For COVID-19, the difference between surviving and not surviving severe disease may be due to the quality, not the quantity, of the patients’ antibody development and response, suggests a new Cell paper published by Galit Alter, a member of the Ragon Institute of MGH, MIT and Harvard.

The study, published in the journal Cell, used Alter’s systems serology approach to profile the antibody immune responses of 193 hospitalized COVID-19 patients, comparing responses from patients with moderate and severe disease and patients who passed away from COVID-19.

While all patients developed antibodies against SARS-CoV-2, the way the antibodies developed, or evolved, differed between the three groups. For patients that didn’t survive the disease, the antibody response never fully evolved.

“There was a significant defect in the development of IgG antibodies, which may be essential in the early control and elimination of the virus, ” Alter says. “Here, we were able to see the global impact of this defective IgG evolution, resulting in a compromised ability to promote essential viral clearing immune functions.”

In a mature immune response, antibodies both block infection and direct the immune system to kill infected cells. To guide the killer immune response, antibodies attach to the Fc-receptor, a “docking site” specific to antibodies that is found on all immune cells. Without strong Fc-receptor binding, antibodies may fail to grab and destroy virus following infection.

Compared to survivors, patients who passed from COVID-19 had antibodies that never fully developed the ability to strongly bind to Fc-receptors and therefore may not have been able to fully trigger immune killing activity.

Alter’s group, led by Tomer Zohar, Carolin Loos, Stephanie Fischinger, and Caroline Atyeo, also found that survivors’ immune systems could recognize and target an area of the SARS-CoV-2 spike protein known as the S2 domain. The S2 domain is found in other coronaviruses that infect humans, so patients whose antibodies can target it may have pre-existing immunity to the S2 domain because of exposure to other, common coronaviruses.

Patients with antibodies that can recognize S2 domains on different coronaviruses may be able to use this pre-existing immunity to generate killer antibodies faster and sooner following SARS-CoV-2 infection.

“If we can further understand the importance of cross-coronavirus immunity,” says Zohar, “researchers may be able to design vaccines able to counteract a much broader range of coronaviruses.”

With studies like these, Alter and her team are working to understand the nature of protective immunity against SARS-CoV-2, including partnering with COVID-19 vaccine developers, to help bring an end to this pandemic.

Steep declines in delta variant outbreaks in India and, more recently, the U.K., are likely not due to the nations reaching “herd immunity” or viral behavior, but rather because of shifts in human behavior prompted by mounting cases and deaths, Harvard experts say.

Those outbreaks appeared to follow similar courses: a rapid increase in cases followed by an equally rapid decline. In India, that progression took roughly three months. Cases began rising in March, took off in April, and declined in May and June, settling at levels slightly higher than those in the spring, according to World Health Organization data. In the U.K., meanwhile, cases rose relatively rapidly in June, peaked in July, and then declined before reaching a rough plateau in recent weeks that, though significantly lower, remains high enough to be a matter of concern to experts.

William Hanage, associate professor of epidemiology at the Harvard T.H. Chan School of Public Health, dismissed speculation that the declines were due to a combination of delta infections, vaccinations, and prior infections that pushed the U.K. past the herd immunity threshold, at which a sufficient number of people have developed resistance to infection, stifling transmission rates.

“When you see huge morbidity and mortality, people change their behavior,” Hanage said. “You need to mandate those non-pharmaceutical interventions in order to prevent the really, really bad outcomes because people generally don’t do them until really bad outcomes are already baked in. You could see that in India, when people started doing that [adopting non-pharmaceutical interventions], the delta starts to come down quite quickly.”

Kasisomayajula “Vish” Viswanath, the Lee Kum Kee Professor of Health Communication and head of the Chan School’s India Research Center, said that as cases and deaths mounted in India, people responded by redoubling efforts to mask, distance, and stay home.

“It is fairly clear that what I call the mitigation measures, that includes a set of behaviors and community actions, seem to be working,” Viswanath said. “In India, people were wearing masks; people were staying home because of the density of the population. … It doesn’t mean it has eradicated the disease because it’s still there, but to a large extent an even larger number of people would have ended up in the hospitals [without the behavior change].”

Viswanath said that pandemic fatigue — people letting their guards down after months of working to stay safe — played a role in delta’s rapid rise. India was enjoying relatively low case numbers in the late winter and early spring before the new variant tore through the country with little warning. The U.K. was also experiencing a bout of pandemic optimism, with vaccination numbers rising and restrictions relaxing. Even in Massachusetts, Viswanath said, despite rising case numbers today, people are largely still going about their business as they did in the spring, when vaccine campaigns provided the mirage of the pandemic’s end.

