroying specific proteins in cells. The protein trim21 recognizes antibodies, and passes whatever the antibody is tagging to the proteasome – the cell’s destroyer of unwanted proteins. By designing antibodies to target specific proteins, or even variants on these proteins, and delivering them alongside extra trim21, the method can selectively destroy particular proteins.
• Google has released DeepVariant, a deep-learning technique for variant calling that it claims produces more accurate results than previously existing software, by transforming the problem into one of image analysis.
• Luna, a blockchain based genomic start-up, have raised $2m in seed-funding. They will reward those who contribute their DNA for research, and provide increased security, with their own blockchain based coin.

• A review of protections against genetic discrimination offered by GINA argues that protections should be strengthened. Currently, a Californian woman with a positive BRCA result could legally be denied a mortgage on the basis of decreased life expectancy.
• New FDA guidelines to implement gene-therapies faster.
• On the 14th Nov the The US Senate Committee on Health, Education, Labor, and Pensions held a hearing on CRISPR genome editing. I have yet to listen to the hearing itself, but this write-up makes it comes across as somewhat self-congratulatory in terms of regulatory approach. The ranking senator apparently called on scientific consensus on the ethical questions, which are not words I expected to ever come across strung together in that order.
• On regulation of somatic panel tests, GenomeWeb summarizes nicely: “The agency authorized Memorial Sloan Kettering Cancer Center’s MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) through the de novo premarket review pathway as a Class II, moderate-risk device, and simultaneously made the New York State Department of Health a third-party reviewer of IVDs, including similar tumor profiling assays. Subsequently, other labs can apply to the FDA for 510(k) clearance — a less onerous path than premarket approval — for their tumor profiling NGS panels. Or, if the test already has approval through the NYSDOH, sponsors can submit that application to the FDA and ask the state regulator to forward its review documents and recommendations.”
• Meanwhile the FDA approved FoundationOne, and the CMS simultaneously agreed to pay for it.
• A perspective in the NEJM that a proposed Act will worsen the regulatory landscape in health. The authors argue that the Regulatory Accountability Act, a version of which will so go before the Senate, will actually stifle innovation because regulation will not be able to keep up with technology, and it will be harder to retire old regulation.
• The FDA has issued a flurry of new proposed guidance, two on running of clinical trials for targeted therapies (one on the design of assays for trials here, one on appropriately exempted diagnostic tests here), and one on clinical and patient decision support software here.
• The NIH has lifted a ban on gain of function viral research. The ban was instituted in 2014 when based on research that developed a virus that was more easily transmitted.
• The Chinese FDA has approved a self-sampling based test for HPV from BGI. 
• A group of gene-drive researchers have put together guiding principles for the use of gene drives, as part of a coordinated response to the NASEM report that concluded that gene drives were not ready for deployment, based on currently available evidence.
• A call for more DNA collection of those charged with crimes, based on data from Denmark, where they massively increased their DNA collection rate: “Our results thereby show that policies that increase the identification of criminal offenders are an effective tool to reduce crime and increase public safety,”