Round-up March 21st – 27th

Last week was the American College of Medical Genetics’ annual conference. I’ve yet to find a good write up or summary anywhere!?

Where do cancer causing mutations come from? Traditionally, we have focused on inherited mutations, and environmentally caused mutations. But there is a third source, arising from errors in DNA replication. A study in science reports that this third source, which are unavoidable, are responsible for two thirds of mutations in cancer. This strong role for “bad luck” (rather than behavior) has previously caused controversy.

study in Nature uses the mutational signatures of cells of adults to elucidate facts about the very earliest stages of embryonic development. They report that each cell division results in three new mutations, and that the two daughter cells tend to contribute to cell numbers in a 2:1 ratio.

GSK and Regeneron have teamed up with the UK BioBank, to sequence the genomes of the 500,000 individuals who are part of the BioBank cohort, with 50,000 expected in 2017. The ten year old UK BioBank is a cohort of individuals with extensive health records, described as “the world’s most comprehensive health resource”.

The chromosomal level abnormalities underlying different types of acute myeloid leukemia (AML) have been known for a while; a large study correlates this with underlying mutational changes, allowing for subtyping the disease.

CAP and AMP publish guidelines for the validation and monitoring of NGS based somatic panels.

personal story about why it is so important that we do not allow GINA’s protections to be eroded, form a woman who speaks of “mutants like me”.

Making the case for the role of bioethicists in a healthy research environment.

As rounded-up last week, the results of the PSCK9 trial were generally perceived as underwhelming. But, Robert Plenge writes, as a proof of concept for genomic based medicine, the results were encouraging.

Variants that affect splicing have a good chance of being disease causing. Its often not possible to assess whether a variant affects splicing computationally; an experimental technique using a hybrid minigene based method.

study showing that recurrent pregnancy loss is associated with lower number of copy number variants in the placenta.

An information-theoretic approach to the epigenome.

variant in MAOA (one of the most controversial genes in the genome, sometimes called the warrior gene), already linked to alcoholism and smoking behavior, has been linked to heroin addiction.



Round-up March 14th-20th

The news this week has been dominated by Trump’s plans to cut the NIH budget by 20%. We’re also bracing for the coming storm of announcements/reported results expected from the American College of Medical Genetics conference, which starts in Phoenix, Arizona, tomorrow.

In the nature-nurture debate, twin studies have played a decisive role in helping tease apart the relative contributions of genetics and environment. A meta-analysis of twin studies covers ~18,000 traits and ~15 million pairs of twins, shows an average heritability of 49% across all traits.

Oxford Nanopore have announced the launch of a new desktop product, the GridION X5. It is five of its MinIONs plus a lot of compute in a box, and much smaller than the PromethION. Written up my Omics! Omics!.


  • A “good news” variant in PCSK9 is associated with lower levels of LDL cholesterol and lower chance of heart disease. A large scale clinical trial of a drug that targets PCSK9reported today that it did work, but not as much as analysts had been hoping for, and perhaps not enough to justify the $14,000 price tag.
  • More tumors than previously thoughtmay be BRCA1/BRCA2 deficient, meaning that more patients could potentially benefit from PARP inhibitors.
  • eGenesis, a spinout of George Church’s lab, has raised $38m in Series A financing. They aim to make pig organs transplantable into humans, using genetic modification to combat organ rejection.
  • A clinic in the UK has been the first to be given the go aheadto make three person babies. The UK recently made the procedure legal.
  • HudsonAlpha is offering an “elective genome”at $7000. 7 of the first 24 patients had actionable information reported. The focus is on rare disease, one only those genes associated to conditions that the patient has a personal or family history of. The test is in large part being offered because patients ask for it — but this isn’t necessarily good reason to offer a test.
  • A number of companies are trying to use DNA as a tracer molecule– an alternative to dyes or radioactive materials.
  • Making the case for building the infrastructure to report on protective variants.

New methods

  • Apaper showing that an antibiotic compound allows some cells to “read through” premature stop codons, giving hope to those who suffer from rare disease caused by such mutations.
  • A group has reported single cell level structural maps of the mammalian genome, at a resolution of less than 100kb. Some things are constant between cells (A and B compartments, lamina-associated domains and active enhancers and promoters), while some vary (individual topological-associated domains and loops).
  • Some tumors can be attacked by a combo of drugs that act synergistically. A CRISPR-based double knockout (CDKO) system, designed for high-throughput detection of which pairs of genes give a phenotype when knocked out, allowing synergistic drug target combinations to be identified. Another study of 142k gene-interaction testsreplicated combinatorial drugs at 75% precision.

