Publisher Health

Thanks to continuous advances in human stem cell research, studies that make use of embryo models are progressing quickly. This research offers both a scientific and ethical alternative to the use of embryos resulting from fertilized human eggs, and the appropriate ethical guidelines have been developed in parallel with the advances being made. In a perspective appearing in the August 17 issue of the journal Cell, a group of biologists and ethicists suggest additions to the current ethical framework that refine thinking about human embryology using embryo models to maximize benefits to society.
“Stem cell research has enabled the formation of models capable of organizing into structures that rudimentarily resemble embryos and reflect various degrees of completeness and developmental stages,” says first author Nicolas Rivron, a development biologist at the Austrian Academy of Sciences. “These new propositions are part of an effort to bring clarity to ongoing research — to better classify the types of structures formed in the laboratory, to refine the legal definition of human embryos, and to pinpoint what currently makes models and embryos different from the legal standpoint.”
These new propositions build on the latest formal guidelines from the International Society for Stem Cell Research (ISSCR), which were issued in 2021 and dealt with emerging advances in the field, including stem cell-based embryo models, human embryo research, chimeras, organoids, and genome editing. Discussions about updated guidelines started after mouse embryo models were formed, in anticipation of major advances in human counterparts.
“It’s important to frequently refine these ethical guidelines and gradually adapt ethical oversights as science advances,” Rivron says. “Here, we propose a refined definition of the human embryo that focuses on what it can become rather than how it came to be. This definition allows us to think about the conditions under which models, if improved, might eventually pass a tipping point and be legally considered embryos.”
The authors propose this definition to be “a group of human cells supported by elements fulfilling extra-embryonic and uterine functions that, combined, have the potential to form a fetus.” They note that current models do not meet legal definitions, but that it’s important to define how to evaluate whether they have passed that tipping point in the future.
Decisions about how to regulate embryo research are guided by scientific societies but are ultimately the responsibility of local authorities. “Some nations ask their ethical committees to adapt or implement the ethical guidelines as established by scientific societies without legislating, while others prefer to engrave decisions in a regulatory context, for example the UK’s rule that restricts the culturing of embryos to 14 days,” Rivron says. “Different approaches allow for a different level of flexibility as science progresses.”
In addition, the authors also reiterate that, according to the ISSCR’s Fundamental Principles, it is the duty of scientists to ensure accurate public understanding and perception of human embryology using embryo models.
“Appropriate, trustworthy, and timely public communication is necessary,” Rivron says. For the structures currently being formed, the terms “embryo models,” “embryonic models,” and “stem cell-derived embryo models” are preferable to the term “synthetic embryos,” which could imply that synthetic elements are being used, rather than the natural cells and developmental programs that are at play.
“The reality is that these embryo models cannot form neonates, but they help us fill an important knowledge gap in our basic understanding of how humans form — something that is normally hidden in the womb,” he says. “We hope that in the future this knowledge will benefit society by supporting the development of medicines to combat infertility and early pregnancy loss and by leading to a better understanding of the origins of congenital malformations and diseases. The field is still in its infancy, but it is opening important and previously inaccessible avenues for science, ethics, and medicine.”

Obesity leads to altered energy metabolism and reduced insulin sensitivity of cells. The so-called “anti-obesity drugs” are increasingly used to treat obesity and have caused tremendous interest, especially in the USA. Researchers at the Max Planck Institute for Metabolism Research in Cologne, Germany, have now shown in people with obesity that reduced insulin sensitivity affects learning of sensory associations. A single dose of the anti-obesity drug liraglutide was able to normalise these changes and restore the underlying brain circuit function.
To control our behaviour, the brain must be able to form associations. This involves, for example, associating a neutral external stimulus with a consequence following the stimulus (e.g., the hotplate glows red — you can burn your hand). In this way, the brain learns what the implication of our handling of the first stimulus are. Associative learning is the basis for forming neural connections and gives stimuli their motivational force. It is essentially controlled by a brain region called the dopaminergic midbrain. This region has many receptors for the body’s signaling molecules, such as insulin, and can thus adapt our behaviour to the physiological needs of our body.
But what happens when the body’s insulin sensitivity is reduced due to obesity? Does this change our brain activity, our ability to learn associations and thus our behaviour? Researchers at the Max Planck Institute for Metabolism Research have now measured how well the learning of associations works in participants with normal body weight (high insulin sensitivity, 30 volunteers) and in participants with obesity (reduced insulin sensitivity, 24 volunteers), and if this learning process is influenced by the anti-obesity drug liraglutide.
Low insulin sensitivity reduces the brain’s ability to associate sensory stimuli.
In the evening, they injected the participants with either the drug liraglutide or a placebo in the evening. Liraglutide is a so-called GLP-1 agonist, which activates the GLP-1 receptor in the body, stimulating insulin production and producing a feeling of satiety. It is often used to treat obesity and type 2 diabetes and is given once a day. The next morning, the subjects were given a learning task that allowed the researchers to measure how well associative learning works. They found that the ability to associate sensory stimuli was less pronounced in participants with obesity than in those of normal weight, and that brain activity was reduced in the areas encoding this learning behavior.
After just one dose of liraglutide, participants with obesity no longer showed these impairments, and no difference in brain activity was seen between participants with normal weight and obesity. In other words, the drug returned the brain activity to the state of normal-weight subjects.
“These findings are of fundamental importance. We show here that basic behaviours such as associative learning depend not only on external environmental conditions but also on the body’s metabolic state. So, whether someone has overweight or not also determines how the brain learns to associate sensory signals and what motivation is generated. The normalisation we achieved with the drug in subjects with obesity, therefore, fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” says study leader Marc Tittgemeyer from the Max Planck Institute for Metabolism Research.
