Every Child is a Genetic Experiment: FAAH Clinical Trials for Hedonic Recalibration as Educated Guesses Rather than Reckless Experimentation

by David Pearce, in response to Quora question: How do you break the hedonic treadmill?


The easiest pain to bear is someone else’s.
(François de La Rochefoucauld)

Could two small genetic tweaks get rid of most of the world’s mental and physical pain?
A tentative answer is: just conceivably. More cautiously, the problem of suffering should be genetically soluble this century. Before launching into a long list of caveats and complications – and outright scepticism – it’s worth considering a case study. The subject has waived anonymity.

Jo Cameron is a retired Scottish schoolteacher, a socially responsible vegan and pillar of the local community. Jo has gone though life in a perpetual state of “mild euphoria”. She has unusually high levels of anandamide (from the Sanskrit for “bliss”) and is never anxious, though her serenity may vary. Jo doesn’t feel pain, or at least not in any sense most of us would recognise: childbirth felt like “a tickle”. She is hyperthymic, but not manic. Unlike previously reported cases of congenital analgesia, Jo didn’t die young or find the need to adopt a “cotton-wool” existence to avoid bodily trauma. She came to the attention of medical researchers only when her disdain of painkillers for what “ought” to have been an excruciating medical procedure – a trapeziectomy on her right thumb – intrigued her doctor. “I had no idea until a few years ago there was anything that unusual about how little pain I feel – I just thought it was normal.
With CRISPR genome-editing, lifelong bliss could be normal.

Jo Cameron is first known case of someone with mutations in both the FAAH gene and its newly-discovered sister gene, FAAH-OUT, which modulates the FAAH gene. The FAAH gene (short for Fatty Acid Amide Hydrolase) is a protein-coding gene responsible for degrading bioactive fatty amides, most notably the endogenous cannabinoid anandamide. Previous mutations of FAAH are known, but the FAAH-OUT gene was previously reckoned a pseudogene. Single FAAH mutations are associated with high pain-tolerance, reduced anxiety and a sunny outlook without Jo’s “extreme” syndrome of well-being. Jo’s son has the single mutation.

Other case studies may be cited. I often use (again with prior consent) the example of my transhumanist colleague Anders Sandberg (“I do have a ridiculously high hedonic set-point”) – although Anders’ pain-sensitivity lies within the normal range. The pain-modulating SCN9A gene, which has dozens of alleles conferring varying pain (in)tolerance, is much better studied (cfHow much do our pain thresholds differ?).

What biologists call the Environment of Evolutionary Adaptation (EEA) ensures such outliers are rare. Although Jo Cameron shows accelerated wound-healing, not being a “normal”, neurotic mother on the African savannah would have carried a fitness-cost. Predators are unforgiving of relaxed moms. Our sugary “wildlife documentaries” barely hint at the cruelties of Nature. Pain, fear and anxiety are intimately linked. “Only the paranoid survive”, said Intel boss Andy Grove; and this bleak diagnosis can be true of market capitalism to this day. But we are not living on the African savannah – or even in a world of unfettered free markets. Looking ahead, all kinds of risks can be offloaded to artificial intelligence. AI and smart prostheses can potentially manage risks moreeffectively than bias-ridden humans. Intuitively, for sure, tampering with our reward circuitry will be hazardous. Genetically modifying or creating superhappy organisms with relative pain-insensitivity and enhanced zest for life will lead to increased personal risk-taking. Yet the story is more complicated. A great deal of risky and self-destructive behaviour in today’s world involves not happy, pain-free people, but the pain-ridden, depressive and psychologically disturbed. Life-loving optimists typically value life more – and seek to preserve and protect it. Anecdotally, I don’t think it’s a coincidence that some of the happiest people I know dedicate their lives to the study and prevention of existential risk.

