Issuu

HARVARD

SPRING/SUMMER 2026

Thinking about thinking

Contents SPRING/SUMMER 2026 VOLUME 99, NUMBER 1

I N E VE RY ISSUE

2 COMMENTARY 54 POP QUIZ 55 IN MEMORIAM 56 ALUMNI REPORT

Features

HARVARD

medicine | THINKING ABOUT THINKING

HARVARD

SPRING/SUMMER 2026

Thinking about thinking

“ I think when we’re done, it will change how we as humans understand ourselves.” SEE PAGE 14

14 Flight Patterns BY CATHERINE CARUSO

BY MOLLY MCDONOUGH

The study of navigation in fruit flies is revealing fundamental principles about nervous systems

Emery Brown’s quest to understand the neuroscience of anesthesia

22 Putting AI in Context

38 Mind Maps

BY ALLISON ECK

BY AMOS ESTY

Researchers are working to make AI tools used for mental health support safer, smarter, and grounded in the full picture of a person’s life

A one-of-a-kind MRI scanner captures the brain’s wiring in unprecedented detail

28 Signals in the Silence BY MOLLY MCDONOUGH

In some patients who appear to be unconscious, brain activity reveals signs of awareness that the body cannot express COVER ILLUSTRATION BY SEBASTIAN KÖNIG

34 Going Under

HARVARD

Amos Esty Molly McDonough Patrick Mitchell/ModMag April Poole Maya Rucinski-Szwec Mike Campbell Catherine Caruso Bobbie Collins Stephanie Dutchen Allison Eck Christina Hernandez Sherwood Contributing Artists Timothy Archibald Valerie Chiang Gretchen Ertl Alex Gagne Nadia Hafid Matt Kalinowski Sebastian König Heather McGrath Oliver Munday Simon Simard Editor Associate Editor Design Copyeditor Digital Art Direction Contributing Writers

Review

Rounds Dean of Harvard

Medical School

A New View of Human Evolution

ALUMNI PROFILE: ROBERT FREEDMAN, MD ’72

An Olfactory Atlas 8

Shining a Light on Superbugs 11

AI Raises the Bar in Clinical Reasoning 12

Match Day

Rethinking the Roots of Schizophrenia 46 BOOKSHELF

Your Gut Is a Brain 48 BOOKSHELF

Books in Brief 50 STUDENT LIFE

The Class of 2026

Executive Dean for Administration Chief Communications Officer

George Q. Daley, MD ’91 Lisa Muto Laura DeCoste

Harvard Medical Alumni Association President President-Elect Vice President

Chair of Alumni

Relations

Louise Aronson, MD ’92 Tamara Fountain, MD ’88 Joanna Choi, MD ’09 Scott Aaronson, MD ’80 Amir Ameri, MD ’19 R. Sonia Batra, MD ’00 David Brown, MD ’97 Robert Daly, MD ’10 Tessa Gardner, MD ’72 Kalon Ho, MD ’87 Timothy Jenkins, MD ’92 Ben Robbins, MD ’16 Marc Sabatine, MD ’95 Kirstin Woody Scott, MD ’20 Ann Taylor, MD ’83 Laura Torres, MD ’88 Nancy Wei, MD ’06 Charmaine Smith Wright, MD ’03 A.W. Karchmer, MD ’64

Harvard Medicine magazine is published in print two times a year. Publishers: Harvard Medical Alumni Association and Harvard Medical School ©The President and Fellows of Harvard College Email: harvardmedicine@hms.harvard.edu Web: magazine.hms.harvard.edu ISSN 2152-9957 PRINTED IN THE U.S.A.

CO M M E N TARY

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HMS students put culinary medicine into practice during a recent cooking class held in the Elements Café at the Veritas Science Center. The students collaborated on a four-course, heart-healthy meal featuring fresh vegetables, legumes, and brown rice, dishes designed to be low in sodium, affordable, and, of course, tasty. The class is part of Culinary Medicine and Nutrition, an eight-week elective launched in 2024 that bridges the gap between nutrition science and practical cooking skills. Pictured, from left, students Anjali Mangla, Darlene Fung, and Brandon Lu, along with Helen Delichatsios, faculty lead for the course and an HMS assistant professor of medicine at Massachusetts General Hospital.

CREDIT

George Q. Daley Dean, Harvard Medical School

GRETCHEN ERTL

Sixty years ago, a small group of researchers founded the Department of Neurobiology at Harvard Medical School, the first department of its kind in the United States. The founding members had already established superlative reputations in their own fields, such as biochemistry, physiology, and neuroanatomy. What brought them together was the belief of Stephen Kuffler, the initial chair of the department, that the task of understanding the brain was so all-encompassing that it required a dedicated field of study, one that drew on a wide range of expertise. Today, the department is home to more than 30 faculty members, and Kuffler’s original vision has expanded to include genetics, molecular biology, high-resolution microscopy, computational modeling, and AI-driven analysis. Both within the department and at HMS-affiliated hospitals, a vast network of researchers and clinicians is focused on asking — and answering — profound questions about the brain and its disorders. The stories in this issue offer a glimpse into where our fascination with the brain is leading us. The research of Rachel Wilson is illustrative. Much of her remarkable career has been devoted to using the fruit fly to investigate some of the most fundamental questions in neuroscience, including how individual neurons and the connections between them give rise to behavior. At the Emerging Consciousness Program at Massachusetts General Hospital, Brian Edlow and Michael Young, MD ’16, are leading efforts to understand covert consciousness — a striking phenomenon in which patients with brain injury appear unresponsive on bedside exams but show signs of awareness on brain scans and other tests. Emery Brown, MD ’87, has spent much of his career exploring similar questions by studying states of consciousness in patients under anesthesia, and his research has reshaped our understanding of how anesthesia affects the brain and how it can be administered as safely as possible. In the field of mental health, access to care remains a persistent challenge, and existing treatments fall short for too many patients. Will AI help close that gap or deepen the crisis? The work of HMS researchers is essential to ensuring AI is harnessed effectively and implemented safely. Scientists are also using a one-of-a-kind MRI scanner, the Connectome 2.0, to visualize the brain in unprecedented detail. Their work offers the promise of creating more personalized treatments for certain neurological and psychiatric conditions. At HMS, we are planning for a future in which new modes of neuro scientific and neuropsychiatric research illuminate how healthy brains support cognition and emotional resilience, and we are laying the groundwork for prevention and treatment at scale. Our leadership in areas like connectomics is making HMS into the definitive institution for deciphering the human brain. Together, our faculty and alumni are revealing how the brain can be so effective at understanding itself.

News & Research from Harvard Medical School

On Our Minds

Review

CREDIT

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HARVARD MEDICINE

G E N E TICS

A New View of Human Evolution

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CREDIT

Since 2010, when the first genome-wide data was recovered from ancient human remains, research on ancient DNA has expanded scientists’ understanding of the relationships among people living in different time periods and regions of the world. But geneticists have struggled to use the technology to illuminate how natural selection has shaped human genetic variation. Now, a massive study of ancient DNA from nearly 16,000 people across more than 10,000 years in West Eurasia reveals that natural selection has shaped modern human genomes far more than previously thought. Prior to this research, studies of ancient human DNA had identified only about 21 instances of directional selection — the type of natural selection that occurs when a gene variant conferring an extreme form of a trait, such as lactose tolerance after infancy, proves advantageous enough that it rapidly rises in frequency across a population. The dearth of evidence suggested that directional selection has been rare since modern humans arose in Africa some 300,000 years ago and began to split into population groups around the world. The new analysis shows instead that directional selection has driven the spread or decline of hundreds of gene variants in West Eurasia since the end of the Ice Age and that selection has actually accelerated since people transitioned from hunting and gathering to farming. The new study, published in Nature in April, leveraged two important innovations. First, Harvard researchers spent seven years building a collection of DNA sequences from ancient people living in West Eurasia — what is now Europe and parts of the Middle East — that would be comprehensive enough in size and time span to support the work. They collaborated with more than 250 archaeologists and anthropologists to report new DNA data from 10,016 ancient individuals from West Eurasia, adding those to another 5,820 published ancient sequences and 6,438 modern ones. “This single paper doubles the size of the ancient human DNA literature,” says David Reich, a professor of genetics in the Blavatnik Institute at HMS, professor of human evolutionary biology at Harvard University, and senior author of the study. “It reflects a focused effort to fill in holes that limited the power of previous studies to detect selection.”

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Review

E P IDE MIOLOGY

PGIAM/CREATAS VIDEO+/GETTY IMAGES PLUS; OLIVER MUNDAY (OPPOSITE)

The second innovation was the development of computational methods to isolate the signal of directional selection from other causes of gene frequency changes, such as population mixing or random genetic fluctuations. This effort, led by Ali Akbari, first author of the study and a senior staff scientist in Reich’s lab, helped the researchers identify specific patterns. By the team’s calculations, directional selection accounted for only about 2 percent of all gene frequency changes. But that still encompasses a lot of DNA. Akbari identified 479 gene versions, or alleles, that were strongly selected for — or against — in West Eurasian genomes. He and colleagues were able to ascertain when and where some of the alleles began to spread through or be pushed out of that gene pool, as well as the overall rate at which selection seemed to occur. More than 60 percent of the individual DNA variants flagged as being strongly selected for — most of them single-nucleotide polymorphisms, or SNPs — have documented links with present-day human traits, such as red hair, light skin tone, higher risk of celiac disease, lower chance of male-pattern baldness, and lower risks of rheumatoid arthritis and alcoholism. In some cases, groups of SNPs appeared to be under selection together to influence polygenic traits. Certain changes raised the frequency of beneficial traits, including some that are interpreted today as “health span” characteristics like faster walking pace or as measures of social status and cognitive function, such as years of schooling, household income, and intelligence test scores.