“While it is encouraging that available drugs have a positive effect on brain activity in obesity, it is alarming that changes in brain performance occur even in young people with obesity without other medical conditions. Obesity prevention should play a much greater role in our healthcare system in the future. Lifelong medication is the less preferred option in comparison primary prevention of obesity and associated complications,” says Ruth Hanßen, first author of the study and a physician at the University Hospital of Cologne.
The study was conducted at the Max Planck Institute for Metabolism Research and supported by the CECAD Cluster of Excellence for Ageing Research at the University of Cologne and the University Hospital of Cologne.

St. Jude Children’s Research Hospital scientists, in collaboration with the Institute of Environmental Science and Research (ESR) Limited, found that immune cells present in people months before influenza (flu) infection could more accurately predict if an individual would develop symptoms than current methods which primarily rely on antibody levels. The study found certain immune cells were associated with increased protection, while other immune cells were associated with increased susceptibility to developing symptoms after catching the virus. The findings have implications for new approaches to public health and were published today in Nature Immunology.
“We’ve been struggling for decades, if not centuries, with why some people get sick with infections and some don’t,” said co-corresponding author Richard Webby, Ph.D., St. Jude Department of Host-Microbe Interactions. “This is one of the best attempts to try and figure that out for influenza. We were able to measure many different immune parameters from a single blood draw and correlate them with protection from, or susceptibility to, infection symptoms.”
Functional diversity improves anti-influenza immune performance
The researchers found that having a more functionally diverse set of immune cells was correlated with increased protection from flu symptoms. The group identified these cells by comparing the immune cells present in the blood of patients who had symptoms from flu infection to those who were asymptomatic or uninfected. The blood samples, taken up to six months before that flu season, showed very different sets of immune cells in the two groups. Those without symptoms not only had a more functionally diverse set of immune cells but those cells were also associated with an influenza-specific long-term response, sometimes called the memory response. Patients with symptoms tended to have a more similar set of inflammatory immune cells, which are more likely to be involved in a nonspecific, functionally narrow and short-term response.
The analysis included volunteers in the surveillance for a community cohort-based influenza-like illness (SHIVERS-II) study in New Zealand. SHIVERS-II includes a unique cohort of volunteer patients that the study tracks over time, including their health information. For this study, the volunteers regularly had their blood drawn so the scientists could characterize their immune cells and find which were associated with protection from flu symptoms.
“The SHIVERS platform, which represents a long-running collaboration between St. Jude and ESR, has been tremendously successful because of the willingness of participants to stay engaged in the study,” said co-corresponding author Sue Huang, Ph.D., principal investigator for SHIVERS-II and the World Health Organization National Influenza Centre director at ESR. “It is great to see their efforts coming to fruition.”
“Our results show that the balance of different immune cells in people can be extremely biased,” said senior and co-corresponding author Paul Thomas, Ph.D., St. Jude Department of Immunology. “You might build up an immune cell army that is exceptional at fighting off one kind of infection, but then that can make you feel sicker from another kind of infection. By understanding which immune cells are the best for fighting the flu, we can start designing vaccines to push for those populations that are most protective.”
“The baseline immune state before vaccination is known to significantly vary across age, sex, vaccination status, infection history and more,” said co-first author Aisha Souquette, Ph.D., St. Jude Department of Immunology. “By understanding the different types of immune profiles that can provide protective responses, we can tailor and optimize our vaccine platforms for populations with distinct baseline immune states.”

“Should I be taking a probiotic?” is a question that Maggie Stanislawski, PhD, assistant professor in the University of Colorado Department of Biomedical Informatics (DBMI), gets asked often.
The answer is complicated. Every person’s gut microbiome is unique, and many probiotic supplements sold in grocery stores may not effectively bolster gut health for everyone, she says. The researcher, who specializes in the role of the gut microbiome in obesity and cardiometabolic disease, instead points to the importance of enhancing a diverse microbiome.
Research by Stanislawski and others in the CU School of Medicine aims to understand the relationship between changes in diet and the microbiome. Some of this work uncovers possible routes by which alterations in gut microbiota may influence metabolism during a dietary weight loss intervention.
Daily caloric restriction vs. Intermittent fasting
Stanislawski collaborated with CU Department of Medicine associate professor Vicki Catenacci, MD, who led a behavioral weight loss intervention study comparing the effects of two popular weight loss regimens — intermittent fasting and the more traditional approach of daily caloric restriction.
Stanislawski examined the effects of the intervention on the gut microbiota of the participants and found that both approaches have a positive impact on helping diversify the microbiome.
In one group, participants were instructed to fast three non-consecutive days per week. On fasting days, the participants were to eat about 25% of what they normally eat, and on non-fast days they could eat whatever they wanted. In the other group, participants were instructed to reduce calories every day by the same amount, about 30% of their weight maintenance needs. Participants were also given behavioral support during the intervention and advised about ways to improve their overall diet quality as well as encouraged to increase their physical activity levels.

Scientists have discovered an additional potential cause of the genetic mutations that result in rare conditions such as Huntington’s disease (HD).
The neurodegenerative diseases, which also include most spinocerebellar ataxias (SCAs), are known to be caused by an expansion in the CAG (cytosine-adenine-guanine) repeats within a gene that in turn leads to an expanded polyglutamine (polyQ) tract in a protein.
Such diseases are inherited, given that the expansion of CAG repeats in a gene can be passed down the generations.
