Approximately 40,000 children in the United States may have lost a parent to COVID-19 since February 2020, according to a statistical model created by a team of researchers. The researchers anticipate that without immediate interventions, the trauma from losing a parent could cast a shadow of mental health and economic problems well into the future for this vulnerable population.
In the researchers’ model, for approximately every 13th COVID-related death, a child loses one parent. Children who lose a parent are at higher risk of a range of problems, including traumatic prolonged grief and depression, lower educational attainment, economic insecurity and accidental death or suicide, said Ashton Verdery, associate professor of sociology, demography and social data analytics and Institute for Computational and Data Sciences co-hire, Penn State.
“When we think of COVID-19 mortality, much of the conversation focuses on the fact that older adults are the populations at greatest risk. About 81% of deaths have been among those ages 65 and older according to the CDC (Centers for Disease Control and Prevention),” said Verdery, who is also an affiliate of the Population Research Institute at Penn State. “However, that leaves 19% of deaths among those under 65 — 15% of deaths are among those in their 50s and early 60s and 3% are among those in their 40s. In these younger age groups, substantial numbers of people have children, for whom the loss of a parent is a potentially devastating challenge.”
Three-quarters of the children who lost a parent are adolescents, but one quarter are elementary-aged children, Verdery said.
The statistics of parental death are grimmer for Black families, which have been disproportionately impacted by the pandemic, according to the researchers, who report their findings in today’s (April 5) issue of JAMA Pediatrics. The team estimated that 20% of the children who lost a parent are Black even though only 14% of children in the U.S. are Black.
The model also suggests that parental deaths due to COVID-19 will increase the country’s total cases of parental bereavement by 18% to 20% over what happens in a typical year, further straining an already stretched system that does not connect all children who are eligible to adequate resources.

A new analysis of the entire genetic makeup of more than 53,000 people offers a bonanza of valuable insights into heart, lung, blood and sleep disorders, paving the way for new and better ways to treat and prevent some of the most common causes of disability and death.
The analysis from the Trans-Omics for Precision Medicine (TOPMed) program examines the complete genomes of 53,831 people of diverse backgrounds on different continents. Most are from minority groups, which have been historically underrepresented in genetic studies. The increased representation should translate into better understanding of how heart, lung, blood and sleep disorders affect minorities and should help reduce longstanding health disparities.
“The Human Genome Project has generated a lot of promises and opportunities for applying genomics to precision medicine, and the TOPMed program is a major step in this direction,” said Stephen S. Rich, PhD, a genetics researcher at the University of Virginia School of Medicine who helped lead the project. “An important feature of TOPMed is not only publishing the genomic data on 53,000 people with massive amounts of data related to heart, lung, blood and sleep disorders but also the great diversity of the participants who donated their blood and data.”
Historic Genome Analysis
The groundbreaking work identified 400 million genetic variants, of which more than 78% had never been described. Nearly 97% were extremely rare, occurring in less than 1% of people. This sheds light on both how genes mutate and on human evolution itself, the researchers say.
Of the groups studied, people of African descent had the greatest genetic variability, the researchers found. The resulting data is the best ever produced on people of African ancestry, the scientists report in the journal Nature.
The work also offers important new insights into certain gene variants that can reduce people’s ability to benefit from prescription drugs. This can vary by race and ethnic group.
“TOPMed is an important and historic effort to include under-represented minority participants in genetic studies,” said Rich, who served on the project’s Executive Committee and chaired the Steering Committee. “The work of TOPMed should translate not only into better scientific knowledge but increase diversity at all levels — scientists, trainees, participants — in work to extend personalized medicine for everyone.”
Rich was joined in the effort by UVA’s Ani Manichaikul, PhD; Joe Mychaleckyj, DPhil; and Aakrosh Ratan, PhD. All four are part of both the Center for Public Health Genomics and UVA’s Department of Public Health Sciences.
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Thousands of our daily activities, from making coffee to taking a walk to saying hello to a neighbor, are made possible through an ancient collection of brain structures tucked away near the center of the cranium.
The cluster of neurons known as the basal ganglia is a central hub for regulating a vast array of routine motor and behavior functions. But when signaling in the basal ganglia is weakened or broken, debilitating movement and psychiatric disorders can emerge, including Parkinson’s disease, Tourette’s syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder.
Despite its central importance in controlling behavior, the specific, detailed paths across which information flows from the basal ganglia to other brain regions have remained poorly charted. Now, researchers at the University of California San Diego, Columbia University’s Zuckerman Institute and their colleagues have generated a precise map of brain connectivity from the largest output nucleus of the basal ganglia, an area known as the substantia nigra pars reticulata, or SNr. The findings offer a blueprint of the area’s architecture that revealed new details and a surprising level of influence connected to the basal ganglia.