This single paper doubles the size of the ancient human DNA literature. DAVID REICH

Other changes reduced the frequency of harmful polygenic traits, such as those interpreted today as reduced risk of bipolar disorder and schizophrenia, lower body fat percentage, and less susceptibility to tobacco smoking. Still other SNPs, including some that today are associated with susceptibility to tuberculosis and multiple sclerosis, at first rose and then fell in frequency over the millennia, indicating shifts in environmental pressures and the traits that prove beneficial, the team found. Some of the links seem logical, others counterintuitive, like the major genetic risk factor for gluten intolerance spiking after people began farming wheat. The authors stress that there are important factors to consider when interpreting these links. First, a variant’s present-day association with a trait does not necessarily explain why it spread in ancient populations. For example, a variant that now correlates with educational attainment must have meant something different in the Stone Age; a variant may raise risk of one disease while protecting against another; and some variants may have come along for the ride with others that were the true targets of selection. Additionally, genetic changes observed in West Eurasia were not necessarily unique to that region. Similar selective pressures may have acted on populations elsewhere. Reich expects future studies will show that shared selective pressures acted on some of the same core traits across diverse human groups, even as those groups split off and migrated to different parts of the world over tens of thousands of years. The team has made its data and methods freely available to spur follow-up analyses and new research. In addition to helping scientists explore other population groups around the world and further back in time, it’s possible the work could point scientists to new genetic factors that improve experts’ ability to assess disease risk, prevent illness, and develop new medicines. The possibilities are enticing for deepening scientists’ appreciation of human diversity, history, and health. “This paper shows how complex selection can be and provides an opportunity to consider the richness of variation in human populations,” Reich says. Stephanie Dutchen

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Exposome Exposed For decades, scientists have been unraveling the role of genes in determining disease risk. But genes only tell part of the story. The other part comes from the exposures a person experiences during their lifetime and the body’s biological response to them, which together make up what scientists call the “exposome.” A team led by HMS scientists has conducted what may be the largest study quantifying the links between exposures and health outcomes. Testing more than 115,000 links, the researchers found that single environmental exposures explained less than 1 percent of the variation in outcomes but also that the effect increased when considering multiple exposures at the same time. For example, a mix of 20 particular exposures — including trans fats, persistent pollutants, and vitamin E levels — explained 43 percent of the variation in people’s triglyceride levels, which is a risk factor for heart disease. While there’s no smoking gun, say the researchers, small exposures can matter a little bit, and exposures matter more when considered in aggregate. The team has made its data and software available so that other research groups can investigate connections revealed by the study.

p PATEL C ET AL., NATURE MEDICINE, MARCH 2026

N E U ROBIOLOGY

Our sense of smell relies on hundreds of types of olfactory receptors in the nose, each of which detects specific subsets of odor molecules. For decades, researchers have been able to identify some of these smell receptors but have struggled to map out how they are organized spatially. Now, in a mouse model, HMS scientists have created the first detailed map of smell receptors in the nose. Analyzing gene expression in about 5.5 million neurons in more than 300 mice, the team discovered that neurons are organized into tight, overlapping, horizontal stripes from the top of the nose to the bottom based on the type of smell receptor they express. This highly organized receptor map was consistent across mice and mirrored the organization of smell maps in the brain. Researchers have previously observed similar overlap between receptor maps in the brain and sensory organs for vision, hearing, and touch. The team is now studying smell receptors in human tissue to understand to what degree the map is consistent across species. Such understanding will inform efforts to develop treatments for loss of smell, such as stem cell therapies or brain- computer interfaces.

A microscope photo of a cross section of a mouse nose. The mouse was genetically modified to express green fluorescent protein in smell neurons. A small subset of dying neurons is labeled in red.

p BRANN D ET AL., CELL, APRIL 2026

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DATTA LAB; OLIVER MUNDAY (OPPOSITE)

An Olfactory Atlas

Review

14.5%

87%

The prevalence of high blood pressure in adults aged 20 to 44, many of whom are likely unaware of their diagnosis — a small increase since 2009

The rise in hypertensionrelated cardiovascular deaths between 2000 and 2019

2011 The year that heart failure-related mortality started rising after a long period of steady decline

3x higher

CAR DIOLOGY

—

U.S. Heart Health by the Numbers

The prevalence of heart failure in Black adults aged 35 to 64 compared to white adults in the same age group

Despite decades of medical breakthroughs, the fight against heart disease in the United States may be stalling. A new report led by Rishi Wadhera, an HMS associate professor of medicine at Beth Israel Deaconess Medical Center, reveals that a long-term trend of improvement in cardiovascular outcomes has not only slowed but, by several measures, started to backslide. The analysis — the first in a new annual series from the Journal of the American College of Cardiology (JACC) — uncovers a brewing crisis among younger adults, a widening ruralurban divide, and a stubborn reality that many patients still lack access to effective therapies and high-quality care.

1 in 2 The approximate proportion of American adults living with high blood pressure, a figure that changed little between 2009 and 2023 despite the availability of effective therapies

Some good news?

53% The massive drop in mortality from coronary artery disease achieved between 2000 and 2020 through better risk management

2 in 3 The proportion of U.S. adults with hypertension who actually receive medical treatment, a figure that has stagnated for about 15 years

1 in 2 The proportion of U.S. adults with coronary heart disease who received the full recommended combination of medical therapies from 2017 to 2020

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HE ALTH ECONOM ICS

PH OTOME DICINE

Shining a Light on Superbugs Boutique Medicine Is Booming

DATTA LAB

How is the growth in concierge and direct primary care transforming the U.S. market for primary care? A new analysis led by researchers at HMS, Oregon Health & Science University, and Johns Hopkins University showed that from 2018 to 2023 the number of such practices grew by 83 percent and the number of clinicians in those types of practices increased by 78 percent. Doctors in both concierge and direct primary care practices typically see fewer patients than doctors in traditional models do, and they offer easier access. Patients pay for services and common prescription drugs out of pocket, often at reduced prices. Patient fees can range from thousands to tens of thousands of dollars a year for concierge membership and several hundred to thousands of dollars a year for direct primary care membership. Concierge practices bill insurance; direct primary care practices do not. These alternative models can be attractive to physicians seeking more autonomy, smaller patient loads, and less administrative hassle. But they raise concerns about exacerbating primary care workforce shortages and inequities in access to care. The study also found that the nature of these types of practices is changing. For example, nurse practitioners and physician assistants increased from 33 to 40 percent of the workforce in these practices. Independent ownership of these practices fell from 84 to 60 percent, and there was a 576 percent increase in practices with corporate affiliations. This last finding is surprising, the researchers say, because autonomy and independence are primary motivators for physicians transitioning into concierge or direct primary care practice. Yet just as more doctors make this career shift, these practices are increasingly corporate-owned.

p ZHU J ET AL., HEALTH AFFAIRS, DECEMBER 2025

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Review

Laisa Negri (left) and Jeffrey Gelfand

MASS GENERAL VACCINE AND IMMUNOTHERAPY CENTER; OLIVER MUNDAY (OPPOSITE)

Bacteria may be among the simplest life forms, but they’re increasingly outsmarting the drugs designed to curtail them. Since the development of penicillin ushered in the “antibiotic era” in the mid-20th century, says Jeffrey Gelfand, an HMS professor of medicine, part-time, at Massachusetts General Hospital, the overzealous use of these drugs “has led to many, many different mechanisms of antimicrobial resistance,” making infected wounds increasingly tough to treat. That’s why Gelfand and other researchers have been exploring a new approach to tackling these so-called superbugs: blue light. Picture a device that looks something like a bandage made of silicone. Its active ingredient is not an antibiotic or other drug, but tiny LEDs that shine at specific wavelengths. The new tool is based on more than a decade of research in preclinical models from Mass General’s Wellman Center for Photomedicine suggesting that blue light can curtail even the most stubborn bacterial pathogens. If proven viable in people, it could add a rare new option to a shrinking arsenal of defenses against drug-resistant infections. Light can exert powerful effects on living things. A light’s wavelength, the distance between the peaks of its waves, determines how we perceive its color, as well as how much energy each light particle, or photon, carries. Those photons interact with matter in different ways depending on how energetic they are. Ultraviolet light, for example, can damage cells’ DNA, making UV very effective at killing bacteria and treating skin infections, says Tianhong Dai, an HMS associate professor of dermatology at Mass General. But UV exposure also damages DNA in human cells, which can lead to harmful side effects like cancer. Earlier in his career, Dai explored using UV light to fight drug-resistant microbes. But as he became frustrated by its side effects, he came across research showing that blue light could curtail the bacteria that cause acne. Blue light sits closer than UV to the low-energy end of the electromagnetic spectrum and is not directly absorbed by cells’ DNA. Dai decided to investigate whether and how blue light might combat wound-infecting bacteria that antibiotics struggle to kill. In one of his first studies on antimicrobial blue light, published in 2013, Dai and colleagues beamed blue light on MRSA — an

antibiotic-resistant bacterium that causes staph infections — in a petri dish before examining its cells with a powerful microscopic camera. Through the lens, they saw an apocalyptic landscape: broken cell debris, cracked cell walls, and mangled insides. The light had seemingly shattered the bacteria. Testing the light on MRSA-infected skin abrasions in mice, they were the first to demonstrate that blue light could halt the growth of the drug-resistant microbe in an animal model. Dai went on to conduct dozens of studies pitting blue light against microbes. He demonstrated its effectiveness against Acinetobacter baumannii, for example, a superbug notorious for infecting combat-related wounds in soldiers, as well as fungal pathogens that thrive alongside bacteria in sticky biofilms. He learned that blue light exploits a convenient vulnerability found in many microbes: high levels of specific molecules, called porphyrins, that carry out key functions. These molecules happen to absorb light very strongly in the blue range of wavelengths. When light hits porphyrins, they get “excited,” says Dai, triggering reactions

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that release bursts of reactive oxygen species into cells. Those highly reactive oxygen molecules crack cells’ membranes, break their DNA, and oxidize proteins and lipids. Damage piles up until the cells die. What makes this process so interesting, Dai says, is that it appears less likely than antibiotic drugs to induce resistance. In contrast to traditional antibiotics, which tend to exploit a precise mechanism in the bacteria, the reactive oxygen molecules generated by blue light damage many processes and parts of cells at once, so there’s no simple way for microbes to evolve an escape route. Dai has even conducted experiments to try to induce resistance but found no evidence that the treatment’s effectiveness waned over time. Another perk of blue light is that animal cells appear to be relatively unharmed by the mechanisms it exploits. Human cells contain far lower levels of porphyrins than most bacterial cells — making them less susceptible to the light — as well as better defenses against reactive oxygen species. While blue light’s effectiveness in the lab has been impressive, researchers caution that it’s still several CONTINUED ON P.10

I M M U N OLOGY

Anything that can reduce microbial resistance will ultimately result in lives being saved, money being saved, misery being saved. JEFFREY GELFAND

Cell Reception

p LU G ET AL., CELL, FEBRUARY 2026

Green fluorescent tags delivered by the new CyCLoPs tool reveal cells that responded to a specific cytokine (IL-17A) in a mouse model.