New genetic associations


Round-up March 7th – 13th

Canada has passed a Genetic Nondiscrimination bill. Insurance groups opposed it. So did PM Justin Trudeau, saying it impinges on Provinces’ rights to regulate the insurance industry.

Meanwhile, a US House Committee approved a bill that will enable companies to inflict financial penalties on employees who do not submit to genetic tests, thus undermining GINA’s (Genetic Information Nondiscrimination Act) ability to protect the genetic data of employees. Employees who refuse testing for “workplace wellness” programs will face reduced pay, fines, or inflated insurance premiums. Tom Price, the HHS Secretary, has said there would be “significant concerns” about the bill, and that they’d be taking a look at it when it got to the department.

The Personalized Medicine Coalition has published a report on current opportunities/challenges.

On the opportunity:

  • Percentage of the patient population for which a particular drug in a class is ineffective, on average: ANTI-DEPRESSANTS 38%; SSRIs ASTHMA DRUGS 40%; DIABETES DRUGS 43%; ARTHRITIS DRUGS 50%; ALZHEIMER’S DRUGS 70%; CANCER DRUGS 75%
  • There are 132 personalized medicines on the market; ~42% of drugs in the development pipeline include biomarker investigation as part of R&D; personalized medicines accounted for 27 percent of new drug approvals in 2016

When it comes to challenges:

  • Lack of regulatory in landscape puts some investors off;
  • Reimbursement, where there is a Catch 22 situation “Widespread insurance coverage of diagnostic tests, for example, will likely require practice-based evidence demonstrating value. Obtaining the real-world data necessary for generating this evidence, however, is difficult unless the products and services in question are covered by insurance policies.”
  • Decreased payment rates, partly because the CMS moved from allowing “stacked codes” to a “gapfill” methodology, which allows regional contractors to set prices
  • A new rule that appeared in the Protecting Access to Medicare Act (PAMA) may put downward pressure on utilization of personalized medicine, as there is no mechanism for capturing the value of targeted treatment
  • Clinical Adoption is slow due to lack of education and lack of IT infrastructure — “most health care organizations do not have formalized plans to leverage advances in genomics and data analytics to personalize patient care, and are unprepared to implement personalized medicine programs”

Scott Gottlieb has been chosen by Trump to head the FDA. The most moderate of the names doing the gossip rounds, he is thought to support maintaining ensuring drugs are both safe and effective before approving them — some other candidates supported dropping the “effective” part.

Science news

  • An article in Naturereports on a new technique for uncovering the 3D architecture of the genome, including mulit-enhancer contacts.
  • Where do circulating DNA fragments come from? A new methodlooks at methylation haplotypes to determine tissue origin — allowing for cancer status and tissue origin to be determined from a blood draw. This could be a big deal in the liquid biopsy space. Singlera Genomics will attempt to commercialize the technology. Sensitivity can be increased by running another methylation test in parallel, based on the open/closed chromatin status.
  • The gene CDH2 has beenimplicated in sudden cardiac death.
  • The gene SEMA4D has beenlinked to obesity in African populations – those with variants in this gene were on average 6lbs heavier. Obesity is more common in those with African ancestry than others, and other populations lack variation in the gene. The study highlights how important it is to study disease associations outside of Caucasian populations.
  • A review on using genetics for transplants.
  • Alarge effort to sequence plants used in Chinese Medicine.
  • And on the subject of prediction, a model that incorporates omic-datato predict years of life post treatment for breast cancer is able to explain some of the variance after more conventional variables are factored in.

In the “healthy exome” space, Arivale have started offering polygenic profiles — i.e. giving their customers risk scores that aggregate over many variants. There is little data that speaks to the scientific validity of this.

George Church is teaming up with brain training game Lumosity to uncover the genetics behind those with outstanding memory.

Geisinger are leading the way with implementing genomic medicine. Here is a Mendelspod interview with their Director of Clinical Genomics.

There are dozens of direct to consumer tests that allow for determining paternity. This study looked at the privacy policies and terms of services of 43 such companies, and concludes that “recreational genetics carries both the risk of unintentionally revealing misidentified paternity, and also the risk that fathers will deliberately use these services to test their children’s paternity without revealing their intentions to the mother or any other third party.”


