Breaking the cycle

Joie Goodkin first noticed something wasn’t right more than 20 years ago when she started having shortness of breath while climbing stairs. She saw a cardiologist, who diagnosed her with cardiomyopathy, a disease where the heart muscle weakens and has difficulty pumping blood as it should. It may have been caused by a thyroid medication she was prescribed for an underactive thyroid, said Goodkin, who is 84 and lives in Carmel, California.

She armed herself with a team of doctors she trusts at Stanford Medicine and, for a long while the cardiomyopathy didn’t slow her down much. She loves getting outside and spends much of her retirement from a busy publishing job on long hikes. But at the end of 2023, she started regularly having shortness of breath.

This time, she was diagnosed with heart failure — her heart wasn’t pumping enough blood for her body. It turned out she has a leaking mitral valve, which caused blood to leak backward between the chambers of her heart. She had surgery to repair it and, at the time, her doctor asked her what she wanted to do that her condition had prevented her from doing. Goodkin told him she wanted to climb mountains again.

While she’s not quite climbing mountains, she does get out with her dog — who also has heart failure — for a few neighborhood walks a day. Goodkin has also been living with chronic lymphocytic leukemia for several years, a type of blood cancer that often grows very slowly. She doesn’t need treatment for it, but it’s regularly monitored. Together with her heart medications and cardiology appointments, there’s a lot to manage, she said.

“You have to play a role in your own health, and you have to recognize you have power in your situation,” Goodkin said. “Once you have a chronic disease, the best thing you can do is accept that you have it, do what you can and think about what you’re grateful for.”

Goodkin is one of the approximately 130 million Americans living with a chronic disease, defined as any disease that persists for a year or more and significantly impacts a person’s life, whether by limiting activities, requiring ongoing medical care or both.

According to RAND, around 6 in 10 adults in the United States have at least one chronic disease, and 40% have two or more. We spend 90% of our $4.5 trillion health care expenditure on chronic conditions, according to the Centers for Disease Control and Prevention. Chronic diseases account for 5 of the top 10 causes of death in this country, the CDC says.

While those numbers sound grim, the reality of chronic disease is nuanced. Many are tightly linked with aging — like Goodkin, 85% of U.S. adults older than 65 have one or more chronic diseases — and Americans have been living longer. That’s thanks to advances in medical treatments for acute diseases like cancer and heart disease. As the number of elderly people increases, so does the number of people with age-related chronic diseases.

Not all chronic diseases are tied to aging, however. Many of them — like mental health conditions, Type 1 diabetes and other autoimmune diseases, and addiction — can strike people of any age, including children, though widespread availability of childhood vaccines has resulted in a drop in childhood mortality.

“You have to play a role in your own health, and you have to recognize you have power in your situation. Once you have a chronic disease, the best thing you can do is accept that you have it, do what you can and think about what you’re grateful for.”

Joie Goodkin, a Stanford Health Care heart patient

Chronic conditions are also increasing in children: According to a study from researchers at the Children’s Hospital of Philadelphia, the percentage of children aged 3-17 with a chronic condition as reported by a parent rose from 26% to 31% between 2011 and 2023. Mental health conditions such as depression and anxiety showed some of the largest increases, as did autism spectrum disorder, although recent improvements in autism screening and diagnosis are likely responsible for at least some of that increase.

While chronic conditions such as high blood pressure or cholesterol levels can return to normal levels with medication or lifestyle changes, others, such as depression or autoimmune diseases, are often lifelong. And experiencing a chronic disease is more complex than suffering an acute ailment, when friends and family tend to rally around to help.

“Besides the burden of the disease, there’s the financial burden on the individual and the emotional burden on the patient, their caregivers and family,” said Euan Ashley, MB ChB, DPhil, the Arthur L. Bloomfield Professor in Medicine and chair of the Department of Medicine.

“There’s a very significant opportunity here to improve people’s mental, physical and financial health by treating and managing these diseases better, and that’s one way that our research can be of huge value to society.”

Policy makers are also grappling with the chronic disease crisis. One concerted area of focus for federal agencies is nutrition, including defining ultraprocessed foods, investigating additives and improving nutrient labels.

Building on a strong foundation of innovative chronic disease treatment at Stanford Medicine, researchers are developing new approaches to cure what were once lifelong ailments, advocate for preventive approaches to stop them before they start, and enable patients to thrive despite these illnesses.

Bringing research to patients

One such project takes aim at hypertension, or high blood pressure, that without proper treatment can increase the risk of heart disease or stroke. Nearly half of adults in the U.S. have hypertension, making it one of the country’s most common chronic diseases, and only one-quarter of those people successfully control their blood pressure.

So Paul Wang, MD, director of the Stanford Cardiac Arrhythmia Service and a professor of cardiovascular medicine, and his colleagues, including Vivek Bhalla, MD, an associate professor of nephrology, built a digital system called HrtEx to track blood pressure at home and update physicians when it’s too high.

This technology can save patients and their care providers a huge amount of time and resources, Wang said. When someone is diagnosed with hypertension, finding the right treatment can take a lot of trial and error as medications are adjusted, often requiring weekly clinic visits that take up time for patients and primary care teams. In a small clinical trial, an early version of HrtEx substantially lowered participants’ blood pressure. The researchers are now enrolling subjects for a larger trial of 600-800 participants.

“The health care system is set up primarily to treat people, and it falls mostly to primary care physicians to do prevention, and we don’t have enough of them, “From a prevention standpoint, we could do a much better job.”

Doug Owens, the Henry J. Kaiser, Jr. Professor and chair of the Department of Health Policy

“We just don’t have the ability in this country to manage all chronic disease patients at the level they need,” said Wang, the John R. and Ai Giak L. Singleton Director. “We believe that we can leverage digital technology to serve a broader group of patients. This is a pretty unusual opportunity where we use fewer resources and actually get better outcomes.”

Stanford Medicine supports several programs that move research and inventions like HrtEx to market and the community. Wang and Bhalla are working within one of these, the Stanford Medicine Catalyst program, in hopes of commercializing HrtEx for broad use.

Another Catalyst project to improve access to care for chronic disease patients targets Parkinson’s disease. Helen Bronte-Stewart, MD, the John E. Cahill Family Professor and a professor of neurology and neurological sciences, is leading the effort to enable physicians to monitor patients’ Parkinson’s disease symptoms remotely and in real time through a brief finger-tapping test on a portable device. The technology, called the Quantitative Digitography platform, is undergoing expedited regulatory review through the U.S. Food and Drug Administration’s Breakthrough Devices Program.

Another innovation that will improve lives of chronic disease patients has made the trip from idea to reality, aided by Stanford Medicine’s SPARK program, which provides funding, education and mentorship to translate research discoveries into patient care. In 2012, Stanford Medicine researchers began working with SPARK to develop a medication for the chronic and life-threatening heart condition transthyretin amyloid cardiomyopathy, which lacked an effective treatment. The new drug, acoramidis, received approval from the FDA last year.

A question of access and resources

Stanford Medicine researchers are also trying to understand the factors that influence chronic disease and patients’ experiences with their illnesses. Epidemiologists, for example, are studying individual lifestyle factors and environmental and societal pressures that contribute to risk, said Melissa Bondy, PhD, chair of the Department of Epidemiology and Population Health. Wildfires and warmer climate in America are increasing allergies and lung disease. Social factors such as where people live, their financial status, and their race and ethnicity can also influence disease risk.

“One of the biggest chronic diseases we have is poverty.”