“I spend a lot of my time studying human behavior under conditions of public health emergencies,” Viswanath said. “And I can tell you that this complacency and fatigue is the most unpredictable part.”

Hanage said the declines in India and the U.K. should be viewed as good news in the U.S., as it means that despite its greater infectivity and ability to cause breakthrough infections in those already vaccinated, delta, like other variants, is susceptible to widely available non-pharmaceutical interventions. In the U.K., Hanage said there were two major drivers of the surge. One was reopened schools with few pandemic precautions. That meant when delta arrived, there was a large, unvaccinated population of schoolchildren vulnerable to infection. The second factor, he said, was a major soccer tournament, the Euro Cup, which not only filled stadiums but also brought people out to pubs and house parties to watch matches. When schools went on summer vacation and the tournament ended, levels subsided, Hanage said.

“It’s not that surprising that delta came down quickly [in India],” Hanage said. “It actually suggests that delta is very, very dependent upon contact networks. And that is consistent with what we saw in the U.K. That tells you that those combinations of contact networks really produce the opportunity for adults to spread it.”

Hanage said another example, that of The Netherlands, reinforces the idea that the variant is susceptible to the kinds of non-pharmaceutical interventions that appear to have been effective against different strains. The Netherlands, Hanage said, opened up widely and then suffered a rapid spike in delta cases. The government immediately imposed what Hanage described as moderate, targeted controls, like closing nightclubs and curbing late hours for restaurants.

“The other interventions in The Netherlands were relatively small, and delta cases just collapsed really quickly,” Hanage said. “We have to be careful about ascribing causation, but I think that, with the combination of the U.K. and India, shows how vulnerable delta is to changes in human contact networks.”

The lesson for the U.S., Hanage said, is that we shouldn’t be fatalistic about delta’s arrival and spread. Despite its increased contagiousness, which has led to soaring cases in some states, we still can be in control of the pandemic, he said. But we have to be willing to take the necessary steps.

“Fatalism is not going to help, especially when the natural history of the outbreaks in places as diverse as India and Scotland, England, Netherlands illustrates that there are things we can do,” Hanage said.

Viswanath said the India Research Center is working to reinforce best practices around non-pharmaceutical interventions. The center has run several webinars recently with hundreds of attendees about proper mask use, physical distancing, and other steps, as well as topics such as when — and when not — to go to the hospital after testing positive for COVID-19. The problem, he said, is if people with mild cases go to the hospital unnecessarily, it can spread the virus, since Indian clinics are often crowded and people are likely to be accompanied by family members.

In the U.S., meanwhile, cases are still rising rapidly amid calls to vaccinate more people and an ongoing nationwide argument about the need to again mask up. According to figures from the U.S. Centers for Disease Control and Prevention, the seven-day moving average of new cases nationally surpassed 100,000 this month and has since risen to 140,000, a level that outstrips three of the four earlier surges and is surpassed only by January’s seven-day average peak of more than 250,000.

One positive trend so far is that though deaths have likewise risen in recent weeks from 150 in early July to a seven-day national average about 750 over the most recent period, they have yet to match the heights of earlier surges.

Hanage said delta’s ability to infect even those who are vaccinated, while worrisome, “is very, very far from catastrophic” because the vaccines retain their ability to protect against severe illness. The speed with which delta can infect large numbers of people means, however, that there is a race between infection and vaccination, and those considering vaccination should keep in mind that protective immune responses after inoculation take weeks to build.

“If you were unvaccinated and in a place where delta is surging and you want to get your first shot of mRNA vaccine, there would still be quite some time before you were fully vaccinated,” Hanage said. “There’s a lot delta can do in a few weeks.”

With just half of U.S. adults fully vaccinated, there are still potential vaccination gains to be made, Viswanath said. He’s conducted surveys that show that only about 15 percent of the population is determined to remain unvaccinated, while the rest can still be persuaded, including those who said they’d get a vaccine if mandated by their workplaces.

“We are learning some things that are working, like masking still works against delta; physical distancing still works; vaccinations still seem to work,” Viswanath said. “There will be surprises, but the nastiness component has been somewhat muted because of the vaccines.”

Hanage said since the alpha variant became widespread in early 2021, the idea that the pandemic would end by eliminating COVID-19 has faded. Instead, the most likely outcome is one in which virtually everyone has been vaccinated, infected, or both, and consequently severe COVID-19 cases would become relatively rare and within the capacity of the health care system to handle.