Round-up Feb 28th – March 6th


  • The first patient to have undergone a particular gene therapy for sickle cell disease has had his disease reversed, with no symptoms in 15 months. A huge success for a field that has struggled, his treatment involved removing his bone marrow, using a (non-CRISPR) gene therapy technique to remove the genetic variant responsible for the disease, and returning the bone marrow.


Germline news

  • Two large studies reporting on the genetics of autism
  • 5205 individuals from autism-effected families, identifying 61 autism risk genes, 18 novel. This is part of the MSSNG project, a joint Google-Autism speaks venture.
  • 686 autism patients sequenced using 10X’s platform for synthetic long read sequencing, one of the largest studies to probe structural variation at scale, revealing a diversity of complex structural variation
  • The American College of Obsteticians and Gynecologists has recommendedexpanded carrier screening for genetic disorders in all women during and before pregnancy.
  • Proove, who have $2m a month revenue test to combat opioid addiction based on genetic markers,  are under the spotlightfor a series of dodgy practices. Their story is being used as an example of why the FDA is right to think that it needs to regulate the genetic testing space.
  • February 28th was Rare Disease Day. To mark the occasion Stephen Kingsmore, he of the 26 hour Whole Genome based diagnosis of newborns, complains: “I think the one thing that I would like technology-wise is better software for going from genome sequence to diagnosis. Right now the software systems that we have are not quite good enough to be scaled up to meet the needs of all the children that we could benefit. There is still way too much manual effort involved.”
  • GenePeeks will let you know how your genome would combine with another — one step beyond carrier screening, the explicit intent is to help you select an egg or sperm donor. They just announced partnershipswith an egg donation agency and a surrogacy.
  • Data harmonizations remains a key challenge in germline analysis. The $280m Centers for Common Disease Genomics (CCDG) program, who aim to sequence and analyze the data of ~150-200,000 individuals in existing cohorts, have just announcedtheir standard sequence analysis pipeline.
  • Emory University School of Medicine and genetics/biobanking company Akesogen are partneringon a study of the genetics of diseases that hit later in life, aiming for 100,000 participants.
  • Noninvasive Prenatal Testing, where the genetics of the fetus is determined based on a sample of the pregnant mother’s blood, has attracted the attentionof the Nuffield Council for Bioethics, who are calling for a moratorium on using it clinically for whole genome sequencing. Currently, the test is only routinely used for detecting trisomies, but whole genome sequencing of the fetus is debatably already here.


Cancer news

  • It was a big week for fund raising in the noninvasive early cancer detection space, with Freenome raising $65m, and Grail $900m. Grail is using some of the money to repurchase some of Illumina’s stake.
  • Foundation Medicine reports dataon use of tumor mutation burden for predicting response to checkpoint inhibitor therapy. “In a cohort of 65 metastatic melanoma patients, the median TMB value was 37.9 mut/Mb in the responder group and 6.6 mut/Mb in the non-responder group.” Similar findings for NSCLC and bladder cancer have previously been reported. (The idea is the following: some cancers avoid the immune system via mutations that lead to over-expression of immune checkpoint proteins; in such cancers, drugs that inhibit/block the inhibitory checkpoint molecules work by “taking the breaks off” the immune system; cancerous cells with more mutations produce more immune-reactive neoantigens, i.e. peptides that the immune system recognizes as non-self; the immune system, when let loose, will be better at attacking and destroying these cells.)
  • Data sharing efforts for cancer genetics: The NCI’s Genomic Data Commonsaims to collect data from >50,000 cases by the end of 2017. Foundation Medicine have contributed data from 18,000 cases; this adds to AACR’s GENIE project, at > 18,000 publicly available samples as of January. Harmonization of data format is one of the key issues. The Global Alliance for Genomic Health sees itself playing the coordinating role across all of these efforts, via the proposed Cancer Gene Trust.
  • Actionable results are found for large numbers of cancer patients, but only a small fraction go on to have their treatment affected by those tests. GenomeWeb have a nice writeup, summarizing the pitfalls at each stage of the process.
  • Once upon a time, cancer’s in different parts of the body were studied separately. With the advent of molecular profiling, the role of pathways and particular driver genes lead to a more body-wide approach. A reviewfocusing attention on organ-specific tumorigenesis.