So a practical question arises.
Should a large, well-controlled clinical trial of CRISPR babies be launched, with some babies carrying Jo’s two mutations, others a single FAAH mutation like her son, and controls?
If the trial is successful, then the controls and (in due course) the wider human population could enjoy remedial gene-therapy to share the benefits.

One of the few publications to recognise the far-reaching significance of Jo’s case is the magazine Wired (cfCrispr Gene Editing Could One Day Cut Away Human Pain). Instead of the double mutation promising “only” better drugs to treat pain, humanity can now tackle the problem of suffering at its source.

Bioconservative critics will be appalled at the idea: “Doctor Mengele!” “Eugenics!” “Designer babies!” “Gattaca!” “Brave New World!” Being malaise-ridden is normal and natural. Creating superbabies would be hubris. Where will it lead? How do we know gene-editing won’t be used by despots to create a race of fearless superwarriors?
In more measured language, how can experimentation with the lives of sentient beings without prior informed consent be ethically justified?

Indeed. Yet all babies born today are unique and untested genetic experiments. All baby-making entails creating involuntary suffering. None of our genetic experiments first passed muster with a medical ethics committee. Any proposal to create transhuman superbabies will probably strike our descendants as genetic remediation, not enhancement. If we reject the arguments of anti-natalists, who view Darwinian life as malware, then all prospective parents are committed to practising genetic experimentation – just not under that inflammatory label. So what’s at issue is not the principle of genetic innovation, only whether we should harness the new tools of CRISPR-Cas9 genome-editing to conduct our experiments more responsibly. If aspiring writers can benefit from proofreaders and editors, why not aspiring parents too – where the stakes are higher?

Your question asks about breaking the hedonic treadmill (cfWhat would people who never suffered be like?). Breaking or otherwise dismantling the hedonic treadmill is worth distinguishing from recalibration of its dial-settings. Hedonic adaptation can be broken in human and non-human animals by experimentally inducing “learned helplessness” and behavioural despair in response to chronic, uncontrollable stress. Hedonic adaptation can be broken at the other extreme by using intracranial self-stimulation of the mesolimbic dopamine system. “Wireheading” shows virtually no tolerance. Pathological cases of a broken hedonic treadmill occur “naturally” in chronic unipolar depression and, much more rarely, in euphoric unipolar mania. Attempts to cheat the hedonic treadmill via drugs are fraught with pitfalls. The most powerful mood-brighteners, namely the opioids, activate the hedonic treadmill rather than mitigate it. Some opioid users end up with a habit hundreds of times their starting dose. Natural selection did not design living organisms to be happy.

Functionally, therefore, genetic recalibration is a more fruitful strategy than abolishing the hedonic treadmill, both for the individual and society at large. For what it’s worth, I personally think we should aim for a hyperthymic civilisation built on a biology of invincible well-being. Future sentience will be underpinned by gradients of bliss. However, nothing so grandiose need be envisaged in order to warrant human CRISPR trials of happy babies. Grant some fairly modest ethical assumptions, e.g. other things being equal, intelligent moral agents should act so as to reduce the burden of suffering, or at least not wantonly add to it. For any genetic intervention that alters default hedonic tone, conserving information-sensitivity to “good” and “bad” stimuli is critical. In other words, we should aim to retain the hedonic treadmill but transform its negative feedback-mechanisms into a hedonistic treadmill – where “hedonism” is understood not in the amoral popular sense of a life of drink, drugs and debauchery, but as embracing Mill’s “higher pleasures”. Hence the hedonistic imperative. If clinical trials of superbabies go well, prospective parents world-wide could be offered the opportunity to have happy, heathy babies via CRISPR genome-editing, preimplantation genetic screening and counselling.

