|Neurodevelopmental disorders|

Minneapolis, Summer of 2006, a teenager punched me in the butt and my life changed forever.

I was half-way through a 10-week neuroscience undergraduate research program at the University of Minnesota. I had fallen in love with the city and its music scene, and spent a good chunk of my time driving off-campus to concerts.

One evening we were on our way to First Avenue to see local favorites Tapes N’ Tapes when I had to stop for gas. Waiting in line to pay, I heard a primal scream and felt my knees collapse from underneath me. I think someone just punched my butt, I thought, followed by That’s ridiculous, who punches butts in the 21st century?

I turned to see a man in his late 20s struggling to hold back a boy no older than 14. The man looked distraught, the boy enraged and ready to land more punches.

I’m so sorry, man. He can’t help it—my little brother, he has autism, I’m so, so sorry.

I told him I understand and that it was ok, but I lied. I didn’t understand. My knowledge of autism as a 20-year-old rising junior in college was not any more advanced than your average viewer of The Rain Man. I didn’t know that people with profound autism could be non-verbal and lack impulse control. I didn’t know a lot of things, but in that moment,  I knew from the look of anguish in the eyes of that young boy and his older brother that this disorder was serious. I was desperate to learn more, so upon graduation I joined the lab of Dr. Guoping Feng, one of the top experts in autism spectrum disorders and other neurodevelopmental disorders.

As a graduate student in the Feng lab, I used genetically-altered mice to study the defective brain circuitry underlying these diseases. I primarily focused on two mouse genes—Shank3 and Ptchd1. Deletions and mutations in the human SHANK3 and PTCHD1 genes account for a significant proportion of monogenic cases of autism and intellectual disability. Like most human diseases of the brain, the knowledge gap between gene disruption and behavioral symptoms is massive.

I generated and characterized novel conditional Shank3b and Ptchd1 knockout mice to fill in some of the mechanistic blanks. My collaborative work on the Shank3b mouse revealed that these mice have faulty synaptic connections in the neurons linking the cortex to the striatum. We believe that this leads to the repetitive behaviors we observed in these mice, which is a hallmark feature of autism. Subsequent work using this mouse identified dysfunctional cortical inhibitory circuitry and abnormal somatosensory neuron activation, which potentially explain additional symptoms associated with mutations in this gene in humans. In collaboration with Michael Halassa’s lab at MIT, I also observed ADHD-like behavioral abnormalities in the Ptchd1 knockout mouse. We were able to attribute these behaviors to dysfunctional thalamic reticular nucleus activity, which is a brain structure that modulates attention and sleep. I left the Feng lab in 2015 feeling a small sense of accomplishment for detecting potentially disease-relevant circuit defects under very specific genetic conditions, while acknowledging that we have so much to do before our work improves the life of a single human being.

My interest in moving closer to the human condition led me to Kevin Eggan’s lab at Harvard and the Broad Institute. I wanted to study these disorders in the same cell types that are malfunctioning in the brains of individuals with autism (I also developed a severe allergy to mice, so really I had no choice but to switch model systems). In my first year in the lab, I created a new protocol for rapidly and reproducibly generating human neural progenitor cells (NPCs) from stem cell starting materials. NPCs play critical roles in fetal brain development, and the coordinated proliferation and differentiation of these cells is the backbone of normal cortical neurogenesis. It comes as no surprise that the onset of many neurodevelopmental disorders can be traced back to NPCs behaving badly.

In 2019, I received funding from the National Institute of Mental Health in the form of a K99/R00 Pathway to Independence award to use these cells, village cultures, and CRISPR-Cas9 editing to study the 16p11.2 microdeletion syndrome. This disease is caused by the absence of a 29 gene segment of chromosome 16 that results in a range of symptoms including autism, intellectual disability, and macrocephaly. I am hoping to answer questions that could shed light on this disorder and other diseases of neurodevelopmental origin. For example, how do gene expression and signaling pathway activities differ between patients and neurotypical control neural cells? How do these cells behave differently from each other? Can we connect differential gene expression and/or pathway activation to differential phenotypes? Perhaps most importantly, can we correct the phenotypic abnormalities, and does this pave the way for 16p11.2 microdeletion syndrome drug treatments?

Only time will tell. I have high hopes for these experiments—that are ongoing in my independent laboratory at UCLA—while also being fully aware that science is fickle and cares little for my hopes. Nevertheless, it is fully my intention to devote a significant proportion of my laboratory’s efforts to the study of neurodevelopmental disorders of genetic origin. If I am lucky, I might even live to see the day that a therapeutic intervention for profound autism receives FDA approval.