Melissa Bondy, chair of the Department of Epidemiology and Population Health

“One of the biggest chronic diseases we have is poverty,” said Bondy, the Stanford Medicine Discovery Professor.

Stanford University health economists and policy researchers are also focused on access and prevention. Trillions of dollars are spent every year in the United States on chronic disease, according to the CDC. Better screening guidelines and prevention efforts could lower costs and improve patients’ health, said Doug Owens, MD, the Henry J. Kaiser, Jr. Professor and chair of the Department of Health Policy.

“The health care system is set up primarily to treat people, and it falls mostly to primary care physicians to do prevention, and we don’t have enough of them,” he said. “From a prevention standpoint, we could do a much better job.”

Owens’ work centers on national guidelines and recommendations for disease prevention. He pointed to a recent study in which he and other Stanford Medicine researchers presented evidence that adults 55 and older should be routinely screened for chronic kidney disease. New medications have dramatically improved outcomes for chronic kidney disease, changing the treatment landscape such that screening more people for the disease, and catching it earlier, is now cost effective.

Managing common problems among those with chronic illness

Kate Lorig, PhD, emerita professor of medicine, has focused her research career on helping people with chronic diseases live better lives.

“We looked at how people live the 99% of the time that they’re not in direct medical care, and the concerns turned out to be very similar across diseases,” Lorig said. “We came up with this crazy idea of trying to put people with all kinds of long-term conditions together in one program at one time.”

That idea became the Chronic Disease Self-Management Program, launched in the early 1990s. It aims to build participants’ self-confidence and help them manage symptoms by teaching them such lifestyle skills as healthy eating, physical activity, dealing with difficult emotions, and better communication with their caregivers and health care providers. Lorig’s research has shown that the program, and others like it, can lower participants’ rates of depression and visits to the emergency room and improve symptoms and well-being.

In 2015, Lorig and her team spun the concept into a company, the Self-Management Resource Center. Its programs, which include disease-specific education for diabetes, cancer and HIV, have been licensed by hundreds of health care systems, community organizations and other groups around the world. Lorig estimates they reach between 50,000 and 75,000 patients every year.

Pioneers in prevention

The late John “Jack” Farquhar, MD, founder of the Stanford Heart Disease Prevention Program, was among the first to recognize the major impacts of lifestyle on heart disease and, with the late Nathan Maccoby, PhD, Stanford professor of communications, took prevention methods directly to local communities.

Starting in the early 1970s, they and their team studied large populations in various Northern California communities, sharing research findings with residents through television and radio programs, billboards, newspaper columns, and other public announcements in English and Spanish. Study participants changed their diets, reduced smoking, and lowered their blood pressure and cholesterol levels.

“That was really quite innovative — to try to change the behavior of a community instead of doing a clinical trial on a person-by-person basis.”

David Maron, a professor of medicine and division chief of the Stanford Prevention Research Center

“That was really quite innovative — to try to change the behavior of a community instead of doing a clinical trial on a person-by-person basis,” said David Maron, MD, the C. F. Rehnborg Professor, a professor of medicine and division chief of the Stanford Prevention Research Center, which evolved out of the Stanford Heart Disease Prevention Program.

Maron and colleagues at the Stanford Prevention Research Center are hoping to prevent not only heart disease but other diseases including Type 2 diabetes, cancer and osteoporosis. Maron has led the development of imaging techniques and AI methods to identify people at high risk of heart disease sooner.

“We need to start our interventions earlier to have a greater chance of keeping people free of disease through their lifespan,” he said.

Read on for more stories of how Stanford Medicine is tackling the chronic disease crisis. — Contact Rachel Tompa at medmag@stanford.edu

REWRITING THE RULES OF SICKLE CELL TREATMENT

Stanford chemical biologist Laura Dassama is on a personal mission to design a simpler, more affordable sickle cell therapy

By Sarah C.P. Williams

By the time Laura Dassama, PhD, was 5, she had already met the disease that would help define her future. The pain was unpredictable and searing, sometimes flaring in her limbs, sometimes in her chest. Sickle cell disease, a hereditary blood disorder, was something she and her sister would learn to navigate together while growing up in Liberia.

Today, as an assistant professor of microbiology and immunology and of chemistry at Stanford University, Dassama is confronting sickle cell disease from a new vantage point: the laboratory.

“I’ve seen it firsthand. I’ve lived with it,” she said. “And I know that, for many people, the current treatments just aren’t enough. We need more options, and we need therapies that are both effective and accessible.”

Sickle cell disease stems from a single mutation in the gene responsible for helping make hemoglobin, the oxygen-carrying protein inside red blood cells. The resulting faulty version of hemoglobin tends to clump, distorting normally round red cells into stiff, crescent-shaped “sickles.” These misshapen cells can clog blood vessels and break down easily, leading to chronic anemia, pain and organ damage.

Doctors have long known that one way to counteract sickle cell disease is to induce the body’s production of a fetal version of hemoglobin, which binds more tightly than the adult form, ensuring that developing fetuses can claim some of the oxygen circulating through their mom’s body.

Shortly after they’re born, babies’ bodies switch to making adult hemoglobin and, for most people, production of fetal hemoglobin stops altogether. But some people keep small amounts into adulthood — and studies have found that people with sickle cell disease who retain some fetal hemoglobin tend to fare far better.

Red blood cells with higher levels of fetal hemoglobin are more resistant to clumping and sickling — even when the sickle cell mutation is still present. “If we could reliably boost fetal hemoglobin levels, we could dramatically reduce symptoms for many people,” Dassama explained.

“I’ve seen it firsthand. I’ve lived with it, And I know that, for many people, the current treatments just aren’t enough.”

Laura Dassama, assistant professor of microbiology and immunology

For decades, researchers have dreamed of turning the production of fetal hemoglobin back on in adults with sickle cell disease. One drug, hydroxyurea, does so in some patients, though no one’s sure why it works — and it doesn’t work for everyone.

More recently, gene-editing therapies have been shown to disable the genetic switch that normally shuts fetal hemoglobin production down, allowing it to turn back on.

But these therapies are complex, expensive procedures that require harvesting, editing and re-implanting a patient’s own bone marrow cells. “It can take over a year,” Dassama said. “And the cells don’t always survive the process.”

Reawakening healthy hemoglobin

Dassama’s lab is exploring a simpler, cheaper and faster way to switch on fetal hemoglobin production. Her team is targeting a protein called BCL11A, which acts as the genetic off switch to prevent most adults’ bodies from making the fetal hemoglobin. Her lab has designed a molecule that tags BCL11A for destruction by the cell’s own waste-disposal system. Her new molecule acts like a “get rid of me” flag for BCL11A, and once BCL11A is cleared away, fetal hemoglobin can reemerge.

“It’s a different kind of precision medicine,” Dassama said. “We’re not rewriting the genome — we’re guiding the cell to do something it already knows how to do.”

While still in early stages, the approach reflects a growing interest in finding druglike molecules that can eliminate disease-driving proteins, especially those long considered “undruggable.” BCL11A is one of them — its structure doesn’t have the usual nooks and crannies that drugs can recognize. But Dassama’s background in chemical biology gives her a unique tool kit.

Her lab has already identified a molecule that binds BCL11A, and they’ve added the flag that sends it to the cellular trash bin. The next step: ensuring the drug can effectively get into blood cells to do its job. Dassama said she hopes the strategies developed in this project will apply to other so-called undruggable targets.

But Dassama’s motivation goes beyond the science. She’s acutely aware of the need for treatments that are not only effective but also accessible — especially in parts of the world where sickle cell is most common, including sub-Saharan Africa.

