
Scientists open the ‘black box’ of schizophrenia with dramatic genetic discovery - salmonet
https://www.washingtonpost.com/news/speaking-of-science/wp/2016/01/27/scientists-open-the-black-box-of-schizophrenia-with-dramatic-genetic-finding/?postshare=3091453948817165&tid=ss_tw-bottom
======
brndn
As a person with a family member who suffers from this disorder, this makes me
really happy. It is truly an awful disorder that has very unexpected and
terrible effects on the whole family. I was thrilled to hear Ted Stanley
donated $650M to the Broad institute in 2014. It looks like that donation
could be paying off.

Edit: I'm glad to hear that he learned of this discovery before his death this
month [0].

[0] -
[http://www.bizjournals.com/boston/blog/bioflash/2016/01/broa...](http://www.bizjournals.com/boston/blog/bioflash/2016/01/broad-
donor-ted-stanley-learned-of-schizophrenia.html)

------
afro88
Armchair hypothesis: This aggressive pruning may not have any affect on normal
brain functioning in some cases. For example, it might prune a whole sub
network off the normal day to day network, leaving a "dark" dysfunctional
subnet disconnected from the regular day to day brain's network.

Then, if someone chooses to be under the influence of a drug that enables new
pathways to form (pot, psychedelics etc), this "dark" network can potentially
be reconnected. The emotional response to this connection (good or bad)
strengthens this "bridge" connection, leaving it connected when the influence
of the drug wears off. Now the person has a faulty pruned network as part of
their normal day to day network. Crap.

The trick from here is to reinforce the normal network and ignore signals from
the faulty network until the bridge path's significance subsides enough to not
enter day to day functioning.

~~~
pbhjpbhj
Similarly armchair: An alternative to reducing the bridge might be trying to
actively increase it - the brain reconfigures (right?) so perhaps we can with
careful drug use open up the dark area and allow the regular brain to use that
sector again. The difference between cleaning a room in your house and nailing
the door shut.

Maybe that is in part what is happening anyway? Or is there evidence to show
that the section of the brain becomes under-utilised. (no I didn't RTFA; will
get right on it!)

~~~
loceng
It's knowing how to manage a person or situation once you open up a 'dark'
area; I'd prefer the terminology that an area is 'dark' is rather referred to
as something you're simply conditioned to (or suppressed/repressed) - it's
underneath your conscious level, as otherwise it would leave you less able to
function in day-to-day life.

~~~
justaman
Practicing meditation is a kin to understanding oneself.

"I found it easier than many to accept the epistemological notions of the
world internal and external as dependent concepts enforced by ignorance and
perceptual challenges."

Source:[https://www.reddit.com/comments/1piku6/](https://www.reddit.com/comments/1piku6/)

~~~
loceng
Indeed. Great read, thanks.

------
dang
See also [http://www.nytimes.com/2016/01/28/health/schizophrenia-
cause...](http://www.nytimes.com/2016/01/28/health/schizophrenia-cause-
synaptic-pruning-brain-psychiatry.html), via
[https://news.ycombinator.com/item?id=10983176](https://news.ycombinator.com/item?id=10983176).

------
lazyjones
How do we distinguish the body's reaction to mental illness from its cause?
Wild unprofessional speculation of course, but what if this mass destruction
of grey matter was just an attempt to "fix" improperly wired neurons causing
schizophrenia in a drastic way? The "synaptic pruning" genes might have
evolved as a solution in lineages where schizophrenia was frequently passed
on/caused by parents' behavior. Too silly / crazy?

~~~
jxdjsks
Ive also heard it said in seemingly respectable articles that no one is sure
if the grey matter dies off because of the disease itself or because of the
medication to treat the psychotic symptoms.

~~~
derefr
You'd think you could just look at some posthumous biopsied brains of
untreated schitzophrenics for comparison.

~~~
kaffeemitsahne
Here's a somewhat relevant study:

"The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size
before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine
in Macaque Monkeys"

[http://www.nature.com/npp/journal/v30/n9/full/1300710a.html](http://www.nature.com/npp/journal/v30/n9/full/1300710a.html)

------
astazangasta
Important caveat: this is a genetic association study, which means that a
small but statistically significant fraction of those studied with
schizophrenia have this variant compared to those who do not have
schizophrenia; I.e., this variant is not responsible for schizophrenia in all
individuals, it just might contribute in some. Even that is not clear yet, we
just know the correlation exists.

------
danieltillett
I am really interested to know if this allele (C4A) has been under selection
or not. The fact that it is in the middle of locus of immunological genes
could mean it has just been carried along with the actual selection being for
immune function against infectious disease.

