StemCell Therapy

In the mid-2000s, Dr. Nadine Burke Harris opened a children's medical clinic in the Bayview section of San Francisco, one of the city's poorest neighborhoods. She quickly began to suspect something was making many of her young patients sick.

She noticed the first clues in the unusually large population of kids referred to her clinic for symptoms associated with attention deficit hyperactivity disorderan inability to focus, impulsivity, extreme restlessness. Burke Harris was struck not just by the sheer number of ADHD referrals, but also by how many of the patients had additional health problems. One child arrived in her clinic with eczema and asthma and was in the 50th percentile of height for a 4-year-old. He was 7. There were kindergarteners with hair falling out, two children with extremely rare cases of autoimmune hepatitis, middle-school kids stricken with depression and an epidemic number of kids with behavioral problems and asthma.

Burke Harris noticed something else unusual about these children. Whenever she asked their parents or caregivers to tell her about conditions at home, she almost invariably uncovered a major life disruption or trauma. One child had been sexually abused by a tenant, she recalls. Another had witnessed an attempted murder. Many children came from homes struggling with the incarceration or death of a parent, or reported acrimonious divorces. Some caregivers denied there were any problems at all, but had arrived at the appointment high on drugs.

Although none of her mentors at medical school back in the early 2000s had suggested that stress could cause seemingly unrelated physical illnesses, what she was seeing in the clinic was so consistentand would eventually so alarm herit sent her scrambling for answers.

"If I were a doctor, and I was seeing incredibly high rates of autism, I'd be doing research on autism," she says. "Or if I saw incredibly high rates of certain types of cancer, I'd be doing that research. What I was seeing was incredibly, incredibly high rates of kids who were experiencing adversity and then having really significant health outcomes, whether it was difficulty learning, or asthma, or weird autoimmune diseases. I was seeing that the rates were highest in my kids who were experiencing adversity. And that drove me to the latest scientific literature."

What Burke Harris found there would eventually thrust her to the forefront of a growing movement that aims to transform the way the medical profession handles childhood adversity. Childhood stress can be as toxic and detrimental to the development of the brain and body as eating lead paint chips off the wall or drinking it in the waterand should be screened for and dealt with in similar ways, in Burke Harris' view. As California's first Surgeon General, a newly created position, she is focusing on getting lawmakers and the public to act.

Earlier this year, thanks in part to her advocacy, California allocated more than $105 million to promote screening for "Adverse Childhood Experiences" (ACEs)10 family stressors, first identified in the late 1990s, that can elicit a "toxic stress response," a biological cascade driven by the stress hormone cortisol that is linked to a wide range of health problems later in life.

In recent years, epidemiologists, neuroscientists and molecular biologists have produced evidence that early childhood experiences, if sufficiently traumatic, can flip biological switches that can profoundly affect the architecture of the developing brain and long-term physical and emotional health. These "epigenetic" changesmolecular-level processes that turn genes on and offnot only make some people more likely to self-medicate using nicotine, drugs or alcohol and render them more susceptible to suicide and mental illness later in life. They can impair immune system function and predispose us to deadly diseases including heart diseases, cancer, dementia and many others, decades later. Not only does childhood stress harm the children themselves, but the effects may also be passed down to future generations.

A groundswell of support has arisen in the world of public health in favor of treating childhood adversity as a public health crisis that requires interventiona crisis that seems to run in families and repeat itself in trans-generational cycles. At last count, at least 25 states and the District of Columbia had passed statutes or resolutions that refer to Adverse Childhood Experiences. Since 2011, more than 60 state statutes aimed at ACEs or intervening to mitigate their effects have been enacted into law, according ACEs Connection, a website devoted to tracking the phenomenon and providing resources. California's effort is among the most aggressive. The state has set aside $50 million for next year to train doctors to provide screening, and $45 million to begin reimbursing doctors in the state's MediCal program for doing so ($29 for each screening). If it proves effective, other states may soon follow.

"The social determinants of health are to the 21st century, what infectious disease was to the 20th century," says Burke Harris. She rose to national prominence after writing a 2018 book on the subject, embarking on a national book tour and recording a TED Talk that has been viewed more than 6 million times. She was tapped for her new post by Governor Gavin Newsom in January 2019.

The research is so fresh that many clinicians are still debating the best way to tackle the problem, most significantly whether the science is mature and the interventions effective enough to implement universal screening. And the details of California's approach to screening are controversial in the world of public health. (The epidemiologist who developed a key questionnaire being used as a screening tool says it was never intended to be used to evaluate individuals.) But there is broad consensus, at least, about one thing. For all the buzz in public health and policy circles about "ACEs," few people have heard the term before. The first task, many people on the front lines of health education agree, will be to change that so that caregivers themselves can learn about the vicious cycle of childhood adversity, and get the help they need to break it.

