Oxytocin and its links through scientific lineage

Abstract

Scientific inquiry and methodology are based on third person objectivity. Yet, as humans we experience everything through our first-person lens and second-person relational learning. The purpose of this review is to share the journey of discoveries about science and oxytocin from this author's unique and diverse perspective. Hormones are signaling molecules and long distant messengers required to regulate an organism's physiology and behavior. Oxytocin has taken the lead as the most investigated neurohormone that modulates social cognition, influences parenting behaviors, facilitates within or across-species bonding, and even biologically buffers against stressors such as isolation. Our increasing understanding that social connection, community belonging, and trust in others influence both physical and mental health outcomes, has led to numerous intervention and treatment oxytocin studies across a myriad of conditions. No longer just a way to facilitate female reproduction and lactation, oxytocin is now viewed as the “social influencer” that affects not just women but also men along with its closely related neurohormone, vasopressin. This review uses the narrative lens to illustrate how scientific lineage shapes what we study and how investigating oxytocin has been a microcosm to macrocosm metaphor for our collective social learning as a scientific community.

Highlights

• •Not just for reproduction or lactation, oxytocin influences biology across sexes and behavior across genders.
• •Purpose is to narrate the journey of discoveries about oxytocin and vasopressin through a woman scientist’s lens.
• •Scientific lineage has motivated research on oxytocin-related genetics, biomarker measurement, and clinical trials.
• •Oxytocin buffers stress like isolation and modulates social cognition, affiliative behavior, and relational bonds within/between species.

1. Origin stories

When someone asks about how I got here, I tell them my scientific lineage comes from two moms and a dad. My moms are legends of behavioral neuroendocrinology (Martha McClintock, PhD and Sue Carter, PhD), and my dad is a serotonin maven (Edwin Cook Jr., MD). My moms instilled scientific process and persistence, and my dad reinforced the “so what” questioning to prioritize replication and impact for interventions that are highly needed for brain-behavior disorders. Although I have investigated estrogens, androgens, vasopressin, and serotonin, oxytocin stands out because it taught me how to integrate evolutionary roles with social neuroscience. Of note, serotonin acts like a hormone in the body and should also be considered a messenger hormone even though it is better known as a neurotransmitter [1]. Researching oxytocin and its molecular partners have offered the opportunity to explore behavioral outcomes that have relevance to human development and clinical psychiatry. In this article, I will describe my unique journey, the role of oxytocin, and the transdisciplinary discoveries that I made along the way with my trailblazing scientific families.

My earliest memory of what I wanted to be when I grew up was astronaut or red-cross nurse. A child of the space age, bound paper books, and old movies, my earliest recollections are set at CMC Vellore--an international medical campus in India that was founded by one of the first women who graduated from Cornell Medical School, Ida S. Scudder. Despite coming from a family of medical missionaries and doctors, Scudder did not intend to become another medical missionary [2]. Yet, during a visit to India, three women died during childbirth over the course of one night and she was devastated by not being able to do more to help them. This motivated her to train to be a pioneering female physician and return to India to start a medical school for young women. This learning center eventually became a coeducational haven for medical training and international communities.

At age 4, my family immigrated to Chicago, and I recall the shift of my mental discourse from a global campus landscape with multilingual fluidity to a predominantly-English-speaking, working-class, urban neighborhood. I attribute my love of understanding communities and my continuing quest for experiential adventures to these contrasting settings. Questioning what is true about our internal and external systems and how they work guided my growth into a PhD-trained scientist. My drive to improve lifelong trajectories and community health fueled my journey to become an MD-trained child, adolescent, and adult psychiatrist. I ascribe my earliest interest in nature-versus-nurture, and more specifically neuroscience and genetics, to my left-handedness. Eschewing cultural norms favoring right-handedness, my mother declared that I was allowed to write and eat with my left hand because that is the way I was born, and this is how my brain works. I glimpsed how scientific and non-scientific cultural narratives influence our actions and outcomes and this lesson continues to help me hold complexities in research and beyond. For example, oxytocin genetics may influence oxytocin function during an environmentally-mediated social behavior, and hormone levels may fall within a trait-like inherited range while still increasing during stressful events [3,4].

2. Unmolded or remolded by education

My high school years were spent at an all-girls liberal arts Catholic school in Chicago's south side. The Sisters of Mercy enforced a strict dress code -- plaid-skirted uniforms paired with blouses in only solid blue or white. Even socks that deviated from regulation colors were considered detention-worthy expressions of rebellion. Yet, juxtaposed with these rules for conformity, progressive educators challenged us to think rigorously and broadly with post Vatican II openness. I found my closest friends in an honors-class cohort; they had grandparents or parents who immigrated from Ireland, England, and Italy. I was fortunate to learn in a close-knit environment with the benefit of global perspectives from within highly segregated, white-versus-black streets. Fear and prejudice drew rigid boundaries around our neighborhoods, restricting our exposure to the immense world outside the southside. We humans are both affiliative and subgroup territorial, and looking back through learned lenses, I recognize how oxytocin partners with its close sibling, vasopressin, to continue engaging us in push-pull mammalian behaviors aimed at subgroup survival [5,6].

