The cruelty of their unequal outcomes — with one pair freed of disabling symptoms and the other’s suffering unabated — stayed with me.Times Insider explains who we are and what we do, and delivers behind-the-scenes insights into how our journalism comes together.As a medical reporter, I regularly write about terrible illnesses and about treatments that can help some, though not most, patients. But the cruel injustice of inequities in access to medical advances in sickle cell disease took my breath away.I didn’t plan it this way, but I ended up writing about two families who, at the start, were strikingly similar. Each had two teenage daughters with sickle cell disease. All four girls suffered episodes of intense pain, damage to organs and bones, and life-threatening lung complications. And one pair of the sisters had strokes.But in one family, both girls were freed from their symptoms and are now living normal lives. In the other, the sisters are still suffering and yearning for the chance to rid themselves of the disease.I followed one of the families for two years and the other for over a year, and I am haunted by the disparities.Helen Obando at the hospital the day she got the good news that her gene therapy was working. Two years later, she is rid of her symptoms of sickle cell.Hilary Swift for The New York TimesThe tale of these two families reveals in a microcosm the state of the science for this terrible disease. Sickle cell is caused by a single mutation in a globin gene needed to make red blood cells. The cells turn sickle shaped and can get stuck in blood vessels, injuring them and impeding blood flow. An estimated 100,000 Americans have the disease — most of them Black and many of modest means. Although the cause of the disease has been known for more than half a century, research has been slow and underfunded. Even discoveries that could improve patients’ lives are often not used.There is a bone-marrow transplant that gives the patient the blood system of a healthy person. But it is rarely used because few sickle cell patients have a donor whose genetics are close enough to the patient’s for the marrow to avoid being rejected as foreign.In the family whose teenagers were rid of their suffering, the mother, Sheila Cintron, was so desperate to find a bone-marrow donor for her daughters that she and her husband drained their bank account and maxxed out their credit cards to repeatedly attempt in vitro fertilization and genetic testing of embryos, hoping to have a baby who could be a donor for her girls.She succeeded at last, but her baby was genetically similar to only one of her daughters, Haylee Obando. Haylee had a bone-marrow transplant with her younger brother’s cells and was cured.The other daughter, Helen, was left behind until she was accepted into a clinical trial at Boston Children’s Hospital testing gene therapy for sickle cell disease.Helen Obando has a new life in a new city and is no longer suffering from sickle cell.Ash Ponders for The New York TimesShe too no longer suffers from the disease.I cheered Helen’s gene therapy. Being freed of the disease turned her from a taciturn adolescent whose future held pain, suffering and death at an early age into a teenager like any other. She told me she no longer even thinks about sickle cell.But the pace of the gene therapy trials seems glacial, with few patients enrolled each year. F.D.A. approval is a year or more away, at best.No one expects gene therapy to be the answer for most patients. The cost — which is likely to be $1 million to $2 million for each patient — will be a barrier. And the grueling treatment requires chemotherapy and a month in a specialized hospital.The other family breaks my heart. Dana Jones, is divorced and raising her daughters, Kami and Kyra, alone. Both had disabling strokes before she learned that there was a simple test the girls should have had every year that identifies children with sickle cell at high risk for strokes — strokes that can largely be prevented with a treatment of blood transfusions. The girls are smiley, solicitous and delightful company. But their suffering is immense — weeks and weeks of hospitalizations every year, missed school, and a life of near constant pain that they have learned to accept and not mention until it’s unbearable.Kami and Kyra, still suffering from sickle cell, receive blood transfusionsIlana Panich-Linsman for The New York TimesI asked Ms. Jones if she would want the girls to have gene therapy.“Oh God yes,” she said.She watches Kami and Kyra bravely hide their pain. She has seen emergency room doctors accuse them of faking it to get narcotics. She has seen her girls struggle in school because their strokes impeded their ability to learn. She sees their disease wreaking more damage on their bodies every day.She called and wrote Boston Children’s, asking if Kami and Kyra could enter its trial. They would have to go to Boston for the arduous treatment, but Ms. Jones, who lives in San Antonio, would gladly take them there.She made sure the girls’ names were on a lengthy waiting list for slots in the trial.Now all she can do is wait. And pray.

If funded, a government program costing several billion dollars could develop “prototype” vaccines to protect against 20 families of viruses.In one sense, the world got lucky with the new coronavirus. By sheer chance, scientists just happened to have spent years studying coronaviruses, developing exactly the tools needed to make Covid vaccines as soon as the virus’s genetic sequence was published.But what will happen if the next pandemic comes from a virus that causes Lassa fever, or from the Sudan strain of Ebola, or from a Nipah virus?Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, is promoting an ambitious and expensive plan to prepare for such nightmare scenarios. It would cost “a few billion dollars” a year, take five years for the first crop of results and engage a huge cadre of scientists, he said.The idea is to make “prototype” vaccines to protect against viruses from about 20 families that might spark a new pandemic. Using research tools that proved successful for Covid-19, researchers would uncover the molecular structure of each virus, learn where antibodies must strike it, and how to prod the body into making exactly those antibodies.“If we get the funding, which I believe we will, it likely will start in 2022,” Dr. Fauci said, adding that he has been promoting the idea “in discussions with the White House and others.”Dr. Francis Collins, director of the National Institutes of Health, also thought it likely that the necessary funds would be allocated, calling the project “compelling.”