“This disease affects millions of people, but too often they don’t have access to cutting-edge therapies,” she said. “My goal is a treatment that you don’t need a specialty clinic or a million-dollar lab to receive. Something people could access.” — Contact Sarah C.P. Williams at medmag@stanford.edu

ENGINEERING A COMEBACK

How T cells are taking on autoimmune disease

By Rachel Tompa

Illustration by Ard Su

Something strange and promising happened to the autoimmune disease patients enrolled in the first studies of an experimental, immune cell-based treatment: They went into complete or near-complete remission after a single infusion of the therapy.

Autoimmune diseases like lupus, Type 1 diabetes and multiple sclerosis are chronic diseases where a patient’s immune system mistakenly attacks healthy tissues in the body. In these early-stage trials, the patients’ immune systems appear to reset themselves after being knocked down by the therapies, roaring back to a healthy immune state without the self-attacking cells and molecules that characterize autoimmunity.

The treatment, called cell therapy, involves removing a patient’s own immune cells from their blood, modifying them in the lab to recognize and attack disease targets, and then reinfusing the cells into the bloodstream to go after the patient’s disease-causing cells.

Over the past decade, cell therapies have successfully treated many patients with blood cancers, and now Stanford Medicine researchers are translating that success to autoimmune disease, including through a first-of-its-kind cell therapy trial for multiple sclerosis. Using cell therapy to treat autoimmune disease was named a runner-up in Science magazine’s 2024 Breakthrough of the Year competition.

The “immune reset” had been observed in patients with both autoimmune disease and blood cancer who underwent bone marrow transplants, one of the first developed cell therapies, for their cancer, said Everett Meyer, MD, PhD, director of Stanford Medicine’s center of operations for trials of cell therapy in autoimmune disease, the Cellular Immune Tolerance Program.

“Within the realm of cell therapy is the potential for much more sophisticated engineering of the immune system. That’s the future we’re trying to push for.”

Everett Meyer, director of Stanford Medicine’s center of operations for trials of cell therapy in autoimmune disease

Because bone marrow transplants have historically been hard on the body, they were typically used only to treat people whose cancer was not responding to other treatments or had relapsed. Now that bone marrow transplants are much safer, they are being tested as an autoimmune disease treatment.

“Safety is a big part of the revolution that’s happening in cancer treatment,” said Meyer, a professor of blood and marrow transplantation and cellular therapy and of pediatrics. “Within the realm of cell therapy is the potential for much more sophisticated engineering of the immune system. That’s the future we’re trying to push for.”

Instead of reversing the underlying cause of autoimmunity, most treatments for autoimmune disease suppress the immune system, which can lead to side effects such as increased risk of infection. Meyer and his colleagues are exploring a treatment that could address the root cause of an autoimmune disease: cell therapy for Type 1 diabetes.

Their approach, which they hope to test in a clinical trial, combines the boosting of immune cells known as regulatory T cells with an islet cell transplant, which replaces nonfunctional insulin-producing cells with functional versions from a deceased donor. Animal studies have shown that regulatory T cells can help ease the transplant without the need for harsh immunosuppressing drugs; the cells may also retrain the immune system to stop attacking the pancreas.

One clinical trial run through the immune tolerance program is testing cell therapy in patients with progressive multiple sclerosis. In this chronic disease, the immune system mistakenly attacks the protective covering of nerve fibers, leading to nerve damage, muscle weakness and fatigue. Many multiple sclerosis patients have periods of remission and relapse, but for those with progressive disease, their symptoms worsen relentlessly.

Suppressing multiple sclerosis

The Stanford Medicine trial, led by Jeffrey Dunn, MD, a clinical professor of neurology, and Robert Lowsky, MD, a professor of blood and marrow transplantation and cellular therapy, is testing a cell therapy similar to those developed for certain blood cancers. In this approach, T cells, a kind of immune cell, are extracted from a patient’s body, engineered in the lab with a special protein (called a chimeric antigen receptor, or CAR) that recognizes other immune cells known as B cells, and then reinfused into the patient. The souped-up T cells, armed with the special protein attached to their surface, home to B cells and direct the immune system to kill them. In the case of blood cancer, the therapy eliminates cancerous and healthy B cells alike, and, if the therapy works, the B cells grow back without cancer.

Researchers hope the same sort of purge and renewal could happen in multiple sclerosis, which also involves bad behavior by B cells: Among a subset of people who’ve been infected by the Epstein-Barr virus, the B cells make an antibody against the virus that damages the protective sheath of nerve fibers. Encouragingly, Dunn and his colleagues have found that the CAR-T cells can enter the central nervous system, where multiple sclerosis does the most damage.

In the early-phase trial, which is the first trial testing a cell therapy in multiple sclerosis patients, researchers have treated four patients of a planned 12. The first patient in the trial is six months past the treatment, and spinal taps have shown a complete absence of inflammation-associated antibodies in the central nervous system.

The team is now determining whether antibodies against Epstein-Barr virus are specifically depleted. All four patients report decreased fatigue. “These are very early numbers, but the data are really exciting and certainly demand that we continue forward,” Dunn said. — Contact Rachel Tompa at medmag@stanford.edu

LIGHTING UP THE GUT TO DETECT CELIAC DISEASE

A clinician and scientist collaborate on new methods to diagnose, treat and track celiac disease

By Sarah C.P. Williams

For Nielsen Fernandez-Becker, MD, PhD, diagnosing celiac disease at times feels like working in the dark.

When a patient complains of abdominal pain, nausea and diarrhea, Fernandez-Becker typically orders a blood test and an intestinal biopsy to screen for celiac disease — a gut-inflaming autoimmune reaction triggered by gluten, a type of protein found in some grains.

But neither test is completely accurate, especially if someone is already avoiding gluten, minimizing the telltale signs of damage caused by the disease.

“It’s frustrating,” said the gastroenterologist, who leads Stanford Health Care’s celiac disease program. “We don’t have a perfect test that can always tell someone with complete certainty whether they have celiac.”

Now, Fernandez-Becker and longtime collaborator Chaitan Khosla, PhD, are testing a more reliable way to detect the disease with the help of Stanford University’s Innovative Medicines Accelerator. The two are launching a clinical trial of a fluorescent compound that literally lights up a celiac disease-triggering molecule. When a doctor peers at intestinal cells under a microscope, the presence or absence of celiac disease will be clearly illuminated. The team’s initial goal is to improve the diagnosis and monitoring of the disease — but their findings could also lay the groundwork for new treatment strategies.

Celiac disease is one of the world’s most common autoimmune conditions, affecting an estimated 1 in 100 people. In people with celiac disease, the body’s immune system overreacts to gluten. But it’s not gluten that sets off the response — it’s gluten that has been chemically altered by an enzyme called tissue transglutaminase 2, or TG2.

“I got interested in TG2 about 25 years ago when I first started looking at celiac disease. This protein seems to play a very important role in causing celiac disease in patients,” said Khosla, the Wells H. Rauser and Harold M. Petiprin Professor and a professor of chemistry. “It seemed like this might be a good target to make a medicine for celiac disease.”

Khosla was inspired to shift his research to celiac disease after his young son was diagnosed with the condition. He reasoned that there must be a way to stop the immune reaction that causes symptoms. Blocking TG2, for instance, would stop the conversion of gluten to its modified form and prevent the inflammatory immune reaction from taking place.

