According to a new paper just out in Nature from the prestigious Salk Institute, schizophrenia may be associated with differences in neural wiring which can be observed in cells grown in the lab, thus offering a window into the normally inaccessible development of the human brain.
The paper is here, and here's an open-access Nature news bit discussing it: Schizophrenia 'in a dish'. It's certainly an incredible piece of biology. They took fibroblasts, a cell found in the skin, from 4 patients with schizophrenia and 6 healthy controls.
Using genetically modified viruses, they turned these cells into human induced pluripotent stem cells (hiPSCs), which have the ability to become any other type of cell in the human body. Then, they made those hiPSCs turn into neurons by putting them in a dish with various brain-related chemicals and culturing them for three months. Not entirely unlike those brains-in-a-vat that philosophers like to talk about...
To test the connectivity of these cells, they then infected them with a modified rabies virus, after first infecting them yet another modified virus to make that work. Rabies can only spread from cell to cell via synapses between cells; they could spot the infected cells because the rabies was modified to carry a special fluorescent protein. So they could tell how many connections the neurons made.
What they found was that cultures derived from schizophrenia patients made fewer connections:
The distinct lack of red in the schizophrenia patient's dish shows that the rabies virus was less able to travel from cell to cell; the normal amount of green, yellow and blue shows that this wasn't just because it couldn't get into the cells in the first place.OK, that's extremely cool. But then it gets a bit tricky. They tried adding five different antipsychotic drugs to the dishes for 3 weeks. Four did nothing; one, loxapine, made the cells form more connections. But it's odd that it was loxapine, a drug with unremarkable efficacy, which did this; they also tried clozapine, the only antipsychotic which is verifiably more effective than any others, and it didn't.
Loxapine is similar to (and metabolized to) amoxapine, an antidepressant; that's an issue, I would say, because we already know that antidepressants cause cells to sprout new connections. It would have been good to have used some antidepressants and some other medications as a control.
They did a lot of other work, but the data are hard to interpret. The cells "mis-expressed" about 600 genes, but we're not hold how many genes they tested. 25% of them had been previously linked to schizophrenia, but you could say that of lots of genes: is that more than would be expected by chance alone?
The patients were also unusual. Patient 1 suffered an onset of schizophrenia at age 6, and died by suicide aged 22; childhood-onset schizophrenia is extremely rare. Patients 2 and 3 were brother and sister; this means their data may not be independent, so there are (being conservative) only really 3 patients here.
Overall it's a great idea, a technical tour-de-force, and I'm sure we'll be seeing much more work along these lines on schizophrenia and other neurological and psychiatric disorders. However, as it stands, schizophrenia remains mysterious.
Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, & Gage FH (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature PMID: 21490598Callaway, E. (2011). Schizophrenia 'in a dish' Nature DOI: 10.1038/news.2011.232
15 comments:
Another thing to think about is what these cells 'remember' from ancestor generations. They are changed into iPSC's like you say, but they may still carry some epigenetic changes from when their ancestors were skin cells in the body of a person with schizophrenia. That includes changes related to ancestor cells being exposed to antipsychotic medication. It could be, for instance, that the 'failure to thrive' findings relate to the fact that the schizophrenia brains-in-a-vat were in a kind of withdrawal state after not having had antipsychotics (or nicotine or etc).
I would call it gee-whiz-flash-bang about nothing :). The method is pretty cool, but it gets us no closer to knowing anything about schizophrenia.
So how does this get us closer to understanding and treating schizophrenia?? Just boys with their toys, this time in a petri dish playground. Yawn.
It seems to me, theories of schizophrenia bounce between focus on nature or nurture, and real progress is elusive. I have to disagree with some here, since the results seem to show that there is some physical difference, even if we're not sure just what it is.