Previously, it had been thought the damage in these genetic diseases was caused solely by increased protein aggregate toxicity.
However, a new study has found an additional source — ribonucleic acid (RNA) — can generate the levels of toxicity to cause damage to the brain in these diseases.
Published in Nature Chemical Biology, the research has revealed that expanded CAG repeat RNA can form RNA aggregates in the cytoplasm through a process called liquid-liquid phase separation and gelation. This reduces global protein synthesis, and leads to neurotoxicity and neurodegeneration.
The study is part of an ongoing international collaboration between experts in neuroscience and genetics from the University of Plymouth (UK), Fudan University and Tsinghua University (China).

Early social and environmental exposures can have large and lasting effects on child development and adult health. One of the systems in the human body that is vulnerable to external influence is the gut microbiome: the community of bacteria that live in the gastrointestinal tract. Some variations in the human gut microbiome are important because they are linked to the incidence and mortality of various diseases.
In the United States, adult gut microbiome diversity correlates with self-reported race and ethnicity, even though there is no genetic or biological reason for this. In this context, scientists believe that race and ethnicity are proxies for inequitable exposure to social and environmental determinants of health due to structural racism.
But the timing and conditions under which gut microbiome differences first appear have been a mystery. A study from Washington University in St. Louis, The Pennsylvania State University and Vanderbilt University highlights a critical development window during which racial differences in the gut microbiome emerge.
Gut microbiome variation associated with race and ethnicity arises after 3 months of age and persists through childhood, according to the new research published Aug. 17 in PLOS Biology.
“The differences that we see are not present at birth, or even shortly after,” said Elizabeth Mallott, an assistant professor of biology in Arts & Sciences at Washington University, first author of the new study. She and her collaborators analyzed data from eight previous studies, including 2,756 gut microbiome samples from 729 U.S. children between birth and 12 years of age.
“Only two of the 82 microbes that differ along the lines of either race or ethnicity are microbes that are maternally transmitted,” Mallott said. “The vast majority are all microbes that we acquire from the environment.”
Babies acquire some of the bacteria that stay with them for the rest of their lives during birth or in close contact with their mothers during breastfeeding, for example. But people also accumulate other types of bacteria as they interact with the world around them. Their life experiences dictate which of these bacteria they encounter and which ones stay with them as part of the internal community of their microbiomes.

Cooking food thoroughly and avoiding some types of vegetables and salad during a course of antibiotic treatment could potentially reduce antibiotic resistance, by preventing bacteria carrying resistance genes getting into the gut, according to a new study.
New research from the University of Nottingham has modelled howantibiotic resistance genes build-up through lifetime exposure from food intake and antibiotic treatment. The research published today in PLOS ONE  gives new insights into long term increase in resistance genes in gut bacteria and how this could be prevented.
Antimicrobial resistant bacterial infections represent one of the most serious contemporary global healthcare crises. Acquisition and spread of resistant infections can occur through community, hospitals, food, water or bacteria that lives inside us or that we may be exposed to — like E. coli.
The research modelled data from a previous study that found antibiotic gene diversity in gut microbiota is age related. The Nottingham studyshows that the long-term increase in resistance in human gut microbiomes can be substantially lowered by reducing exposure to resistance genes found in food and water, alongside reduced medical antibiotic use.
The research suggests that reducing intake of resistance genes is particularly effective during periods of antibiotic treatment where there is an increased risk of the retainment of genes. The researchers suggest that dietary advice should be given to those undergoing antibiotic treatment to avoid products at higher risk of carrying ARGs, (even on otherwise harmless bacteria), as well as ensuring that all food consumed during treatment is fully cooked.
Dov Stekel, Professor of Computational Biology at the University of Nottingham has led the study and said: “When you’re taking antibiotics is exactly when you are most susceptible to creating longer term problems due to drug resistant bacteria from food. If you eat something that has bacteria on it that doesn’t cause you any harm, but which contains some drug resistant genes and you happen to be taking antibiotics when you eat it then those resistances could become established in your gut ecosystem so next time you need antibiotics they may not work effectively.”
The study also demonstrates other factors that can reduce the long-term acquisition and retainment of genes providing resistance to different classes of antibiotics. As genes build up over a lifetime the less exposure to these the better so a conservative approach to antibiotic availability and dosing guidelines, as already implemented in many countries, and as advocated in much of literature on antibiotic resistance, would be a practical approach to reducing the long-term number of acquired resistances.
Reducing the number of acquired genes over a lifetime could also be achieved by policy and practice changes in the food supply chain, including agriculture and post-harvest food production. Research from Nottingham Vet School is looking into this using artificial intelligence to monitor the gut microbiome in livestock.
Professor Stekel adds: “The level of benefit to be gained from alterations in medical treatment and dietary changes is highly dependent upon the level of antibiotic use, which varies greatly between countries. While our general model demonstrates benefit across all levels of prescribing, a more nuanced approach that considers region- and country-specific practices, along with specific details of antibiotic classes and associated resistance genes, would provide a better means of quantifying the potential advantages of these changes.”