Roadblocks to celiac solutions

But the enzyme is a tricky target. It doesn’t just hang out in an “on” state, ready to wreak havoc at the first bite of bread. In healthy people, the enzyme is usually off — it’s quiet, inactive, just sitting there. In people with celiac disease, however, TG2 becomes persistently active, modifying gluten and triggering gut inflammation.

Over several decades, Khosla’s laboratory studied how TG2 is activated. His team’s work led to the launching of a company, Sitari Pharma, that exploited their findings to develop a drug that inhibits the active form of the enzyme.

Following the acquisition of Sitari by GlaxoSmithKline, the drug entered early clinical trials as a potential treatment for celiac disease. But after a successful Phase 1 clinical trial, the company repurposed the drug for further studies in a different disease. So, Khosla felt he had no choice but to go back to the drawing board in search of a solution for celiac patients.

The same challenges that Fernandez-Becker faces in initially diagnosing celiac disease also plague clinical trials for drugs designed to treat this condition. Other than asking a patient about their symptoms, how can doctors — without a definitive test for celiac — track whether a drug is working?

“This represented a huge problem for the pharmaceutical industry in developing a celiac medicine,” explained Khosla. “There were no benchmarks to show whether the disease was improving,” he said.

“This could have a profound impact on how we diagnose and treat celiac disease. We can give patients a much more definitive answer that, yes, this immune reaction against gluten is causing your symptoms.”

Nielsen Fernandez-Becker, a clinical professor of gastroenterology and hepatology

This roadblock led to a new idea for Khosla — one could convert a medicinal TG2 blocker into a kind of tracker. So, Khosla and his students made a new variation of the drug bearing a fluorescent tag that would light up only in the presence of active TG2.

“This could have a profound impact on how we diagnose and treat celiac disease,” said Fernandez-Becker, a clinical professor of gastroenterology and hepatology. “We can give patients a much more definitive answer that, yes, this immune reaction against gluten is causing your symptoms.”

In the new clinical trial, enabled by the Innovative Medicines Accelerator and slated to start once the team receives approval from the Food and Drug Administration, patients will drink a solution containing the TG2-binding molecule a few hours before a scheduled endoscopy, during which doctors collect an intestinal biopsy. If TG2 is switched on, the probe will light it up in the biopsy.

Fernandez-Becker and her colleagues will first study the safety of the probe and then begin asking questions about how well it detects celiac disease and monitors disease progression.

For patients, the potential benefits go well beyond diagnosis. The researchers hope the probe will also show whether a gluten-free diet is working — or if lingering symptoms point to ongoing disease or another condition. That’s a particularly important distinction, Fernandez-Becker said, because some patients continue to struggle even after eliminating gluten — and it’s not always clear why. The presence or absence of TG2 activity could help clarify.

“Right now, we don’t have a way to measure mucosal healing in real time,” Fernandez-Becker said. “But if we could use this to see whether the gut is still inflamed, we’d have a powerful new way to guide treatment.”

Probing for answers

It might also clear a path for future therapies. A definitive test for active TG2 could finally give researchers the biomarker they’ve been missing to study how well TG2-blocking drugs work — it would provide a way to track whether a drug is making a meaningful difference inside the gut, not just easing symptoms on the surface.

“Often times, people begin to heal from celiac disease enough that it’s hard for a pathologist to tell whether their intestines are normal just from a biopsy. With a molecular marker for active TG2, we may be able to give them a much better idea,” Khosla said. — Contact Sarah C.P. Williams at medmag@stanford.edu

TRACKING PAIN’S PATHWAYS

Research on clusters of nerve cells in a dish refines our knowledge about pain and how to treat it

By Bruce Goldman

Illustration by Ard Su

Stanford Medicine investigators have replicated, in a lab dish, one of humans’ most prominent nervous pathways for sensing pain. This nerve circuit transmits sensations from the body’s skin to the brain. Once further processed there, these signals will translate into our subjective experience, including the uncomfortable feeling of pain. The advance promises to accelerate progress in understanding how pain signals are processed in humans and how best to alleviate pain.

A study published in Nature led by Sergiu Pasca, MD, the Kenneth T. Norris, Jr. Professor II of Psychiatry and Behavioral Sciences, describes the successful assembly of four miniaturized parts of the human nervous system to reconstitute what’s known as the ascending sensory pathway. The sensation of pain travels from skin to the brain in a relay involving nerve cells, or neurons, centered in four different regions of this pathway: the dorsal root ganglion, dorsal spinal cord, thalamus and somatosensory cortex.

Human pain has often proven tough to study in laboratory animals, Pasca said. “Their pain pathways are in some respects different from ours. In addition, these animals experience pain. Our dish-based construct doesn’t,” he said.

“Pain is a huge health problem,” said Vivianne Tawfik, MD, PhD, associate professor of anesthesiology, perioperative and pain medicine, who wasn’t involved in the study. “Some 116 million Americans — more than 1 in 3 people in the United States — are dealing with chronic pain of one kind or another.” This pain often persists even when observable damage is no longer evident, possibly the result of lasting changes in the ascending sensory pathway.

Yet treatments for chronic pain are few and far from ideal. “I can’t even tell you how sad it is to sit in front of a patient who’s suffering from chronic pain after we’ve tried everything, and there’s nothing left in our arsenal,” Tawfik said.

The most effective painkillers today are opioid drugs, which have the severe drawback of being habit-forming, leaving chronic-pain sufferers susceptible to addiction.

“I can’t even tell you how sad it is to sit in front of a patient who’s suffering from chronic pain after we’ve tried everything, and there’s nothing left in our arsenal.”

Vivianne Tawfik, associate professor of anesthesiology, perioperative and pain medicine

Tawfik said she thinks the team’s new construct is highly relevant to the study of chronic pain. “The pathway they’ve reconstructed is the most important one for conveying pain-related information,” she said.

The regions that compose the ascending sensory pathway are linked by three sets of neuronal connections: The first set relays sensory information from the skin through the dorsal root ganglion to the spinal cord; a second set of neurons passes the signals from the spinal cord to a brain structure called the thalamus; and the third relays this information from the thalamus to the somatosensory cortex for further processing of the signal originating from the periphery.

Until now, nobody has been able to watch information being transmitted through this entire pathway. But Pasca and his colleagues witnessed never-before-seen waves of electrical activity travel from the first component of their construct to the last. They were able to enhance or disrupt the wavelike patterns by gene alterations or chemical stimulation of elements of the circuit.

Pasca, the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program, has pioneered the creation of what he calls regionalized neural organoids, grown in a lab dish from stem cells and representing various brain regions. In recent years, Pasca has pushed this technology forward, pairing organoids of one type with organoids of another type in a dish so they fuse into what he’s named assembloids. Neurons from one organoid can penetrate the other organoid to form working circuits similar or even identical to those they’re meant to mimic.

Stimulating neuronal activity

In the new study, Pasca and his colleagues developed human organoids recapitulating the ascending sensory pathway’s four key regions, then fused them together in a series to form an assembloid mimicking the pathway. Starting with cells from skin samples from volunteers, the team first transformed them into induced pluripotent stem cells, which are essentially de-differentiated cells that can be guided to become virtually any cell type in the human body. The researchers used chemical signals to coax these cells into aggregating into neural organoids — tiny balls less than a tenth of an inch in diameter — representing each of the four regions of the pathway.

Pasca and his colleagues lined up the organoids of those four different types side by side and waited. By 100 days later, they had fused into an assembloid consisting of nearly 4 million cells — less than 1/42,000 of the number in an adult human brain.

