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.


Round-up Nov 10th – Dec 21st

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

Gene-editing and gene therapy
  • The first genetic variant protective against aging has been discovered by analysis of an Amish population. Two copies of the variant in SERPINE1 lead to a rare bleeding disorder; one copy leads to longer telomeres and an increased live-span averaging 10%.
  • Based on analysis of flies that had been selected based on whether they were extreme short or long sleepers, many candidate loci that can help explain the differences between how long we each need to sleep have been uncovered. These overlap heavily with the usual suspect genes i.e. genes involved in major pathways: The involvement of highly pleiotropic pathway genes suggests that sleep duration in natural populations can be influenced by a wide variety of biological processes, which may be why the purpose of sleep has been so elusive.” There was no difference in lifespan between naturally shorter- and longer- sleeping flies.
  • Genetic sequencing of a  family who are insensitive to pain has led to the pinpointing of a mutation that researchers hope will eventually help our understanding of chronic pain. 
  • The Personal Genome Project, a George Church brainchild whose members contribute their genomic and phenotypic data to the research community, has expanded to China, where it will be the country’s first open science initiative. Says Church,  I have ridiculously high hopes.”
  • An update from Regeneron, who have sequenced >100,000 exomes to date and are headed to a 400-500,000 exomes a year. Their strategy is to partner with groups who have large cohorts of patients with phenotypic data attached, most notably Geisinger Health System and the UK BioBank. They then look for the genetic outliers for ideas of drugs to develop.
  • Some heart-warming stories of extreme parenting”, i.e. the fight that some parents take-up when faced with a diagnosis of an extremely rare condition for a child.
  • Three dozen genomes of supercenterians (age >110) have been made publicly available. Supercenterians, unlike centerians, tend to live healthy lives up until the end. This NYT article goes into the tribulations of collecting the samples.
  • Genetic variation in the GPCR family of genes (G-protein-coupled receptors), which are targets of about a third of FDA approved therapies, are thought likely to alter drug response in about 3% of individuals.
  • A write-up of a conversation at the AMP conference on the legal challenges of variant classification reporting.
  • A sketch based on DNA of a suspect in a murder case lead to his arrest and confession.
  • An overview of the evidence that there were multiple points at which humans left Africa to populate the rest of the world.
  • UK biobank data has been used to demonstrate ways in which humans are still evolving.
Other Science
  • Bacteriophages viruses that affect bacteria were formerly believed not to interact with eukaryotic cells, but have now been shown to be absorbed into human cells in the gut, prompting talk of the human phageome, and hypotheses about its role in human health and disease.
  • Scientists have added two new functional letters to the genetic code, claiming The resulting semi-synthetic organism both encodes and retrieves increased information and should serve as a platform for the creation of new life forms and functions.”
  • The introduction of a new tool, trim-away, for targeting and destroying specific proteins in cells. The protein trim21 recognizes antibodies, and passes whatever the antibody is tagging to the proteasome the cell’s destroyer of unwanted proteins. By designing antibodies to target specific proteins, or even variants on these proteins, and delivering them alongside extra trim21, the method can selectively destroy particular proteins.
  • Google has released DeepVariant, a deep-learning technique for variant calling that it claims produces more accurate results than previously existing software, by transforming the problem into one of image analysis.
  • Luna, a blockchain based genomic start-up, have raised $2m in seed-funding. They will reward those who contribute their DNA for research, and provide increased security, with their own blockchain based coin.
Regulation and coverage
  • A review of protections against genetic discrimination offered by GINA argues that protections should be strengthened. Currently, a Californian woman with a positive BRCA result could legally be denied a mortgage on the basis of decreased life expectancy.
  • New FDA guidelines to implement gene-therapies faster.
  • On the 14th Nov the The US Senate Committee on Health, Education, Labor, and Pensions held a hearing on CRISPR genome editing. I have yet to listen to the hearing itself, but this write-up makes it comes across as somewhat self-congratulatory in terms of regulatory approach. The ranking senator apparently called on scientific consensus on the ethical questions, which are not words I expected to ever come across strung together in that order.
  • On regulation of somatic panel tests, GenomeWeb summarizes nicely: The agency authorized Memorial Sloan Kettering Cancer Center’s MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) through the de novo premarket review pathway as a Class II, moderate-risk device, and simultaneously made the New York State Department of Health a third-party reviewer of IVDs, including similar tumor profiling assays. Subsequently, other labs can apply to the FDA for 510(k) clearance a less onerous path than premarket approval for their tumor profiling NGS panels. Or, if the test already has approval through the NYSDOH, sponsors can submit that application to the FDA and ask the state regulator to forward its review documents and recommendations.”
  • Meanwhile the FDA approved FoundationOne, and the CMS simultaneously agreed to pay for it.
  • A perspective in the NEJM that a proposed Act will worsen the regulatory landscape in health. The authors argue that the Regulatory Accountability Act, a version of which will so go before the Senate, will actually stifle innovation because regulation will not be able to keep up with technology, and it will be harder to retire old regulation.
  • The FDA has issued a flurry of new proposed guidance, two on running of clinical trials for targeted therapies (one on the design of assays for trials here, one on appropriately exempted diagnostic tests here), and one on clinical and patient decision support software here.
  • The NIH has lifted a ban on gain of function viral research. The ban was instituted in 2014 when based on research that developed a virus that was more easily transmitted.
  • The Chinese FDA has approved a self-sampling based test for HPV from BGI
  • A group of gene-drive researchers have put together guiding principles for the use of gene drives, as part of a coordinated response to the NASEM report that concluded that gene drives were not ready for deployment, based on currently available evidence.
  • A call for more DNA collection of those charged with crimes, based on data from Denmark, where they massively increased their DNA collection rate: Our results thereby show that policies that increase the identification of criminal offenders are an effective tool to reduce crime and increase public safety,”