A biohappiness revolution would be extremely cost-effective. Depression, anxiety disorders and chronic pain-syndromes significantly reduce economic growth worldwide. By conserving hedonic adaptation, but ratcheting up hedonic range and hedonic set-points, humanity can conserve and enhance empathetic understanding, social responsibility and critical insight while enriching default quality of life. By conserving hedonic adaptation, we can also conserve cherished traditional values, if so desired. Yesterday’s utopias involved overriding the preferences of others, whether for their own notional good or in pursuit of some higher cause. By contrast, elevating your pain-tolerance and raising your hedonic set-point would radically enrich your life but wouldn’t challenge your values and preferences – unless one of your core values is preserving the genetic status quo.

What could go wrong with a biohappiness revolution?
Cue for vast treatises and a sci-fi movie.
However, as well as seriously – indeed exhaustively – researching everything that could conceivably go wrong, I think we should also invesigate what could goright. The world is racked by suffering. The hedonic treadmill might more aptly be called a dolorous treadmill. Hundreds of millions of people are currently depressed, pain-ridden or both. Hundreds of billions of non-human animals are suffering too. If we weren’t so inured to a world of pain and misery, then the biosphere would be reckoned in the throes of a global medical emergency. Thanks to breakthroughs in biotechnology, pain-thresholds, default anxiety levels, hedonic range and hedonic set-points are all now adjustable parameters in human and non-human animals alike. We are living in the final century of life on Earth in which suffering is biologically inevitable. As a society, we need an ethical debate about how much pain and misery we want to preserve and create.

Triple S Genetic Counseling: Predicting Hedonic-Set Point with Commercial-Grade DNA Testing as an Effective Altruist Project

The term “Transhumanism” has many senses. It is a social movement, a philosophy, a set of technologies, and a conceptual rallying flag. David Pearce pins down the core sentiment behind the term like this:

If we get things right, the future of life in the universe can be wonderful beyond the bounds of human imagination: a “triple S” civilisation of superlongevity, superintelligence and superhappiness.

– David Pearce, in The 3 Supers

The concept of a “triple S” civilization is very widely applicable. For example, one can imagine future smart homes designed with it in mind. Such smart homes would have features to increase your longevity (HEPA filters, humidity control, mold detectors, etc.), increase your intelligence (adaptive noise-canceling, optimal lighting, smart foods), and happiness (mood-congruent lighting, music, aromas, etc.). Since there are trade-offs between these dimensions, one could specify how much one values each of them in advance, and the smart home would be tasked with maximizing a utility function based on a weighted average between the three S’s.

Likewise, one could apply the “triple S” concept to medical care, lifestyle choices, career development, governance, education, etc. In particular, one could argue that a key driver for the realization of a triple S civilization would be what I’d like to call “triple S genetic counseling.” In brief, this is counseling for prospective parents in order to minimize the risks of harming one’s children by being oblivious to the possible genetic risk for having a reduced longevity, intelligence, or happiness. Likewise, in the more forward-looking transhumanist side of the equation, triple S genetic counseling would allow parents to load the genetic dice in their kid’s favor in order to make them as happy, long-lived, and smart as possible.

Genetic counseling, as an industry, is indeed about to explode (cf. Nature’s recent article: Prospective parents should be prepared for a surge in genetic data). Predictably, there will be a significant fraction of society that will question the ethics of e.g. preimplantation genetic diagnosis for psychological traits. In practice, parents who are able to afford it will power ahead, for few prospective parents truly don’t care about the (probabilistic) well-being of their future offspring. My personal worry is not so much that this won’t happen, but that the emphasis will be narrow and misguided. In particular, both predicting health and intelligence based on sequenced genomes are very active areas of research. I worry that happiness will be (relatively) neglected. Hence the importance of emphasizing all three S’s.

In truth, I think that predicting the hedonic set-point of one’s potential future kids (i.e. the average level of genetically-determined happiness) is a relatively more important project than predicting IQ (cf. A genome-wide association study for extremely high intelligenceBGI). In addition, I anticipate that genetic-based models that predict a person’s hedonic set-point will be much more accurate than those that predict IQ. As it turns out, IQ is extremely polygenetic, with predictors diffused across the entire genome, and it is a very evolutionary recent axis of variance across the population. Predictors of hedonic-set point (such as the “pain-knob gene” SCN9A and it’s variants), on the other hand, are ancient and evolutionarily preserved across the phylogenetic tree. This makes baseline happiness a likely candidate for having a straight-forward universal physiological implementation throughout the human population. Hence my prediction that polygenetic scores of hedonic-set point will be much more precise than those for IQ (or even longevity).