“As we begin to contemplate a successful end to the Covid-19 pandemic, we must not shift back into complacency,” Dr. Collins said.Much of the financial support would come from Dr. Fauci’s institute, but a project of this scope would require additional funds that would have to be allocated by Congress. This year’s budget for the infectious diseases institute is a little over 6 billion dollars. Dr. Fauci did not specify how much additional money would be needed.If surveillance networks detected a new virus spilling over from animals into people, the logic goes, scientists could stop it by immunizing people in the outbreak by quickly manufacturing the prototype vaccine. And if the virus spread before the world realized what was happening, the prototype vaccines could be deployed more widely.“The name of the game would be to try and restrict spillovers to outbreaks,” said Dr. Dennis Burton, a vaccine researcher and chairman of the department of immunology and microbiology at Scripps Research Institute.Vaccine research at the Center for Virology and Vaccine Research at Beth Israel Medical Deaconess Center in Boston last year.Tony Luong for The New York TimesThe prototype vaccines project is the brainchild of Dr. Barney Graham, deputy director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. He presented the idea in February of 2017 at a private meeting of institute directors.Year after year, viruses had threatened to turn into pandemics, Dr. Graham said: the H1N1 swine flu in 2009, Chikungunya in 2012, MERS in 2013, Ebola in 2014, Zika in 2016. Each time scientists scrambled to try to make a vaccine. Their only success was a partial one, with an Ebola vaccine that helped control the epidemic but would not work against other Ebola strains. The other epidemics waned before the vaccines could be made or tested.“We were tired,” Dr. Graham said.But researchers had new tools developed over the past decade that could make a big difference. They allowed scientists to view molecular structures of viruses, isolate antibodies that block the viruses and find out where they bind. The result was an ability to do “structure-based design” for new vaccines that target the pathogen more precisely.When he heard Dr. Graham’s pitch in 2017, Dr. Fauci was inspired. “It struck me and others in the executive committee as something that is really doable,” Dr. Fauci said.Dr. Graham published a review paper outlining the proposal in Nature Immunology in 2018. But without the urgency of a threatening pandemic, his idea remained just that.Now, though, many think the time has come.The allergy and infectious diseases institute has created a spreadsheet for each of the 20 virus families showing what is known about each pathogen’s anatomy and vulnerabilities, said Dr. John Mascola, director of the Vaccine Research Center at the institute..css-1xzcza9{list-style-type:disc;padding-inline-start:1em;}.css-3btd0c{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:1rem;line-height:1.375rem;color:#333;margin-bottom:0.78125rem;}@media (min-width:740px){.css-3btd0c{font-size:1.0625rem;line-height:1.5rem;margin-bottom:0.9375rem;}}.css-3btd0c strong{font-weight:600;}.css-3btd0c em{font-style:italic;}.css-w739ur{margin:0 auto 5px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-weight:700;font-size:1.125rem;line-height:1.3125rem;color:#121212;}#NYT_BELOW_MAIN_CONTENT_REGION .css-w739ur{font-family:nyt-cheltenham,georgia,’times new roman’,times,serif;font-weight:700;font-size:1.375rem;line-height:1.625rem;}@media (min-width:740px){#NYT_BELOW_MAIN_CONTENT_REGION .css-w739ur{font-size:1.6875rem;line-height:1.875rem;}}@media (min-width:740px){.css-w739ur{font-size:1.25rem;line-height:1.4375rem;}}.css-9s9ecg{margin-bottom:15px;}.css-uf1ume{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-box-pack:justify;-webkit-justify-content:space-between;-ms-flex-pack:justify;justify-content:space-between;}.css-wxi1cx{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-flex-direction:column;-ms-flex-direction:column;flex-direction:column;-webkit-align-self:flex-end;-ms-flex-item-align:end;align-self:flex-end;}.css-12vbvwq{background-color:white;border:1px solid #e2e2e2;width:calc(100% – 40px);max-width:600px;margin:1.5rem auto 1.9rem;padding:15px;box-sizing:border-box;}@media (min-width:740px){.css-12vbvwq{padding:20px;width:100%;}}.css-12vbvwq:focus{outline:1px solid #e2e2e2;}#NYT_BELOW_MAIN_CONTENT_REGION .css-12vbvwq{border:none;padding:10px 0 0;border-top:2px solid #121212;}.css-12vbvwq[data-truncated] .css-rdoyk0{-webkit-transform:rotate(0deg);-ms-transform:rotate(0deg);transform:rotate(0deg);}.css-12vbvwq[data-truncated] .css-eb027h{max-height:300px;overflow:hidden;-webkit-transition:none;transition:none;}.css-12vbvwq[data-truncated] .css-5gimkt:after{content:’See more’;}.css-12vbvwq[data-truncated] .css-6mllg9{opacity:1;}.css-qjk116{margin:0 auto;overflow:hidden;}.css-qjk116 strong{font-weight:700;}.css-qjk116 em{font-style:italic;}.css-qjk116 a{color:#326891;-webkit-text-decoration:underline;text-decoration:underline;text-underline-offset:1px;-webkit-text-decoration-thickness:1px;text-decoration-thickness:1px;-webkit-text-decoration-color:#326891;text-decoration-color:#326891;}.css-qjk116 a:visited{color:#326891;-webkit-text-decoration-color:#326891;text-decoration-color:#326891;}.css-qjk116 a:hover{-webkit-text-decoration:none;text-decoration:none;}“For each virus family we are in a different state of knowledge and vaccine development,” Dr. Mascola said. Vaccines for Lassa fever and Nipah virus, for example, are in early stages. Vaccines for Chikungunya and Zika are further along.The work to fill in the gaps in vaccine development would be done with research grants to academic scientists. “There is a lot of enthusiasm” among academic researchers, said Dr. Barton Haynes, director of the Duke Human Vaccine Institute. Although the proposal is not well known among the general public, Dr. Fauci said he has discussed it in talks to scientific audiences.The program would also establish collaborative agreements with pharmaceutical companies to produce prototype vaccines quickly, Dr. Fauci said.That is what happened with the shots for Covid-19. The SARS and MERS epidemics led scientists to work on a coronavirus vaccine. That led to the discovery that coronaviruses use a spike protein to infect cells, but the spike changes shape readily and needs to be held in one position to be useful as a vaccine. That could be done, researchers discovered, with tiny molecular changes in the spike protein.Days after the new coronavirus’s sequence was published, scientists had designed vaccines to fight it.That, Dr. Fauci said, is what pandemic preparedness can do. He’d like to have prototype vaccines for 10 out of the 20 virus families in the first five years of work.“It would require pretty large sums of money,” Dr. Fauci acknowledged. “But after what we’ve been through, it’s not out of the question.”

