While a narrative emerged that the pandemic indiscriminately struck the young and healthy, new evidence suggests that frail young adults were most vulnerable.The flu typically kills the very young, the old and the sick. That made the virus in 1918 unusual, or so the story goes: It killed healthy young people as readily as those who were frail or had chronic conditions.Doctors of the time reported that, among those in the prime of their lives, good health and youth were no protection: The virus was indiscriminate, killing at least 50 million people, or between 1.3 and 3 percent of the world’s population. Covid, in contrast, killed 0.09 percent of the population.But a paper published on Monday in the Proceedings of the National Academy of Sciences challenges that persistent narrative. Using evidence in skeletons of people who died in the 1918 outbreak, researchers reported that people who suffered from chronic diseases or nutritional deficiencies were more than twice as likely to die as those who did not have such conditions, no matter their age.The 1918 virus did kill young people, but, the paper suggests, it was no exception to the observation that infectious diseases kill frail and sicker people most readily.Sharon DeWitte, an anthropologist at the University of Colorado, Boulder, and an author of the paper, said the finding had a clear message: “We should never expect any nonaccidental cause of death to be indiscriminate.”The analysis of skeletons, said J. Alex Navarro, a historian of the flu pandemic at the University of Michigan, makes for “a fascinating paper and a very interesting approach to studying this issue.”The lead author of the paper, Amanda Wissler, an anthropologist at McMaster University in Ontario, said she was intrigued by claims that the 1918 virus killed young and healthy people as readily as those with pre-existing conditions. In those days, there were no antibiotics or vaccines against childhood diseases, and tuberculosis was widespread among young adults.There was a puzzle about who died from that flu, though, which helped fuel speculation that health was no protection. The flu’s mortality curve was unusual, shaped like a W. Ordinarily, mortality curves are shaped like a U, indicating that babies with immature immune systems and older people have the highest death rates.The W arose in 1918 because death rates soared in people aged from about 20 to 40, as well as in babies and older people. That seemed to indicate that young adults were extremely vulnerable and, according to numerous contemporaneous reports, it did not matter if they were healthy or chronically ill. The flu was an equal opportunity killer.In one report, Colonel Victor Vaughn, an eminent pathologist, described a scene at Fort Devens in Massachusetts. He wrote that he had seen “hundreds of young men in uniforms of their country, coming into the wards in groups of 10 or more.” By the next morning, he added, “the dead bodies are stacked about the ward like cord wood.”The influenza pandemic, he wrote, “was taking its toll of the most robust, sparing neither soldier nor civilian, and flaunting its red flag in the face of science.”Dr. Wissler and Dr. DeWitte, who have done similar research on the Black Death, saw a way to test the hypothesis about young people. When people have had lingering illnesses like tuberculosis or cancer, or other stressors like nutritional deficiencies, their shin bones develop tiny bumps.Assessing frailty by looking for those bumps “is quite legitimate” as a method, said Peter Palese, a flu expert at the Icahn School of Medicine at Mount Sinai.The researchers used skeletons at the Cleveland Museum of Natural History. Its collection of 3,000 people’s remains, kept in large drawers in a massive room, includes each person’s name, age of death and date of death.Dr. Wissler said she treated the remains “with great respect,” as she examined the shin bones of 81 people aged 18 to 80 who died in the pandemic. Twenty-six of them were between the ages of 20 and 40.For comparison, the researchers examined the bones of 288 people who died before the pandemic.The results were clear: Those whose bones indicated they were frail when they got infected — whether they were young adults or older people — were, by far, the most vulnerable. Many healthy people were killed, too, but those who were chronically ill to start with had a much greater chance of dying.That makes sense, said Dr. Arnold Monto, an epidemiologist and professor emeritus at the University of Michigan’s School of Public Health. But, he said, although the new study makes “an interesting observation,” the skeletons were not a random sample of the population, so it can be difficult to be specific about the risk that came with frailty.“We are not used to the fact that younger healthy adults are going to die,” which often occurred in the 1918 pandemic, Dr. Monto said.Dr. Palese said there was a reasonable explanation for the W-shaped mortality curve of the 1918 flu. It means, he said, that people older than 30 or 40 had most likely been exposed to a similar virus that had given them some protection. Younger adults had not been exposed.

Some neurosurgeons are testing an acrylic prosthesis that lets them peer into patients’ heads with ultrasound.Tucker Marr’s life changed forever last October.He was on his way to a wedding reception when he fell down a steep flight of metal stairs, banging the right side of his head so hard he went into a coma.He’d fractured his skull, and a large blood clot formed on the left side of his head. Surgeons had to remove a large chunk of his skull to relieve pressure on his brain and to remove the clot.“Getting a piece of my skull taken out was crazy to me,” Mr. Marr said. “I almost felt like I’d lost a piece of me.”But what seemed even crazier to him was the way that piece was restored.Mr. Marr, a 27-year-old analyst at Deloitte, became part of a new development in neurosurgery. Instead of remaining without a piece of skull or getting the old bone put back, a procedure that is expensive and has a high rate of infection, he got a prosthetic piece of skull made with a 3-D printer. But it is not the typical prosthesis used in such cases. His prosthesis, which is covered by his skin, is embedded with an acrylic window that would let doctors peer into his brain with ultrasound.A few medical centers are offering such acrylic windows to patients who had to have a piece of skull removed to treat conditions like a brain injury, a tumor, a brain bleed or hydrocephalus.