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A Neuroscientist reads… Daniel Keyes’ Flowers for Algernon

What was once science-fiction may one day become a reality…

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Charlie Gordon has an IQ of 68. He works in a bakery sweeping floors, and in the evening, he attends adult learning classes delivered by his beloved Alice Kinnian. He’s sweet, he’s kind, and all he wants to do is learn. So when Professor Nemur and Dr Stauss, scientists from Beekman University, approach him and offer him a radical new operation to make him “normal”, he jumps at the chance.

Flowers for Algernon was released as a novel 1966, following the success of Daniel Keyes’ short story first published in The Magazine of Fantasy & Science Fiction. It has gone on to inspire a number of other science-fiction projects, including a 1968 film adaptation. Flowers for Algernon follows Charlie through a series of self-written progress reports, and although not initially aware of his improvement, details his rise from struggling to spell even the simplest words to a sophisticated intellect. Along the way he meets Algernon, a laboratory mouse who also received this innovative surgery who mirrors his profound intelligence.

At first, Charlie relishes his new-found intelligence, connecting on a new level with his teacher Alice and discovering details about his childhood that explain who he is today. However, he quickly becomes disillusioned with the experiment, isolating himself from those he once thought friends and realising he’d spent his life being belittled, ridiculed and dehumanised. He also begins to overtake even those he considered “geniuses”, no longer being able to relate to Alice, the scientists running the experiment, or even the students he once wished to debate with at the local college. But as Algernon’s performance begins to decline, becoming erratic and irritable, Charlie realises with horror that his surgery was not permanent, and he would soon follow Algernon’s decline. In a frantic attempt to make the most of the time he’s got left, Charlie throws himself into working on his own case, finally producing a hypothesis to explain his mind’s own inevitable decay.

Could it really happen?

I will admit that when I started the novel, I knew little of it or its context, not even being aware of when it was written. However, its dystopian feel and the derogatory language used to describe Charlie quickly places this book as a story of science of the past. But despite the clearly science-fiction case presented here, these kinds of experiments were not unheard of in the 1960s. Testing on those believed to have lower social status or intelligence was not uncommon — for example, in the US black patients were used in cancer trials without their knowledge or consent. There were also some disturbing psychological experiments, including the 1971 Stanford Prison Experiment, where volunteers told they were “guards” and hence had power over the “prisons” quickly became sadistic and viciously mistreated their inferiors.

A key theme of both these real-life experiments and Charlie’s surgery is the lack of ethical review that is now necessary for any experiment involving humans. The lack of evidence that the surgery even worked — Algernon was the first mouse to demonstrate a prolonged improvement in intelligence — would have prevented the operation on Charlie from ever taking place. Moreover, Charlie himself points out one the critical flaws of the experiment:

They had made a mistake — of course!… Professor Nemur’s conclusions have been premature. For both Algernon and myself, it would take more time to see if this change would stick.

Progress report 13, p. 124

Charlie realises that the scientists had jumped to conclusions, that they hadn’t proved the increase in either his or Algernon’s intelligence was permanent. If this experiment was to be conducted today, many operated mice would have to be followed over their entire lifetimes to prove its benefit before it could be trialed in humans. Even then, pilot experiments would be needed to check the procedure wouldn’t cause any lasting physical or psychological harm to the animal before it was further tested. These simple observational experiments would now unquestionably be conducted and would likely have prevented Charlie from ever being approached about the experiment.

So the ethics of Charlie’s experiment are obviously questionable. However, the science itself is not too far-fetched. Although the exact method of Charlie’s operation is never explicitly stated, the condition they attribute to Charlie’s cognitive deficits is real and the rough theory behind his intelligence is eluded to:

“We don’t know exactly what causes the type of phenylketonuria that Charlie was suffering from as a child… whatever it was resulted in a defective gene which produces a, shall we say, “maverick enzyme” that creates defective biochemical reactions. And, of course, newly produced amino acids compete with the normal enzymes causing brain damage…

The destruction to the tissue [is] irreversible, not the processes itself. Many researchers have been able to reverse the process through injections of chemicals which combine the defective enzymes… This is central to our own technique as well. But first, we remove the damaged portions of the brain and permit the implanted brain tissue which has been chemically revitalised to produce brain proteins at a supernatural rate–”

Progress report 13, p. 113–14

What this description tells us is that Charlie’s cognitive deficits were attributable to phenylketonuria (PKU), a condition caused by low levels of the enzyme phenylalanine hydroxylase, which results in the neurotoxic build-up of the amino acid phenylalanine. There is some evidence that the effects of PKU can be reduced by a diet low in protein (and hence phenylalanine), according to MRI scans in PKU patients after 9 months of a strict low-phenylalanine diet (Clearly et al., 1995). Moreover, the FDA recently approved an enzyme substitute that reduces blood phenylalanine, although this has yet to be associated with an improvement in mental performance.

