Dr. Abha Gupta
Associate Professor of Pediatrics Yale School of Medicine
Postdoctoral Fellow Yale School of Medicine
Residency and Clinical Fellowship Children's Hospital of Philadelphia
MD-PhD University of Pennsylvania
Dr. Abha Gupta found her life’s passion in an issue of Newsweek. Flipping through offhandedly during graduate school, she stumbled upon a one-page article describing autism. She hadn’t heard of autism before but found it piqued her interest. Autism affects many complex cognitive functions, such as abstract thought and self-reflection, and she was curious about the biological mechanisms underpinning these changes in cognition. At the time, she was simply looking for the perfect topic for her upcoming PhD qualifying exam and did not yet realize that this topic would eventually become the focus of her career. Now an Associate Professor of Pediatrics at the Yale School of Medicine, Abha continues to study the biological underpinnings of autism.
Before autism became her major focus, Abha’s general interest in the biology of complex cognitive function emerged during an artificial intelligence course she took as part of her undergraduate curriculum. The class had a section on using code to mimic human decision-making. Although she enjoyed the coding element of the class, she found herself fascinated by this introduction to cognitive science. As this interest developed, she became particularly intrigued by social cognition: how do we think about ourselves in the larger world, how does that influence our interactions with those around us, and how are these represented in the brain?
As she began an MD-PhD program at Penn, Abha hoped to study these questions through the lens of psychiatric conditions. Changes in social cognition and behavior are symptoms of many psychiatric conditions. Abha hoped that studying the molecular processes that go awry in models of these conditions would be a good way to ascertain which molecular processes are crucial to understanding social cognition. However, the investigators leading labs at Penn that focused on these topics discouraged Abha, claiming that the field was too primitive at the time and pursuing a graduate degree in the field was akin to embarking on a doomed fishing expedition. Disheartened by these conversations, she opted instead to do her dissertation research in the ophthalmology lab of Dr. Jean Bennett. Abha thrived in the lab, studying methods of gene therapy for retinal disorders.
At the end of her PhD, Abha was offered a faculty position in the ophthalmology department at Penn upon the completion of her medical degree. This was an incredible offer; the department offered her lab space and start-up money, a very rare opportunity for a freshly minted PhD. However, she was eager to return to her long-standing scientific fascination with the biology of psychiatric conditions, particularly autism. Abha took a risk and turned down the job offer, instead choosing to do her clinical rotations and then residency in the pediatrics department at the Children’s Hospital of Philadelphia to learn more about autism in the clinical realm and how patients’ lives were impacted. This was the first time she had interacted with individuals with autism. Abha’s initial interest in autism primarily stemmed from a desire to study the basic science of social cognition. After her experience in pediatrics, she more viscerally understood the gravity of the diagnosis, and the need for increased research on the topic to help the affected families.
Her determination strengthened by her experience working with families and patients affected by autism, she sought out a lab studying the genetics of autism for her postdoctoral fellowship. She cold-emailed several professors and secured a position at Yale in the lab of Dr. Matthew State. The decision to leave Penn was a challenging one as she had planned to stay in Philadelphia near her parents and begin starting a family. However, she took the leap to pursue this long-held interest. She participated in one of the first large-scale whole-exome sequencing projects aimed at identifying genes associated with autism. The team uncovered a number of potentially causative mutations, including in a gene called EFR3A. EFR3A was more likely to harbor deleterious mutations in those with autism. This gene is involved in the metabolism of phosphoinositides, molecules that are important to signaling at the cell membrane and are crucial players in proper synaptic function.
As Abha transitioned to starting her own lab at Yale, she found her niche focusing on the genetics of understudied populations on the autism spectrum. One of her projects focuses on females with autism. Because autism is less commonly diagnosed in females (four times as many males are diagnosed as females), females are often included in autism research at lower numbers. Abha’s work is playing a crucial role in helping correct this sex bias in autism research. She is leading the genetics portion of a nationwide study characterizing a sex-balanced cohort of individuals with autism using neuroimaging, EEG, and genetic methods. The first comprehensive neurogenetic paper from this study was published in Brain in 2021 and demonstrated that females with autism have larger copy number variants, a particular kind of genetic mutation, than males with autism. These variants were enriched for genes expressed during the development of the striatum. This finding, combined with other neuroimaging work, suggests the striatum may play a particularly important role in female autism.
She also focuses on another subpopulation of the autism community: those with childhood disintegrative disorder (CDD). CDD is characterized by a delayed and profound regression, or loss of previously learned skills, in childhood. While one third of all children with autism show regression of some form, CDD is specifically characterized by a dramatic regression at an average age of four to five years over the span of several weeks to months. These children go from having complex social interactions to becoming nonverbal or speaking only a few words. However, this distinction is lost in the DSM-5, the most recent version of a guide clinicians use to diagnose conditions of the brain. Instead, all autism-related conditions — including CDD — are grouped under the broader “autism spectrum disorder” classification. Although there are some advantages to this broad grouping, information about sub-diagnoses like CDD are lost. CDD may require different treatment than ASD broadly and thus should be studied separately as well. However, it is now harder for researchers to find these individuals for studies or analyze population-level information about the condition, because CDD is no longer being documented in medical records. This change has also affected Abha’s ability to get grants – funding bodies often question the merit of studying a condition no longer listed as a diagnosis. Thankfully, with support from the Simons Foundation - a private organization that funds autism research - she has begun a study using questionnaires and home videos to find a cohort of individuals with CDD from around the world. She hopes in the future to perform neuroimaging and genetic testing of these patients to delve into the neurobiological underpinnings that make this condition so unique within ASD.
Abha has become particularly attached to her work with CDD. She has grown close to the families she has recruited for the study and these deep connections, combined with her long-standing scientific interest, fuel her passion for this research. However, the removal of CDD as an official diagnosis and the funding challenges that arise from this change mean the research is slower. Abha often must tell affected families that she has “nothing new to tell [them].” The “label has disappeared [for CDD],” she implores, but “the families have not.” This experience fielding so many rejected grants impacted her self-confidence, but her commitment to the families helped her persist. If she were to drop her research on CDD, the families will lose a vital source of support.
A recurring theme in Abha’s narrative is her determination to continue working on understudied research topics, even in the absence of reliable funding, easy answers, or clear next steps. A professor once asked Abha, “why would you study autism if you can’t see any clear signs of it in the brain?” Instead of sidestepping the challenge of researching phenomena without clear labels, definitions, or markers - Abha faces it head-on. Working with families navigating these borderlands out of necessity, Abha experiences first-hand the human impact of rare, less characterized conditions and the importance of continuing to try and understand how these conditions arise. It is this dogged patient advocacy and unflinching scientific curiosity that makes her such an exemplary clinician-scientist – one who will continue to push the autism field forward for years to come.
Find out more about Abha and her lab’s research here.
Listen to Sabrina’s full interview with Abha from July 2022 below!
