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Genetically Modified Mice: PDE4B Inhibition Increases Intelligence, Reduces Anxiety

Perhaps you’ve heard of the fictional story “Flowers for Algernon” about a laboratory mouse named Algernon.  The mouse undergoes a nootropic-esque surgical procedure that dramatically amplifies his intelligence.  The experiment is deemed so successful, that scientists decide to test the procedure in a human character named Charlie Gordon.

Prior to the artificial enhancement of Charlie’s intelligence, he has a lowly IQ of just 68 – due to a condition known as Phenylketonuria.  Charlie isn’t capable of any cognitively demanding work, and is appropriately employed as a janitor – a menial labor job in a plastic manufacturing facility.  Following the surgical procedure, Charlie experiences a substantial increase in IQ score from an estimated 68 to 204.

Assuming this tripling of intelligence were non-fictional, it would put Charlie Gordon well above Stephen Hawking, Albert Einstein, and chess prodigy Garry Kasparov.  Charlie’s intelligence spike allows him to form relationships with people he never thought possible (e.g. his former teacher), and he begins to realize that he had no true friends due to his retardation; people only wanted him around to make fun of his blunted intellectual capacity.  The story takes an unexpected twist when Algernon’s intelligence begins to significantly regress.

Like Algernon’s regression of intelligence back to his baseline, Charlie’s follows suit – eradicating the transitory enrichment of intellect that he had experienced.  While the story “Flowers for Algernon” has a relatively sorrowful ending, scientists in the real (non-fiction) world may have come up with a more full-proof procedure. This procedure involves altering a specific gene to engineer super-intelligence mice, like an entire fleet of little Algernons.

Genetically Modified Super Intelligent Mice (PDE4B)

Scientists from the University of British Colombia (UBC) were able to alter the genetic code of mice to dramatically enhance their intelligence.  The research was headed by Dr. Alexander McGirr, a medical resident of University of British Colombia’s Department of Psychiatry.  He joined forces with researchers from the University of Toronto, University of Leeds, and MRC Harwell.

The alterations made to the genetic code were not considered complex in that they involved strategic manipulation of just one gene.  Their goal was to determine how manipulation of this gene would influence memory function and cognitive performance in mice.  Results from the study indicated that the mice exhibited significantly less anxiety, as well as dramatic enhancement of memory abilities.

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition (2015)

Intro:  The findings from the study were published in the journal of Neuropsychopharmacology (August 2015 edition).  Researchers noted that PDE (phosphodiesterases) function as regulators of intraneuronal cAMP (cyclic adenosine monophosphate).  Cyclic adenosine monophosphate (cAMP) is an important signaling messenger in the brain derived from ATP (adenosine triphosphate).

Phosphodiesterase-4 is known as an enzyme responsible for metabolizing cAMP.  When PDE4 is inhibited, it prevents the full metabolism of cAMP, which increases levels of intraneuronal cAMP.  It has long been known that administration of cAMP inhibitors elicit nootropic effects, promoting enhanced cognitive function, better long-term memory, and vigilance.  There is some evidence to suggest that PDE4 inhibitors act as neuroprotective agents.

Mechanisms: In this study, researchers honed in on PDE4B, a specific phosphodiesterase involved in the formation of the hippocampal region.  It appears as though PDE4B interacts with DISC1 via binding and is associated with psychiatric abnormalities.  Researchers attempted to isolate the effects of PDE4B inhibition by engineering a mutation of PDE4B (Y358C).

The Y358C mutation of PDE4B results in decreased metabolization of cAMP.  It was also discovered that the mutant form of PDE4B was less likely to bind to DISC1.  The result was that the Y358C mutation promoted CREB phosphorylation and upregulation of both DISC1 and beta-Arrestin within the amygdala and hippocampus.

Results: Behavioral assessments among those with the Y358C mutation of PDE4B revealed that the mice exhibited significantly less anxiety and increased exploratory behaviors.  They also were noted to have enhanced cognitive function across a variety of performance tests involving learning and memory.  Moreover, this specific mutation resulted in enhancement of LTP (long-term potentiation) and impaired depotentiation.

Researchers also documented the fact that the Y358C mice experienced marked increases in the growth of new brain cells via neurogenesis.  It was not noted as to whether BDNF levels were simultaneously increased and may have prompted the neurogenesis.  Fear-memory appeared to be significantly decreased within just one week of the Y358C mutation.