Other Research

  • The FANTOM project has been investigating long non-coding RNAs, and thinks there may be ~19,000 of them that are functional, and some of which already have evidence of disease association.
  • Linking genotype to other things happening in the cell…
  • “Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites” – a paper looking at genotypes and levels of 644 metabolites in 1960 adults
  • What significance GWAS hits? A high-throughput method to detect associations between protein levels and genetic variants (pQTLs). Move over eQTLs.


In Other News

  • Another milestonein using DNA as a storage medium. Some researchers encoded a bunch of files (including a film) using a method they call DNA fountain, sent the DNA across the country, where it was decoded with zero errors by another group.
  • By comparing a 45,000 year old wooly mammoth’s genome to a 4,300 year old specimen, researchsuggests that the last Wooly Mammoths (of which the second sample would be one) were so inbred (“low effective population size”) that their genomes were riddled with deleterious mutations, in work that could shed light on conservation efforts for still extant species.
  • Some local police departments in the US have created their own DNA databases, because getting results of a sample’s match to the state or national data base can take 18 months, and they can turn analysis around in under 1 month by outsourcing to private labs. This is proving controversial, for example with the ACLU filed a lawsuit against San Diego. The concern is that local authorities are side-stepping all the regulations put in place at the state and national levels to protect citizens from a surveillance state.


Round-up Feb 20th-27th

Do you remember when 1000 genomes sounded like a large number? The team that gave us ExAC released GnomAD in its full form today, which includes the exomes of 123,126 individuals and the genomes of a further 15,496 individuals.

And just in case that didn’t sound ambitious, this week the Earth BioGenome Project was announced, a plan with a name, an estimated $20b price tag and no funding to date, which aims to be a Noah’s ark of genomes: “the first step would be to sequence in great detail the DNA of a member of each eukaryotic family (about 9000 in all) to create reference genomes on par or better than the reference human genome. Next would come sequencing to a lesser degree a species from each of the 150,000 to 200,000 genera. Finally, EBP participants would get rough genomes of the 1.5 million remaining known eukaryotic species.”

My favorite read of the week is a STAT interview with Jeantine Lunshof, a bioethicist embedded in George Church’s group — a very unusual setup for a very unusual lab.

Meanwhile, in the somatic world:

  • NewGuidelines for “Molecular Biomarkers for the Evaluation of Colorectal Cancer” have been set. The 21 recommendations make it clear that NGS has a clear future in the treatment of this type of cancer.
  • The NCI-MATCH Trial, which aims to assess the effectiveness of molecular based treatment decision for cancer patients, has enrolled 4500 patients to date, 4000 who have had results returned. They reporta 18% match rate (lower than expected) to one of 24 treatment arms, with 72% of patients enrolling in the matched trials (higher than expected)
  • In an oncology sample, you have dozens of somatic variants, but only a small handful will be “drivers” (functional roles that confer cell fitness advantages), and the rest will be hangers along, or passengers. Which are the driver mutations? Many efforts have focused on molecular level properties, such as frequency and amino acid effect. Here’s an approachbased on patient outcomes.
  • new computational toolfrom UCSD for somatic samples, Haploinsufficient/Triplosensitive Gene (HAPTRIG), which focuses on single gene copy number losses/gains and how these may aggregate up to effect a cancer pathway, has demonstrated utility for Serous Ovarian cancer patients, and is expected to be useful for other cancer types.
  • Cynvenio, who offer ClearID, a test for late stage breast cancer patients, and Color, who offer a hereditary cancer screening test, have partneredto enable a low cost, high convenience option for oncologists.

23andMe and Celmatix are launching a 4,500 women project aimed at understanding factors underlying fertility

Korean start up 3billion is launching an exome DTC for rare disease patients at a TBD price tag less than $1000. They will be presenting “annotated rare disease variants along with published information about them”, and thus hope to avoid the ire of the FDA

In the world of bacteria:

  • studyreports that ribozomal mutations in bacteria cause resistance to a broad range of antibiotics.
  • A group trying to use CRISPR to fight bacterial resistance, this time with the “chainsaw” Cas3 as supposed to the “scissors” of Cas9.
  • studyon the use of an NGS test to detect meningitis and encephalitis is being run to assess both clinical utility and cost-effectiveness. The clinical pathway involved use of a clinical microbial sequencing board. The group, which is also developing a test for Lyme disease, is already looking at complementing the metagenomic DNA data with RNA expression data.