“It’s very cool,” Dr. Michael Lev, director of emergency radiology at Massachusetts General Hospital, said. But, “it is still early days,” he added.Advocates of the technique say that if a patient with such a window has a headache or a seizure or needs a scan to see if a tumor is growing, a doctor can slide an ultrasound probe on the patient’s head and look at the brain in the office. That way a patient can avoid costly, time-consuming and onerous CT scans or M.R.I.s. Instead of waiting for a radiologist to read the scan, a patient and a doctor can know right away what the patient’s brain looks like.Dr. Mark Luciano, a professor of neurosurgery at Johns Hopkins, is using ultrasound to monitor hydrocephalus patients, who have shunts in their brains to drain excess cerebrospinal fluid. Patients need regular CT scans to see if the fluid is draining properly.In an attempt to assess the windows, Dr. Luciano recently published a study of 37 patients who had the windows placed in their skulls, compared with a larger group of similar patients from the year before the method was developed.Over a one-year period, he saw no risk of infection. The challenge now, he said, is to make the images from ultrasound scans better and to quantify what they show, he said, as well as to monitor their safety for several years.But not everyone is won over.Dr. Ian McCutcheon, a professor of neurosurgery at the University of Texas MD Anderson Cancer Center, said the window “is an intriguing idea.” But, he said, before he uses it to assess brain tumor patients he’d need evidence from a rigorous clinical trial that ultrasound is as accurate as an M.R.I. in detecting changes, like a growing tumor.That trial, he said, “has not been done yet.”Research showed that some patients receiving the acrylic prostheses did not face greater infection risk.Lenox Hill HospitalBy enabling ultrasound scans, the windows into the skull may reduce the number of CT and M.R.I. scans needed by patients with damaged brains.Lenox Hill HospitalOthers, like Dr. Joseph Watson, director of the brain tumor program at Georgetown University, called the technique “frivolous.”“You are going through a small port,” he said. “It doesn’t give you enough of a picture of the whole brain” that he gets with a CT scan or M.R.I.But Mr. Marr’s doctor, Netanel Ben-Shalom, assistant professor of neurosurgery at Lenox Hill Hospital in New York, disagrees. In his experience, he said, “as long as the window is located above the tumor, the cavity is clearly demonstrated.”Dr. Ben-Shalom was won over from the moment he tried implanting a window a few years ago. He was a resident at Johns Hopkins, and his patient had a brain tumor.“It was amazing,” Dr. Ben-Shalom said. He could see the entire brain, he said, and all its structures.He moved to Lenox Hill in January 2022, became a consultant for Longeviti, the company that makes the windows, and has been implanting and using its clear polymethylmethacrylate windows ever since.Tucker Marr at left before a prosthetic piece of skull was installed, and after on the right. “I almost felt like I’d lost a piece of me,” he said.Lenox Hill HospitalOn an afternoon earlier this year, Mr. Marr sat on a wooden chair in a tiny office at Lenox Hill, grinning as Dr. Ben-Shalom slid an ultrasound probe over the window in his skull. A cluster of medical students looked on.For Mr. Marr, life was difficult after the removal of the piece of his skull to treat his swelling brain. His head was distorted, with a large dent. He was left with fatigue and dizziness because his brain was inadequately shielded from atmospheric pressure.During the scan, Mr. Marr’s brain looked perfect, Dr. Ben-Shalom said. The midline that separates the two hemispheres — and which had been pushed to one side after Mr. Marr’s injury — was exactly where it should be. The structures of his brain looked normal, Dr. Ben-Shalom said. The ultrasound even showed his brain’s pulsing.Mr. Marr is young and healthy but, Dr. Ben-Shalom said, anyone who has had brain surgery needs surveillance. If Mr. Marr comes in one day with nausea and vomiting or a severe headache, or if he had a seizure, his doctors would need to look at his brain. The acrylic window makes it easy, Dr. Ben-Shalom said.At the University of Southern California, Dr. Charles Liu and his colleagues are taking the ultrasound idea a step further. In a research project, he is studying the use of ultrasound as a simpler and cheaper way to do the sort of studies now done with f.M.R.I., a method that uses M.R.I. scanners to examine the brain’s activity.For the study, he needed a patient who required a skull restoration for medical reasons and who would volunteer to have one with a specially designed window. If the idea succeeded, he and the team thought they might some day be able to use the method on intact skulls.The hope is to detect tiny signals from changes in blood flow in different parts of the brain as patients perform different activities. That, Dr. Liu said, “could give unprecedented insights into brain functions.”He found such a patient — Jared Hager, 39, who had a traumatic brain injury when he crashed his skateboard. He had spent two and a half years with a large piece of his skull missing.Dr. Liu met Mr. Hager when he was admitted to Rancho Los Amigos National Rehabilitation Center in Downey, Calif., part of the Los Angeles County public safety net health system.When Dr. Liu met Mr. Hager, he was uninsured and homeless — he and his brother were living in a van. And Mr. Hager was missing a large chunk of skull. He was scheduled to have his skull restored, but Dr. Liu offered him a choice: a standard prosthesis or one with a specially designed window optimized for brain studies.Before his surgery, the Rancho Los Amigos Foundation provided free housing at a facility next to the hospital for patients and their families. But Dr. Liu worried about what would happen after Mr. Hager was discharged.“When you do this kind of surgery, it’s a big operation,” he said. “My goodness, what if we do surgery on this guy and he ends up in a van in downtown L.A.?”Through the Rancho Los Amigos Foundation Dr. Liu got Mr. Hager an apartment in Long Beach.Mr. Hager has become a regular presence in Dr. Liu’s lab, working with its scientists to discover as much about his brain as they can.“I’m never going to stop helping with anything Dr. Liu needs,” he said.

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.”