And other time-tested ways to cope with extreme heat from cultures around the world.As I hurried to an appointment one recent afternoon in New York City, the harsh sun seemed to set my skin and hair on fire. Sweat pooled under my sunglasses, and my T-shirt and shorts stuck to my damp skin. I was miserable.I should have been used to the heat. I grew up in southern India, where the temperature routinely swept past 100 degrees Fahrenheit. But I had abandoned all the tricks and strategies I had used then.To begin with, I was walking outside at about 3 p.m. In India, I rarely ventured out between 11 a.m. and 4 p.m., or if I did I was fully equipped to face the sun. I usually carried an umbrella, much as women in Victorian England carried parasols, to shield my head and face. And I wore salwar kameez, a tunic and loosefitting bottoms made of thin, gauzy cotton.It turns out that these methods, employed all over South Asia, are rooted in solid science, even though I didn’t realize it then. As climate change sends temperatures soaring around the world, people who are not used to coping with heat could stand to adopt a few strategies from regions that have faced hot weather for generations.Covering upIn New York I only ever carry an umbrella when it’s rainy, and rarely wear a hat except at the beach. “But in a situation where you’re out in the direct sun, having something to protect you from that direct sun radiation is important,” said Dr. Jill Tirabassi, a sports medicine expert at the University at Buffalo.Likewise, wearing little clothing in an attempt to stay cool (or cultivate a tan) exposes you to dangerous solar radiation. A better option is to cover up. “You actually want to have breathable layers that will help transfer your heat out,” Dr. Tirabassi said.People in hot regions, including African deserts, similarly dress in thin, loosefitting clothes, in light colors that reflect the sun’s rays, let in air and facilitate the evaporation of sweat, rather than trap the heat as darker colors do. Clothes made of thin cotton, linen or bamboo are the most breathable, and synthetic fabrics, like polyester and nylon, the least.“Having that sweat evaporate is a really important way to cool your body when you’re moving or exercising,” Dr. Tirabassi said.Getting wetOne habit I picked up after observing the locals during summers in France is to spritz my face with water. It can also cool the skin — as long as it’s not too humid — when the water evaporates.“It’s kind of replicating what the body does when it sweats,” said Dr. Cecilia Sorensen, an emergency medicine physician and director of the Global Consortium on Climate and Health Education at Columbia University.“Having that layer of cool water or precipitation on your skin actually speeds up your body’s ability to release heat,” she said.Atul Loke for The New York TimesCool, damp cloths can accomplish the same goal. In northern India, men often wrap a wet scarf or towel around their neck or their head, said Sanjiv Phansalkar, a rural development expert at the nonprofit VikasAnvesh Foundation.In Nagpur, Dr. Phansalkar’s hometown, “anybody going out in the street in the summer without their head and ears being covered by a cloth will be immediately stopped by a stranger and made to do so,” he said.Dr. Sorensen said this practice makes scientific sense: The neck is replete with blood vessels, which widen at high temperatures. The dilated vessels carry more hot blood from the core of the body to the skin, where heat dissipates into the air. In fact, when people turn up in emergency rooms with a heat illness, doctors often pack the neck area with ice and cold towels to rapidly lower their body temperature, she said.Hydrating with fruit and vegetablesSweating is the body’s natural cooling mechanism, but the moisture lost must be promptly replaced. That can be accomplished by drinking water, eating watery vegetables and fruit like cucumbers, watermelon and mangoes, or liquids like soups — yes, soups. People in the tropics often eat hot soups, in order to cool off by sweating.“Everybody knows hydration, hydration, hydration, but what we miss is that hydration doesn’t necessarily mean only drinking water,” said Dr. Asim Shah, a professor of community and family medicine at Baylor College of Medicine in Houston who has studied the impact of heat. He said water should be combined with electrolytes, electrically charged minerals like sodium, calcium and potassium that are needed for nerve and muscle function and maintaining pH levels.When I was growing up in India, bottled water was not as ubiquitous as it is today. Coconuts, heaped high in roadside stalls, offered an inexpensive, safe and delicious alternative. Vendors would use a small machete to slice open the top of the coconut. When I’d had my fill of the cool, sweet water, I would break the coconut open and eat its moist white meat.Coconut water is more beneficial than plain water because it has electrolytes. (Most brands of bottled coconut water preserve them, but some also come with unwanted added sugar or artificial flavors.)Doctors generally warn against drinking alcohol in the heat because it is a diuretic and can lead to dehydration. If you do drink, margaritas make a good option because the salt on the rim can replenish sodium lost to sweat, said Dr. Sorensen, whose family is from Ecuador.Smarter schedulesThe best way to protect yourself from the sun is to avoid it as much as possible. In various cultures, that means scheduling work for the hours when the daylight is less intense.Many people in southern India, and especially those who toil outside, begin their workday around 4 a.m. and work until no later than noon. The afternoon often includes a nap. Work then resumes at 4 or 5 p.m. for a few more hours.Getty Images“There was like a completely different rhythm of life,” recalled Krishna AchutaRao, a climate scientist at the Indian Institute of Technology in Delhi who grew up in the South Indian state of Tamil Nadu. The routine is now less common than it was in his childhood, he said, as Western rhythms and office life have taken over Indian cities.Some Central and South American countries and some in Europe, Asia and Africa follow a similar schedule, with a nap built into the hottest afternoon hours. As unrelenting heat grips Europe, countries like Germany, which once sneered at the idea, are now considering taking midday breaks too.Naturally cool homesFew Indian households have air conditioning; traditional homes manage to stay cool using other techniques.One key approach is to open windows early in the day and close them before it begins to warm up. Heavy, dark curtains block light and heat from entering the house, and ceiling fans circulate the cool air trapped inside. My family home had curtains made of khus, a native Indian grass, which we sprayed with water every couple of hours. The curtains transformed hot gusts into cool, fragrant breezes.Many traditional Indian homes have verandas, high ceilings and walls of mud that keep the interior cool. New Orleans, where Dr. AchutaRao lived for nine years, is famous for its shotgun houses — linear buildings in which a bullet shot through the front door can in theory exit through the back door without hitting anything on the way — that allow the air to flow freely. Because heat rises, high ceilings and ceiling fans also keep the living spaces cool.Not having such simple strategies in place can make even milder temperatures unbearable. Dr. AchutaRao recalled being in Oxford, England, when it was around 90 degrees Fahrenheit, lower than the triple-digit temperatures he was used to. But there was no ceiling fan, and the windows could let light in but wouldn’t open wide enough to allow a breeze.That temperature “is a routine day in India, but it felt so much worse,” Dr. AchutaRao recalled.He lamented that some of these older strategies may have become useless — for example, early mornings are frequently so warm now that even waking up at 4 a.m. may not always offer a comfortable start to the day.Climate change’s rapid pace demands solutions that can keep houses and bodies cool even when the mercury keeps rising, he added.“You’re no longer adjusting to one hot day or a couple of hot days, you’re looking at weeks upon weeks of having to deal with this,” Dr. AchutaRao said. “This is the cultural shift that people have to make in their heads.”