The wooly mammoth may be de-extinct soon, but do we want to go there?  “It’s better to spend the money on the living than the dead.” says one commentator, in reaction to a study that looks at whether de-extinction will be good for conservation efforts.

Most translation starts with an AUG. Before this week, we knew of a couple of other “non-canonical” start codons. But now, translation start has been shown from 47 of the 64 codons.


Round-up Feb 13th – 19th

What a week. On Tuesday, a report a year in the making said that germline genome modification should not be prohibited — an update on the previous position that it would be irresponsible to proceed without broad societal consensus. The story was picked up just about everywhere. I’ve been thinking about it for a couple of days, and have summarized my disagreement with the report here.

Then on Wednesday the CRISPR patent dispute went in favor of the Broad/MIT/Harvard rather than UC Berkeley/University of Vienna. The latter group were the first to show use of CRISPR as a genome editing technique in bacteria, and filed patents covering all cell types. But the Boston set were the first to show that it also worked in eukaryotic cells, and filed for this use. The California group claimed that these patents overlapped with their own, but the Patent Trial and Appeal Board judged that the Boston patents did not interfere: “because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in an eukaryotic environment”. Editas, which has an exclusive license to medical breakthroughs resulting from the patents in dispute, saw its stock jump by more than 30% on the news. Summaries from the Broad and from UC, the latter stating they are “pleased that its patent application covering the use of CRISPR-Cas9 gene editing technology for all cell types can now move closer to issuance”. That is, this is not over yet.

In other gene therapy related news, researchers have successfully made a mouse glow after injecting it with the mRNA of the same protein that makes fireflies glow. This type of gene therapy would be transient, and particularly suitable for vaccinations — current vaccines involve introducing viral material in order to get the bodies immune system to respond; this technology could potentially directly instruct the body to produce its own antigens. The key to the work was the development of a molecule that helps get mRNAs into cells.

High overall tumor mutational burden (TMB) is an indicator for response to immunotherapy, probably because more mutations means more neoantigens, means more targets for the immune system in combating the cancer. PGDx are developing a circulating tumor DNA test, targeted at regions in the genome that their previous exome sequencing work has indicated are good surrogates for overall TMB.

The move to pre-prints in biology is heating up, with ASAPBio launching its plan to become a centralized repository. The twittersphere reacted strongly, saying that we already have that with the bioRxiv.

There are dozens of genetic changes that have an impact on presence of genetic diseases. A group in Michigan published something that they think many of them have in common: they fall in regions where the transcription factor “Regulatory Factor X” is predicted to bind in islets, groups of cells in the pancreas that produce insulin.

In an article entitled “The next pseudoscience health craze is all about genetics“, Gizmodo argues, using very specific advice given out by DNA Lifestyle Coach as an example, that “lifestyle advice has a tendency to sound more like it was divined from a health-conscious oracle than from actual science”.

For clinical adoption of genetic tests, health providers want to see evidence it works. Startup Geneticure are launching an 800 person prospective randomized controlled trial of their pharmacogenomics test for hypertension drugs, hoping to show that their test enables patients to get to controlled blood pressure faster, with less medication.

Okay, this isn’t actually from this week, but I missed it, and its worth rounding-up. In October those involved in the Genome write project launched a white paper. “The Genome Project-write (GP-write) will use synthesis and genome editing technologies to understand, engineer and test living systems.” Its main goal is to drive technology development, and particularly to lower the cost of writing genomes. A sub goal is to “understand the functional properties and phenotypic consequences” of the human genome. Possible pilot projects mentioned include:

  • Making cancer resistant human organs in vitro
  • Making human cell lines able to produce vitamins and all amino acids (which humans, unlike some bacteria, have not evolved the ability to do)
  • Transforming the pig genome to make it “far more amenable” for human organ transplantation
  • Making an “ultrasafe” human cell line (its worth checking out what properties they’re aiming for on p14, includes virus resistant, radiation resistant, cancer resistant, to name but a few)

They want to launch the project with over $100m pledged, and have a tentative roadmap. A proportion of funding should go to ethical, social and legal issues raised: “We encourage public discourse to occur surrounding HGP-write, and that having these conversations well in advance of deliverables will help society better prepare for and guide emerging capabilities.”