Given all of the above, I would posit that a great place to start would be to develop a model that predicts hedonic set-point using all of the relevant SNPs offered by 23andMe*.  Not only would this be “low-hanging fruit” in the field of genetic counseling, it may also be a project that is way up there, close to the top of the “to do” list in Effective Altruism (cf. Cause X; Google Hedonics).

I thought about this because I saw that 23andMe reports on health predispositions based on single SNPs. From a utilitarian point of view, of particular interest are SNPs related to the SCN9A gene. For example, I found that 23andMe has the rs6746030 SNP, which some studies show can account for a percentage of the variance associated with pain in Parkinson’s and other degenerative diseases. The allele combination A/A is bad, making you more prone to experience pain intensely. This is just one SNP, though, and there ought to be a lot of other relevant SNPs, not only of the SCN9A gene but elsewhere too (e.g. involved in MAO enzymes, neuroplasticity, and pleasure centers innervation).

Concretely, the task would involve making two models and then combining them:

The first model uses people’s responses to 23andMe surveys to come up with a good estimate of a person’s hedonic set-point. Looking at some of the questions they ask, I would argue that there are more than enough dimensions to model how people vary in their hedonic set-point. They ask about things such as perception of pain, perception of spiciness, difficulty sleeping, stress levels, whether exercise is pleasant, etc. From a data science point of view, the challenge here is that number of responses provided by each participant is very variable; some power users respond to every question (and there are hundreds and hundreds), while most people respond to a few questions only, and a substantial minority respond to no questions at all. Most likely, the distribution of responses per participant follows a power law. So the model to build here has to be resilient against absent data. This is not an insurmountable problem, though, considering the existence of Bayesian Networks, PGMs, and statistical paradigms like Item Response Theory. For this reason, the model would need to both predict the most likely hedonic set-point of each participant, and provide confidence intervals specific to the participant based on the quality and relevance of the questions answered.

The second model would involve clustering and dimensionality reduction applied to the SNPs that are likely to be relevant for hedonic set-point. For example, one dimension would likely be a cluster of SNPs that are associated with “maximum intensity of pain”, another might be “how quickly pain subsides once it’s stimulated”, another “how much does pleasure counter-balance pain”, and so on. Each of these dimensions is likely to be determined by different neural circuits, and interact in non-linear ways, so they deserve their own separate dimension.

And finally, one would make a third model that combines the two models above, which predicts the hedonic set-point of a person derived from the first model using the genetic dimensions found by the second model. If you are an up-and-coming geneticist, I would like to nudge you in the direction of looking into this. As a side effect, you might as well get filthy rich in the process, as the genetic counseling field explodes in the next decade.

Bonus Content: What About Us?

Admittedly, many people will note that predicting a fraction of the variance of people’s hedonic set point with commercial DNA testing products will only really alleviate suffering in the medium to long term. The people who will benefit from this technology haven’t been born yet. In the meantime, what do we do about the people who currently have low hedonic set-points? Here is a creative, politically incorrect, and enticing idea:

Let’s predict which recreational drugs have the best cost-benefit profile for individuals based on their genetic makeup.

