Charting the path to a biologically informed system of mental illnesses
Willa Goodfellow ~ Mar '20
A moonshot exploring the human brain at single-cell resolution
Andrew Neff ~ Mar '20
Mindfulness combats apathy by offering a taste of transcendence
Andrew Neff ~ Feb '20
written and illustrated by Andrew Neff
10-15 minute read
how to Crispr your way to happiness
In the past decade we’ve seen a revolution in gene editing technologies.
We’ve gotten so good at it that even you could do it.
I mean, you’d definitely mess it many times, but you’d pick it up pretty quickly.
Crispr gene editing is allowing scientists to change genes like mechanics change tires,
and it’s primed to revolutionize the way we treat genetic disease.
Once we’re through with the boring stuff
like safety and efficacy studies,
and treating incurable genetic diseases,
then the real opportunity presents itself,
to make ourselves how we wish to be made.
Let’s all be tall and good looking and athletic,
and let’s be smart and nice and funny and happy.
Inside our cells is a molecular universe,
tens of thousands of genes coding for just as many proteins,
each of these molecular machines as fascinating and mysterious as the next,
and the concerted function off all these genes producing miraculous results,
making hearts pump, lungs breath, and brains think.
We are genes,
and the things genes make,
we’d be nothing without them.
At the same time,
we’re also humans,
more than just genes.
Genetic predispositions overlaid with experience.
But how much of us is genes, and how much is experience?
And how much do we know?
As the Crispr revolution ripens,
will the genetics of psychology be ready to provide us some recommendations?
Do we know how we would mutate our genes if we could?
Is a mutant serotonin transporter what made Donald Trump's hair so great?
or why Hillary Clinton owns so many pantsuits?
Is Mark Zuckerberg so annoying because of a few unfortunate gene mutations,
or a few unfortunate experiences?
Were living in scientific reality
where we can edit genes,
all the genes,
in a living adult animal (Yin, 2014).
We’ve now done it in human embryos (Liang, 2015),
and we're not stopping there.
It’s a brave new world out there people,
and if you’re smart,
you’d be preparing for the strange and exciting and terrifying world of human genetic modifications
that we’re soon going to have to acknowledge is nearly upon us.
Are genetics important?
Before scientists invented the magical and wonderful technologies of modern gene sequencing,
researchers cared less about the question of “which genes are important”,
and more about the basic question of “are genes important”.
There were identical twin studies,
either looking at identical twins separated at birth (Tellegen, 1988),
or looking at how similar identical twins are
compared to how similar fraternal twins are.
Some reasons why this research isn’t that great
- the fetus’ experience in the womb seems important (Ryan, 2002).
- identical twins lifetime experiences are more alike than non-identical twins.
not the only way to do this
And there are adoption studies.
Several ways to do this,
one option is to compare how similar biological siblings are
to how similar adoptive siblings are.
Some reasons why this research isn’t that great
- if you don’t snatch the kids up early enough,
early life experience and prenatal effects are going to be a problem.
- adoptive parents are often genetically similar to the adopted child.
not the only way to calculate this.
The biggest limitation to both is that the design is ultimately correlational,
they’re looking at which genes tend to correlate with which traits.
If you really want to prove that something causes something else,
you need to recruit a group of subjects, and randomly perform some manipulation
while trying to control for all other differences,
then see if you get the outcome you’re interested in.
Human research is clearly limited,
we can’t, quite yet, randomly mutate a group of humans.
So this is sorta the best we can do,
but we need to be careful not to confuse best we can do with sufficient evidence.
If you don’t conduct interventional studies,
you start to see relationships between genes and behaviors
that are mediated through something completely different and unexpected.
For example, identical twins are more similar than fraternal twins in personality (Ryan, 2002),
so you might think that genetics accounts some of personality.
But genetics also accounts for appearance.
When it comes to identical twins, they both look the same,
but with fraternal twins, sometimes you get a good-looking one
and a not quite as good looking one.
In this case, the fraternal twins are going to have different experiences growing up,
unfortunately, one’s going to get a lot more attention and be much more liked.
So the genes that you thought accounted for personality
are more understandable as genes that account for physical attractiveness.
For a much more comprehensive, accurate, and interesting review
of behavioral genetics, please watch this video by Robert Sapolsky.
Design-Oriented Science Media:
Skeptical Perspectives, Independently Produced.
Some report on what scientists report - we're here for the real thing.
Support us today on Patreon.
Let’s start mutating
Then again, the future is upon us.
Let's forget about the question of “do genes impact behavior”,
get with the times,
we want to know which genes impact which parts of psychology,
so we can crispr-out the bad ones and crispr-in the good ones.