The panel also called on countries to ensure that beneficial forms of genetic alteration be shared equitably.A committee of experts working with the World Health Organization on Monday called on the nations of the world to set stronger limits on powerful methods of human gene editing.Their recommendations, made after two years of deliberation, aim to head off rogue science experiments with the human genome, and ensure that proper uses of gene-editing techniques are beneficial to the broader public, particularly people in developing countries, and not only the wealthy.“I am very supportive,” said Dr. Leonard Zon, a gene therapy expert at Harvard University who was not a member of the committee, but called it a “thoughtful group.” Recent gene-editing results are “impressive,” he said, and the committee’s recommendations will be “very important for therapy in the future.”The guidelines proposed by the W.H.O. committee were prompted in large part by the case of He Jiankui, a scientist in China who stunned the world in November 2018 when he announced he had altered the DNA of human embryos using CRISPR, a technique that allows precision editing of genes. Such alterations meant that any changes that occurred in the genes would be replicated in every cell of the embryo, including sperm and egg cells. And that meant that the alterations, even if they were deleterious instead of helpful, would arise not just in the babies born after gene editing but in every generation their DNA was passed on to.Dr. He’s goal was to alter the DNA of babies in an attempt to make them genetically unable to contract H.I.V. from their parents. A court in China determined he had forged ethics documents and misled subjects in the experiments who had not realized what his gene-editing experiment consisted of. He was sentenced to three years in prison in December 2019.Dr. He Jiankui, during a November 2018 announcement in Hong Kong, where he revealed he had altered the genomes of two babies using CRISPR.Anthony Wallace/Agence France-Presse — Getty ImagesThe fact that such an experiment, known as germline editing, could take place raised the question of how to control gene editing and how to be sure it was used to benefit people.The W.H.O. standards say that Dr. He’s use of germline editing was unacceptable and that it is irresponsible to even consider using it now. But other sorts of gene editing are a different story.Scientists already are attempting gene editing to correct the mutation that causes sickle cell disease. The edited gene would be in blood-forming bone marrow cells of people who have the disease, not in sperm or egg cells, so the changes would not be passed down through the generations. But even that use of CRISPR raises other questions.The W.H.O. committee described an invented scenario where researchers from a rich country want to do a clinical trial of sickle-cell gene editing in sub-Saharan Africa, where the disease is prevalent. If the trial succeeds, the gene-editing treatment would be too expensive for all but very few citizens of the country where it is to be tested.Another hypothetical situation involves a gene-editing trial to correct a gene mutation that causes Huntington’s disease, a progressive brain disorder. People who inherit the mutated gene will develop Huntington’s disease with absolute certainty. If the gene-editing experiment succeeds, it may spare them that horrific disease. And because the editing does not involve sperm and eggs, the changes will not be heritable.But it would take years, perhaps even decades, to know if study participants whose genes were edited were protected from Huntington’s disease. Participants would not be freed of the terrible fear that, despite the gene editing, they might still develop the fatal brain disease.In such a scenario, the W.H.O. group asked if there were more rapid ways of assessing the treatment’s effectiveness. It also proposed that researchers consider the psychological burden on participants who are left hoping they are cured but not knowing for sure.Yet gene editing is here and holds enormous promise, the committee said. The W.H.O. has started a registry of studies underway and says it already includes 156 experiments involving genes that are not in sperm or eggs.The W.H.O. committee stressed that each country must have guidelines to be sure the research is conducted ethically and with appropriate oversight, and with conditions in place to ensure access and social justice. With the costs of treatment expected to be very high, at least at first, the group said the goal must be to ensure that the benefits of gene editing accrue equitably to people around the world.“That is not an easy challenge,” said Françoise Baylis, a committee member who is a medical ethics researcher at Dalhousie University in Halifax, Nova Scotia.

Obesity has stalked Marleen Greenleaf, 58, all of her life. Like most people with obesity, she tried diet after diet. But the weight always came back.With that, she has suffered a lifetime of scorn and stigma. Jeering comments from strangers when she walked down the street. Family members who told her, when she trained for a half-marathon, “I don’t think it’s good for you.”Then, in 2018, Ms. Greenleaf, an administrator at a charter school in Washington, D.C., participated in a clinical trial for semaglutide, which is a new type of obesity drug, known as incretins.Over the course of the 68-week study, Ms. Greenleaf slowly lost 40 pounds.Until then, she had always believed that she could control her weight if she really tried.“I thought I just needed more motivation,” she said. But when she took semaglutide, she said that “immediately, the urge to eat just dissipated.”Incretins appear to elicit significant weight loss in most patients, enough to make a real medical and aesthetic difference. But experts hope that the drugs also do something else: change how society feels about people with obesity, and how people with obesity feel about themselves.If these new drugs allow obesity to be treated like a chronic disease — with medications that must be taken for a lifetime — the thought is that doctors, patients and the public might understand that obesity is truly a medical condition.“We all believe this drug will change the way we see obesity being treated,” said Dr. Caroline Apovian, an obesity specialist at Brigham and Women’s Hospital. (Dr. Apovian, like most leading obesity researchers, consults for several drug companies. She is on the advisory board of Novo Nordisk, the maker of semaglutide, and is paid for attending advisory board meetings.)Decades of studies have repeatedly showed that there are powerful biological controls over individual body weights. Identical twins reared apart had nearly identical body weights. Adopted children ended up with body mass indexes like those of their biological parents, not those of their adoptive parents. Metabolism slows as people lose weight, forcing them to regain it.And yet, obesity “is like having a mark on your forehead,” said Dr. Scott Kahan, chair of the clinical committee for The Obesity Society, a scientific membership organization.People with obesity are more likely to be passed over for jobs, be paid less than others with the same abilities and training, and be treated poorly by doctors, who spend less time with them and offer fewer preventive services.But people with obesity haven’t had many places to turn for help. The current obesity drugs lead to an average weight loss of only 5 percent to 10 percent. And because some of these drugs are approved only for limited time frames, the lost pounds almost always come back when the intervention ceases.According to these studies, incretins seem to be different. Unlike other weight-loss drugs, they are naturally occurring hormones