“Delta makes that a virtual certainty,” Hanage said. “I said at one point that the quickest route toward not wearing a mask is getting a shot. That was before delta, unfortunately.”

In 2019, nearly 50,000 Americans died from opioid-related overdoses. In 2020, a record year for drug overdoses, that number rose to nearly 70,000, an increase driven in part by limited health care resources, shortages of overdose antidotes, and increased isolation during the pandemic. It’s not surprising that many people think of opium as a menace and nothing else.

Michael Pollan, whose books include “The Omnivore’s Dilemma,” “How to Change Your Mind,” and, most recently, “This Is Your Mind on Plants,” reminds us that opium can sometimes be a blessing. Many surgical procedures would be unbearable without it, and an opioid prescription can ease a patient’s suffering during palliative care. Opium, like all drugs, requires context, he notes.

In his latest work, Pollan, the Lewis K. Chan Arts Lecturer and Professor of the Practice Non-Fiction, writes about three drugs derived from plants: opium in poppies, caffeine in coffee beans and tea leaves, and mescaline in peyote. We asked him about the research behind the book and the changing nature of how we think about and use drugs. The interview was edited for clarity and length.

Q&A

Michael Pollan

GAZETTE: Harvesting a drug from a plant is a labor-intensive process. Why are we so dedicated to altering our minds?

POLLAN: Something about us is just not satisfied with normal consciousness. We seek to vary it and transcend it in many ways. Relief of boredom or of pain could be motivations. There’s also something in us that seeks to transcend the ego and the limitations of our narrowly circumscribed identities. Whatever the reason, it’s a universal human drive to change consciousness, right there with the sex drive or the drive to find food. It just seems less obvious what its purpose is.

GAZETTE: In the first section of the book, which covers opium, you include an updated version of an essay you wrote in 1997 about growing poppies in your backyard and navigating the legality of that process. What thoughts did you have when you revisited the piece?

POLLAN: I was writing about this muffled crackdown by the Drug Enforcement Administration of people growing Papaver somniferum, a perfectly legal flower that many people have in their gardens. Today that seems so overwrought, fearful, and paranoid. I learned that if a poppy is grown with the knowledge and intent to turn it into opium, it’s a serious federal crime. At that time, the government was worried that a fad for growing opium would explode. They put a lot of resources into intimidating florists, garden centers, and gardeners. They even removed the poppies in Monticello from Thomas Jefferson’s garden.

Yet at the same time, unbeknownst to me and to the government, Purdue Pharma was introducing OxyContin. It was a legally approved drug that launched the opioid crisis, while my poppies were illegal. That’s a significant historical irony. That article really is a parable of the drug war and how misguided it was

GAZETTE: Meanwhile, caffeine is a drug that is widely accepted in our society. Most of us have it every day in coffee or tea.

POLLAN: Caffeine lubricates the machinery of modern life. Drugs either contribute to the smooth workings of society and the economy, or they muck it up. Caffeine fosters a kind of consciousness that’s very sober and focused, and it gives people energy. It’s a great boon to capitalism that way.

GAZETTE: The book also discusses peyote, a plant from which mescaline is derived. The Native American Church has long conducted peyote ceremonies, as a means for healing. You write about the cultural appropriation of peyote by non-Native people. Can you describe what’s happening?

POLLAN: Peyote only grows in a very narrow band in Texas along the Rio Grande. There’s a literal appropriation happening when non-Native people harvest or buy peyote. By doing so, they are diminishing a very precious resource that belongs to Native Americans. It’s a resource that is critical to their well-being.

There’s also the issue of non-Native people imitating the Native American ceremony. There are deep principles of psychedelics use that are shared across indigenous populations. At a peyote ceremony, there is always an elder involved. It’s done with great reverence, and a sense of clear intention. While writing this book, I heard many stories of non-Native people conducting peyote ceremonies that, without these principles, trivialize the Native American Church and further diminish the resource.

GAZETTE: You’ve said that drugs are generally defined by being helpful or harmful to society. Can a drug change its identity?

POLLAN: The identity of drugs is always changing. Look at cannabis. Marijuana is now legal for recreational use in 19 states. That was a drug that was very much at the heart of the drug war. I think it’s also happening with psychedelics. In the 1960s, they were considered disruptive, but today, we’re facing a serious mental health crisis and psychedelics may offer some relief.

Each drug should be looked at in terms of its specific history, pharmacology, and social effects. They do have dangers — it’s not obvious how to have a productive relationship with something like an opiate. [But] if we can figure out how to safely and constructively fold them into our society, drugs can be tools with legitimate uses.