Tianhong Dai (right) and student Yingbo Zhu use bioluminescence imaging to assess the efficacy of antimicrobial blue light in treating bacterial wound infections.

steps away from use in the clinic. Some blue light devices are already approved and used to treat acne in humans, but “those types of devices use lower power than the one we’re studying now,” says Laisa Negri, an HMS research fellow in dermatology who developed the silicone blue light device alongside Gelfand. Last year, Negri, Gelfand, and colleagues tested their treatment on MRSA infected wounds in a swine model — the closest correlate to human skin. It was the first published study of this type of more powerful, superbug-killing device in a large animal model. Attaching the silicone bandage atop the wounds, they beamed blue light for about an hour and a half each day. By day two, MRSA levels in the treated wounds dropped by more than 99.99 percent compared with wounds that weren’t treated. The researchers say these findings bring the device a step closer to clinical trials in humans. Additional devices being developed by HMS scientists could soon follow, even delivering the treatment to places light typically doesn’t reach. For example, Dai and colleagues have been developing an ear CONTINUED FROM P.9

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tube embedded with a tiny glowing laser that could one day be used to combat the bacterial biofilms that cause recurrent ear infections in children who receive the tubes. Other researchers are finding ways to amplify blue light’s effects. Mei X. Wu, an HMS professor of dermatology at Mass General, found that pairing a gentle dose of blue light with a topical solution containing the active ingredient in oregano essential oil eliminated around 80,000 times more MRSA bacteria than blue light alone. The compound works as a “pro-photosensitizer,” Wu says, magnifying the production of reactive oxygen molecules in bacteria beamed with blue light. These treatments represent important progress in a broader, multipronged strategy that will be needed to fight the mounting threat of superbugs. “We don’t expect blue light will replace antibiotics; rather, it will augment antibiotic therapy,” says Gelfand. “Anything that can reduce microbial resistance will ultimately result in lives being saved, money being saved, misery being saved. It behooves us to find every mechanism we can possibly use to achieve that goal.” Molly McDonough

HUH LAB (FAR LEFT); COURTESY OF TIANHONG DAI; OLIVER MUNDAY (OPPOSITE)

Immune cells use molecules called cytokines to communicate with other cell types. These messages play many important roles in protecting the body and maintaining a stable, steady internal environment. Scientists have known a lot about how, when, and why immune cells create and send out cytokines, but they have had a tougher time identifying which cells receive those signals as well as how the cells respond. Now, HMS and MIT scientists have created a new family of tools that fills the gap. Called cytokine cellular locating platforms (CyCLoPs), the tools allow researchers to tag the cells that respond to specific cytokines. It works like a biological highlighter: When a cytokine binds to its receptor on a cell, the tool tags the cell with a fluorescent marker. The research could provide a transformative view of immune responses and could inform new treatments for infectious diseases, cancer, allergies, and autoimmune conditions.

Review

ART IF IC IAL INT E LLIGENCE

AI Raises the Bar in Clinical Reasoning In one of the largest-yet studies to compare artificial intelligence and doctors across a wide array of clinical reasoning tasks, a team of physicians and computer scientists at HMS and Beth Israel Deaconess Medical Center evaluated whether a large language model (LLM) could do what doctors do every day: review a messy patient chart and decide what to do next. Their study, published April 30 in Science, found that the LLM, OpenAI’s o1-preview model, outperformed physicians across many common clinical reasoning tasks. Its performance indicated that long-standing ways of testing medical AI may no longer capture current systems’ performance, pointing to a possible turning point for the field. “We tested the AI model against virtually every benchmark, and it eclipsed both prior models and our physician baselines,” says co-senior author Arjun (Raj) Manrai, an assistant professor of biomedical informatics in the Blavatnik Institute at HMS. The results make the case that medical AI is ready to be studied the same way as all new medical interventions: through carefully controlled, rigorous, prospective clinical trials in real care settings. Manrai noted that these trials are necessary to evaluate whether, how, and where such tools should be deployed in clinical care as aids to human practitioners. Incorporating standards first created in the 1950s to train and evaluate doctors, the CONTINUED ON P.12

I thought it was going to be a fun experiment but that it wouldn’t work that well. That was not at all what happened. ADAM RODMAN

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CA MPUS NEWS

Match Day 2026 researchers compared how the model performed against hundreds of clinicians. The comparisons included case study diagnostic challenges, reasoning exercises, and real emergency department cases. In one experiment, the team tasked the LLM with evaluating patients at various points in an emergency department setting, ranging from early triage to later admission decisions. At each stage, the model was given only the information available at that point — drawn directly from actual electronic health records — and asked to generate likely diagnoses and recommend next steps. Unlike in prior studies, the team did not smooth out the messiness of real-world care before testing the AI. The emergency department cases were presented exactly as they appeared in the electronic health record. At the early decision points in the real-world emergency department cases, the model matched or exceeded attending physicians in diagnostic accuracy, surprising even the researchers. “I thought it was going to be a fun experiment but that it wouldn’t work that well,” says co senior author Adam Rodman, an HMS assistant professor of medicine at Beth Israel Deaconess. “That was not at all what happened.” The researchers emphasize that their results do not suggest that AI systems are ready to practice medicine autonomously, or that physicians can be removed from the diagnostic process. “A model might get the top diagnosis right but also suggest unnecessary testing that could expose a patient to harm,” says Peter Brodeur, an HMS clinical fellow in medicine at Beth Israel Deaconess and the study’s co-first author. “Humans should be the ultimate baseline when it comes to evaluating performance and safety.” CONTINUED FROM P.11

p BRODEUR P ET AL., SCIENCE, APRIL 2026

On March 20, students stood with their classmates, family members, friends, and teachers, taking pictures, holding bouquets of flowers, and excitedly awaiting noon, when a bell would ring and let them know it was time to open the envelopes containing the names of the institutions where they had matched for their residencies. HMS student Caroline Diggins, joined by her parents and brother, said she felt grateful for her time at the School. “It’s been such a great journey, and amazing people have supported me along the whole way,” Diggins said. “Today feels like a reflection of all of that.” At noon, Jennifer Potter, interim dean for students at HMS, rang the bell. Cheers and joyful tears erupted as students discovered where they will be spending the next several years. Friends and family embraced. Some jumped for joy. Others called loved ones who couldn’t attend in person to share their big news. Megan Goh learned she had matched with the Harvard Combined Orthopaedic Residency Program, her top choice. “It’s been a dream come true,” Goh said. “I could not have asked for a better Match Day. I’m so thankful for my education here, and I’m excited to continue to be part of the Harvard family.” In addition to professional goals, many have personal reasons for hoping to match at a particular hospital. For Lois Owolabi, matching in general surgery at Beth Israel Deaconess Medical Center meant she’d be able to stay in the Boston area with her fiancé, Naahanna Akahara, a second-year resident in obstetrics and gynecology at Brigham and Women’s Hospital. “That was a prayer, to be here with her in Boston,” Akahara said. In this year’s National Resident Matching Program (NRMP), 145 HMS students matched in clinical specialties. Almost half of those (66 students) will continue their training at HMS-affiliated hospitals, while others will join leading institutions across the United States. In addition, three students will train in oral and maxillofacial surgery, and nine will pursue nonclinical paths. Jiwoo Lee was thrilled to learn she had matched at Beth Israel Deaconess in vascular surgery.

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“I spent a month at Beth Israel on rotation, and all the mentors and attendings and residents are people who I wanted to be as a surgeon when I grew up,” Lee said. “That’s where I wanted to be, and I wanted to train with them.” Lee was joined by her parents and her boyfriend, Jules Allbritton-King, a student in the Harvard-MIT Program in Health Sciences and Technology (HST). “I’m not matching for another four years, but the energy today is palpable,” Allbritton-King said. After the celebration, he planned to go upstairs to the lab of Guillermo Garcia-Cardeña, an HMS associate professor of pathology at Brigham and Women’s, where Allbritton-King is working on a medical engineering project involving cardiac organoids. Matthew Reynolds said he was extremely excited to match with Brigham and Women’s in internal medicine. “I just love the way that in internal medicine, you really get exposure to all areas of medicine,” Reynolds said. “You can care for all aspects of a patient, holistically.” Reynolds was also pleased his match meant he could stay in the Boston area with his partner, Deanna Gutierrez, an MBA candidate at the MIT Sloan School of Management. They have been together since they were undergraduates at Harvard College. “I’ve seen his journey,” Gutierrez said of Reynolds. “He’s worked so hard for this accomplishment.” Match Day serves not only as a moment of celebration, but also as a reminder of the responsibility that accompanies the practice of medicine, reflected HMS Dean George Q. Daley in brief remarks before the noon bell. “Becoming a physician is a privilege,” Daley said. “You’re going to have the opportunity to impact lives at their most vulnerable. With that privilege comes an enormous responsibility. But balancing the gravity of that privilege will be tremendous joy. There is just nothing more wonderful than using your talents for the betterment of others, for the health and well-being of all.” “We are so proud of you at Harvard Medical School for all that you have done while you’ve been here and all that you are going to do in your future careers,” Daley concluded. Mike Campbell

Review

157

Total number of students

Nonclinical

Oral and maxillofacial surgery

145 Clinical

STEVE LIPOFSKY

Matches at HMS-affiliated hospitals

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F L I G H T THE STUDY OF NAVIGATION IN FRUIT FLIES IS REVEALING FUNDAMENTAL PRINCIPLES ABOUT HOW NERVOUS SYSTEMS OPERATE BY CATHERINE CARUSO PHOTOGRAPHS BY SIMON SIMARD

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P A T T E R N S

Rachel Wilson points to one of a series of “fruit fly holders” framed on her office wall (see the full display on page 21). The plastic and metal platforms were specially designed by Wilson and her lab members to position flies during experiments. The display, which she describes as a “living museum,” contains 20 years of instruments arranged chronologically, from crude, early versions built with petri dishes and tinfoil to increasingly sophisticated versions made with 3D-printed and custom manufactured parts. Each one improves on the last and represents an incremental but critical step forward for the research. Eventually, Wilson says, she will add newer versions — they just have to be invented first.

