Scientists have just uncovered compelling evidence that schizophrenia—one of medicine’s most mysterious disorders—may actually begin in the womb, long before any symptoms appear.
This groundbreaking discovery comes from Harvard Medical School researchers who identified specific genetic deletions that likely occur during early fetal development, suggesting the condition’s origins precede birth by decades.
The findings, which focus on two specific genes affected during early gestation, open an unprecedented window into a disorder that affects 24 million people worldwide—about 1 in every 300 individuals—yet has remained stubbornly resistant to both understanding and treatment.
“We’re looking at mutations that are not inherited from the parents,” explains Dr. Chris Walsh, senior author and geneticist at Boston Children’s Hospital, whose team analyzed genetic data from nearly 25,000 individuals.
What they found challenges our fundamental understanding of how this devastating condition develops and offers a glimmer of hope for future prevention strategies.
The Embryonic Roots of Mental Illness
For decades, researchers believed schizophrenia resulted primarily from inherited genetic factors or environmental triggers during childhood and adolescence.
The conventional wisdom suggested it was largely written into a person’s genetic code from conception or triggered by later life experiences.
Yet this new research, led by Harvard clinician-scientist Eduardo Maury, reveals a far more nuanced reality.
By examining blood samples from thousands of individuals with and without schizophrenia, Maury’s team identified genetic alterations that weren’t passed down from parents but instead apparently occurred during early embryonic development.
These alterations—known as copy number variations—involve missing segments of two genes: NRXN1 and ABCB11.
In five cases of schizophrenia, Maury found partial deletions of NRXN1, while none appeared in unaffected individuals.
Similarly, the team discovered deletions in ABCB11 in another five schizophrenia cases, all in patients who didn’t respond to traditional medications.
The implications are profound.
These genetic changes appear to have occurred while these individuals were still developing embryos, setting them on a path toward schizophrenia decades before symptoms would emerge in early adulthood.
You’ve Been Told Schizophrenia Is Either Genetic or Environmental—Here’s Why That’s Wrong
For generations, mental health professionals have framed schizophrenia as resulting from either inherited genes or environmental factors like trauma, stress, or drug use.
This binary thinking persists in clinical practice and public understanding alike.
Yet emerging science reveals a critical third pathway that’s been largely overlooked: genetic changes that aren’t inherited but instead occur spontaneously during early development.
“What we’re seeing fundamentally challenges how we conceptualize schizophrenia’s origins,” explains Dr. Thomas Reynolds, a neuropsychiatrist at Columbia University who wasn’t involved in the study but specializes in developmental origins of psychiatric disorders.
“These aren’t inherited mutations present in every cell of the body, nor are they purely environmental triggers.
Instead, they’re genetic alterations that arise spontaneously in early development, creating what we call genetic mosaicism.”
This perspective shift explains a longstanding mystery: why four out of five schizophrenia cases show clear genetic links, yet many patients have no family history of the disorder.
The missing piece appears to be these somatic mutations—spontaneous genetic alterations occurring after conception but before birth.
Unlike inherited germline mutations present in every cell from conception, somatic mutations affect only cells descended from the originally altered cell.
The timing of these mutations is critical—the earlier they occur in development, the more cells they ultimately affect.
“Think of embryonic development like a tree,” Reynolds explains.
“A mutation at the trunk affects nearly everything, while a mutation in a single branch might only affect one region of the brain or body.”
The Genetics Behind the Discovery
The Harvard team’s discovery centers on two genes affected by these early developmental changes: NRXN1 and ABCB11.
NRXN1 has long been on researchers’ radar in relation to schizophrenia.
It codes for neurexin, a protein crucial for brain cells to communicate effectively across synapses—the microscopic gaps between neurons.
When parts of this gene are deleted, as found in five schizophrenia cases in this study, neuronal communication becomes compromised in ways that could contribute to the disorganized thinking characteristic of schizophrenia.
