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.”

Harvard T.H. Chan School of Public Health’s Barry Bloom, Joan L. and Julius H. Jacobson Research Professor of Public Health, offers context about the news that two experimental vaccines appear to confer a high level of protection from the coronavirus.

Q&A

Barry Bloom

Chan School: Within the space of a week, we’ve heard about not one, but two potentially extremely effective coronavirus vaccines — one from Pfizer/BioNTech, reportedly 90 percent effective, and now one from Moderna, nearly 95 percent effective. How encouraged should we be about these preliminary results?

Bloom: I think we have to be very grateful that we have two vaccines off the bat that look to be relatively safe, except for some minor short-term inconveniences — such as fevers and muscle pain, that you get from almost every vaccine — and have a much higher degree of protection than I think most experts would have predicted.

There’s a lot of science still to be done. We don’t yet know how long the antibody responses last that correlate with protection. We know that the vaccines are producing an immune response against the [coronavirus’s] spike protein. But do we know that the key response is neutralizing antibodies — the type of antibodies that can stop infection? If that were the case, can we measure levels of neutralizing antibodies for every new vaccine and have a pretty good guess that they too will be 90 percent or 95 percent effective? In the case of the Moderna vaccine, there were 95 recipients of the placebo who got COVID disease, but there were five in the vaccine group. We’d love to know: Did those five fail to make neutralizing antibodies? Or did they make neutralizing antibodies, but not enough, or not efficiently enough?

This is a terrific first start and we’re just going to have to follow along to see how long the immune responses that appear to be protective will endure in the vast majority of the population.

Chan School: What do we know about the safety of these two vaccines?

Bloom: For safety, you really want to follow participants in trials for two years. We don’t have the luxury of doing that. We’re in the middle of a pandemic that’s killing people and hospitalizing people.

We know that the most serious adverse effects that come from vaccines primarily occur within two months after the last shot. So the Food and Drug Administration will be looking at the people who were vaccinated and followed over two months after their last shot. The hope is that there will not be any serious adverse effects. If that’s the case, I think we can be pretty confident that the vaccines are safe. But ideally the vaccine recipients should be followed up for rare adverse effects for two years in post-licensure surveillance.

Chan School: Should people keep taking public health precautions even when vaccines become widely available?

Bloom: There will still be lots of people who are not vaccinated in the first six months or year after vaccines are available, and they will have the capacity to transmit infection. And I would point out that vaccines are wonderful but they’re not perfect. You can overwhelm an immune response with a high level of virus or bacteria, so we will need to wear masks, we will need to be protective, even if we have vaccines, until a high proportion of people are immune.

There are three worries that the public health community has now. The first is, can the country get the various vaccines to people and keep records on when they need boosters and any serious adverse effects? Another is, now that some vaccines appear to be effective, will people take them? A third is, if they take them, will they engage in risky behavior and not wear masks and feel they can congregate in bars all night, where even with the vaccine they may not be protected and be at some risk? Those are challenges for communications, for education, and for political advocacy, best done at the community level to persuade people to protect themselves and everyone else, with or without a vaccine, until everybody is protected, by carrying out the simplest of public health measures.

Harvard Medical School scientists report they have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function.

The team’s work, described Dec. 2 in the publication Nature, represents the first demonstration that it may be possible to safely reprogram complex tissues, such as the nerve cells of the eye, to an earlier age.

In addition to resetting the cells’ aging clock, the researchers successfully reversed vision loss in animals with a condition mimicking human glaucoma, a leading cause of blindness around the world.

The achievement represents the first successful attempt to reverse glaucoma-induced vision loss, rather than merely stem its progression, the team said.

If replicated through further studies, the approach could pave the way for therapies to promote tissue repair across various organs and reverse aging and age-related diseases in humans.

“Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said senior author David Sinclair, professor of genetics in the Blavatnik Institute at Harvard Medical School, co-director of the Paul F. Glenn Center for Biology of Aging Research at HMS and an expert on aging.

Sinclair and colleagues caution that the findings remain to be replicated in further studies, including in different animal models, before any human experiments. Nonetheless, they add, the results offer a proof of concept and a pathway to designing treatments for a range of age-related human diseases.

“If affirmed through further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and to the fields of biology and medical therapeutics for disease at large,” Sinclair said.

For their work, the team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes — Oct4, Sox2, and Klf4 — that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors.

The treatment had multiple beneficial effects on the eye. First, it promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss in aging animals without glaucoma.

The team’s approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.

This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction — giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue.

Yet, whether DNA methylation drives age-related changes inside cells has remained unclear. In the current study, the researchers hypothesized that if DNA methylation does, indeed, control aging, then erasing some of its footprints might reverse the age of cells inside living organisms and restore them to their earlier, more youthful state.

Past work had achieved this feat in cells grown in laboratory dishes but fell short of demonstrating the effect in living organisms.

The new findings demonstrate that the approach could be used in animals as well.

Overcoming an important hurdle

Lead study author, Yuancheng Lu, research fellow in genetics at HMS and a former doctoral student in Sinclair’s lab, developed a gene therapy that could safely reverse the age of cells in a living animal.

Lu’s work builds on the Nobel Prize winning discovery of Shinya Yamanaka, who identified the four transcription factors, Oct4, Sox2, Klf4, c-Myc, that could erase epigenetics markers on cells and return these cells to their primitive embryonic state from which they can develop into any other type of cell.

Subsequent studies, however, showed two important setbacks. First, when used in adult mice, the four Yamanaka factors could also induce tumor growth, rendering the approach unsafe. Second, the factors could reset the cellular state to the most primitive cell state, thus completely erasing a cell’s identity.

