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.”