Despite their restrictive rules of comportment, I am grateful for the freedoms afforded by a liberal arts curriculum that fostered a sisterhood space-time to perform in plays, dance, sing, to study French/Greek/Latin etymology and read the great works of Camus and Molière in their original French. What a privilege it was to be challenged to think critically, speak clearly, write elegantly -- all in a supportive environment where women could do anything they worked to accomplish. My mother taught nursing and her students sometimes came to our home to study for board exams. Inspired by their discussions, I immersed myself in biology coursework to learn details of oxytocin's key role in labor, delivery, and nursing in mammals. I was intrigued when my mom shared that she breastfed me longer than my younger brother because she was swayed by promises of improved health and convenience from the later American formulas. Yet empirical comparisons showed that “newer and faster” do not always mean “better” than traditional practices in maternal [7] and child outcomes [8]. As an immigrant child, I was experienced with holding different times, spaces, and cultures concurrently. Nevertheless, my curiosity impelled me to question societal influences on biological truths. Later in my medical/scientific training, l gained a better understanding of the social influences of oxytocin and its consequences. When humans forget their biological origins and weave elaborate narratives of their own specialness, they ignore their interconnectedness with the evolution of their own body-brain-mind systems and physiological processes.

3. So, what will you be when you grow up?

It is such an odd yet common question to ask children what they want to be when they grow up. A career or job requires you take on a role, but we should never be limited by a single role because we are so much more than a performer of socially-defined tasks. Like Ida Scudder, I didn't want to merely follow the course expected by culture or family. My parents worked at universities in the service and teaching fields of pharmacy and nursing. I initially avoided those “practical” paths. With a passion for books and writing, I envisioned my future as an international journalist or maybe even an art historian. Although I was already fascinated by how biology influences social behavior, I was more inclined to dream of becoming a space explorer or, as a back-up, world traveler. I consumed the contents of my father's National Geographic magazines voraciously and spent many rewarding pre-internet hours in the public library perusing any tomes that caught my eye.

Both my mother and grandmother had long careers as teachers in colleges and secondary schools, respectively. Thus, there was never any question that I would be able to work and have a family like they did. Although my friends’ stay-at-home moms often questioned my independence as a latch-key kid, as a hyper-responsible eldest child I usually went straight home after school to read or watch television. I embraced lessons emphasizing how science is a process of inquiry and not just facts. Growing up before digital access, I waited eagerly for weekends or evenings when I could scour my library for new sources of information and viewpoints. My appreciation of the liberal arts education that I received in high school was critical in my decision to attend the University of Chicago; it was important that I be able to continue broadening my horizons across fields while beginning to hone my studies in scientific processes and methods. On the UChicago campus, I dove into classics, explored core fields of study, and discovered novel concepts like “flow” from innovative faculty [9]. In my undergraduate years, I met incredible peers and lifelong friends, including my then-future husband. It is there where I also met my first scientific mom, Martha McClintock.

Martha guest-lectured in several of my college classes. I'll never forget how she described the post-ejaculatory singing of male rats and how she recorded those songs for analysis. Both wild and laboratory-bred rats were observed in enriched playgrounds constructed to study social and reproductive behaviors. Martha and her students investigated how female rats (and humans) coordinated their reproductive cycles to allow them to birth healthier offspring through communal or sequential timing of nursing and child rearing [10]. When I applied to a combined MD/PhD program, a pediatric endocrinologist encouraged me to train with Martha because of my interest in social neuroscience, just emerging as a distinct field. One unique and especially influential aspect of Martha's approach was that she studied how social behaviors directly modulate our biology in addition to how biology changes our brain-body processes through group interactions. Ultimately, my dissertation research focused on androgen and estrogen metabolites that acted as chemical communicators. I investigated if compounds exerted effects similar to pheromones or undetected olfactory cues to influence mood, perceptions, behaviors, brain metabolism, autonomic nervous system responses, or directly modified biology by shifting variables and phases of the reproductive cycle [[11], [12], [13], [14]].

Although oxytocin was not the focus of my dissertation, I did delve into how single chemicals with slight variations in structure have the cascading and feedback power to alter biology and shift behavioral responses in individuals through social interaction [15,16]. It was a generative time to be in a dynamic academic community. We were able to work on animal and human research alongside remarkable colleagues who studied everything from reptiles to baboons in the wild. Martha applied her funding from a foundation to conduct novel research as she planned her next NIH grant, and we dove into mechanisms of how biobehavioral processes worked in natural environments. Although I was the first MD/PhD student in the lab, I was soon followed by the skillful Natasha Spencer and the very wise Gretchen Hermes, along with other outstanding PhD students from wide-ranging programs in biology and social sciences. My memories hold this as a rare and precious time, a time when we were not under pressure to prematurely deliver treatment targets or engineer over-promising scientific products to sustain and justify our academic existence. Instead, we tried to make discoveries about how biopsychosocial processes worked in real time and how variables changed under specific contexts [13]. Within these environs, the politics and the competition of science were relegated to background while we generated integrative and interdisciplinary work. Meanwhile, molecular advances continued to favor reductionistic methods focused on singular mechanisms without incorporating context and impact.

I juggled several time-intensive research projects and completed my preliminary exams while pregnant with my daughter. Setting up ongoing data collection with my project team of students, I was at our lab late at night before my water broke. The next 48 h felt like a non-stop roller coaster. I was fortunate to have a progressive female obstetrician help me deliver a healthy daughter and avoid the systemic pressures on the staff to speed up the process through surgical and intensivist interventions. Two years of medical school and then two years of graduate school could not have prepared me for the agile flexibility required to be a mother as well as a woman in science. My mother and grandmother had paved the way for working women of my generation. My parents helped babysit so I could work on weekends at the lab in addition to my weekday tapestry of shared childcare. My husband worked and took courses in the evening so we could trade off on primary childcare hours. My nights were filled with my daughter and brief windows to catch-up on highly needed rest. Our lab of extraordinary women and forward-thinking students and friends encouraged me. The Pump-In-Style breast pump that I carried everywhere was met with entertaining reactions each time I went through the library bag checking process. Martha encouraged me to breastfeed or pump with my baby's photo before I gave talks and presentations because the oxytocin would help me feel at ease. I can attest to its calming effect on my public-speaking anxieties, and its anxiolytic properties were recently tracked in a published study [17].