Lu and colleagues circumvented these hurdles by slightly modifying the approach. They dropped the gene c-Myc and delivered only the remaining three Yamanaka genes, Oct4, Sox2, and Klf4. The modified approach successfully reversed cellular aging without fueling tumor growth or losing their identity.

Gene therapy applied to optic nerve regeneration

In the current study, the researchers targeted cells in the central nervous system because it is the first part of the body affected by aging. After birth, the ability of the central nervous system to regenerate declines rapidly.

To test whether the regenerative capacity of young animals could be imparted to adult mice, the researchers delivered the modified three-gene combination via an AAV into retinal ganglion cells of adult mice with optic nerve injury.

For the work, Lu and Sinclair partnered with Zhigang He, HMS professor of neurology and of ophthalmology at Boston Children’s Hospital, who studies optic nerve and spinal cord neuro-regeneration.

The treatment resulted in a two-fold increase in the number of surviving retinal ganglion cells after the injury and a five-fold increase in nerve regrowth.

“At the beginning of this project, many of our colleagues said our approach would fail or would be too dangerous to ever be used,” said Lu. “Our results suggest this method is safe and could potentially revolutionize the treatment of the eye and many other organs affected by aging.”

Reversal of glaucoma and age-related vision loss

Following the encouraging findings in mice with optic nerve injuries, the team partnered with colleagues at Schepens Eye Research Institute of Massachusetts Eye and Ear Bruce Ksander, HMS associate professor of ophthalmology, and Meredith Gregory-Ksander, HMS assistant professor of ophthalmology. They planned two sets of experiments: one to test whether the three-gene cocktail could restore vision loss due to glaucoma and another to see whether the approach could reverse vision loss stemming from normal aging.

In a mouse model of glaucoma, the treatment led to increased nerve cell electrical activity and a notable increase in visual acuity, as measured by the animals’ ability to see moving vertical lines on a screen. Remarkably, it did so after the glaucoma-induced vision loss had already occurred.

“Regaining visual function after the injury occurred has rarely been demonstrated by scientists,” Ksander said. “This new approach, which successfully reverses multiple causes of vision loss in mice without the need for a retinal transplant, represents a new treatment modality in regenerative medicine.”

The treatment worked similarly well in elderly, 12-month-old mice with diminishing vision due to normal aging. Following treatment of the elderly mice, the gene expression patterns and electrical signals of the optic nerve cells were similar to young mice, and vision was restored. When the researchers analyzed molecular changes in treated cells, they found reversed patterns of DNA methylation — an observation suggesting that DNA methylation is not a mere marker or a bystander in the aging process, but rather an active agent driving it.

“What this tells us is the clock doesn’t just represent time — it is time,” said Sinclair. “If you wind the hands of the clock back, time also goes backward.”

The researchers said that if their findings are confirmed in further animal work, they could initiate clinical trials within two years to test the efficacy of the approach in people with glaucoma. Thus far, the findings are encouraging, researchers said. In the current study, a one-year, whole-body treatment of mice with the three-gene approach showed no negative side effects.

Other authors on the paper include Benedikt Brommer, Xiao Tian, Anitha Krishnan, Margarita Meer, Chen Wang, Daniel Vera, Qiurui Zeng, Doudou Yu, Michael Bonkowski, Jae-Hyun Yang, Songlin Zhou, Emma Hoffmann, Margarete Karg, Michael Schultz, Alice Kane, Noah Davidsohn, Ekaterina Korobkina, Karolina Chwalek, Luis Rajman, George Church, Konrad Hochedlinger, Vadim Gladyshev, Steve Horvath, and Morgan Levine.

This work was supported in part by a Harvard Medical School Epigenetics Seed Grant and Development Grant, The Glenn Foundation for Medical Research, Edward Schulak, the National Institutes of Health (grants R01AG019719,R37AG028730, R01EY026939, R01EY021526, R01AG067782, R01GM065204, R01AG065403, R01EY025794, R24EY028767 and R21EY030276), and the St. Vincent de Paul Foundation.

Experts are working out a broad strategy to vaccinate Americans, with an eventual plan likely to prioritize health care and essential workers, as well as the vulnerable elderly and those with risk factors for severe disease.

Even with a strategy in place, however, the devil will very likely be in the myriad details if it is to be a success, experts said. For example, even if initial distribution is limited just to health care workers alone, that’s not an inconsiderable cohort: There are 20 million of them. If you want to add essential workers that’s another 60 million. In addition, even minor side effects that mirror the disease will sideline those who have to report that they are symptom-free before coming to work each day. That means, for example, a campaign that inoculates an entire intensive care unit’s workforce on the same day could have disastrous consequences if a significant number report symptoms the next day and can’t come to work.

Those examples, offered by Rochelle Walensky, chief of Massachusetts General Hospital’s Division of Infectious Diseases and a professor at Harvard Medical School, represent just some of the potential hurdles to be overcome in a vaccine rollout that promises to be not only vast, but also vastly complicated. However, experts said Friday that the vaccine rollout presents another opportunity to get the fight against the coronavirus right, despite the nation’s failure to take steps needed to prevent infection on a massive scale.

“I am struck by the challenges that we have ahead of us in thinking about rollout,” said Sarah Fortune, chair of the Department of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health, who appeared on a recent online panel with Walensky. “We, as a society, have not done necessarily the best job in terms of getting our prevention measures in place, our response measures in place, and now we face an enormous challenge but an enormous opportunity to get this next phase right.”