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It’s a typical afternoon in the Wilson Lab. Graduate students and postdocs are scattered throughout the open space, peering through microscopes on lab benches, scanning multimonitor computer setups, working at specialized “fly rigs.” Bits of conversations create a constant, low hum. The fruit flies — the dark, sesame-seed-sized stars of the show — are easy to miss at first. Each colony is contained in a glass tube with food at the bottom and a papery white stopper at the top. The insects cling to the sides, occasionally hovering in place or leaping to a new position. The tubes are stored upright in carefully labeled cardboard boxes stacked on every surface. At the center of the action is Rachel Wilson herself, first huddled next to a fly rig, coaching a research technician step-by-step on how to insert an electrode into an individual neuron in a fruit fly brain to record electrical activity — a technique she pioneered in the early 2000s. Later, she works with a graduate student at a computer, offering suggestions as they carefully talk through the results of a recent set of experiments. Wilson’s hands-on, highly engaged approach in the lab is one reason she has been able to tackle such big questions in neurobiology. Over the past 20-plus years, her detailed, mechanistic work in fruit flies has pushed forward an entire field of neuroscience by revealing fundamental principles of how nervous systems operate. “She’s one of these generational scientists who thinks extremely incisively about both the details and the big-picture frameworks,” says Yvette Fisher, a former postdoctoral fellow in Wilson’s lab who now leads her own lab at the University of California, Berkeley. This ability has allowed Wilson, the Joseph B. Martin Professor of Basic Research in the Field of Neurobiology in the Blavatnik Institute at HMS, to pivot from studying olfaction and other sensory systems to navigation, and to venture into a newer field of neuroscience called connectomics — while making major contributions to each area along the way. “Rachel has a deeply ingrained internal compass that guides her toward new and amazing science,” says John Tuthill, also a former postdoc, who now leads a lab at the University of Washington. But for all of the progress she has made, Wilson herself seems focused on what she doesn’t know. She describes the current state of neuroscience as a vast but somewhat disjointed collection of facts: Researchers have identified many key genes in neurons and figured out many of the functions of the proteins they encode, and they have linked brain regions to general processes such as memory, planning, and language. “But we still don’t really understand how neurons work together to implement the big tasks that the nervous system needs to do,” Wilson says. “We do not really understand for any organism how neurons give rise to thoughts and intelligent behaviors.” It is clear that there is no end to the questions she wants to pursue — questions that move her ever closer to her overarching goal: figuring out how the basic building blocks of the nervous system work together to shape what an animal does. Eventually, she hopes to reveal the nervous system’s overarching logic, including how behavior arises from computations made by neural circuits. “Our goal is to understand the nervous system with the same level of detail and explicitness that an engineer seeks in trying to understand an electronic device that they did not design,” she says.

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“ Our sense of body position is close to our notion of selfhood, so it’s an issue that touches on our fundamental sense of ourselves.” Rachel Wilson (right)

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How To Study a Fruit Fly At the heart of Wilson’s research is what’s called a fruit fly rig (shown above): a complicated-looking apparatus consisting of a microscope, cameras, and various metal implements surrounding a fruit-fly-sized virtual reality setup. Most lab members have their own rigs tailored to their specific projects. At the center of the rig, a fly is tethered in place while it walks on a small ball — a spherical treadmill floating on air. As the fly alters its speed and direction, sensory cues move in sync with the insect to give it the impression that it is navigating through the world. Often, these cues are in the form of visuals projected onto a panoramic screen, or sometimes as wind or odors piped in at antennae level. At the same time, researchers use two main approaches to record activity from genetically labeled neurons in a fly’s brain. The first is the patching technique that Wilson developed, in which an electrode is placed on an individual neuron and directly records electrical activity from that neuron, which spikes when the cell becomes active. The second is a technique that involves pumping photons into the fly brain, where a specific population of neurons has been modified to light up when calcium — a proxy for electrical activity — enters the cells as they become active. Together, the techniques offer the fine-scale precision of studying activity at the single-neuron level and the broad perspective of watching activity in an entire population of neurons. The researchers also use optogenetic and chemistry-based techniques to perturb neural networks — activating, silencing, or disrupting neurons to see how the fly responds. “Our specialty is to design and interpret tricky experiments that allow us to observe neural activity in fruit flies and correlate it with their behavior,” Wilson says. “We know what a fly is thinking not just based on what they do in the environment but also based on watching activity in their brain.”

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Sensory Systems In 2002, two years into her postdoctoral fellowship at the California Institute of Technology, Wilson was feeling burned out. And for good reason: She was trying to study a locust species, but her experiments were frustrating. Even though Wilson had figured out how to make stable electrical recordings from individual neurons in a living locust, she couldn’t consistently target neurons of interest with those recordings. She was stuck. So, Wilson and another postdoc, Glenn Turner, now a group leader at Howard Hughes Medical Institute’s Janelia Research Campus, approached their advisor with a risky pitch: They would take a three-month hiatus from their projects to study fruit flies. Fruit flies seemed promising because they readily perform many of their typical behaviors in the lab — likely because they’re opportunists that evolved to live alongside humans in a wide range of environments. Moreover, Norbert Perrimon, the James Stillman Professor of Developmental Biology at HMS, and his team had recently figured out how to insert yeast genes into fruit flies to label cells of interest with green fluorescent protein. Neuroscientists quickly adopted the approach and began developing strains of fruit flies in which specific neurons were labeled to glow green. Suddenly, Wilson had a way of repeatedly targeting the same specific neurons in a fruit fly brain to record electrical activity — she just needed to place an electrode on the glowing green cells. Once she did that, she could monitor activity in those neurons in real time while presenting flies with various sensory stimuli. “Thoughts and behaviors unfold very rapidly, but by putting electrodes directly on neurons, we can record things that are superfast, which opens up all sorts of new questions,” Wilson says. The technique that Wilson and Turner brought to fruit fly research, known as in vivo patch-clamp recording, or “patching,” was a technical breakthrough “that basically laid the path for our entire field,” Tuthill says. It became the foundation of research in Wilson’s future fly lab and many others. Fruit flies have a storied history as a scientific model. In 1909, geneticist Thomas Hunt Morgan began breeding the fruit fly (Drosophila melanogaster) because of its rapid reproduction, large number of offspring, and ability to thrive in the lab. Soon his fly experiments had produced the first solid evidence that genes are located on chromosomes. From there, scientists created thousands of specialized lines of fruit flies genetically modified to label different cells. In 2000, they published the first complete fly genome. In recent decades, research groups have focused on developing neuroscience-specific tools, including fly lines in which specific subsets of neurons are genetically labeled and a detailed wiring diagram of the entire central nervous system — a comprehensive list of neurons and their connections. The fruit fly is a relatively simple organism, with a central nervous system made up of around 160,000 neurons (by contrast, the human brain has around 86 billion). This makes it feasible to understand a fly’s nervous system in its entirety. Yet despite their simplicity, fruit flies exhibit complex behaviors in the lab: They can learn about new environments, often returning to locations of interest based on memory; they also sing, fight, perform courtship rituals, and sleep. When Wilson launched her lab at HMS in 2004, the tools for studying neurons in fruit flies were limited to a few hundred genetic lines — covering only a fraction of the fly’s 160,000 neurons — and

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Fly Minds

Wilson discusses ongoing research with doctoral students Janki Patel (center) and Pablo Reimers (left).

i ncomplete wiring diagrams. At first, her focus was on the flies’ sense of smell. “The olfactory system has a really orderly organization that made it pretty easy to come up with hypotheses, even if we didn’t have many genetic tools and didn’t understand how all the neurons were connected,” Wilson says. The lab discovered that many of the same principles govern the architecture of olfactory systems in both fruit flies and mammals, even though fruit flies detect odors with antennae and mammals use a nose. For example, in both cases, olfaction starts with odor molecules in the environment binding to receptors in the antennae or nose. The signals from those receptors are pooled together in the brain, allowing the organism to quickly and accurately sense the odor. Over time, as the number of genetic lines increased, the Wilson Lab expanded to more sensory systems, including hearing. Again, the researchers found evidence of overlap between fruit flies and mammals — this time in the form of the map of auditory space in the brain, which for both consists of different stripes of brain space that correspond to different sound frequencies. “Even though some of the details are really different, the basic principles are remarkably similar,” Wilson says, illustrating how evolution can independently “solve” problems the same way in unrelated lineages — a process called convergent evolution.

Turning Toward Navigation After nearly a decade of studying sensory systems in fruit flies, Wilson pivoted to studying a different type of behavior: navigation. Wilson defines navigation as purposeful locomotion through space. The topic initially attracted her because it is easy to get fruit flies to navigate in the lab. Moreover, their movements can be completely captured by simple measurements such as speed, distance, and direction. Perhaps most importantly, researchers can get a sense of what a fly is thinking based on where it goes. “Navigation is a way to study thought by studying behavior,” Wilson says. “When you watch a fruit fly navigate in virtual reality while tracking its neural activity, you can literally see in its brain the moment it becomes confused or decides to change direction.” Fisher, who has continued studying fruit fly navigation in her own lab, sums up the two big questions driving the research: “Where am I? And given that, where should I go next?” Traditionally, Fisher says, learning experiments in neuroscience have centered on training an animal to do a specific task a specific way. By contrast, navigation is a form of unsupervised learning — learning in which there is no right or wrong answer. Thus, she thinks navigation could provide a foundation for understanding more complicated unsupervised learning tasks performed by other species or even machine-learning systems.

