Henry Stanley

Be grateful for MDMA

Wed, 07 Dec 2011 22:42:00 +0000

Sasha Shulgin is a legendary chemist and psychonaut and inventor of hundreds of psychedelics. In 1991, he and his wife, Ann, published a book. Part-novel and part-cookbook, PiHKAL—Phenethylamines I Have Known And Loved—told his story and the stories of the compounds he and his friends had ingested, a process he ironically termed ‘LAB’, or Large Animal Bioassay.

It’s a gorgeous book, and a work that is still unmatched in its candour and novelty (and notoriety).

Flip to the back, and there are 179 entries on various substituted phenethylamines, each with intricate synthesis notes and experience reports detailing the effects each compound had on him and his close friends.

My favourite is #109.

MDMA (MDM; ADAM; ECSTASY; 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE)

As the material came on I felt that I was being enveloped, and my attention had to be directed to it. I became quite fearful, and my face felt cold and ashen. I felt that I wanted to go back, but I knew there was no turning back. Then the fear started to leave me, and I could try taking little baby steps, like taking first steps after being reborn. The woodpile is so beautiful, about all the joy and beauty that I can stand. I am afraid to turn around and face the mountains, for fear they will overpower me. But I did look, and I am astounded. …

I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great, or believed this to be possible. The cleanliness, clarity, and marvelous feeling of solid inner strength continued throughout the rest of the day, and evening, and through the next day. I am overcome by the profundity of the experience … All the next day I felt like ‘a citizen of the universe’ rather than a citizen of the planet…

Everyone must get to experience a profound state like this. I feel totally peaceful. I have lived all my life to get here, and I feel I have come home.

I am complete.

Shulgin saw that MDMA had huge potential. A gentle empathogen and entactogen (meaning literally “to touch within”), it allows deep but unthreatening introspection. He was certain it would be of use in therapy, and only now are its medicinal properties being scientifically evaluated. He also knew that if it became a street drug, its use in psychotherapy would be drastically limited. He was right.

The MDMA experience tells us something important about being human. It shows that states of transcendence and emotional bliss beyond our normal capacity are possible. It proves that our brains are capable of amazing things, and that the substrates of superhappiness exist within our current wetware, even if such states are not normally available to us.

Shulgin was struck when he realised that the psychedelic experiences he had were not contained within the few hundred milligrams of white powder at the bottom of the glass, but were contained within him. The drug was merely a catalyst for revealing what was already there.

We should be grateful that we are already so rich, and that there is so much inside for us to discover.

Don't confuse consuming and producing

Sun, 06 Nov 2011 22:31:07 +0000

I’m trying to figure out what to do with my life. Give me your thoughts.

Michael Idov writes in his piece Bitter Brew in Slate:

I never realized how ubiquitous the dream of opening a small coffeehouse was until I fell under its spell myself. It seemed that just about every boho-professional couple had indulged in this fantasy at some point or another.

The dream of running a small cafe has nothing to do with the excitement of entrepreneurship or the joys of being one’s own boss—none of us would ever consider opening a Laundromat or a stationery store… The small cafe connects to the fantasy of throwing a perpetual dinner party… To a couple in the throes of the cafe dream, money is almost an afterthought. Which is good, because they’re going to lose a lot of it.

This article is the story of a young married couple who decide to run a cute little coffee shop (in New York, but any big city’ll do). They’re enamoured with the idea of it, not because they want financial independence, to set their own hours or to be their own boss(es), but because they’ve fallen in love with the notion that providing that service will be just as fun as consuming it.

The thing is, running a coffee shop is nothing like drinking lattes in a coffee shop. It’s gruelling, expensive and hugely risky. That’s why so many people fail—because they were in love with an aspect of the job that doesn’t exist.

My love of science, of biology and biogerontology and finding practical ways of slowing ageing can be subjected to a similar analysis. I’ve made the mistake of thinking that reading about/talking about/enjoying the fruits of scientific advance will be just as fun as actually doing the benchwork myself.

It’s the distinction between what you do day-to-day and the narrative you invent to describe your job—a distinction I’ve been deliberately (if unconsciously) blurring by describing my work in a biogerontology lab as making a grand contribution to understanding and ending ageing. It’s a great story but it’s not the truth, and wouldn’t be even if I had some scintillating project analysing rat brain ageing or dietary restriction in flies. I would still be a technician, just like the coffee shop owner is still a vendor and not a coffee connoisseur.

I could just as easily enjoy science from afar, and that way, I might be able to stay a consumer.

What's the point of OpenPCR?

Mon, 31 Oct 2011 20:59:00 +0000

For those not in the know, PCR is a standard biological technique that lets you make lots of copies of a piece of template DNA. It’s crucial because a lot of molecular biology relies on having a large amount of a particular DNA, so it makes possible everything from DNA fingerprinting to genomics to forensics to getting bacteria to express a gene of interest. Its invention changed the face of modern biology.