that affect systems central to obesity. The drugs slow stomach emptying, regulate insulin and decrease appetite, with mostly mild to moderate short-term gastrointestinal side effects.The drugs will not banish obesity or make people truly thin. But people who take them can look and feel very different. For some, the medications lead to weight loss approaching that of bariatric surgery.If incretins pass the approval process, they might help convince the most important constituency of all — doctors — that obesity is a chronic disease and that it can be treated, said Dr. Robert F. Kushner, an obesity researcher and clinician at Northwestern University. One reason many doctors don’t help patients with obesity is that they don’t know how, Dr. Kushner said. Diets and exercise, the usual nostrums, almost always provide short-term weight loss, at best.Dr. Robert F. Kushner, an obesity researcher and clinician at Northwestern University. “I tell them this is a chronic ongoing medical problem, just like diabetes,” he said.Taylor Glascock for The New York TimesThe incretin taken by Ms. Greenleaf, semaglutide, made by Novo Nordisk, is before the Food and Drug Administration, with a decision expected in June. On average it elicited a 15 percent weight loss, but a third of those who took it lost 20 percent or more of their body weight in the study, similar to the amount lost with lap-band bariatric surgery.Eli Lilly has a similar drug, tirzepatide, which combines two incretins. The company is testing it against semaglutide and hopes that it will be even more powerful.Dr. Louis J. Aronne, an obesity specialist at Cornell Medical School, said that the combination of semaglutide and another experimental Novo Nordisk drug, cagrilintide, could produce as much as a 25 percent weight loss in a year, an amount like that achieved with sleeve gastrectomy, a popular form of bariatric surgery.Although more than a half-dozen new hormonal drugs are being tested, Dr. Kushner said, only with long-term use can researchers learn if the new drugs control the many medical consequences of obesity, like diabetes and high blood pressure.There is also the larger riddle of biological destiny: Are the body’s multiple and redundant systems to maintain body weight so powerful that they will exert control in the end, diminishing the effectiveness of the drugs?Like other obesity specialists, Dr. Rudolph L. Leibel, a researcher at Columbia University who conducted many of the pivotal studies showing obesity is a disease, deplores society’s bias against his patients. But he has his doubts that perceptions will change with new treatments.“My guess is that bias will persist and might even be exacerbated by the availability of ‘an easy way out,’” he said.Dr. Kushner is more hopeful and points to the example of statins, which lower cholesterol and became available in the late 1980s. Until then, doctors could only suggest that patients with high cholesterol cut back on eggs and red meat.Doctors “embraced statins,” Dr. Kushner said, because they could at last treat this condition. More powerful incretins, he added, could have the same effect on the medical profession.He is unsure, though, whether patients will accept the disease label. They’ve been conditioned, he said, to believe that their weight is their own fault; all they have to do is eat healthier and exercise more.When talking with patients, he doesn’t spend 20 minutes trying to convince them that they have a disease. In fact, he deliberately avoids using the word “disease” and instead says “condition” or “problem.”“I tell them this is a chronic ongoing medical problem, just like diabetes,” he said.Members of the general public pose a different challenge, Dr. Kushner said. With them, he said, “we may need to use a term like ‘disease.’”He likens the situation to that of alcoholism or drug addiction, which was once thought to be indicative of a weak will or a moral failing. Researchers have successfully changed the conversation; many people now know that those who abuse alcohol or drugs have a disease and need treatment.As for Ms. Greenleaf, she wants to take semaglutide again. The pounds crept back when the trial ended.Obesity, she now realizes, “is not your fault.”

A new study shows that a 20-year-old drug prevents scarring in mice. If it works on humans, it could change the lives of those with disfiguring wounds.Cleft palates that close without scars. Burn wounds that recover without a trace of injury. Years-old disfiguring scars that disappear, leaving skin smooth and flawless.It sounds like science fiction, but healing without scarring may become a tantalizing possibility. In a study published Thursday in Science, two researchers at Stanford University report that they have figured out the molecular signals that make scars form and found a simple way to block them — at least in mice.A 20-year-old drug, verteporfin, already on the market as an intravenous treatment for macular degeneration, can prevent scarring if it is injected at the edge of a wound.As the verteporfin-treated wounds heal, the skin that forms looks perfectly normal, nothing like skin that heals with scars, those lumpy wound closures that are not only unsightly but also much weaker than normal skin and have no hair, or oil and sweat glands.The study involved mice, but the researchers, Dr. Michael Longaker, Stanford’s vice chair of surgery, and Geoffrey Gurtner, Stanford’s vice president of surgery for innovation, have now moved on to pigs, whose skin is closest to that of humans. With these new subjects, the surgeons made an incision as wide as a thumb and five inches long. When they sutured the cut and injected verteporfin around the edge, there was dramatically less scarring.“It’s pretty spectacular,” Dr. Longaker said.Researchers who study wounds and who were not associated with the study were enthusiastic.“It is unusual for me to read a paper and say, ‘Wow, this is really a major advance,’” said Valerie Horsley, a tissue developmental biologist at Yale who studies wound healing. “But this is a major advance.”Marjana Tomic-Canic, director of the wound healing and regenerative medicine program at the University of Miami Miller School of Medicine, said that the study is “really a leap,” adding, “everyone will get excited about this work.”Dr. Longaker said that he hoped to get permission from the Food and Drug Administration by the end of the year to test the safety and efficacy of the drug in babies with cleft lips and palates.For Dr. Longaker, speed is of the essence if the treatment works and is safe. “I don’t want this to be a 10-year journey,” he said.Stanford has filed patents for the use of verteporfin in scar formation.Although verteporfin is available, and doctors can prescribe drugs for unapproved uses, Dr. Longaker says that it’s crucial to wait for F.D.A. approval before using the drug to try to prevent scars.“Obviously we want to help patients as soon as possible,” he said. “But we’ve got to make sure this drug is tested in a way that ensures safety and efficacy.”The history of medicine, he said, offers a sobering picture of treatments that looked good in animals but failed in clinical trials.If the drug works on humans, the discovery stands to be lucrative and life transforming. Hundreds of millions of people are seriously scarred each year, and many of those scars are disfiguring — from accidents, as well as from heart bypass surgeries, mastectomies and burns.