In the 1950s and 1960s, dual degree programs started to develop integrated MD-PhD training programs at top US research universities. I followed the typical trajectory of a four-year liberal arts undergraduate degree, two years of medical science coursework, an initial national board exam, before entering an unmodified and full PhD program. These were the years that I worked with Martha McClintock and met clinical mentors such as Ed Cook. After completing my doctoral and postdoctoral research on how hormones and chemosensory mechanisms affect brain and behavior, I returned to complete my last two years of medical school. True to my origins, I even found a way to fit in two humanities classes during grad-med school to gain insight from the wisdom of philosophy and literature. My scientific tools were enhanced with expert teams in neuroimaging, mood and emotion psychological testing, and autonomic and hormonal measurement with our lab's fine-tuned approach of tracking menstrual and lactation cycles. A unique postdoctoral project was conceived around the time I became pregnant with a second child and then suffered a miscarriage. I recall holding all the complexity of the biology within me as a mother, medical student, and scientist, and the emotions of the complexity of it all – the ebbs and flows of life. With the path I had chosen, I was training to be in a metaphorical ultra-marathon, or more accurately, a never-ending series of triathlons. It gave me the opportunity to view things from multiple perspectives and to pursue a life focused on curiosity-inspired learning through scientific questioning aimed towards discoveries.

With Carole Ober, PhD, and her bioanthropological expertise, we designed a field study to investigate how reproductive physiology and genetics influence mate choice and reproductive outcomes. We had the unique opportunity to study how an isolated, ethnically homogeneous religious group managed to avoid higher rates of miscarriage by choosing spouses who were not too genetically similar to themselves. We found that women preferred the olfactory cues of some men over those of others because of specific genes inherited paternally [18,19]. I have continued to explore the wide-ranging influence of social behaviors on mammalian biology and mate selection [20]; the intricate information passed on by multiple generations of genetic code illustrates how basic biology scaffolds the shaping of behavioral processes. The power of using a transdisciplinary approach to understand genetic mechanisms was what later drew me to study the genetics of oxytocin and vasopressin systems.

4. What's Up, Doc?

MD-PhD students return to medical school after completing their dissertation and two years of intensive and elective clinical rotations, prior to being awarded their MD and starting their medical internship and residency programs. For many, the clinical years of medical school and choosing a specialty are challenging. I relished the earlier “undifferentiated” years when I could explore and discover any and all pursuits with unfettered potential. Yet, experience has shown me that external pressures tend to steer us down increasingly narrow paths. With my training in endocrinology, I expected to learn that oxytocin helps to organize neural circuits in the developing brain that may later influence social behaviors. However, as a true developmental messenger, this remarkable molecule plays multiple roles across systems. For example, oxytocin is integral to the formation of coronary vessels and cardiomyogenesis [21] before it even engages in reproductive and lactation biology. So why should I limit myself? The child who was eager to understand how her brain and genes “made her left-handed” could certainly become a physician-scientist who studies both brain and body development.

Going through my clerkship rotations, I learned about more than medical practice; I also gained insight into the pervading views and cultures in each subspecialty which had to factor into my decisions. Adult medicine and pediatrics were the king and queen of specialties, and this specific patriarchal medical system prioritized the status of affluent adults over stereotyped minorities, have-nots, or children who had limited means or abilities to pay directly for their care. In contrast, most of the rest of the world opted for less individualistic and personal-wealth or employer-wealth based ways to fund healthcare. Having completed a PhD, I found the assertions made in some fields about “what was scientific” or “what was the best way” to be superficial and unsatisfactory. For example, despite proving less efficacious in adults of African or Asian descent, one blood-pressure medication that works well for a European-descendant male served as the universal standard. Without a full understanding of the biophysiological steps resulting in these observed outcomes, we should not draw definitive conclusions about a treatment. It is not sufficient to apply overgeneralized algorithms to treat all patients with medication X when X works differently in individuals A, B, and C. Furthering our knowledge of underlying mechanisms and confounding factors can only serve to expand possibilities and improve care.

I valued rotating in the operating room, loving my time observing and assisting with surgeries, especially neurosurgery. What a privilege to be able to, literally, cut out or mend a problem. These experiences allowed me to learn and collectively assist in anatomical modifications affecting physiological outcomes of health and longevity. Yet the culture of many surgical specialties reminded me of militaristic hierarchies. Even to this day, the subcultures within medical specialties often shift their behavioral norms and expectations based on the clinician's gender or the number of women versus men in the practice group. Even though I loved direct access to the brain, I knew that I would not have enough time to focus on scientific research and discovery if I became a surgeon. Obstetrics and gynecology gave me an opportunity to see so many aspects of reproductive biology including how we treated women and babies. Children were never supposed to die so control trumped compassion and patience to ensure adverse events wouldn't happen under the clinician's watch. The culture of obstetrics and other fields were continually clouded by fear of any negative outcomes. The stigma and fear associated with illness, aging, and death perpetuate a culture of blame and scapegoating in hospital systems. There is much unpredictability in birth outcomes, so oxytocin continues to be used to speed things along [22]. However, manipulating timelines by changing a single variable often gives an illusion of control while its repercussions across many systems have not yet been measured or fully understood [7].