Panelists gave high marks for recently released early results of Phase 3 vaccine trials, saying the work has been conducted to high scientific standards, and the efficacy rates of 90 percent for the preventative from Pfizer, which applied for an FDA emergency use authorization on Friday, and 94.5 percent from one by Moderna Inc. are not only encouraging, but better than they had hoped. (AstraZeneca also reported early numbers on Monday, with effectiveness of up to 90 percent, depending on dosage.) That, together with reports of relatively minor side effects, makes experts optimistic that these and other vaccines may represent a light at the end of the pandemic tunnel.

But that light is still a way off, panelists cautioned. The Pfizer and Moderna vaccines have a couple of drawbacks: Both have to be stored in cold temperatures — the Pfizer vaccine at minus 70 degrees Fahrenheit, and Moderna’s at minus 20 — and both also require two doses to be effective. Those characteristics not only mean that regions with the equipment to handle the storage demands — urban areas — are likelier to get the vaccines first, but also that any vaccine education campaign should emphasize that people can’t abandon public health precautions after the first shot because they won’t be immune until shortly after their second shot, some five or six weeks later. Complicating all of that, Walensky said, is the fact that 25 percent of Americans don’t have a primary care doctor, the normal administrant of things like vaccinations.

“The day you get your vaccine is not the day you take off your mask,” Walensky said. “We’ll be in a much better place once the population is vaccinated, but we won’t be without masks for a while.”

Vaccines being tested by AstraZeneca and Johnson & Johnson were created by more traditional means than the messenger RNA preventatives of Pfizer and Moderna. Depending on the final outcome of those still-ongoing Phase 3 trials, those treatments will likely be more forgiving with regard to storage and have differing efficacy and side effects, which may make them better suited to distribution in parts of the country distant from minus 70-degree freezers.

Walensky and Fortune were joined by Barry Bloom, the Joan L. and Julius H. Jacobson Research Professor of Public Health, and epidemiology Professor Marc Lipsitch, who heads the Chan School’s Center for Communicable Disease Dynamics, at a Facebook Live event on Friday that was sponsored by The Forum at Harvard T.H. Chan School of Public Health and NPR.

With cases and hospitalizations soaring nationally, and a corresponding rise in deaths likely not far behind, Lipsitch said it’s important that we not let the prospects of a vaccine cause us to ease up on the public health steps we know will work and that, even now, can still make a difference in the course of the pandemic if adopted more widely.

“The future is in our hands,” Lipsitch said.

While much has been made of the potential problem of vaccine reluctance, Lipsitch said he thinks it may not be as high a hurdle as some surveys have shown. People may answer a hypothetical question one way but behave differently when friends and neighbors are getting vaccinated and resuming a semblance of normal behavior, he said.

It is, however, important that education campaigns include the fact that side effects from the vaccines are possible, panelists said. While the clinical trials so far haven’t found problems severe enough to call their safety into question, some who received the Moderna and Pfizer vaccines experienced soreness at the injection site, aching muscles, and fatigue that faded after a few days. It’s important, Lipsitch and Fortune said, that people are aware of that ahead of time, so resulting alarm doesn’t feed any anti-vaccine sentiment.

“There’s a tendency just to say, ‘Vaccines are safe. It’s no problem,’ and people don’t trust that if their lived experience is different,” Fortune said. “If we don’t have those conversations, then I think our credibility is eroded.”

Fortune said it’s important to talk not only about common side effects but also the potential for very, very rare side effects, such as neurological issues that caused some trials to be paused. Without transparency and openness, Fortune said, the vaccination campaign’s credibility will be damaged.

“If we’re not honest about that, the public can sniff those out and the credibility of the vaccination effort is undermined,” Fortune said.

After the vaccines are deployed, the studies won’t stop, Bloom said. Instead they’ll enter what he termed “Phase 4” — post-approval monitoring for rare side effects in a much broader population over a longer time than the original trials. They’ll also look for clues to other unanswered questions, primarily whether the vaccines not only prevent illness, but also prevent infection, and how long vaccine immunity lasts. Additional outstanding questions include how well the vaccine works in the elderly — the preliminary results released recently didn’t include data for subgroups — and children, on whom it is unethical, Bloom said, to even begin a trial until safety data is confirmed in adults.

“It’s not all over when the government issues an emergency use,” Bloom said. “The science has come through for us. The real challenge now is to get public acceptance of the vaccines that will be forthcoming.”

Public health officials have warned for months of the possibility of a serious post-Thanksgiving surge in COVID-19 cases. If it does happen, a Harvard epidemiologist says, the signs should become apparent this week, and she cautioned those who gathered with family and friends for the holiday to get tested or act under the assumption that they’ve been infected.

“We expect a rise in cases and a rise in deaths, unfortunately, over the next few weeks,” said Megan Murray, professor of epidemiology at the Harvard T.H. Chan School of Public Health and the Ronda Stryker and William Johnston Professor of Global Health at Harvard Medical School. “The main thing is to recognize that you could have been exposed and to assume you’re exposed — or test frequently. Assume one might be infectious rather than otherwise.”

Murray, who offered her prediction on Tuesday during a Facebook Live event sponsored by The Forum at Harvard T.H. Chan School of Public Health and PRI’s “The World,” balanced the dismal outlook for the immediate future with the likelihood that vaccine distribution could begin later this month. If the FDA approves the vaccine developed by Pfizer and Germany-based BioNTech — a step taken Wednesday by British authorities — distribution could begin very quickly, she said.