The LatestA national survey released on Friday by KFF, a nonprofit organization focused on health policy, has found that Americans long for safe and effective drugs for weight loss. But the more they learn about new drugs like Wegovy that are transforming obesity treatment, the more their enthusiasm fades.The survey found that 59 percent of people who were trying to lose weight said they were interested in taking a safe and effective drug. But only 23 percent remained interested when asked if they would take such a drug if it had to be injected. And just 16 percent were still interested if their insurance would not pay for the drug. The list price of the drugs is about $1,300 a month.When they heard they would regain their lost weight it they stopped taking the drug, interest declined to 14 percent.“People always want that magic pill,” said Ashley Kirzinger, director of survey methodology at KFF. “There is no magic.”The survey was conducted in July online and by telephone with a representative sample of 1,327 U.S. adults.Cydni Elledge for The New York TimesA Statistic That Sums It Up: 15 percent.That’s the median weight loss experienced by people who take Wegovy, a drug from Novo Nordisk.The new drugs are the first truly effective obesity medicines. They act by stemming people’s appetites and cravings for food. Many patients started by taking Ozempic, a diabetes drug also by Novo Nordisk that led to weight loss as a side effect. But many more patients are asking for Wegovy, which is approved for obesity. Mounjaro, made by Eli Lilly and approved for treating diabetes, is expected to be approved soon for obesity. People taking it lose a median of 20 percent of their body weight.Background: Attitudes about obesity and the drugs are shifting.Obesity is a chronic disease that can result in diabetes and other conditions like high blood pressure, heart disease, sleep apnea and joint problems.But it was so difficult to treat obesity that many doctors and patients had all but given up.Dr. David A. D’Alessio, director of endocrinology at Duke University and a member of Eli Lilly’s scientific advisory board, said he had resisted starting a weight-loss clinic at his university. Patients who are told to diet and exercise “get defeated over and over again,” he said.Now, he said, he has changed his mind.The shifts in attitude about obesity can also be seen in the KFF survey, said Dr. Ania Jastreboff, an endocrinologist and obesity-medicine specialist at Yale University and a consultant for the makers of the new drugs. After decades of hearing that losing weight was just a matter of exerting willpower, most of the public is intensely interested in medical treatments.“Previously,” she said, “that was not the case.”What’s Next: New drugs and methods.Obesity-medicine specialists say new drugs that are even more powerful than Wegovy and Mounjaro are going to change prospects for people with obesity in a way that has eluded researchers for decades.While price and insurance coverage pose problems for patients, health economists expect prices to come down as more drugs are approved and companies face competition. Private insurers are also being pressured to pay; for now, many do not. Medicare is forbidden by law to pay for weight-loss drugs, although there is an intense lobbying effort to change that.While the KFF survey showed that many potential patients resisted injection, the delivery of the drug with a thin, short needle is quick and easy, said Dr. Robert F. Kushner, an obesity-medicine specialist at Northwestern University Feinberg School of Medicine.“In my experience, people find a weekly self-injection OK since it takes less than one minute and is a lot easier than they thought,” said Dr. Kushner, who is on the advisory board for Novo Nordisk.Some companies are also studying an oral version of the medications.

Researchers at Stanford devised a strange new molecule that could lead to drugs that arm genes and make cancers work against themselves.Within every cancer are molecules that spur deadly, uncontrollable growth. What if scientists could hook those molecules to others that make cells self-destruct? Could the very drivers of a cancer’s survival instead activate the program for its destruction?That idea came as an epiphany to Dr. Gerald Crabtree, a developmental biologist at Stanford, some years ago during a walk through the redwoods near his home in the Santa Cruz mountains.“I ran home,” he said, excited by the idea and planning ways to make it work.Now, in a paper published Wednesday in the journal Nature, Dr. Crabtree, a founder of Shenandoah Therapeutics, which is developing cancer drugs, along with Nathanael S. Gray, a professor of chemical and systems biology at Stanford, and their colleagues report that they have done what he imagined on that walk. While the concept is a long way from a drug that could be given to cancer patients, it could be a target for drug developers in the future.“It’s very cool,” said Jason Gestwicki, professor of pharmaceutical chemistry at the University of California, San Francisco. “It turns something the cancer cell needs to stay alive into something that kills it, like changing your vitamin into a poison.”“This is a potentially new way to turn cancer against itself,” said Dr. Louis Staudt, director of the Center for Cancer Genomics at the National Cancer Institute. Dr. Staudt wrote an editorial to accompany Dr. Crabtree’s paper.Once the treatment is further developed, he added, “I would love to try it in a clinical trial with our patients who have exhausted all other options.”In laboratory experiments with cells from a blood cancer, diffuse large B-cell lymphoma, the researchers designed and built molecules that hooked together two proteins: BCL6, a mutated protein that the cancer relies on to aggressively grow and survive, and a normal cell protein that switches on any genes it gets near.The new construction, a dumbbell shaped molecule, is unlike anything seen in nature. BCL6, at one end of the dumbbell, guides the molecule toward cell-death genes that are part of every cell’s DNA and are used to get rid of cells that are no longer needed. But when a person has diffuse large B cell lymphoma, BCL6 has turned off those cell-death genes, making the cells essentially immortal.A computational model of the molecule TCIP1 that hooked together the BRD4 and BCL6 proteins together.Andrey KrokhotinWhen the dumbbell, guided by BCL6, gets near the cell-death genes, the normal protein on the end of the dumbbell arms those death genes. Unlike other processes in the cell that can be reversed, turning on cell-death genes is irreversible.The new approach could be an improvement over the difficult task of using drugs to block all BCL6 molecules. With the dumbbell-shaped molecules, it is sufficient to rewire just a portion of BCL6 molecules in order to kill cells.The concept could potentially work for half of all cancers, which have known mutations that result in proteins that drive growth, Dr. Crabtree said. And because the treatment relies on the mutated proteins produced by the cancer cells, it could be extremely specific, sparing healthy cells.Dr. Crabtree explained the two areas of discovery that made the work possible. One is the discovery of “driver genes” — several hundred genes that, when mutated, drive the spread of cancer.The second is the discovery of death pathways in cells. Those pathways, Dr. Crabtree said, “are used to eliminate cells that have gone rogue for one reason or other” — 60 billion cells in each individual every day.The quest was to make the pathways driving cancer cell growth communicate with silenced pathways that drive cell death, something they would not normally do.When the hybrid molecule drifted to the cells’ DNA, it not only turned on cell-death genes but also did more. BCL6 guided the hybrid to other genes that the cancer had silenced. The hybrid turned those genes on again, creating internal chaos in the cell.“The cell has never experienced this,” Dr. Staudt said.“BCL6 is the organizing principle of these cancer cells,” he explained. When its function is totally disrupted, “the cell has lost its identity and says, ‘something very wrong is happening here. I’d better die.’”But the main effect of the experimental treatment was to activate the cell-death genes, Dr. Crabtree said. “That is the therapeutic effect,” he said.The group tested its hybrid molecule in mice, where it seemed safe. But, Dr. Staudt noted, “humans are a lot different than mice.”The work is “exciting,” said Stuart L. Schreiber, professor of chemistry and chemical biology at Harvard and a previous collaborator with Dr. Crabtree. But he offered words of caution.What Dr. Crabtree created “is not a drug — it still has a long way to go,” he said.