The Science of Toxic StressThe research on ACE stems from a seminal 17,000-person epidemiological study published in 1998. The first clue came years earlier, however, with the plight of an obese, 29-year-old woman from San Diego named Patty.

Over the course of a 52-week trial of a weight-loss diet, Patty dropped from 408 lbs. all the way down to 132. Then, over a single three-week period, she abruptly gained 37 pounds of it backa feat that her doctors didn't even know was scientifically possible.

Patty's dramatic weight swings got the attention of Vincent Felitti, the head of the preventative medicine program at the massive managed care consortium Kaiser Permanente, and the man who had designed the obesity study. Felitti had been astounded at the rapid pace with which the study subjects lost weight. "In the early days of the obesity study, I remember thinking 'wow, we've got this problem licked,'" Felitti recalls. "This is going to be a world-famous department!"

Then, for reasons nobody could explain, patients began dropping out of the program in droves. Felitti found it particularly alarming because the ones leaving the fastest seemed to be the ones losing the most weight. When Felitti heard about Patty, he arranged a chat. Patty claimed she was just as mystified by her massive weight gain as he was; she assured him she was still vigilantly sticking to the diet. But then she offered up a suggestive clue: Every night when she went to bed, she told Felitti, the kitchen was clean. Yet when she woke up, there were boxes and cans open and dirty dishes in the sink. Patty lived alone and had a history of sleepwalking. Was it possible, she wondered, that she was "sleep eating?"

When Felitti asked her if anything unusual had happened in her life around the time the dirty pots and pans began to appear, one event came to mind. An older, married man at work had told her she looked great and suggested they have an affair. After further questioning, Felitti learned Patty had first started gaining weight at age 10, around the time her grandfather began sexually molesting her.

Felitti came to believe that for Patty, obesity was an adaptive mechanism: she overate as a defense against predatory men. Felitti began asking other relapsing study participants if they had a history of sexual abuse. He was shocked by their answers. Eventually, more than 50 percent of his 300 patients would admit to such a history.

"Initially I thought, 'Oh, no, I must be doing something wrong. With numbers like this, people would know if this were true. Somebody would have told me in medical school,'" he recalls.

Felitti started bringing patients together in groups to talk about their secrets, their fears and the challenges they facedand their weight loss began to stick. Within a couple years, the program was so successful that Felitti was receiving regular invitations to speak about his program to medical audiences. Whenever he brought up sexual abuse and its apparent link to obesity, however, audience members would "storm explosively" out of the room or stand up to argue with him, he says. Nobody, it seemed, wanted to hear what he had to say.

At least one person was intrigued by his findings. Robert Anda, a researcher at U.S. Centers for Disease Control (CDC), had been studying chronic diseases and the counterintuitive links between depression, hope and heart attacks. He knew firsthand what it was like to deal with colleagues who considered his work flaky. Anda and Felitti got to talking. They realized there was only one way that both of them would be able to overcome the skepticism they were encountering: they needed to do a rigorous study. At Anda's urging, Felitti agreed not just to recruit a larger sample but to expand its scope to examine the link between a wide array of common childhood stressors and health later in life.

This became the ground-breaking "ACE Study," a 17,000-person retrospective project aimed at examining the relationship between childhood exposure to emotional, physical and sexual abuse and household dysfunction, and risky behaviors and disease in adulthood. Starting in 1998, and continuing with follow-ups well into the 2000s, Felitti and Anda's team published a series of counterintuitive papers that upended much of what we thought we knew about the mind-body connection.

To gather the data, Felitti persuaded Kaiser Permanente-affiliated doctors to recruit patients in Southern California undergoing routine physical exams. The patients were asked to complete confidential surveys detailing both their current health status and behaviors, and the types of adversity they've endured: physical, emotional and sexual abuse, neglect, domestic violence, parental incarceration, separation or divorce, family mental illness, the early death of a parent, alcoholism and drug abuse. To analyze the data, the researchers added up the number of ACEs, calculated an "ACE score," then correlated those scores with high-risk behaviors and diseases to see if they could find any patterns.

The first shocker was just how common these ACEs were. More than half of those participating had at least one, a quarter had two or more and roughly 6 percent reported four or more. This was not just a problem of the poor. Childhood emotional adversity cut across all racial, ethnic and economic lines. Even more surprising was the impact of these stressors later in life. When the researchers ran their analysis, they discovered a direct, dose-dependent link between the number of ACEs and behavioral issues like alcoholism, smoking and promiscuitythose who had experienced four or more categories of childhood exposure had a four- to 12-fold increased risk of alcoholism, drug abuse, depression and suicide attempts.