Authors of the study mentioned that the PDE4B-Y358C mutation had no significant effects on forced swim tests nor pre-pulse inhibition.  This research may be considered groundbreaking as PDE4B inhibition may be a novel therapeutic intervention for treatment of anxiety, eliminating fear-based memories (e.g. those associated with PTSD), and enhancing many aspects of cognitive performance.

  • Source: http://www.nature.com/npp/journal/vaop/naam/abs/npp2015240a.html

Effects of PDE4B Inhibition via Genetic Mutation (Synopsis)

Below are all of the effects that were noted from the aforementioned research.  It seems as though PDE4B inhibition via genetic mutation results in decreased anxiety, decreased influence of fearful memories, enhanced cognitive function (learning and memory), and neuroprotection.  Most of the effects are considered conducive to overall performance, but certain traits like decreased anxiety may be less favorable in the wild.

  • Anxiety reduction: Researchers reported that the genetically engineered mice with inhibited PDE4B were significantly less anxious. This anxiety resulted in increased exploratory behavior in the laboratory setting.  The anxiety reduction may have stemmed from a blunting of past fearful memories.
  • Fear-based memory inhibition: When the PDE4B inhibited mice were tested for “fear memory” after one day, they performed better than normal mice for recall of these fearful memories. However, after a full week, they were unable to remember the fearful events.  This means that the mice were less affected by any past fear-provoking experiences.
  • Learning enhancement: The learning abilities of the mice was markedly enhanced as evidenced by superior performance on various tests of cognitive function. Researchers noted significant improvements in memory function as well as learning.  It is likely that PDE4B inhibition resulted in increased cAMP, which increased long-term potentiation and aided the mice in learning.  Mice with this mutation were able to complete tasks that were “impossible” for standard mice.
  • Memory enhancement: One of the primary reasons for testing PDE4B inhibition was to determine whether it could improve memory. The mice were better able to remember locations in a maze, find hidden platforms, and remember mice that they had previously met (suggesting improved social memory).  In addition, they mice appeared to be better problem solvers – indicating an increase in cognitive flexibility.
  • Neurogenesis: Biomarkers revealed increases in neurogenesis, or the ability of the brain to produce new brain cells. Neurogenesis is generally thought to be beneficial for psychological wellbeing and cognitive function, specifically memory formation.  Researchers noted that the genetically-engineered mice had a greater neuron count and the neurons had more connections.
  • Neuroprotective effect: It is thought that the mechanisms associated with PDE4B inhibition may result in prevention of neurodegeneration and brain cell death. While it is unclear as to whether these mice are at reduced risk of developing dementia, most would theorize that this is likely.  The neuroprotection derived from PDE4B inhibition may provide benefit to individuals at risk for neurodegenerative disorders (e.g. Alzheimer’s).
  • PTSD-resistance: Some researchers speculate that the mice may be resistant to developing PTSD due to the fact that they are unaffected by fear-based memories. It appears as though the genetically modified mice are so unaffected by fear or trauma-inducing stimuli such as cat urine.  This modification could be useful for humans living in a world that is less threatening than throughout history.
  • Uninhibited behavior: Despite the fact that a blunting of fear processing may be beneficial for mice in a laboratory setting, it’s probably not as beneficial for these mice in a wild setting. The mice with the PDE4B inhibition weren’t even phased by cat urine, a stimuli that normally provokes fear.  While a majority of the traits associated with PDE4B inhibition are favorable, the lack of response to fearful stimuli may be problematic.

Genetic Modification (or PDE4B Inhibition) in Humans: A Future Reality?

Is it possible that new medical technologies and pharmaceutical developments could transform a fleet of Charlie Gordon’s into an army of Stephen Hawking’s.  That said, it is unknown as to how substantial the increases in intelligence would be solely as a result of PDE4B inhibition.  However, should researchers develop a way to target other genes that may support enhancement of intelligence, perhaps a protocol may create more geniuses.

It is also important to consider that certain humans likely have genetic polymorphisms that support their high levels of intelligence.  Should someone have been born with a PDE4B polymorphism, perhaps modification wouldn’t have any significant enhancement effect on cognitive function.