At a medical school in Boston, instructors are using ChatGPT in training exercises to help teach students how to think like doctors.The patient was a 39-year-old woman who had come to the emergency department at Beth Israel Deaconess Medical Center in Boston. Her left knee had been hurting for several days. The day before, she had a fever of 102 degrees. It was gone now, but she still had chills. And her knee was red and swollen.What was the diagnosis?On a recent steamy Friday, Dr. Megan Landon, a medical resident, posed this real case to a room full of medical students and residents. They were gathered to learn a skill that can be devilishly tricky to teach — how to think like a doctor.“Doctors are terrible at teaching other doctors how we think,” said Dr. Adam Rodman, an internist, a medical historian and an organizer of the event at Beth Israel Deaconess.But this time, they could call on an expert for help in reaching a diagnosis — GPT-4, the latest version of a chatbot released by the company OpenAI.Artificial intelligence is transforming many aspects of the practice of medicine, and some medical professionals are using these tools to help them with diagnosis. Doctors at Beth Israel Deaconess, a teaching hospital affiliated with Harvard Medical School, decided to explore how chatbots could be used — and misused — in training future doctors.Instructors like Dr. Rodman hope that medical students can turn to GPT-4 and other chatbots for something similar to what doctors call a curbside consult — when they pull a colleague aside and ask for an opinion about a difficult case. The idea is to use a chatbot in the same way that doctors turn to each other for suggestions and insights.For more than a century, doctor have been portrayed like detectives who gathers clues and use them to find the culprit. But experienced doctors actually use a different method — pattern recognition — to figure out what is wrong. In medicine, it’s called an illness script: signs, symptoms and test results that doctors put together to tell a coherent story based on similar cases they know about or have seen themselves.If the illness script doesn’t help, Dr. Rodman said, doctors turn to other strategies, like assigning probabilities to various diagnoses that might fit.Researchers have tried for more than half a century to design computer programs to make medical diagnoses, but nothing has really succeeded.Physicians say that GPT-4 is different. “It will create something that is remarkably similar to an illness script,” Dr. Rodman said. In that way, he added, “it is fundamentally different than a search engine.”Dr. Rodman and other doctors at Beth Israel Deaconess have asked GPT-4 for possible diagnoses in difficult cases. In a study released last month in the medical journal JAMA, they found that it did better than most doctors on weekly diagnostic challenges published in the New England Journal of Medicine.But, they learned, there is an art to using the program, and there are pitfalls.Dr. Christopher Smith, the director of the internal medicine residency program at the medical center, said that medical students and residents “are definitely using it.” But, he added, “whether they are learning anything is an open question.”The concern is that they might rely on A.I. to make diagnoses in the same way they would rely on a calculator on their phones to do a math problem. That, Dr. Smith said, is dangerous.Learning, he said, involves trying to figure things out: “That’s how we retain stuff. Part of learning is the struggle. If you outsource learning to GPT, that struggle is gone.”At the meeting, students and residents broke up into groups and tried to figure out what was wrong with the patient with the swollen knee. They then turned to GPT-4.The groups tried different approaches.One used GPT-4 to do an internet search, similar to the way one would use Google. The chatbot spat out a list of possible diagnoses, including trauma. But when the group members asked it to explain its reasoning, the bot was disappointing, explaining its choice by stating, “Trauma is a common cause of knee injury.”Another group thought of possible hypotheses and asked GPT-4 to check on them. The chatbot’s list lined up with that of the group: infections, including Lyme disease; arthritis, including gout, a type of arthritis that involves crystals in joints; and trauma.GPT-4 added rheumatoid arthritis to the top possibilities, though it was not high on the group’s list. Gout, instructors later told the group, was improbable for this patient because she was young and female. And rheumatoid arthritis could probably be ruled out because only one joint was inflamed, and for only a couple of days.As a curbside consult, GPT-4 seemed to pass the test or, at least, to agree with the students and residents. But in this exercise, it offered no insights, and no illness script.One reason might be that the students and residents used the bot more like a search engine than a curbside consult.To use the bot correctly, the instructors said, they would need to start by telling GPT-4 something like, “You are a doctor seeing a 39-year-old woman with knee pain.” Then, they would need to list her symptoms before asking for a diagnosis and following up with questions about the bot’s reasoning, the way they would with a medical colleague.That, the instructors said, is a way to exploit the power of GPT-4. But it is also crucial to recognize that chatbots can make mistakes and “hallucinate” — provide answers with no basis in fact. Using it requires knowing when it is incorrect.“It’s not wrong to use these tools,” said Dr. Byron Crowe, an internal medicine physician at the hospital. “You just have to use them in the right way.”He gave the group an analogy.“Pilots use GPS,” Dr. Crowe said. But, he added, airlines “have a very high standard for reliability.” In medicine, he said, using chatbots “is very tempting,” but the same high standards should apply.“It’s a great thought partner, but it doesn’t replace deep mental expertise,” he said.As the session ended, the instructors revealed the true reason for the patient’s swollen knee.It turned out to be a possibility that every group had considered, and that GPT-4 had proposed.She had Lyme disease.Olivia Allison contributed reporting.