The results went beyond these common trauma-related health risks. The study also linked childhood trauma to a host of seemingly unrelated physical problems, including ischemic heart disease, cancer, chronic lung disease, skeletal fractures and liver disease.

What made the study so shocking was that the data suggested that even those who didn't drink, use drugs or act out in risky ways still had a far higher rate of developing ischemic heart disease, cancer, chronic lung disease, skeletal fractures and liver disease. Unexpectedly, the researchers had discovered that childhood adversity seemed to be an independent risk factor for some of the leading causes of death decades later.

"We found a strong graded relationship between the breadth of exposure to abuse or household dysfunction during childhood and multiple risk factors for several of the leading causes of death in adults," the authors wrote.

The study dropped like a bomb in the world of public health. But the scientific work was just beginning. In the years since, scores of researchers have begun to dig into the biological mechanisms in play. And with emerging brain scanning technologies and advances in molecular biology, an explanation for the ACE study has begun to emerge. Some clinicians and scientists have begun to turn these findings into concrete interventions and treatments they hope can be used to reverse or at least attenuate the impact.

Much of the research has focused on how ACEs affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, a biological system that plays a key role in the mind-body connection. The HPA axis controls our reactions to stress and is crucial in regulating an array of important body processes including immune function, energy storage and expenditureeven our experience of emotions and mood. It does so by adjusting the release of key hormones, most notably cortisol, the release of which is increased by stress or low blood sugar levels.

Cortisol has many functions. On a daily basis, it regulates the level of energy we have as the day progresses: we generally experience our highest levels of cortisol, and energy, upon waking up. These levels gradually diminish throughout the day, reaching very low levels just prior to bedtime.

Cortisol also serves a role in the body's energy allocation during times of crisis. When all is calm, the body builds muscle or bone and socks away excess calories for future consumption as fat, performs cellular regeneration and keeps its immune system strong to fight infection. In the case of a child, the body fuels normal mental and physical development.

In an emergency, however, all these processes get put on hold. The HPA axis floods the bloodstream with adrenaline and cortisol, which signals the body to kick into overdrive immediately. Blood sugar levels spike and the heart pumps harder to provide a fast boost in fuel. If an 11-foot-tall grizzly bear is lumbering in your direction and licking his chops, the additional burst of energy helps you run screaming through the woods or wrestle the critter to the ground and plunge a Bowie knife into its heart.

However, when the emergency goes on for a long timeperhaps over an entire childhood of abusethe resulting high levels of cortisol take a big and lasting toll.

Almost as soon as the ACE study was published, dysregulated cortisol levels seemed a likely culprit to explain the study's startling implications. Was it possible that the chronic stressors identified by Felitti and Anda led to elevated cortisol levels in children? And could those elevated levels account for seemingly unrelated diseases and the range of additional problems that researchers were beginning to link to ACEs?

In the decade after the 1998 ACE study, researchers began seeking out children in Romanian orphanages and measuring cortisol levels, in the hopes of verifying this hypothesis. When researchers began to compare their levels to that of children who had not faced adversity, they found substantial differences. But the results were difficult to interpret.

"There was growing evidence that there was an impact, but the studies were contradictory," says Jackie Bruce, a research scientist at the Oregon Social Learning Center, an NIH-funded research center in Eugene that studies child development. "Sometimes people were finding kids with early adversity had low cortisol and sometimes they were finding they had high cortisol."

In 2009, Bruce and her colleagues demonstrated a possible explanation for the discrepancies. Since morning cortisol levels play such an important role in getting well-functioning individuals ready for the day, they sought out a group of 117 maltreated 3- to 6-year-old children transitioning into new foster care placements in the United States. The researchers then trained the children's caregivers to collect saliva samples before breakfast. For comparison, they recruited a control group of 60 low-income children living with their biological parents who had no previous record of abuse or maltreatment.

Children who had experienced more severe emotional, physical and sexual maltreatment did indeed have abnormally high morning cortisol levels. But scientists also found that children who experienced more severe neglect had abnormally low morning cortisol levels. Different types of adversity, in other words, had different impacts on the HPA system. But whether the adversity took the form of an absence of stimulation or the presence of negative, threatening stimulation, the effect was bad for normal development.

"Low cortisol levels, particularly in the morning, had been linked to externalizing disordersthings like delinquency and alcohol usewhereas high cortisol levels have been linked to more anxiety and depression," and post-traumatic stress disorder, Bruce says.