Infectious disease experts and epidemiologists tracking the coronavirus have warned that holiday gatherings have the potential to fuel virus transmission and boost an ongoing national surge that has seen 1.1 million new cases over the last seven days alone and pushed total deaths above 267,000. Those numbers, which continue to climb, have prompted dire predictions for the coming months, even as hope for an eventual end to the pandemic has risen with the apparent success of coronavirus vaccines.

Despite the mounting good news on vaccines, Murray said their distribution faces considerable hurdles, including such practical matters as how to store vaccines that need very cold temperatures in locales without the necessary equipment. Other issues include deciding who should be vaccinated first. States will have a significant say on this question, and the Centers for Disease Control and Prevention advisory board this week advised that front-line health care workers and vulnerable elderly should be first in line. Another issue, Murray said, is whether enough people are willing to be vaccinated to interrupt transmission. If just 50 percent of the population lines up, it would be “a real problem,” she said.

“It’s not easy, but it’s doable,” Murray said.

Murray gave the clinical trials high marks for scientific quality but pointed out that trials of such short duration don’t give researchers a sense of a vaccine’s characteristics over the long term, including how durable immunity will be.

Public health officials have likewise noted that it is also unclear whether it’s possible to carry the disease and infect others even if you are immunized.

It’s likely that a vaccine won’t be widely available for months, Murray said, and in the interim people are left to continue to deal with the daily reality of the pandemic. There is a new tool to help, however. An at-home test by Lucira Health Inc. is the first that provides results without having to send a sample to a lab. While the new test represents progress in the march toward rapid and frequent at-home testing — which has been suggested as a way to interrupt transmission and control the pandemic — Murray said because this test is only available by prescription and costs $50, it may be too pricey to be the answer for daily or weekly testing.

Overall, the testing landscape is “chaos,” Murray said, marred by inconsistencies where some get tested immediately and see results quickly, while others wait in long lines for tests and results take days. The situation, she said, illustrates a lack of public health governance.Will there be a serious post-Thanksgiving COVID surge?

“It can be done; it just hasn’t been done,” Murray said of a fair and fluid testing scheme.

Nobody was prepared for 2020, but a public talk on collective trauma in December 2019 was prescient. At Harvard Medical School’s live-streamed “Talk@12,” Bala Subramaniam, Ellison “Jeep” Pierce Associate Professor of Anesthesia, engaged in a conversation with Thomas Hübl, author and founder of the nonprofit The Pocket Project, which educates the public on the impact of collective traumas and trains professionals to facilitate events focused on healing. For the past 18 years, Hübl has helped hundreds of thousands of people spark dialogue and work toward restoring some of humanity’s worst transgressions. Since April, Hübl has been offering workshops to Harvard faculty and staff to help them meet the challenges of the COVID-19 pandemic. The next three-part series, “Mindfulness in Action: Leading & Communicating During Challenging Times,” offered through the Harvard Longwood Campus Office of Employee Development & Wellness, will begin on Jan. 26, 2021.

Q&A

Thomas Hübl

GAZETTE: Most of us would agree we are currently living in a time of collective trauma. What are your thoughts on how we should be thinking about what we are facing?

HÜBL: First I’d love to talk about collective trauma as traumatic events that a bigger part of a population, a nation, or the world, goes through collectively. This results in individual traumatizations or difficulties, but also, there is a shared cultural space, I believe, that we need to take into account. So often trauma is seen as a personal issue, and now we are talking about the collective or systemic dimensions. There are two phenomena: a very stressful current situation, like COVID-19, or the climate crisis, which is already intensifying. But these events meet in all of our shared history, which I refer to as the unintegrated parts of our shared past. That shared past is, in a way, like the sand in the engine in how we respond to the current crisis. I believe when we talk about collective trauma, we’re usually talking about the root causes that lead up to the current crises and the way we respond to a current crisis. They’re entangled.

GAZETTE: What are the effects of all these interconnected traumas on people?

HÜBL: When we look at a trauma there are two major sets of symptoms: One is hyperactivity, which comes with a tremendous amount of stress and reactivity, and the other one is numbness and indifference. So trauma comes with the underlying sense that we are separate, at least at times. And the more stress, which comes with two or three adversities in the system, the more trauma becomes intensified.

Integrated history is presence and unintegrated history is the past. When I refer to the past in this way, I mean the emotions, thoughts, and body sensations that overshadow my current experience. So how can we together create environments that help us to be truly present and relate more meaningfully to support our mutual past so it can become integrated into the present?

GAZETTE: I met you in 2017 when you came to speak at the MIT Innovation Center in Boston. You said then, “The Holocaust sits in the room with us right now.” And I couldn’t really say I heard that before or could really understand exactly how it sat, but I felt the truth in that. I wonder if you could say more.

HÜBL: I often say trauma is taking a loan from our own future. This means when I’m in traumatic situations, I’m so overwhelmed that I numb a part of myself to survive. So the trauma response is a very intelligent function within us, within our nervous systems, but there is a price. We need to pay back that debt along with interest, so to speak. In the last decades, the notion of trauma has become public knowledge, but it’s also important to learn about the attachment stress that hasn’t been integrated in children who have been neglected or abused. That adversity is still living deep in their bodies as adults. We just don’t know about it because it became so normal. So I might say “That’s me.” But it’s not me. That’s me in a hurt place. It’s very important to name it.

The same is true for millions of people who were in concentration camps and needed to dissociate. Some of the atrocities I’ve heard that people have survived are heartbreaking and unbelievable. People can survive those situations only heavily dissociated. But all that suppressed and fragmented information doesn’t disappear, and I think we are seeing more and more the transgenerational transmission of trauma.