A  paper, summarized with implications by GenomeWeb, illustrates just how widespread the problem of DNA damage is, induced for example by library prep. They find evidence for DNA Damage in the 1000 genomes data, for example. They come up with a score to quantify the amount of damage in a sample. A computational approach can be taken to reduce the effect of these errors: “One way to deal with damaged-induced sequencing errors is to filter out affected reads, which can be flagged because the G to T mutations occur only in one read direction but not the other.”

A great success story from the Cincinnati Children’s Cancer and Blood Diseases Institute, who report on the successful use of sequencing for patients with histiocytic disorders, with impacted clinical outcomes.

In other research news: The Oxford MinION is sensitive enough to pick up methylation patternsCoffee consumption is associated with DNA methylation levels of human blood; evidence that “Untimely expression of gametogenic genes” can cause uniparental disomy (UPD) — UPD in humans usually leads tocongenital disease; some replicated, exome wide significant associations to bipolar disorder, including rare coding variants for the first time; genetics of self-reported tiredness.


Some thoughts on the recommendation to “proceed with caution” on human germline modification

On Tuesday, a report a year in the making on human genome editing was released, prompting media coverage from just about everywhere. Whereas this report’s predecessor said it would be “irresponsible to proceed” with clinical human germline modification without “broad societal consensus, this update recommends against a prohibition.

In this post, I discuss how they couch this recommendation. Ultimately, I don’t think they offer any convincing arguments for the shift in attitude. While the debate is still hypothetical (there are ongoing scientific issues; the practice is currently illegal in the US), this report does have the ability to “change the tone” on the use of the technology, and it has seized that opportunity.

Overall Recommendations

Published by the National Academy of Science and the National Academy of Medicine, the report follows on from the International Summit on Human Gene Editing, convened in December 2015. The broad purpose of the efforts are to respond to the rapid technological advancement of genome-editing tools (particularly CRISPR-Cas9): to consider their potential medical uses, and the ethical, social and legal issues that arise.

For all research applications, the authors contend that existing ethical norms and regulatory frameworks will work just fine1.

Recommendations for clinical applications are organised under two main distinctions: Somatic (non-heritable) versus Germline (heritable), and Therapy versus Enhancement. The recommendations:

Therapy Enhancement
Somatic (non-heritable) Existing ethical norms and regulatory regimes satisfactory2 Do not proceed at this time; engage with the public
Germline (heritable) Approach with caution, but do not prohibit; ensure stringent oversight system3

It was the failure to recommend an outright ban on germline modification that caused some surprise. As Francis Collins, Director of the NIH, noted in 2015, the “concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed”. And as the authors state in the report: “Given how long modifying the germline has been at the center of debates about moral boundaries, as well as the pluralism of values in society, it would be surprising if everyone were to agree with this recommendation.”

In addition to putting frameworks in place to ensure due consideration of health and safety concerns, the authors want to ensure

  • there are no “reasonable alternatives”
  • societal benefits and risks are balanced, and that the public should be involved in this process
  • the principle of transnational cooperation is adhered to
  • there are “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition”

I expand on these considerations below. I also look at the strategies for public engagement they propose.

When would there be no “reasonable alternative” to germline genome modification?

In brief, prenatal genetic diagnosis (PGD) – which is routinely offered as part of an IVF cycle –  would almost always be a reasonable alternative to germline modification, because selection of embryos will suffice to prevent the birth of individuals with severe genetic disease. Hank Greely makes this case in his book “The End of Sex”. There is one exception involving the incredibly rare case of co-dominance.4

The authors give two other potential scenarios under which there would be no reasonable alternative to germline genome modification. One is that PGD involves “discarding affected embryos, which some find unacceptable”. This is hard to take seriously. Germline modification would also involve an IVF cycle, and not all embryos that get produced in a cycle are implanted, PGD or no. In other words, it seems hard to imagine someone who would be okay with the use of germline editing, but not with the use of PGD.

The authors argue that germline genomic modification could also be the only option as it could increase the number of viable embryos available for implantation — lack of viable embryos is a common failure mode for IVF cycles, and PGD reduces this number yet further. This seems to me to be a more reasonable consideration. However, this would assume the technology was perfect, and that prospects on the horizon such as using stem cells to make egg cells do not materialize.

All of this of course assumes that being something other than the biological parent of a child is not a “reasonable alternative”.