Thermocyclers, the machines which do PCR, are expensive. Thousands of dollars expensive. And there’s no good reason for it because they’re pretty simple: they just need to reliably heat up and cool down sample tubes to allow the chemicals inside to do their job. In fact, early PCR machines were just three water baths, each at a specific temperature, between which a technician would move their samples.

OpenPCR is an open-source PCR machine. From Why we built OpenPCR:

There are really two core benefits I see to a machine like OpenPCR. The first is a drastically lower price point. … The second … was to create a substrate for further hacking.

I love it. I want one. It’s a really gorgeous machine, too, made of laser-etched wood panels with black rivets. And it’s cheap, with kits costing $599 and taking around three hours to assemble.

But who’s it for?

Hobbyists will certainly be attracted by the low price, but molecular biology requires a lot of kit. Thermocycler aside, you need primers for each reaction you want to carry out which often have to be custom-made, all the enzymes and reagents for the PCR itself, plus restriction enzymes and the equipment to run a gel to visualise the DNA you’ve amplified (so that’s agarose, buffer, DNA dye, an electrophoresis tank and a UV visualiser). Most of which has to be shipped refrigerated by companies which probably won’t sell to individuals.

I want to see home-brew biology flourish. I love the idea that you can analyse your own DNA to see if you have a particular polymorphism, or identify unlisted plant ingredients in commercial teas. But molecular biology has always been capital-intensive and as long as that’s the case, the kind of “garage biology” that OpenPCR’s inventors want to encourage will be out of reach for most.

Shortcuts for supercentenarians

Wed, 26 Oct 2011 23:09:00 +0100

First posted on Nature Student Voices. It’s a long and relatively technical piece on ageing and how there might be shortcuts to slowing it down without knowing much about its molecular mechanism.

The aging process is complex and multifaceted, but slowing it may be easier than we thought—and in biogerontology, there might be such a thing as a free lunch.

In the 1930s, biogerontologist Clive McKay found that rats whose diets were reduced to sixty per cent of what they would eat normally were living healthily, with glossy fur and eyes unclouded by cataracts, at ages where their normally-fed compatriots were dying[1]. McKay thought wrongly that it was stunting development that extended lifespan; Ed Masoro would later find that caloric restriction could be started during adulthood and cause a similarly profound drop in mortality[2]. Calorie restriction (or CR) has been found to work in mice, rats, worms, fruit flies and yeast, and probably works in higher organisms as well[3]. A trial at the University of Wisconsin–Madison is attempting to determine the effects of CR in rhesus macaques, the most humanlike animals yet used in such experiments. While the final results of the trial are many years away—these monkeys do live for 25 years on average, after all—already the animals on CR show signs of increased lifespan and ‘youthspan’, with normally-fed monkeys dying at three times the rate of calorie restricted ones[4].

Biogerontology’s grand claim—that we can control and slow aging—is thus made credible. If simple interventions can reliably increase lifespan in animals, they almost certainly work in humans, too. The island of Okinawa off the southernmost point of Japan harbours the world’s largest population of supercentenarians (those lucky few who live for a century or longer), and it is likely no coincidence that the Okinawan Japanese have a culture of leaving the stomach part empty at the end of every meal.

Of course, calorie restriction is hardly fun. The regimen has side-effects and few would be able to stomach a one-third reduction in their calorie intake. But as proof-of-principle, CR shows that there are low-hanging fruit in life extension: simple biological switches that can increase longevity. Finding a simple way of flicking those switches is a major goal of modern biogerontology.

As a phenomenon, CR is intriguing: if we have genes that specifically lengthen animal lifespan, as xenometabolic enzymes, heat stock proteins and protein chaperones seem to[5], why aren’t those genes switched on all the time? Certainly if living longer was evolutionarily favourable, they would be. But the opportunity cost of expending energy on cellular maintenance is investing less in reproduction. In species where early and prolific reproduction is evolutionarily favored, faster aging is promoted at the expense of extended lifespans and long reproductive careers. The battery of life-extending genes that lie dormant within so many species are only activated in times when food is scarce and conditions harsh, delaying reproduction to concentrate on surviving the drought before returning to full reproductive capacity. Simply, CR probably switches on a form of reproductive diapause—a way of adjusting the balance between reproduction and longevity.

Sirtuins are a major candidate in the search for ‘CR mimetics’, or drugs that trick the body into thinking calories are few and far between, so simulating CR. Notable among them is resveratrol, a compound found in grape skins and present in red wine, which stirred much enthusiasm in the field (and not a few high-profile headlines). If these chemicals could trick our bodies into thinking their calorie intake was being drastically reduced—if they could switch on longevity genes—we could enjoy longer lifespans and healthspans. With most people having few children late in life, the cost of reduced fertility would not be a hard one to bear.

David Sinclair was formerly a postdoctoral researcher working for Leonard Guarente in MIT where he discovered that the protein Sir2 prevents the formation of ERCs (extrachromosomal rDNA circles, a key biomarker of aging in yeast). Another postdoc in that lab, Matthew Kaeberlein, found that overexpressing the Sir2 gene extended yeast lifespan. The gold rush for CR mimetics began, with Sinclair founding Sirtris, a company trying to develop and commercialise sirtuin-based anti-aging compounds[6]. His firm was later acquired by pharmaceutical giant GlaxoSmithKline for a staggering $720million, symbolic of the commercial significance a drug that could slow aging would have.