Cutting 20 percent of sugar from packaged foods and 40 percent from beverages could prevent 2.48 million cardiovascular disease events (such as strokes, heart attacks, cardiac arrests), 490,000 cardiovascular deaths, and 750,000 diabetes cases in the U.S. over the lifetime of the adult population, reports a study published in Circulation.

A team of researchers from Massachusetts General Hospital (MGH), the Friedman School of Nutrition Science & Policy at Tufts University, Harvard T.H. Chan School of Public Health, and New York City Department of Health and Mental Hygiene (NYC DOH) created a model to simulate and quantify the health, economic, and equity impacts of a pragmatic sugar-reduction policy proposed by the U.S. National Salt and Sugar Reduction Initiative (NSSRI).

A partnership of more than 100 local, state and national health organizations convened by the NYC DOH, the NSSRI released draft sugar-reduction targets for packaged foods and beverages in 15 categories in 2018. This February, NSSRI finalized the policy with the goal of industry voluntarily committing to gradually reformulate their sugary products.

Implementing a national policy, however, will require government support to monitor companies as they work toward the targets and to publicly report on their progress. The researchers hope their model will build consensus on the need for a national-sugar reformulation policy in the U.S. “We hope that this study will help push the reformulation initiative forward in the next few years,” says Siyi Shangguan, lead author and attending physician at MGH. “Reducing the sugar content of commercially prepared foods and beverages will have a larger impact on the health of Americans than other initiatives to cut sugar, such as imposing a sugar tax, labeling added sugar content, or banning sugary drinks in schools.”

Ten years after the NSSRI policy goes into effect, the U.S. could expect to save $4.28 billion in total net health care costs, and $118.04 billion over the lifetime of the current adult population (ages 35 to 79), according to the model. Adding the societal costs of lost productivity of Americans developing diseases from excessive sugar consumption, the total cost savings of the NSSRI policy rises to $160.88 billion over the adult population’s lifetime. These benefits are likely to be an underestimation since the calculations were conservative. The study also demonstrated that even partial industry compliance with the policy could generate significant health and economic gains.

The researchers found that the NSSRI policy became cost-effective at six years and cost-saving at nine years. The policy could also reduce disparities, with the greatest estimated health gains among Black and Hispanic adults, and Americans with lower income and less education — populations that consume the most sugar as a historical consequence of inequitable systems.

Product reformulation efforts have been shown to be successful in reducing other harmful nutrients, such as trans fats and sodium. The U.S., however, lags other countries in implementing strong sugar-reduction policies, with countries such as the UK, Norway, and Singapore taking the lead on sugar-reformulation efforts. The U.S. may yet become a leader in protecting its people from the dangers of excessive sugar consumption if the NSSRI’s proposed sugar-reduction targets are achieved. “The NSSRI policy is by far the most carefully designed and comprehensive, yet achievable, sugar-reformulation initiative in the world,” says Shangguan.

Consuming sugary foods and beverages is strongly linked to obesity and diseases such as type 2 diabetes and cardiovascular disease, the leading cause of mortality in the U.S. More than two in five American adults are obese, one in two have diabetes or prediabetes, and nearly one in two have cardiovascular disease, with those from lower-income groups being disproportionately burdened.

“Sugar is one of the most obvious additives in the food supply to reduce to reasonable amounts,” says Dariush Mozaffarian, co-senior author and dean of the Friedman School of Nutrition Science and Policy at Tufts University. “Our findings suggest it’s time to implement a national program with voluntary sugar-reduction targets, which can generate major improvements in health, health disparities, and healthcare spending in less than a decade.”

Major funding for this study was provided by the National Institutes of Health.

Shangguan is an attending at MGH and an instructor of medicine at Harvard Medical School. Mozaffarian is dean of the Friedman School of Nutrition Science and Policy at Tufts University. Thomas Gaziano is associate professor at Brigham and Women’s Hospital and assistant professor of medicine at HMS. Renata Micha is research associate professor at the Friedman School of Nutrition Science and Policy at Tufts University and associate professor at the University of Thessaly in Greece.

Short bursts of physical exercise induce changes in the body’s levels of metabolites that correlate to an individual’s cardiometabolic, cardiovascular, and long-term health, a study by Harvard-affiliated Massachusetts General Hospital (MGH) has found.

In a paper published in Circulation, the research team describes how about 12 minutes of acute cardiopulmonary exercise affected more than 80 percent of circulating metabolites, including pathways linked to a wide range of favorable health outcomes, thus identifying potential mechanisms that could contribute to a better understanding of cardiometabolic benefits of exercise.