Yet, the construct regenerated the pathway’s circuitry, and its four constituent organoids were anatomically connected: Neurons from the first had formed working connections with neurons from the second, the second with the third and so on. Plus, the circuit worked as a unit: Neuronal activity in the sensory organoid tripped off similar action in the spinal organoid, then in the thalamic organoid and finally in the cortical organoid.

Stimulating the sensory organoid with capsaicin — the ingredient in chili peppers that produces a burning sensation in our mouths — triggered immediate waves of neuronal activity.

“We think screening for drugs that tame sensory organoids’ ability to trigger excessive or inappropriate waves of neuronal transmission through our assembloid, without affecting the brain’s reward circuitry as opioid drugs do — which is why they’re addictive — could lead to better-targeted therapies for pain.”

Sergiu Pasca, the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program

Mutations in a protein called Nav1.7, which abounds on the surfaces of peripheral sensory neurons but is scarce elsewhere, can lead to debilitating hypersensitivity to pain or, conversely, a life-threatening inability to experience pain — radically increasing the physical dangers, routine or otherwise, that life serves up.

The scientists made an assembloid with its initial sensory component’s normal version of Nav1.7 replaced by the mutant pain-hypersensitivity version. The resulting assembloids displayed more-frequent waves of neuronal transmission from the sensory organoid all the way to the cerebral-cortex organoid.

When Pasca’s team instead rendered Nav1.7 non-functional, firing from that organoid in response to a pain-inducing chemical continued — but the synchronized wavelike transmission of pain information through the circuit mysteriously vanished.

The assembloids represent an early phase of fetal development. Pasca’s lab is working on ways to accelerate development of the assembloids to better understand how the pathway they represent works — or doesn’t — in adults.

“We think screening for drugs that tame sensory organoids’ ability to trigger excessive or inappropriate waves of neuronal transmission through our assembloid, without affecting the brain’s reward circuitry as opioid drugs do — which is why they’re addictive — could lead to better-targeted therapies for pain,” Pasca said. — Contact Bruce Goldman at goldmanb@stanford.edu.

TRAINING DOCTORS TO TREAT ADDICTION

A pioneering program prepares physicians to tackle addiction — with heart and science

By Nina Bai

If someone in a diabetic crisis walks into an emergency room, the doctors know what to do. They recall their training and have well-established protocols to follow.

But if a person struggling with addiction and desperate to stop using walks into an emergency room, the reception is less predictable. Many emergency rooms — and health care settings in general — still lack the resources and trained staff to help patients with substance use disorders.

“Early in my career, if someone came in withdrawing from alcohol, you would just keep them in the emergency room long enough to sober them up and then discharge them — with few resources to help them make connections to addiction treatment,” said Anna Lembke, MD, professor of psychiatry and behavioral sciences.

Lembke completed her medical training in psychiatry in the early 2000s, during which she recalls receiving limited dedicated teaching on addiction. Later, as a young psychiatrist at Stanford Health Care, she was at first reluctant to take on patients with addictions, in part because she was unaware that effective treatments — including medications and behavioral therapies — were available. But there was no avoiding the growing number of patients with concurrent mental health disorders and substance use disorders.

“It was very evident that we were seeing more and more people struggling with all different forms of addiction. But we had too few doctors trained in addiction medicine to be able to meet the need, and we had limited infrastructure inside the house of medicine to treat patients with addiction.”

Anna Lembke, professor of psychiatry and behavioral sciences

By 2010, she had founded a clinic to focus on these patients — the Stanford Addiction Medicine Dual Diagnosis Clinic. The opioid crisis brought addiction into view for many Americans, and doctors were grappling with their role in overprescribing opioids.

“It was very evident that we were seeing more and more people struggling with all different forms of addiction,” she said. “But we had too few doctors trained in addiction medicine to be able to meet the need, and we had limited infrastructure inside the house of medicine to treat patients with addiction.”

In 2012, with the support of the then new chair of the Department of Psychiatry and Behavioral Sciences, Laura Roberts, MD, Lembke started Stanford Medicine’s addiction medicine fellowship.

Three years later, it became one of the first addiction medicine fellowships to be authorized by the accreditation organization for U.S. graduate medical training programs. For the first few years, there was enough funding for only one fellow a year.

Chinyere Ogbonna, MD, was the fellow in the third year of the program. Trained in family medicine and psychiatry, her work with veterans and underserved populations motivated her to learn more about addiction medicine. The fellowship showed her that addiction touches everyone. “One of the biggest lessons I learned was to be aware of my biases about who’s affected by addiction,” she said. “You really can’t look at someone and say that person has addiction or that person would never have addiction.”

Though the fellowship is part of the psychiatry department, Lembke wanted the program to welcome doctors from all fields. “Most people with addiction are not showing up in psychiatric settings,” Lembke said. “They’re showing up in emergency rooms, hospitals and trauma centers. They’re showing up in primary care doctors’ offices.” Now in its 13th year, the addiction medicine fellowship has trained doctors from a wide variety of specialties — including family medicine, pediatrics, emergency medicine, anesthesiology and psychiatry.

Bobby Singh, MD, had worked for eight years as a hospitalist in Santa Cruz, California, where he’d become well-versed in treating withdrawals and overdoses. Yet he knew little about options for patients outside the hospital.

He’d seen friends and family struggle in treatment programs that took a punitive approach, lacked evidence-based treatments and offered no support afterward. “I thought things could be done differently, but I just didn’t know how to do it back then,” he said. He took a midcareer leap of faith to attend the fellowship in 2021, while still working part time.

“One of the biggest lessons I learned was to be aware of my biases about who’s affected by addiction. You really can’t look at someone and say that person has addiction or that person would never have addiction.”

Chinyere Ogbonna, who was the fellow in the third year of Stanford Medicine’s addiction medicine fellowship program, which Anna Lembke developed

Unlike most fellowships, which have fellows rotating through a different site each month, the Stanford Medicine program is structured longitudinally, with fellows working at multiple sites in parallel over six months or a year. For example, on Mondays they might work at Stanford Hospital, on Tuesdays they might work at Stanford’s dual diagnosis clinic for people who have both mental health and substance use disorders, and on Wednesdays they might work at the VA Palo Alto Health Care System.

The continuity is key, Lembke said, because addiction is a chronic relapsing and remitting disease. “We wanted our fellows to be with patients long enough to see the natural ebbs and flows of the disease process, to see people get better, but also to see what relapse looks like.”

Sara Marie Cohen-Fournier, MD, who trained in psychiatry in Montreal, Canada, attended the fellowship in 2021. She was drawn to its humanist approach, which allowed doctors to connect with patients, many of whom have faced rejection by their peers, family or community.

“The idea of putting the story of the person at the forefront, instead of the problems of the person, is a big shift in psychiatry, where a lot of times our interviews are focused on ‘What’s your problem? Why did you come here?’” she said. Often the whole-person perspective reveals the angle from which to best tackle their addiction — whether it’s their love for their children or a need to find stable housing.

Seeding change

The fellowship now accepts six fellows a year. Its 56 graduates have dispersed to varied careers in addiction medicine, seeding change wherever they practice.

Less than two years after finishing the fellowship, Ogbonna became the medical director of addiction medicine and recovery services at the Kaiser Permanente San Jose Medical Center, where addiction treatment is very much a part of the ecosystem. “All the doctors know about our department and know they can refer patients to us,” she said.

Shortly after graduating in 2022, Singh co-founded an addiction treatment clinic in Santa Cruz with residential and outpatient programs. It offers science-based medication management and emphasizes long-term planning and the patient’s dignity. It’s what he wishes had been available for his family and friends.

