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.

Many police departments prohibit their officers from employing the kind of neck restraints a man used in fatally subduing Jordan Neely in the New York City subway.When a subway rider in New York used a chokehold that ended up killing a 30-year-old homeless man, Jordan Neely, he was employing a technique that many neurologists warn is so dangerous that it should not be allowed in law enforcement.Chokeholds or strangleholds are known also as neck compressions, which involve applying pressure to both sides of the neck. They are allowed in some martial arts competitions, and certain U.S. military personnel in ground-combat units may learn to apply chokeholds, and associated safe releases, in training.But in the past few years, police departments have increasingly banned the use of chokeholds, following events such as the deaths of Eric Garner and George Floyd.There are few data on how often police have used the holds, or what the consequences were. Among the few studies is one reporting that officers in Spokane, Wash., used neck restraints 230 times in the eight years before May 2021, when Washington State banned them.While there were no fatalities recorded in the use of the holds by that department, neurologists say the dangers of neck compression are indisputable.Dr. Altaf Saadi, a neurologist at Massachusetts General Hospital, explained that chokeholds and strangleholds could kill or cause brain injuries in two ways. They can compress the trachea, preventing the person from getting air into the lungs. And they can compress the carotid arteries, which are on either side of the neck, adjacent to the trachea. Seventy percent of the blood going to the brain passes through the carotids, Dr. Saadi said. If that blood flow is cut off in a chokehold or a stranglehold, some people can become unconscious in three to four seconds. If the flow continues to be restricted, a person can die within three to four minutes.

Donanemab is not a cure and comes with significant side effects, but patients had longer periods of independent living while on the drug.The drug manufacturer Eli Lilly announced on Wednesday that a clinical trial of an experimental Alzheimer’s drug showed it can slow progress of the feared disease and allow patients to have more time when they can still live independently, performing tasks like cooking meals, going to the store and driving a car.Lilly announced its results, from a trial involving 1,736 patients, in a news release, as required by the Securities and Exchange Commission. A peer-reviewed paper will follow.The drug, donanemab, is not a cure, but along with two other drugs recently approved by the Food and Drug Administration, it may be a turning point in the long and frustrating quest to find an Alzheimer’s treatment. “These all point in the same direction,” said Dr. Ronald Petersen, the director of the Alzheimer’s Disease Research Center at the Mayo Clinic. He added that the donanemab results were “modest” but “meaningful.” Dr. Petersen has done paid consulting work for pharmaceutical companies, including Lilly. He was not involved in the design or execution of any of the recent trials.Dr. Samuel Gandy, a professor of Alzheimer’s disease research at Mount Sinai, was more subdued.“Families and researchers are stuck with what we know now, which is that two drugs have a statistically meaningful but only modest clinical benefit,” he said, echoing Dr. Petersen’s assessment. He has consulted and received research support from pharmaceutical companies but was not involved in the Lilly trial.Dr. Petersen said that patients and their families must be counseled about a dire side effect of donanemab — a risk of brain swelling that can result in death. Three patients in the Lilly trial died.A similar percentage of deaths from the same side effect followed in the clinical trial of Leqembi, an F.D.A.-approved Alzheimer’s drug from the company Eisai. A third drug, Aduhelm, was also approved by the F.D.A., but is rarely used because of concerns about its effectiveness and its high price. Brain swelling was reported in its clinical trial and deaths were reported in patients taking Aduhelm after it was approved.The results come after decades of failed attempts, despair, discouragement and billions of dollars spent. Most big pharmaceutical companies simply gave up on Alzheimer’s drugs.After those failures, some researchers decided that a leading hypothesis about the disease — that it is driven by hard, Brillo-like plaques in the brain made of amyloid protein — was incorrect. But the successes of the new drugs, which attack amyloid, bolster the hypothesis.Taking the drugs is not like taking an antibiotic and seeing a fever go away. To measure the new drug’s effectiveness, the Lilly researchers instead looked at how likely patients were to progress through the categories of Alzheimer’s disease, going from mild cognitive impairment to mild dementia, or from mild to moderate dementia. These are significant changes that have a profound effect on patients and their families.The company reported that two to three out of 10 patients taking donanemab progressed over the next 18 months as compared to the expected three to four patients who did while taking a placebo.They also studied how likely it was that a patient’s disease would remain absolutely stable over a period of time.