Round-up Nov 11 – Dec 21

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

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.
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Lulu and Nana: the children who will help change our morals

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.

Round-up Oct 1 – Nov 10

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

  • 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

 

Regulation

Catch-up June 28th – Sept 30th

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

Regulation

Science

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.

Catch-Up Feb 19th – June 27th, Buenos Aires edition

Well, an embarrassing amount of time has passed since I posted last. I am on the road in South America, but was feeling increasingly angsty about being behind on genomics happenings. So I have spent the last three days catching up. Here is my pick of the most interesting developments:

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

New science

Genetic modification

Spotlight on genetics and intelligence

Pedigree-based analysis, in particular twin based studies, give us estimates that variance in intelligence is about 50-80% inherited. Previous work in genetics had not identified much of this variance (for intelligence and all other complex traits), leading to a “heritability gap”. A study of over 20,000 individuals, many from the same families, who had been SNP genotyped at 700,000 locations claims it can explain about 54% of the variance in general intelligence with genetics, substantially closing the heritability gap. They were able to close the gap through assessing the contribution of rarer variants, finding that variants with a frequency less than 1% contribute 23% of the variance. It looks like prior genotype based work missed causal variants in low linkage disequilibrium with genotyped SNPs — variants they were able to find because of the related individuals in their dataset. 
One might wonder, why bother studying the genetics of intelligence? The justification given by these papers is through the fact that intelligence correlates with health outcomes, and so a better understanding could lead to better health outcomes.

Spotlight on genetics and race

And finally, an op-ed by Harvard geneticist David Reich titled “How Genetics Is Changing Our Understanding of ‘Race’” has stirred up an old can of worms, by claiming that political correctness is stifling science by refusing to acknowledge genetic differences between the “races”. The likes of Sam Harris have jumped on the bandwagon. The sentence “But as a geneticist I also know that it is simply no longer possible to ignore average genetic differences among ‘races.’” is the most controversial (in the book that the op-ed is mostly taken from, the same sentence uses the term “populations”). Here is an extract from an open letter that drives home the difference between races and populations: “In short, there is a difference between finding genetic differences between individuals and constructing genetic differences across groups by making conscious choices about which types of group matter for your purposes. These sorts of groups do not exist “in nature.” They are made by human choice. This is not to say that such groups have no biological attributes in common. Rather, it is to say that the meaning and significance of the groups is produced through social interventions.” Its clear how socially constructed of a term “race” has been, particularly in the US, where e.g. a single black ancestor would make you “black” under the one-drop rule. Many of Reich’s points would stand if he stuck to the terms “ancestry” or “population”. Possibly even the point that the proximity between ancestral populations and race makes some scientists timid in their explorations and communications.  
(The whole debate reminds me that race, when gathered in scientific studies, is always self-reported, and hence any links to biology are very suspect. This point has been made by bioethicists in connection with the FDA’s approval of the drug BiDil just for those who identify as black.) 

Round-up Dec 22nd – Feb 18th

Hot topics over the past few weeks have included genetic privacy, blockchain-genetics start-ups, reimbursement. There have also been some surprising new science.

Ethical, Social, Legal
  • 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.
Adoption
  • 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.
Concerns around ownership of genetic data, in a world where anybody who gathers data knows that it has value and hence is reluctant to share it.
  • 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
Products and Projects
  • 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%.
Block chain based companies, that will store your DNA and allow you to sell it to pharma companies:
Science

Our Posthuman Future

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.