“What was striking to us was the effects a brief bout of exercise can have on the circulating levels of metabolites that govern such key bodily functions as insulin resistance, oxidative stress, vascular reactivity, inflammation, and longevity,” said investigator Gregory Lewis, section head of Heart Failure at MGH and senior author of the study.

The MGH study drew on data from the Framingham Heart Study to measure the levels of 588 circulating metabolites before and immediately after 12 minutes of vigorous exercise in 411 middle-aged men and women.

The research team detected favorable shifts in a number of metabolites for which resting levels were previously shown to be associated with cardiometabolic disease. For example, glutamate, a key metabolite linked to heart disease, diabetes, and decreased longevity, fell by 29 percent. And DMGV, a metabolite associated with increased risk of diabetes and liver disease, dropped by 18 percent. The study further found that metabolic responses may be modulated by factors other than exercise, including a person’s sex and body mass index, with obesity possibly conferring partial resistance to the benefits of exercise.

“Intriguingly, our study found that different metabolites tracked with different physiologic responses to exercise, and might therefore provide unique signatures in the bloodstream that reveal if a person is physically fit, much the way current blood tests determine how well the kidney and liver are functioning,” notes co-first author Matthew Nayor of the Heart Failure and Transplantation Section in the Division of Cardiology at MGH. “Lower levels of DMGV, for example, could signify higher levels of fitness.”

The Framingham Heart Study, which began in 1948 and now embraces three generations of participants, allowed MGH researchers to apply the same signatures used in the current study population to stored blood from earlier generations of participants. By studying the long-term effects of metabolic signatures of exercise responses, researchers were able to predict the future state of an individual’s health, and how long they are likely to live.

“We’re starting to better understand the molecular underpinnings of how exercise affects the body and use that knowledge to understand the metabolic architecture around exercise response patterns,” says co-first author Ravi Shah of the Heart Failure and Transplantation Section in the Division of Cardiology at MGH. “This approach has the potential to target people who have high blood pressure or many other metabolic risk factors in response to exercise, and set them on a healthier trajectory early in their lives.”

Lewis is associate professor of medicine at Harvard Medical School and director of the Cardiopulmonary Exercise Testing Laboratory at MGH. Nayor is a cardiologist at MGH and instructor of medicine at Harvard Medical School, and Shah is a cardiologist at MGH and assistant professor of medicine at Harvard Medical School. Other co-authors include Ramachandran Vasan, professor of medicine at Boston University and principal investigator of the Framingham Heart Study, and Clary Clish, senior director of Metabolomics at the Broad Institute of MIT and Harvard.

The study was supported by the American Heart Association’s Grand Challenge Award and the National Institutes of Health.

James Sturm has spent his life crafting comics, from a miniseries on the lives of Marvel superheroes to history-themed graphic novels. But following the fraught 2016 presidential election, Sturm turned his attention to a different kind of storyline.

“It seemed as if the very idea of democracy was under assault and at that point I just wondered ‘What can I do as a cartoonist, that is my civic duty, with the skills that I have?’” said Sturm, founder of the Center for Cartoon Studies (CCS) in White River Junction, Vermont, and the 2020-21 Mary I. Bunting Institute Fellow at Harvard Radcliffe Institute.

His answer? Work with some like-minded artists on a 32-page illustrated primer on the nation’s political system titled “This Is What Democracy Looks Like: A Graphic Guide to Governance.” The booklet became a popular teaching tool in classrooms across the country, with copies shipped to schools in more than a dozen states and distributed to teachers at summer conferences and various other educational and literacy events. It also inspired Sturm’s recent Radcliffe project: a comic book aimed at demystifying the nation’s health care system, a horrendously complex industry affecting millions of Americans each year.

“As more people are putting material out there and addressing this issue, the hope is that there is some kind of inflection point,” said Sturm of his latest effort, a collaboration with a graduate student from CCS and several Harvard College students. “Our job was to make this comic as accessible and clear and accurate and engaging as possible, and my hope is that ‘Health and Wealth’ proves useful to organizations who are advocating for health care reform.”

The 32-page graphic guide addresses a range of topics, including the earliest days of Medicare, a history of the hospital, and the convoluted way patients are billed for services depending on how doctors and insurers choose to describe procedures. “It’s really Orwellian,” said Sturm. “Thousands of dollars depend on what word you use.”