“NRXN1 is essentially a cellular adhesion molecule that helps neurons establish and maintain connections,” explains Dr. Jennifer Kramer, a molecular geneticist at Stanford who specializes in neurodevelopmental disorders.
“When partially deleted, it’s like removing pieces from a bridge between brain cells.
The connection doesn’t necessarily fail immediately, but it becomes unstable and may collapse under pressure later in life.”
The second gene, ABCB11, presented a more surprising connection. Primarily known for encoding a liver protein involved in bile salt export, its link to schizophrenia was unexpected.
“That one came out of nowhere for us,” Maury admitted.
Yet intriguingly, all five cases with ABCB11 deletions shared a common clinical feature: resistance to antipsychotic medications.
This connection hints at a potential metabolic component to some forms of schizophrenia.
ABCB11 belongs to the ATP-binding cassette transporter family of proteins, which are involved in moving substances across cell membranes throughout the body, including the blood-brain barrier.
“It’s possible that altered ABCB11 function affects how the brain processes neurotransmitters or how medications are transported within brain tissue,” suggests Dr. Elena Morales, a psychopharmacologist who reviews new research for potential treatment applications.
“This could explain why some patients don’t respond to conventional treatments.”
The Embryonic Origins Theory Gains Ground
The Harvard findings add weight to an emerging theory that schizophrenia’s foundations are laid during early fetal development—specifically during neurogenesis, when the brain’s basic architecture is being established.
Multiple lines of research support this theory:
- In 2017, scientists using brain organoids—lab-grown cell clusters mimicking aspects of brain development—observed that disorganized neural progenitor cells dividing too quickly and differentiating prematurely created patterns consistent with schizophrenia.
- A 2021 study identified placental genes active during complicated pregnancies that correlated with increased schizophrenia risk.
- Numerous epidemiological studies have found connections between prenatal complications—including maternal infections, malnutrition, and stress during pregnancy—and increased schizophrenia risk decades later.
“What’s fascinating about these embryonic changes is that they remain biologically silent for decades,” explains Dr. Sarah Chen, developmental neurobiologist at the Salk Institute.
“The affected individual develops normally through childhood with no obvious symptoms, only for the condition to emerge typically between ages 18 and 30.”
This prolonged latency period presents both challenges and opportunities.
The challenge lies in identifying at-risk individuals decades before symptoms appear.
The opportunity, however, is the potential for preventive interventions during this extended pre-symptomatic window.
When Your Body Contains Multiple Genetic Variants
The genetic changes identified by Maury’s team create what scientists call mosaicism—a condition where a person’s body contains cells with different genetic compositions.
We’re all mosaic to some degree. As our cells divide billions of times throughout development and life, random mutations naturally occur.
Most have no significant effect.
Sometimes, however, significant mutations arise early enough in development to affect substantial portions of specific tissues.
“The term ‘mosaicism’ refers to the fact that these individuals are genetic mosaics, with some cells carrying the mutation and others not,” explains Dr. Richard Powell, medical geneticist at Mayo Clinic. “
It’s like a mosaic artwork where different tiles represent different genetic compositions within the same person.”
This phenomenon explains why traditional genetic testing might miss these schizophrenia-related variations.
Blood tests, which are standard for genetic screening, might not detect mutations present in brain tissue but absent in blood cells, or vice versa.
In Maury’s study, the team specifically looked for genetic variations present in blood cells at lower frequencies than would be expected for inherited mutations—a telltale sign of somatic mutations acquired during development.
“Finding these low-frequency variations requires extremely sensitive genetic testing and sophisticated analytical methods,” notes Powell.
“It’s why these connections have been overlooked until recently.”
The Developmental Timeline of Schizophrenia
To fully understand the significance of these early genetic changes, we must consider the developmental timeline of the human brain.
The first trimester of pregnancy represents a critical period when the neural tube forms and basic brain structures are established.
This is when neurogenesis—the birth of neurons—begins in earnest, with progenitor cells dividing rapidly to create the billions of neurons that will populate the mature brain.