The results, spearheaded by Assistant Project Scientist Lauren McElvain and carried out in the Neurophysics Laboratory of Professor David Kleinfeld at UC San Diego, and the laboratory of Zuckerman Institute Principal Investigator Rui Costa, are published April 5 in the journal Neuron.
The research establishes a new understanding of the position of the basal ganglia in the hierarchy of the motor system. According to the researchers, the newly identified pathways emerging from the connectivity map could potentially open additional avenues for intervention of Parkinson’s disease and other disorders tied to the basal ganglia.
“With the detailed circuit map in hand, we can now plan studies to identify the specific information conveyed by each pathway, how this information impacts downstream neurons to control movement and how dysfunction in each output pathway leads to the diverse symptoms of basal ganglia diseases,” said McElvain.
With support from the NIH’s Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, the researchers developed the new blueprint working in mice by applying a modern neuroscience toolset that combines techniques from genetics, virus tracing, automated microscopic imaging of whole-brain anatomy and image processing. The results revealed surprising new insights about the breadth of connections.
“These results are an example of how researchers supported by the BRAIN Initiative are using the latest brain mapping tools to change in a fundamental way our understanding of how the connections in the brain’s circuits are organized,” said John J. Ngai, director of the NIH’s BRAIN Initiative.
Previous work had emphasized that the basal ganglia architecture is dominated by a closed-loop with output projections connecting back to input structures. The new study reveals the SNr broadcasts even to lower levels of the motor and behavior system. This includes a large set of brainstem regions with direct connections to the spinal cord and motor nuclei that control muscles via a small number of intervening connections.
“The new findings led by Dr. McElvain offer an important lesson in motor control,” said Kleinfeld, a professor in the Division of Biological Sciences (Section of Neurobiology) and Division of Physical Sciences (Department of Physics). “The brain does not control movement though a hierarchy of commands, like the ‘neural networks’ of self-driving cars, but through a scheme of middle management that directs motor output while informing the executive planners.”
Remarkably, according to the researchers, the SNr neurons that project to the low levels of the motor system have branched axons that simultaneously project back up to the brain regions responsible for higher-order control and learning. In this way, the newly described connectivity of SNr neurons fundamentally links operations across high and low levels of the brain.
“The fact that specific basal ganglia output neurons project to specific downstream brain nuclei but also broadcast this information to higher motor centers has implications for how the brain chooses which movements to do in a particular context, and also for how it learns about which actions to do in the future,” said Costa, a professor of neuroscience and neurology at Columbia’s Vagelos College of Physicians and Surgeons, as well as director and chief executive officer of the Zuckerman Institute.

Researchers in the Oregon State University College of Science have taken a key step toward new drugs and vaccines for combating COVID-19 with a deep dive into one protein’s interactions with SARS-CoV-2 genetic material.
The virus’ nucleocapsid protein, or N protein, is a prime target for disease-fighting interventions because of the critical jobs it performs for the novel coronavirus’ infection cycle and because it mutates at a comparatively slow pace. Drugs and vaccines built around the work of the N protein carry the potential to be highly effective and for longer periods of time — i.e., less susceptible to resistance.
Among the SARS-CoV-2 proteins, the N protein is the viral RNA’s biggest partner. The RNA holds the genetic instructions the virus uses to get living cells, such as human cells, to make more of itself, and the N protein binds to the RNA and protects it.
Published in Biophysical Journal, the findings are an important jump-off point for additional studies of the N protein and its interactions with RNA as part of a thorough look at the mechanisms of SARS-CoV-2 infection, transmission and control.
Elisar Barbar, professor of biochemistry and biophysics at Oregon State, and Ph.D. candidate Heather Masson-Forsythe led the study with help from undergraduate students Joaquin Rodriguez and Seth Pinckney. The researchers used a range of biophysical techniques that measure changes in the size and shape of the N protein when bound to a fragment of genomic RNA — 1,000 nucleotides of the 30,000-nucleotide genome.
“The genome is rather large for a virus and requires many copies of the N protein to stick to the RNA to give the virus the spherical shape that is necessary for the virus to make more copies of itself,” Barbar said. “Our study helps us quantify how many copies of N are needed and how close they are to each other when they stick to the RNA. ”
Biophysical studies of N with large segments of RNA by nuclear magnetic resonance are rare, Barbar said, because of the difficulty of preparing the partially disordered N protein and long RNA segments, both prone to aggregation and degradation, but these kinds of studies are a specialty of the Barbar lab. Other researchers’ studies generally have been limited to much smaller pieces of RNA and smaller pieces of the N protein.