“Scars in general cause pain and itching and prevent us from moving the way we should,” said Dr. Benjamin Levi, a burn specialist who directs the Center for Organogenesis and Trauma at the University of Texas Southwestern Medical Center. The possibility of blocking the scarring process “has huge potential,” he said.Dr. Jason A. Spector, professor of plastic surgery and otolaryngology at Weill Cornell Medical College, said that when he does reconstructive surgery on patients with head and neck cancer, many “are more concerned about the scar through their lip and skin than about the cancer itself.”Dr. Longaker’s obsession with scars began with an experiment in 1987 as a new postdoctoral fellow in the lab of Dr. Michael R. Harrison at the University of California, San Francisco. Dr. Harrison, who was studying fetal surgery, suggested that Dr. Longaker operate on a fetal lamb two-thirds of the way through pregnancy and then return the fetus to its mother’s womb to continue developing.Dr. Longaker gasped when he later delivered the baby lamb. Its skin was intact. There were no scars to be seen.“I will never forget that moment,” he said.He went on to become a pediatric plastic surgeon and saw firsthand the scarring on children after they had undergone operations for cleft lips or palates. And he ran a lab devoted to figuring out how to prevent scars.He learned that for the first two trimesters of fetal life, skin is gelatinous, “like a bowl of Jell-O,” Dr. Longaker said. Then, as the fetus develops to live outside the sterile liquid world of the womb, the skin forms a barrier to prevent water loss and block the entry of microorganisms. At that point, breach of the skin barrier could be deadly, so the body switches on a system that lets it quickly seal it.But there is a trade-off for speed in healing a wound, Dr. Longaker noted. “The cost is loss of form and function.” And scar formation.Dr. Tomic-Canic described the process: When there is a wound, the strong muscle under the skin contracts and brings the edges of the wound together. A clot forms as a temporary barrier over the wound, and under it, the body makes thick coils of collagen rope that form a bridge so skin cells can migrate across the gap and fill in the opening. Those collagen ropes remain — they are the scar.As molecular biology and molecular genetics advanced, Dr. Longaker seized on the new tools to probe the molecular pathways needed to form scars. The key starting point for scarring is mechanical tension when a wound tears skin that should be taut. (Older people with loose skin are less likely to scar because their skin is under less tension.) The tear in the layers of skin prompts a type of skin cell — fibroblasts — to create collagen ropes and initiates a chain reaction of molecular events inside the skin cells. The reactions culminate in the activation of a protein called YAP, for Yes-associated protein. YAP then binds to DNA, and scarring begins.Dr. Longaker and Dr. Gurtner bred mice without the YAP protein. Because mice have loose skin, the two had to hold the wounds open with a ring, like an embroidery hoop, to mimic the tension in human skin. The wounds healed. No scars.They then asked: Could verteporfin have the same effect as the absence of YAP? So in another experiment, they wounded mice that could make YAP and once again held the loose skin taut with rings. They injected verteporfin around the wound. They waited to see what would happen.Dr. Longaker remembers the moment. “Holy guacamole,” he said. The healed wounds looked just like normal skin. They were the same under the microscope. They grew hair. They had oil glands.His imagination soared. He might be able to prevent scars with a few quick injections of verteporfin. And there was no reason to think he couldn’t go even farther. A patient who had a disabling and disfiguring scar could go to a surgeon who could dab the scar with lidocaine to numb the skin, cut open the scar, inject verteporfin around the edges, and close the wound. Would it reheal without the scar?“That could change their lives,” Dr. Longaker said.Dr. Spector said he doubted all doctors would wait until F.D.A. approval if early clinical data supported the laboratory studies. Some are sure to jump ahead and try it because there is nothing now to stop scarring.Dr. Longaker hopes doctors hold off. Clinical trials must come first, he stressed, and safety must be assured.“I get it,” he said. “No one is more excited than me.”“To be honest,” he added, “I’ve been waiting for 34 years. I would love to use it. This is a big deal. But that doesn’t mean we shortcut the process.”

Despite the urgent need for treatments to slow or stop Alzheimer’s disease, finding patients for clinical trials has been difficult and frustrating.Patients are often older. Their doctors may not be part of a research network. And many with dementia never get a diagnosis — their doctors do not tell them what is wrong or they avoid finding out that they have the dreaded disease.“How do you recruit when patients do not realize they are eligible?” said Michelle Papka, director of the Cognitive and Research Center, a clinical trial site in Springfield, N.J.Her center is one of 290 now seeking participants for a new study by the drugmaker Eli Lilly and Company that plans to enroll 1,500 patients. The company hopes it will confirm results from its smaller study, lasting 76 weeks, of 257 patients. It found the experimental drug donanemab significantly slowed the progress of Alzheimer’s — the first time a study of a disease-modifying Alzheimer’s drug met its primary goals.“I will be shocked if it is not a popular study,” said John Dwyer, president of the Global Alzheimer’s Platform Foundation, a network of clinical trial sites hired by Lilly to help speed the recruitment of patients.But where will patients come from?They have to have just the right amount of brain deterioration — too much and it probably is too late. Too little and it may take too long to see a drug effect, if there is any. They often have to find out about the study on their own. They have to agree to have regular infusions of what might be a placebo for more than a year.On top of all that, if they or their family members have been paying attention to the state of Alzhemier’s drug research, they would know that study after study of what looked like a promising treatment for Alzheimer’s has failed, to such an extent that some companies, after spending billions in futile attempts, decided to get out of the business of developing Alzheimer’s drugs.Three who arrived at a clinical trial site in New Jersey on March 26, a misty Friday morning provide some answers about who might enroll, and why.HE SAID, “NO WAY, NOT ME”Michael Gross, a lifelong Yankees fan, was unnerved when he forgot the name of one of the team’s former managers — Casey Stengel — and was determined to keep it in his memory.Jackie Molloy for The New York TimesA few years ago, Michael Gross, 73, of Mahwah, N.J., began to realize something was wrong. “I was confused about words,” he said, “and it continued to get worse.”But Mr. Gross, the retired head of an advertising agency, was taken aback when a doctor suggested a spinal tap to look for proteins that are a sign of Alzheimer’s. He could not have that disease, Mr. Gross thought.“I said, ‘No way, not me,’” he said.But he did.He wept, he despaired.Then he asked, What could he do about it?He switched to the Mediterranean diet. He started exercising. He began doing crossword puzzles and subscribed to a challenging brain-training program. He found a study in mice claiming a bright light shined at their heads helped with Alzheimer’s. He bought the light.The disease kept progressing. Now he cannot remember the details of a news story as he reads it.Mr. Gross, a lifelong Yankees fan, was unnerved the day he forgot the name of the team’s former manager, Casey Stengel, and became determined to keep it in his memory.