Possible Methods of PDE4B Inhibition

There are likely a variety of methods to elicit PDE4B inhibition.  After the finding in mice that PDE4B inhibition increases intelligence and decreases anxiety, it is only a matter of time before pharmaceutical companies begin developing and investigating analogues.  Another technique that may be viable for gene inhibition within the next several decades is RNA interference.

  1. Pharmaceutical drugs (PDE4 Inhibitors)

Due to the fact that it is unknown as to whether a similar PDE4B mutation would provide the same benefit in humans as it does for mice, we cannot assume that PDE4B inhibitor drugs would provide anxiolytic and cognitive enhancement effects.  That said, assuming there are parallels between PDE4B inhibition in mice and humans, development of novel PDE4B inhibitors by pharmaceutical companies may be warranted.

An example of an already-developed PDE4 inhibitor is Rolipram, a prototypical antidepressant devised in the 1990s.  Rolipram didn’t survive clinical trials as a result of triggering severe gastrointestinal side effects.  That said, most PDE4 inhibitors are thought to promote cognitive function (long-term memory) and wakefulness, while decreasing inflammation and providing neuroprotection.

Many PDE4 inhibitors are being investigated for a variety of neurological conditions including: anxiety, depression, Parkinson’s, Alzheimer’s, schizophrenia, ADHD, multiple sclerosis, and autism spectrum disorder.  Specifically, PDE4A and PDE4D inhibitors are thought to promote antidepressant effects, whereas PDE4B inhibitors are thought to promote antipsychotic effects.

It appears as though the therapeutic potential of PDE4B inhibitors may (significantly) differ between rodents and humans.  Therefore elucidating the specific therapeutic mechanisms of various PDE4-subtypes in humans is necessary before the development of drugs.  Currently the only PDE4B inhibitor for humans in development is “AN2728” – a drug devised for the treatment of psoriasis and eczema (skin conditions).

That said, PDE4B is thought to play a role in dopaminergic processes and modulation of behaviors related to stress.  It is unclear as to whether certain pharmaceutical agents targeting PDE4B would provide therapeutic relief from certain conditions.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/17933689
  • Source: https://books.google.com/books/about/Phosphodiesterases_as_Drug_Targets.html
  1. RNA Interference

Another futuristic technology called RNA interference (RNAi) is a technique by which RNA molecules are able to inhibit the expression of certain genes.  In other words, it is thought that scientists will be deliberately able to silence maladaptive genes. RNA interference has been successfully demonstrated in nematodes (C. elegans), and will eventually prove therapeutic in humans.

Researchers have determined that small interfering RNAs (called “siRNAs”) with an estimated 21-base-pair double-stranded RNA can promote RNA interference in the cells of mammals without an interferon response.  RNA interference is already being investigated in a small subset of humans to treat cancers via a nanoparticle delivery system.  As this technology continues to improve, and new genetic underpinnings of certain conditions are discovered – expect RNA interference to gain momentum.

Humans could be genetically modified using safe RNAi techniques that target certain genes like PDE4B to alleviate anxiety and enhance cognition.  While PDE4B may not prove to be a therapeutic target in humans, another PDE4 subtype could.  It is important to consider the potential of RNA interference in forthcoming decades.

  • Source: http://www.nature.com/nature/journal/v464/n7291/full/nature08956.html

Potential Uses of PDE4B Inhibition in Humans

Assuming PDE4B inhibition had similar effects in humans as it did the aforementioned group of mice involved in the study, there would be many potential therapeutic avenues worth exploring.  These include the treatment of anxiety, enhancing cognitive function, preventing and/or helping people overcome PTSD, and possibly offsetting likelihood of neurodegenerative diseases.

  • Anxiety disorders: There are a significant number of people diagnosed with anxiety disorders. Even among those without endogenous forms of anxiety, there are many people that are highly prone to anxiety as a result of environmental factors (e.g. working long hours).  Perhaps something like a PDE4B mutation could prevent overwhelming manifestation of anxiety.
  • Cognitive enhancement: It is clear that in the study, PDE4B inhibition resulted in significantly enhanced cognitive function. The mice had better memory functions and problems solving skills compared to those without the mutation.  Should this mutation provide similar cognitive enhancement in humans, many people would likely want it to make them smarter.
  • Depression treatment: With a reduction of anxiety, enhancement of cognitive function, and a decreased sense of overwhelm from fear-filled memories – many people would be less prone to depression. It is known that anxiety in excess can actually trigger feelings of depression.  Perhaps manipulation of this gene could help many people with major depressive disorder.
  • Neurodegenerative diseases: It appears as though the mutation of PDE4B in mice stimulates neurogenesis and increases in long-term potentiation (LTP). This means that new brain cells are being created, and regions of the brain become more interconnected.  While it isn’t known as to whether these mice are less susceptible to dementia, many speculate that they are.
  • PTSD treatment (or prevention): Individuals attempting to overcome PTSD often face incessant flashbacks and fear-based memories of the trauma that they endured. No matter how hard they try to rid their brain of these traumatic thoughts and escape, they cannot.  The person ends up in a high state of arousal characterized by adrenaline rushes, cortisol spikes, and constant fight-or-flight symptoms.  Manipulation of the PDE4B gene appeared to attenuate or inhibit the impact of fear-based memories on behavior and cognition.