Rather than just looking at the RNA-binding regions of the N protein on their own, the 1,000-nucleotide view allowed scientists to learn that the protein binds much more strongly when it’s a full-length dimer — two copies attached to one another — and to identify regions of the protein that are essential for RNA binding.
“The full protein has structured parts but is actually really flexible, so we know that this flexibility is important for RNA binding,” Masson-Forsythe said. “We also know that as N proteins start to bind to the longer RNA, the result is a diverse collection of bound protein/RNA complexes as opposed to one way of binding.”
Drugs that thwart the N protein’s flexibility would thus be one potential avenue for pharmaceutical researchers, she said. Another possibility would be drugs that disrupt any of those protein/RNA complexes that prove to be of special significance.
A National Science Foundation Early-concept Grant for Exploratory Research (EAGER) supported this research through the NSF’s Division of Molecular and Cellular Biosciences. The Oregon State nuclear magnetic resonance facility used in the study is funded in part by the National Institutes of Health and the M.J. Murdock Charitable Trust, and the NIH also supported the native mass spectrometry data acquisition portion of the research.
Zhen Yu, Richard Cooley, Phillip Zhu and Patrick Reardon of Oregon State and James Prell and Amber Rolland of the University of Oregon were the other researchers on the project.
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Materials provided by Oregon State University. Original written by Steve Lundeberg. Note: Content may be edited for style and length.

Researchers at the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center have developed DeepTCR, a software package that employs deep-learning algorithms to analyze T-cell receptor (TCR) sequencing data. T-cell receptors are found on the surface of immune T cells. These receptors bind to certain antigens, or proteins, found on abnormal cells, such as cancer cells and cells infected with a virus or bacteria, to guide the T cells to attack and destroy the affected cells.
“DeepTCR is an open-source software that can be used to answer questions in research into infectious disease, cancer immunology and autoimmune disease; any place where the immune system has a role through its T-cell receptors,” said lead study author John-William Sidhom, an M.D./Ph.D. student at the Johns Hopkins University School of Medicine and Department of Biomedical Engineering working in the Bloomberg~Kimmel Institute for Cancer Immunotherapy.
The research was published March 11 in Nature Communications.
Sidhom was inspired to develop the software after attending a presentation on the use of deep learning for the medical sciences at the 2017 meeting of the American Association for Cancer Research. “I was doing research on T-cell receptor sequencing, and it struck me that this was the right technology to better analyze T-cell sequencing data,” he says.
Deep learning is a form of artificial intelligence that roughly mimics the workings of the human brain in terms of pattern recognition. “Deep learning is a very flexible and powerful way to do pattern recognition on any kind of data. In this paper, we use deep learning to identify patterns in sequencing data of the T-cell receptor,” says Sidhom, adding that the way the software explores T-cell receptors is analogous to an internet search. “When someone performs an internet search for an image of cats or dogs, the query doesn’t involve looking for images that have a caption that labels the image as a cat or dog, but rather applies an algorithm that explores the features of the images and recognizes patterns that identify the images as a cat or dog. This is deep learning.”
DeepTCR is a comprehensive deep-learning framework that includes both unsupervised and supervised deep learning models that can be applied at the sequence and sample level. Sidhom says the unsupervised approaches allow investigators to analyze their data in an exploratory fashion, where there may not be known immune exposures, and the supervised approaches will allow investigators to leverage known exposures to improve the learning of the models. As a result, he says, DeepTCR will enable investigators to study the function of the T-cell immune response in basic and clinical sciences by identifying the patterns in the receptors that confer the function of the T cell to recognize and kill pathological cells.
One of the main challenges of analyzing TCR sequencing data is distinguishing meaningful sequencing data from inconsequential data, and DeepTCR helps perform this analysis. “There are a lot of sequences in someone’s immune repertoire. There are a lot of pathogens that someone can be infected by, so the immune response is very broad. As a result, there is a sea of noise in the immune response, and only parts of it are important at a certain time for a certain infection,” Sidhom explains. “I may have T-cell responses to a thousand different viruses, but when the flu impacts me, I only need to utilize a small subset of those T cells to fight the flu. The main thing that the algorithm can do is isolate and match the right T cells to specific responses.”
The software package, which employs a type of deep-learning architecture called a convolutional neural network, provides users the ability to find T-cell sequencing patterns that are relevant to a specific exposure, like a flu infection, a cancer or an autoimmune disease.