The research has already paid off for Sturm, who was able to reduce a recent $3,000 medical bill for an eye procedure to less than $1,000 by negotiating with the hospital over the phone. But Sturm knows most people don’t have any idea how to navigate the system, and that bartering isn’t a sustainable fix. That’s where the comic comes in. “The system is complex and secretive and cruel,” said Sturm, “and the more it remains in the dark the longer it can operate.”

During the semester Sturm and a team of College students who were part of Radcliffe Research Partnerships program dove into the literature. They read “American Sickness: How Healthcare Became Big Business and How You Can Take It Back” by Elisabeth Rosenthal, listened to health-care-related podcasts, and pored over articles on the U.S. health care system.

“I can’t say enough about working with the students. They were so enthusiastic. They brought so much knowledge, and they were so supportive of a creative process that can sometimes result in dead ends,” said Sturm. “But they just buckled in and were just so great, from research to sketching out pages to copy editing.”

One of those students was Marissa Diggs ’22, a history of science concentrator with plans for medical school. As a child Diggs was diagnosed with Kawasaki disease, an inflammatory condition that can affect the arteries of the heart. In the ensuing years, precautionary heart scans every several years have been accompanied by her fears about rising costs. “There’s just so much anxiety that follows from not understanding the system that is so essential for your health and well-being,” said Diggs, who sees Sturm’s project as a way to shine some much-needed light on a poorly understood system.

A self-described “visual person,” Diggs also embraced the chance to put her drawing skills to the test. Sturm encouraged the students to develop a visual plan for the comic, no matter how basic, stick figures welcome. Every iteration helped inform the final product. “I think that that was probably what I enjoyed most about the project, getting to explore that side in parallel to doing the research in the history of medicine that I love,” said Diggs.

Alisha Yi ’22 was equally attracted by the possibility of helping people better understand the health care system.

“This project was just so interesting to me, because it was using the idea of art to talk about something that’s really important, and so necessary,” said Yi, who is also a history of science concentrator on a premed track. “It’s kind of hard to go online and read the things that we really need to hear. Having this comic combines the best of both worlds, of literature and of science, enabling us to think about things that are really important.”

Together the team also developed a GoFundMe page to pay for printed copies of the comic that they plan to deliver to every member of Congress. “So much of this stuff is a moral issue,” said Sturm. “And ultimately, the book is framed as such.” But it’s done with a clever, comic eye, he added, and conveys an important message without being too strident.

The book’s final visual look is informed by the Schoolhouse Rock! videos — a series of explainer animated shorts for children popular in the 1970s and ’80s that covered topics such as government, science, history and math — retro board games like Monopoly and Operation, and the work of American author and illustrator Richard Scarry, a master at “explaining complicated things very clearly,” said Sturm.

“There’s some fun stuff you can do using this style that you might not be able to do otherwise,” said Sturm. “It’s kind of like a court jester who reveals a truth.”

To download a free copy visit “Health and Wealth.”

When a patient with cancer is told the devastating news that their disease has spread, or metastasized, to a new part of their body, it has most often moved to their lungs. There are no treatments approved for lung metastasis, which is the leading cause of death from metastatic disease. That grim prognosis may soon be less grim thanks to a new technique developed by researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School for Engineering and Applied Sciences (SEAS).

Rather than viewing lung metastasis as unfortunate fallout from a primary tumor elsewhere, the team focused on treating the metastasis itself by delivering immune-cell-attracting chemicals into lung cancers via red blood cells. Not only did this approach halt lung tumor growth in mice with metastatic breast cancer, it also acted as a vaccine and protected the animals against future cancer recurrences. The research is reported in Nature Biomedical Engineering.

“Our approach is the exact opposite of conventional cancer treatments that focus on getting the immune system to recognize and attack the primary tumor, because those tumors are often large and difficult for immune cells to penetrate,” said co-first author Zongmin Zhao, a postdoctoral fellow at the Wyss Institute and SEAS. “We recognized that the high density of blood vessels in the lungs provides much better access to tumors there, offering a unique opportunity to induce an immune response by targeting the metastasis.”

An EASI solution to a hard problem

Delivering therapies to their intended target while sparing the rest of the body is one of the grand challenges of medicine. The liver and spleen are incredibly efficient at filtering out any foreign substances from the blood, meaning that drugs often need to be given at a high dose that can cause harmful off-target side effects. Overcoming this barrier to effective treatment is a major focus of Wyss core faculty member Samir Mitragotri’s work, and his lab recently discovered that attaching drug-filled nanoparticles to red blood cells allows them to escape detection and stay in the body long enough to deliver their payloads while minimizing toxicity.