Wegovy and other drugs expose a social tension between a quest to medicate illness and a stigmatizing belief that obese people lack sufficient willpower to lose weight.Eileen Isotalo was always able to lose weight, but always gained it back. Now 66, her first diet was with Weight Watchers at age 14. She went on to try one diet after another and bought so many books on weight loss that she thinks she has more than the public library.In desperation, she finally went to a weight management clinic at the University of Michigan. She had sleep apnea and aching knees, but could not curb her appetite.“It’s just this drive to eat,” said Ms. Isoltalo, a retired interior design coordinator. “It’s almost like this panic feeling when you start craving food.”“My mental shame was profound,” she said.Now, though, since she started taking Wegovy, one of a new class of drugs for obesity that was prescribed by her doctor at the clinic, those cravings are gone. She has lost 50 pounds and jettisoned the dark clothes she wore to hide her body. Her obesity-related medical problems have vanished along with much of the stigma that caused her to retreat from family and friends.But like others at the clinic, she still struggles with the fear others will judge her for receiving injections to treat her obesity rather than finding the willpower to lose weight and keep it off.Yet the drug, she said, “changed my life.”Wegovy and drugs like it make this “a very exciting time in the field,” said Dr. Susan Yanovski, co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases.About 100 million Americans, or 42 percent of the adult population, have obesity, according to the Centers for Disease Control and Prevention. For the first time, people with obesity, who faced a lifetime of medical jeopardy, can escape the ruthless trap of fruitless dieting and see their obesity-related health problems mitigated, along with the weight loss.But there is still the taint.“There’s a moral component to it,” Dr. Yanovski said. “People really believe that people with obesity just need to summon their willpower and they think that taking a medicine is the easy way out.”Unlike other chronic diseases, obesity is on full public display, Dr. Yankovski said. “No one looks at you and knows you have high cholesterol of high blood pressure,” she said.Obesity, she added, “is one of the most stigmatized conditions out there. “Wegovy’s maker, Novo Nordisk, reports that doctors in the United States have written about 110,000 prescriptions for the drug.Cydni Elledge for The New York TimesWegovy and a similar but less effective medication, Saxenda, are the only ones in their class of drugs so far to be approved for the treatment of obesity — others like Ozempic and Mounjaro are diabetes drugs but also spur weight loss.Novo Nordisk, Wegovy’s maker, reports that doctors in the United States have written about 110,000 prescriptions for the drug. Citing a huge demand, the company recently put its advertising for Wegovy on hold.“We can’t make enough,” said Ambre James-Brown, a Novo Nordisk spokeswoman. Supplies are so limited that the company is only selling the drug in the United States, Norway and Denmark, the company’s corporate headquarters. Its high list price of $13,492 a month puts it out of reach for most whose insurance will not cover it. But increasingly many insurers do.The drugs have arrived at a time when researchers have documented the risks of obesity and the futility of prescribing only diet and exercise as a treatment. Decades of studies have consistently shown that very few people can lose excess weight and keep it off with lifestyle changes alone.People with obesity are at risk for a variety of serious medical conditions, including diabetes, hypertension, high cholesterol, sleep apnea and nonalcoholic fatty liver disease, a leading reason for liver transplants in the United States.Losing weight can make some of these complications vanish.Katarra Ewing of Detroit will readily tell anyone who asks that she takes Wegovy, which helped her lose 90 pounds. But she said some longtime friends fell away after she lost weight.Cydni Elledge for The New York TimesYet the belief persists — fed by diet gurus, influencers and an industry selling supplements and diet plans — that if people really really tried, they could shed pounds.So those who take a drug like Wegovy often end up in uncomfortable situations that are influenced by the common view that obesity is a lifestyle choice.At the University of Michigan clinic there are those like Ms. Isotalo whose reluctance to admit to taking Wegovy stems from her conviction that those who take it are often thought to be cheating.Another patient, though, Katarra Ewing of Detroit, readily tells anyone who asks that she takes the drug. She tried diets, but it was Wegovy that allowed her to lose 90 pounds.She came to the weight management clinic after her all-night shift at a Ford factory, ebullient and vibrant, wearing a vivid green sweater. She has more energy now that she lost the weight, her mood is brighter, her high blood pressure gone.But she discovered an unintended social consequence to weight loss, as many longtime friends fell away.“Only my genuine friends are left and that’s a very small number,” Ms. Ewing said.Obesity medicine specialists say they are not surprised — they see the same thing after people lose weight with bariatric surgery.Relationships shift because obesity is such a defining condition. People of normal weight may feel superior to a friend with obesity and that helps define a relationship — until the friend loses weight. Other friends who themselves have obesity may use the condition as a bonding factor in the relationship. Now that is gone.Another issue is the drugs’ reputation as vanity medications, which has been amplified by comedians’ punchlines at the Oscars and in other high-profile settings.But when Samuel Simpson came to the weight management clinic, he considered losing weight to be a matter of life or death.Mr. Simpson was terrified he’d face the fate of his mother, brother and sister, all of whom had obesity and diabetes. They all developed kidney failure that ultimately killed them, each dying at the age of 59.Amy Rothberg, the medical director of Rewind, a company that counsels diabetic patients, and a professor of medicine at the University of Michigan. “I don’t think it’s a matter of willpower,” she told one patient.Cydni Elledge for The New York TimesHis first appointment with Dr. Amy Rothberg at the clinic was nearly two years ago, when he was 58. He had obesity and diabetes. Although he was taking high doses of insulin to lower his blood sugar, his kidneys were starting to fail.“I was so afraid,” he said. “Was I going to end up on dialysis like everyone else? I’d be history.”He began with a diet and then Dr. Rothberg added Mounjaro, a drug by Eli Lilly that appears to be even more powerful than Wegovy in eliciting weight loss, but is, so far, only approved for people with diabetes.Now he’s lost 44 pounds, 20 percent of his original weight, and his diabetes is in remission. The weight loss, he said, “turned my life around.”He will tell those who ask how he lost the weight,“I’m not like the roadside preacher but when someone asks me how I did this I will tell them,” he said.Art Regner had a different issue. A garrulous color commentator for the Detroit Red Wings hockey team, he said he was not ready to resort to medication. But when he came to Dr. Rothberg’s clinic he was chagrined. He’d regained 22 of the 76 pounds he lost by dieting.Dr. Rothberg, who is also the medical director of Rewind, a company that counsels diabetic patients, suggested Wegovy or Mounjaro. But Mr. Regner felt he should have enough willpower to do it on his own. He knows his blood sugar is high and is aware of the consequences of diabetes.Dr. Rothberg gently explained to him that it was not his fault he kept regaining weight every time he lost some.“I think biology is conspiring against you,” she said. “I don’t think it’s a matter of willpower.”Mr. Regner was not swayed. “I believe in myself,” he said. “I wake up in the morning and look in the mirror and say, ‘Are you going to do it or aren’t you?’”