Cohen-Fournier works as an addiction medicine specialist in remote areas of northern Quebec, Canada, helping indigenous populations and other local communities. Many of her patients contend with addiction and trauma. In addition to providing screening, psychotherapy and medications, a major part of her job is advocating for her patients — to receive the right care in a system that often dismisses them.

Lembke can see the tide shifting with a new generation. “People are much more aware of addiction. They want to learn about it,” she said. “Some people even want to specialize in it.” — Contact Nina Bai at nina.bai@stanford.edu

AI GETS SPECIFIC ON TYPE 2 DIABETES

Data from continuous glucose monitors can predict prediabetes subtypes

By Rachel Tompa

Illustration by Ard Su

When Stanford Medicine geneticist Michael Snyder, PhD, was diagnosed with prediabetes, he decided to hit the gym.

In prediabetes, blood sugar is elevated past normal levels but not yet to the levels that indicate Type 2 diabetes. An estimated one-third of American adults have prediabetes; more than 1 in 10 have Type 2 diabetes, which makes up around 95% of all diabetes cases.

Snyder, the Stanford W. Ascherman, MD, FACS Professor in Genetics, lifted weights, knowing that exercise and increasing muscle mass can lower blood sugar levels. He put on 10 pounds of muscle, he said, but his blood glucose stayed stubbornly high and he eventually developed Type 2 diabetes.

While many with prediabetes and diabetes have what’s known as insulin resistance, where certain cells respond abnormally to insulin, Snyder’s condition had a different underlying cause: beta cell dysfunction. This kind of diabetes doesn’t respond to exercise the way insulin resistance does. It took Snyder a few years to identify his diabetes subtype and develop a working treatment plan.

“We’re still lumping all Type 2 diabetes patients together, but they’re not all the same. It’s like telling someone they have autoimmune disease or mental health problems without getting more specific — it’s too big a bucket,” said Snyder, who is also director of the Stanford Center for Genomics and Personalized Medicine. “We can get a lot more precise in our diagnostics, and I’m a great example of how tailoring the right treatment can be beneficial or not.”

Recently, Snyder paired up with Tracey McLaughlin, MD, a Stanford Medicine professor of endocrinology, to make prediabetes and Type 2 diabetes diagnoses more precise and help patients more quickly find lifestyle management practices or medications that work for their specific disease.

The team used a machine learning algorithm to analyze data from continuous glucose monitors, which use tiny sensors placed under the skin of the upper arm to assess the body’s glucose levels every few minutes. Their approach identified several known subtypes among the 29 participants who had normal-range or prediabetes-range glucose values.

“We’re still lumping all Type 2 diabetes patients together, but they’re not all the same. It’s like telling someone they have autoimmune disease or mental health problems without getting more specific — it’s too big a bucket.”

Michael Snyder, director of the Stanford Center for Genomics and Personalized Medicine

“Over the years, we’ve noticed a lot of people who have glucose abnormalities who aren’t insulin resistant, which is unexpected because the dogma says that insulin resistance is the first step toward diabetes,” McLaughlin said. “We’d been doing continuous glucose monitoring studies and we noticed that the shapes of the curves differ a lot between people.”

In a paper published in the journal Nature Biomedical Engineering in late 2024, the researchers studied participants’ responses to an oral glucose tolerance test, in which the volunteers drank a syrupy liquid containing 75 grams of sugar. The scientists applied their algorithm to continuous glucose monitoring data for three hours after participants took the drink, following participants’ blood sugar levels as they rose and fell. Higher blood sugar spikes and slower returns to baseline are both hallmarks of prediabetes and diabetes, but with their AI approach, the scientists found more subtle differences among the data.

The algorithm accurately predicted several prediabetes subtypes about 90% of the time. These subtypes represent distinct metabolic processes that all lead to elevated blood sugar. Insulin resistance is perhaps the most well-known; others include beta cell dysfunction, where the pancreas can’t produce insulin efficiently, and incretin deficiency, characterized by defects in a hormone that also regulates insulin. Most participants in the study had one dominant subtype; some had two co-dominant subtypes contributing to their prediabetes.

At-home testing for wider access

The team also applied their approach to specific foods. In another study, published June 4, 2025, in the journal Nature Medicine, they showed that people varied in their responses to different carbohydrates and that some prediabetes subtypes affect food-specific responses. For example, people with insulin resistance were more likely to be “potato spikers,” (people whose blood sugar spiked highest to potatoes versus other same-carbohydrate foods) while “grape spikers” (people whose blood sugar spiked highest to grapes versus other same-carbohydrate foods) tended not to have insulin resistance.

With more than 30 million Americans living with Type 2 diabetes, the health advantages and cost reductions that would stem from less reliance on trial-and-error approaches to treatment could be huge. Insulin resistance also carries health risks besides increasing the risk of Type 2 diabetes, such as stroke and cardiovascular disease. So patients who have this subtype of prediabetes might choose to more aggressively pursue lifestyle changes like exercising more and losing weight. The team also showed the glucose tolerance test can be performed at home, and many people already use continuous glucose monitors.

“What’s exciting is this approach can be scaled to reach a large number of people,” McLaughlin said. “We think it’s going to be really helpful to identify patients at highest risk of worse outcomes and tailor interventions to help more people get their blood sugar under control and prevent progression to Type 2 diabetes.” — Contact Rachel Tompa at medmag@stanford.edu

CHIPPING AWAY AT THE MYSTERIES OF ME/CFS

Renowned geneticist has spent the past 12 years focused on the disease that has taken so much from his son

By Rachel Tompa

Last year, Whitney Dafoe did something extraordinary: He started eating regular food.

Dafoe, 41, has severe chronic fatigue syndrome, also known as myalgic encephalomyelitis or ME/CFS, and had relied on a feeding tube for all his nutrition for years.

Dafoe is also the son of Stanford Medicine’s Ron Davis, PhD, a pioneer in the field of genetics who has devoted the past decade-plus of his life and career to studying and understanding the disease that has robbed Dafoe of so much.

For people with very severe forms of ME/CFS, life is often curtailed by the same symptoms Dafoe experiences: unexplained pain, exhaustion, and sensitivity to noise and light. Also, as with Dafoe, their symptoms can become so severe that they are unable to talk, read, eat, drink or get out of bed.

“I’ve talked to quite a few doctors who say, ‘We don’t cure chronic diseases.’ And my comment back to them is, ‘Because you think you can’t cure them, you never try.’ ”

Ron Davis, a pioneer in the field of genetics who has devoted the past decade-plus of his life and career to researching severe chronic fatigue syndrome

Davis said his son has seen some improvement in his symptoms recently by taking an off-label medication, but he’s not cured. A photographer who, before his illness, traveled the world for his work, Dafoe now makes self-portraits and short videos that capture the realities of life with ME/CFS and is active on ME/CFS forums and his blog.

Much of ME/CFS treatment is built on trial-and-error solutions for each patient — the Food and Drug Administration has not approved any drugs to treat the disease. The treatments that do exist focus on managing symptoms rather than addressing the root cause of the disease, which is still unknown.

Though at least 3.3 million people live with ME/CFS in the United States, federal funding for researching the disease has been minimal, and many medical professionals still dismiss the illness as psychological or due to other conditions.

Since 2013, when Davis pivoted from researching genetics to studying ME/CFS, his work has largely been supported by private donations that have helped him make strides in cracking the mysteries of the disease. In 2015, he and his colleagues launched a “big data” approach to understanding the disease, deeply profiling several different types of molecular systems in 20 patients with severe ME/CFS who were bed-bound and 10 healthy control volunteers. The resulting dataset, the largest ever generated in ME/CFS, was completed in 2018.