Having studied olfactory systems, I thought an ear, nose, throat specialty would be as fascinating as the neuroanatomy and nasal endoscopy studies we conducted earlier [23]. However, I found end organ specialties like ophthalmology to be a mere window to the brain. Like walking in the neighborhood at night, you could see past the window glass and into decorated rooms only when the lights were on and while it was dark outside. The brain was on the inside and was so central to understanding behavior. With neurosurgery off the list, the final contenders were neuroradiology, neurology, and psychiatry. Although I enjoyed neuroradiology, I did realize that I was not interested in spending five years focused on image reading every other part of the anatomy before getting back to the brain.

If I hadn't completed a PhD in neurobiology, I think I would have chosen neurology for my medical specialty. It was satisfying to be presented with a clinical puzzle that I could solve systematically with a series of exams and tests [24]. If a stroke occurs in one part of the brain, it affects specific neural pathways and the resulting deficits or patterns of behavior could be explained. Before starting graduate school, I'd had the privilege of honor of working with the pioneer of developmental cognitive neuroscience, Peter Huttenlocher [25]. Based on the rich experiences I acquired in the clinics of such a preeminent pediatric neurologist, I thought I had found my calling. However, unlike Peter's clinics, most pediatric neurology clinics saw many seizure patients, some children with headaches, and few rarer disorders.

I completed my psychiatry rotation last because I was uncertain that I would choose it. What I learned was that I enjoyed the non-reductionistic approach and time spent seeing the patient, the family, and even groups “as a whole”. Patients with the same disorders had a variety of symptoms and range of presentations. I needed a large toolbox of biopsychosocial interventions [26] to help patients and their family get better and live more fulfilling functional lives. There was something deeply humanistic about maintaining the art of listening and the skill of observation that was the essence of psychiatry, a focus that had been lost in most other fields. Hence, after completing my fourth-year sub-internship in neurology and a specialty rotation in neuroradiology, I explored residency options in programs that excelled in behavioral neurology as well as psychiatry. A long-time mentor and neuropsychologist thought I should go into neurology. Even my inspiring medicine attendings urged me to consider other specialties than psychiatry. My parents were not thrilled with my choice but knew that I would pursue my passion based on my own explorations and journey. The stigma around mental health issues, patients, and psychiatrists were prominent even amongst my well-educated, beloved clinical mentors. Our medical system favors specialties that bring in money through costly surgeries and procedures; I was shocked to find the financial system offered more reimbursement for clearing earwax than a complex neuropsychiatric evaluation. Yet I followed my gut into a field that embraces complexity, not unlike my pursuit of investigating hormones and social behaviors across the lifespan. Over the years, I have learned that even the perceived certainty of reductionistic science in other fields is illusory because it ignores context and the full range of interdependent factors that produce any outcome.

5. Bridging the divide

It was graduation day, and medical students were given a special ceremony on the lawn in front of UChicago's Crerar library. Throughout my college and graduate years, I'd spent so many hours in this and other beautiful libraries on this campus, with the quiet needed for me to focus without myriad distractions from peers and family. Three months before the end of my fourth year of medical school, my son was born having traveled in utero with me to all my residency interviews and keeping me company in the library as I prepared for the next board exam. Even though I chose midwives to assist and circumvent difficulties, I had a challenging labor and delivery that was delayed into C-section surgery, highlighting multiple problems in our medical systems. I strongly advise women to enlist your support system to ensure you receive sufficient and appropriate perinatal care. When I started residency three months later, I was relieved that I had dissolvable stiches since the traumatic birth experience left me little room to complete optimal post-operative care and its cumulative issues took years to uncover.

Before the graduation ceremony, a male friend approached me who knew me over the latter years of clinical rotations after I returned to complete medical school and after my PhD training. He noted I was the only woman that he knew in our graduating class whose partner would be following her across the country for her career and her program of choice. I was surprised by this observation given the era and that around half of my class was female. He remarked that while all women were doing residencies, they'd prioritized their locations by where husbands or families wanted to be. I, on the other hand, was moving my husband to a new job, moving my children to find new daycare and schools, moving my complicated and messy life far across the country to pursue a top program for my chosen specialty. I was fortunate to have the support of my family, but I still felt a lot of guilt when I made career choices requiring changes that were not the easiest options for them. My tendency is to prioritize the needs of others first and then see if my own desires can also be met. In a me-first male-dominated culture, it is difficult to recognize that there is a continuum of healthy and nonhealthy interdependence. Much more common is to vacillate between the extremes of our societally-lauded independence and then periods of regressive dependence because of our dualistic-minded culture. We so easily fall into following cultural norms and expectations and rarely support someone who does not historically “look the part” to become all that they can be.