“One of the common things we always hear from patients who have Alzheimer’s but are very early in the disease is, ‘If I could just stay at this level I could get by,’” said Dr. Daniel Skovronsky, chief medical and scientific officer at Eli Lilly and Company.With the new drug, 47 percent of patients stayed stable over the subsequent year compared with 29 percent who took the placebo.In the Lilly trial, 24 percent of patients had the side effect of brain swelling and bleeding, and 6 percent had symptoms like dizziness, headache or fainting. That is twice the rate observed with Leqembi, the Eisai drug.But, Dr. Skovronsky said, it is difficult to compare data across trials because the studies had different patient populations — the Leqembi patients had less severe Alzheimer’s — and different designs. The M.R.I. scans were done on different schedules, and the way the scans are read can vary.Deaths from brain swelling and bleeding are rare, but still these drugs “are not for everyone,” Dr. Petersen said.“They do not make you better but they slow the disease,” he said.Dr. Petersen added that what is really needed is a drug that stops the disease before symptoms arise.With that goal in mind, Eisai and Lilly are testing their drugs in new studies of people who have large amounts of amyloid in their brains but no symptoms yet of Alzheimer’s.Advocacy groups applauded the data in the Lilly trial.George Vradenburg, chairman and co-founder of UsAgainstAlzheimer’s called the donanemab results “exciting news.” Lilly, along with other companies, gives the group general funding but not for any specific project.In a news release, he said, “Talk to anyone with early-stage Alzheimer’s and they will tell you that living independently and having a higher quality of life for a longer period of time are among the most important things to them.”

On the evening of Jan. 15, 2021, in a remote Arizona desert town, Christine Benton saved a life.She and her husband, Brian Benton, were traveling the country in a recreational vehicle and had parked near other R.V.ers at a winery in Willcox. As the couple were eating dinner, someone started shouting from an R.V. behind them. A woman had collapsed and was in cardiac arrest. She had no pulse. Frantic, her husband called 911 while two other people started cardiopulmonary resuscitation.“She looked like she was gone,” said Ms. Benton, a retired paramedic firefighter.But Ms. Benton had made a consequential decision before she and her husband started out: She had bought a personal automated external defibrillator, or A.E.D., which can shock a person’s heart back to life if it suddenly stops beating. Her plan was to to keep it with her, just in case. It was expensive, it was highly unlikely she would ever use it and her husband was hesitant. But she was adamant.“If I were ever in a situation where I could save a life and I didn’t have an A.E.D., I could never live with myself,” she told her husband at the time.As a firefighter, Ms. Benton had been trained to use a defibrillator. She knew that if someone’s heart stopped, a rescuer should start CPR immediately, pushing hard and rhythmically on the chest, while another rescuer went to get an A.E.D. As soon as that second rescuer returned, the A.E.D. should be used.And Ms. Benton knew that A.E.D.s were easy to use, even for someone with no training. The device speaks to rescuers and tells them how to proceed.But even though all states have laws requiring that A.E.D.s be available in public places, Ms. Benton worried that if someone had a cardiac arrest in a place where the nearest A.E.D. was miles away, the person might die — minutes count when reviving someone in cardiac arrest. For every one-minute delay in resuscitation, the likelihood of survival falls by up to 10 percent.For Ms. Benton, the decision to buy an A.E.D. made perfect sense. I also ordered one for myself after reporting on the football player Damar Hamlin’s on-field cardiac arrest. When it arrives I am going to tell my neighborhood’s Google group that I have it.Christine Benton, a retired paramedic firefighter, had been trained to use a defibrillator, but also knew that A.E.D.s are easy to use, even for people with no training.Ash Ponders for The New York TimesBut emergency medicine specialists are divided on whether it makes sense for anyone to buy one.They know that A.E.D.s in public places like airports, where thousands of people pass by every day, can make a difference and they urge people to use them if they see someone who needs help. In the U.S., 85 to 90 percent of people who have sudden cardiac arrests do not survive and many cannot be revived, often because resuscitation attempts start too late.But the situation is different in the home.For one, there is the expense — the devices often cost more than $1,000, making them far less affordable to the average person