~~~
redwood
Well a lot of mental illness associates with "promiscuousness" (hate that
moralistix word) so there is an easy argument for heritability especially for
onset at peak fertility

~~~
danieltillett
Historically being promiscuous was associated with a low effective fertility.
The reason why is if you are a peasant the resources required to raise a child
to adulthood need both a mother and a father. The children of single mothers
just starved to death.

------
ackfoo
The disordered thinking of schizophrenia invariably reflects the cultural
biases of the individual. Pruning, if that is a cause, must affect the filter
that allows most of us to reject the thousand crazy ideas that pop into our
heads each day, while permitting the few reasonable ones.

This may be why there is an environmental component. If a potential
schizophrenic with an overly-pruned filter is exposed to the idea that a
magical god came to earth and sacrificed himself to give us eternal life, and
if that idea is presented culturally as real, it may be impossible for the
schizophrenic to filter that and place it in the DMZ of fantastical-but-
culturally-prevalent notions that the rest of us use.

Imagine how disordered one's thinking might become if we had no ability to
interpret the spew with "a grain of salt".

~~~
iheartmemcache
The odd thing is that 'disorder' might contribute to one's ability to think
'laterally'. Some schizophrenic tend to exhibit certain amounts of clanging.
In extreme instances it turns into what's referred to as 'word salad'
(presumably the desire to have the alliterative sounds overwhelms one to the
point where one no longer cares about conveying meaning). At the same time, a
'normal' mind definitely appreciates clanging when used as a well executed
literary component (say, exhibited by Larkin or Cummings).

Schizophrenia is a real interesting mental disorder because it touches on so
many other disorders (e.g. speech impediments like echolalia often seen in
those on the autistic spectrum) and it's tendency to exhibit itself relatively
late in life (early to mid 20s is _very_ late for on-set as I understand it
re: mental disorders).

The _Post_ did a pretty good job conveying a complicated concept in an
approachable manner to those who aren't in the field, but as always the
primary source is useful, so here's the pre-print:
[http://www.ncbi.nlm.nih.gov/pubmed/26814963](http://www.ncbi.nlm.nih.gov/pubmed/26814963)

n.b. My father is in the field and I sent this to him when I saw the mention
of Eric Lander (they worked together at Whitehead before Lander left to direct
Broad). He regards Lander as highly as I regard DJB. Often the media blows
things up, I'd imagine these findings are fairly major within their field, if
only because it survived the peer-review process into _Nature_.

~~~
brazzledazzle
What does your father think of the whole CRISPR fiasco?

------
nathan_f77
> In patients with schizophrenia, a variation in a single position in the DNA
> sequence marks too many synapses for removal and that pruning goes out of
> control. The result is an abnormal loss of gray matter.

I find this to be a terrifying thought. Just the idea that I have some code
inside me that's marking synapses for removal, and then they get removed.
Those are my memories!

But I'm very excited about this. I'm not a geneticist by any means, but I hope
the answer is as simple as replacing this gene with CRISPR.

~~~
astazangasta
CRISPR won't help for this, it is too imprecise for gene therapy.

~~~
Obi_Juan_Kenobi
That is incorrect: off-target activity is virtually non-existent in CRISPR-
CAS9 mediated transformation. Targeting oligonucleotides can be deliberately
designed to be less specific, thereby targeting a family of sequences, which
is very desirable for e.g. knocking down a gene family. However, specificity
is trivial to achieve when desired.

~~~
astazangasta
Precision has two components: specificity and sensitivity. While recent
versions of CRISPR make it possible to avoid off-target sequences, its
impossible to guarantee cutting. Also, while you can make a cut, engineering a
specific substitution is still largely a crap shoot. Not suitable for gene
therapy.

------
CamperBob2
I'd be curious to hear how we developed successful pharmaceutical treatments
for schizophrenia without knowing how the disease works. Was it just luck?

~~~
DanBC
I'd go careful with that "successful" label there. Anti-psychotic medications
are good at some narrow range of stuff, but come with considerable side
effects. People with schizophrenia die earlier (by about 20 years) than other
people, and some of that is because of the damage done by medication.

The only reason the medication is used is because untreated psychosis is often
catastrophic.