Balancing societal benefits and risks and involving the public

This report explicitly aimed to continue the dialogue initiated by an earlier effort, which concluded in December 2015 that it would be “irresponsible to proceed” with clinical human germline modification without “broad societal consensus”. This report, in contrast, calls for “continued reassessment of both health and societal benefits and risks, with broad on-going participation and input by the public” – a significant watering down of the importance of public opinion and attitudes to impact on society.

Embracing their own methodology of a risk-benefit analysis (which is far from the only take), how do the benefits and risks of the use of germline genomic modification stack up?

Benefits the report mentions are:

  • Enabling prospective parents to have biological children free from serious disease (assuming no other alternative). It could be argued that this is a fundamental right in need of protection. “The number of people… might be small, but the concerns of people facing these difficult choices are real.”
  • The creation of a more level playing field for those whose traits put their children at a disadvantage
  • Public health benefits (though note these same benefits prompted the eugenics abuses of the past)

Potential risks mentioned fall under several themes:

  • Inability to prevent inappropriate or abusive applications
  • Recurrence of the abusive forms of eugenics practiced in the past
  • Further stigmatization of disability
  • Exacerbation of social inequalities
  • Creation of social pressure for people to use technologies they would not otherwise choose
  • Children being seen as “constructed products”
  • Parents increasingly viewed as responsible for the qualities of their offspring

The authors note that whereas most of the benefits accrue to individuals and are more immediate in nature, the risks mostly relate to society and are more diffuse. Because of this, arguments for the benefits and risks “can fail to engage each other directly.” That the benefits are more immediate can end up shaping how the risks are perceived: new technologies cause cultural change, partially mediated by the fact that individual decisions change societal norms. Regulations are based on cultural views, and, as the authors themselves note “it is the underlying change in cultural views that is precisely the slippery slope”. In other words, although the risks seem more diffuse, unless we give them due weight now, the sands will have shifted with early application of the technology, and we may find ourselves committed to a particular type of future.

Marcy Darnovsky, executive director of the Center for Genetics and Society, states that although the report does acknowledge the risks, “Strangely, there’s no apparent connection between those dire risks and the recommendation to move ahead.”I would agree that while the report is clearly written, it is often unclear how the recommendations arise out of the considerations raised.

Even if one agreed with the recommendation to “proceed with caution”, it still seems at odds with the very strong emphasis on the importance of public engagement throughout the report. Edward Lanphier, chairman of the DNA editing company Sangamo Therapeutics argues: “It changes the tone to an affirmative position in the absence of the broad public debate this report calls for.”Another example of the report not coming across as entirely internally consistent.

Transnational cooperation

Science and technology are transnational pursuits, but how we chose to apply them to our societies is necessarily contextual: “It is important to note that such concepts as “reasonable alternatives” and “serious disease or condition” embedded in these criteria are necessarily vague. Different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities.”

The authors simultaneously call both for respect of cultural differences, and the promotion of regulatory standards. The latter is necessary to prevent medical tourism.The authors conclude their chapter on Germline modification with the observation that the current US legislation that prohibits the practice serves “to drive development of this technology to other jurisdictions, some regulated and others not.” It is unclear how much this consideration motivates the recommendation to “proceed with caution”. Bioethicist George Annas finds this position unconvincing: “the fact that something could be done even if outlawed is hardly a [reason] not to outlaw it if you think it should not be done.”8

I very much appreciated that the report actually gave some examples of cultural attitudes that could influence perspectives on genomic modification. We are familiar with the fear of “Playing God” from the Christian tradition. In contrast the authors note that: “In the Jewish tradition, on the other hand, there is an explicit obligation to build and develop the world in any way that is beneficial to people, and such improvements are viewed as a positive collaboration between God and humans, not as an interference with creation. Similarly, many Muslims and Buddhists view genetic engineering as just one of many welcome interventions to reduce suffering from disease”.

What of the distinction between Curing Disease and Enhancement?

The report does a good job of illustrating just how hard it is to draw the line between curing disease and enhancement, including:

  • What should be considered “natural” or “normal”?
  • What of preventative, rather than curative, measures (e.g. reducing chances of developing a disease or contracting an infection)?
  • What counts as a disease (homosexuality used to)?  
  • What about late onset diseases?

At the very least, we need some concept of a “problematic enhancement” – perhaps one that “confers a social advantage beyond that which an individual possesses by fate or through personal effort, and that does not benefit the rest of society in any way or undermines the implicit goals of a competition.”