than home medical devices like a blood pressure monitor or a pulse oximeter. While there are efforts to develop cheaper A.E.D.s, they are still underway, according to Monica Sales, a spokeswoman for the American Heart Association.The price is not the only thing that gives some specialists pause. The odds are so stacked against a dramatic save that it has proved impossible to show that personal A.E.D.’s make a difference.An estimated 1,000 people a day in the U.S. have sudden cardiac arrests, in which the heart stops beating and the person is technically dead. But that represents a minuscule portion of the American population.Even people at high risk of a sudden cardiac arrest were not helped by home A.E.D.s, a large study showed. It involved 7,001 people who had previously had heart attacks and who were randomly assigned to receive an A.E.D. or to be in a control group.Despite the huge number of study participants, very few had cardiac arrests and, even when they did, the arrests often did not occur at home or were not witnessed. In the end, just eight people in each group were resuscitated at home. The authors concluded that even if the study’s size were doubled, there would be too few events to detect an effect of home A.E.D.s.But think of an A.E.D. like a fire extinguisher, said Dr. Benjamin Abella, an emergency medicine specialist at the University of Pennsylvania. You might never use it, but having one might one day save a life.“I think it’s a terrific idea” to own one, Dr. Abella said. He recently ordered an A.E.D. for himself.For the same reason, the American Heart Association supports anyone who wants to get an A.E.D., said Dr. Comilla Sasson, a vice president at the American Heart Association and an emergency medicine physician at the University of Colorado Denver.“If we could just reduce the stigma around, ‘Hey, I can’t do this because I’m not a medical professional,’” she said. “And you don’t need to have CPR certification to use an A.E.D.”But Dr. Sumeet S. Chugh, director of the Center for Cardiac Arrest Prevention at Cedars Sinai in Los Angeles, has his doubts.“I don’t think we have the data to support widespread prophylactic purchases of A.E.D.s even if you can afford it,” he said. And, he added, many who go into cardiac arrest do not have a shockable condition. One example is asystole, a flat line on the heart monitor indicating there is no electrical activity in the heart. An A.E.D. cannot revive people with unshockable rhythms. Other patients are not discovered in time for their heart to be shocked back to life.Karen Schluter, whose life was saved in 2021 after Ms. Benton shocked her heart back into action after she had a cardiac arrest. Without the A.E.D., Ms. Schluter would have died.Andy Manis for The New York TimesThat was the situation that Mary Newman found herself in. Ms. Newman, co-founder of the Sudden Cardiac Arrest Foundation, which promotes awareness of cardiac arrest and has a support group for survivors, has an A.E.D. But when her mother collapsed in the bathroom during a family vacation, no one realized she was missing. By the time the family found her, it was too late to save her.Yet there are rare examples of people who did save a life with a personal A.E.D.One involved Esley Thorton, Jr. of Bismarck, N.D.At about 8 a.m. on Nov. 25, 2019, Mr. Thornton sank into his favorite chair, inexplicably tired.A few minutes later his wife, Melinda, heard an odd noise and came running into the room. “His body was contorted,” she said. “He was gasping for air.”Then he stopped breathing. His heart had stopped.Ms. Thornton screamed for her son Rhannon, who called 911 and grabbed an A.E.D. that another son, who works for the A.E.D. maker Stryker, had given his parents as a gift two years earlier.Rhannon put the device’s pads on his father’s chest. It said, “No pulse, administer shock,” Ms. Thornton recalled.He pressed a button.“Shock administered,” the device said.“We heard him take a deep breath,” Ms. Thornton said. Her husband’s heart was beating again.An ambulance came eight minutes after the 911 call — long enough that without Rhannon’s help, Mr. Thornton might have died or had serious brain damage.One of the paramedics was astonished, telling the family that he had been a paramedic for 22 years but had never before seen a personal A.E.D. used in a patient’s home.In Ms. Benton’s case, the woman whose heart had stopped began breathing again less than 20 seconds after Ms. Benton shocked her heart with the A.E.D.Without the A.E.D., the woman, Karen Schluter, would have died — CPR alone would not have been sufficient in that remote location where it took about half an hour for an ambulance to arrive.Yet no one would have predicted that Ms. Schluter was at risk. She was 52 and athletic — an avid bicyclist.Now Ms. Benton and Ms. Schluter are good friends. Ms. Schluter has purchased an A.E.D. and so have others whose R.V.s were parked there that evening.When the Bentons returned to their R.V. after their A.E.D. saved Ms. Schluter’s life, Mr. Benton looked at his wife and said, “I am sure glad you didn’t listen to me about buying that A.E.D.”