6. Why neurodevelopment and father figures

Looking back at my undergraduate years, I pursued research by sliding my resume and cover letter under the door of every psychology faculty member's office in the old gothic-style building that housed the department. Through this effort I was connected to Wendy Heller, PhD and Neil Pliskin, PhD, who were not actually in the department but doing clinical neuropsychology research in the medical center. While working on their project studying the cognitive effects of immunotherapy, I conducted neuropsychology tests at the bedside of cancer patients undergoing novel immune treatments. These skills sparked my self-designed project that became my honors thesis on the hemispheric asymmetry of attention processing of young adults. During this time, I was introduced to several incredible child psychiatrists and future mentors like Ed Cook, MD, Bennet Leventhal, MD, and Kathleen Kelly, MD, along with brilliant PhDs who led clinical research. Wendy's advising connected me to Jerre Levy, PhD, and her integrative perspectives on how hemispheric pathways need to work together for almost everything and how they cannot be taken out of context from the whole. My early questions about my own left handedness and right footedness, ambidextrous brains, and how they were organized similarly or differently from the “typical and averaged right-handed brain” brought me here. With programming guidance from John Metz, PhD, I had the opportunity to design and implement a tachistoscopic task with variables presented only to the left or right visual field to investigate brain asymmetries. Drs. Levy and then Heller were from the direct scientific lineage of Roger Sperry, who also received his PhD from UChicago and was a Nobel laureate for his work with “split-brain" patients. As a developmentalist, I have long been fascinated with what our biological and environmental parents pass on to us as well as how our siblings and cohorts shape us. Our developmental gains and losses are influenced by multidimensional systemic networks. When we hear “the apple does not fall far from the tree”, we overlook the vast distances their seeds can travel through animals that consume their fruit.

So how does this work relate to oxytocin or what I do now? In hindsight, this was where I first saw how clinical practice could be married to scientific investigation for discovery. They were joined with the fierce and furious hope of birthing babies who hold the answers to future treatments and prevention mechanisms. Between completing my rigorous UChicago undergraduate studies and surviving my first two years of medical school, I worked with Carol Gosselink, PhD at La Rabida Children's hospital studying how chronic illnesses like cerebral palsy and diabetes impact caregiver stress and family systems. This taught me qualitive skills about how to interview parents. I also learned about the pain inflicted by losing many months of intense effort with a time-consuming coded dataset to a computer crash. Back up, back up in many places, back up in different formats, and remember to jump back into the work when your memory is fresh. The lessons of loss create deeper grooves in in our minds and memories. After my honors thesis, I continued to work with John Metz, who was the thoughtful, modest, kind, and steady force behind neuroscience projects at the UChicago Positron Emission Tomography (PET) Center. This center housed one of the first four PET imaging scanners and its own cyclotron. It was a nerd haven where I had the privilege of contributing to cutting-edge brain research. These remarkable experiences and mentors motivated me to pursue the MD, PhD program, but only after a brief but memorable international medicine experience in England and some long-awaited travel visiting museums and monuments before medical school.

During the final years of medical school, I had let go of neurosurgery and neuroradiology, but was stuck about whether to choose neurology or psychiatry. Ed Cook, with whom I'd overlapped while working with John Metz in the PET Center, learned of my dilemma and asked me to meet him on the soccer field of his child's game to discuss options. Ed agreed to be my clinical psychiatry mentor and became my scientific dad. His genetics laboratory also trained some of my most beloved child psychiatry siblings, Jeremy Veenstra-Vanderweele, MD, and Soo-Jeung Kim, MD. I later integrated Ed's example of clinical and intellectual drive with my psychology mentors' models of rigorous methodology to measure behavior and its biopsychosocial effects. These mentors included Kate Keenan, PhD, Laurie Wakschlag, PhD, and Sue Carter, PhD, all who embodied the “fire in the belly” drive to pursue scientific questions while creatively juxtaposing their valued family and community roles. How fortunate to have both social and biological scientists who taught me how to dive deep and approach clinical questions by also going as far as we need to go to improve our patients' lives.

7. Home to oxytocin with abundant maternal love

When I met Sue Carter at University of Illinois at Chicago (UIC), I was already a mother of two and held two doctorates, but the medical world of residency-fellowship was intense and my bandwidth for being a scientist-scholar in addition to being a physician was limited. Sue embodied my grandmother and mother's passion for teaching with her deep determination, open-handed ingenuity, rooted humility, and a steadfast focus on her scientific domain like no one else. I thrived under her guidance and generosity, a reprieve from the weight of clinical training and seemingly never-ending hurdles. It was not lost on me that Sue is the mother of oxytocin research from its lifespan influence on mammals such as voles to humans. Sue connected me to leaders in the field as well as to my scientific siblings with multispecies expertise, including my prolific and resilient collaborators, Karen Bales, PhD, and Karen Parker, PhD. With Sue Carter and Ed Cook at UIC, my genotyping and wet lab skills blossomed and provided the opportunity to answer questions about oxytocin and vasopressin through funding from the National Alliance for Research on Schizophrenia & Depression (now the Brain & Behavior Research Foundation), Department of Defense (DOD), and National Instiute of Health (NIH).

8. The promise of genetics

By adding a genetics research-focus year to my final clinical fellowship year, I pipetted, PCR'd (polymerase chain reaction technology), and thoughtfully designed assays for the carefully obtained samples of families affected by autism. The phenotyped samples from early family studies spanned Cathy Lord, PhD, and her Chicago years of diagnostic refinement with the Autism Diagnostic Observation Scale (ADOS) and Autism Diagnositc Interview (ADI and ADI-Revised) instruments, to the Cook lab's careful following of cohorts with comprehensive assessment, and later to multisite consortia level collaborations. My extensive genotyping experience with - SNPs (single nucleotide polymorphisms), CNVs (copy number variations), and microsatellite regions was earned working at the bench alongside Kathy Hennessy, lab manager extraordinaire in the Cook lab. Ed was one of first to investigate the genetics underlying autism and other psychiatric disorders. Of note, genetic samples can sit at room temperature and became increasingly easy to access and assay as we moved from blood to saliva collection strategies with human research. Much easier than temperature and time sensitive peptide oxytocin assays that I also learned to do. Later as faculty and with my genetics background, I became the co-director of the wet lab with Ed and I valued the rigor of the wide-ranging methods we used to sample, genotype, and phenotype large populations for our studies.