Even so, Bruce and her colleagues noted that within both groups, "some kids are doing really well, some kids are not doing well." This suggested other factors were also involved. And in recent years, much of the research has focused on understanding the complex interaction between external stressors, genetics and interpersonal interventions.

One of the most important findings to emerge recently is that the experience of childhood adversity, by itself, does not appear to be enough to lead to toxic stress. Genetic predispositions play a role. But even among those predisposed, the effects can be blunted by what researchers call emotional "buffering"a response from a loving, supportive caregiver that comforts the child, restores a sense of safety and allows cortisol levels to fall back down to normal. Some research suggests that this buffering works in part because a good hugor even soft reassuring words from a caregivercan cause the body to release the hormone oxytocin, sometimes referred to as the "cuddle" or "love" hormone.

One of the reasons the ACE study was so effective at highlighting the potential long-term health effects that early childhood adversity can have on health, says Burke Harris, was the nature of the stressors measured. The stressors took place within the context of a family situation that often reflected the failure of a caregiver to intervene as a needed protector.

"The items that are on the ACE screening have this amazing combination of being high stress and also simultaneously taking out the buffering protected mechanisms," Burke Harris says. "If you're being regularly abused, often it's partially because your parents are not intervening."

This hypothesis is supported by experiments in rodents. Back in the 1950s, the psychiatrist Seymour Levine demonstrated that baby rats taken away from their mothers for 15 minutes each day grew up to be less nervous and produce less cortisol than their counterparts. The reason, he suggested, was due to affection from their distressed parent in the form of extra licking and grooming. Studies in the 1990s confirmed that the extra affection and comfort offered by the affectionate parents seemed to have flipped biological "epigenetic" switches that caused their offspring to internalize the sense of safety that had been provided and replicate it biochemically as adults.

Scientists have since documented many biochemical mechanisms by which emotional buffering can help inoculate children exposed to adversity to long-term consequences, and how chronic overactivation of the HPA axis can interfere with developmentor, as one widely cited scientific paper put it, can have an impact akin to "changing the course of a rocket at the moment of takeoff." Neglected and abused Romanian orphans were shown to have smaller brains as a population than those placed in loving foster homes, suggesting a lack of stimulation interfered with normal neuronal growth. Adversity and stress without adequate buffering can turn on genes that flood the system with enzymes that prime the body to respond to further stress by making it easier to produce adrenaline and reactivate the fight-or-flight response quickly, which can make it harder for children with toxic stress to control their emotions.

Toxic stress can also have powerful influences on the developing immune system. Too much cortisol suppresses immunity and increases the chance of infection, while too little cortisol can cause an inflammatory immune response to persist long after it is needed. That can act directly on the brain to produce "sickness behavior," characterized by a lack of appetite, fatigue, social withdrawal, depressed mood, irritability and poor cognitive functioning, according to a 2013 review paper aimed at bringing pediatricians up to speed on the emerging science. As adults, children maltreated during childhood are more likely to have elevated inflammatory markers and a greater inflammatory response to stress, the researchers reported. Chronic elevations in cortisol have also been linked to hypertension, insulin resistance, obesity, type 2 diabetes and cardiovascular disease.

In recent years, Fellitti and Anda's original 1998 paper has been cited more than 10,000 times in further studies. And as awareness in the public health community has risen, so too has the amount of data available to work with, and the vast body of research documenting the far-reaching consequences of ACEs. Last fall, the CDC analyzed data from 25 states collected between 2015 and 2017, and more than 144,000 adults (a sample 8.5 times larger than the original 1998 study). The authors noted that ACEs are associated with at least five of the top 10 leading causes of death; that preventing ACEs could potentially reduce chronic diseases, risky health behaviors and socioeconomic challenges later in life and have a positive impact on education and employment levels. Reducing ACEs could prevent 21 million cases of depression; 1.9 million cases of heart disease; and 2.5 million cases of obesity, the authors said.

Hundreds of new studies are published every year. In just the last month, studies have come out analyzing the "mediating role of ACEs in attempted suicides among adolescents in military families," the impact of ACEs on aging and on "deviant and altruistic behavior during emerging adulthood."

How to Save the KidsWhile these findings help explain the link to chronic diseases, Harris Burke and other public health officials believe they also provide the basis for some of the most promising interventions in the clinic today. Not surprisingly given her background, Burke Harris looks to pediatric caregivers and other doctors to lead the effort to detect and treat patients suffering from toxic stress. To help them do it, late last year, California released a clinical "algorithm": basically a chart spelling out how doctors should proceed once they compiled a patient's ACE score.