“Every day I wake up and tell myself ‘Casey Stengel, Casey Stengel,’” he says.Then he forgot the word “sardines,” a staple of his Mediterranean diet. “For a week I said to myself, ‘sardines, sardines,’” Mr. Gross said.But what he really wanted was a treatment powerful enough to stop Alzheimer’s in its tracks.Mr. Gross saw an ad on Facebook for the Lilly clinical trial. That Friday morning he arrived for a test to see if he was eligible. It consisted of a brain scan for a protein, tau, that is found in dead and dying brain neurons. If he had too little tau, he would not be eligible.He had another test, an M.R.I. scan of his brain and discovered that he was accepted for the trial.And now, if he does not get the drug? Or if the drug fails?Then he will look for other trials, Mr. Gross said. He would even consider a treatment he recently heard about. “They shoot something into your nostril, and it supposedly cures you,” he said.His wife, Peggy, chimed in.“We haven’t gotten to a point where we admitted there is no help for him,” she said.“IT GOT TO A POINT WHERE IT WAS VERY, VERY REAL”The next patient to arrive was a 63-year-old woman who is enrolled in the trial and has already had two infusions of either the drug or the placebo. She and her husband asked that their names not be used because they have not yet revealed her diagnosis to their friends and family.She’s a bubbly optimist, but because of her disease, let her husband do most of the talking. When her memory started faltering a few years ago, she and her husband attributed it to the stress of her job as an occupational therapist.“I don’t think we thought about Alzheimer’s,” her husband said.But her memory problems continued, even after she left her job. She would go grocery shopping, taking a list with her, and forget things on the list. She would forget appointments.“It got to a point where it was very, very real,” her husband said.Dr. Michelle Papka, the director of the Cognitive and Research Center in New Jersey. “How do you recruit when patients do not realize they are eligible?” she said of the difficulty in finding participants for clinical trials of Alzheimer’s drugs.Jackie Molloy for The New York TimesHe took his wife to a neurologist who administered a battery of tests. The results were not good.“For the first time it went from a memory issue to something alarming,” the husband said. On March 6, a spinal tap confirmed the likely diagnosis: Alzheimer’s.The man and his wife were distraught. No drug, no lifestyle change, had been shown to alter the course of the disease. Their doctor did not refer them to a clinical trial, but their oldest son, a second-year medical student, found the Lilly trial for them.The woman does not expect a cure, but she said, “I hope I don’t decline any farther. I don’t want to turn into a babbling idiot. If I can stay like this, I would be happy. I crochet, I color, I walk the dog.”Her husband tries not to think of the future.“I don’t know if I am in denial or what, but I haven’t fully grasped what life will be like five, 10 years down the road.”“THERE WOULDN’T BE A COVID VACCINE IF PEOPLE HAD NOT VOLUNTEERED”Marlene Lippman and Bob Lippman outside their home in Summit, N.J. Bob Lippman is a patient of a new Alzheimer’s clinical trial.Jackie Molloy for The New York TimesBob Lippman, 78, of Summit, N.J., got his Alzheimer’s diagnosis in November 2017 after a year and a half of mounting symptoms. He learned about the Lilly trial from Dr. Papka and was accepted. He had his second infusion at the New Jersey center that Friday morning.Conversation is difficult for Mr. Lippman now, so his wife, Marlene, told his story.“He was repeating things a lot and asking me the same things over and over,” she said. “He was forgetting whole conversations. At first I thought it was normal aging.”But after she heard a speaker from the Alzheimer’s Association at Sage Eldercare, a nonprofit organization near their home in Summit, N.J., she realized that what her husband was experiencing was not normal.Memory tests confirmed those fears, and a brain scan that detects amyloid, the stiff balls of plaque that are the hallmark of Alzheimer’s disease, cinched the diagnosis.It was life-shattering news.“Bob had a very strong intellect,” Ms. Lippman said. “It is hard that that part of him is being attacked.”She started making plans — redoing wills and power of attorney. She found a support group for caregivers at Sage. And she found the Lilly trial.Ms. Lippman is cleareyed about what to expect. If her husband is getting the drug and not the placebo and if the drug is as effective as it was in the initial small study, “at best it might delay the course of his decline,” she said. “It certainly is not going to cure him.”“Our main incentive is to help other people and to move research forward,” Ms. Lippman added. “There wouldn’t be a Covid vaccine if people had not volunteered.”Bob and Marlene Lippman in their home. “Bob had a very strong intellect,” Ms. Lippman said. “It is hard that that part of him is being attacked.”Jackie Molloy for The New York Times

The coronavirus may help scientists understand why some people with common viral infections develop severe complications, like heart damage or blood clots.Barie Carmichael lost her sense of taste and smell while traveling in Europe. She remembers keeping a dinner date at a Michelin-starred restaurant but tasting nothing. “I didn’t have the heart to tell my host,” she said.It may sound like a case of Covid-19. But Ms. Carmichael, 72, a fellow at the University of Virginia’s business school, lost her ability to taste and smell for three years in the 1990s. The only respiratory infection she’d had was bronchitis.Medical scientists say that although the complications of Covid have riveted peoples’ attention, many symptoms — like a loss of smell — are not unique to Covid. Heart inflammation, lung and nerve damage and small blood clots in the lining of lungs occur in a small but noticeable percentage of patients who have had other respiratory and viral infections. And these patients, too, can also have their own version of “long Covid.”No one is saying Covid is the equivalent of, say, the flu that circulates each year. The usual seasonal flu has not killed millions worldwide in a single year, and more than half a million Americans, while upending society and ravaging economies. But Covid-19 is providing a new opportunity to understand the complications of many common viral infections.Before the pandemic, research grants to study a loss of smell were hard to come by, said Danielle R. Reed, associate director of the Monell Chemical Senses Center, a nonprofit research group, in Philadelphia.“It seemed like nobody cared,” she said. But now, “there is an explosive growth of interest among funders.” (She added that most who say they have lost a sense of taste have really lost a sense of smell.)Monell researchers want to compare how often people lose their sense of smell after a bout with the flu versus a bout with Covid-19 — and how long the loss lasts. Is there a genetic predisposition to this complication?Researchers at other institutions want to know who is susceptible to heart infections, blood clots or lung damage after having a respiratory virus like the flu. For the most part, little is known. Part of the problem was that only a minority of patients with respiratory viruses were affected with these conditions, and until the coronavirus, that tended not to be a big number. Many of these effects were noticed but then forgotten.Heart problems following a viral infection are among the best studied. Myocarditis — an inflammation of the heart muscle — affects as many as 1.5 million people worldwide each year, most of whom had a prior respiratory virus infection. Most recover fully.But symptoms like fatigue are often not recognized as being related to myocarditis. And Dr. McManus suspects that the fatigue that sometimes follows a bout with Covid-19 might be caused by this heart problem.