It is no secret that people react differently to drugs. 23andMe, among others, is currently doing research to predict your particular reaction to a drug based on your genetic makeup (cf. 23andMe can now tell you how you’ll react to 50+ common drugs). Unfortunately for people with anxiety, depression, chronic pain, and other hedonic tone illnesses, most psychiatric drugs are rather subtle and relatively ineffective. No wonder, compared to heroin, an SSRI is not likely to make you feel particularly great. As David Pearce argued in his essay Future Opioids, there is substantial evidence that many people who become addicts are driven to take recreational substances due to the fact that their endogenous opioid system is dysfunctional (e.g. they may have bad variants of opioid receptors, too many endorphin-degrading enzymes, etc.). The problem with giving people hard drugs is not that they don’t work in the short term; it is that they tend to backfire in the long-term and have cumulative negative health effects. As an aside, from the pharmaceutical angle, my main interest is the development of Anti-tolerance Drugs, which would allow hard drugs to work as mood-enhancers indefinitely.

This is not to say that there aren’t lucky people for whom the cost-benefit ratio of taking hard drugs is, in fact, rather beneficial. In what admittedly must have been a tongue-in-cheek marketing move, in the year 2010 the genetic interpretation company Knome (now part of Tute Genomics) studied Ozzy Osbourne‘s entire genome in order to determine how on earth he has been able to stay alive despite the gobs and gobs of drugs he’s taken throughout his life. Ozzy himself:

“I was curious, [g]iven the swimming pools of booze I’ve guzzled over the years—not to mention all of the cocaine, morphine, sleeping pills, cough syrup, LSD, Rohypnol…you name it—there’s really no plausible medical reason why I should still be alive. Maybe my DNA could say why.”

Ozzy Osbourne’s Genome (Scientific American, 2010)

Tentatively, Knome scientists said, Ozzy’s capacity to drink entire bottles of Whisky and Gin combined with bowlfuls of cocaine and multiple packs of cigarettes over the course of… breakfast… without ending up in the hospital may be due to novel mutations in his alcohol dehydrogenase gene (ADH4), as well as, potentially, the gene that codes for CLTCL1, a protein responsible for the intake of extra-cellular material into the cell’s inside. These are wild speculations, to be clear, but the general idea is brilliant.

Indeed, not everyone reacts in the same way to recreational drugs. A recent massive study on the health effects of alcohol funded by the Bill and Melinda Gates Foundation (cf. No amount of alcohol is good for your overall health) suggests that alcohol is bad for one’s health at every dosage. This goes against the common wisdom backed up with numerous studies that light-drinkers (~1 alcohol unit a day) live longer and healthier lives than teetotalers. The new study suggests that this is not a causal effect of alcohol. Rather, it so happens that a large fraction of teetotalers are precisely the kind of people who react very badly to alcohol as a matter of poor metabolism. Hence, teetotalers are not unhealthy because they avoid alcohol; they avoid alcohol because they are unhealthy, which explains their shorter life expectancy on average. That said, the study did show that 1 alcohol unit a day is, although damaging, very minimally so:

Anyhow, the world’s cultural fascination with alcohol is bizarre to me, considering the existence of drugs that have a much better hedonic and cost-benefit profile (cf. State-Space of Drug Effects). Perhaps finding out with genetic testing that you are likely to be an above-average alcohol metabolizer might be good to lessen your worry about having a couple of drinks now and then. But the much bigger opportunity here would be to allow you to find drugs that you are particularly compatible with. For example, a genetic test might determine based on a polygenetic score that you might benefit a whole lot from taking small amounts of e.g. Khat  (or some such obscure and relatively benign euphoriant). That is, that your genetic make-up is such that Khat will be motivation enhancing, empathy-increasing, good for your heart and lungs, reduce the rate of dopamine neuron death, etc. while at the same time producing little to no hangovers, no irritability, no sleep issues, or social dysfunction. Even though you may have thought that you are “not an uppers person”, perhaps that’s because, genetically, every other upper you have ever tried is objectively terrible for your health. But Khat wouldn’t be. Wouldn’t this information be useful? Indeed, I would posit, this might be a great step in the right direction in order to achieve the goal of  Wireheading Done Right.

*23andMe is here used as a shorthand for services in general like this (including Ancestry, Counsyl, Natera, etc.)

Featured image credit: source.