“When presented with a lot of data, our algorithms can learn rules of these TCR sequence patterns. For example, we may not know the rules for how the body responds to flu, but with enough data, our software can learn those rules and then teach us what they are,” says Sidhom. “It is very well-suited to identify complex patterns in a very, very large immune repertoire to identify the interacting partners between a T-cell receptor and its antigen.”
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As the world awaits the upcoming Olympic games, a new method for detecting doping compounds in urine samples could level the playing field for those trying to keep athletics clean. Today, scientists report an approach using ion mobility-mass spectrometry to help regulatory agencies detect existing dopants and future “designer” compounds.
The researchers will present their results today at the spring meeting of the American Chemical Society (ACS).
Each year, the World Anti-Doping Agency (WADA) publishes a list of substances, including steroids, that athletes are prohibited from using. However, it can be difficult to distinguish an athlete’s natural or “endogenous” steroids from synthetic “exogenous” ones administered to boost performance.
And regulatory bodies face another challenge: “As quickly as we develop methods to look for performance-enhancing drugs, clandestine labs develop new substances that give athletes a competitive advantage,” says Christopher Chouinard, Ph.D., the project’s principal investigator. Those designer drugs evade detection if testing labs don’t know to look for their specific chemical structures.
Chouinard’s team at Florida Institute of Technology is trying to outsmart cheaters with an assay that can differentiate endogenous and exogenous steroids and can also anticipate the structure of new compounds that might show up in athletes’ urine samples.
Currently, testing labs analyze samples using tandem mass spectrometry (MS) and gas or liquid chromatography. These approaches break up molecules in the sample and separate the fragments, yielding spectra that can reveal the identity of the original, intact compounds. But it can be tough to differentiate molecules with minor structural differences — including isomers — that distinguish endogenous steroids from exogenous ones, such as the synthetic anabolic steroids athletes take to build muscle.
To accentuate those differences, Chouinard pairs MS with ion mobility (IM) spectrometry, a separation technique he learned as a graduate student with Richard Yost, Ph.D., at the University of Florida. Yost’s team and others found that the differences between isomers could be made even more apparent if the molecules in a sample were modified prior to IM-mass spec analysis by reacting them with other compounds. After Chouinard set up his own lab in 2018, he applied this technique by reacting steroid samples with ozone or acetone in the presence of ultraviolet light — reactions already well-established among researchers who study lipid isomers, but new in the anti-doping arena.
Last year, Chouinard’s team reported they had successfully used these reactions with IM-MS to improve isomer separation, identification and quantification for a few steroids in sample solutions. Now, the researchers report they have tested this technique in urine against nearly half the prohibited steroids on WADA’s list and have shown it can successfully characterize and identify these compounds. They also showed the method can characterize and identify banned glucocorticoids, such as cortisone, that improve athletic performance by suppressing inflammation from injuries. Detection limits are below one nanogram per ml.
In addition to tracking down known dopants, the team wants to be able to find newly created illicit steroids not yet known to WADA. With Florida Institute of Technology collaborators including Roberto Peverati, Ph.D., they are developing computational modeling and machine learning techniques to try to predict the structure, spectra and other characteristics of these molecules. “If we can develop methods to identify any theoretical steroids in the future, we could dramatically reduce doping because we would be able to detect these new species immediately, without the lag time that’s been associated with anti-doping testing over the last 40 years,” Chouinard says.
Though the assays themselves are quick, simple and inexpensive, IM instruments are costly, with a price ranging up to roughly a million dollars, Chouinard notes. However, he adds, with the support of anti-doping funding organizations like the Partnership for Clean Competition (PCC), more labs might be willing to foot that bill, so long as the method offers a significant advantage in detection and deterrence.
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For centuries, people in Baltic nations have used ancient amber for medicinal purposes. Even today, infants are given amber necklaces that they chew to relieve teething pain, and people put pulverized amber in elixirs and ointments for its purported anti-inflammatory and anti-infective properties. Now, scientists have pinpointed compounds that help explain Baltic amber’s therapeutic effects and that could lead to new medicines to combat antibiotic-resistant infections.
The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). 
Each year in the U.S., at least 2.8 million people get antibiotic-resistant infections, leading to 35,000 deaths, according to the U.S. Centers for Disease Control and Prevention. “We knew from previous research that there were substances in Baltic amber that might lead to new antibiotics, but they had not been systematically explored,” says Elizabeth Ambrose, Ph.D., who is the principal investigator of the project. “We have now extracted and identified several compounds in Baltic amber that show activity against gram-positive, antibiotic-resistant bacteria.”