But the effectiveness and pututative mechanism of resveratrol has been called into question. It extends the lifespan of mice, but only those fed a high-fat diet. Later work by Kaeberlein failed to find any life-extending effect of resveratrol on several strains of yeast[7]. The compound was found to increase the lifespan of the humble nematode C. elegans, but its activity may be unique to that species alone (a ‘private’ rather than ‘public’ mechanism of aging). More worryingly, a 2010 study by David Gems and Linda Partridge at UCL’s Institute for Healthy Ageing found that sirtuin overexpression left fly lifespans unchanged and caused only minimal life extension in worms, casting doubt over the entire premise that firms like Sirtris are counting on[8].

Gems recently made newspaper headlines when his laboratory published a paper claiming poor-quality research was to blame for the conflicting results[9]. Specifically, poorly-controlled genetics (such as sirtuin overexpressing animals picking up other life-extending mutations) seem to account for the life-extending properties described by previous researchers, and Gems showed this by demonstrating that sirtuin overexpression and lifespan extension were separable genetically. Guarente challenges this in the same issue of Nature, claiming that he used the best techniques available at the time, and that carefully-controlled followup work confirms a (somewhat smaller) life-extending effect[10].

It might be years before sirtuins’ mysteries are properly described. Some think that these compounds don’t activate the sirtuin pathway at all, perhaps acting via TOR (target of rapamycin) signalling. Other sirtuin activators with potencies orders of magnitude greater than resveratrol are under development and may work where resveratrol failed. But even if Sirtris fails to be the jewel in GlaxoSmithKline’s crown and sirtuins act by entirely different pathways, CR mimetics might be a quick and dirty way to extend lifespan without needing to know much at all about the underlying processes of aging.

References

1. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr. 1935;10:63–79.

2. Masoro EJ. Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms, Biochimica et Biophysica Acta 2009, 10:1040–1048. doi:10.1016/j.bbagen.2009.02.011. PMID: 19250959

3. McDonald RB, Ramsey JJ. Honoring Clive McCay and 75 Years of Calorie Restriction. J Nutr. 2010;7:1205–1210. PMID: 20484554.

4. Colman RJ et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009 Jul 10;325(5937):201-4. PMID: 19590001

5. Gems D, McElwee JJ. Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech Ageing Dev. 2005 Mar;126(3):381-7. PMID: 15664624

6. Garber, K. A mid-life crisis for aging theory. Nature Biotechnology 26, 371 - 374 (2008) doi:10.1038/nbt0408-371

7. Kaeberlein M et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17038-45. PMID: 15684413

8. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev. 2007 Oct;128(10):546-52. PMID: 17875315

9. Burnett, C et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011 Sep 21;477(7365):482-5. doi: 10.1038/nature10296. PMID: 21938067

10. Viswanathan M and Guarente L. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 2011 Sep 21;477, E1–E2. doi: 10.1038/nature10440.

Ambitious psychology

Wed, 16 Mar 2011 18:25:00 +0000

This month’s Lates night at the Science Museum—described as an evening of ‘free adults-only entertainment’—put the spotlight on the study of happiness. One event, a talk by Glenn Wilson, touched on a number of aspects of happiness research. In its modern form, positive psychology is a relatively young field, and it focuses specifically on evidence-based methods for improving happiness.

Positive psychology has a few perhaps obvious things to tell us: being employed (or better, self-employed) and having big, external life goals are all sources of happiness. People with a small group of intimate friends are happier than those with large groups of superficial friends. Commuting is miserable, but being jobless is worse. Negative self-talk is poisonous to happiness, which is why so many treatments for depression focus on quashing it.

There were some strange ones, too: the anticipation of a holiday is more enjoyable than the holiday itself, so perhaps several short breaks are advisable to maximise pre-vacation euphoria. Churchgoing rather than theological belief brings happiness to the religious. And women, in spite of increased equality and opportunity, have been becoming more unhappy for years. This is the counterintuitive dark side of the study of happiness.

But the talk felt trite. Drugs, for example, were quickly dismissed as reducing happiness long-term. Of course, highly addictive drugs like heroin likely produce net unhappiness. But volunteers given psilocybin, the active ingredient of magic mushrooms, overwhelmingly enjoyed the experience—and the majority said it had a lasting positive effect on their lives when asked 18 months later. Few would debate that, while it can be harmful, alcohol’s societal role could be a net good if it encourages people to make friends and enjoy rich social experiences. Yet an honest, evidence-based appraisal of different drugs’ harms and benefits—one that considers the enjoyment they bring as a benefit—is presumably too unpalatable to ever get funding at a time when every nation on the planet has drug prohibition laws of one sort or another.