Given the regulatory role that both oxytocin (OXT) and vasopressin (AVP) play in mammalian social and affiliative behaviors, it made sense to explore genetic variation and risk with autism spectrum subphenotypes and diagnosis. With high estimated autism heritability in twin studies [27], genetic linkage, genome-wide associations, and gene expression studies have explored individual genes as well as different genetic mechanisms (SNP mutations, CNVs, chromosomal abnormalities) contributing to ASD phenotypes [[28], [29], [30]]. Our laboratory found that significant associations between the oxytocin receptor (OXTR) and ASD vulnerability varied by population differences in allele frequencies. Specifically, the G allele in Caucasian populations and and the A allele in Chinese Han populations had an increased association with ASD vulnerability in SNP rs2254298 [31]. This variation suggested that mechanistic and functional outcomes of specific allele variations needed further study across ethnic variances. This region could also be in linkage disequilibrium with another yet unspecified susceptibility variant. Later work highlighted that the level of social functioning versus diagnostic category may be a better phenotypic association with some of these OXTR SNPs [32].

In follow up autism studies, my laboratory showed that that rs2254298 was significantly associated with the ADOS domain of social affect and its alleles were part of the significantly associated haplotypes [33]. Phenotypic measures of social dysfunction (e.g., ADOS social affect domain and ABC's social withdrawal) capture more specific subphenotypes of ASD and widen oxytocin's potential role in other disorders affecting social development. Fewer studies have investigated the many genes of the OXT/AVP pathways, and our lab demonstrated that SNPs near OXT and AVP are associated with ASD related social behaviors and repetitive behaviors, IQ, plasma oxytocin, and whole blood serotonin WB5HT [34]. Earlier, collaborations with Elizabeth Hammock allowed us to compare both human and Oxtr knock-out mouse data to demonstrate how serotonin and oxytocin systems interact during development in autism [35]. Subsequent animal research has connected the coordinated activity of oxytocin and serotonin (5-HT) in the nucleus accumbens showing their essential roles in the social reward system [36].

My focus on OXT and AVP genetic variation and ASD risk associations were initiated when mechanism-inspired candidate gene studies were frequent, genome-wide technology was emerging, and before an “agnostic approach” via computation became the favored method over hypotheses driven studies. Watching methods and hot topics come and go, I have learned not to throw the baby out with the bathwater. With new approaches, the perceived promise is overexuberant because we have yet to find methodological flaws. The best science is often multimethod and rigorously challenges findings from every angle as new discoveries emerge. In retrospect, my study of the intervention potential of OXT-AVP in autism was valuable because of the extensive animal research of OXT and AVP, reverse translation approaches with human-animal collaborative designs, methodology to collect biomarker data, and better intermediate phenotype data as the clinical views of autism shifted over time. Cross-species approaches have demonstrated evolutionarily conserved influences on phenotype and behaviors [37] and enhance knowledge of mechanisms that are difficult to study in humans [38]. The backlash against candidate gene and SNP allele approaches has to do with the failures of reductionism with oversimplification of a single factor; underestimating factors driving variation, and ignoring that complex phenotypes evolve from multiple contributing factors with specific timing across developmental processes. A more contextual and evolving research model including interacting biopsychosocial pathways will yield additional insights into outcomes that contribute to dysfunctional developmental processes that influence clinical outcomes.

9. Clinical targets and utilities of oxytocin

Since the 1950's and the synthesis of Pitocin, oxytocin has been used as a drug for the induction and pacing of labor in mammals. As oxytocin's social influences on the brain and behavior were uncovered, clinical applications to increase social affiliation and trust, decrease anxiety and pain, or modify physiological states were explored as potential treatments for social anxiety, generalized anxiety, depression, post-traumatic stress disorder, migraine pain, substance use, relationship counseling, epilepsy, Parkinson's disease, eating disorders, schizophrenia, as well as many studies on developmental disorders like autism [39,40]. As a lifespan healthcare provider focused on neurodevelopment, I have limited ways to assist families who have missed developmental milestones driven by the core symptom challenges of autism.

With Evdokia Anagnostou, MD, we attained funding to explore the treatment potential of intranasal oxytocin after assessing safety and tolerability in adolescents before children [41]. This research and subsequent studies demonstrated that daily administration of intranasal oxytocin at 0.4 IU/kg in children and adolescents with autism was both safe and well tolerated. The subsequent trial demonstrated that adolescents with autism showed improvement on a social recognition task, suggesting that daily intranasal administration may influence performance on specific components of social cognition [42]. Because oxytocin also influenced overall quality of life scales instead of symptom-focused subscales, we have yet to identify ways to replicate its effects by using current standardized ratings completed by parents or autistic individuals. Oxytocin has not been consistently superior to placebo in caregiver ratings of social behaviors in larger trials [43] and meta-analyses have demonstrated that caregiver ratings result in high placebo responses [44]. Reliance on caregiver and clinician reports as outcome measures increase susceptibility to placebo response in clinical trials. Additionally, autism heterogeneity contributes to null overall results in trials with a broad age range, participants with variable IQ, varied concomitant treatments, expectation bias, and inconsistent social contexts [45,46].