Ambrose’s interest originally stemmed from her Baltic heritage. While visiting family in Lithuania, she collected amber samples and heard stories about their medicinal uses. The Baltic Sea region contains the world’s largest deposit of the material, which is fossilized resin formed about 44 million years ago. The resin oozed from now-extinct pines in the Sciadopityaceae family and acted as a defense against microorganisms such as bacteria and fungi, as well as herbivorous insects that would become trapped in the resin.
Ambrose and graduate student Connor McDermott, who are at the University of Minnesota, analyzed commercially available Baltic amber samples, in addition to some that Ambrose had collected. “One major challenge was preparing a homogeneous fine powder from the amber pebbles that could be extracted with solvents,” McDermott explains. He used a tabletop jar rolling mill, in which the jar is filled with ceramic beads and amber pebbles and rotated on its side. Through trial and error, he determined the correct ratio of beads to pebbles to yield a semi-fine powder. Then, using various combinations of solvents and techniques, he filtered, concentrated and analyzed the amber powder extracts by gas chromatography-mass spectrometry (GC-MS).
Dozens of compounds were identified from the GC-MS spectra. The most interesting were abietic acid, dehydroabietic acid and palustric acid — 20-carbon, three-ringed organic compounds with known biological activity. Because these compounds are difficult to purify, the researchers bought pure samples and sent them to a company that tested their activity against nine bacterial species, some of which are known to be antibiotic resistant.
“The most important finding is that these compounds are active against gram-positive bacteria, such as certain Staphylococcus aureus strains, but not gram-negative bacteria,” McDermott says. Gram-positive bacteria have a less complex cell wall than gram-negative bacteria. “This implies that the composition of the bacterial membrane is important for the activity of the compounds,” he says. McDermott also obtained a Japanese umbrella pine, the closest living species to the trees that produced the resin that became Baltic amber. He extracted resin from the needles and stem and identified sclarene, a molecule present in the extracts that could theoretically undergo chemical transformations to produce the bioactive compounds the researchers found in Baltic amber samples.
“We are excited to move forward with these results,” Ambrose says. “Abietic acids and their derivatives are potentially an untapped source of new medicines, especially for treating infections caused by gram-positive bacteria, which are increasingly becoming resistant to known antibiotics.”
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A new formulation entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic.A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make.Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world.If NVD-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NVD-HXP-S for themselves or acquire it at low cost from neighbors.“That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center.First, however, clinical trials must establish that NVD-HXP-S actually works in people. The first phase of clinical trials will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects.“It’s a home run for protection,” said Dr. Bruce Innes of the PATH Center for Vaccine Innovation and Access, which has coordinated the development of NVD-HXP-S. “I think it’s a world-class vaccine.”2P to the rescueThe molecular structure of HexaPro, a modified version of the SARS-CoV-2 spike protein, with its six key alterations shown as red and blue spheres.University of Texas at AustinVaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them.In the case of the coronavirus, the best target for the immune system is the protein that covers its surface like a crown. The protein, known as spike, latches onto cells and then allows the virus to fuse to them.But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies.Jason McLellan, a structural biologist at the University of Texas at Austin. His research on coronavirus spike proteins aided the development of the Pfizer, Moderna, Johnson & Johnson and Novavax vaccines.Ilana Panich-Linsman for The New York TimesThis insight emerged long before the Covid-19 pandemic. In 2015, another coronavirus appeared, causing a deadly form of pneumonia called MERS. Jason McLellan, a structural biologist then at the Geisel School of Medicine at Dartmouth, and his colleagues set out to make a vaccine against it.They wanted to use the spike protein as a target. But they had to reckon with the fact that the spike protein is a shape-shifter. As the protein prepares to fuse to a cell, it contorts from a tulip-like shape into something more akin to a javelin.Scientists call these two shapes the prefusion and postfusion forms of the spike. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don’t stop it.Dr. McLellan and his colleagues used standard techniques to make a MERS vaccine but ended up with a lot of postfusion spikes, useless for their purposes. Then they discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline.The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus.The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans.But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike.Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike.Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year.Two prolines are good; six are betterDr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.”But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more.“It made sense to try to have a better vaccine,” said Dr. McLellan, who is now an associate professor at the University of Texas at Austin.In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations.The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. Dr. McLellan called the new spike HexaPro, in honor of its total of six prolines.The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine.Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines.“The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said.To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties.Meanwhile, Dr. Innes and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own.With a little help from eggsThe first wave of authorized Covid-19 vaccines require specialized, costly ingredients to make. Moderna’s RNA-based vaccine, for instance, needs genetic building blocks called nucleotides, as well as a custom-made fatty acid to build a bubble around them. Those ingredients must be assembled into vaccines in purpose-built factories.The way influenza vaccines are made is a study in contrast. Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines.The PATH team wondered if scientists could make a Covid-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make Covid-19 shots as well.In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans.For years, scientists had been experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes.The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins.At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S.PATH arranged for thousands of doses of NDV-HXP-S to be produced in a Vietnamese factory that normally makes influenza vaccines in chicken eggs. In October, the factory sent the vaccines to New York to be tested. The Mount Sinai researchers found that NDV-HXP-S conferred powerful protection in mice and hamsters.“I can honestly say I can protect every hamster, every mouse in the world against SARS-CoV-2,” Dr. Peter Palese, the leader of the research, said. “But the jury’s still out about what it does in humans.”The potency of the vaccine brought an extra benefit: The researchers needed fewer viruses for an effective dose. A single egg may yield five to 10 doses of NDV-HXP-S, compared to one or two doses of influenza vaccines.“We are very excited about this, because we think it’s a way of making a cheap vaccine,” Dr. Palese said.A nurse administering the NDV-HXP-S  vaccine to a volunteer at Mahidol University in Bangkok during the country’s first human trial.Government Pharmaceutical Organization of Thailand, via Agence France-Presse — Getty ImagesPATH then connected the Mount Sinai team with influenza vaccine makers. On March 15, Vietnam’s Institute of Vaccines and Medical Biologicals announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S.Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form.To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok.From left, Dimas Covas, director of the Butantan Institute in Brazil; João Doria, governor of the state of São Paulo; and Jean Gorinchteyn, the state health secretary, announcing the ButanVac Covid-19 vaccine candidate against in São Paulo on March 26. Miguel Schincariol/Agence France-Presse — Getty ImagesIn Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.”Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.”Madhavi Sunder, an expert on intellectual property at Georgetown Law School, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said.Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said.In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro.“There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’”

A new formulation entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic.A new vaccine for Covid-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make.Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients. In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world.If NVD-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Low- and middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NVD-HXP-S for themselves or acquire it at low cost from neighbors.“That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center.First, however, clinical trials must establish that NVD-HXP-S actually works in people. The first phase of clinical trials will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects.“It’s a home run for protection,” said Dr. Bruce Innes of the PATH Center for Vaccine Innovation and Access, which has coordinated the development of NVD-HXP-S. “I think it’s a world-class vaccine.”2P to the rescueThe molecular structure of HexaPro, a modified version of the SARS-CoV-2 spike protein, with its six key alterations shown as red and blue spheres.University of Texas at AustinVaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them.In the case of the coronavirus, the best target for the immune system is the protein that covers its surface like a crown. The protein, known as spike, latches onto cells and then allows the virus to fuse to them.But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That’s because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies.Jason McLellan, a structural biologist at the University of Texas at Austin. His research on coronavirus spike proteins aided the development of the Pfizer, Moderna, Johnson & Johnson and Novavax vaccines.Ilana Panich-Linsman for The New York TimesThis insight emerged long before the Covid-19 pandemic. In 2015, another coronavirus appeared, causing a deadly form of pneumonia called MERS. Jason McLellan, a structural biologist then at the Geisel School of Medicine at Dartmouth, and his colleagues set out to make a vaccine against it.They wanted to use the spike protein as a target. But they had to reckon with the fact that the spike protein is a shape-shifter. As the protein prepares to fuse to a cell, it contorts from a tulip-like shape into something more akin to a javelin.Scientists call these two shapes the prefusion and postfusion forms of the spike. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don’t stop it.Dr. McLellan and his colleagues used standard techniques to make a MERS vaccine but ended up with a lot of postfusion spikes, useless for their purposes. Then they discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline.The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus.The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans.But in late 2019 a new coronavirus, SARS-CoV-2, emerged and began ravaging the world. Dr. McLellan and his colleagues swung into action, designing a 2P spike unique to SARS-CoV-2. In a matter of days, Moderna used that information to design a vaccine for Covid-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike.Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike.Other vaccine makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year.Two prolines are good; six are betterDr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.”But once Dr. McLellan and his colleagues handed off the 2P spike to vaccine makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more.“It made sense to try to have a better vaccine,” said Dr. McLellan, who is now an associate professor at the University of Texas at Austin.In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations.The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. Dr. McLellan called the new spike HexaPro, in honor of its total of six prolines.The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Dr. McLellan hoped that its rugged design would make it potent in a vaccine.Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world — especially low- and middle-income countries, which so far have received only a fraction of the total distribution of first-wave vaccines.“The share of the vaccines they’ve received so far is terrible,” Dr. McLellan said.To that end, the University of Texas set up a licensing arrangement for HexaPro that allows companies and labs in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties.Meanwhile, Dr. Innes and his colleagues at PATH were looking for a way to increase the production of Covid-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own.With a little help from eggsThe first wave of authorized Covid-19 vaccines require specialized, costly ingredients to make. Moderna’s RNA-based vaccine, for instance, needs genetic building blocks called nucleotides, as well as a custom-made fatty acid to build a bubble around them. Those ingredients must be assembled into vaccines in purpose-built factories.The way influenza vaccines are made is a study in contrast. Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines.The PATH team wondered if scientists could make a Covid-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make Covid-19 shots as well.In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans.For years, scientists had been experimenting with Newcastle disease virus to create vaccines for a range of diseases. To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus’s own set of genes.The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins.At Mount Sinai, the researchers set out to do the same thing, using coronavirus spike proteins instead of Ebola proteins. When they learned about Dr. McLellan’s new HexaPro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S.PATH arranged for thousands of doses of NDV-HXP-S to be produced in a Vietnamese factory that normally makes influenza vaccines in chicken eggs. In October, the factory sent the vaccines to New York to be tested. The Mount Sinai researchers found that NDV-HXP-S conferred powerful protection in mice and hamsters.“I can honestly say I can protect every hamster, every mouse in the world against SARS-CoV-2,” Dr. Peter Palese, the leader of the research, said. “But the jury’s still out about what it does in humans.”The potency of the vaccine brought an extra benefit: The researchers needed fewer viruses for an effective dose. A single egg may yield five to 10 doses of NDV-HXP-S, compared to one or two doses of influenza vaccines.“We are very excited about this, because we think it’s a way of making a cheap vaccine,” Dr. Palese said.A nurse administering the NDV-HXP-S  vaccine to a volunteer at Mahidol University in Bangkok during the country’s first human trial.Government Pharmaceutical Organization of Thailand, via Agence France-Presse — Getty ImagesPATH then connected the Mount Sinai team with influenza vaccine makers. On March 15, Vietnam’s Institute of Vaccines and Medical Biologicals announced the start of a clinical trial of NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S.Meanwhile, the Mount Sinai team has also licensed the vaccine to the Mexican vaccine maker Avi-Mex as an intranasal spray. The company will start clinical trials to see if the vaccine is even more potent in that form.To the nations involved, the prospect of making the vaccines entirely on their own was appealing. “This vaccine production is produced by Thai people for Thai people,” Thailand’s health minister, Anutin Charnvirakul, said at the announcement in Bangkok.From left, Dimas Covas, director of the Butantan Institute in Brazil; João Doria, governor of the state of São Paulo; and Jean Gorinchteyn, the state health secretary, announcing the ButanVac Covid-19 vaccine candidate against in São Paulo on March 26. Miguel Schincariol/Agence France-Presse — Getty ImagesIn Brazil, the Butantan Institute trumpeted its version of NDV-HXP-S as “the Brazilian vaccine,” one that would be “produced entirely in Brazil, without depending on imports.”Ms. Taylor, of the Duke Global Health Innovation Center, was sympathetic. “I could understand why that would really be such an attractive prospect,” she said. “They’ve been at the mercy of global supply chains.”Madhavi Sunder, an expert on intellectual property at Georgetown Law School, cautioned that NDV-HXP-S would not immediately help countries like Brazil as they grappled with the current wave of Covid-19 infections. “We’re not talking 16 billion doses in 2020,” she said.Instead, the strategy will be important for long-term vaccine production — not just for Covid-19 but for other pandemics that may come in the future. “It sounds super promising,” she said.In the meantime, Dr. McLellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than HexaPro.“There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’”