And it uncovered a lot. Maybe too much. “Oh my god, there’s an unbelievable number of things wrong,” Davis said. “Then it’s a matter of trying to take this apart and figure out what could be going on.”

Davis and his colleagues published a study in the journal Healthcare in 2021 describing clinical symptoms of the 20 patients, including the similarity between their symptoms and those of long COVID, and another in the journal Frontiers in Human Neuroscience early in 2025 that investigated the genes and networks that go awry in the disease.

Zeroing in on metabolism

Many of the molecular differences between the people in the study with ME/CFS and the healthy volunteers were related to their metabolism. Davis has developed a theory that infection permanently changes a specific aspect of metabolism in people with ME/CFS, many of whom see their conditions develop after a severe viral infection. In fact, ME/CFS and long COVID — caused by infection with the virus SARS-CoV-2 — have many parallels, and some scientists, Davis included, think the two might be the same disease.

In this hypothesis of the root cause of ME/CFS, immune cells make a certain product of metabolism in response to infection. This metabolite, known as itaconate, ramps up other parts of the immune system’s virus-fighting abilities, but it also shuts down the normal energy production pathway in favor of one that’s less effective, which is part of the reason we feel tired when we have a cold or flu. Normally, this switch is short-lived, but in ME/CFS it could become permanently stuck in the lower energy mode. Several molecules are involved in this process and Davis believes different parts of the process might go wrong in different patients.

Another hypothesis from the big data study centers on the body’s production of nitric oxide, a small molecule with many important roles in biology, including regulating the brain-signaling molecules dopamine and serotonin, levels of which are often out of whack in ME/CFS. Davis and his colleagues have also found mutations in several genes related to the metabolic and nitric oxide pathways in people with ME/CFS.

Finding hope in the research

Although these hypotheses need further testing, Davis is buoyed by the fact that several drugs exist that target the pathways involved. A few patients taking a JAK-STAT inhibitor, a drug that affects the metabolic pathway, have seen a reversal of their symptoms, but it doesn’t work for other people and side effects can be severe, Davis said. Still, the successful cases give him hope that research will find a better way forward.

“I’ve talked to quite a few doctors who say, ‘We don’t cure chronic diseases.’ And my comment back to them is, ‘Because you think you can’t cure them, you never try,’” he said. “With ME/CFS, we’re left in that mode of no, it’s not curable. Well, I’m not quite sure I believe that.” — Contact Rachel Tompa at medmag@stanford.edu.

FROM DATA OVERLOAD TO DIABETES CARE OPTIMIZATION

How a collaboration between medicine and engineering is reshaping pediatric diabetes management

By Erin Digitale

Illustration by Ard Su

Thanks to continuous glucose monitors, diabetes has morphed into a disease of data management.

People develop diabetes when their bodies stop making or lose sensitivity to the sugar-regulating hormone insulin. In the past, to guide their decisions about diet and insulin doses, patients measured their blood sugar levels manually, pricking their fingers five or six times per day and squeezing a drop of blood into a handheld glucometer each time.

With continuous glucose monitors, patients wear a sensor wire that’s inserted under their skin. It measures blood sugar every five to 15 minutes around the clock — meaning they get more detail about their disease without sore fingers. In theory, the data that is automatically transmitted to patients’ phones can unlock insights to better diabetes management.

But in practice, many children and teens need help from an expert to translate their blood sugar measurements into action.

In the past five years, the pediatric endocrinology team at Stanford Medicine Children’s Health has collaborated with experts from Stanford’s School of Engineering to build a digital dashboard that filters blood sugar data — up to 288 measurements per patient per day — so endocrinologists and certified diabetes educators can easily identify struggling patients.

“It helps our team shift their focus to the kids who need it most.”

David Maahs, chief of pediatric endocrinology.

The project has required a just-right balance between artificial intelligence and human knowledge. Commercial products were inadequate; one app the team tried made unhelpful recommendations for diabetes care.

“It didn’t know the patients like I do,” said diabetes educator Jeannine Leverenz, RN, who played a big role in developing Stanford’s diabetes dashboard. “It wouldn’t know, ‘This is a 2-year-old, and he’s not meeting his blood sugar targets because he’s snacking all day’ versus ‘This is a teen who is really into sports and is not meeting targets because of her practices and games.’”

To check on these kids in the past, Leverenz was at a computer manually switching between her list of patients and an app that gave access to two weeks of blood sugar data for one person at a time. It was cumbersome to spot patterns: For instance, who was having a lot of dangerously low blood sugars?

To redesign and improve a simple early version of the dashboard, Johannes Ferstad, PhD, then a graduate student in management science engineering, observed Leverenz at work and asked what she and her colleagues needed. David Scheinker, PhD, clinical professor of pediatrics and of medicine, brought Ferstad to the project when he took Scheinker’s classes on health care systems design.

Scheinker also runs a program called Systems Utilization Research for Stanford Medicine that connects physicians, engineers and mathematicians to build data-filtering tools for medicine. The diabetes dashboard, which became Ferstad’s dissertation project, has been one of the program’s most successful initiatives.

“First, we put the list of patients and the most important summaries of weekly glucose data into a single view, so Jeannine could see the summary statistics without having to click around a bunch,” Ferstad said. “We also came up with a way of ordering the patients so those who needed the most attention were shown at the top and didn’t fall through the cracks.”

Flagging struggles to reduce risk

The idea sounds simple but it required a lot of behind-the-scenes engineering to obtain data from different sources, matching the clinic’s internally stored list of patients with their individual data from the glucose monitors, which was stored in the cloud, then processing it with the algorithm Ferstad developed, and running it all on the health system’s computer servers.

The endocrinologists and engineers refined the dashboard to detect key flags, including if patients were not wearing the continuous glucose monitor at all, spent too little time in the target blood sugar range, or had too much time with hazardously low blood sugar levels.

People with diabetes try to keep their blood sugar levels in a range that would be normal for a person without the disease. Very low blood sugar can make a person lose consciousness or even result in death. High sugar levels increase the risk for long-term complications, including blindness, kidney failure and nerve damage in the feet.

The flags now help the care team prioritize who needs to receive messages about adjusting their insulin doses.

“Automating some of the process, in a way that is based on the real needs of our clinical team, helps us target their attention to where it’s really needed.”

David Maahs

The team published a scientific study in 2021 in Pediatric Diabetes showing that the dashboard sped up review of patients’ glucose data, increasing by 56% the estimated clinic capacity — how many patients the clinic could accommodate.

Patients who were struggling could get messages from their caregivers as often as every week, while those doing well received the usual checkups every three months.

“It helps our team shift their focus to the kids who need it most,” said David Maahs, MD, the Lucile Salter Packard Professor in Pediatrics and chief of pediatric endocrinology.

Eyeing more automation options

The dashboard is part of a larger research project, published in Nature Medicine in 2024, which showed that the right automated tools and management — initiated soon after a diabetes diagnosis — can result in long-term improvements in kids’ blood sugar levels, which are linked to lower risk for diabetes complications later in life. Patients in the study also used insulin pumps, which are worn all the time and deliver insulin automatically, avoiding the need for injections.

Maahs and Scheinker are leading an effort to make the dashboard available to other hospitals. The team also wants to integrate other kinds of information, such as data from patients’ insulin pumps, in the dashboard — though pump data is often locked in proprietary manufacturers’ software.