Zhao and his co-authors decided to use that technique to see if they could deliver immune-system-stimulating chemicals to metastatic lung tumors rather than chemotherapy, which can damage lung tissue. They chose a chemokine, a small protein that attracts white blood cells, called CXCL10 as their payload.

When cancer goes through metastasis, the branching blood vessels that allow oxygen to diffuse from the lungs’ air sacs into red blood cells are so tiny that a rogue cancer cell circulating in the bloodstream can easily get stuck there and take up residence, eventually growing into a secondary tumor. Once established, metastatic tumors unleash a campaign of chemical cues that thwart the body’s defenses, hampering efforts to induce an immune response.

With the delta variant surging in the United States just as the school year begins, parents are wondering — and worried — about the threat to children. To address their fears, Marc Lipsitch, an epidemiologist and director of the Harvard T.H. Chan School of Public Health’s Center for Communicable Disease Dynamics, answered questions from journalist Elana Gordon, producer of “The World,” in an online discussion on Tuesday.

Although, as Gordon pointed out, cases are increasing rapidly, data on deaths and hospitalizations show that children continue to be spared the worst of the virus, Lipsitch said. “Compared to adults, children are much lower risk, even with delta, of getting severe disease,” he said. However, as the overall numbers rise, so do the risks. “A sliver of severe cases are in children,” he said, which means a growing number of cases will bring an increase in the number of seriously ill children as well.

Less clear, said Lipsitch, is whether delta itself is a driver of more severe illness. What we do know is that the variant is exponentially more transmissible. This represents a shift from earlier in the year, when the risk of vaccinated people transmitting the virus was considered minimal. To explain the change, Lipsitch cited the combination of delta being more contagious and better able to get through vaccine protection, and the possible waning of vaccine efficacy over time.

In any case, vaccines for children should not be rushed, he said: “The time being spent to ensure that the vaccines are safe and effective in children is well spent.” Although the delay makes it unlikely that children under 12 will be vaccinated this year, “it would be much worse to find that there was a side effect that we haven’t accounted for.

While it is primarily a respiratory disease, COVID-19 infection affects other organs, including the brain.

One of the first spectroscopic imaging-based studies of neurological injury in COVID-19 patients has been reported by researchers at Harvard-affiliated Massachusetts General Hospital (MGH) in the American Journal of Neuroradiology. Looking at six patients using a specialized magnetic resonance (MR) technique, they found that COVID-19 patients with neurological symptoms show some of the same metabolic disturbances in the brain as patients who have suffered oxygen deprivation (hypoxia) from other causes, but there are also notable differences.

It is thought that the disease’s primary effect on the brain is through hypoxia, but few studies have documented the specific types of damage that distinguish COVID-19-related brain injury. Several thousand patients with COVID-19 have been seen at the MGH since the outbreak began early this year, and this study included findings from three of those patients.

The severity of neurological symptoms varies, ranging from one of the most well-known — a temporary loss of smell — to more severe symptoms such as dizziness, confusion, seizures, and stroke.

“We were interested in characterizing the biological underpinnings of some of these symptoms,” says Eva-Maria Ratai, an investigator in the Department of Radiology and senior author of the study. “Moving forward, we are also interested in understanding long-term lingering effects of COVID-19, including headaches, fatigue, and cognitive impairment. So-called ‘brain fog’ and other impairments that have been found to persist long after the acute phase,” adds Ratai, also an associate professor of radiology at Harvard Medical School.

The researchers used 3 Tesla Magnetic Resonance Spectroscopy (MRS), a specialized type of scanning that is sometimes called a virtual biopsy. MRS can identify neurochemical abnormalities even when structural imaging findings are normal. COVID-19 patients’ brains showed N-acetyl-aspartate (NAA) reduction, choline elevation, and myo-inositol elevation, similar to what is seen with these metabolites in other patients with white matter abnormalities (leukoencephalopathy) after hypoxia without COVID. One of the patients with COVID-19 who showed the most severe white matter damage (necrosis and cavitation) had particularly pronounced lactate elevation on MRS, which is another sign of brain damage from oxygen deprivation.

Two of the three COVID-19 patients were intubated in the intensive care unit at the time of imaging, which was conducted as part of their care. One had COVID-19-associated necrotizing leukoencephalopathy. Another had experienced a recent cardiac arrest and showed subtle white matter changes on structural MR. The third had no clear encephalopathy or recent cardiac arrest. The non-COVID control cases included one patient with white matter damage due to hypoxia from other causes (post-hypoxic leukoencephalopathy), one with sepsis-related white matter damage, and a normal, age-matched, healthy volunteer.

