The Science Behind Laura Sichlinger

The Science: Human Induced Pluripotent Stem Cells

Figure 1: Evolution of induced pluripotent stem cells from their neuroprogenitor stage, top images, to their neuron stage, see the bottom images. We can clearly see a change from more concentric and heterogenous shapes to a defined neuron form with its characteristic cell body and elongated axon. Images taken by Laura Sichlinger composition by Laia Mallafré to emulate a Warhol like composition.

Induced pluripotent stem cells, iPSCs, are a subtype of stem cells. Stem cells are a sort of human cells that are not specialized to execute any function. They have two main characteristics they can self-renew i.e., grow, and reproduce indefinitely, and differentiate which means they can become tissue-specific cells. What makes them pluripotent is their ability to differentiate into different tissues depending on the conditions they are exposed to (1).

iPSCs are derived from somatic cells which are all body cells except the gametes i.e., the egg cells and sperm. Their discovery awarded Gurdon and Yamanaka the Nobel Prize in Physiology or Medicine in 2012. The Yamanaka factors (OCT4, SOX2, KLF4 and C-MYC) were discovered in mice in 2006. They are required to transform adult fibroblasts, the skin’s cells, into iPSCs (2).

Since then, these factors have been used to generate pluripotent cells from patient’s fibroblasts or keratinocytes, hair cells, to generate other cell types that are otherwise hard to study like neurons (3). Neurons are the cell type in the brain in charge of communicating information through the central nervous system. Neurons are the final product of this process which we can see in the lower panels of our image. The Yamanaka factors are used to generate the neural progenitors in the top panels of figure 1 from iPSCs. From these neural progenitors we can generate neuroblasts, which are in turn the progenitors of neurons.

Figure 2: Diagram showing the process of generation of neuroblasts, neuron’s progenitors, from iPSCs generated from fibroblasts or keratinocytes from patients. Created with BioRender

This process, see figure 2, will allow us to maintain the unique genetic makeup of the patient’s fibroblasts or keratinocytes (4), which is vital when studying neurodevelopmental disorders and psychiatric conditions that have a genetic component (5) as is our case at the Srivastava lab. Neurodevelopmental disorders are a group of diseases that have an onset in early life stages during development and can affect the central nervous system in terms of learning, intellect, social skills, or executive functions (6).

At the lab, Laura Sichlinger uses this technique generating her model system which she uses to study the development and plasticity of the synapse in the context of psychosis. Psychosis the main feature characterizing schizophrenia spectrum disorders (7), which in turn are characterised by abnormalities in at least one of the following: delusions, hallucinations, disordered speech, motor behaviour and negative symptoms (6).

The Scientist: Laura's Story

Laura Sichlinger is a 3rd year PhD candidate at the N.C.N.D laboratory. Her research aims to uncover the role of a known genetic risk factor in psychosis. More specifically how this factor can affect the development, maintenance, and plasticity of the synapse. But what is a synapse? To put it simply, a synapse is the gap between two neurons through which signals travel from one neuron to the next (8).

To investigate the biomolecular basis of psychosis Laura uses human forebrain neurons generated from iPSCs as a model system, see the science of iPSCs above to refresh your memory on this topic. The forebrain is the outermost part of the vertebrate brain during development (9). Additionally, she uses CRISPR a technique to genetically engineer these cells with the risk factor gene of interest or without it, to investigate how this factor alters the synapse and contributes to development of psychosis.

Laura Sichlinger drawn and designed by Laia Mallafré

Her interest in academia stems from her undergraduate in Speech Sciences and then her Neuroscience master’s and what’s most appealing to her is the notion that new hypotheses and scientific knowledge only can be formed from what other scientists have found. So, to her, ‘science is always a team effort; not only with our current lab members and principal invertigators but also with generations who came before us’.

Aside from her PhD, Laura is involved in the Women of the Wohl, a network of students and staff that aim to promote gender equality in STEM. She believes that to fight discrimination against scientists from diverse backgrounds, we first must acknowledge that problems exist. Women of the Wohl aims to provide a platform to discuss these issues through an intersectional lens, because only through recognition will we be able to find solutions. But as Laura says, ‘we have a long way to go until academia and science are accessible for everyone’.

References

1. Yamanaka S, Li J, Kania G, Elliott S, Wersto RP, van Eyk J, et al. Pluripotency of embryonic stem cells. Cell Tissue Res [Internet]. 2008 Jan [cited 2022 Mar 28];331(1):5–22. Available from: https://pubmed.ncbi.nlm.nih.gov/18026755/

2. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell [Internet]. 2006 Aug 25 [cited 2022 Mar 28];126(4):663–76. Available from: https://pubmed.ncbi.nlm.nih.gov/16904174/

3. Chang EA, Jin SW, Nam MH, Kim SD. Human Induced Pluripotent Stem Cells : Clinical Significance and Applications in Neurologic Diseases. J Korean Neurosurg Soc [Internet]. 2019 Sep 1 [cited 2022 Mar 28];62(5):493. Available from: /pmc/articles/PMC6732359/

4. Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature [Internet]. 2014 Nov 20 [cited 2022 Mar 28];515(7527):414–8. Available from: https://pubmed.ncbi.nlm.nih.gov/25132547/

5. Deng B. Mouse models and induced pluripotent stem cells in researching psychiatric disorders. Stem Cell Investigation [Internet]. 2017 Jul 1 [cited 2022 Mar 28];4(7). Available from: /pmc/articles/PMC5539390/

6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 2013 May 22 [cited 2022 Mar 29]; Available from: https://psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596

7. Arciniegas DB. Psychosis. Continuum : Lifelong Learning in Neurology [Internet]. 2015 Jun 5 [cited 2022 Mar 29];21(3 Behavioral Neurology and Neuropsychiatry):715. Available from: /pmc/articles/PMC4455840/

8. Wong MY, Kaeser PS. Active Zone☆. Reference Module in Biomedical Sciences. 2014;

9. The forebrain - Queensland Brain Institute - University of Queensland [Internet]. [cited 2022 Mar 28]. Available from: https://qbi.uq.edu.au/brain/brain-anatomy/forebrain