The authors state that: “Of course, somatic or germline genome editing for enhancement is very unlikely to be the most profound source of inequality in any setting.”

In the US off-label drug use is generally permitted. The authors give one example, of genomic modification for muscular dystrophy being of interest to those who wish to become even stronger. They go on to state that “other examples are more difficult to envision” – something that may well turn out to be a failure of imagination.

Given the above, how “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition” could be envisioned is left by the report authors as an exercise for the reader.

There is another option for public policy that the authors note – work to make advantageous enhancements broadly available.

Strategies for Engaging the Public

The authors state that: “A robust public discussion about the values to be placed on the benefits and risks of heritable germline editing is needed now so that these values can be incorporated as appropriate into the risk/benefit assessments that will precede any decision about whether to authorize clinical trials.”

Two of the main components in the approval of clinical trials are Institutional Review Boards (IRBs) and the FDA, and neither considers societal implications: IRBs are explicitly forbidden from doing so, and the FDA has no statutory mandate to consider public views.

There is a committee that considers public opinion and societal impact, the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC). It publishes non-binding guidelines. It does have public review, intended “to enhance public awareness of and build public trust in such research, allowing for a public voice in the review of the research”. Which sounds suspiciously like “educate the public about what’s good for them”.

The report argues that we will need more formalized efforts than are currently in place to enable the robust discussion called for, and that federal agencies “would need to consider” funding such efforts. Although they do go into detail about what this public engagement could look like, this call to action could have been considerably stronger.  


I would summarize the landscape thus. There are 1 in a millionpeople that cannot have biological children free of serious disease unless use of this technology is approved. Once this technology is developed for this use case, the technological barriers to applying it in other use cases, including for enhancement, will be low. The societal barriers will also likely be lowered. There is a concern of a slippery slope to applications that challenge our current societal values. There is also the possibility that other jurisdictions will authorize this technology. We need to involve the public in this discussion now.

On the report itself: It is very comprehensive and covers a lot of ground in a thoughtful manner; Perhaps inevitably given that it was written by 20 people, it is not always clear how the issues raised are aggregated into the overall recommendations.

  • The excitement around CRISPR-Cas9 and germline modification has eclipsed the fact that the cases in which it would bring benefit over preimplantation genetic diagnosis are few
  • The “proceed with caution” recommendation for germline modification is at odds with an insistence on public debate
  • I come away from the report further convinced that a slippery slope from curing severe disease to enhancement is inevitable

For these reasons, I do not support the shift in tone from prohibition to “proceed with caution”. Additionally, an opportunity has been missed to make a more actionable call to promote public discourse, particularly around funding of this research.

The report, at 150 pages long plus appendices, not a short read, but it is very accessible, and gives digestible overview both of the current state of the science and of several of the bioethical themes. Recommended reading!



1 In the US, there is a bar on federal funding being used in any research that involves destroying human embryos. In other countries, such as the UK and Sweden, there are no such bars and research is ongoing.

2 My co-author Sarah Polcz and I have argued that there are issues in somatic application worthy of particular attention, for example consent issues for minors.

3 Note that due to a budgetary provision in effect until at least April 2017, the FDA cannot consider clinical trials involving germline genetic modification, making the practice illegal.

4 The reasons that PGD suffices in almost all cases comes from basic principles of inheritance of genetic conditions: the fact that you get two copies of every gene, one from Mum and one from Dad, means that for dominant diseases (where one bad copy leads to disease), you make sure not to select the one in two embryos that have that one copy, and for recessive disease (where you need a bad copy of both genes) when both parents have one bad copy, you just make sure to not select the one in four that inherits both bad copies. There is one scenario that PGD would not work for: one of the parents has a dominant disorder, but actually has TWO bad copies of the gene. In this case, no embryos would be free from disease. Such “co-dominance” is exceptionally rare.

5 Quoted in an article in the Washington Post

6 Quoted in an article in Science

7 I can’t help but mention that in the utopia of the Star Trek universe, the Federation bans genetic modification for all except the correction of severe genetic disease. However, as Dr Bashir’s parents knew, there were some planets on the outer reaches of Federation territory where you could go to improve your genetics…

8 Quoted in an article in STAT

9 I made this number up based on an incredibly generous estimate of how many individuals with co-dominant alleles for severe diseases there are