Patients are found to be high-risk for negative health outcomes if the doctor, using a questionnaire, can identify four or more of the adverse childhood experiences or some combination of psychological, social or physical conditions found in studies to be associated with toxic stress. For children, that's obesity, failure-to-thrive syndrome and asthma, but also other indicators such as drug or alcohol use prior to the age of 14, high-school absenteeism and other social problems. For adults, the list includes suicide attempts, memory impairment, hepatitis, cancer and other conditions found to be higher in populations with high ACE scores.

Doctors are encouraged to educate all patients about ACEs and toxic stress regardless of their ACE scores. For patients found to be at intermediate or high risk, additional steps are recommended. The first step in the case of children is to make sure parents or caregivers understand the links ACEs can have to adverse health outcomes. That way, they can be on the lookout for new conditions and take action to prevent them.

Key to this educational process is making sure caregivers understand the protective role buffering can play in countering the corrosive effects of stress. Buffering includes nurturing caregiving, but it can include simple steps like focusing on maintaining proper sleep, exercise and nutrition. Mindfulness training, mental health services and an emphasis on developing healthy relationships are other interventions that Burke Harris says can help combat the stress response.

The specifics will vary on a case-by-case basis, and will rely on the judgment and creativity of the doctor to help adult caregivers design a plan to protect the childand to help both those caregivers and high-risk adults receive social support services and interventions when necessary. In the months ahead, the protocols and interventions will be further refined and expanded. "Most of our interventions are essentially reducing stress hormones, and ultimately changing our environment," says Burke Harris. "But some of the things that I think are really exciting are on the horizon."

In recent years researchers have begun to explore whether the "love drug," oxytocina hormone released when a parent hugs a child might form the basis for potent pharmaceutical interventions. For now, however, "we're on the scientific frontier," she says.

The relatively young state of the science and the fuzziness and subjective nature of the tools California plans to use to evaluate the threat have alarmed some public-health experts. They worry that the state is moving too fast, before more is known about the science of toxic stress. Robert Anda, for one, is uncomfortable with the use of screening tools that rely on an ACE score. He worries it might be misused in the doctor's office because it doesn't measure caregiver buffering or genetic predispositions that might prove protective. The questionnaire he and Felitti developed for the original study was always meant to be a blunt instrumentsuited for a survey of a huge population of patients. The problem with applying it to individual patients, he says, is that it doesn't take into account the severity of the stressor. Who's to say, for instance, that someone with an ACE score of one who was beaten by a caregiver every day of their life is less prone to disease than someone with an ACE score of four who experienced these stressors only intermittently? On a population level, surveying thousands, the outliers would cancel each other out. But on the individual level they could be misleading.

It's a concern echoed by others. "I think the concept behind ACE screening, if it's about sensitizing all of us to the importance of looking for that part of the population that's experiencing adversity, I'd say that's good," says Jack Shonkoff, a professor of child health and development who directs the Center on the Developing Child at Harvard University. "But if it's used as an individual diagnostic test or indicator child by child, I would say that's potentially dangerous in terms of inappropriate labeling or inappropriate alarm. We need to make sure that people don't misuse this information so that parents don't feel like they've just been given some kind of deterministic diagnosis. Because it's not that. It's also dangerous to totally give a clean bill of health for a kid who may be showing symptoms of stress."

Burke Harris notes that she has been using ACE scores as part of her clinical care for more than a decade. When used correctly, it is only one part of a larger screening process. And she points out that despite the early phase of the field, the stakes are too high to wait any longer. "This is extremely urgent," she says. "It's a public health crisis. We have enough research now to act. And once we have enough research to act, not acting becomes an unconscionable path."

In the years ahead, more precise methods of detection will likely be available. Harvard's Shonkoff recently completed a large, nationwide feasibility study aimed at developing and rolling out a saliva test which could be used to screen for biomarkers that indicate a toxic stress response in both children and adults. The test, developed as part of a six-year, $13 million grant, measures the level of inflammatory cytokines present in the spit sample. Shonkoff and his colleagues are in the process of taking the next step, which involves gathering enough data to develop benchmarks that indicate normal and abnormal levels for stress markers by age, sex, race and ethnicity.

Even the cautious agree a little education will go a long way. "The most important fundamental prevention idea is that people who are caring for children, who are parenting children, need to understand that childhood adversities are likely leading to issues in their own lives," Shonkoff says. "And if they don't find a way to do things differently with support, they will be embedding that same biology back in their children."

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Yes, Stress Really Is Making You Sick - Newsweek

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