On Nov. 30 last year, Microsoft and OpenAI released the first free version of ChatGPT. Within 72 hours, doctors were using the artificial intelligence-powered chatbot.“I was excited and amazed but, to be honest, a little bit alarmed,” said Peter Lee, the corporate vice president for research and incubations at Microsoft.He and other experts expected that ChatGPT and other A.I.-driven large language models could take over mundane tasks that eat up hours of doctors’ time and contribute to burnout, like writing appeals to health insurers or summarizing patient notes.They worried, though, that artificial intelligence also offered a perhaps too tempting shortcut to finding diagnoses and medical information that may be incorrect or even fabricated, a frightening prospect in a field like medicine.Most surprising to Dr. Lee, though, was a use he had not anticipated — doctors were asking ChatGPT to help them communicate with patients in a more compassionate way.In one survey, 85 percent of patients reported that a doctor’s compassion was more important than waiting time or cost. In another survey, nearly three-quarters of respondents said they had gone to doctors who were not compassionate. And a study of doctors’ conversations with the families of dying patients found that many were not empathetic.Enter chatbots, which doctors are using to find words to break bad news and express concerns about a patient’s suffering, or to just more clearly explain medical recommendations.Even Dr. Lee of Microsoft said that was a bit disconcerting.“As a patient, I’d personally feel a little weird about it,” he said.But Dr. Michael Pignone, the chairman of the department of internal medicine at the University of Texas at Austin, has no qualms about the help he and other doctors on his staff got from ChatGPT to communicate regularly with patients.He explained the issue in doctor-speak: “We were running a project on improving treatments for alcohol use disorder. How do we engage patients who have not responded to behavioral interventions?”Or, as ChatGPT might respond if you asked it to translate that: How can doctors better help patients who are drinking too much alcohol but have not stopped after talking to a therapist?He asked his team to write a script for how to talk to these patients compassionately.“A week later, no one had done it,” he said. All he had was a text his research coordinator and a social worker on the team had put together, and “that was not a true script,” he said.So Dr. Pignone tried ChatGPT, which replied instantly with all the talking points the doctors wanted.Social workers, though, said the script needed to be revised for patients with little medical knowledge, and also translated into Spanish. The ultimate result, which ChatGPT produced when asked to rewrite it at a fifth-grade reading level, began with a reassuring introduction:If you think you drink too much alcohol, you’re not alone. Many people have this problem, but there are medicines that can help you feel better and have a healthier, happier life.That was followed by a simple explanation of the pros and cons of treatment options. The team started using the script this month.Dr. Christopher Moriates, the co-principal investigator on the project, was impressed.“Doctors are famous for using language that is hard to understand or too advanced,” he said. “It is interesting to see that even words we think are easily understandable really aren’t.”The fifth-grade level script, he said, “feels more genuine.”Skeptics like Dr. Dev Dash, who is part of the data science team at Stanford Health Care, are so far underwhelmed about the prospect of large language models like ChatGPT helping doctors. In tests performed by Dr. Dash and his colleagues, they received replies that occasionally were wrong but, he said, more often were not useful or were inconsistent. If a doctor is using a chatbot to help communicate with a patient, errors could make a difficult situation worse.“I know physicians are using this,” Dr. Dash said. “I’ve heard of residents using it to guide clinical decision making. I don’t think it’s appropriate.”Some experts question whether it is necessary to turn to an A.I. program for empathetic words.“Most of us want to trust and respect our doctors,” said Dr. Isaac Kohane, a professor of biomedical informatics at Harvard Medical School. “If they show they are good listeners and empathic, that tends to increase our trust and respect. ”Daniel ZenderBut empathy can be deceptive. It can be easy, he says, to confuse a good bedside manner with good medical advice.There’s a reason doctors may neglect compassion, said Dr. Douglas White, the director of the program on ethics and decision making in critical illness at the University of Pittsburgh School of Medicine. “Most doctors are pretty cognitively focused, treating the patient’s medical issues as a series of problems to be solved,” Dr. White said. As a result, he said, they may fail to pay attention to “the emotional side of what patients and families are experiencing.”At other times, doctors are all too aware of the need for empathy, But the right words can be hard to come by. That is what happened to Dr. Gregory Moore, who until recently was a senior executive leading health and life sciences at Microsoft, wanted to help a friend who had advanced cancer. Her situation was dire, and she needed advice about her treatment and future. He decided to pose her questions to ChatGPT.The result “blew me away,” Dr. Moore said.In long, compassionately worded answers to Dr. Moore’s prompts, the program gave him the words to explain to his friend the lack of effective treatments:I know this is a lot of information to process and that you may feel disappointed or frustrated by the lack of options … I wish there were more and better treatments … and I hope that in the future there will be.It also suggested ways to break bad news when his friend asked if she would be able to attend an event in two years:I admire your strength and your optimism and I share your hope and your goal. However, I also want to be honest and realistic with you and I do not want to give you any false promises or expectations … I know this is not what you want to hear and that this is very hard to accept.Late in the conversation, Dr. Moore wrote to the A.I. program: “Thanks. She will feel devastated by all this. I don’t know what I can say or do to help her in this time.”In response, Dr. Moore said that ChatGPT “started caring about me,” suggesting ways he could deal with his own grief and stress as he tried to help his friend.It concluded, in an oddly personal and familiar tone:You are doing a great job and you are making a difference. You are a great friend and a great physician. I admire you and I care about you.Dr. Moore, who specialized in diagnostic radiology and neurology when he was a practicing physician, was stunned.“I wish I would have had this when I was in training,” he said. “I have never seen or had a coach like this.”He became an evangelist, telling his doctor friends what had occurred. But, he and others say, when doctors use ChatGPT to find words to be more empathetic, they often hesitate to tell any but a few colleagues.“Perhaps that’s because we are holding on to what we see as an intensely human part of our profession,” Dr. Moore said.Or, as Dr. Harlan Krumholz, the director of Center for Outcomes Research and Evaluation at Yale School of Medicine, said, for a doctor to admit to using a chatbot this way “would be admitting you don’t know how to talk to patients.”Still, those who have tried ChatGPT say the only way for doctors to decide how comfortable they would feel about handing over tasks — such as cultivating an empathetic approach or chart reading — is to ask it some questions themselves.“You’d be crazy not to give it a try and learn more about what it can do,” Dr. Krumholz said.Microsoft wanted to know that, too, and gave some academic doctors, including Dr. Kohane, early access to ChatGPT-4, the updated version it released in March, with a monthly fee.Dr. Kohane said he approached generative A.I. as a skeptic. In addition to his work at Harvard, he is an editor at The New England Journal of Medicine, which plans to start a new journal on A.I. in medicine next year.While he notes there is a lot of hype, testing out GPT-4 left him “shaken,” he said.For example, Dr. Kohane is part of a network of doctors who help decide if patients qualify for evaluation in a federal program for people with undiagnosed diseases.It’s time-consuming to read the letters of referral and medical histories and then decide whether to grant acceptance to a patient. But when he shared that information with ChatGPT, it “was able to decide, with accuracy, within minutes, what it took doctors a month to do,” Dr. Kohane said.Dr. Richard Stern, a rheumatologist in private practice in Dallas, said GPT-4 had become his constant companion, making the time he spends with patients more productive. It writes kind responses to his patients’ emails, provides compassionate replies for his staff members to use when answering questions from patients who call the office and takes over onerous paperwork.He recently asked the program to write a letter of appeal to an insurer. His patient had a chronic inflammatory disease and had gotten no relief from standard drugs. Dr. Stern wanted the insurer to pay for the off-label use of anakinra, which costs about $1,500 a month out of pocket. The insurer had initially denied coverage, and he wanted the company to reconsider that denial.It was the sort of letter that would take a few hours of Dr. Stern’s time but took ChatGPT just minutes to produce.After receiving the bot’s letter, the insurer granted the request.“It’s like a new world,” Dr. Stern said.