What of the role of personality in happiness? In a culture where connections and networking are emphasised as crucial to building a career, do extroverts fare better than introverts? Malcolm Gladwell writes extensively about the role of ‘soft skills’ in people’s success—skills which he believes middle-class parents pass onto their children but working-class parents do not—like assertiveness, social graces and other learned behaviours which aren’t formally taught but can drastically alter life outcomes and signal membership of a particular social group, for better or for worse.

Wilson also mentioned the ‘hedonic treadmill’, the notion that people return to a particular happiness set-point over time. Positive life events don’t affect long-term happiness—but nor do negative ones. (That paraplegics are no less happy than the able-bodied in spite of their loss is proof of this.) The hedonic treadmill guarantees that the we have much less control over our happiness than we would like, and that, in the end, it might be impossible to move our happiness significantly away from some immutable mean.

Later in the evening came a brief talk in a tiny, packed room from a curator at the Museum seeking to expand their collections. The resident Historian of Psychology reviewed the history of animal models of addiction. It was a useful lesson in experimental bias: the first animal models of addiction used rats placed in a Skinner box (a metal box with an assortment of levers) to see whether they would prefer to self-administer morphine delivered straight into the brain to to press a lever to get a food pellet. The mice preferred the morphine over food and water, even when they were dying of starvation. Ever since, this has been the prevailing model of addictive drugs - that the sheer force of the desire to consume them is overwhelming.

But a protégée of Skinner’s, Bruce K. Alexander, wasn’t convinced. He worried that by moving caged rats around when they were experimented on, the rats were responding more to the attention they were getting than to the drug, and that the results Skinner had seen were just an artefact of this. He set up Rat Park—an open space with toys, other rats and faux greenery—which he thought more accurately emulated rats’ natural environment. In Rat Park, he found that rats actually preferred water to morphine water, perhaps because the morphine made them asocial and unable to play with other rats. Adding naloxone to the drugged water neutralised the effect of the morphine, and the rats were then happy to drink it.

The outcome probably wasn’t as stark as was presented in the talk—other researchers succeeded only partially in reproducing the experiment—but the result is striking enough. Alexander’s experiments failed to have the intended effect on his peers, though, and the models of addiction he purported to have rubbished live on in contemporary academia. He now spends his days studying human drug addiction through history and anthropology, and his latest book is based on the premise that addiction is a social phenomenon, not a pharmacological one. He wants to ‘reshape society with enough force and imagination’ that people would be able to find meaning in their lives—meaning that he thinks would take the place of addiction in many cases.

Positive psychology is increasingly seen as a highly respected discipline. Studying mood and developing the tools to improve people’s happiness is a noble and ambitious goal. So is Bruce Alexander’s attempt to reframe addiction as a social disease—and to build a new society whose properties don’t allow it to exist. Both require an unflinching devotion to empiricism. But at their core, they are fields driven by a desire to understand what makes people tick, and an ambition to improve the human condition.

The youth of synthetic biology

Sat, 06 Nov 2010 17:00:00 +0000

In May 2010, Craig Venter produced the world’s first ‘synthetic organism’, dealing vitalism a final death blow in the process. Created from a bacterium with its nucleus removed, he inserted an entirely synthetic chromosome bearing DNA famously ‘watermarked’ with quotes from James Joyce and Richard Feynman. The cell promptly took on the identity written into its new genome, like a computer rebooted from a new hard disk.

Understandably, then, you might think that synthetic biology is in its youth. But while making entirely synthetic organisms is very new, genetic engineering definitely isn’t: from the first E. coli cells ‘programmed’ with extra genes to produce human insulin in the late 1970s, tinkering with an organism’s DNA is a decades-old practice. What has changed is the ease and rapidity with which it can be done—Venter’s work, producing a whole genome artificially, being the most extreme example of what’s possible. iGEM, the International Genetically Engineered Machines competition, gives undergraduates a chance to try their hand at real, cutting-edge synthetic biology. Over the course of a few months, they will go from students to genetic engineers, working with other students to produce microorganisms which have never before existed in nature.

Every summer, teams of young bioscientists assemble and, under the guidance of professors at their respective universities, try to build a synthetic organism. They are required to draw from a central repository of BioBricks, genetic building blocks which can be chained together seamlessly in a genetic ‘circuit’ without reworking. Teams can also design their own BioBricks, adding them to the central repository for others to use. Teams present their work online as a wiki and as a presentation at the iGEM jamboree which takes place at MIT. Though there are a number of medals and prizes to be won, the Grand Prize Winner gets to take home the BioBrick trophy which, fittingly, is a large aluminium Lego brick.

A ten-strong team of University College London bioscientists spent their summer working long hours getting their genetically-engineered organism up and running. Though this is only the second time UCL has entered the competition (competing last year with a team of three), their creation is remarkable.