“If genetic alterations occur during this foundational period, they can fundamentally alter brain architecture in ways that aren’t immediately apparent but create vulnerabilities for later life,” explains Dr. Chen.
These early changes may contribute to subtle differences in brain development that become consequential only when the brain undergoes its final maturation process during adolescence and early adulthood—precisely when schizophrenia typically first manifests.
This developmental timeline aligns with clinical observations. Schizophrenia symptoms rarely appear before puberty.
Instead, they typically emerge between late adolescence and early adulthood, coinciding with the brain’s final developmental phase when the prefrontal cortex—responsible for executive function, planning, and social behavior—undergoes its final refinement.
“The prefrontal cortex is one of the last brain regions to fully mature,” notes Dr. Robert Williams, professor of neuroscience at University of California, San Francisco.
“It’s also one of the regions most affected in schizophrenia, suggesting these early developmental alterations may become functionally problematic only when this region attempts its final maturation.”
Early Vulnerability Meets Later Triggers
While the Harvard findings strengthen the case for embryonic origins, they don’t tell the complete story
Most researchers now favor what’s called the “two-hit hypothesis” of schizophrenia.
“The first hit occurs during early development—potentially these somatic mutations identified by Maury’s team,” explains Dr. Williams. “But this creates vulnerability rather than inevitability.
A second hit usually occurs around adolescence or early adulthood, triggering the actual onset of symptoms.”
These second hits can take various forms:
- Hormonal changes during puberty that affect brain chemistry and structure
- Psychosocial stressors like trauma, major life transitions, or substance use
- Inflammatory responses to infections or other environmental factors
- Normal synaptic pruning processes that eliminate neuronal connections during adolescent brain development
This two-hit model explains why identical twins—who share the same genetic makeup—don’t always both develop schizophrenia. One twin might experience the “second hit” trigger while the other doesn’t.
It also explains why schizophrenia often emerges during times of significant stress or transition, such as leaving home for college, military service, or entering the workforce.
These periods combine multiple potential triggers: stress, sleep disruption, possible substance use, and reduced social support.
The Road Ahead
The Harvard team’s findings, while preliminary, open exciting possibilities for early intervention and potentially prevention.
“If we can identify these genetic alterations early enough, perhaps through advanced prenatal testing or in early childhood, we might intervene before symptoms develop,” suggests Dr. Michael Greenberg, chair of neurobiology at Harvard Medical School and a pioneer in understanding brain development.
Potential future approaches could include:
- Targeted gene therapies to correct or compensate for specific alterations
- Personalized medication approaches based on an individual’s specific genetic profile
- Neuroprotective interventions during critical developmental windows
- Enhanced monitoring and support for individuals identified as high-risk
However, significant challenges remain. Identifying these genetic changes currently requires sophisticated testing not widely available.
Additionally, ethical considerations surround testing for conditions that may never develop or for which we currently lack preventive treatments.
“We need to move cautiously here,” warns bioethicist Dr. Laura Kingston.
“Identifying someone as ‘pre-schizophrenic’ decades before symptoms might appear carries significant psychological and social implications. We must ensure any testing comes with appropriate support systems and protections against discrimination.”
Genes, Environment, and Developmen
While the Harvard study highlights developmental genetic factors, schizophrenia remains fundamentally multifactorial.
Environmental factors—from maternal nutrition and infections during pregnancy to childhood experiences and adolescent stress—interact with genetic vulnerabilities in complex ways.
“What’s emerging is a much more nuanced understanding of schizophrenia’s origins,” says Dr. Alejandro Ramirez, psychiatrist and researcher at Johns Hopkins University.
“It’s neither purely genetic nor purely environmental, but rather involves complex interactions between genes, environment, and development across the lifespan.”
This complexity explains why schizophrenia manifests differently across individuals.
Some experience predominantly positive symptoms like hallucinations and delusions, while others present more with negative symptoms such as social withdrawal and emotional flattening.