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To date, one of the Wilson Lab’s biggest contributions to understanding navigation in fruit flies relates to the internal compass that underpins a fly’s sense of direction. In parallel with other labs, the team characterized the navigation regions of the fruit fly brain, which house a group of specialized neurons, aptly named “compass” neurons, arranged in a circle. Much like a physical compass, these neurons track which way a fly is pointed — for example, north versus south. What this looks like, Wilson says, is a hot spot of neural activity that moves around the compass based on a fly’s current orientation. Wilson and Fisher showed how the compass can anchor to visual landmarks so that it accurately tracks the fly’s orientation over time. In later work, Wilson and colleagues found that the compass can anchor to wind direction and that it can rapidly learn the arrangement of different landmarks in an environment. Wilson also discovered two other types of navigational neurons that track the direction a fly is moving in the environment to create a map of travel direction in the brain. The hot spot of activity in this “travel map” is the same, regardless of whether the fly is pointed north and moving forward, or whether it is pointed south and moving backward: In both cases, it is traveling north. In this work, Wilson turned to collaborators at the Caltech who designed behavioral experiments in which a fly walks around a circular maze searching for a reward it had previously found. Interfering with the inputs to the “travel map” prevented a fly from finding the reward again, further revealing how this system helps the fly navigate through space. “This research shows how the brain can keep track of the direction you’re moving in, regardless of the direction you’re facing,” Wilson says. “It suggests a remarkably elegant and simple solution to what seems like a complicated problem.” Head-direction cells — the non-insect equivalent of compass neurons — have been identified in a wide range of other animals, including rodents, bats, primates, and birds. Recently, other researchers applied similar methods to studying navigation in zebrafish. They discovered that the fish have an internal compass system that works much the same way as it does in fruit flies. “This is a really exciting finding because it means that a vertebrate is navigating in a similar way,” Fisher says. Wilson adds that it’s becoming increasingly clear that sense of direction in insects and mammals has the same basic organization,

and so the principles of navigation her lab is uncovering in fruit flies may be directly relevant to various mammal species. The big question, Wilson acknowledges, is how navigation in fruit flies relates to humans. She points out that scientists don’t yet fully understand how navigation works in humans, including how humans perceive their body position in space. Therefore, it’s impossible to say exactly what will be similar in the human and insect navigation systems. That said, Wilson is betting that there are some important similarities. In humans, problems with spatial navigation and body sensing can be an early sign of certain neurodegenerative disorders, and so any clues from fruit flies may prove valuable in helping clinicians to understand what goes wrong when patients lose their sense of space. “Our sense of body position is close to our notion of selfhood, so it’s an issue that touches on our fundamental sense of ourselves,” she says. The Wilson Lab is also studying other facets of fruit fly navigation. In a 2024 Nature study, the researchers described how the compass and steering regions of the brain work together. They uncovered three groups of neurons that help a fruit fly correct its path after being knocked off course: one that nudges it to the right, another that nudges it to the left, and a third that tells it to turn around completely. Another project is investigating the role of dopamine in a fly’s internal compass. The researchers discovered that when a fly enters a new environment, dopamine floods into its compass neurons as it moves around, priming the compass to be quickly recalibrated based on new directional cues. The findings suggest a new function for dopamine in the brain, beyond its established involvement in motivation and learning. Now, doctoral student Pablo Reimers is studying a type of neuron that seems to play a central role in this recalibration process. “We think this is a way to link learning to action so that the compass system can be plastic and flexible when new information becomes available,” Wilson says. As the Wilson Lab and other researchers continue to fill in the details of fruit fly navigation, Wilson expects that a complete picture of the behavior will begin to emerge. “I think we’re going to have a satisfying understanding of the logic that organizes navigation within my lifetime, and that will be a huge achievement for the field,” Wilson says.

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AMY STERLING FOR FLYWIRE/PRINCETON UNIVERSITY

A view of a wiring diagram that captures the connections between neurons in the central nervous system of a fruit fly. The diagram shows how neurons in the fly's brain (at left) connect to those in its body (at right) via its spinalcord equivalent, called a nerve cord. The comprehensive map is allowing researchers to explore questions about how neural circuits control behavior.

Fly Minds

Connecting Connectomes Wilson first began collaborating with Wei-Chung Allen Lee, an associate professor of neurobiology at HMS and associate professor of neurology at Boston Children’s Hospital, over a decade ago, when Lee’s field — connectomics — was taking off. Connectomics involves creating maps of all the connections between neurons in the nervous system, and the compact nervous system of a fruit fly was a natural fit. “It’s hard to overstate how well connectomics has slotted into all the amazing fruit fly anatomy and genetic tools,” Fisher says. “People were already labeling really precisely defined neurons, and when connectomics came, those things linked up.” Starting with the olfactory system, Wilson and Lee began creating fruit fly connectomes — comprehensive wiring diagrams of the connections between neurons. Recently, Wilson, Lee, and a large international team of collaborators published the most complete fruit fly connectome to date: a map of all the connections between neurons in a fruit fly central nervous system (which includes its brain and connected spinal cord equivalent, called a nerve cord). Previously, Wilson says, researchers had produced separate connectomes of a fruit fly brain and nerve cord but hadn’t combined them. “We were basically looking at a disembodied brain,” Wilson says. “Putting the two together and seeing the organization of the whole central nervous system was a revelation.” The research is changing the way Wilson and other fruit fly researchers approach their work. Now, they use the connectome as a

“ I’m just not sure that we, as neuroscientists, have fully grappled with the implications of what we already know.”

starting point to make detailed predictions about neurons and neural circuits and design experiments that test those predictions. “Basically, researchers go to the connectome, find their neurons of interest, look at all the inputs and outputs, and form new hypotheses,” Lee says. “The connectome is a hypothesis-driving engine because everything is there — as others have also said, there are no neurons that can be overlooked.” A Challenging Finding With a connectome of the fruit fly central nervous system in hand, Lee and Wilson agree that the future research directions are endless. To begin, they have started to analyze the patterns of neural connectivity that produce coordinated control of all “output cells” of the nervous system — namely, motor neurons, internal organs, and endocrine cells. What they found surprised them. Instead of being controlled by some higher-level brain region — a centralized controller, or what Wilson calls the “flyunculus,” in a nod to the human homunculus — all of these output cells are most influenced by sensory signals in the same body part. For example, the motor neurons that control feeding are most influenced by sensory cells in the mouth region, whereas the motor neurons that control a specific limb are most influenced by sensory cells in that limb. Coordinated behavior seems to emerge from interactions between local modules. “What’s clear from our anatomical analyses is that there is no flyunculus,” Wilson says. “The main influences on any body part are the local signals from that body part, and high-level brain regions are not required for most actions.” Wilson and Lee think that the higher-level regions of the brain, such as the navigation regions Wilson studies, are essentially “supervising” behavior rather than directly driving it. Wilson draws an analogy to a large manufacturing company: Decisions about changing the speed of a machine on the production line are primarily made by the operator, with some influence from the next operator over. The middle manager might indirectly weigh in on the decision, and the CEO would only make a loose suggestion. The finding highlights the power of studying fruit flies, Wilson says, in that researchers now have a complete wiring diagram of the central nervous system and the tools to watch activity in almost any brain region. “It’s all in front of you — there’s nowhere to hide. You can’t fool yourself by saying ‘Well, this brain function probably happens somewhere else,’ ” Wilson says. Wilson adds that she tends to think about her identity as being tied to a homunculus that lives in her brain — a little person making decisions about what she should do next. So she finds the idea of decentralized decision-making somewhat destabilizing. “Looking at the fruit fly nervous system, it’s pretty clear that there is no ‘me,’ which actually threatens my sense of who I am,” she says. If decentralized control doesn’t turn out to apply to humans and other species, then Wilson wants to know where in the animal kingdom a centralized sense of self emerges. And if it is confirmed more broadly, it may signal something even bigger for the field. “Forcing ourselves to be very explicit about what we think might be happening here is intellectually bracing in a way that you cannot imagine,” Wilson says. “I’m just not sure that we, as neuroscientists, have fully grappled with the implications of what we already know.” It’s yet another example of how Wilson and other fruit fly researchers are moving closer to a broader goal: understanding the fruit fly in its entirety by characterizing its every neuron, connection, and behavior. “I think when we’re done, it will change how we as humans understand ourselves,” she says. “It’s profound, and I feel proud to be contributing to this effort.” CATHERINE CARUSO IS A SENIOR SCIENCE WRITER AND EDITOR IN THE HMS OFFICE OF COMMUNICATIONS AND EXTERNAL RELATIONS.

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MILLIONS OF AMERICANS ALREADY TURN TO AI FOR MENTAL HEALTH SUPPORT. RESEARCHERS ARE WORKING TO MAKE THESE TOOLS SAFER, SMARTER, AND GROUNDED IN THE FULL PICTURE OF A PERSON’S LIFE. BY ALLISON ECK ILLUSTRATION BY SEBASTIAN KÖNIG

Putting AI in Context

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On November 18, 2025, John Torous, MMSc ’18, testified before Congress about an issue that has drawn bipartisan concern even in a polarized political climate. “AI tools that were never designed for mental health support are being used by millions of Americans each week,” he told a subcommittee of the House Committee on Energy and Commerce. “In late October, OpenAI reported that over 1 million users per week have conversations with ChatGPT that include explicit indicators of potential suicide planning.” But, he added, “we have to acknowledge that millions of Americans also find some degree of support from AI, and our research has shown that there can be benefit.” Torous, an HMS associate professor of psychiatry at Beth Israel Deaconess Medical Center, occupied the middle seat on a three person panel of witnesses for a hearing on the risks and benefits of AI chatbots. His position on the panel seemed appropriate: Torous, a dual board-certified psychiatrist and clinical informaticist, is at the center of an increasingly complicated, high-stakes debate around the safety and efficacy of AI chatbots for mental health support. ChatGPT and Google's Gemini chatbot are already used regularly by hundreds of millions of people. About one in six U.S. adults use AI chatbots at least once a month to find health information and advice. And a poll conducted in November 2025 found that 12 percent of U.S. adults say they are likely to use AI chatbots for mental health support in the next six months. Despite the extraordinarily wide use of these tools, they still aren’t regulated consistently or in a manner that promotes safety and privacy. Torous’ aim during the hearing was to temper the palpable anxiety in the room with a message of cautious optimism. He pointed out that Congress has the power to mandate standards the NIH or FDA could apply to AI tools used for mental health purposes. With AI chatbots in their relative infancy, Torous knows he has a chance to make a difference by convincing Congress to act. Yet, critical as these issues are, Torous is on a mission to raise awareness of the possibilities for a transformation of mental health care: AI chatbots that are thoroughly investigated through clinical science, that are used with human guides, and that are linked with technologies like wearable sensors have the potential to reconceptualize mental health care. Sabine Wilhelm, the HMS Donovan-Chien Family Professor in the Field of Psychology and director of the Center for Digital Mental Health at Massachusetts General Hospital, is likewise cautiously optimistic about the opportunities created by AI. Media headlines tend to highlight the frightening aspects of AI chatbots, she says. “But these articles often don’t distinguish between the tools that have been specifically developed by clinicians and researchers for patients, versus general-purpose chatbots. These are two very different things.” Torous, Wilhelm, and other clinicians and researchers are taking on the issue of AI in mental health care on two fronts: first, trying to ensure that general-purpose AI chatbots are made as safe as possible, and second, working to create new tools that harness AI specifically for mental health treatment. “I think there’s going to be a quiet revolution in reconceptualizing mental illnesses,” Torous says. “For example, we may be able to better understand and stratify certain mental health conditions. And that can lead to new treatments, repurposed drugs, and better care. I’m excited about that bigger picture.”