“A key question is whether it is just the decrease in oxygen to the brain that is causing these white matter changes or whether the virus is itself attacking the white matter,” says MGH neuroradiologist Otto Rapalino, who shares first authorship with Harvard-MGH postdoctoral research fellow Akila Weerasekera.

Compared to conventional structural MR imaging, “MRS can better characterize pathological processes, such as neuronal injury, inflammation, demyelination, and hypoxia,” adds Weerasekera. “Based on these findings, we believe it could be used as a disease and therapy monitoring tool.”

The research was supported by the James S. McDonnell Foundation, National Institutes of Health and National Institute of Neurological Disorders and Stroke.

This Thanksgiving, it may be better to forget about even trying to pretend things are normal.

Instead, Karestan Koenen suggested acknowledging up-front that it will be different, difficult even. Family traditions will be disrupted, gatherings — when they occur at all — will be smaller and stranger, possibly in chilly November backyards, masked and a little awkward among those you know best. If there are empty seats at the table, the Harvard psychiatric epidemiologist said it’s important to communally remember loved ones lost during this COVID year.

Koenen, a professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health, addressed the upcoming holiday as well as the broader issue of mental health in the pandemic’s autumn and winter depths during a Facebook Live event Tuesday. Sponsored by The Forum at Harvard T.H. Chan School of Public Health and PRI’s” The World,” the event featured moderator Elana Gordon and viewers online asking Koenen questions about COVID-19’s mental health toll.

Koenen suggested trying to find ways to make this Thanksgiving something positive. Reach out to family members you might normally be sharing the day with via phone, videoconference, or even an online game. Plan an activity to give the day meaning, even if it is different from your annual rite. Koenen, for example, is foregoing what has been her family’s big yearly gathering but is considering alternatives like delivering meals to those less fortunate.

“[I’ve been] thinking about ways that I can give back, that might make me feel better and actually be helpful,” Koenen said. “And at the same time just recognizing that it’s going to be hard and that’s OK and thinking about creative ways that you can still do things that you used to enjoy.”

Americans are dealing not only with the coronavirus’ threat to their health, but also bereavement from lost family members and friends. Distancing and other public health measures have disrupted daily lives, millions are out of work, and the early government stimulus is running out.

There’s also been a summer of social unrest around racial-justice issues and one of the most bitterly contested presidential elections in memory. Despite all of that, she said, there’s been little support for mental health care from federal and state governments, even though there’s demonstrable need. Koenen said more Americans are reporting feeling depressed and anxious — an August survey by the CDC showed 40 percent of respondents suffering mental health impacts — and increasing numbers having seriously considered suicide.

Most of the response to this dimension of the crisis has been at the grassroots level, leaving clinics at maximum capacity and waitlists long. On the positive side, insurers have approved telehealth visits for therapy for the first time, helping providers reach patients reluctant to come to the office, and the market has created an array of interventions in the form of smartphone apps for things like mindfulness and yoga.

Ironically, Koenen said, if state and federal lawmakers are looking for the best intervention, it wouldn’t be targeted mental health legislation but rather another shot of economic stimulus. That’s because two of the biggest stressors in life are losing a job and the roof over one’s head. Providing assurance that won’t happen, she said, would go a long way toward easing the pressure on Americans.

On a personal level, Koenen said it’s important to understand that you have tools at your disposal to salve your own mental health. Acknowledge emotions and take care of the body with exercise and diet. Taking a short walk can help ease stress and boost health, while some might also consider taking a breather from society’s constant, aggravating drumbeat: Koenen takes breaks from the news and recently deleted Twitter from her phone. For those feeling exhausted and listless, she suggested thinking of things that made you feel better in the past and trying those.

Despite the dread that the coming cold, dark months may instill, Koenen said to keep reasons for optimism in mind. We know a lot more about the virus than we did during the spring surge; we know how to prevent its spread — even if we don’t always take that advice. We know a lot more about treating it and have more tools at our disposal to do so, with new treatments on the way. In addition, she said, surveys of health care workers show lower levels of negative mental health outcomes than expected at this point in the pandemic.

“We’ve been amazed, actually, at how resilient the providers are,” Koenen said.

In addition, she said, news about vaccines has been positive, highlighting a key lesson from earlier pandemics.

“I try to remind myself that there is a light at the end of the tunnel,” Koenen said. “The 1918 pandemic was horrible, and it ended. … There will be an end. We will not be in this forever, keep our eye on that.”