“We think of Covid-19 and influenza as respiratory diseases, and in fact they are,” said Dr. Bruce M. McManus, an emeritus pathology professor at the University of British Columbia. “But the reason many patients reach their demise in many instances is myocardial.”Some severely ill Covid patients have lung damage. That too can also occur with other viruses, said Dr. Clemente Britto-Leon, a lung researcher at the Yale School of Medicine. He lists some possibilities.“You can have lung injury and scarring with influenza, with herpes viruses and with cytomegalovirus infections, for example,” Dr. Britto said, referring to a common virus that usually causes no symptoms. All these viruses can wreak damage on rare occasions, he said. “You can have a very severe injury and a lot of tissue destruction.”Influenza can cause blood clots in the lining of the lungs that look just like the small clots seen in the lungs of some Covid patients, said Marco Goeijenbier of Erasmus University in the Netherlands. It happens when flu viruses infect the lower respiratory tract, an unusual event because most people have some pre-existing protective immunity.Dr. Goeijenbier wants to study the blood clots that occur in these cases, but previously, with so few patients, he and others resorted to reproducing and studying the effect in laboratory studies and in ferrets — the preferred animals to study flu.“It was hard to get funding, he said. “Big journals or funders didn’t think it was interesting enough,” he explained.Covid is changing that.There is now “a huge cohort of people to study,” said Pamela Dalton, a smell researcher at Monell. But “the big question is, even if you learn everything about SARS-CoV-2” — the formal name of the coronavirus — “how generalizable is it?”

A drug that unleashes the immune system offers a rare glimmer of hope for those with a cancer that resists most treatments.For decades, esophageal cancer has defied scientific attempts to discover a therapy that extends patients’ survival, year after year claiming the lives of such illustrious people as Humphrey Bogart, Christopher Hitchens and Ann Richards, the former governor of Texas.Now a large clinical trial offers hope, finding that a drug that unleashes the immune system to attack cancer cells can double the disease-free survival times in patients from 11 months to 22 months. The study was published on Wednesday in the New England Journal of Medicine.“It is a game changer,” said Dr. David Ilson, an esophageal cancer expert at Memorial Sloan Kettering Cancer Center in New York, who wrote an editorial accompanying the research. “We’ve waited a long time for this.”In the trial, sponsored by Bristol-Myers Squibb, 794 patients in 29 countries were randomly assigned to receive infusions of the drug, nivolumab, or a placebo.The patients had all had chemotherapy and radiation followed by surgery to remove their cancers. As usually happens, pathology reports showed that the surgery did not remove all of the cancer cells, which still lurked in lymph nodes and elsewhere, setting the stage in these patients for their cancers to return as incurable metastases.Nivolumab is approved for some patients with other cancers, like Hodgkin’s lymphoma, melanoma and colorectal cancer. With the new study, experts expect the drug will readily win approval for treatment of early-stage esophageal cancer.Dr. Ronan Kelly, director of the Charles A. Sammons Cancer Center at Baylor University Medical Center and lead author of the new study, said he and the other researchers urgently wanted to help the 75 percent of patients who go through extraordinarily difficult sequences of radiation, chemotherapy and surgery that disfigures the digestive system, only to learn that cancer is still present or has a high likelihood of recurring.Without some other form of treatment, “we knew many would recur quickly,” Dr. Kelly said. Additional chemotherapy not only was difficult for patients to tolerate, but it also did not seem to help. Nivolumab has few side effects and seemed worth a try.Esophageal cancer is rare in the United States, accounting for 1 percent of all cancers; about 15,000 patients die each year. But it is the seventh most common cancer globally, and frequently seen in East Asia, although it is not clear why, Dr. Ilson said.Smoking is a risk factor, but researchers do not think the high smoking rates in China, for example, explain the high incidence. “We don’t think it’s environmental,” Dr. Ilson said.Other risk factors include alcohol consumption and acid reflux disease.Because the cancer is so rare in the United States, it has not gotten much research attention. While new treatments have revolutionized prospects for other cancer patients, those with esophageal cancer could only look on longingly.That has weighed heavily on people with the disease, said Mindy Mordecai. Her husband, John, died of esophageal cancer in March 2008. She started an advocacy group called Esophageal Cancer Action Network.“You can’t even imagine how demoralizing it is to see all the progress around you. ‘Please sir, may I have some more gruel?’” she said, quoting Oliver Twist, the Charles Dickens character in the eponymous novel, asking for a pittance.The new findings must be seen in the context of what patients go through when they develop esophageal cancer, experts said. Most learn they have the cancer after it has progressed to a point where they are unlikely to survive.But every patient hopes to be one of the lucky ones. “Our patients are always waiting for the other shoe to drop,” Ms. Mordecai said. “You have to understand what it’s like to live with that every day.”The first step for most is chemotherapy and radiation. The treatment is so harsh that an oncology nurse told Mr. Mordecai it “brings Navy Seals to their knees,” Ms. Mordecai recalled.The chemotherapy has difficult side effects, and the radiation causes a burning sensation that makes it difficult to swallow. “Food won’t go down,” Ms. Mordecai said. “You just feel rotten.”The next step is major surgery. A doctor takes out most of the patient’s esophagus, the tract leading from the mouth to the stomach, and then grabs the stomach and pulls it up, attaching it to a stump of esophagus left behind.The result is a stomach that is vertical, not horizontal, and lacks the sphincter muscle that normally keeps stomach acid from spilling out. For the rest of their lives, patients can never lie flat — if they do, the contents of their stomach, including acid, pours into their throats. They can choke, cough and aspirate.Recovery is difficult, and morbidity and mortality are high. But most patients go through with the operation once they weigh their options. To refuse the treatment means giving up and letting the cancer close off the esophagus to the point where some cannot even swallow their own saliva, said Dr. Paul Helft, a professor of surgery and an ethicist at Indiana University School of Medicine.The treatment is so long and harrowing that Dr. Helft often uses it to teach medical students and other trainees about informed consent — about how patients must be fully informed before they start any given treatment. Esophageal cancer patients in particular must be told that they are likely to have a recurrence within the first year.Ms. Mordecai said her husband had his surgery at the end of September 2008. By Dec. 6, he had untreatable metastases in his liver. Now, she said, patients may have a glimmer of hope.Dr. Ilson, who has spent his career trying to develop therapies to help patients with esophageal cancer, said that he did not expect this treatment to succeed: “We all get nihilistic when faced with years of negative studies.”“This is really a landmark paper,” he added, and the drug “will become a new standard of care.”