In my work over the past 18 years, I’ve seen that whenever we touch the collective denial in a group and we meet the collective unconscious, so to speak, everyone in the room can sense this in their bodies and in the stress present in the room. After, we have seen the denial turn into a kind of release. I’ve observed that this form of denial can live in our nervous systems 24/7. We just aren’t aware of this because the focus of our consciousness is somewhere else.

GAZETTE: You said one of the symptoms of collective trauma is a chronic level of dissociation or numbness. Can you speak more about this?

HÜBL: First, it starts with honoring and respecting the function of dissociation and an appreciation of the capacity of the nervous system to dissociate from overwhelming experiences. Dissociation and overwhelm for a 2-month-old baby are completely different than for a 30-year-old. I think it’s very important that we don’t measure overwhelm just by what’s overwhelming to us. Overwhelm has many different flavors.

For example, when I read the news, how much can I really take in? I think that more often than not, we see things like wars or racist actions and it’s so hard to stay with it and feel what it means, what’s happening to the person, what’s happening in our society. So we might decide it’s better to be absent and only cognitively informed, rather than allowing ourselves to truly feel.

GAZETTE: In your book “Healing Collective Trauma: A Process for Integrating Our Intergenerational and Cultural Wounds,” you discuss the process that you do with groups. How does it work?

HÜBL: The process works on the principle that individual or systemic coherence is the power to integrate the fragmentation of the system. And sometimes the system doesn’t have enough inner coherence. So then we need to build this through group processes. And we need to supplement — just as a trauma therapist might do for a client — the missing element. We need an infusion of coherence into the group to integrate with the traumatization, which can lead to inner stability and structure, and help them develop a more fluid way to respond to the world. We have had many groups that focused on the Second World War and the Holocaust legacy in Germany and Israel. And then we expanded the topics to include colonialism, gender traumatization, racism in the U.S., and others.

GAZETTE: What kind of enthusiasm and perspective does one need to engage in such a challenging and heavy topic?

HÜBL: At first, the topic of collective trauma appears heavy, and this is because we are dealing with the major ethical catastrophes on this planet. But underneath trauma there’s always healing, which means an ethical restoration and ethical upgrade. Post-traumatic growth is an ethical realignment.

There have been uncountable genocides and wars, and all kinds of transgressions. When we come to the place of restoration, there’s a kind of illumination, a self-healing mechanism that heals the tissue of life. And I believe that collective healing will support individual healing and help us learn even more about individual health. We will see these two systems as unified, as they are. The collective and individual are not separate. They work as an interdependent system.

This conversation has been edited and condensed.

Mortality rates after cancer surgery declined for Black as well as white patients during a recent 10-year period, although the mortality gap between the two groups did not narrow, according to new research by Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard University investigators.

The findings, published online today by JAMA Network Open, present a mixed picture for health care policymakers: While postsurgical mortality rates have fallen for patients generally, more targeted efforts are needed to reduce disparities between Black and white patients undergoing such surgery, study authors say.

“Black Americans are likely to be diagnosed with more advanced cancer than whites and, historically, have had higher mortality rates following cancer surgery,” said lead author Miranda Lam of Dana-Farber, Brigham and Women’s Hospital, Harvard T.H. Chan School of Public Health, and Harvard Medical School. “Hospitals have put a variety of policies in place to improve surgical cancer care over the past 15 years. This study provided an opportunity to gauge the effects of those measures for patients in general and for Black and white [people] specifically.”

Investigators used national Medicare data to examine the trends in mortality rates for the years 2007-2016 in Black and white patients who had undergone surgery for any of nine major types of cancer. (The racial group was determined by patients’ self-identification in Medicare documentation.) The data covered 870,929 cancer operations in all.

The researchers found that national mortality trends following cancer surgery improved for Black and white patients by 0.12 percent and 0.14 percent per year, respectively. Because mortality rates for Black patients were higher to begin with than for white patients, the equal decline in rates for both groups meant the gap between them did not shrink.

“The findings tell us that even though policies designed to improve cancer surgery outcomes are working better for all patients, none of them have been specific enough to close the gap in mortality between Black and white [people],” Lam said. “It’s possible that part of the gap may be due to upstream and/or downstream issues from the surgery itself, such as late referrals which may lead to late presentation at time of surgery, fragmented follow-up after discharge, and limited resources in the community, and that different policies and interventions may be needed to address disparities in cancer surgery.”

The senior author of the study is Jose F. Figueroa of Harvard T.H. Chan School of Public Health, Brigham and Women’s, and Harvard Medical School. Co-authors are Katherine Raphael and Jessica Phelan of Harvard T.H. Chan School of Public Health; and Winta T. Mehtsun, E. John Orav, and Ashish K. Jha of Harvard T.H. Chan School of Public Health, Brigham and Women’s, and Harvard Medical School.

Obesity has been linked to increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive.

Now, in a study in mice, Harvard Medical School (HMS) researchers have uncovered a new piece of this puzzle, with surprising implications for cancer immunotherapy: Obesity allows cancer cells to outcompete tumor-killing immune cells in a battle for fuel.

Reporting in Cell on Dec. 9, the research team shows that a high-fat diet reduces the numbers and antitumor activity of CD8+ T cells, a critical type of immune cell, inside tumors. This occurs because cancer cells reprogram their metabolism in response to increased fat availability to better gobble up energy-rich fat molecules, depriving T cells of fuel and accelerating tumor growth.