In oxytocin trials, differing dosage and frequency, genetic backgrounds, drug and placebo formulations, sources, method of delivery, and study designs complicate interpretation of the effects in autism [47]. Advancing approaches to clinical trial design and using methods such as Sequential Multiple Assignment Randomized Trials will facilitate adaptive intervention studies to obtain more detailed data on each participant to identify optimized regimens for individuals [46]. Exogenous hormones, including oxytocin, are not likely to work outside of physiological, environmental, or social stimulatory contexts. For example, insulin is administered to match food intake and ideally with digital feedback on current glucose levels, and anabolic steroids are used to increase physical bulk when individuals exercise to build muscle mass. Future studies may also find compounds that affect the oxytocin pathways better than the hormone receptor agonists that have very limited time courses.

Given all the unknowns about mechanism of actions and long term sequalae in children, our human trial design was done in parallel with reverse translational studies in voles, mice, and titi monkeys through the multispecies expertise of Karen Bales. The study was designed to administer intranasal oxytocin to voles in a similar manner to our human autism trial. As with human research, oxytocin administrationresulted in acute increases in social behavior in male voles with familiar partners [48]. Long term results were more complicated to interpret in the context of partner preference and pair bonding, and subsequent male specific effects have been reported in voles [49] and some human studies [50,51]. In mice, oxytocin induced complex differences in sniffing time during tasks that varied with sex and strain differences of the BTBR and C57BL/6J cohorts [52]. With titi monkeys and their primate evolution closer to humans, early developmental intranasal administration of oxytocin resulted in more social outcomes on preference tests, more time grooming family members, enhanced female preference for parents, increased male time spent with unfamiliar pairs, and higher glucose uptake across the social salience network after one month of treatment [53]. Later, these same adult monkeys had more affiliative behaviors across a number of measures, including tail twining [54]. However, nonspecific and global brain changes were found using 18FDG imaging, but only in females. This longitudinal study also demonstrated no major male or female fertility outcomes and reproductive effects with early intranasal administration, although there was a delay of testosterone secretion in males, induction of precocious ovulation in females, and a suppression of general weight gain even after treatment [38]. These innovative projects highlighted the value of doing reverse-translational multispecies research to examine mechanistic and long term sequala to probe future human studies, especially when reproductive outcomes and developmental timelines make answering questions directly in humans prohibitive.

Biomarkers to assess and follow intranasal delivery of oxytocin versus placebo are important to track successful administration and may correlate with outcomes. Heterogeneity in autism and methodological variance have made it difficult to compare and consistently measure endogenous oxytocin levels, even though atypical levels in plasma were reported over twenty-five years ago [55]. A recent metanalyses has shown that group differences of lower endogenous levels of oxytocin were found specifically in males and younger children [56]. Recently, we found larger effect sizes and more clearly differentiated pre–post oxytocin level changes after intranasal oxytocin administration when it was measured in urine versus plasma [57]. Utilizing a two-step cluster (TSC) blinded backward-chaining approach, we were able to identify if individuals belonged to active or placebo groups by changes in their urinary oxytocin measurement alone. Specifically, urinary oxytocin levels were able to serve as an accessible and accurate systemic biomarker for oxytocin dose–response because it was less susceptible to fluctuations in the timing of plasma sample collection. A collaboration with Harriet de Wit measured significant increases in both urinary and plasma levels after the administration of MDMA as well as intranasal oxytocin in the same participants [58]. MDMA resulted in much higher levels of oxytocin released between 90-120min than even intranasal oxytocin during a shorter interval of 30-60min [59]. Note that oxytocin is not likely to be the sole mechanism of the prosocial effects of MDMA. MDMA also produced a range of prosocial effects: It increased feelings of sociability, increased choice to engage in a social activity, and decreased recognition of anger and sadness in others. In contrast, intranasal oxytocin produced small increases in selected ratings of sociability and enhanced negative emotion recognition in adults who received both in a double blinded comparison [60].

10. Unexpected learnings: systems and organizational leadership

During my residency training at UCLA, I had learned about a model of studying how humans behave in groups and experience different organizations around them. Its origins occurred after World War II through the group work and theories of British psychoanalyst, Wilfred Bion [61]. The model explores how societies are macrocosms mirroring our organismal microcosms; this is seen in our internal as well as our external fight versus flight behaviors. Whatever is stated and is the formal purpose, a group has implicit biases and drives to preserve itself by fighting (e.g., aggression, scapegoating, and physical attack) or by fleeing the task (e.g., withdrawal, passivity, avoidance, and ruminating on history). The Group Relations model, theory, research, and practice pushed my own framework beyond individuals, couples, and families by giving me an ability to see and understand what events occur and how roles are repeated in groups whether we are aware of them or not. Having chosen psychiatry, I was already integrating how the body and brain influence each individual psyche as well as how different experiences shape a person's internal and shifting models of their world and themselves. Spanning from the individual to small, large, and multisystem group experiences gave me an invaluable insights and tools to navigate the growing challenges of increasingly complex and diverse organizations, communities, and workplaces.

Americans and other international enthusiasts put their own lens on these British approaches by emphasizing its historically predominant psychoanalytic lens and then integrating open-systems theory to interpret events as they occur in any organization. Institutes were created for authorizing and conducting experiential Group Relations Conferences, where temporary organizations are designed and formed to study the behavioral dynamics of groups and how subgroups represent aspects of larger social systems [62]. I first became a member of these conferences in Los Angeles with Charla Hayden, MA, and then in Chicago I observed how different leaders, like Jeffrey Roth, MD, and Sonny Cytrynbaum, PhD, shared their own interpretations through this approach. These temporary experiential learning conferences allowed members and staff to elucidate lived experiences of leadership, authority, organizational structure, boundaries, and to see formal as well as “unseen” informal work tasks and roles. I met incredible leadership mentors and colleagues through this work, including Zachary Green, PhD, René Molenkamp, PhD, Eliat Aram, PhD, Janice Wagner, MSW, Leslie Brisset, PhD, and Evangeline Sarda, JD. Multi-perspective learning was enhanced by becoming aware of unconscious processes that give rise to non-rational behavior of individuals, groups, and large organizations including universities, medical systems, corporations, countries, religious and cultural societies, and even global relations. The pandemic and political wars of the last decade reinforced the validity and utility of understanding behavior patterns of subgroups and repeated pathways of outcomes. In addition to being a member in local, national, and international conferences, I completed a training process to become a consultant and then have helped with administration, staff, and director roles in group relations conferences and workshops in the US, India, UK, Hong Kong, and several times in China.

