Welcome to the first instalment of The O' Ryan Lab Research Notes! For anyone new to the page, you can find a brief introduction to this blog series and what it aims to do here. But before I plunge headfirst into our past few years of molecular data, I thought it was important to start by setting the scene - especially against the fairly complex sociological backdrop of autism research.
First, I should say that many more qualified authors have recently discussed the rapidly evolving context of our research with far more expertise than I can. For anyone interested, I have listed some of these references (ranging from formal academic papers to some more informal, really brilliant blog posts, social media platforms and talks) at the end of this post. I am writing from the perspective of a typical PhD student in the biomolecular sciences: I am much better with cells than I am with people, and I feel a bit out of my depth when it comes to writing about the sociological aspects of autism research, even in this more informal context. But the more I read about the current issues at the intersection between the psychosocial and molecular research in the field, the more I think that, maybe, other molecular researchers feel this way too. And maybe that's partly why it has been so difficult for molecular autism research to evolve with its sociological context. So I think it is important to share our journey as a lab, as we are trying to integrate ongoing discussions in the psychosocial fields of autism research, and within the broader autistic community, into the framework for our molecular work.
At this point, I think it is probably necessary to clarify that the language used to talk about autism is still evolving. There is an ongoing debate over whether to use person-first or identify-first language in this context. With reference to this study, here is a quick primer on what these terms mean if they are new to you:
Identity-first language | Person-first language |
|---|---|
I am an autistic person. | I am a person with autism. |
"It defines who I am." | "It's something I have." |
We know that each individual experiences their own autism differently. Here, I am referring to different internal experiences of autism, rather than how autism can present differently externally. This means that each person might prefer to use different language to talk about their own experience. If you would like to read more about some of the nuances to this discussion, ASAN (Autistic Self Advocacy Network) has collated a diverse set of references written by autistic individuals about their different perspectives on this topic. In these posts, I may use person-first and identity-first language interchangeably, because both have their limitations in certain contexts. But I hope you know that this is with an understanding that there is no generic rule that works best for everybody. I think that the only “right” language to use is that which respects the specific experience of each person you are talking to.
" ..there is an increasing recognition of some key limitations in the way molecular autism research was approached in the past .."
As current conceptualizations of autism are being challenged, researchers are changing the way they approach molecular autism research. Some frequent concerns surrounding molecular autism research include the fact that it doesn’t appear to consider autistic experiences or include an element of autistic involvement. Many people are worried about the ethical use of their genetic data, and sometimes, people are unsure why we conduct molecular research in the first place, because it seems to be so far removed from lived experiences.
The growing awareness around these issues has driven an increasing recognition of some key limitations in the way molecular autism research was approached in the past. Previous conceptualizations of autism were based on how it presents externally to neurotypical observers rather than an understanding of internal autistic experiences. Much of the work to-date has also over-relied on the deficits-based medical model of disability. This meant that a lot of the research was based on an idea that therapeutic interventions would aim to decrease external autistic behaviours. As our understanding of autism is evolving, however, it is becoming clear that this is not always a good indicator of health, quality of life or well-being for autistic individuals. To address these limitations, the field is moving towards a more comprehensive integration of the biopsychosocial disability model, incorporating participatory research practices and shifting its goals away from decreasing autistic behaviours and towards improving quality of life.
So, where does our research fit in to all of this?
The subsequent blog posts in this series will go into some of the nitty gritty of our molecular investigations. In this post, I will focus more on the nature of our molecular questions. I think that this is one those things that tends to get lost in translation when it leaves the context of the laboratory. This might cause confusion or harm because context matters when we talk about the aims and directions of molecular research. So, I think it might be helpful for me to briefly "set the molecular stage" before I share how I have been trying to make sense of the convergence of both the sociological and molecular questions that are informing our work.
The underlying molecular aetiology of autism is immensely complex, and when we talk about the autism spectrum as a whole, many people might be surprised to know that there will never be one causative gene or diagnostic biomarker. Consider the 3.2 billion base pairs of DNA and approximately 25 000 genes that make up a human genome. Now imagine the 3.2 billion factorial combinations of different mutations that could occur at each one of those base pairs. But it doesn’t stop there!
The function of each of those genes depends on the regulation of gene transcription, which is the process that converts a DNA sequence into a form that can be used to build proteins. Transcription is controlled by a range of different epigenetic modifications or "DNA tags". These sort of "twirl" the DNA genome into coils called chromatin, and the shape of chromatin alters how genes are expressed. On top of this, each epigenetic mechanism is dependent on interactions between thousands of genes that modulate epigenetic enzymes or "DNA-tagging machines". Even once a gene is transcribed, specific molecular processes have to be tightly regulated to translate that sequence into a protein. After all of that, this protein might need specific modifications before it can function in the way that it needs to.
Importantly, each of these "layers" of gene regulation are different in each different cell type and during each different stage of development. Now consider that interactions between different genes and different "layers" of regulation also change the endpoint function of a protein. Interactions between many functioning proteins will affect the expression of one specific trait or phenotype. Ultimately, autism is a result of interactions between many different traits leading to physiological, psychological, cognitive and emotional differences that are dynamic and context- and life-stage-dependent.
Layers of molecular regulation (Created with Biorender.com): Interactions between genes, epigenetic mechanisms, chromatin structure, and processes that control transcription, translation, and protein modification and function ultimately determine the function of a single cell. Interactions between thousands of different cells and different cell types affect the end point phenotype or trait that is expressed externally. Autism can be understood as a culmination of interactions between lots of different traits that results in the expression of a specific set of support needs and physiological, psychological, cognitive and emotional differences.