Round-up Sept 30th – Nov 9th

The annual American Society of Human Genetics conference happened in October in Orlando, ensuring that there was plenty of research news. The N of some studies is truly outstanding, with >10,000 seeming normal. Meanwhile, self-CRISPRing has definitely started, the role of multiple driver mutations in a given tumor is increasingly clear, and an eclectic mix of stories make it into a section I decided to call Social Backdrop”.
A moment to stop and reflect that October 24th marked the 20th anniversary of the screening of GATTACA. This is a film that I have seen raised by genetics professionals several times in the context of concern about the future we are headed to. 
Genetic modification
Social backdrop

Catch-up July 31st – Sept 29th

I have once again fallen behind in Rounding Up the news, so here play catch up, over what has been a very busy two months.
Genome editing
  • In a world first, a Chinese group have used a technique called base-editing to cure a genetic disease in a human embryos. Whereas CRISPR cuts DNA, base editing directly changes the base, leaving the DNA strand intact. The paper is from the same group that published the first CIRSPRing of human embryos. 
  • A survey of Americans found that about two thirds were generally accepting of genome editing for therapeutic purposes. About a third were supportive of genome editing for enhancement reasons.
  • First in human gene therapy trial in the US started, using Zing fingers to target Hemophilia A. Meanwhile, Reuters reports that the two gene therapies approved in Europe have seen sales of only 3
  • The scientist who edited the first human embryo in the US stresses that the main result of his work was that the embryo did not incorporate the supplied healthy” DNA, but instead preferentially incorporated an extra copy of the mother’s DNA. This puts the prospect of designed babies further off.
  • Following news of germline human genome modification, several genetic professional societies published a joint statement on the future of the technology, covering the following positions: (1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy. (2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research. (3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.”
  • A version of CRISPR that acts on RNA, with potential clinical applications e.g. to Huntingtons.
  • CRISPRcon, help in Berkeley in August, was designed to pull people to talk about a world with genome editing.
  • A great quiz from the New York Times for seeing how up to the times you are on genetic engineering. Contains reference to several of the recent major stories. 
  • Meanwhile the Onion tackles the pros and cons of genome editing. 
  • And a nice summary from Ed Yong of what the recent human embryo editing means and doesn’t mean.
And on making babies
  • Some men are infertile because they have XXY or XYY sex chromosomes. Scientists have demonstrated a technique in mice where they create sperm from ear cells via stem cells, loosing one of the extra chromosomes along the way.  
  • On that note, a review of where we’re at with infertility technology, with a particular focus on making artificial gametes.
  • The FDA has sent a cease and desist letter to the NYC based doctor who was offering mitochondrial transfer to couples (so called three person babies, legal in the UK).

Round-up July 18th – 30th

Reports of the first genetic modification of embryos in the US by scientist Shoukhrat Mitalipov, who previously created the first cloned monkeys and has cloned human embryos via cloning. The as yet un-published work applied CRISPR at the point of fertilization, thus “getting in early”, and presumably avoiding mosaicism. Previous modification of human embryos was reported by Chinese teams. At one stage it looked like a moratorium would be issued for human germline modification in the US, but a NASAM report in February of this year stopped short of that. My take on that report is here. Although clinical applications of such research would not be legal in the US, the research paves a way to a genetically modified future for humanity.