Typically, bacterial cultures grown in fermenters have to be ‘induced’. They first divide again and again, growing exponentially, until their growth plateaus. At this stationary point, where cell growth and cell death are occurring at equal rates, an inducer is added to the mix and the gene of interest is expressed, producing the desired protein—whether that be human insulin or vegetarian rennet. Ensuring the inducer is added at the correct time requires constant monitoring of the culture’s density. The UCL team has developed a modified bacterium that self-induces—senses when the culture’s oxygen levels spike (signalling a plateau in growth) and begins protein production all by itself.

They call it Hypoxon, and UCL’s Biochemical Engineering department thinks it could be a huge hit. Fermenters full of recombinant E. coli are so common that the self-inducing bacteria could be used in thousands of different labs and plants around the world. More importantly, the system works: the team picked green fluorescent protein for their proof-of-concept and sure enough, as the Hypoxon culture reached the right growth stage, the cells started producing the protein and fluorescing under UV light.

The team’s co-operation with the University of Bristol team has already guaranteed them a gold medal at the jamboree, but winning the Grand Prize will be tough. A promising vaccine against stomach ulcers was a previous winner, and this year’s entries include a bacterium for rapid waterborne parasite detection, a project to alter mosquitoes’ gut flora to kill the malaria parasite and bacteria that would produce yoghurt rich in miraculin, a protein which binds to taste buds to temporarily make bitter foods taste sweet.

From the first international competition in 2005, iGEM has grown from 13 to 128 teams. The final award ceremony is now too big to take place on campus; it will instead fill a Boston convention centre. Initially a cute demonstration of the potential of assembling a few genes to make bacteria produce pulses of light, the competition has become an annual maelstrom of innovation and boundary-pushing. And as teams and universities improve their skills, better solutions emerge from their labs, and MIT’s registry of BioBricks grows. The potential of synthetic biology is just beginning to be seen, and it’s young undergraduates who are pioneering some of its most interesting applications. Cut-and-paste biology is getting serious.

First published in the October 2010 issue of Pi Newspaper.

Learning to learn

Sat, 23 Oct 2010 00:43:00 +0100

The approach usually taken to learning is to repeat. A good revision timetable will allow lots of time for reviewing material several times; a bad one will allow less time. With each repetition, each review of a list of bullet points or a slide in a lecture, you learn a little bit more, and the memory sticks a little better. A simple linear relationship between the number of repetitions and the amount remembered.

Except that memory works nothing like this. Linearly spaced repetitions are a poor way of memorising facts. Cramming works, for sure, but only to retain information for a brief period of time. And it’s true: the more you repeat material, the better you learn it. But what if you could invest that same amount of time spent cramming—or endlessly repeating—in a different way? What would be the most efficient way to learn?

Learning is best described in terms of forgetting. Plotting the chance of remembering a fact against time shows something interesting: it’s an exponential decay described as a ‘forgetting curve’, and it explains why even a couple of days after poring over a Latin vocabulary list you can piece together very little of it. The curve makes a rapid path downwards before levelling off. At first, memories fade very quickly.

But every time you review material, not only do you reset your forgetting curve by bumping it back up but you move onto a new, shallower curve. Now you can easily recall reviewed facts for five or six days before they fade. Another repetition, a new forgetting curve. The trick is repeating those facts at the right interval—too early and repetition is ineffective; too late and the memories are already gone.

This is the system that Piotr Wozniak spent the last forty years refining. A Polish memory researcher, Wozniak was frustrated as an undergraduate that he and his fellow students seemed unable to improve their English beyond a clumsy pidgin. Starting from the premise that repeating facts aids in their memorisation, he spent hundreds of hours optimising the best spacing for learning English words and tracking the ease with which he could recall them. By the late 1980s his efforts had been met with failure, but he continued to adjust the spacing between repetitions, mostly on paper or with primitive punch-card programs.

Years later, Wozniak eventually cracked the timing and developed a computer-based method for scheduling repetitions. His algorithm was the basis for his own program, SuperMemo, and later repackaged into more elegant open-source equivalents—Anki being one which remains the king of spaced repetition software.

You enter facts as question-answer pairs, whether a foreign word with its translation, an equation with a solution or a sentence with a fact missing. These pairs are the atomic unit of spaced repetition, and the less information they contain, the better your chance of learning them. You do a daily review, not usually longer than ten minutes, during which you are shown a question, try to recall the answer and then hit ‘show’ to see it. You grade your response; easy cards are scheduled for more distant repeats (they lie on shallower forgetting curves) and hard ones sooner (on steeper forgetting curves).

Digesting material into small question-answer pairs is an irritation, but as reviews are scheduled at increasing intervals determined automatically for each fact, you spend very little time actually reviewing each card. More accurately, you review each fact at the optimal time to strengthen its memory: just as you are about to forget it. The software knows which facts you are on the cusp of forgetting and gives you a prod at the right moment to bring them back to the front of your mind.

This phenomenon—that people learn much more efficiently and remember facts much better when they are spaced at increasing intervals rather than at linear intervals—is the spacing effect. By scheduling your learning in this way you do the fewest possible repeats per item to keep it in your long-term memory. Because of the huge efficiency gain over conventional memorisation methods, Wozniak predicts that most people can learn, and remember forever, a few million such items in a lifetime. Naturally, he sticks to his learning regimen religiously.