Does even this relate to oxytocin? Biobehavioral pathways influencing mammalian behavior vary within social subgroups, and with sex differences, reproductive, or developmental phases. Oxytocin research has demonstrated its effects on social behaviors, particularly with differences of women and men and their response to stressors. In contrast to the fight-or-flight response, the Tend-and-Befriend theory suggests that oxytocin serves an evolutionarily adaptive role by engaging social support behaviors in order to reduce vulnerability during threatening situations [63]. Subsequent studies have suggested that oxytocin increases desire for social contact in response to stress, especially in women. Others have focused on oxytocin's role in motivating social bonding by interacting with dopaminergic and endogenous opioid systems [64], or reorienting attention towards informative social cues through mesocorticolimbic dopamine in the brain [65]. These recent biopsychosocial findings highlight how some aspects of our mammalian behaviors continue to be overlooked or considered less important because of their less dominant or valued narratives. For example, affiliative drives strongly determine outcomes and have their own impact in passing on our genes in addition to fighting, freezing, and fleeing from outcomes in our increasingly interconnected societies. My current interest in computational approaches [66] is motivated to understand what happens when biobehavioral variables are weighted differently to contribute to scientific outcomes. Modeling methodology gives us opportunities to explore many different variables and their relationships beyond our preconceived expectations and biases.

Given space constraints, I will save for a future essay the complex history of how I went from UCLA back to the University of Chicago and then to University of Illinois at Chicago (UIC) to work closely with Sue Carter during my child psychiatry fellowship. These large organizations and specific events exemplified and reinforced my learning on subliminal and sometimes devastating group processes. To my surprise, repetitions occurred in many places related to the same societal stigma of mental health disorders. This was reflected in financial hierarchies of lower reimbursement rates, limiting resources, internal and external leadership challenges, reenactments of scapegoating, or even the out-casting of departments from preferred physical spaces.

Accompanying the lows were the many highs of academic pursuits with incredible mentors, teachers, friends, and colleagues who made my journey so meaningful. This includes working with phenomenal residency and fellowship cohorts in top programs. One pivotal experience solidified my drive to complete the extra years of clinical and research training to become a child psychiatrist. While treating a teenager with a hormone-related brain disorder with James McCracken, MD, at UCLA, we found that this patient's hormonal treatments triggered severe obsessive compulsive symptoms. They required a series of biopsychosocial interventions including inpatient and partial programs, medication management, family/school partnering, multidisciplinary care teams, and therapies like exposure and response prevention to address symptom severity and shift of a developmental trajectory. With Kate Keenan at UChicago, I had the opportunity to work on a neonatal project [67]; Kate and Laurie Wakschlag reinforced my love of working with young children and developing new interventions for them and their families. Ed Cook and the legacy of Cathy Lord's work helped me find a home where social neuroscience meets autism spectrum as well as related disorders.

After working closely with Ed and Sue in Chicago, I spent over a decade at the University of Minnesota to complete more than six clinical trials as well as some of the oxytocin and vasopressin projects that I described above. As my research has moved to innovating methods for phenotyping complex neurodevelopmental conditions, my mentees and colleagues like Sunday Francis, PhD, Harry Freeman, PhD, Annie Haynos, PhD, Carol Peterson, PhD, and the talented Angela Tseng, PhD have made it possible for me to return to questions about neuropeptide hormones. I've also had the privilege of serving as an associate director for UMN's Medical-Scientist Training Program (MD/PhD) and to work with leaders like Yoji Shimizu, PhD, to help train a diverse, resilient, and dynamic group of next generation physician-scientists. Inspired by the collaborative leadership and sustainability approaches of Pat Pulice, MA, Rochelle Brandl, PhD, Diane Cross, MS, and Sophia Vinogradov, MD, I have had the unique opportunity to co-lead the Converging Approaches to Neurodevelopment lab (CANlab) with my creative colleague, Christine Conelea, PhD. For over six years, our team has focused on related developmental disorders including tic disorders, OCD, ADHD, and autism to advance diagnoses and community-informed interventions. Sharing resources, support, and ideas is counter to traditional hierarchical competition-fueled lab structures and is more network connection “oxytocin” informed.

Striving to learn more about mammalian sociality and healthy neurodevelopmental trajectories, oxytocin has been central in my narrative and scientific community and will continue to play an integral part of my life endeavors.

CRediT authorship contribution statement

Suma Jacob: Writing – review & editing, Writing – original draft, Resources, Project administration, Investigation, Conceptualization.

Declaration of competing interest

Suma Jacob, MD, PhD has received research funding from NIH, DOD, HRSA, SFARI-Simon's Foundation, NARSAD, and Roche; has served on advisory boards for Roche, MN Department of Human Services, Minnesota Independence College and Community, and Fraser Community Behavioral Health Clinics.