Every so often a drug comes along that has the potential to change the world. Medical specialists say the latest to offer that possibility are the new drugs that treat obesity — Ozempic, Wegovy, Mounjaro and more that may soon be coming onto the market.It’s early, but nothing like these drugs has existed before.“Game changers,” said Jonathan Engel, a historian of medicine and health care policy at Baruch College in New York.Obesity affects nearly 42 percent of American adults, and yet, Dr. Engel said, “we have been powerless.” Research into potential medical treatments for the condition led to failures. Drug companies lost interest, with many executives thinking — like most doctors and members of the public — that obesity was a moral failing and not a chronic disease.While other drugs discovered in recent decades for diseases like cancer, heart disease and Alzheimer’s were found through a logical process that led to clear targets for drug designers, the path that led to the obesity drugs was not like that. In fact, much about the drugs remains shrouded in mystery. Researchers discovered by accident that exposing the brain to a natural hormone at levels never seen in nature elicited weight loss. They really don’t know why.“Everyone would like to say there must be some logical explanation or order in this that would allow predictions about what will work,” said Dr. David D’Alessio, chief of endocrinology at Duke, who consults for Eli Lilly among others. “So far there is not.”Although the drugs seem safe, obesity medicine specialists call for caution because — like drugs for high cholesterol levels or high blood pressure — the obesity drugs must be taken indefinitely or patients will regain the weight they lost.Dr. Susan Yanovski, a co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases, warned that patients would have to be monitored for rare but serious side effects, especially as scientists still don’t know why the drugs work.But, she added, obesity itself is associated with a long list of grave medical problems, including diabetes, liver disease, heart disease, cancers, sleep apnea and joint pain.“You have to keep in mind the serious diseases and increased mortality that people with obesity suffer from,” she said.The drugs can cause transient nausea and diarrhea in some. But their main effect is what matters. Patients say they lose constant cravings for food. They find themselves satisfied with much smaller portions. They lose weight because they naturally eat less — not because they burn more calories.And results from a clinical trial reported last week indicate that Wegovy can do more than help people lose weight — it also can protect against cardiac complications, like heart attacks and strokes.But why that happens remains poorly understood.“Companies don’t like the term trial and error,” said Dr. Daniel Drucker, who studies diabetes and obesity at the Lunenfeld-Tanenbaum Research Institute in Toronto and who consults for Novo Nordisk and other companies. “They like to say, ‘We were extremely clever in the way we designed the molecule,” Dr. Drucker said.But, he said, “They did get lucky.”A Lonely Origin StoryDr. Joel Habener in 2007.Ruby Arguilla-Tull/Bloomberg NewsIn the 1970s, obesity treatments were the last thing on Dr. Joel Habener’s mind. He was an academic endocrinologist starting his own lab at Harvard Medical School and looking for a challenging, but doable, research project.He chose diabetes. The disease is caused by high blood sugar levels and is typically treated with injections of insulin, a hormone secreted by the pancreas that helps cells store sugar. But an insulin injection makes blood sugar plummet, even if levels are already low. Patients have to carefully plan injections because very low blood sugar levels can result in confusion, shakiness and even a loss of consciousness.Two other hormones also play a role in regulating blood sugar — somatostatin and glucagon — and little was known then about how they are produced. Dr. Habener decided to study the genes that direct cells to make glucagon.That led him to a real surprise. In the early 1980s, he discovered a hormone, GLP-1, that exquisitely regulates blood sugar. It acts only on insulin-producing cells of the pancreas, and only when blood sugar rises too high.It was perfect, in theory, as a targeted treatment to replace sledgehammer-like insulin injections.Another researcher, Dr. Jens Juul Holst at the University of Copenhagen, independently stumbled on the same discovery.But there was a problem: When GLP-1 was injected, it vanished before reaching the pancreas. It needed to last longer.Dr. Drucker, who led the GLP-1 discovery efforts on Dr. Habener’s team, labored for years on the challenge. It was, he said, “a pretty lonely field.”When he applied to the Endocrine Society to give talks, he found himself scheduled at the very end of the last day of the annual meetings.