Of course, spaced repetition is no magic bullet. Unstructured memorisation will never by itself teach you a language, nor will it get you through your degree. It’s not a replacement for teaching. The usual advice still stands: take good notes, review them often, take pains to understand material you didn’t get first time round. And at first, progress can be slower than conventional methods (you really are better off cramming for that test in a week’s time). But Wozniak’s discovery and the software that makes use of it can help with what many people, at all stages of life, find the most tedious part of learning: bulk memorisation of raw facts.

By the sixth repeat, you now sit on a forgetting curve which projects years into the future. A further couple of reviews guarantees life-long remembering of that fact. Some would argue that they simply don’t want to remember everything they are taught, or don’t have time to break down their whole degree into individual facts. But Wozniak’s goal was never to tell people to remember everything they encounter or to digest whole textbooks into flashcards. With dedication, spaced repetition gives you the power to choose which memories to retain and which to allow to naturally atrophy. Those you do focus on you can remember for the rest of your life.

First published in Pi Newspaper, September 2010.

Pause

Sat, 30 Jan 2010 18:24:00 +0000

Queen Square, London.

It seems strange that, though this square is almost totally silent—not a car and barely a person in sight—I am metres away from hundreds of people, mostly very unwell, lying or sleeping silently in their beds. Most of humanity, and most phases of our lives, are so loud and violent that it seems eerie that so many people could so resign themselves to silence.

Fashionable pharmaceuticals

Fri, 18 Dec 2009 14:58:00 +0000

The pharmaceuticals industry has an obsession with novelty. We want better drugs with fewer side-effects, but too often newness is correlated (wrongly) with an improvement in quality. One new drug that is twice as good at treating an illness as its predecessor is better than five drugs each offering a one per cent improvement on the first. ‘New’ drugs which appear on the market often seem to be derivatives of the well-tested substances which precede them and not genuinely novel drugs.

Consider escitalopram, a relatively new SSRI antidepressant. This is not a new drug in any meaningful way—rather, it is an enantiomerically pure form of the older, off-patent antidepressant citalopram. (In chemistry, a chemical’s connectivity—the order in which groups are bonded to one another—is referred to as its stereochemistry, and chemicals can have different forms or enantiomers as a result of these different ways of connecting the groups together.) Citalopram is a mixture of two enantiomers; isolate one and you’ve got escitalopram.

While escitalopram does seem to have better clinical efficacy at treating depression, it can’t really be said to be new in the way that, say, fluoxetine (Prozac) was when it hit the market in the late 1980s. Fluoxetine was seen as revolutionary when it was introduced, but its efficacy—and that of its more modern siblings—is still only barely better than placebo. Is it possible that nothing better has come along in more than twenty years?

A number of other drugs—amineptine, tianeptine, moclobemide and selegiline among them—have shown great promise in treating depression and, may indeed be suitable for general mood enhancement. Amineptine was withdrawn from the market because of its slight stimulant effects, never to be manufactured again. (Surely a substance which could genuinely and consistently improve one’s mood would be addictive by definition?)

The other three drugs have been shown to be promising antidepressants and mood enhancers but there seems little interest in comparing their efficacy with that of fluoxetine, the de facto treatment for depression in a number of countries. We are eager to test new drugs but no-one is willing to spend money testing ‘old’ drugs. Tianeptine isn’t even licenced for sale in the US, presumably because it is now off-patent and no company has any incentive to push for FDA approval.

Yohimbine is another interesting drug which languishes in scientific obscurity. Potentially quite a useful aphrodisiac and treatment for erectile dysfunction, this study into its effectiveness asks why so little data on it is available, concluding that its off-patent status is a serious disincentive for further investigation into its clinical efficacy:

Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigid human clinical trials. … Recent studies have been designed with a lack of insight and complete disregard of those fundamental studies. … Dose-response investigations are not available, alternative routes of administration have not been investigated… Synergistic activity with other drugs was last studied nearly four decades ago. Assessments of various populations were carried out in very limited cohorts and only in the most general terms. …
Yohimbine is an old drug. As such it does not enjoy patent protection or commercial viability. Until molecular/formulation changes can be brought about … serious investigation of the drug will remain in limbo.

If big pharma isn’t going to look into vintage pharmacotherapies, shouldn’t governments be willing to do so? If the purpose of bodies like NICE is to find the most effective treatment at the lowest cost, don’t they have an incentive to investigate other drugs; to scour the literature for candidate substances and fund studies of drugs which showed promise but were left languishing?

The immortality brigade

Fri, 27 Nov 2009 17:43:00 +0000

A fifty-seat room was never going to be big enough. People fill the aisles, sit on the ground and peer around the door. A man comes in a little late clutching a box bearing the LifeExtension ‘nutriceutical’ brand. Sunlight glints through the windows, dappling the trademark grey-speckled beard and ponytail of today’s speaker, the somewhat notorious Aubrey de Grey. For the next two hours, this room will house discussions of whole-brain emulation, ‘strong’ (self-improving) artificial intelligence and molecular medicine’s promise of immortality. For the moment, this was a room of Singularitarians.