One of the ideas I always found interesting, was the "trans-methylation" idea: natural brain chemicals made into or into analogs of things like DMT, 5-MeO DMT, mescaline, and some offbeat chemicals like adrenochrome ("dren chrom" in A Clockwork Orange.) I remember the studies about high doses of Vitamin C and niacin or its amide reversing symptoms of schizophrenia, and also can be used as antidotes for hallucinogens. (I've heard from users, C gives a "smoother trip.) Does it help, and if so why not try it more, even now that we have "truly effective" drugs like clozapine.
Also, in a documentary I heard about some schizophrenics getting relief by dialysis. One who was an artist, would give that up for awhile so she could produce her signature weird art. Wish I could remember more.
"Fine minds make find distinctions."
Too many viruses spoil the genes.
Were they testing viruses or schizophrenia? Did they do cognitive tests on the deceased person? Doesn't seem much thought to the schizophrenia bit. If they were going to relate this to behavioural/neurological/genes phenomena then why not something basic like "smart" people have different cell reactions, but I suppose that wouldn't sell. An artificial cell culture is not a substitute for the real thing when I'm sure they could've obtained real brain tissue. How can one even replicate such a big undertaking and account for all these confounded variables? The use of stem cells smells like a virus experiment. I'm curious as to what their actual experiment was.
Dwight: Good point. Ideally you would want to use cells taken from before they became ill - if they had a blood test for whaetever reason when they were a kid, and the cells were still in a freezer somewhere, that would be handy...
Also, random thought: if this is right, would we expect people with schizophrenia to have a slower progression of rabies?
This seems like a very powerful early diagnostic tool, and also very useful as a way to pre-test personalized medication regimes without the usual trial and error process - at least by drug type.
Biomarker tests for schitzophrenia seem to only have validity in the early symptomatic (or subclinical) stage, while something based on genes could theoretically be done on newborns or two year olds that have a family history of the disease.
It would also be interesting to see if the same technique used to distinguish cells from non-schitzophrenic individuals from cells from schitzophrenic individuals could be used to diagnose subtypes of schitzophrenia or to answer questions like whether schitzophrenia and bipolar are overlapping conditions that just happen to manifest differently in different people or are diagnostically distinct at a genetic level.
Andrew, your comment makes some good points overall (altho, do you realize the find that the reactions of these cells to drugs wasn't always as expected, e.g. loxapine caused more connections but clozapine did not.) However, your frequent use of the odd spelling "schitzophrenia" suggests that's not a typo, and you're one of those heroic types who promtes their own preferred spelling (or, is it influence of another language?) tx
I don't understand the yawns. Many of the coolest breakthroughs in science are quasi-methodological: show that with a relatively new method you can observe changes structure or function. This is clearly not a breakthrough conclusion in schizophrenia research, but it's a phenomenal statement about the ability to ask questions in an unprecedented manner.
It would be like calling calcium imaging or fMRI "gee-whiz-flash-bang about nothing" because it doesn't immediately unveil the computations neurons are performing.
Kevin - spot on!
BTW, what do you know/think of "ortho molecular psychiatry"?
Yes. Pre-treatment cells would be an interesting test for this method -- and lots of other molecular biology questions too. Might be easier logistically (though less compelling) to start with unaffected sibling cells and see whether mini-brains from sibs show an intermediate level of connectivity after culturing, in between the level shown in controls and that shown in probands.
The rabies question is an interesting thought experiment . . .
I think the rabies question would be difficult to determine (unless it could be tracked day to day) because the virus spends such a variable amount of time in incubation and is completely unique depending on where the bite is. Some people have not shown symptoms for years after the infection.
Naive question. I wonder if combining treatment of loxapine with clozapine would show more efficacy than clozapine alone? The loxapine might promote cell growth, which could be beneficial but not enough for some reason.
Next question, have brains of patients on different drug regimins been studied after death to look for differences?
Skm, good point. I think too that in general, people don't consider or try out enough combination regimens becasue of a deep, misdirecting psychological attraction to purity and simplicity.
Fibroblast-derived iPSCs from schizophrenic patients don't wire up "properly" when converted to neurons in culture... Yeah, this paper is a bit of a stretch.
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