“Everyone had left for the airport — people were taking down the exhibits,” he said.From the late 1980s to the early 1990s, he spoke to nearly empty auditoriums.Dr. Eng’s MonsterPeter DaSilva for The New York TimesSuccess came from a chance discovery that was not appreciated at the time.In 1990, John Eng, a researcher at the Veterans Affairs medical center in the Bronx, was looking for interesting new hormones in nature that might be useful for medications in people.He was drawn to the venomous Gila monster when he learned that it somehow kept its blood sugar levels stable when it did not have much to eat, according to a report from the National Institutes of Health, which funded his work. So Dr. Eng decided to search for chemicals in the lizards’ saliva. He found a variant of GLP-1 that lasted longer.Dr. Eng told The New York Times in 2002 that the V.A. had declined to patent the hormone. So Dr. Eng patented it himself and licensed it to Amylin Pharmaceuticals, which began testing it as a diabetes drug. The drug, exenatide or Byetta, went on sale in the United States in 2005.But Byetta had to be injected twice a day, a real disincentive to its use. Drug company chemists sought even longer-lasting versions of GLP-1.At Novo Nordisk, chemists began by using a well-known trick. They loosely attached GLP-1 to a blood protein that kept it stable enough to remain in circulation for at least 24 hours. But when GLP-1 slips off the protein, enzymes in the blood quickly degrade it. So chemists had to alter the hormone’s building blocks — a chain of amino acids — to find a more durable variant.After tedious trial and error, Novo Nordisk produced liraglutide, a GLP-1 drug that lasted long enough for daily injections. They named it Saxenda, and the F.D.A. approved it as a treatment for diabetes in 2010.It had an unexpected side effect: slight weight loss.A Dismal HistoryDr. Jeffrey Friedman, who discovered the hormone that tells the brain how much fat is on the body, in 1995.Remi Benali/Gamma-Rapho, via Getty ImagesObesity had become a dead end in the pharmaceutical industry. No drug that was tried worked very well, and every one that led to even modest weight loss had serious side effects.For a flickering moment in the late 1990s, there was hope when Dr. Jeffrey Friedman at Rockefeller University in New York found a hormone that told the brain how much fat was on the body. Lab mice genetically modified to have none of the hormone ate voraciously and grew enormously fat. Researchers could fine-tune an animal’s weight by altering how much of the hormone it got.Dr. Friedman named the hormone leptin. Amgen bought the rights to leptin and, in 1996, began testing it in people. They did not lose weight.Dr. Matthias Tschöp at Helmholtz Munich in Germany tells of the frustration. He left academia three decades ago to work at Eli Lilly in Indianapolis, excited by leptin and determined to use science to find a drug for weight loss.“I was so inspired,” Dr. Tschöp said.When leptin failed, he tried a different gut hormone, ghrelin, whose effects were the opposite of leptin’s. The more ghrelin an animal had, the more it would eat. Perhaps a drug that blocked ghrelin would make people lose weight.“Again, it wasn’t that simple,” said Dr. Tschöp, who left Lilly in 2002.The body has so many redundant circuits of interacting nerve impulses and hormones to control weight that tweaking one simply did not make a difference.And there was another obstacle, noted Dr. Tschöp’s former colleague at Lilly, Dr. Richard Di Marchi, who also was an executive at Novo Nordisk.“There was very little interest in the industry in doing this,” said Dr. Di Marchi, now at Indiana University. “Obesity was not thought to be a disease. It was looked at as a behavioral problem.”Dr. Friedman studied mice that had been genetically modified to have none of a hormone that told their brains how much fat was on their bodies. Researchers could fine-tune an animal’s weight by altering its hormones, but the study failed in humans.Remi Benali/Gamma-Rapho, via Getty ImagesStarving RatsNovo Nordisk, which today has 45.7 percent of the global insulin market, thought of itself as a diabetes company. Period.But one company scientist, Lotte Bjerre Knudsen, could not stop thinking about tantalizing results from studies with liraglutide, the GLP-1 drug that lasted long enough to be injected just once a day.In the early 1990s, Novo researchers, studying rats implanted with tumors of pancreas cells that produced copious amounts of glucagon and GLP-1, noticed that the animals had nearly stopped eating.“These rats, they starved themselves,” Dr. Knudsen said in a video series released by the Novo Nordisk Foundation. “So we kind of knew there was something in some of these peptides that was really important for appetite regulation.”Other studies by academic researchers found that rats lost their appetites if GLP-1 was injected into their brains. Human subjects who got an intravenous drip of GLP-1 ate 12 percent less at a lunch buffet than those who got a placebo.So why not study liraglutide as both a diabetes drug and an obesity drug, Dr. Knudsen asked .She faced resistance in part because some company executives were convinced that obesity resulted from a lack of willpower. One of the champions of investigating GLP-1 for weight loss, Lars Rebien Sorensen, chairman of the board at Novo Nordisk, said in the video posted by the company’s foundation that he “had to spend half a year convincing my C.E.O. that obesity is not just a lifestyle condition.”Dr. Knudsen also noted that the company’s business division had struggled with the idea of promoting liraglutide for two distinct purposes.“It’s either diabetes, or it’s a weight loss,” she recalled in the foundation video series.Finally, after liraglutide was approved in 2010 for diabetes, Dr. Knudsen’s proposal to study the drug for weight loss moved forward. After clinical trials, the F.D.A. approved liraglutide, or Saxenda, for obesity in 2014. The dose was about twice the diabetes dose. Patients lost about 5 percent of their weight, a modest amount.But Dr. Martin Holst Lange, executive vice president of development at Novo Nordisk, said in a telephone interview that it was at least as good as other weight-loss drugs, and without side effects like heart attacks, strokes and death.