The precise definition of the Singularity depends on who you ask, but popular variations usually involve the principle of exponentially accelerating returns in technology, invoking Moore’s law which states that transistor density, and hence computer speed, doubles every eighteen months. We quickly end up on the nearly vertical slope of the exponential curve, with colossal advances occurring near-instantaneously. At present, we can adapt to new technologies like the internet because they progress relatively slowly. If the scale and pace of modern research caused such advances came much more quickly, humans might have trouble keeping up with the cutting edge.

Consider what might happen if we were able to significantly augment human intelligence with machines. We would then be able to use our newfound intellect to build better machines, which would further improve us, allowing us to further improve on them… A point of explosive exponential increase.

Quite what a post-Singularity world will look like is impossible to say, but the potential payoffs are large: the end of ageing, the ability to augment, back up and restore one’s brain, collective consciousness and a life of leisure enabled by the advent of strong AI are a few of the benefits touted by advocates.

Most striking is the apparent inevitability the advance of computing technology: since its inception in 1965, Moore’s law has held unwaveringly. It presumably has some physical limit above which further improvements are not possible. Some predict that it may not last more than five or ten years more. Of course, such prophesies have been made for the last thirty years, and still processing power grows apparently unabated.

It’s de Grey’s turn to speak. His appearance is no less striking than his talk: he wears a loose, lime-green check shirt, sleeves rolled up, and sports a ponytail and bushy beard that comes down practically to his navel. He resembles a biblical prophet working dress-down Friday at an internet startup. de Grey’s organisation—Strategies for Engineered Negligible Senescence, or SENS—promotes the development of techniques that can maintain and repair the ageing body.

“When this does become a possibility,” de Grey explains, “no government will fail to deliver this technology universally as the cost of maintaining an ageing population is so vast. And when the prospect of immortality is on the cards for all of us, perhaps we’ll take other existential risks—climate change among them—more seriously.”

Strikingly, de Grey presents a model showing that the quality of molecular medicine need only double once every forty-two years to allow those alive today to live forever with sufficient regenerative treatments. “For fuck’s sake,” he exclaims, “that’s the time it took to go from the Hindenberg to Concorde.” Murmurs of approval from the audience, though his talk contains a dispiriting vacuum of information on how sophisticated our abilities currently are or whether any projects in the pipeline are keeping us on track for the goal of immortality within our lifetime.

The debate in the room quickly turns intense, with a gamut of views expressed and discussed. Unsurprisingly, a meeting such as this tends to involve detailed discourse on the vagaries of developing AI or of whole-brain emulation, rather than on the basic feasibility of the Singularity. de Grey expressed his own, rather serious, doubts: a key necessity is the ability for an artificially intelligent machine to recursively improve upon its own intelligence, but de Grey suggested that there might be a mathematical upper limit to the rate of this improvement. Beyond this, though, there is little more than superficial discussion of how likely the Singularity is to come to pass, which for a field as apparently fantastical and potentially revolutionary as this is disappointing.

Even de Grey’s speech on ending ageing went mostly unchallenged, despite the implications his work could have. Many contemporary philosophers, transhumanist Nick Bostrom among them, have opined on the ways in which engineered immortality would radically change the way society operates, but de Grey himself is oddly silent on the matter. This seems surprising—public opinion of Singularitarians seems to be generally apathetic or negative, with the Singularity painted as a ‘geek religion’ of sorts, and views on ending ageing are even less accepting, so those espousing post-human viewpoints need to make the moral case for their convictions. In this room in Birkbeck, though, de Grey is probably preaching to the converted.

The term ‘Singularity’ is likely to see frequent use among technojournalists in search of an impressive but baseless story in the years between now and whenever the Singularity actually comes to pass. An important point is that some of the technological advances promised are very feasible and almost inevitably are right outside the door. Public discussion of the ethical quandries invented along with smart drugs or personal genome sequencing is important if we are to avoid these innovations causing damage rather than good due to imprudent or unscrupulous use.

After a brief adjournment to the Marlborough Arms, the Singularitarians disperse into Bloomsbury. de Grey cycles off to get a train back to Cambridge, beard flowing behind him. For a man who plans to live forever, it’s a little surprising he doesn’t wear a helmet.

First published in a ‘science in London’ feature in Pi Newspaper, November 2009.

Thinking of the children

Mon, 24 Aug 2009 13:04:00 +0100

I was given the task of writing a piece on the primary school science club I help run which is to appear in UCL’s Volunteering Services Unit (VSU) annual review as a showcase of the work the Unit funds. This is what I came up with—comments and suggestions are much appreciated.

The scant paragraph in the VSU’s weekly email asked simply for ‘two or three enthusiastic scientists to assist with running a school science club’. Not wanting to turn down an opportunity to affirm our scientific prowess, four volunteers-to-be enlisted and met for coffees in the Bloomsbury Café opposite the monolithic facade of the Chemistry building.