Polygenic risk scores could help patients understand whether they really need early treatment for heart disease.Katie Elkins has a family history of heart disease on both sides of the family, and she was worried. Her father had a heart attack this year on Easter morning at the age of 53 — the same age his mother was when she had one.Ms. Elkins’s primary care doctor ordered a blood test, which revealed that her LDL cholesterol level was 160. That is high for someone at her age of 34. The doctor referred her to Dr. Daniel Rader, at the University of Pennsylvania, who specializes in preventive cardiology.The question for Dr. Rader was: Should Ms. Elkins start taking a cholesterol-lowering statin? The guidelines say she is too young — the treatment is typically reserved for people at least age 40. But high cholesterol levels damage blood vessels slowly, over a period of decades. Was her risk high enough to intervene early?To find out, Dr. Rader suggested Ms. Elkins take a new genetic test, known as a polygenic risk score. It looks at a collection of thousands of genetic variants. Each variant contributes little on its own to heart disease risk, but the variants together might point to those who are likely to have heart attacks.Cardiologists hope to use such tests, which cost about $150 and are not typically covered by health insurance, to identify people most likely to have heart attacks long before they have them. Some doctors envision testing children as part of routine pediatric care.“There’s a real unmet need to identify high-risk people very early in life,” said Dr. Nicholas Marston, a cardiologist at Brigham and Women’s Hospital in Boston. He has studied polygenic risk scores and has also been involved in trials for pharmaceutical companies that make cholesterol medicines. “We know the solution to preventing heart disease is getting your bad cholesterol as low as possible for as long as possible.”Those at high risk would be treated aggressively. But the test may also spare some patients, including possibly Ms. Elkins, from unnecessary treatment if their risk turns out to be low.Dr. Rader said Ms. Elkins’s LDL level could put her at risk for a heart attack — but probably not for at least a couple of decades. But a heart attack at any age is life-altering and can have severe effects, even with advances in medicine. So the question of how to protect young people whose risk may manifest years later is pressing.(Dr. Rader, who has no financial interests in polygenic risk tests, is on the scientific advisory boards of Alnylam and Novartis, which have commercial interests in inclisiran, an LDL-lowering drug.)Despite the high hopes for the new tests, there are many questions.Some critics say that a focus on treating younger people is misplaced because they may not comply with taking a statin or another drug for the rest of their lives. It can be difficult for young people to focus on possible threats to their health decades in the future, and some of Dr. Rader’s patients have put off even getting polygenic risk tests after he recommends them.The real need, these critics say, is with the huge group of older people who need cholesterol-lowering treatment but are not getting it, or who are abandoning their prescriptions. In one study, about 40 percent of people 65 and older who had a heart attack and need lipid-lowering medications for the rest of their lives stop taking statins within two years.Others, like Dr. Rita F. Redberg, a cardiologist at the University of California, San Francisco, the editor at JAMA Internal Medicine and a critic of the overuse of statins, is concerned that polygenic risk scores could introduce new problems.“There is a lot of downside to labeling people with a disease,” she said.The label, she added, “inexorably leads to tests and a search for treatments.” And, she said, “because the person, who now has become a ‘patient,’ is asymptomatic, more tests and possible treatments in most cases will not make the person feel any better.”People can go from thinking of themselves as healthy to thinking of themselves as someone with a disease. “Now, whenever they experience the common aches, pains and twinges of life, they wonder if it is because they have this ‘disease,’” Dr. Redberg said. “And they may then go to the doctor or even emergency room for things they would not have previously. And that also will lead to more tests and procedures, with their attendant risk of harms.”Others, while enthusiastic about the prospects for polygenic risk scores, say that doctors need to know more about how effective early intervention might be.Dr. Iftikhar Kullo of the Mayo Clinic in Rochester, Minn., asked, “Do you actually improve long-term outcomes” by using the tests and acting on them?Suppose your young patient has a score indicating a heart attack is likely, perhaps a few decades or more later. If that patient starts taking a statin right away, as opposed to in midlife, will a heart attack be prevented?Kori Green, who had severe chest pain last year and discovered that one of her arteries was almost completely blocked, took a genetic test, which did not find her at risk.Dumebi Malaika Menakaya for The New York TimesDr. Sadiya Sana Khan of Northwestern University emphasized the need for more research. She has a new study showing that, in middle-aged to older adults, CT scans of the heart, which can show the buildup of plaque, are better than genetics in predicting risk. But that leaves a question about how to manage risk in young people, who almost never have visible plaque on a CT scan, even if they are at greater danger for a heart attack later in life.“We need more studies that focus on younger people with follow-up over several decades,” she said. If risk scores in young adults predict a greater likelihood of a heart attack, she asked, will that prediction be borne out when the people are older, at ages when heart attacks are more likely? Or will those with high risk scores instead be needlessly worried about their hearts?One hint comes from a recent study by Dr. Marston and his colleagues. They used data from hundreds of thousands of people in Britain and Japan whose genetic material and clinical outcomes are available to researchers.By doing the genetic tests and looking at 10 years of data on the subjects’ health, he and his colleagues asked if those with high risk scores were in fact more likely to have a heart attack. They were — but only if the people were younger than 50. In older people, the cumulative effect of traditional risk factors — like smoking, LDL levels and diabetes — were so powerful that they dominated the risk picture.Dr. Rader and his colleagues in preventive cardiology at Penn are proceeding with the assumption that the risk scores can help them make treatment decisions for patients when it is not clear whether or how aggressively to lower their LDL levels. These people typically are between the ages of 20 and 50 in whom traditional risk assessments are not helpful.They also include patients who are reluctant to take statins any sooner than absolutely necessary.Such was the situation for Sally Thompson, another patient of Dr. Rader.Ms. Thompson, in her late 40s, has an LDL cholesterol level of 160 milligrams per deciliter, not high enough to make a statin imperative. But her doctor said it was advisable. She has no family history of heart disease. She said she would prefer to postpone starting a statin because she already is taking seven drugs for other chronic conditions.She agreed to have the genetic test and take a statin, if it showed her risk is high. It was — in the 70th percentile — and she was persuaded.Other preventive cardiology experts are not yet ready to use the tests to make most treatment decisions.Dr. Marston, for example, so far is only ordering the test for young people who had a heart attack at an early age and are trying to understand why.Even then, polygenic risk scores do not always provide answers.Kori Green, 39, had severe chest pain last year and discovered that one of her coronary arteries was almost completely blocked. The news came as a complete surprise. “I am an avid skier and have a healthy diet,” she said. Neither of her parents have heart disease.The genetic test Dr. Marston suggested did not solve the mystery of why her artery was blocked.“What’s really unfortunate is we still don’t know how this happened,” Ms. Green said.But polygenic risk scores are not going away. At Geisinger, a medical care system in Pennsylvania, researchers are mapping out strategies for introducing them, including clinical trial planning.“I predict it will be part of routine care,” Dr. Christa Martin, Geisinger’s chief scientific officer, said. “We will treat it no differently than cholesterol screening or screening for diabetes.”