In other big genetic modification news, CRISPR has been used to restore muscle function for mice with Muscular Dystrophy. Whereas most approached to date rely on homology-directed repair, this study uses nonhomologous end-joining.

The next round of the CRISPR patent battle commences, with an appeal led by UC Berkeley against their East Coast rivals, led by the Broad. The UC group unquestionably first demonstrated use of CRISPR for genome editing. But the Boston group first applied the technique to eukaryotic cells. The California group’s case turns on their argument that this use was obvious.

Meanwhile, the FDA is one step closer to approving the first ever gene therapy.

Helix have launched their app store for your genome”. For an initial $80, costumers will have their exome sequenced. They will then be able to buy Apps on the Helix store, each of which will plug in to a bit of this data and return information to the customer. The idea is that customers will come back again and again. Geneticist Daniel MacArthur has concerns: “Promoting tests with little or no scientific backing runs the risk of inflating customer expectations and ultimately undermining consumer confidence in genuinely clinically useful genetic tests,” Another geneticist, Stephen Montgomery, has launched a satirical take on direct-to-consumer genetic tests, which then went viral.

MRSA, methicillin-resistant Staphylococcus aureus, has long been supposed to have evolved following the widespread adoption of methicilin in clinical practice. But new research suggests that MRSA evolved before the adoption of methicilin, and the resistance instead evolved in response to penicillin and other first generation drugs.

A key combination immunotherapy trial failed, stoking criticisms that this approach ahs been over-hyped.

A biotech executive and cancer patient on resetting expectations about cancer treatments: “I think everybody thinks cancer’s just about to be cured, when we have a little bit more work to do… I think if we can pop that bubble or at least reset people to have dialed down expectations for some of these breakthroughs make that in the public’s best interest.”

A bill that continues to allow the FDA to charge pharma companies to review their products must be passed by Congress, but is being held up by a Senator who wants to insert a “Right to Try” clause as an amendment. A medical ethicist argues why the inclusion of a right to try” clause would undermine clinical trials.

Why are dogs more friendly than wolves? The canine equivalent of a region associated with Williams-Beuren syndrome in humans — a condition marked by hypersocialability amongst other things — has been found to be under positive selection in domestic dogs.


Round-up July 10th-17th

The first CAR-T therapy, this one for Leukemia, is one step closer to approval after an FDA advising committee gave it a unanimous thumbs up.  The therapy takes out a patient’s T-cells, modifies them to express Chimeric Antigen Receptors (that are good at recognizing tumor cells), and injects them back in.

A new German center that will sequence 1000 genomes a year in an aim to capture species biodiversity.

A controversial genetic test for gum disease has been withdrawn. The test had been drawing criticism for many years as overselling the clinical utility of genetic testing in this area, and is given as an example of why the FDA needs to wade in to regulate lab developed tests.

Trace Genomics will analyze which bacteria are present in soil to give input to farmer’s making planting decisions.

Doudna’s group publishes on the discovery of an “anti-CRISPR DNA mimic” that can reduce the off-target effects of CRISPR-Cas9.

A study using CRISPR in a ScanDel approach — tiling 1-2kb deletions, to see which regions near a gene were essential for its expression.

Public outreach shouldn’t just mean convincing the public that we know best. Biotechnologist Esvelt has plans to do R&D in a radically open way.

Verily (parent company, Alphabet) are releasing millions of mosquitos infected with a bacteria to make them sterile, in an effort to combat zika.

A study claims that ~75% of the genome is junk”, where junk means something like not under selective pressure. This is in stark contrast to ENCODE, which claims there is evidence for ~80% of the genome to be functional. The new study seems to claim that for a site to be function, a rare variant would make the individual non-viable.

Its been known that epigenetic effects can be inherited for quite some time, but its now been shown that inherited epigenetic modifications effect gene expression.


Round-up May 31st – July 9th

I have slipped in my resolution for a weekly round-up. Here is another catch-up. And there has certainly been a lot to catch up on!

Germline news

In the first ever randomized controlled trial of whole genome sequencing for healthy adults, which reported on variation across genes linked to Mendelian disease, many participants were found to have variants believed to definitively cause disease by adulthood, even though they were living disease free. STAT has a write-up.