~~~
dvdcxn
Just look at the effects the anti-psychotics have had on Daniel Johnston. That
it's preferable to untreated schizophrenia shows just how awful schizophrenia
is.

------
tokenadult
As usual, the press releases and the stories based on those somewhat overstate
how far the new study finding takes us on the way to an effective treatment.
One of my mentors is a very eminent psychologist (Irving Gottesman) who has
spent much of his lifetime (he is old enough to be my father, and I am middle-
aged) studying schizophrenia from the genetic point of view.[1] His early
paper with an older collaborator

Gottesman, I. I., and J. Shields. "Schizophrenia: geneticism and
environmentalism." Human heredity 21.6 (1971): 517-522.

was controversial when it was published, because as Freudianism waned, there
was still the supposition among most psychologists then living that parenting
was the single biggest influence on the development of mental illness.

When a behavioral trait runs in families, the working assumption is that it is
passed from parent to child, but the tricky issue to figure out is whether it
is passed mostly by parenting practices (culturally) or by descent
(genetically). Gottesman used to be almost alone among psychologists in
proposing that the greater influence on development of schizophrenia is
genetic, and it took many studies of twins and other close relatives and other
study methodologies gradually to make genetic studies of schizophrenia the
mainstream approach to research.

That said, there are known cases of identical (monozygotic) twins who are
discordant for schizophrenia,[2] so everyone who is active in research on
schizophrenia agrees that environmental influences after birth of some kind
matter in the development of schizophrenia in an individual patient. Moreover,
"the risk to schizophrenia is influenced by quite a large number of common
variants, each with a very small effect on risk. How large is not yet clear,
but Purcell's analyses suggest that hundreds and more likely thousands of
individual genes contribute to the liability to schizophrenia."[3]

The current study, covered in many different popular press reports, indicates
a likely gene locus for influence on one clinical finding found in many but
not all cases of schizophrenia. Discordant identical twins make very clear
that something else matters for the development of schizophrenia. To date, we
are a long way from taking the recent genome analysis finding to a stage of
testing out any kind of intervention in human patients. First we will have to
be sure that the finding replicates in another human patient data set, and
then characterize how often that finding occurs in schizophrenic patients, and
how often it is missing in healthy controls. There will have to be careful
work to find out if any treatment based on the new finding is both safe and
effective. But it's a start, and finding out things like this is the research
to support basic science research.

[1]
[http://www.psych.umn.edu/people/profile.php?UID=gotte003](http://www.psych.umn.edu/people/profile.php?UID=gotte003)

[https://news.virginia.edu/content/irving-gottesman-
retired-p...](https://news.virginia.edu/content/irving-gottesman-retired-
psychology-professor-awarded-groundbreaking-research)

[2]
[http://www.virginia.edu/topnews/textonlyarchive/March_1994/9...](http://www.virginia.edu/topnews/textonlyarchive/March_1994/94-03-10_Identical_Twins_Do_Not_Have_Identical_Risk_of_Mental_Illness,_New_Book_Shows.txt)

[https://www.youtube.com/watch?v=lzDPlktZrGI](https://www.youtube.com/watch?v=lzDPlktZrGI)

[3] [https://global.oup.com/academic/product/how-genes-
influence-...](https://global.oup.com/academic/product/how-genes-influence-
behavior-9780199559909?cc=us&lang=en&)

~~~
antillean
Do you know what the estimate is for the proportion of monozygotic twins that
are discordant for schizophrenia?

~~~
tokenadult
I don't know that off-hand, but the book I cited may provide enough of the raw
data to suggest a magnitude. By memory, I venture to say that more than 10
percent of monozygotic twins of schizophrenia cases (probands) do not have a
schizophrenia diagnosis of their own--but I'll revise this figure if someone
can find a good reference. What's clear in general about the research is that
schizophrenia is a polygenic condition (influenced by many genes) and
multifactorial (also influenced by factors other than genes).

------
amelius
IANAB (not a biologist), so I wonder if the same approach can be used to study
other mental disorders, such as anxiety and depression.

~~~
Obi_Juan_Kenobi
This is a very general technique called quantitative trait association mapping
(such a locus is called a QTL). It's a technique that has been used for
decades, back when we used genetic markers and linkage maps (no genomes).

What's interesting about this work is simply the degree of difficulty finding
QTLs for mental illness; it's not the only genetic factor, and not
particularly strong, so the signal to noise is quite poor. It required
assembling a high-quality data set to identify a locus.

It's good work, but nothing revolutionary. Once you can start to pin down the
genetic factors, it can make future work easier, so it does bode well.