It was March 1827 and Ludwig van Beethoven was dying. As he lay in bed, wracked with abdominal pain and jaundiced, grieving friends and acquaintances came to visit. And some asked a favor: Could they clip a lock of his hair for remembrance?The parade of mourners continued after Beethoven’s death at age 56, even after doctors performed a gruesome craniotomy, looking at the folds in Beethoven’s brain and removing his ear bones in a vain attempt to understand why the revered composer lost his hearing.Within three days of Beethoven’s death, not a single strand of hair was left on his head.Ever since, a cottage industry has aimed to understand Beethoven’s illnesses and the cause of his death.Now, an analysis of strands of his hair has upended long held beliefs about his health. The report provides an explanation for his debilitating ailments and even his death, while also raising new questions about his genealogical origins and hinting at a dark family secret.The paper, by an international group of researchers, was published Wednesday in the journal Current Biology.It offers additional surprises: A famous lock of hair — the subject of a book and a documentary — was not Beethoven’s. It was from an Ashkenazi Jewish woman.The study also found that Beethoven did not have lead poisoning, as had been widely believed. Nor was he a Black man, as some had proposed.And a Flemish family in Belgium — who share the last name van Beethoven and had proudly claimed to be related — have no genetic ties to him.Researchers not associated with the study found it convincing.It was “a very serious and well-executed study, “ said Andaine Seguin-Orlando, an expert in ancient DNA at the University Paul Sabatier, Toulouse, in France.The detective work to solve the mysteries of Beethoven’s illness began on Dec. 1, 1994, when a lock of hair said to be Beethoven’s was auctioned by Sotheby’s. Four members of the American Beethoven Society, a private group that collects and preserves material related to the composer, purchased it for $7,300. They proudly displayed it at the Ira F. Brilliant Center for Beethoven Studies at San Jose State University in California.But was it really Beethoven’s hair?The Hiller lock, which the study found did not come from Beethoven but a woman, with its inscription by its former owner, Paul Hiller.William Meredith/Ira F. Brilliant Center for Beethoven Studies, San Jose State UniversityThe story was that it was clipped by Ferdinand Hiller, a 15-year-old composer and ardent acolyte who visited Beethoven four times before he died.On the day Beethoven died, Hiller clipped a lock of his hair. He gave it to his son decades later as a birthday gift. It was kept in a locket.The locket with its strands of hair was the subject of a best-selling book, “Beethoven’s Hair,” by Russell Martin, published in 2000, and made into a documentary film in 2005.An analysis of the hair at Argonne National Laboratory in Illinois found lead levels as high as 100 times normal.In 2007, authors of a paper in The Beethoven Journal, a scholarly journal published by San Jose State, speculated that the composer might have been inadvertently poisoned by medicine, wine, or eating and drinking utensils.That was where matters stood until 2014 when Tristan Begg, then a masters student studying archaeology at the University of Tübingen in Germany, realized that science had advanced enough for DNA analysis using locks of Beethoven’s hair.“It seemed worth a shot,” said Mr. Begg, now a Ph.D. student at Cambridge University.William Meredith, a Beethoven scholar, began searching for other locks of Beethoven’s hair, buying them with financial support from the American Beethoven Society, at private sales and auctions. He borrowed two more from a university and a museum. He ended up with eight locks, including the hairs from Ferdinand Hiller.First, the researchers tested the Hiller lock. Because it turned out to be from a woman, it was not — could not be — Beethoven’s. The analysis also showed that the woman had genes found in Ashkenazi Jewish populations.Dr. Meredith speculates that the authentic hair from Beethoven was destroyed and replaced with strands from Sophie Lion, the wife of Ferdinand Hiller’s son Paul. She was Jewish.Lab work on the Moscheles lock at the University of Tübingen in Germany.Susanna SabinAs for the other seven locks, two were inauthentic, four had identical DNA and one could not be tested. The four locks with identical DNA were of different provenances and two had impeccable chains of custody, which gave the researchers confidence that they were hair from Beethoven.Ed Green, an expert in ancient DNA at the University of California, Santa Cruz, who was not involved with the study, agreed.“The fact that they have so many independent locks of hair, with different histories, that all match one another is compelling evidence that this is bona fide DNA from Beethoven,” he said.When the group had the DNA sequence from Beethoven’s hair, they tried to answer longstanding questions about his health. For instance, why might he have died from cirrhosis of the liver?He drank, but not to excess, said Theodore Albrecht, a professor emeritus of musicology at Kent State University in Ohio. Based on his study of texts left by the composer, he described what is known of Beethoven’s imbibing habits in an email.