For years, families have been left searching for answers after an autism diagnosis. Was it genetics? Something that happened during pregnancy? An illness, an infection, stress, or an environmental exposure? The reality is that autism has never fit neatly into a single explanation, and that uncertainty has been both frustrating and painful for parents looking for clarity.

A new study from the University of California, San Diego School of Medicine offers a long-awaited shift in perspective. Instead of pointing to a single cause, researchers propose that autism develops when three biological factors converge during early development, disrupting how cells communicate and how the brain utilizes energy at its most vulnerable stage.

This “three-hit” model reframes autism as a disorder of cellular stress and metabolic signaling, rather than a fixed genetic condition or a purely behavioral diagnosis. Even more striking, the research suggests that many autism cases may be modifiable and potentially preventable with early identification and intervention.

The implications are enormous, not just for scientists, but for families who have long been told that autism is either inevitable or unknowable.

Autism has never behaved like a typical genetic disorder. There is no single gene that causes it, and even children with the same genetic variants can have vastly different outcomes. Identical twins can share DNA, yet only one may be autistic. Known genetic syndromes increase autism risk, but they don’t guarantee a diagnosis. Environmental exposures raise risk too – but no single exposure explains autism on its own.

Over the years, researchers have proposed many theories to explain autism, including immune dysfunction, mitochondrial abnormalities, gut microbiome changes, neuroinflammation, and sensory processing differences. Each of these models has contributed valuable insight, but none has been able to explain autism in its entirety.

The UC San Diego study brings these ideas together under one biological framework. The unifying concept is something called the cell danger response, a natural survival mechanism that exists in every human cell.

The Cell Danger Response: A Survival System That Can Go Too Far

Every cell in the body has a built-in alarm system designed to protect it from harm. When a cell senses danger, such as infection, inflammation, toxic exposure, or physical injury, it activates the cell danger response, or CDR. This response shifts the cell into defense mode, redirecting energy away from growth and toward protection and repair.

During this state, mitochondria change how they produce energy, immune signals are released, and chemical messages alert nearby cells that something is wrong. Under normal circumstances, this response is temporary. Once the threat passes, the cell returns to a calm, growth-focused state.

Problems arise when the danger response does not shut off.

When the CDR becomes chronic, cells remain locked in survival mode. Instead of supporting normal development, they prioritize defense, altering communication between cells and changing how tissues — including the brain — develop over time.

Why Early Development Is Especially Vulnerable

Late pregnancy and the first few years of life are a once-in-a-lifetime window for brain development. During this period, the brain is forming neural circuits, strengthening important connections, and pruning away those that are unnecessary. These processes are highly energy-dependent and require precise coordination between cells.

If the cell danger response stays activated during this critical window, energy is diverted away from brain development and toward managing stress and inflammation. The brain is still growing, but it is doing so under conditions that are biologically unfavorable.

According to the study’s lead author, Dr. Robert K. Naviaux, when the body remains in defense mode, fewer resources are available for the developing brain. Over time, this imbalance can alter how neural circuits form, potentially leading to the core features associated with autism.

The Three-Hit Model: How Autism Develops

Rather than blaming autism on a single cause, the three-hit model explains it as the result of three interacting biological factors, none of which is sufficient on its own.

The First Hit: Genetic Sensitivity

Some children are born with genetic traits that make their cells, particularly their mitochondria, more sensitive to stress. These genes do not cause autism outright, nor do they guarantee that a child will develop it. Instead, they create a biological vulnerability, a system that reacts more strongly to environmental or metabolic challenges.

This sensitivity can affect how cells regulate energy, calcium signaling, immune responses, and chemical communication. In many children, this genetic predisposition remains silent unless it is activated by additional stressors.

The Second Hit: An Early Environmental Trigger

The second hit occurs when an early-life stressor activates the cell danger response during pregnancy or infancy. This trigger can take many forms, including maternal infection or fever, immune activation, metabolic stress, exposure to environmental pollutants, or inflammatory events.

These exposures are often common and unavoidable, which helps explain why autism risk cannot be traced to a single incident. In children with underlying genetic sensitivity, even routine stressors may provoke a stronger or longer-lasting cellular response.

When this happens during early development, the cell danger response switches on at a time when the brain is still forming its foundational architecture.

The Third Hit: When the Stress Response Doesn’t Turn Off

The third hit is what transforms risk into long-term impact. If the cell danger response remains activated for months – or is repeatedly triggered – during early development, it can permanently alter the brain’s developmental trajectory.

Instead of returning to a calm, growth-oriented state, cells stay in defense mode. Over time, this prolonged stress interferes with synapse formation, neural pruning, sensory processing, and the balance between excitation and inhibition in the nervous system.

According to the study, it is this chronic state — not a single gene or exposure — that underlies the core features of autism.

Why Autism Often Comes With Other Medical Conditions

One of the most compelling aspects of the three-hit model is how well it explains the medical complexity seen in many autistic children. Autism rarely appears alone. Many children also experience gastrointestinal issues, immune dysfunction, sleep disturbances, seizures, sensory sensitivities, or metabolic challenges.

Under the cell danger response framework, these conditions are not separate problems layered on top of autism. Instead, they reflect the same underlying biological stress affecting multiple systems at once. Because the CDR operates throughout the entire body, prolonged activation can influence digestion, immunity, metabolism, and neurological function simultaneously.

This perspective helps explain why addressing co-occurring medical issues can sometimes improve quality of life and functional outcomes in autistic children.

What the PKU Comparison Teaches Us About Prevention

To illustrate how early intervention can change outcomes, Dr. Naviaux compares autism to phenylketonuria (PKU), a well-known genetic disorder. PKU causes severe intellectual disability if left untreated, yet when it is identified early through newborn screening and managed appropriately, the vast majority of affected children develop normally.

The genes remain the same. The outcome does not.

The study suggests autism may follow a similar principle. While genetics cannot be changed, the biological environment in which development unfolds can be influenced. If children at highest risk can be identified early and supported before symptoms appear, an estimated 40 to 50 percent of autism cases might be prevented or significantly improved.

What Early Prevention Could Look Like

Prevention, as described in this research, does not mean eliminating neurodiversity or predicting outcomes with certainty. Instead, it focuses on identifying biological stress early and supp...

Growing Your Baby

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