“Putting the same tumor in obese and nonobese settings reveals that cancer cells rewire their metabolism in response to a high fat diet,” said Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS and co-senior author of the study. “This finding suggests that a therapy that would potentially work in one setting might not be as effective in another, which needs to be better understood given the obesity epidemic in our society.”

The team found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets. Because CD8+ T cells are the main weapon used by immunotherapies that activate the immune system against cancer, the study results suggest new strategies for improving such therapies.

“Cancer immunotherapies are making an enormous impact on patients’ lives, but they do not benefit everyone,” said co-senior author Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology in the Blavatnik Institute.

“We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity,” Sharpe said. “Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways.”

Haigis, Sharpe and colleagues investigated the effects of obesity on mouse models of different types of cancer, including colorectal, breast, melanoma and lung. Led by study co-first authors Alison Ringel and Jefte Drijvers, the team gave mice normal or high-fat diets, the latter leading to increased body weight and other obesity-related changes. They then looked at different cell types and molecules inside and around tumors, together called the tumor microenvironment.

Fatty paradox

The researchers found that tumors grew much more rapidly in animals on high-fat diets compared to those on normal diets. But this occurred only in cancer types that are immunogenic, which can contain high numbers of immune cells; are more easily recognized by the immune system; and are more likely to provoke an immune response.

Experiments revealed that diet-related differences in tumor growth depended specifically on the activity of CD8+ T cells, immune cells that can target and kill cancer cells. Diet did not affect tumor growth rate if CD8+ T cells were eliminated experimentally in mice.

Strikingly, high-fat diets reduced the presence of CD8+ T cells in the tumor microenvironment, but not elsewhere in the body. Those remaining in the tumor were less robust — they divided more slowly and had markers of decreased activity. But when these cells were isolated and grown in a lab, they had normal activity, suggesting something in the tumor impaired these cells’ function.

The team also encountered an apparent paradox. In obese animals, the tumor microenvironment was depleted of key free fatty acids, a major cellular fuel source, even though the rest of the body was enriched in fats, as expected in obesity.

These clues pushed the researchers to craft a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat diet conditions.

The analyses revealed that cancer cells adapted in response to changes in fat availability. Under a high-fat diet, cancer cells were able to reprogram their metabolism to increase fat uptake and utilization, while CD8+ T cells did not. This ultimately depleted the tumor microenvironment of certain fatty acids, leaving T cells starved for this essential fuel.

“The paradoxical depletion of fatty acids was one of the most surprising findings of this study. It really blew us away and it was the launch pad for our analyses,” said Ringel, a postdoctoral fellow in the Haigis lab. “That obesity and whole-body metabolism can change how different cells in tumors utilize fuel was an exciting discovery, and our metabolic atlas now allows us to dissect and better understand these processes.”

Hot and cold

Through several different approaches, including single-cell gene expression analyses, large-scale protein surveys and high-resolution imaging, the team identified numerous diet-related changes to metabolic pathways of both cancer and immune cells in the tumor microenvironment.

Of particular interest was PHD3, a protein that in normal cells has been shown to act as a brake on excessive fat metabolism. Cancer cells in an obese environment had significantly lower expression of PHD3 compared to in a normal environment. When the researchers forced tumor cells to overexpress PHD, they found that this diminished a tumor’s ability to take up fat in obese mice. It also restored the availability of key free fatty acids in the tumor microenvironment.

Increased PHD3 expression largely reversed the negative effects of a high-fat diet on immune cell function in tumors. Tumors with high PHD3 grew slower in obese mice compared to tumors with low PHD3. This was a direct result of increased CD8+ T cell activity. In obese mice lacking CD8+ T cells, tumor growth was unaffected by differences in PHD3 expression.

The team also analyzed human tumor databases and found that low PHD3 expression was associated with immunologically “cold” tumors, defined by fewer numbers of immune cells. This association suggested that tumor fat metabolism plays a role in human disease, and that obesity reduces antitumor immunity in multiple cancer types, the authors said.

“CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T,” Sharpe said. “These approaches need T cells to have sufficient energy to kill cancer cells, but at the same time we don’t want tumors to have fuel to grow. We now have amazingly comprehensive data for studying this dynamic and determining mechanisms that prevent T cells from functioning as they should.”

More broadly, the results serve as a foundation for efforts to better understand how obesity affects cancer and the impact of patient metabolism on therapeutic outcomes, the authors said. While it’s too early to tell if PHD3 is the best therapeutic target, the findings open the door for new strategies to combat cancer through its metabolic vulnerabilities, they said.

“We’re interested in identifying pathways that we could use as potential targets to prevent cancer growth and to increase immune antitumor function,” Haigis said. “Our study provides a high-resolution metabolic atlas to mine for insights into obesity, tumor immunity and the crosstalk and competition between immune and tumor cells. There are likely many other cell types involved and many more pathways to be explored.”

Additional authors on the study include Gregory Baker, Alessia Catozzi, Juan García-Cañaveras, Brandon Gassaway, Brian Miller, Vikram Juneja, Thao Nguyen, Shakchhi Joshi, Cong-Hui Yao, Haejin Yoon, Peter Sage, Martin LaFleur, Justin Trombley, Connor Jacobson, Zoltan Maliga, Steven Gygi, Peter Sorger and Joshua Rabinowitz.

This study was supported by the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (grants U54-CA225088, R01CA213062, R01DK103295, P01AI56299, 5F31CA224601 and T32CA207021), the Ludwig Center at Harvard Medical School, the Evergrande Center for Immunologic Disease, the Glenn Foundation for Medical Research and the American Cancer Society.