“There’s a challenge with who owns that data — the manufacturer, the health system or the patient,” said Priya Prahalad, MD, PhD, clinical associate professor of pediatrics.

The researchers hope to bring all this data into an integrated platform that makes it more efficient for diabetes clinicians to care for their patients.

After all, we’ve known for three decades — since the landmark Diabetes Control and Complications Trial was published in the 1990s — that patients do better when they have timely input from their diabetes team.

“That can be really hard to do given the resources of real clinics,” Maahs said. “Automating some of the process, in a way that is based on the real needs of our clinical team, helps us target their attention to where it’s really needed.” — Contact Erin Digitale at digitale@stanford.edu

SCALING UP WEIGHT LOSS

A weight management program for young people expands access

By Erin Digitale

For more than two decades, experts at the Stanford Medicine Children’s Health Pediatric Weight Control Program have helped families who live near Stanford learn how their kids with obesity can reach and maintain healthy weights. The program, which guides children and families on eating better and increasing their activity levels, was in the vanguard of behavior-based pediatric weight management programs when it was developed in the late 1990s. It has enabled more than 80% of participants to achieve healthier weights.

Now, the program’s leaders are taking a Silicon Valley-inspired approach to sharing that success across the country: They are using design thinking and technology to package the weight control program, available only at Stanford Medicine, into a format that can be delivered by health professionals and community leaders anywhere.

“It’s important to provide pediatric weight management programs that are accessible, acceptable and affordable for the populations with the greatest need,” said Thomas Robinson, MD, MPH, professor of pediatrics and of medicine at the Stanford School of Medicine.

Fewer than two dozen well-regarded behavioral pediatric weight control programs exist around the country, mostly at academic medical centers, Robinson said, but most children and teens don’t live near centers that offer this care. The U.S. Preventive Services Task Force, which makes evidence-based recommendations for primary care, endorses such programs as the mainstay of pediatric obesity treatment.

Some physicians are beginning to prescribe weight loss drugs such as semaglutide (the active ingredient in Ozempic) for certain adolescents with obesity; these newer drugs mimic glucagon-like peptide-1 hormone and suppress appetite signals in the brain. But because there are few studies in adolescents and the medications’ long-term effects on youth who are still growing is uncertain, the task force has not recommended their use in teens. That leaves behavioral programs that focus on healthy eating and exercise as the main method for addressing obesity in young people.

Unlike drugs or medical devices, widespread rollout of public health interventions is unusual, said Robinson, who holds the Irving Schulman, MD, Professorship in Child Health.

“We have an efficacious program. The challenge is: How do we get it out there?”

Childhood obesity rooted in social inequality

Since the 1970s, pediatric obesity rates have nearly quadrupled, according to the CDC, putting millions of young people at risk for medical problems such as high blood pressure and Type 2 diabetes. Disadvantaged children and teens, including those who are racial or ethnic minorities or from low-income families, are the most likely to be affected.

“That’s the group at greatest need, and it also tends to be the group that has the least access to effective weight management programs,” Robinson said.

The expansion his team is planning was funded through a five-year grant from the CDC’s Childhood Obesity Research Demonstration Project 3.0, intended to give low-income families access to safe, evidence-based weight management programs. The Stanford Children’s Pediatric Weight Control Program fit that bill. Robinson’s team is now gearing up to offer the program nationwide and is starting the final phase of testing whether their rollout will work as planned.

Children and teenagers in the program attend six months of weekly group meetings with one or more parents or guardians, learning how to incorporate healthy eating habits and physical activity into their lifestyles while receiving support from other families facing similar challenges. They learn to classify foods with a traffic-light system — red designates calorie-dense foods to eat much less of, yellow is for foods to eat in moderate portions and green indicates the healthiest foods.

“Children need to be motivated to set their own goals and make changes themselves. Otherwise it’s them versus the parents, and that rarely works.”

Pediatrician Thomas Robinson, professor of pediatrics and of medicine

They are encouraged to get more physical activity and reduce sedentary behaviors, especially screen time. To make all these changes, they tap into well-tested behavioral tactics, such as using journals to track everything they eat, all their physical activity and their screen time. They practice setting goals and solving problems regarding food, activity and screen use. They also learn how to establish a healthy balance of decision-making between parents and kids.

“Children live in the context of families, and their parents have so much control over resources like nutritious foods, physical activity opportunities and screen time,” Robinson said. Parents also set the tone in their families — for instance, by modeling and supporting diet and activity changes for the sake of the whole family’s health, rather than singling out one child.

“But children need to be motivated to set their own goals and make changes themselves,” Robinson said. “Otherwise it’s them versus the parents, and that rarely works.”

As Robinson’s team expands access to the program, they are also always looking for ways to make it more effective for participants who struggle to succeed. They are collaborating with Stanford University psychologists to explore whether two brief social psychological interventions will help families overcome barriers to success.

They will test the benefits of helping participants adopt a growth mindset, a state of mind in which one believes in one’s own ability to gain new skills through effort. They are also studying activities that help people escape stereotypes about groups they belong to, such as those about children and families with obesity.

The researchers want to know whether adding these elements to the existing program helps participants reach their goals. This research project was recently funded by the National Institutes of Health, and collaborators include Carol Dweck, PhD, the Lewis and Virginia Eaton Professor, a professor of psychology and a pioneer of the growth mindset concept; Geoffrey Cohen, the James G. March Professor of Organizational Studies in Education and Business; and Gregory Walton, a professor of psychology.

Empowering community leaders

One key aspect of the program — face-to-face interaction — will be preserved in the new rollout. “I believe it’s part of the secret sauce of why these family-based, group programs have worked,” Robinson said.

The newly packaged curriculum, which will be available through an online platform known as Stanford HEALTHY, will help pediatricians, hospitals, community organizations, public health departments and employers deliver effective weight management programs to groups of families in their own communities across the country. 

“Many primary care providers, after-school programs and other community organizations want to be able to do this,” Robinson said. “But it’s not something they have much training in.”

The Stanford researchers have developed an array of online materials — including videos and animations; assessment, monitoring and feedback tools; and group-management resources — to help people lead the weight loss program. Training for group leaders will be incorporated online as well and is designed to be accessible to leaders with minimal experience.

“It’s really a huge step for us, being able to share a program we strongly believe in, that has great evidence supporting it. Now we can make it available, hopefully, to everyone.”

Thomas Robinson

“We want to make it easy for anyone, whether they’re a health care provider, a high school teacher or a youth leader at the Y, to be able to deliver the program in a way that maintains fidelity to what we do here at Stanford,” Robinson said. Providers will pay an annual subscription fee based on the size of their organization and their ability to pay.

To create a road map for scaling his team’s work, Robinson drew on insights he gained in an eight-month Stanford Mussallem Center for Biodesign faculty fellowship, which provided advanced training in health technology innovation and prepared fellows to bring those solutions to market.

“We are exploring business models to create a sustainable program for many different provider types,” he said, noting that the team hopes the program can ultimately be delivered not only by health care professionals but also, for example, by community leaders at public health agencies or after-school programs. Another hurdle is that insurance reimbursement for behavioral pediatric obesity treatments is poor. “We’re thinking about how to make it both affordable and sustainable over time.”

Components of his team’s plan have been influenced by Silicon Valley concepts, such as business-to-business and software-as-a-service models, he said.

“It’s really a huge step for us, being able to share a program we strongly believe in, that has great evidence supporting it,” Robinson said. “Now we can make it available, hopefully, to everyone.” — Contact Erin Digitale at digitale@stanford.edu