Nonetheless, the idea that Charlie received a “chemical injection” that could improve the function of this “defective” enzyme is not beyond the realms of possibility. If a drug could be found to drastically increase the activity of whatever enzymatic capacity Charlie had this may reduce the resultant neuronal damage. However, the idea that this would lead to any substantial structural brain changes in an adult receiving this treatment is unlikely, and his intelligence overshooting that of a neurotypical adult is highly improbable. Nonetheless, modern non-invasive neuroimaging techniques could now be utilised to assess any potential treatment effect — diffusor tensor MRI could be used to analyse white matter tracts and hence connectivity of a brain being treated to “increase intelligence”.

The description also suggests that damaged areas of Charlie’s brain were removed during the operation, to make room of the reconditioned tissue. Classical psychological experiments demonstrate that the physical manipulation of the brain can have an enormous effect on learning and memory. For example, the famous patient H.M. had part of his brain removed in 1953 to reduce epileptic seizures, an operation that left him with profound anterograde amnesia, meaning he was unable to form new memories (Squire, 2009). This experiment was integral to discovering the function of the hippocampus, now thought to be the seat of learning and memory. It is therefore likely that any surgery Charlie would have had would somehow have been aimed at his hippocampi.

Can we actually increase “intelligence”?

Although the procedure undertaken on Charlie is unlikely to result in any real improvement in learning and memory, that’s not to say other methods haven’t been attempted to increase “intelligence”. For example, one study compared the learning ability of mice kept in normal cages compared to those that lived in cages with running wheels. This study found that mice that ran more had more neurogenesis (the birth of new neurons) in the dentate gyrus region of the hippocamp. This was associated with enhanced performance on a number of spatial memory tasks, as well as cellular indications of increased learning capacity (van Praag et al., 1999). Another study also found some task-specific increases in spatial memory in mice with a key protein involved in endocannabinoid neurotransmission “knocked-out” (genetically removed), although this did not translate into a general increase in “intelligence” of the mouse (Kishimoto et al., 2015).

Other, seemingly more radical approaches have also been trialed in animals. For example, in 2014 the world was shocked to hear of a mouse that had had human progenitor cells injected into its brain. The initial 300,000 cells had multiplied to over 12 million astrocytes, a type of support cell found in the brain. These mice performed up to 4 times better than control mice in a number of learning and memory tests. Although the natural mouse neural circuitry was still intact, it is thought that the injected human cells had increased the efficiency of these pathways and hence were allowing the mice to learn faster (Windrem et al., 2014). This is a real-world example of how an injection into the brain, similar to what Charlie would have experienced, produced a real, and this time long-lasting, increase in intelligence in these mice!

So are human astrocytes the way forward in increasing intelligence? Well, analysis performed on Albert Einstein’s brain suggests he had more astrocytes than control subjects in this left inferior parietal cortex, a region of the brain associated with mathematical ability (Diamond et al., 1985). Although these additional astrocytes cannot be shown to be causal in Einstein’s increased intelligence, they show a strong correlation, mirroring what was seen in the mice injected with human astrocytes.

But injecting more human astrocytes into humans is unlikely to ever get through an ethical review — it involves too many fetal neurons and injections into babies to ever be a possibility. But that’s not to say other approaches haven’t be trialed in humans. Several tech start-ups have developed products that can electrically stimulate the brain in hopes of increasing connections and improving learning. In 2016, Kernel announced they would spend $100 million developing an implantable device that could record and stimulate neurons in the hopes of increasing intelligence (read more about it in this New Scientist article). If an implantable device sounds a bit too much like science-fiction, a study in Australia found that electrically stimulating different regions of the brain using a head-set can increase creativity and enhance problem-solving (Chi & Snyder, 2011), just as Charlie and Algernon learned to traverse mazes faster. Aside from electrical stimulation, a number of “smart drugs” are now available on prescription, such as modafinil. However, it’s argued these drugs don’t actually improve your intelligence, they simply increase your capacity to pay attention and study, ultimately improving test scores.