~~~
amelius
Interesting, thanks!

------
bitL
Funny, nature's off-by-one/buffer overflow error...

------
Estragon
Oh, look, another genome-wide association study found a suggestive
correlation. Didn't we learn our lesson about this kind of bullshit in the
Zeros?

~~~
mediocrejoker
Can you elaborate on why you think this particular correlation is not
significant?

~~~
unchocked
In the zeroes, we didn't correct for multiple hypothesis testing in a very
good manner. I don't know if that's changed; it's a hard problem.

------
lutusp
Wait, what? Does this means schizophrenia isn't caused by refrigerator moms,
as psychiatry once claimed
([https://en.wikipedia.org/wiki/Refrigerator_mother_theory](https://en.wikipedia.org/wiki/Refrigerator_mother_theory))?
And that endless therapy won't actually do any good, contrary to what
psychiatrists and psychologists have held?

I expect to watch neuroscience nibble away at the territory now held by
psychology, until (as Lewis Carroll wrote about the Cheshire Cat) there's
nothing left but the smile.

~~~
DanBC
Yes, 70 years ago psychiatry had some odd ideas. It's frustrating that you
only make these comments about psychiatry - you don't pop up in geography
threads to say "Wait, what? Does this mean geographers don't still believe in
fixed immovable continents?".

Endless therapy is not recommended for anything, and certainly not for
schizophrenia. There are recommended lifestyle interventions, but these are
aimed to reduce or stop smoking, to control weight gain, to keep people out of
hospital, or to help people gain and keep employment.

A therapy might be involved if a person is hearing voices, but isn't
particularly bothered by them. In that situation it doesn't make much sense to
medicate away those voices (because the medication has severe side effects) so
the person might get a "therapy" that helps them cope with voices, and learn
when and how to seek help if the voices become too much.

~~~
saurik
Fixed immovable continents is a theory that has reasonable prediction power:
if you assume that, you can do lots of things without having results that are
too inaccurate to be worth calculating. That is not true of the kinds of
highly-specific theories that people seem to be more prone to come up with in
some fields. The kinds of things that even fairly recent "science" in fields
such as psychology and (sadly, all too often) medicine reads more like "the
world is balanced on the back of a tortoise" or "there is an evil genie that
makes things fall to the ground; his name is Fred and he wears a black cape"
than "continents are fixed" or "physics is deterministic, particulate, and
local".

~~~
Tiksi
Well to be fair, having parents be "warmer" to their children and engage with
them more probably also has positive results, regardless of the flawed
reasoning for it.

And yes, young scientific fields quickly disprove themselves, that's kinda the
point of science. Hard sciences like physics and chemistry also had some very
very flawed theories in their youth, like aethers, alchemy, etc. but have had
a few hundred years to get past that.

~~~
gus_massa
> _Well to be fair, having parents be "warmer" to their children and engage
> with them more probably also has positive results, regardless of the flawed
> reasoning for it._

I agree, but imagine this:

You have a children with a bad illness. Then some moron comes and accuses you
of being the cause of the illness. Let's hope he is right, otherwise he
deserves to burn in hell for the eternity. (Or whatever infinite penalty is
compatible with your beliefs.)

------
mc_hammer
Fake and gay.

Founder of psychiatry drove around in a lobotomobile for 40 years giving
lobotomies to haunted people for $25 each.

(With an icepick) (Check the movie/wikipedia lobotomobile)

the treatments since then have gotten only slightly less barbaric, like being
tied down for 20 hours a day, or drugged and locked away.

still none of their bullshit has worked. and 75 - 150,000,000 cases of mental
illness today (if you add the un-reported cases estimate) aka 1/4 the
population (maybe 1/2).

~~~
rangibaby
Can everyone please stop downvoting this guy because he said a bad word? He
appears to have a mental condition, but lots of people do. I found his posts
interesting.

~~~
pc86
Aside from their fondness for PHP and lack of fondness for the shift key, I
see no evidence for mental illness that can be gleaned from internet comments
aside from a few curse words and minority opinions.

~~~
rangibaby
It's something about his pattern of writing that seems different to me. Maybe
I'm just projecting.

~~~
pc86
I mean it's certainly possible I just meant it wasn't obvious to me, that's
all.