Under the wing of Dr Andrea Sella, UCL Chemistry lecturer and demonstrator extraordinaire, we set about planning a series of hour-long sessions suitable for the seven- to eleven-year-olds we would eventually be working with. Never short of innovation, UCL’s online learning environment became the electronic home of the Gillespie Science Club as we worked to collaborate on designing sessions and assemble a rota for the four of us, scheduling two people per session while ensuring that everyone was worked evenly as their respective schedules allowed.

The sessions themselves had a central theme—demonstrating the properties of dry ice, making glow-in-the-dark jelly, simulating a scale meteor strike; the usual—and involved giving a brief presentation on what we would be doing and then moving our aspiring young seekers of knowledge to a demo area where we performed our experiment, either a demonstration if dangerous substances were involved or in small groups in which they could each have a go.

The first few sessions went fairly smoothly, though for most of us it was the first time we’d worked with children and our charges’ capacity for belligerence (of the most endearing and inquisitive kind) did, at times, seem unending. After a time, however, something remarkable happened: we started to get comments from parents, some of whom had never before heard of the science club, expressing their admiration for our work. We had, it seemed, gained a reputation as bringers of empiricism—and of fun.

We had not only become men and women of some repute in the primary school community (with Dr Sella, the man behind the scenes, being nothing short of a celebrity) but we gradually learned how best to capture the attention of the students and keep them engaged while developing in them the skills needed of future scientists, and indeed of future non-scientists if they are to fully understand the world around them. Long-winded presentations were a no-no, but any opportunity for the kids to show off their knowledge was lapped up. Some children were louder than others, but with some effort we worked to ensure the quieter ones were heard.

One thing that every one of us noticed and was astounded by was the children’s curiosity. Almost all of our tutees asked lots of questions, some of them very astute, and we did our best to encourage it. Most people, it seems, learn to suppress this curiosity for one reason or another. With luck, there will be ten boys and girls out there who continue to ask questions of their teachers and superiors, and never stop doing so. See if you can spot them.

Pharmacotherapy

Thu, 20 Aug 2009 01:10:00 +0100

I like to think I’m quite good at picking birthday presents. A loaded Oyster card for an aspiring Londoner, a copy of Gray’s Anatomy for a soon-to-be medic, and those trinkets, of little monetary value and which without context would be meaningless but, given to the right person, invoke a fond memory—mementoes of events shared.

For some years I’ve been interested in the writings of David Pearce, a philosopher who describes in lucid detail his vision for eliminating suffering from sentient life. His chef d’œuvre, The Hedonistic Imperative, is a philosophical manifesto proselytising and elaborating upon the moral urgency of this goal and how it might technically be achieved and is as much a philosophical text as a scientific and literary one. He combines mellifluous prose with a solid understanding of the bioscience needed for ‘paradise-engineering’: genetics, molecular biology, nanotechnology and what he lyrically calls “the biochemistry of bliss.” It’s an undoubtedly provocative read.

What better gift, then, for a blossoming polymath?

HI is not yet mainstream, and it’s not available in book form at all. Unafraid of intellectually challenging birthday presents, I set about binding my own copy of the treatise.

The method is not exact, but after looking at as many DIY bookbinding tutorials as I could bear I settled on what I thought was the best and most efficient way of making a hardy, hand-bound book. Typeset in nicely-kerned Helvetica and Univers 45, the book was printed on A4 paper, two-to-a-side, four-to-a-page in eight-sheet signatures (the industry term for a single ‘fold’ of sheets. Have a look at the spine of a commercial book; you’ll see them). Each signature had four holes put through its centre, and with the folded signatures stacked on top of each other they were sewn one to the second, the second to the third and so on; a kettle-stitch.

The book-block assembled, a simple card cover was cut and glued to the spine. A day of drying later and a contrasting navy slip case assembled to protect the book, it was ready for the finishing touch: a decal symbolic of Pearce’s message.

It’s highly stylised, but it’s there: the molecular structure of MDMA, the so-called ‘penicillin of the soul’ the empathogenic-entactogenic effects of which provide perhaps a glimpse of a possible world which Pearce believes, someday, we may inhabit.

For my favourite pharmacologist.

Hello, world.

Tue, 07 Jul 2009 10:28:00 +0100

So, here it is. The very first in what will hopefully become a long line of posts.

Ultimately, I want this to become a corner of the internet I can call my own—part stream of consciousness, part formal essays. The idea that this domain has been unused for years surprises me a little when I think of it, as I classically enjoyed tinkering with my website and showing off my work. Some frisson of self-consciousness must have brought an end to that as it has most of my online projects, but here I am again, come full circle, with a website once more—hopefully a little more refined than the hand-codings of a thirteen-year-old—and with it a new-found online presence.

In a few hours’ time this post will be indexed and cached by Google and the Internet Archive, a fossilised carbon copy of this tract. To some that immortality might be reason alone to publish; to me it’s a reason not to. But then, everyone is afraid of sucking. And everyone is afraid of starting. So let’s begin.