Amid the COVID-19 pandemic, it’s been easy to forget that a number of longstanding deadly global health problems remain with us, in some cases exacerbated by the outbreak. More people are hungry this year than last; childhood vaccinations and polio eradication have taken a step back; and AIDS, malaria, and TB continue to kill millions annually. In early December, a group of public health leaders recommended an “action agenda” for the incoming Biden administration that looked at the damage done to global health programs by the pandemic and plotted a path forward. Authors of the plan, published in The Lancet, include Harvard T.H. Chan School of Public Health Dean Michelle Williams, former Chan School Dean Barry Bloom, former Health and Human Services Secretary Donna Shalala — now a U.S. representative from Florida — and experts from Georgetown University, Emory University, and the University of North Carolina at Chapel Hill. The Gazette recently talked with Williams about what needs to happen.

Q&A

Michelle Williams

GAZETTE: Your comment in The Lancet mentioned “major setbacks” in reducing poverty, hunger, and disease. What is the status of global health today, and has the intense focus on COVID-19 globally hurt efforts in other areas?

WILLIAMS: Public health connects the dots between structural problems such as poverty and racism and a range of poor health outcomes, including increased risk of complications and death from COVID-19. The pandemic has put the spotlight squarely on the primacy of public health, so when speaking to the current status of global health, we must take into consideration the social determinants of health as well. Among the most critical areas in need of attention are education, food systems, environmental protection, economic stability, and behavioral and mental health.

GAZETTE: Clearly COVID-19 is the most pressing health concern today, both in the U.S. and globally. Are there resources available to address these more traditional health concerns and COVID at the same time, or have public health leaders been forced to choose?

WILLIAMS: We speak about the “COVID slide” in terms of the learning losses suffered by students, but the term can be applied to global health as well. The need to take an all-hands-on-deck approach to the pandemic has meant that other pressing public health efforts have been waylaid. In July, for example, the WHO released a report showing that prevention and treatment efforts for noncommunicable diseases have suffered during the pandemic.

And public health leaders are only human, after all. We are seeing exhaustion and burnout not just among frontline health care workers, but among public health experts as well. For many, there are only so many hours in a day to devote to causes other than COVID-19.

Long before the pandemic began, the U.S. public health system was severely underfunded but now the world has seen what a failure to invest in public health really means — and not just in lives lost. COVID-19 has also represented the greatest threat to value creation since World War II. Having now been brought to our knees, we need to stop making do with less and instead start investing more in public health infrastructures — not only for our collective well-being, but for our economic health as well.

GAZETTE: You and your co-authors mention a variety of steps to fight COVID-19. How, in your mind, can the U.S. most effectively help efforts abroad?

WILLIAMS: First and foremost, the U.S. should do everything it can to regain its leadership role in the world. This means leading by example, certainly, but also leading by investing in key initiatives that ensure our collective safety in a way that recognizes our interconnectedness. A threat anywhere is a threat to all of us, and this is true for viral threats as well as inattention to, say, planetary sustainability.

The incoming administration could make an immediate, meaningful impact across several areas, such as mobilizing partners to fund the U.N. COVID-19 Global Humanitarian Response Plan (GHRP) to re-engage with and strengthen WHO. WHO covers a whole range of global health threats, from maternal and child health to noncommunicable diseases and universal health care. However, WHO’s $5.8 billion biennial budget falls far short of its enormous global mandate. Of course, all of this in addition to working to ensure equitable worldwide distribution of COVID-19 vaccines.

GAZETTE: Given the U.S.’ dismal record fighting COVID-19, why is U.S. help needed and is its “leadership” even wanted?

WILLIAMS: With innumerable health crises worldwide, U.N. humanitarian appeals are facing massive deficits. As the wealthiest nation in the world, the U.S. has the means and the resources to help bridge this gap, and we must begin to do so as soon as possible. COVID-19 has proven U.S. interests are linked to global health security, and international cooperation related to COVID-19 could become a model for defeating other global health threats. We believe it’s important for the Biden administration to build on the tradition of U.S. humanitarian leadership, not just because the world needs it, but because the world is waiting for it.

GAZETTE: The Trump administration’s withdrawal from the World Health Organization was well-publicized. What are your recommendations for Biden with regards to WHO?

WILLIAMS: Placing WHO in this untenable position was enormously destructive. As Sen. Patrick Leahy put it this spring, “Withholding funds for WHO in the midst of the worst pandemic in a century makes as much sense as cutting off ammunition to any ally as the enemy closes in.” In reality, it’s even worse than that. It’s cutting off our own ammunition, our armor, and our battle plan — not to mention our reserves for the next conflict.

The U.S. must not add to the politicization of WHO. Instead, along with other member states, the U.S. should work toward maintaining the scientific integrity and neutrality of WHO. Biden can help strengthen WHO, not only for the response to COVID-19, but also for the full range of health issues. The fact is, most of the money the U.S. provides is not earmarked for emergency response or outbreak mitigation; instead, the majority of these funds go to essential global health programs like polio eradication, mental health initiatives, and cancer and heart disease prevention.

GAZETTE: Is reform of WHO needed? Are any of the Trump administration’s criticisms of WHO well-founded?

WILLIAMS: Reform of WHO is absolutely needed, for it was not designed to be independent, nor is it vested with the power or resources it needs. In fact, WHO’s annual budget is less than that of most university hospitals. And yes, WHO did make mistakes at the outset of the pandemic, but so did many other organizations and countries. As for China’s undue influence and the U.S. response of pulling the plug, in both cases, bold political bullying was in clear effect. Through reform and proper funding, the WHO can play an even more meaningful role in global health. Too many countries, especially poor ones, depend on WHO for medical guidance and supplies and need this assistance now more than ever.