Potential Problems with PDE4B Inhibition in Humans

There are some potential problems with PDE4B modification in humans.  Perhaps the biggest problem is that PDE4B in humans is likely far from eliciting the same effects as mice.  While there may be similarities, the differences matter.  In addition, assuming we could safely modify this gene in humans, would it really make a therapeutic difference?  It’s debatable.

  • Different effects than mice: It currently appears as though pharmaceutical PDE4B inhibitors in humans may be useful for the treatment of various skin conditions. That said, humans didn’t undergo similar genetic modification as the mice.  Inhibiting PDE4B with a pharmaceutical agent may yield very different results compared to genetic engineering.  It is important to consider that just because the mice became super smart and less anxious via PDE4B modulation, doesn’t mean humans would.
  • Efficacy: Assuming we could mimic this technique in humans, it is unknown as to whether the anxiety reduction and cognitive enhancement would be significant.  It also wouldn’t be understood as to whether individuals would derive greater benefit than others from this modification compared to others.  Perhaps select humans would actually find that it impairs certain processes.
  • Ethical concerns: Many people would not tolerate modification of human genetics because they’d suggest scientists are “playing god.”  Individuals in opposition to genetic modification would likely be fundamentalist religious groups and right-wing politicians.  In addition, those who may not want the modifications, but feel as if they would be necessary to compete in society may be against the idea.
  • Safety: It is unclear as to whether there are any safety concerns associated with genetic modulation.  It was apparent that responses to fear-based memories changed within a week.  The cumulative neurophysiological changes associated with an engineered PDE4B mutation may be problematic over an entire lifespan (i.e. long-term).  More data regarding the safety of these mutations needs to be collected.

Would you subject yourself to PDE4B inhibition if it was safe and enhanced your cognitive function?

When it comes to genetic modification in humans, it’s not a matter of “if” it’ll occur, it’s just a matter of “when.”  Many fundamentalist religions deny evolution and other science to perpetuate the propaganda associated with their particular creed.  While most of these fundamentalist nutcases are the first to protest things like genetic modification, many of them would be first in line to get a modification procedure done if they were affected by a debilitating condition like dementia.

While they may argue against genetic modification for blatant cognitive enhancement, they may be in support of it for those who have no other option.  Assuming it’s safe, I think everyone should have the right to choose whether they want to modify their genetics – regardless of whether they have an illness.  Someone who wants to make themselves smarter via genetic modification will likely be an asset to society.

As a person who suffers relatively debilitating anxiety and avoidant personality traits, I would certainly allow a procedure like RNA-interference to modulate my PDE4B gene (assuming it was safe and effective).  Feel free to share a comment as to whether you would subject yourself to a PDE4B inhibition via genetic modulation assuming it was safe and effective.  Would you be in support of future children (e.g. your own children) getting this modification before they were born to potentially prevent psychiatric disorders?

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{ 3 comments… add one }
  • navr November 30, 2015, 12:49 am

    Of course I (and million others) would.

  • Alan Sargeson December 31, 2015, 1:43 pm

    If the opportunity gave itself to increase cognitive functions then surely we should take it with open arms. Even at this stage where human trials are necessary to understand the effects, we must progress. I would be first in line to participate in human trials. Science and the revolution we are experiencing in 2015 is clear and present. We must allow our race to progress and understand how we can become better, this surely will help in our longevity. Sign me up for human trials and, I’m sure, millions of others.

  • VVK June 13, 2016, 3:21 pm

    So, where can we sign up for human trials?… Or, how do we know, such trials about to start?

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