“We were super excited,” he said.Beyond DiabetesA Novo Nordisk site outside Copenhagen.Scanpix Denmark/ReutersDespite the progress on weight loss, Novo Nordisk continued to focus on diabetes, trying to find ways to make a longer-lasting GLP-1 so patients would not have to inject themselves every day.The result was a different GLP-1 drug, semaglutide, that lasted long enough that patients had to inject themselves only once a week. It was approved in 2017 and is now marketed as Ozempic.It also caused weight loss — 15 percent, which is three times the loss with Saxenda, the once-a-day drug, although there was no obvious reason for that. Suddenly, the company had what looked like a revolutionary treatment for obesity.But Novo Nordisk could not market Ozempic for weight loss without F.D.A. approval for that specific use.In 2018, a year after Ozempic’s approval for diabetes, the company started a clinical trial. In 2021, Novo Nordisk got approval from the F.D.A. to market the same drug for obesity with a weekly injection at a higher maximum dose. It named the drug Wegovy.But even before Wegovy was approved, people had begun taking Ozempic for obesity. Novo Nordisk, in its Ozempic commercials, mentioned that many taking it lost weight.Hinting turned out to be more than enough. Soon, said Dr. Jeffrey Mechanick, an endocrinologist at Mount Sinai’s Icahn School of Medicine, patients latched onto Ozempic. Doctors prescribed it off label for those who did not have diabetes.“There was a little bit of gaming going on,” Dr. Mechanick said, with some doctors coding patients as having pre-diabetes to help them get insurance coverage.By 2021, fed by social media, a general frenzy for weight loss and aggressive marketing by Novo Nordisk, the news that Ozempic made people lose weight had reached a tipping point, said Dr. Caroline Apovian, a co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital and a consultant for Novo Nordisk and other companies. Ozempic was on everyone’s lips, even though Wegovy was the drug approved that year for obesity.But Wegovy caught up.In July, doctors in the U.S. wrote about 94,000 prescriptions a week for Wegovy compared with about 62,000 a week for Ozempic. Wegovy is in such demand, though, that the company is unable to make enough, its spokeswoman Ambre James-Brown said. So for now, while it ramps up production, the company sells the drug only in Norway, Denmark, Germany and the United States. And at pharmacies in those countries, shortages are frequent.And Dr. Apovian, like many other obesity medicine specialists, is now booked with patients a year in advance.Cydni Elledge for The New York TimesMore Medicines, More MysteriesThe reason Ozempic and Wegovy are so much more effective than Saxenda remains a mystery. Why should a once-a-week injection produce much more weight loss than a once-a-day injection?The drugs, said Randy Seeley, an obesity researcher at the University of Michigan, are not correcting for a lack of GLP-1 in the body — people with obesity make plenty of GLP-1. Instead, the drugs are exposing the brain to hormone levels never seen in nature. Patients taking Wegovy are getting five times the amount of GLP-1 that they would produce in response to a Thanksgiving dinner, Dr. Seeley said.And, he added, in the brain, “the drugs go to unusual places.” They are not just going to areas thought to involve control overeating.“If you were designing a drug, you would say that’s a bad idea,” said Dr. Seeley, who has consulted for Novo Nordisk and Eli Lilly, among others. Drug designers try for precision — a drug should go only to the cells where it is needed.GLP-1, because of its chemical structure, should not even get into some areas of the brain where it slips in.“Nobody understands that,” Dr. Seeley said.Wegovy, though, is just the start.Lilly’s diabetes drug, tirzepatide or Mounjaro, is expected to get F.D.A. approval for obesity this year. It hooks GLP-1 to another gut hormone, GIP.GIP, on its own, produces, at best, a modest weight loss. But the two-hormone combination can allow people to lose a median of about 20 percent of their weight.“No one fully understands why,” Dr. Drucker said.Lilly has another drug, retatrutide, that, while still in early stages of testing, seems to elicit a median 24 percent weight loss.Amgen’s experimental drug, AMG 133, could be even better, but is even more of a puzzle. It hooks GLP-1 to a molecule that blocks GIP.There is no logical explanation for why seemingly opposite approaches would work.Researchers continue to marvel at these biochemical mysteries. But doctors and patients have their own takeaway: The drugs work. People lose weight. The constant chatter in their brains about food and eating is gone.And, while the stigma of obesity and the cultural stereotype that obese people aren’t trying hard enough to lose weight endures, some experts are optimistic. Now, they say, patients no longer have to blame themselves or feel like failures when they can’t lose weight.“The era of ‘just go out and diet and exercise’ is now gone,’” said Dr. Rudolph Leibel, a professor of diabetes research at Columbia University Irving Medical Center. “Now clinicians have tools to address obesity.”