This is not to say that molecular research is fruitless. But it is important to understand that molecular research can only aim to peel apart some of these layers to find key molecular players that affect the health of autistic individuals. What we do know is that autistic people have profoundly different underlying molecular signatures compared to neurotypical people. And it is important to understand these differences in order to inform relevant and specific healthcare. So we ask questions like "what is different and why does it matter?" rather than "what causes autism and how can we fix it?". This is with an understanding that distinct physiological and molecular differences in autism can predispose autistic individuals to negative clinical outcomes; like psychopathologies, autoimmune conditions, pathophysiological responses to stress and autistic burnout. People sometimes worry that molecular research considers autism itself a form of "pathology" or "disease", that is in contrast to the "healthy" unaffected control condition. But if we understand that autism is not an intrinsic pathology, we don't consider "health" to be its opposite. The ultimate goal of our research is to promote health in autistic individuals, allowing for the fact that this can look different in different neurotypes.
Here, it is again important to emphasize that different people will have different experiences. This extends to whether each person might consider their autism intrinsically disabling. But an experience of disability often results from interactions between underlying physiology and existing societal structures. Importantly, this is distinct from a diagnosis of pathology, which typically places the "burden of disease" solely on underlying physiological differences. In this context, we are increasingly aware of the need to consider both sociological and underlying biological factors when it comes to understanding disability and this means integrating both psychosocial and molecular research into our work. We hope that this approach can point to the intersection between disparate disciplines, or highlight novel molecular mechanisms that form a link between psychosocial stress and clinical outcomes in autism. Ultimately, we want to ask molecular questions within this biopsychosocial framework to find ways to improve the health and well-being of autistic individuals.
The bio-psycho-social approach to health (adapted from Levy-Storms et al, 2018). Our work aims to use a similar model to explore interactions between molecular mechanisms, socioeconomic structures, and psychosocial stress, and how they impact the health, quality of life and well-being of autistic individuals.
All of that being said, this is a highly complicated, nuanced discussion with no concrete answers. Experts are still debating over how to define ASD. Clinicians are re-evaluating standard diagnostic procedures and therapeutic interventions. And advocates are still unsure if molecular research can ever be translated into something that is useful and transformative for the autistic community. Even as I am writing this, I am thinking of more questions to ask than the field is able to answer. But I hope that what you can take away from this initial discussion is that, as a group, our approach to this complexity is dynamic, evolving, and always open to new viewpoints. We especially understand the value of lived experience - and we want to meaningfully engage with anyone who is involved in, or affected by, our work. We might not have all the answers yet - or anytime soon - but this is just to say that we are asking the questions. And we want you to know that it is always safe and welcomed for you to ask them too.
References & further reading (or "the people who explain it better"):
1. Pukki, H. et al. Autistic perspectives on the future of clinical autism research. PsyArXiv (2022).
2. Jolene Stockman. Autism: How to be normal (and why not to be)| TEDxNewPlymouth. https://www.youtube.com/watch?v=vSLdzdwlb_I
3. Fletcher-Watson, S. et al. Making the future together: Shaping autism research through meaningful participation. Autism 23, 943–953 (2019).
4. Katherine May. Autism From the Inside| Aeon Essays. Psyche. https://aeon.co/essays/the-autistic-view-of-the-world-is-not-the-neurotypical-cliche.
5. Leadbitter, K., Buckle, K. L., Ellis, C. & Dekker, M. Autistic Self-Advocacy and the Neurodiversity Movement: Implications for Autism Early Intervention Research and Practice. Front. Psychol. 12, 782 (2021).
6. More Than One Neurotype | Facebook. https://www.facebook.com/morethanoneneurotype/
7. Milton, D. E. M. Autistic expertise: A critical reflection on the production of knowledge in autism studies. Autism18, 794–802 (2014).
8. Milton, D. E. M. On the ontological status of autism: the ‘double empathy problem’. Disabil. Soc. 27, 883–887 (2012).
9. Mykola Bilokonsky. How To Talk About Autism Respectfully. Public Neurodiversity Support Forum. https://coda.io/@mykola-bilokonsky/public-neurodiversity-support-center/how-to-talk-about-autism-respectfully-84
10. Whiteley, P., Carr, K. & Shattock, P. Research, Clinical, and Sociological Aspects of Autism. Front. Psychiatry12, 560 (2021).
11. Lydia Brown. The Significance of Semantics: Person-First Language: Why It Matters. https://www.autistichoya.com/2011/08/significance-of-semantics-person-first.html
12. Radulski, E. M. Conceptualising Autistic Masking, Camouflaging, and Neurotypical Privilege: Towards a Minority Group Model of Neurodiversity. Hum. Dev. 1–15 (2022) doi:10.1159/000524122.
13. Botha, M. Academic, Activist, or Advocate? Angry, Entangled, and Emerging: A Critical Reflection on Autism Knowledge Production. Front. Psychol. 12, 4196 (2021).
14. Bury, S. M., Jellett, R., Spoor, J. R. & Hedley, D. “It Defines Who I Am” or “It’s Something I Have”: What Language Do [Autistic] Australian Adults [on the Autism Spectrum] Prefer? J. Autism Dev. Disord. (2020)
15. Divan, G. et al. Annual Research Review: Achieving universal health coverage for young children with autism spectrum disorder in low- and middle-income countries: a review of reviews. J. Child Psychol. Psychiatry 62, 514–535 (2021).
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