Mitigating Risk Anyone who has engaged with OpenAI’s ChatGPT or Anthropic’s Claude has experienced its warm, supportive responses. But researchers have found that this behavior can veer into sycophancy all too often, a phenomenon designed to increase user retention. “Technology was built to optimize engagement, not mental health,” says Nina Vasan, MD ’13, a clinical assistant professor of psychiatry at Stanford University and director of Stanford Brainstorm, which partners with companies like Pinterest, Apple, and TikTok to redesign their platforms with mental health in mind. Repeated affirmations have, over time, been linked to AI mediated delusions — often referred to as AI psychosis — and in a few extreme cases, suicide. Even in less dire circumstances, AI chatbots have blind spots when it comes to responding to users’ crisis moments, and they routinely violate mental health ethics standards even when they are prompted to use evidence-based psychotherapy techniques. Vasan’s work has suggested that current large language models (LLMs) are not ready to act like autonomous mental health assistants, but their usefulness varies by disorder. She says that LLMs can be game-changing in helping healthy people better understand their thoughts, emotions, and behaviors, and they show real promise for depression and anxiety. But nearly all models can struggle to recognize manic, psychotic, or obsessive content, especially if expressed gradually. “We’ve seen real progress on content related to suicide and self-harm, but these platforms still routinely miss the full picture of someone in crisis,” Vasan says. But, she adds, “There are huge therapeutic benefits to integrat-

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John Torous

AI and Mental Health

“ I think there’s going to be a quiet revolution in reconceptualizing mental illnesses.”

ing AI into regular care, and in some ways, AI alone can reach patients that traditional care never could.” Torous notes that the discourse around AI chatbots has mostly ignored the possible association between AI-mediated delusions and a person’s predisposition to mental illness. “There’s a subtype of people who clearly should not be using AI chatbots — just like there are patients at high risk for schizophrenia who should not be using cannabis,” he says. But Torous also thinks there are solutions to these problems. Throughout the congressional hearing, he pressed for increased NIH funding to support high-quality, longitudinal studies on the mental health benefits and dangers of AI chatbots, which are based on LLMs — a type of generative AI that is evolving more quickly than research can keep up with. As importantly, he said that companies need incentives to securely share information with regulators and researchers. Torous and his fellow panelists argued that certain specific steps could go a long way toward making AI chatbots safer when used for mental health purposes. These might include, for example, instituting crisis protocols, decreasing chatbot sycophancy, enacting federal privacy laws, and making training data transparent. Without that data, any attempt to understand what’s happening when people use chatbots, Torous told the subcommittee, is like “looking at shadows and patterns of shadows.” Congress, he said, can help remove those shadows by recasting the light — that is, by facilitating greater transparency and trust through gathering evidence and building consensus between model developers, hospitals, researchers, and lawmakers. In her work with Stanford Brainstorm, Vasan focuses on holding model developers accountable. “Every physician takes an oath: First, do no harm,” she says. “We want technology companies to take that same oath.”

personalized over the course of the treatment,” Wilhelm says. “That’s why we were excited to see if ChatGPT can possibly help.” The researchers put together a set of simulated, hypothetical patient vignettes and fed them to ChatGPT, asking it to generate exposure hierarchies for each of the patients. Then they compared the results to what clinicians at Mass General who have expertise in OCD came up with. The plans were evaluated by experts on OCD who were not involved in creating them. Although the real clinicians’ exposure hierarchies were deemed more thorough and better suited to the patients’ needs, “it was clear there was promise” for ChatGPT’s handiwork, says Wilhelm, especially because she and her colleagues hadn’t fine-tuned the model at all. Models that have been tweaked for specific purposes and tested by clinicians could expand access to care and effectively serve patients. “But we have to make sure that we involve clinicians and have ethical guidelines to make sure that this doesn’t go sideways.” Building on this work, Wilhelm and her colleagues are currently developing clinician‑ and patient‑facing AI tools tailored for mental health care, with the goal of safely supporting personalization of evidence‑based treatments. Integrating Context Like Wilhelm, Torous resists the “for or against” framing of typical public discourse around AI. With his undergraduate degrees in electrical engineering and computer science and a master’s degree in biomedical informatics from HMS, it’s not surprising that he has an Sabine Wilhelm

Meeting Needs Wilhelm acknowledges the risks created by the use of general-purpose chatbots to address mental health issues. But she also thinks there are costs to ignoring the opportunities afforded by AI, especially given barriers to receiving care amid a continued nationwide mental health crisis. “Right now, people are turning to these tools for emotional support at an unprecedented scale,” she says. “Patients like the convenience, and they like the feeling of being heard. We have to meet them where they are.” Wilhelm’s work centers on digital interventions for obsessivecompulsive disorder (OCD). She was the senior author of a study published last year in which she and her colleagues assessed how well ChatGPT could assist patients and clinicians with creating exposure hierarchies: a series of exercises — akin to a treatment plan — in which a clinician exposes a patient to a situation that they might otherwise avoid due to the anxiety it provokes. In these scenarios, the patient should also refrain from any self-soothing rituals that have helped in the past (hand-washing after touching a doorknob they perceived to be contaminated, for example). “Clinicians are often very good at educating patients about their disorder, but they struggle a bit with the exposure and response prevention piece — especially how to make it more challenging and

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Ipsit Vahia

analytical and data-driven personality. And for most of his career, he has applied that analytical approach to figuring out how to adopt technology safely for mental health treatment. About 10 years ago, Torous led the American Psychiatric Association’s technology evaluation framework, created to help guide informed decision-making around the use of smartphone apps in clinical care. Subsequently, he served on the FDA’s Digital Health Advisory Committee. Taken together, these experiences make Torous one of the foremost experts in the United States in evaluating new mental health tools. The key to unlocking the ultimate promise of AI in mental health care, says Torous, is context. Rather than replace therapists and physicians, AI chatbots can assist them by making sense of continuous data, such as step count, hours and quality of sleep, and cortisol levels — that is, the dynamic context of a person’s mental health situation. In Torous’ vision, separate streams of chatbot conversations, biosensor readings, and human relationships feed into a single, vast reservoir of experience; on their own, each stream doesn’t carry much water, but together, they gain the depth needed to understand the complexity of a person’s mental health. A multimodal approach — built to read these converging currents at once — could push the field of mental health far beyond its current capabilities. “Imagine someone writing a goodbye letter to colleagues,” Torous says. “Is this a planned retirement or a suicide note? The chatbot doesn’t know.” But if the person had a wearable sensor feeding the LLM real-time behavioral and physiological data (such as changes in phone activity or time spent at home), it might be able to detect clinical patterns more readily. In fact, Torous and colleagues found that when they fed 153 mock clinical cases with this kind of “digital phenotyping”

Personalizing Care Ipsit Vahia, an HMS assistant professor of psychiatry and chief of geriatric psychiatry at McLean Hospital, is also excited about the possibility of combining AI tools with information about the larger context of a person’s health. “Technologies can give us entire dimensions of important information about a person’s mental health that are just not possible without the use of sensors,” he says. Vahia heads the Technology and Aging Laboratory at McLean, which occupies a niche space in medicine. “There is a fairly substantial research body on AI in mental health, but it’s still quite limited when it comes to older adults,” he says. He believes that digital phenotyping can supplement care of adults with dementia by helping caregivers and physicians evaluate their experiences of pain, which can affect their mental health and overall well-being. Especially for people who cannot verbally report pain — and for whom pain often manifests as aggression or agitation — caregivers and providers can find themselves grappling with incomplete information about a patient’s needs. With colleagues, Vahia has found that digital phenotyping can help detect subtle behaviors (changes in gait or frequency of movement, for example) that lead to more objective assessments of pain. Apps that measure vocal intonation or facial expressions (which can contain mini signs of pain) could theoretically amass data that is then funneled into an LLM engineered to recognize and respond to those nuances, potentially leading to early intervention and even preventive care. Vahia says this is a perfect example of how AI can be deployed for very precise and sophisticated clinical applications. “In aging care, one size seldom fits all. Every older adult has circumstances, physical conditions, medication sensitivities, and social environments that are really unique to them — each person’s reality is so different,” Vahia says. “Rather than measure 100 people at the same time in a research study, AI is allowing us to measure 100 distinct individuals, one at a time, relative to themselves. And that is far more precise and impactful.”

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data (a term Torous coined) into GPT‑4o, the model correctly identified worsening depression 100 percent of the time and worsening anxiety 83 percent of the time, although its overall accuracy across all tested clinical patterns was 52 percent. If AI could ethically integrate this kind of contextual data to give a holistic picture of how someone is doing, it could help clinicians better understand patients’ real‑time situations, enabling earlier, more personalized, preventive care. In another such effort, Torous’ lab is coordinating with Harvard’s Center for Geographic Analysis to enhance information from LLM conversations with phone-based GIS data — such as a person’s green space exposure, their neighborhood’s pollution levels, and other geographic indicators of mental health — which they think might increase a chatbot’s ability to respond appropriately. Torous notes that this may be the way of the future, beyond academic labs. Over the past year, both Apple and Google have published research on the use of LLMs to interpret data from sensors, such as smartwatches. “You can see the big tech companies are thinking about moving beyond language,” Torous says.

AI and Mental Health

“ Every physician takes an oath: First, do no harm. We want technology companies to take that same oath.”