At one point, it was thought that diseases such as obesity, or traits such as height might be polygenic in nature, i.e. affected by variation in some set of closely involved genes. Genome Wide Association Studies are premised on this idea. But it is challenged by a recent paper that puts forward the case for the omnigenic model i.e. almost every gene effects every trait, because of how interconnected the networks are. If true, this suggests that we should be concentrating on mapping out the networks operating in different cell types. Ed Yong has a good write-up.

Veritas has launched myBabyGenome in China. For $1500 parents can find out about a series of traits (e.g. how novelty seeking” their child may be) and disease risks. But as genetics prof Jim Evans says You run the risk of predestination based on bad science”. They won’t be told about e.g. variation that leads to an increased risk if Alzheimers. Instead, they will be offered the chance to purchase that information later on.

A study of families in Scotland involving 20,000 individuals reports that brainier people have fewer variants that impair general health and intelligence, rather than possessing variants that make them smarter. While twin studies suggest that 50-80% of intelligence is based on genetics, studies to date had been able to attribute only about 30% of the variance to genetics the gap is known as the mystery of missing heritability”. This study was able to explain this gap, because it could isolate the effect of very rare variants usually too rare to be missed, but because of their presence in families, detectable by this study. The results are support for the mutational load” paradigm for thinking of genetic endowment.

Huntington’s sufferers have one normal and one altered copy of the gene HTT. A study that used CRISPR-Cas9 to knock out both copies of HTT in mice found no negative effects and improvements in symptoms.

Over 1000 new reference genomes of bacteria and archaea have been deposited by the JGI.

New York fertility doctor, Dr Zhang, who evaded US regulations and went to Mexico to oversee use of the three-person baby technique, has started a company to market this technique. It will market not only to couples wishing to avoid passing on mitochondrial disease, but also for age-related issues.

A study that looked at the combination of pre-implantation genetic diagnosis (PGD, performed for Mendelian diseases such as Cystic Fibrosis) and screening (PGS, performed to test for aneuploidies such as Downs), found that the combination resulted in more pregnancies given embryo transfers, but fewer transfers, as for more couples no viable embryos remained. After PGD, 56% of embryos were deemed transferable. After PGS, only 27.5% of blastocysts were deemed transferable. Standardly, about 34% of transfers result in pregnancies. Following both PGD and PGS in this study, the number was 49%.

How much of heritability comes from common (>5% frequency) variants? A new study suggests about 43%.

Why hasn’t natural selection reduced the amount of coronary heart disease? This study provides novel evidence that CAD has been maintained in modern humans as a by-product of the fitness advantages those genes provide early in human lifecycles” paper here

Analysis of mummy DNA suggests Ancient Egyptians individuals were more similar to present day people from the Near East than to populations residing in Egypt today

The Precision Medicine Initiative, launched in 2015, has just started beta enrollment in its All Of Us program, which aims to be a 1 million strong cohort. 

Age-related somatic mutations have typically been of interest because of cancer. But they are also of potential relevance for other disease types. A large-scale study finds that a particular type of somatic change in blood cells doubles the risk of coronary heart disease. Which is a good segway into…


Somatic related news

Encouraging results from a small cancer-vaccine study: 6 melanoma patients given a cancer vacine unique to their tumor saw no recurrence. The technique works by first sequencing the tumor, to work out which sections of the DNA make antigens that the immune system is most likely to respond to, and that are different from germline cells. Next, millions of copies of each of 13-20 of these neoantigen regions are injected.  The idea is that the patient’s immune system learns to recognize these sequences as other”, and will then target the cancerous cells.

Evidence that PARP inhibitors perform better than chemotherapy for women with metastatic breast cancer who also have germline BRCA mutations. There are three PARP inhibitors approved for ovarian cancer on the market.

A study of a regulatory region that is well conserved between humans and mice finds when this region is deleted a) mice develop normally, and b) mice are resistant to tumor development, making it a promising drug target. 

Following Keytruda’s approval based on a bimarker indication across all cancer types, new FDA commissioner Gottleib has promised more guidance to allow more drugs to follow this path. 

Flatiron and Foundation have shown the utility of their joint molecular-clinical dataset, including the demonstration that those with an actionable variant have a survival time of 35 months, compared to 19 months for those without.

 A nice synopsis of oncologists’ thinking about genetic testing, arising out of ASCO.

Merck paused two studies of Keytruda in combination with other therapies for multiple myeloma, because of unexplained deaths.

Accurate software for distinguishing germline variants from a tumor without the need for a matched normal sample.