At first, it seemed like an exercise injury. But it wouldn’t go away.“My hip hurts most of the time now,” the 20-year-old woman explained to Dr. Samantha Smith, a sports-medicine doctor at Yale New Haven Hospital and the second specialist she had seen since the pain in her left hip started two years earlier. She ran her hand down the side of her hip and over the thigh to her knee. It used to just happen at night, she continued. And only every now and then. But these past few months, the pain was present just about every day and absolutely every night. It started sometime in the first flush of the pandemic in 2020. She was 18 and stuck at home. Her social life was limited, and she and her high school pals would work out together over FaceTime, moving to the beat of one of the exercise videos that went viral that summer. Her favorite was a brutal 20-minute drill of lunges and squats designed to build a better butt. At first, she wondered if she just pulled a muscle. The pain was dull and came on slowly as she lay in bed. She couldn’t pinpoint the exact location — it seemed as if her whole hip ached — but when she woke the next day, the pain was gone. She changed videos, and the pain went away, but not for long. After weeks of this on-and-off ache, she mentioned it to her parents. They were doctors, and they peppered her with questions. It probably was some muscle injury, they agreed. She should take a few days off. And she did. But the pain kept its irregular nocturnal schedule. When rest didn’t work, she tried physical therapy. But the pain kept coming. Not every night, but often. And strangely, never in the daytime. That fall she started college at Vassar. The excitement made her forget all about the pain — until just after Halloween, when her nights were interrupted once more. She signed up for more P.T. It didn’t help. The only thing that did help, she discovered, was ibuprofen. Indeed, a dose of that drug right before bed practically guaranteed a good night’s sleep. Just before the Thanksgiving break, she had a video visit with her pediatrician. She moved her leg as her doctor instructed, rotating, lifting, kicking this way and that. All looked fine. She pressed and squeezed the various muscles. Again, fine. Her doctor sent her for an X-ray: normal. The doctor encouraged her to continue with P.T. With the help of the prophylactic doses of ibuprofen, she made it through her first semester. But just as spring greened the branches of the Poughkeepsie campus, her nighttime pain drifted into her days. It wasn’t every day. It wasn’t all day. But it was now an intense pain. She carried her ibuprofen with her all the time. As the hours of her pain expanded, so too did its location. It crept from her hip down her thigh to her knee. And on really bad days, it strayed almost to her foot. Walking somehow made it better. If this was an injury, she thought, that didn’t make any sense. But really nothing about this pain made sense. The girl’s mother was worried. During school breaks, she took her daughter to her pediatrician and to lots of physical-therapy appointments. It had to be a muscle problem. But why was she getting worse? One of the girl’s legs was slightly longer than the other. Was that the problem? Probably not, doctors and therapists assured her. Her daughter described an occasional clicking sensation in that hip when she stretched. Was it snapping-hip syndrome? If so, why hadn’t the therapy helped? Finally one friend had a recommendation: “You should take her to see Sam Smith.” Smith trained in both adult and pediatric medicine at Yale New Haven Hospital and had followed that up with a year focused on sports medicine at the Hospital for Special Surgery in Manhattan before coming back to New Haven. “She is really the best doctor I know,” the friend said. Photo illustration by Ina JangAn Overlooked AbnormalityAnd so now, just a few weeks later, mother and daughter were in with Smith. Smith noticed that the patient had some tenderness at the top of the thigh bone, over the part of the bone that stuck out farthest, a prominence known as the greater trochanter. She was also tender down the side of her thigh, over what is known as the IT band, a thick strip of tissue that extends from the top of the hip bone — known as the iliac crest — down to the upper tip of the tibia. The IT band provides stability to the leg during strenuous activities like running and can be irritated by rubbing against the bony hip prominence. Smith tested each of the muscles of the young woman’s hips and legs. The right leg was completely normal. But there was subtle weakness on the left. When asked to do a squat using only the right leg, the patient could do it easily, but she wobbled noticeably on the left. Smith gave the young woman a series of exercises designed to strengthen the specific muscles that were weak and scheduled her to come back in a month, just before she left for a semester abroad in England. At the end of August, when mother and daughter returned, Smith was surprised to see that although the girl’s muscles were stronger, the pain hadn’t changed. So it wasn’t greater trochanteric pain syndrome; what else could it be? The mother mentioned that there was an abnormality in one of the blood tests done when the pain first started. It was a marker of inflammation known as a C-reactive protein, or more familiarly, CRP. There are many reasons this protein can spike — physical trauma can do it; so can a minor infection. But a persistently elevated CRP would suggest something more than a muscle or ligament issue. That can be seen in autoimmune diseases or chronic infections, even cancer. No one knew what to make of it at the time, given that the X-ray was normal and the blood tests sent to look for infectious and rheumatologic causes of this kind of inflammation came back normal as well. That could be an important clue, Smith said. She ordered a new X-ray and repeated the test. The results came back the following day: The X-ray again read as normal. But the CRP was now three times the level it had been. A whole new list of possibilities sprang to mind. Smith called the patient. She needed to get an M.R.I. of that hip. The patient had her scan three days later. When she emerged, the technician told her that her doctor would be in touch. There was something on the M.R.I., Smith told her. A tumor. She was pretty sure it was not malignant, but to be certain, the patient would need a CT scan. Smith explained that she thought the young woman had something known as an osteoid osteoma — an inflammatory tumor that can be seen in people her age. It hadn’t been what she was looking for, and an M.R.I. was not the best way to diagnose it. The young woman looked up the M.R.I. report on her electronic medical record. What she saw scared her. It was, as Smith said, a small tumor, but the report listed other, scarier possibilities as well. Most prominent on that list: cancer. An infection in the bone was also possible. The benign tumor that Smith suspected wasn’t even mentioned. The CT scan was mercifully quick, and Smith called right away with the answer: It was an osteoid osteoma. Although these poorly understood tumors will resolve on their own after several years, most people who have them end up having them removed. The tumors are quite painful, and the treatment is simple and safe. Under CT guidance, a tiny catheter is introduced through the skin to the tumor, and a probe blasts the tumor with heat. Because the procedure is painful, it is usually done under general anesthesia. Smith told me that she had seen three patients who had osteoid osteomas. Each time, she discovered it while looking for something else. The tumor is called the great mimicker because it looks like so many other possibilities that are more common or more dangerous. The patient chose to defer the procedure until after her semester abroad. Then, just at the start of Hanukkah, she went to the operating room. Once the pain medicine she received at the hospital wore off, her hip hurt as it had never hurt before. Her parents discouraged her from using the opiates the surgeon had prescribed, and she survived on ibuprofen and acetaminophen for her first week at home. By the second week, she was fine. “I was lucky,” she told me. Her parents were doctors. They knew how to get her the specialists and tests she needed. Still, it took two years to figure this out. It must, she said, be so much harder for those without these advantages.Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share, write her at Lisa.Sandersmdnyt@gmail.com.