Creating Benchmarks Across almost all available AI tools, Torous says there’s a dearth of empirical evidence or standardized guidance to help patients, clinicians, and developers evaluate their safety and effectiveness. He argues that clinical validation of these products — that is, assessing how they are used by actual people — is a crucial part of the biomedical process and essential for verifying safety claims and establishing standards. That’s the impetus behind MindBench.ai, a platform that evaluates how AI tools behave when real people use them for mental health support. Developed by the Beth Israel Deaconess Division of Digital Psychiatry (which Torous directs) in partnership with the National Alliance on Mental Illness (NAMI), MindBench. ai provides profiles of AI tools — including their privacy protections, technical features, and conversational style — based on patient reported use cases across the country. It also benchmarks their performance and turns those findings into a public, continuously updated resource. For instance, Torous says, a young person might discover that their mental health chatbot has provided an incorrect suicide hotline number. They could then flag the issue in MindBench.ai. NAMI is actively introducing MindBench.ai to populations who are using these chatbots for mental health purposes and can therefore be “on-theground” reporters of their flaws. “We’ve never had that before in the app world,” Torous says. In the past, the only path forward would be to file a complaint directly with the company, which would not necessarily be motivated or equipped to investigate it further. This is not a trivial shortcoming — people in the midst of a severe mental health episode may see such roadblocks as proof that seeking help is futile. Nor is this example merely a hypothetical; in 2024, Torous and colleagues conducted a thorough review of the mental health app marketplace and found that only 15 percent of the apps referred users to 988, the national suicide prevention hotline. In addition, 14 apps that had collectively been downloaded more than 3.5 million times provided incorrect or nonfunctional alternative crisis hotlines. The problem has become an issue for AI chatbots as well. MindBench.ai builds on the example of an earlier project led by Torous — MindApps, which provides a similar platform for smartphone apps that offer mental health support. MindBench.ai aims to evaluate LLMs and LLM-based tools with objective and transparent criteria from a health care standpoint, so that anyone can browse and select the best chatbot for their needs, circumstances, and vulnerabilities. One issue Torous hopes MindBench.ai will address is creating more reliable benchmarks for AI tools. For example, he says, in psychiatric practice, a four-point decrease in depression severity scores, such as those measured by the Patient Health Questionnaire-9, is generally considered clinically significant in many treatment contexts. This isn’t a perfect indicator, but perfection is not the goal — consensus and standardization are. In contrast, no one has yet agreed on certain standards in digital mental health, like what constitutes harm. “We all agree that suicide is the worst case possible,” Torous says. “But we don’t have a clear set of definitions of the different degrees of harm, which means it’s hard for any regulator to hold companies accountable. An effort like MindBench.ai can help us converge on what we mean by harm so that we are all speaking the same language and have the same goals.”

Looking Ahead In early January 2026, just a couple of months after Torous’ testimony, the FDA released guidance that reinterpreted regulatory exemptions for wellness products, meaning that companies have more concrete criteria with which to position themselves as wellness products and therefore avoid FDA medical device regulation. While this clarity reduces the risk that companies will unknowingly cross into regulated territory, Torous is concerned that it gives companies more leeway to rebrand their products so as to not assume responsibility for unintended consequences. Even OpenAI’s recently launched ChatGPT Health skirts HIPAA requirements since it’s branded as a “supplement” to — rather than a replacement for — guidance from medical professionals. And while some AI companies are forming advisory committees to address some of the concerns around their chatbots, many continue to operate in isolation. Other virtual mental health companies like Talkspace are hatching their own plans to develop LLM products in short order, and startups are beginning to look to chatbots for help prescribing medications. Soon, researchers will have to wrestle with an even more saturated AI marketplace. Still, Torous is optimistic that companies are starting to see the light when it comes to balancing progress in AI with ethical restrictions. In April, Google announced that it would bolster access to crisis support for Gemini users, initiate model improvements to provide better response to acute mental health situations, and direct $30 million to crisis hotlines worldwide. “As such general AI models invest in mental health safety, we are likely entering a new era where they will not only be the most powerful, but perhaps also the safest,” Torous says. He and colleagues have found that smaller models fine-tuned for mental health purposes currently have no meaningful advantages in terms of safety and performance over larger, more sophisticated models. Lawmakers are starting to wake up, too. Torous says that Congress sees social media as a cautionary tale. “No one’s happy with what happened with social media,” he says. “It took a long time for people to see the perils of Facebook. There’s a chance to do better with AI.” Torous also hopes to drum up more recognition of the multimodal approach to AI and mental health that he maintains will reconceptualize how humans care for each other’s well-being. And he thinks Harvard is an ideal launching pad for such a mission. “This is not just about psychiatry — it’s about policy, it’s about public health, it’s about law,” he says. “You really need an environment like Harvard where you can do all of this in collaboration with other teams.” Or, as Vahia says, “It’s our responsibility to grapple with these difficult questions — because if we don’t do it, who will?”

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ALLISON ECK IS THE SENIOR EXECUTIVE COMMUNICATIONS MANAGER IN THE HMS OFFICE OF COMMUNICATIONS AND EXTERNAL RELATIONS.

p IF YOU OR SOMEONE YOU KNOW MAY BE EXPERIENCING

A MENTAL HEALTH CRISIS, CALL OR TEXT 988 TO REACH THE SUICIDE & CRISIS LIFELINE.

Signals in the Silence IN SOME PATIENTS WHO APPEAR TO BE UNCONSCIOUS, BRAIN ACTIVITY REVEALS SIGNS OF AWARENESS THAT THE BODY CANNOT EXPRESS BY MOLLY MCDONOUGH ILLUSTRATION BY VALERIE CHIANG

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“The question is, once you identify someone as being covertly conscious, what now?”

Brian Edlow

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“This just blew my mind,” recalls Edlow. “It completely reframed the way that we think about consciousness and opened up the possibility that a substantial number of patients may be conscious even if we cannot detect purposeful behavior at the bedside.” He didn’t know it then, but nearly two decades following those formative experiences, his research would help to reveal that at least one-quarter of seemingly unresponsive patients with brain injury harbor evidence of awareness on brain scans. Today, he and colleagues at HMS and beyond are working to improve methods of detecting that phenomenon, known as covert consciousness, and to untangle the thorny scientific, ethical, and clinical questions that it poses. Charting Consciousness When treating patients with brain injury, Edlow and other doctors have always faced a conundrum: To infer how conscious a person may or may not be, they rely on what they can observe from the outside. They use bedside exams to walk patients through tasks, looking for hints of arousal or awareness. Then they determine, based on standardized scales, which “disorder of consciousness” a patient has. “I’ll sort of go up the ladder,” explains Joseph Giacino, an HMS professor of physical medicine and rehabilitation at Spaulding Rehabilitation Hospital, who developed the Coma Recovery Scale–Revised, one of the most widely used scales, in the early 2000s. First, he’ll check if the patient purposefully responds to any stimulus, like turning in the direction of his voice. If they remain totally unresponsive and their eyes stay closed, they’re in a coma. Within about two weeks of injury, most patients open their eyes, but if they still don’t respond to stimuli on purpose, they’re considered to be in a vegetative state. If they start showing signs of awareness — brushing hair from their eyes, squeezing a hand when prompted — they’re in a minimally conscious state. When is a patient considered conscious? There are two “exit criteria,” Giacino explains: They can give reliable and consistent responses to a series of six consecutive yes or no questions, and they can use an object functionally — for example, putting a cup to their mouth. These diagnostic labels are important. Outcome predictions, rehab plans, and even life-and-death choices depend on them. But exams that rely on observable behavior can’t always capture a patient’s subjective experience. That fact came into sharper focus once researchers began employing advanced imaging technologies to glimpse inside the brains of unresponsive patients. The first such studies, in the late 2000s, used fMRI, which maps the flow of blood to active brain regions, translating those shifts in thought into bursts of color. Then researchers started experimenting with electroencephalography, or EEG, which records the rhythmic firing of neurons through small electrodes placed on the scalp. Both tools are now used to detect covert consciousness because they let researchers see the neural signature of a thought, even if the body remains still. “What’s really interesting about the brain is that when it’s imagining doing something, it acts in the same way as it does when it’s actually doing it,” says Giacino. “For both EEG and fMRI, the patterns of electrical activity, or the blood flow changes, have a sort of signature that says, ‘This person’s doing or imagining doing the task.’ We know that because we’ve done the task with people who are perfectly healthy.”

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HEATHER MCGRATH

Brian Edlow has cared for countless patients in a coma. But there’s one phenomenon that still gives him the chills every time he experiences it: the moment a previously unresponsive patient shows the first hints of consciousness. Edlow, now a critical care neurologist and an HMS associate professor of neurology at Massachusetts General Hospital, remembers the first time it happened. He was a medical student, and his patient, a young man, was unconscious after being hit by a car while riding a bike. The man had been unresponsive for two weeks. But that morning, Edlow grasped the patient’s hand and asked him to squeeze it — and the young man squeezed back. Around the same time, Edlow heard about a paper published in Science that stunned him. The 2006 study focused on a patient who sustained extensive brain injuries following a traffic accident. Six months later she was still in a vegetative state. She showed no evidence of purposeful behaviors, such as following commands or making intentional movements. But then the researchers put her in an fMRI machine. While scanning her brain, they asked her to imagine walking through her house, moving slowly from room to room. And they told her to imagine playing a game of tennis, swinging for the ball with forehand and backhand strokes. What the researchers saw on the scan was a bit like Edlow’s hand squeeze, but rendered in colorful 3D pixels. Her brain responded to the commands with activity patterns that matched those of a healthy person, as if to say, I’m still here.

Covert Consciousness TENNIS IMAGERY

SPATIAL NAVIGATION IMAGERY

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Thoughts, Visualized These fMRI scans, adapted from a study by Adrian Owen and colleagues at the University of Cambridge, showed early evidence of conscious awareness in a patient diagnosed as being in a vegetative state. When asked to imagine playing tennis (left column), both the patient (top row) and healthy controls (middle row) showed similar activity in the supplementary motor area. When asked to imagine navigating the rooms of their houses (right column), they showed indistinguishable activity in the parahippocampal gyrus and other regions involved in spatial navigation. The bottom row shows healthy controls who heard the same keywords but weren’t instructed to imagine doing the tasks, indicating that the observed brain activity wasn’t just an automatic reflex.

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IMAGE ADAPTED FROM OWEN AM, COLEMAN MR, DETECTING AWARENESS IN THE VEGETATIVE STATE, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 2008.