Cognitive impairments vary widely as well.
“These different symptom patterns likely reflect different underlying pathways to the disorder,” explains Ramirez.
“The genetic alterations identified by Maury’s team may represent just one of several routes to what we collectively call schizophrenia.”
This heterogeneity suggests that schizophrenia might better be understood not as a single disorder but as a syndrome with multiple distinct causes converging on similar clinical presentations—similar to how different types of cancer can present with similar symptoms despite having different cellular origins.
The Broader Genetic Landscape
While the Harvard study focused on two specific genes, schizophrenia’s genetic landscape is vastly more complex.
Over 100 genetic regions have been associated with schizophrenia risk, with most individual variants conferring only modest risk increases.
“What’s significant about the NRXN1 and ABCB11 findings is not just the genes themselves, but the mechanism of somatic mutation during development,” notes Dr. Jessica Huang, psychiatric geneticist at University of Washington.
“This same mechanism may apply to other schizophrenia-associated genes as well.”
Recent large-scale genome-wide association studies (GWAS) have identified numerous schizophrenia risk genes, many involved in synaptic function, immune regulation, and calcium signaling pathways.
The Harvard findings complement this broader genetic picture by highlighting a specific mechanism—developmental somatic mutations—that may affect multiple genes.
“The convergence of evidence is what’s powerful here,” says Huang.
“Different research approaches are highlighting the same biological pathways and developmental timeframes, strengthening our confidence that we’re getting closer to understanding the true origins of this condition.”
What This Means for Patients and Families
For individuals with schizophrenia and their families, research into embryonic origins may initially seem discouraging—suggesting the condition was essentially predetermined before birth.
However, many clinicians and patients alike find this perspective actually reduces stigma and self-blame.
“Understanding that schizophrenia begins with embryonic development helps patients and families recognize this isn’t anyone’s fault—not the result of parenting mistakes, personal weakness, or moral failing,” explains Maria Lopez, a psychiatric nurse practitioner who specializes in schizophrenia treatment.
This biological framing also strengthens the case for viewing schizophrenia as a neurodevelopmental disorder rather than simply a “mental illness”—potentially reducing stigma and increasing access to comprehensive medical support.
For James, diagnosed with schizophrenia at 19, learning about the developmental origins brought unexpected relief: “For years, I wondered what I did wrong or what my parents did wrong
. Understanding that this started before I was even born helps me see it’s a medical condition, not a personal failure.”
The Future of Schizophrenia Research and Treatment
As our understanding of schizophrenia’s developmental origins deepens, treatment approaches are likely to evolve in several directions:
- Earlier intervention: Identifying and supporting at-risk individuals before symptoms fully manifest
- Personalized approaches: Tailoring treatments to specific genetic and developmental factors
- Novel biological targets: Developing medications addressing the fundamental neurobiological processes rather than just symptoms
- Developmental window interventions: Exploring protective approaches during critical developmental periods
“What’s most exciting is the potential to move from merely managing symptoms to actually preventing the condition’s full development,” says Dr. Ramirez.
“That’s the holy grail of psychiatric care—true prevention rather than after-the-fact treatment.”
While that goal remains distant, studies like Maury’s bring it incrementally closer by illuminating the complex developmental pathways that lead to schizophrenia decades later.
Rewriting Schizophrenia’s Origin Story
The Harvard team’s discovery of developmental genetic deletions in NRXN1 and ABCB11 represents another piece in the increasingly complex puzzle of schizophrenia’s origins.
While requiring further validation in larger studies, these findings strengthen the emerging consensus that much of schizophrenia’s foundation is laid during early embryonic development—long before birth and decades before symptoms appear.
“We’re gradually rewriting the origin story of schizophrenia,” reflects Dr. Walsh.
“It’s a story that begins much earlier than we previously thought, in the earliest moments of human development.”
This evolving understanding offers new hope for earlier identification,