Biologists have long held that a fetus needs a living uterus to develop. Maybe not anymore.Mouse embryos, their beating hearts visible, grown outside the womb after four days. Video by A. Aguilera-Castrejon et al., Nature 2021The mouse embryos looked perfectly normal. All their organs were developing as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute.But these embryos were not growing in a mother mouse. They were developed inside an artificial uterus, the first time such a feat has been accomplished, scientists reported on Wednesday.The experiments, at the Weizmann Institute of Science in Israel, were meant to help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.In a study published in the journal Nature, Dr. Jacob Hanna described removing embryos from the uteruses of mice at five days of gestation and growing them for six more days in artificial wombs.At that point, the embryos were about halfway through their development; full gestation is about 20 days. A human at this stage of development would be called a fetus. To date, Dr. Hanna and his colleagues have grown more than 1,000 embryos in this way.“It really is a remarkable achievement,” said Paul Tesar, a developmental biologist at Case Western Reserve University School of Medicine.Alexander Meissner, director of genome regulation at the Max Planck Institute for Molecular Genetics in Berlin, said that “getting this far is amazing” and that the study was “a major milestone.”But the research has already progressed beyond what the investigators described in the paper. In an interview, Dr. Hanna said he and his colleagues had taken fertilized eggs from the oviducts of female mice just after fertilization — at Day 0 of development — and had grown them in the artificial uterus for 11 days.Until now, researchers were able to fertilize eggs from mammals in the laboratory and grow them for only a short time. The embryos needed a living womb. “Placental mammals develop locked away in the uterus,” Dr. Tesar said.That prevented scientists from answering fundamental questions about the earliest stages of development.“The holy grail of developmental biology is to understand how a single cell, a fertilized egg, can make all of the specific cell types in the human body and grow into 40 trillion cells,” Dr. Tesar said. “Since the beginning of time, researchers have been trying to develop ways to answer this question.”The only way to study the development of tissues and organs was to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like snapshots than video.What was needed was a way to get inside the uterus, watching and tweaking development in mammals as it happened. For Dr. Hanna, that meant developing an artificial uterus.He spent seven years developing a two-part system that includes incubators, nutrients and a ventilation system. The mice embryos are placed in glass vials inside incubators, where they float in a special nutrient fluid.Viable embryos spinning in vials in a mechanical womb.A. Aguilera-Castrejon et al., Nature 2021Development of a mouse embryo over a five-day period.A. Aguilera-Castrejon et al., Nature 2021The vials are attached to a wheel that slowly spins so the embryos do not attach to the wall, where they would become deformed and die. The incubators are connected to a ventilation machine that provides oxygen and carbon dioxide to the embryos, controlling the concentration of those gasses, as well as the gas pressure and flow rate.At Day 11 of development — more than halfway through a mouse pregnancy — Dr. Hanna and his colleagues examined the embryos, only the size of apple seeds, and compared them to those developing in the uteruses of living mice. The lab embryos were identical, the scientists found.By that time, though, the lab-grown embryos had become too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient.Getting past that hurdle is the next goal, Dr. Hanna said in an interview. He is considering using an enriched nutrient solution or an artificial blood supply that connects to the embryos’ placentas.In the meantime, experiments beckon. The ability to keep embryos alive and developing halfway through pregnancy “is a gold mine for us,” Dr. Hanna said.The artificial womb may allow researchers to learn more about why pregnancies end in miscarriages or why fertilized eggs fail to implant. It opens a new window onto how gene mutations or deletions affect fetal development. Researchers may be able to watch individual cells migrate to their ultimate destinations.The work is “a breakthrough,” said Magdalena Zernicka-Goetz, professor of biology and biological engineering at Caltech. It “opens the door to a new age of studying development in the experimental mouse model.”A developing mouse embryo inside its glass vial. Video by A. Aguilera-Castrejon et al., Nature 2021A recent development provides another opportunity. Researchers have directly created mouse embryos from mouse fibroblasts — connective tissue cells — making early embryos without starting with a fertilized egg.Combine that development with Dr. Hanna’s work, and “now you don’t need mice to study mouse embryo development,” Dr. Meissner said. Scientists may be able to make all the embryos they need from connective tissue.If scientists could make embryos without fertilizing eggs and could study their development without a uterus, Dr. Meissner said, “you can get away from embryo destruction.” There would be no need to fertilize mouse eggs only to destroy them in the course of study.But the work might eventually extend beyond mice. Two other papers published in Nature on Wednesday report on attempts that edge near creating early human embryos in this way. Of course, Dr. Meissner said, creation of human embryos is years away — if it is permitted at all. And for now, international regulations prohibit studying human embryos beyond 14 days of fertilization.In the future, Dr. Tesar said, “it is not unreasonable that we might have the capacity to develop a human embryo from fertilization to birth entirely outside the uterus.”Of course, even the suggestion of this science fiction scenario is bound to horrify many. But it is early days, with no assurance human fetuses could ever develop entirely outside the womb.Even assuming they could, Dr. Tesar noted, “whether that is appropriate is a question for ethicists, regulators and society.”