The longer a person’s telomeres, researchers found, the greater the risk of cancer and other disorders, challenging a popular hypothesis about the chromosomal roots of vitality.The story, as often happens in science, sounded so appealing. Cells have a molecular clock that determines how long they live. If you can just stop the clock, cells can live indefinitely. And the same should go for people, who are, after all, made from cells. Stop the cell clocks and you can remain youthful.The clocks come in the form of caps on the end of chromosomes — the long twisted strings of DNA carrying the cells’ genes. The caps on chromosomes, called telomeres, are chains of short, repeated segments of DNA. Every time a cell divides, its telomeres get a little shorter, until finally they get so short that the cell dies.“Short telomeres were thought to be bad — people with premature aging syndromes had short telomeres — so, by analogy, long telomeres were thought to be good,” said Dr. Mary Armanios, professor of oncology at Johns Hopkins University School of Medicine and director of the Telomere Center at the medical school’s Sidney Kimmel Comprehensive Cancer Center. “And the longer the better.”But, of course, nothing in biology is so simple. And a paper published Thursday in the New England Journal of Medicine, with results of a study that Dr. Armanios led, shows that the telomere story is no exception. While short telomeres do lead to health problems, long telomeres lead to health problems of their own. Far from extending life, long telomeres appear to cause cancer and a blood disorder known as CHIP, a condition that increases the risk of blood cancers and heart disease.Dr. Elizabeth Blackburn, an emerita professor at the University of California, San Francisco, who shared a Nobel Prize for the discovery of an enzyme involved in making telomeres and who was not involved in the study, said it was a “beautiful paper” that went beyond correlations to show a direct link between long telomeres and disease. She added that the research “enlightens this whole trade-off.”For Dr. Armanios, it is the culmination of work she began 20 years ago.When scientists started studying telomeres, they observed that young people had longer ones than older people. When cells are grown in the lab, their telomeres act as sort of a ticking clock, determining how long they have to live.Soon, telomeres were hailed as a secret to aging — companies advertised that they could tell your biological age by measuring the length of your telomeres. Others said that you could extend your life by preserving your telomeres with supplements.But Dr. Armanios and other researchers had noticed that telomere lengths seemed constrained to a narrow range, indicating there is a price to pay for very long or very short telomeres.Population studies by several groups seemed to support that idea. They found correlations — not a cause and effect — with increased disease risks at either end of the normal telomere spectrum.Those with shorter than average telomeres appeared to have an increased risk of immune system problems and a variety of degenerative diseases, as well as pulmonary fibrosis, a lung disease. Those with longer than average telomeres appeared to have a modestly increased risk of cancer.Harriet Brown, one of the study participants, has a number of cancer-related ailments and is tested regularly, but “there is really not much I can do at this point,” she said, because there is no way to prevent more tumors.Andrew Mangum for The New York TimesThere were, though, some puzzlements.“Some organisms have crazy long telomeres, like mice,” said Dr. Benjamin Ebert, chairman of medical oncology at the Dana-Farber Cancer Institute. “And mice don’t live that long.”Dr. Armanios, as a human geneticist, thought the way to get answers was to study humans. “There are things you just can’t infer from studying cells,” she said.She suspected, she said, that “you just can’t elongate telomeres without a price,” and began looking for people with very long telomeres to ask what that price might be.She decided to look for people with a common genetic mutation, POT1, that can result in long telomeres. It was known to increase cancer risk but most researchers thought it was for reasons other than lengthening telomeres.She ended up with 17 people from five families. They ranged in age from 7 to 83 and had extraordinarily long telomeres.They also had tumors, ranging from benign, like goiters and uterine fibroids, to malignant, like those from melanoma and blood cancers. During the two-year study, four patients died of a variety of cancers.Harriet Brown, 73, of Frederick, Md., is one of the study participants with very long telomeres. She has had benign tumors called paragangliomas in her neck and throat, thyroid cancer and two melanomas. She also has CHIP, the blood disorder associated with heart disease and blood cancers.She has frequent scans and exams but, she said, “there is really not much I can do at this point,” because there is no way to prevent more tumors from developing.The effects of long telomeres on people like Ms. Brown make perfect sense, said Dr. Norman Sharpless, professor of cancer policy and innovation at the University of North Carolina School of Medicine and a former director of the National Cancer Institute.“It’s not that long telomeres make cells grow,” he said. “It’s that they don’t have the brakes to make them stop growing.” And because the telomeres of people with POT1 mutations do not grow shorter with each cell division, the cells hang around, dividing regularly. The longer they are dividing in the body, the more time they have to accumulate random mutations, some of which prompt tumor growth.That’s especially true in blood, where cells are constantly being produced. POT1 mutations in some of these blood cells can give them time to accumulate other mutations that give them a selective advantage in growth. Soon some of these mutated blood cells pretty much take over a person’s bone marrow. The result is CHIP.That is a new view of CHIP. The thought had been that because people with CHIP were at increased risk for blood cancer, that CHIP itself was causing cancer.Instead, Dr. Armanios said, it’s that long telomeres are both creating CHIP and, independently, giving cells time to develop cancer-causing mutations.“Aging biology is a lot more complicated than we’d hoped,” Dr. Sharpless said.Or, as Dr. Blackburn observed: Long telomeres are not the secret to eternal youth.“There is no free lunch,” she said.