I would also be remiss in not mentioning how delighted I am with the choice of Dr. Rochelle Walensky, M.P.H. ’01, to lead the CDC. Her appointment represents a renewed investment in the scientific and humanitarian assets that can be brought to bear on both domestic and global public health pursuits.

GAZETTE: You mention acute hunger doubling in 2020. Why is that and how much damage has been done to efforts to end hunger? Are there solutions?

WILLIAMS: The World Food Programme (WFP) projects a doubling of children and adults facing acute hunger globally by the end of 2020. Beyond illness and death, this virus has had a tremendous impact on the global economy, supply chains, food supplies, and access to humanitarian aid. COVID-19 has created a pandemic on top of a pandemic — food insecurity is a real and present threat all over the world. To address this crisis, we need long-term policy solutions to hunger, food waste, and climate change. Food donation is only one piece of the puzzle. Countries must bridge the gap between surplus food and the growing need for food for the most vulnerable. (One-third of all food produced for human consumption goes to waste, according to the Food and Agriculture Organization of the United Nations.)

In terms of solutions, we need a globally coordinated, multifaceted effort. Here in the U.S., a new stimulus bill must include an increase in SNAP benefits [formerly known as food stamps] for families — and such a bill should be passed as soon as possible. The safe reopening of schools and day care centers around the world would also make a huge difference, in part because so many children receive meals there. The pandemic has also caused a disruption in food supply chains that will need to be addressed on a global scale.

This spring, the Food and Agriculture Organization, the International Fund for Agricultural Development, the World Food Program, and the World Bank put out a joint statement calling for collective, international action to ensure that our food supply chains are not further threatened by the pandemic and that we begin work now to avoid future disruptions to our food and agricultural systems.

GAZETTE: What about slowed childhood vaccination efforts? That seems an area whose potential consequences are severe.

WILLIAMS: The slowing of childhood vaccination efforts will undoubtedly have long-term, dire consequences. COVID has disrupted the ability of global health care systems to deliver routine, preventative vaccinations; parents are also restricted by lockdowns and the fear of contracting COVID in a doctor’s office. The delayed transportation of much-needed vaccines is exacerbating the situation. Since March 2020, routine immunizations have been scaled back in the extreme. According to data from WHO and UNICEF, the lack of vaccinations has put at least 80 million children under the age of 1 at risk for diphtheria, polio, and measles. Child vaccination campaigns have also stalled, even as measles deaths increased by 50 percent from 2016 to 2019. And that’s before we even get to the U.S. The irony of having the most effective vaccination programs known to mankind attenuated during the pandemic is not lost on me. We can and must do better to assure the stability of programs like childhood immunization programs during times of duress.

All of this comes also before we’ve even talked about vaccinating children against COVID-19. There are so many issues we will need to confront in terms of introducing children and adolescents into clinical trials, and which age groups should get vaccinated and when. The last thing we need in our fight against the pandemic is to see an unnecessary delay in children receiving the COVID-19 vaccine.

GAZETTE: You call for an increase in the domestic research and development budget by $1 billion. Why is that needed? Hasn’t an enormous amount of money flowed into disease research this year?

WILLIAMS: It’s not just about the size of the research and development; it’s about where and how it’s spent in order to bring forward the best outcomes. There are areas in domestic research that have been chronically underfunded, and we are paying the price by not having strong evidence upon which to build public health programs and to generate new policies. For example, it has become very clear that we need an evidence-based approach in the behavioral and communication sciences. In particular, we need better data to inform how to overcome misinformation and, for example, how to promote vaccine acceptance. We can celebrate what the STEM fields have brought forward all we want, but if we don’t have the investments to inform vaccination campaigns that are confronted with the clear and present danger posed by misinformation, that is going to be a real public health challenge in the months ahead.

To accelerate scientific advances, we will need to increase domestic research and development funding by at least $1 billion annually, as the National Academy of Medicine has recommended. Research and development help us attack the world’s most pressing global health challenges and make major health improvements worldwide. We will always need cutting-edge technology, drugs, vaccines, and diagnostics — without these innovations, we will not be able to unleash science to combat global health risks. We must stay ahead of the curve, on infectious disease most especially.

GAZETTE: You also call for renewed focus on climate change, which Biden has indicated he supports, and on microbial drug resistance. Climate change has gotten a lot of attention recently. Why do you think microbial drug resistance is as urgent?

WILLIAMS: Antimicrobial resistance (AMR) threatens our ability to treat common infections and increasingly threatens the health of people both in the U.S. and globally. Back in 2016, the Review on Antimicrobial Resistance concluded that by 2050, drug resistance would claim 10 million lives a year and would wipe out a cumulative $100 trillion of economic output. Here in the U.S., the CDC has estimated that 2 million people will suffer drug-resistant infections every year, and that 23,000 will die — and those numbers are considered underestimates. In other words, we simply cannot afford to ignore AMR. The Biden administration should incentivize pharmaceutical and biotech companies to develop new antimicrobials and support multilateral efforts to confront antimicrobial resistance. In the context of pandemic preparedness, nothing is more important.

In fact, antimicrobial resistance represents one of the greatest public health challenges of the 21st century, one in which I am confident we will eventually prevail. We will do that in the same way we have historically triumphed over other public health threats, from infectious diseases to drunken driving: through a sustained, coordinated, multifront campaign.