When Does Schizophrenia Really

Begin?
Old Ideas Revisited with New Technology

Michael Notaras Ph.D.

NHMRC CJ Martin Fellow
Colak Lab, Center for Neurogenetics
Feil Family Brain & Mind Research Institute
Weill Cornell Medical College, Cornell University

Feil Family Brain & Mind

Research Institute
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

The Growing Societal Impact of Mental Disorders

• 20% of the population will meet the criteria of a 12-month mental disorder
• 45.6% of the population will meet the criteria of a lifetime mental disorder
• Females (48.1%) are more susceptible than males (43%)
Source: ABS (2013) Mental Health Dataset
• Cost to fund all cancer treatments in Aus (2009-10): $4.5 billion
Cost to fund all mental health treatments in Aus (2009-10): $6.45 billion
Source: Australian Institute of Health & Welfare 2009-10 Expenditure Reports
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

The Real Impact of Mental Disorders

Top 10 Diseases Classes Impacting
Disability Adjusted Life Years (DALYs)

Data: World Health Organization; analysis: NIMH.

 Mental Brain Disorders Schizophrenia The Problem New Tech->New Solutions

Mental Brain Disorders Begin Early

UPMC Health Beat Schmitt et al. (2014)

 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

A Primer of Schizophrenia
• Occurs in approx. 1% of the population
• Mean age of onset is early 20s
• Symptoms develop years prior
• Defined by psychosis & cognitive symptoms
• Antipsychotics only effective in 40%~ cases
• No specific treatment for cognitive symptoms
• Cognitive symptoms cause long-term disability
• Causes unknown:
>1000 associative gene variants
“Electricity makes you float”
>Genetic parsing suggestive of biological subtypes Karen Blair, Artist living w/ Schizophrenia
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

When Does Schizophrenia Begin?

Häfner et al.(2017)
 Introduction Project Results Conclusion

Schizophrenia is a Profound Brain Disorder

↓Cortical
↓Cortical
Growth Factors
GABAergic Function

↓Cortical Grey ↓Cortical

Matter Density Oligodendroglia

↑Ventricular
↑Cerebellar
Enlargement
Atrophy (10%)
Mesocorticolimbic
Dopaminergic Function ↑HPA Axis
Reactivity
Nigrostriatal
Dopaminergic Function
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

When Does Schizophrenia Really Begin?

What happens in utero?!? Early Adulthood

Symptoms Emerge
Kesby et al. (2013) Catts et al. (2013)
Mental Disorders Schizophrenia The Problem New Tech->New Solutions

When Does Schizophrenia Really Begin?

 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

The Problem: How do we get “in there”?

Studying Schizophrenia In Utero is objectionable,
1) Because its ethically perverse
2) It’s technically implausible
3) The data would be statistically ambiguous

Stem Cell Tech Offers New Opportunities

Healthy Schizophrenia
Control Patient

iPSCs

Latent iPSC 2D Directed 3D Organoid

Characteristics Differentiation Differentiation

Intrinsic
Limited Disease Exogenous Endogenous
Modelling Cell-Specific Data Developmantal
Programming

Lancaster et al. (2013), Nature

 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

Mini-Brains: They’re Pretty Cool

Footprint of Approximately 430 Cerebral Organoids

MH0159020, NIH control iPSC, ~70 days old

 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

Can We Use 3D Stem Cell Systems to Resolve

When Schizophrenia Begins?
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

If the Mini-Brains Could Speak,

What Would they Say?
Step 1: Let’s stem those cells 🔥🔥💯
Healthy Controls Idiopathic Schizophrenia
Ctrl

Step 2: Let’s grow some mini-brains 🤘 🤘

Scz

Step 3: What’s different about

schizophrenia mini-brains? 🤷♂️ 🤷♂️
🤷♂️
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

What Goes Wrong in the Schizophrenia Mini-Brains?

↑ Neural Stem + ↓ Neurons / Brain Cells 😢

Cell Death 😢
= Smaller Schizophrenia Mini-Brains
Qian et al. (2016), Cell 😢😢
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

What does it matter and who cares?

(i.e. is any of this clinically informative for treating schizophrenia?)
 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

Conceptual & Therapeutic Implications

• Defining pioneer pathology onset as in utero confirms an earlier timeline for disease
• Redrafts treatment: “Ultra Early” intervention becomes rationalized and plausible
• Developmentally staged treatments will be required for full disease prevention
• Schizophrenia is very-likely a special case as a protracted neurodevelopmental disorder

treatment ultra early

intervention

Schizophrenia Risk
Schizophrenia Risk

onset onset

risk
mitigation

in utero Adult in utero Adult

 Mental Disorders Schizophrenia The Problem New Tech->New Solutions

Acknowledgements

☺ Colak Lab ☺
Dr. Dilek Colak
Dr. Megan Allen
Nicole Volk
Nicole Sayles (fmr rotation)
Collaboration
Dr. David Greening (bioinformatics)
La Trobe Institute of Molecular Science

Infrastructure:
Center for Neurogenetics, BMRI,
WCMC Flow Cytometry Core, WCMC Proteomics Core

Funding Source:
National Health & Medical Research Council