For some, the decision to die is more complicated than a wish to reduce pain. At a time when so many are dying against their will, it may seem out of sync to discuss the option of having a doctor help people end their lives when they face intolerable suffering that no treatment can relieve.It’s less a question of uncontrollable physical pain, which prompts only a minority of requests for medical aid in dying, than it is a loss of autonomy, a loss of dignity, a loss of quality of life and an inability to engage in what makes people’s lives meaningful.Intractable suffering is defined by patients, not doctors. Patients who choose medical aid in dying want to control when they die and die peacefully, remaining conscious almost to the very end, surrounded by loved ones and able to say goodbye.Currently, nine states and the District of Columbia allow doctors to help patients who meet well-defined criteria and are on the threshold of dying choose when and how to end their lives. The laws are modeled after the first Death with Dignity Act, passed in Oregon in 1997.A similar law has been introduced repeatedly, and again this January, in New York. Last year, Maryland came within one vote of joining states that permit medical aid in dying. Diane Rehm, the retired National Public Radio talk show host, says in a new film she created on the subject, “Each of us is just one bad death away from supporting these laws.”Most people who seek medical aid in dying would prefer to live but have an illness that has in effect stripped their lives of meaning. Though often — and, proponents say, unfortunately — described as “assisted suicide,” the laws hardly give carte blanche for doctors to give people medication that would end their lives quickly and painlessly. The patient has to be terminally ill (usually with a life expectancy of less than six months), professionally certified as of sound mind, and able to self-administer the lethal medication without assistance. That can leave out people with advanced dementia or, in some cases, people with severe physical disabilities like those with amyotrophic lateral sclerosis (A.L.S., or Lou Gehrig’s disease).A desire to broaden access to medical aid in dying prompted Ms. Rehm to create the film “When My Time Comes” to air on public television starting April 8. (A free livestream of the film preview and discussion will be available on April 8, at 12:45 p.m. Eastern, at weta.org/WhenMyTimeComesFilm.) The film follows the 2020 publication of Ms. Rehm’s book of the same title, subtitled “Conversations About Whether Those Who Are Dying Should Have the Right to Determine When Life Should End.” Both the book and film were inspired by the protracted death in 2014 from Parkinson’s disease of John Rehm, her first husband, to whom she was married for 54 years.Mr. Rehm, then living in Maryland, could no longer stand, feed or toilet himself, but his doctors could not legally grant his plea to help him die quickly. Instead, the only recourse he was given was to refuse all food, liquid and medication, which ended his life 10 days later.This is still the only option doctors can legally “prescribe” for the overwhelming majority of Americans who live in the 41 states that have yet to pass a medical aid-in-dying law. The approach does indeed work, but it’s not an acceptable choice for many dying patients and their families.Ms. Rehm said her goal is that no patient should have to suffer the indignity her husband experienced at the end of his life. She described his death as “excruciating to witness,” even though after about two days the absence of food and water is usually quite tolerable for the patient.Dr. Jessica Nutik Zitter, a palliative care physician at Highland Hospital in Oakland, Calif., said in an interview, “The concept of medical aid in dying is gaining acceptance, but it takes a while for people to be comfortable with it. Doctors are trained to just keep adding technology to patient care regardless of the outcome, and withdrawing technology is anathema to what we’re taught.”As a result, doctors may convince dying patients and their families to accept treatments “that result in terrible suffering,” said Dr. Zitter, author of the book “Extreme Measures: Finding a Better Path to the End of Life.” In her experience, a fear of losing control is the main reason patients request medical aid in dying, but when they have access to good palliative care, that fear often dissipates.Only a third of patients who qualify for medical aid in dying actually use the life-ending drugs they get, she said, explaining that once given the option, they regain a sense of autonomy and no longer fear losing control. In a study of 3,368 prescriptions for lethal medications written under the laws in Oregon and Washington state, the most common reasons for pursuing medical aid in dying were loss of autonomy (87.4 percent); impaired quality of life (86.1 percent), and loss of dignity (68.6 percent).Of course, many doctors consider medical aid in dying contrary to their training, religious beliefs or philosophy of life. Dr. Joanne Lynn, a geriatrician in Washington, D.C., who is not a supporter, said the emphasis should be on providing better care for people who are very sick, disabled or elderly.“We should resist medical aid in dying until we can offer a real choice of a well-supported, meaningful and comfortable existence to people who would have chosen a medically assisted death,” Dr. Lynn said. “There’s currently no strong push for decency in long-term care. It’s not a real choice if a person’s alternative is living in misery or impoverishing the family.”Barbara Coombs Lee, president emerita of Compassion & Choices, a nonprofit organization in Portland, Ore., that seeks to expand end-of-life options, said, “The core principle of medical aid in dying is self-determination for someone who is terminally ill.”Still, Ms. Lee, the author of “Finish Strong: Putting Your Priorities First at Life’s End,” said that there are options for the majority of dying patients who still lack access to an aid-in-dying law. In addition to voluntarily refusing to eat and drink, everyone has the right to create an advance directive that stipulates the medical circumstances under which they would want no further treatment.For example, people in the early stages of Alzheimer’s disease could specify that when they reach a certain stage — perhaps when they no longer know who they are or recognize close relatives — they do not want to be treated if they develop a life-threatening infection.Leaving such instructions when a person is still able to give them “is a gift to the family, relieving loved ones of uncertainty,” Ms. Lee said. She suggested consulting the website compassionandchoices.org for tools that can help families who want to plan ahead.