Let’s say were a bit in the future.
After having proven that Crispr gene editing can be used to cure genetic diseases in adult animals,
which has been done in real life (Yin, 2014),
rogue researchers have started testing crispr gene editing technology
on prisoners and poor people and North Koreans,
or maybe just on people with incurable and debilitating genetic disease.
With these studies,
researchers have proven they can modify the cells of living adult humans
without any serious side effects from the procedure itself,
and maybe cured Cystic fibrosis and Tay-Sachs while they were at it.
But I'm already bored just thinking about that,
so let’s get right to it,
right to psychology and behavior.
Where should we start?
Which genes are we thinking?
BDNF stands for Brain Derived Neurotrophic Factor.
When neurons are grown in a petri dish, if a dash of BDNF is added to that dish,
your neurons tend to survive better, and grow more branches (Hyman, 1991).
Administer BDNF to animals triggers that same neuronal growth,
leading to an increased volume of a brain structure important in memory and emotion
called the hippocampus (Bath, 2012).
Some humans have this particular mutation
that impacts their cells ability to secrete BDNF (Egan, 2003).
this mutation can produce kinda-anxiety-like-behavior (Chen, 2006).
this mutation tends to be associated with impaired memory (Egan, 2003),
reduced hippocampal volume (Bueller, 2006),
and more anxiety (Montag, 2010),
or maybe less anxiety (Lang, 2005),
or maybe neither (Frustaci, 2008).
At this point,
not everyone thinks these studies in humans will withstand further scrutiny (Molendijk, 2012),
mostly on account of small sample sizes and small effect sizes,
and science just generally not being reproducible.
But there is a lot of converging evidence and theoretical support
for the concept that BDNF mutations impact human psychology.
Think we should start out with this one?
COMT stands for Catechol-O-methyltransferase,
it’s an enzyme that metabolizes neurotransmitters like Dopamine and Epinephrine.
Dopamine is involved in a bunch of great stuff,
like producing representations of how much you want things (Berridge, 1998),
and some not as cool stuff like deciding you like things a little too much,
like heroin or instagram (Berke, 2000).
There’s a human mutation that can alter the activity of COMT (Lotta, 1995),
influencing the amount of dopamine you metabolize.
People with this mutant perform a little worse on a psychological test
of mental flexibility called the wisconsin card sorting task (Rybakowski, 2006; Egan, 2001),
although, this may not be true for people with schizophrenia (Barnett, 2007).
COMT mutations might even impact your susceptibility to developing a drug addiction,
although, maybe only for nicotine (Tammimäki, 2010).
How about this one?
5HTTLPR is the 5-HydroxyTryptamine Transporter Linked Polymorphic Region.
Sorry about that,
It’s fairly simple though,
5-hydroxytryptamine is the neurotransmitter serotonin,
you know serotonin right, turkey? sleeping? being happy? sure.
Your neurons release serotonin as a signalling molecule,
and the serotonin that doesn’t bind to another neuron will be transported back into the original cell.
More transporters means faster re-uptake, and less opportunity for serotonin to bind with receptors.
The Polymorphic Region part just means there’s a part of the gene that comes in different forms,
one form produces a lot of serotonin transporter, one form produces only a little bit.
The most common antidepressant drugs prevent serotonin transport,
so it made sense when researchers found that the low-level gene variant
was associated with higher levels of emotional mental illness (Collier, 1996).
It was then also no surprise,
based on the tragedy that is basic research in psychiatry,
when a study looked back on all the subsequent replications
and found there’s probably no association (Culverhouse, 2018).
So I guess this wasn’t the best choice…
There’s a world of other interesting genes out there,
way more than can be talked about here.
Which takes me to an important point.
Psychology is extremely complex,
there’s never going to be one gene that elicits one function.
One of the hard truths we’re having to cope with in psychiatric research,
besides the fact that government agencies have publically
announced that psychiatric diagnoses lack validity (Insel, 2013),
is that there are extremely few examples of a gene for any one thing,
and that fact is making research very challenging.
We’re certainly not ready for gene editing to end unhappiness,
and we’re probably not ready for gene editing in psychology at all,
and probably in most people’s opinions,
we’re not ready for gene editing in humans at all.
But it’s gonna happen.
Remember when you didn’t have the entirety of human knowledge in your pocket?
wasn’t that long ago right?
We are on the brink of being able to use this technology,
and if we, as humans, were able to have any perspective,
we’d be excited and terrified beyond belief.
Good thing is, perspective isn’t something we’re very good at.