Therefore, although we are some suggestions that we can increase human intelligence beyond that of a normal, healthy adult, these techniques are still in their infancy and will need much more robust testing before it ever becomes routine to increase intelligence in people.

What parallels can we draw from Charlie’s story?

An accelerated and exaggerated case of both intellectual and emotional learning that ended in a rapid cognitive decline. It is easy to draw comparisons to the natural learning and development that occurs as we grow from children into adults that can also decline in old age. This is similarly eluded to in the description of Algernon’s brain in his autopsy:

Compared to the normal brain, Algernon’s had decreased in weight and there was a general smoothing out of the cerebral convolutions as well as a deepening and broadening of brain fissures.

Progress report 16, p. 198

The decreased weight of Algernon’s brain is similar to the progressive atrophy observed in a number of forms of dementia, including Alzheimer’s disease (O’Brien et al., 2001). Smoothing of the brain surface also occurs in lissencephaly, a set of rare brain disorders characterised by extensive psychomotor retardation and an extremely limited life expectancy. In general, the greater the extent of the convolution of the brain surface, the more intelligent the organism, with more-evolved primates having a greater brain surface area than lesser ones (Zilles et al. 1989). Furthermore, brain volume is also known to decrease with normal aging, with MRI imaging showing a 0.22% decrease in brain volume between the age of 20 and 80, with the decline accelerating with age (Fotenos et al., 2008). It is therefore quite feasible that Charlie’s rapid decline could result from catastrophic neuronal loss. Consequently, this life that Charlie had was almost a normal one of rapid learning and development (his childhood and adolescence), followed later by cognitive decline and memory loss (old age). His adult life was simply compressed into a series of months, with the rate of improvement proportional to the rate of decline, which Charlie himself names the “Algernon-Gordon hypothesis”.

Charlie’s story is both heart-breaking and disconcerting. He wished that being intelligent would bring him happiness, but as he becomes more self-aware, he only becomes more isolated and resentful. Moreover, there is a palpable sense of panic as his mind rapidly declines, this time aware of how little he knows and being conscious of what he has lost. Although this story seems unlikely, the reassurance that Charlie’s fate was merely science-fiction is of course just as premature as Professor Nemur’s predictions. Populations are aging, with neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease becoming increasingly common. The feeling of slowly losing your mind is one that we could all one-day face and is simply terrifying. But as medical sciences continue to advance, we may well be able to treat these neurological deficits, with the potential of going beyond our current cognitive capacity. The issue of increasing human intelligence is likely to be a pressing question that society will need to consider in our quest to advance human intelligence in the not too distant future.

References

Chi RP & Snyder AW (2011) Facilitate Insight by Non-invasive Brain Stimulation. PLoS One, 6(2): e16655.

Clearly MA et al. (1995) Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr., 127(2): 251–5.

Diamond MC et al. (1985) On the brain of a scientist: Albert Einstein. Exp Neurol., 88(1): 198–204.

Fotenos AF et al. (2008) Brain Volume Decline in Aging. Evidence for a Relation Between Socioeconomic Status, Preclinical Alzheimer Disease, and Reverse. Arch Neurol., 65(1): 113–20.

Kishimoto Y et al. (2015) Task-specific enhancement of hippocampus-dependent learning in mice deficient in monoacylglycerol lipase, the major hydrolysing enzyme of the endocannabinoid 2-arachidonoylglycerol. Front Behav Neurosci., 9: article 134.

O’Brien JT et al. (2001) Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD and vascular dementia. Neurology, 56(10): 1386–88.

Squire LR. (2010) The Legacy of Patient H.M. for Neuroscience. Neuron, 61(1): 6–9.

van Praag H (1999) Running enhances neurogenesis, learning and long-term potentiation in mice. PNAS, 96(23): 13427–431.

Windrem MS et al. (2014) A Competitive Advantage by Neonatally Engrafted Human Glial Progenitors Yields Mice Whose Brains Are Chimeric for Human Glia. J Neurosci., 34(48): 16153–161.

Zilles K et al. (1989) Gyrification of the cerebral cortex of primates. Brain Behav Evol., 24: 143–50.

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Helen M Collins

Helen M Collins

DPhil Student in Neuroscience at the University of Oxford 🔬 Science 🧠 Neuroscience 🎓 University Life

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