“In none of these activities did Beethoven exceed the line of consumption that would make him an ‘alcoholic,’ as we would commonly define it today,” he wrote.Beethoven’s hair provided a clue: He had DNA variants that made him genetically predisposed to liver disease. In addition, his hair contained traces of hepatitis B DNA, indicating an infection with this virus, which can destroy a person’s liver.But how did Beethoven get infected? Hepatitis B is spread through sex and shared needles, and during childbirth.Beethoven did not use intravenous drugs, Dr. Meredith said. He never married, although he was romantically interested in several women. He also wrote a letter — although he never sent it — to his “immortal Beloved,” whose identity has been the subject of much scholarly intrigue. Details of his sex life remain unknown.The Stumpff lock, from which Beethoven’s whole genome was sequenced, with an inscription by its former owner Patrick Stirling.Kevin BrownArthur Kocher, a geneticist at the Max Planck Institute for Evolutionary Anthropology in Germany and one of the new study’s co-authors, offered another possible explanation for his infection: The composer could have been infected with hepatitis B during childbirth. The virus is commonly spread this way, he said, and infected babies can end up with a chronic infection that lasts a lifetime. In about a quarter of people, the infection will eventually lead to cirrhosis of the liver or liver cancer.“It could ultimately lead someone to die of liver failure,” he said.The study also revealed that Beethoven was not genetically related to others in his family line. His Y chromosome DNA differed from that of a group of five people with the same last name — van Beethoven — living in Belgium today and who, according to archival records, share a 16th-century ancestor with the composer. That indicates there must have been an out-of-wedlock affair in Beethoven’s direct paternal line. But where?Maarten Larmuseau, a co-author of the new study who is a professor of genetic genealogy at the University of Leuven in Belgium, suspects that Ludwig van Beethoven’s father was born to the composer’s grandmother with a man other than his grandfather. There are no baptismal records for Beethoven’s father, and his grandmother was known to have been an alcoholic. Beethoven’s grandfather and father had a difficult relationship. These factors, Dr. Lamarseau said, are possible signs of an extramarital child.Beethoven had his own difficulties with his father, Dr. Meredith said. And while his grandfather, a noted court musician in his day, died when Beethoven was very young, he honored him and kept his portrait with him until the day he died.Dr. Meredith added that when rumors circulated that Beethoven was actually the illegitimate son of Friedrich Wilhelm II or even Frederick the Great, Beethoven never refuted them.The researchers had hoped their study of Beethoven’s hair might explain some of the composer’s agonizing health problems. But it did not provide definitive answers.The composer suffered from terrible digestive problems, with abdominal pain and prolonged bouts of diarrhea. The DNA analysis did not point to a cause, although it pretty much ruled out two proposed reasons: celiac disease and ulcerative colitis. And it made a third hypothesis — irritable bowel syndrome — unlikely.Hepatitis B could have been the culprit, Dr. Kocher said, although it is impossible to know for sure.The DNA analysis also offered no explanation for Beethoven’s hearing loss, which started in his mid-20s and resulted in deafness in the last decade of his life.An 1827 lithograph of Beethoven on his deathbed by Josef Danhauser, after his own drawing.Josef Danhauser, via Beethoven-Haus BonnThe researchers took pains to discuss their results in advance with those directly affected by their research.On the evening of March 15, Dr. Larmuseau met with the five people in Belgium whose last name is van Beethoven and who provided DNA for the study.He started right out with the bad news: They are not genetically related to Ludwig van Beethoven.They were shocked.“They didn’t know how to react,” Dr. Larmuseau said. “Every day they are remembered by their special surname. Every day they say their name and people say, ‘Are you related to Ludwig van Beethoven?’”That relationship, Dr. Larmuseau said, “is part of their identity.”And now it is gone.The study’s findings that the Hiller lock was from a Jewish woman stunned Mr. Martin, author of “Beethoven’s Hair.”“Wow, who would have imagined it,” he said. Now, he added, he wants to find descendants of Sophie Lion, the wife of Paul Hiller, to see if the hair was hers. And he’d like to find out if she had lead poisoning.For Dr. Merrill, the project has been an amazing adventure.“The whole complex story is astonishing to me.” he said. “And I’ve been part of it since 1994. One finding just leads to another unexpected finding.”