The gene editing revolution will come,
23andme will start setting up editing clinics around the country,
and a slickly designed menu will advertise the “heart-health package ”
the “physical fitness package”,
and next to that you’ll see the “emotional welfare package”,
including BDNF, serotonin and dopamine transporters and enzymes,
and that will be that.
Are you ready for it?
Alberts-Corush, Jody, Philip Firestone, and John T. Goodman. "Attention and impulsivity characteristics of the biological and adoptive parents of hyperactive and normal control children." American Journal of Orthopsychiatry56.3 (1986): 413.
Bath, Kevin G., et al. "BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity." Neuropsychopharmacology 37.5 (2012): 1297.
Barnett, J. H., et al. "Effects of the catechol-O-methyltransferase Val 158 Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls." Molecular psychiatry 12.5 (2007): 502.
Berke, Joshua D., and Steven E. Hyman. "Addiction, dopamine, and the molecular mechanisms of memory." Neuron 25.3 (2000): 515-532.
Berridge, Kent C., and Terry E. Robinson. "What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?." Brain research reviews 28.3 (1998): 309-369.
Bueller, Joshua A., et al. "BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects." Biological psychiatry 59.9 (2006): 812-815.
Chen, Zhe-Yu, et al. "Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior." Science 314.5796 (2006): 140-143.
Culverhouse, Robert C., et al. "Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression." Molecular psychiatry 23.1 (2018): 133.
Egan, Michael F., et al. "Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia." Proceedings of the National Academy of Sciences 98.12 (2001): 6917-6922.
Egan, Michael F., et al. "The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function." Cell 112.2 (2003): 257-269.
Frustaci, Alessandra, et al. "Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits." Neuropsychobiology 58.3-4 (2008): 163-170.
Hyman, Carolyn, et al. "BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra." Nature 350.6315 (1991): 230.
Insel, T. "Post by former NIMH director Thomas Insel: Transforming diagnosis." Accessed November 18 (2013): 2016.
Kendler, Kenneth S., et al. "A Swedish national twin study of lifetime major depression." American Journal of Psychiatry 163.1 (2006): 109-114.
Kety, Seymour S., et al. "Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic." Behavior Genetics 6.3 (1976): 219-225.
Kety, Seymour S., et al. "Mental illness in the biological and adoptive relatives of schizophrenic adoptees: replication of the Copenhagen study in the rest of Denmark." Archives of general psychiatry 51.6 (1994): 442-455.
Lang, Undine E., et al. "Association of a functional BDNF polymorphism and anxiety-related personality traits." Psychopharmacology 180.1 (2005): 95-99.
Liang, Puping, et al. "CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes." Protein & cell 6.5 (2015): 363-372.
Lotta, Timo, et al. "Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme." Biochemistry34.13 (1995): 4202-4210.
Molendijk, Marc L., et al. "A systematic review and meta‐analysis on the association between BDNF val66met and hippocampal volume—A genuine effect or a winners curse?." American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 159.6 (2012): 731-740.
Montag, Christian, et al. "The BDNF Val66Met polymorphism and anxiety: support for animal knock-in studies from a genetic association study in humans." Psychiatry Research 179.1 (2010): 86-90.
Notaras, M., R. Hill, and M. Van Den Buuse. "The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy." Molecular psychiatry 20.8 (2015): 916.
Page, Grier P., et al. "“Are we there yet?”: deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits." (2003): 711-719.
Ryan, Bryce C., and John G. Vandenbergh. "Intrauterine position effects." Neuroscience & Biobehavioral Reviews 26.6 (2002): 665-678.
Rybakowski, Janusz K., et al. "Performance on the Wisconsin Card Sorting Test in schizophrenia and genes of dopaminergic inactivation (COMT, DAT, NET)." Psychiatry Research 143.1 (2006): 13-19.
Savitz J, Solms M, Ramesar R. The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav 2006; 5: 311–328.)
Sprich, Susan, et al. "Adoptive and biological families of children and adolescents with ADHD." Journal of the American Academy of Child & Adolescent Psychiatry 39.11 (2000): 1432-1437.
Tammimäki, Anne Emilia, and Pekka T. Männistö. "Are genetic variants of COMT associated with addiction?." Pharmacogenetics and genomics20.12 (2010): 717-741.
Tellegen, Auke, et al. "Personality similarity in twins reared apart and together." Journal of personality and social psychology 54.6 (1988): 1031
Yin, Hao, et al. "Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype." Nature biotechnology 32.6 (2014): 551.
Cajal’s frustration with neuroscience communication
Andrew Neff ~ Nov '19
Appreciating external contributors to mental illness
Natalia Lomaia ~ Nov '19
J.D. Salinger and the science of mantra meditation
Andrew Neff ~ July '19