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Michael Young

High Stakes, Low Clarity In the ICU, where Edlow spends his time, even just the awareness that

an unresponsive patient could be conscious has immediate implications. Research suggests that 70 percent of ICU deaths from traumatic brain injury result from the withdrawal of life-sustaining therapy, often within the first three days. “A substantial proportion of people die in the ICU because it’s assumed that they have minimal or no cognition and that they’re not going to recover,” Bodien says. “The ventilators are turned off and the patients die.” Even patients who are kept alive but remain unresponsive tend not to meet relatively stringent criteria for admission to rehabilitation facilities. As a result, they usually end up in long-term care settings with limited access to helpful interventions. If consciousness can’t be ruled out, the calculus changes. Michael Young, MD ’16, an HMS assistant professor of neurology at Mass General, says that a patient’s level of consciousness weighs heavily in the decisions families and clinicians make about whether to continue life-sustaining care and what kinds of treatments to pursue. “That really speaks to the centrality of consciousness to our concept of personhood and, for many, what makes life worth living,” he says. The most obvious question decision-makers ask is whether exhibiting covert consciousness means that someone is more likely to recover. The evidence so far is mixed. Some studies have found that its presence does not predict prognosis. But research in acute settings shows more promising links. A 2019 study by researchers at Columbia University found that among patients in the ICU, 41 percent of those who showed signs of cognitive motor dissociation shortly after injury

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HEATHER MCGRATH

A Silent Minority The tasks used in the 2006 study — imagining a tennis match and visualizing the rooms of one’s home — were not chosen at random; these prompts are known to reliably activate distinct patterns in healthy brains. And when researchers looked at that one patient’s fMRI scans, the images were indistinguishable from those of the healthy controls. “That really stunned me. I think it stunned a lot of people,” says Yelena Bodien, an HMS lecturer on physical medicine and rehabilitation, part-time, at Spaulding, and an assistant professor at Vanderbilt University Medical Center. She decided to pivot from studying schizophrenia to disorders of consciousness when she first learned about the research. That first paper focused on just one patient. In the following years, as researchers recruited more participants, they identified additional patients with signs of covert consciousness. But those studies were still relatively small and in siloed research groups. A few years ago, Bodien helped organize a group of 30 international researchers, including Edlow and Giacino, to publish what she calls “a kind of magnum opus in a large sample.” The researchers sought a more reliable estimate of how many patients might exhibit “cognitive motor dissociation,” a type of covert cognition specific to patients in coma, vegetative state, or minimally conscious state who do not follow bedside prompts, like squeezing a hand or giving a thumbs-up, but do follow prompts that are detected on brain scans. Their study, published in the New England Journal of Medicine in 2024, found that among 241 adults who could not follow bedside commands, 60 (about 25 percent) could follow cognitive tasks in the fMRI scanner or during EEG testing, suggesting that they could think and understand despite being unable to demonstrate it with their bodies. These patients spanned different injury types — from traumatic brain injuries to stroke to cardiac arrest — as well as recovery stages, from acute to chronic. “There was not a subset of patients in which we didn’t find this phenomenon at all,” Bodien says. The study also included 112 patients who could follow commands at the bedside. The findings among these patients are what surprised Bodien most: 69 of those clearly conscious patients (over 60 percent) did not generate the necessary signals on fMRI or EEG to pass the brain scan tests. In other words, even patients who show outward signs of consciousness can struggle to pass the tests. That suggests the tests are demanding enough to miss some conscious people — and that cognitive motor dissociation could be even more common than the reported 25 percent. While the tests don’t necessarily show the upper limits of a patient’s cognitive capacity, the researchers say that demonstrating those responses to commands on brain scans requires a meaningful level of awareness. “There’s probably a broad spectrum of levels of consciousness that individuals with this diagnosis have, but many of us feel confident that if somebody can do these tasks, their level of consciousness might be quite high,” Edlow says. “The question is, once you identify someone as being covertly conscious, what now?”

Covert Consciousness

“ The reality is that the evaluation of consciousness is an inherently gray and somewhat abstract thing.”

reached functional independence within a year — for example, they were able to eat, go to the bathroom, and get dressed — compared with only 10 percent of those who did not. Yet outside of a few specialized centers like Mass General, most patients worldwide still lack access to the technologies required to undergo these tests, as well as to the experts needed to interpret them. Mass General’s Emerging Consciousness Program, co-led by Edlow and Young, is tackling both of these limitations at once. In addition to offering extensive fMRI and EEG evaluations, they’re enrolling patients in clinical trials designed to ensure the science is strong enough to guide care. They’re tackling the field’s most pressing questions, such as how to standardize testing, how to reconcile results when fMRI and EEG contradict one another, how to optimize testing characteristics, how to talk about results with families, and what treatments should follow when covert consciousness is detected. To expand access, the program currently offers “TeleConsciousness” assessments to provide expert guidance and second opinions remotely. Ultimately, Edlow and Young envision a “hub-and-spoke” model in which data could be acquired at community hospitals nationwide and then interpreted by Mass General experts. Unlocking Voices For now, though, even those who have access to tests still face fraught decisions. “I think it’s not all that helpful to physicians or to families to say that their loved one is conscious and that’s it,” says David Fischer, MD ’16, an assistant professor of neurology at the Hospital of the University of Pennsylvania. “The logical next question after you infer that someone is conscious is to say, ‘Well, how do we actually communicate with them?’ And we haven’t been able to answer that question.” But researchers are trying. Some have attempted using the typical visualization tasks to ask patients questions — for example, by asking them to imagine playing tennis for “yes” and navigating rooms for “no” — but that approach has only worked on rare occasions. Fischer has been testing a novel technique that could both improve detection of covert consciousness and facilitate communication with those who experience it. Called neural decoding, the method exposes a patient to different stimuli — sounds, words, images — while scanning their brains using fMRI or EEG. Researchers use machine learning to analyze brain patterns that consistently happen when that individual sees or hears a certain thing. Then, when exposed to new stimuli, the algorithm “reads” the person’s brain activity to decode what they’re experiencing. The hope is that someday a computer might translate those thoughts into text or sound. Another promising technology is the brain-computer interface. Researchers have had some success enabling communication in patients with “locked-in syndrome” — cognitively normal but paralyzed by conditions like ALS or stroke — by putting microelectrodes on the surface of the brain to turn thoughts into action. Eventually, Edlow says, this technology might progress enough to facilitate communication with patients with disorders of consciousness. By understanding what causes a state of covert consciousness, scientists might also be able to find treatments that help patients recover. Some evidence suggests that the phenomenon involves damage to the thalamocortical motor fibers, which act as a bridge between

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the thalamus, the brain’s central relay station, and the cortex, which handles high-level thinking and movement planning. Young just enrolled the first participant in a new study that will test the use of focused ultrasound to stimulate the thalamus and restore its communication with the cortex in a noninvasive way. To gauge the effect, he’ll use the same fMRI and EEG mental imagery tasks that detect covert consciousness — this time as biomarkers of response and not just diagnostic tools. No Evidence of Absence In addition to exploring treatment strategies, Young spends a lot of time untangling the ethical questions that covert consciousness raises: Is there a moral duty to test for it? Does sharing uncertain findings create false hope? How can clinical trials enroll patients who may be conscious but unable to provide traditional consent? Young earned a master’s degree in philosophy before attending medical school, so he’d already spent years pondering big questions about consciousness and personhood. He recalls being struck by how medicine tended to neatly “define and operationalize” concepts of consciousness that philosophers and ethicists had grappled with for ages. Perhaps not coincidentally, Fischer also has a background in philosophy. It helps him feel more comfortable facing concepts that defy easy explanation. “I think physicians by nature like things to be in neat buckets,” he says. “But the reality is that the evaluation of consciousness is an inherently gray and somewhat abstract thing.” The more he’s learned about covert consciousness, the humbler Fischer has become about making assumptions. Families of patients often ask him, “Do they know I’m here?” He tells them he doesn’t know, because current tests can rule in the presence of some level of consciousness, but they can’t completely rule it out. The most important lesson to glean from this research, says Fischer, is that it is often impossible to know for sure that a person is unconscious. Young has recently been interviewing patients who have recovered from states of covert consciousness, trying to learn about their point of view. He spoke with one man who vividly recalled experiences and conversations he’d heard at times when others did not realize that he was cognizant. Perhaps if that man’s consciousness had been detected, he would have been treated differently at the time, sparing him “memories that remain traumatic to him to this day,” Young says. “That case, even if an outlier, underscores the importance of diagnostic humility.” Humility is an understandable response to a phenomenon that currently raises more questions than answers. But with the science advancing, what these researchers discover about covert consciousness could ultimately transform how patients with brain injury are understood, cared for, and treated. “These advances are coming at a really exciting time,” Young says. “There is a clinical and ethical imperative to unlock the voices of people who are there but cannot speak for themselves.”

MOLLY MCDONOUGH IS THE ASSOCIATE EDITOR OF HARVARD MEDICINE MAGAZINE.

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EMERY BROWN’S QUEST TO UNDERSTAND THE NEUROSCIENCE OF ANESTHESIA BY MOLLY MCDONOUGH PHOTOGRAPH BY MATT KALINOWSKI

Under

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On October 16, 1846, physicians filled the surgical amphitheater at Massachusetts General Hospital to watch dentist William Morton test a bold new idea. Morton held a glass inhaler filled with an ether-soaked sponge and asked a patient, Gilbert Abbott, to breathe in. Within minutes, Abbott lay motionless. Surgeon John Collins Warren then made an incision in Abbott’s neck and removed a tumor. When Abbott awoke, he reported having felt no pain. It was the first public demonstration of the use of ether for surgical anesthesia, and a moment that changed medical history. About 140 years later, in the same hospital, medical student Emery Brown, MD ’87, started his rotation in anesthesiology. He was quickly hooked. He loved channeling his knowledge of physiology and pharmacology to manage a patient moment-by-moment in the operating room. But there was one problem that began to bug him: Although general anesthesia had been used millions of times since 1846, nobody in the field seemed to really know — or even care — how the practice actually worked. “If the anesthetic drugs are acting in the brain and we know the brain’s circuits,” wondered Brown, who is now the HMS Warren M. Zapol Professor of Anaesthesia at Mass General, “can’t we start to think about where and how they’re acting in the brain?” Brown’s insistence on that question may have stemmed from his unique path. The son of high school math teachers in Ocala, Florida, he studied applied mathematics at Harvard before pursuing an MD-PhD. Earning his PhD in statistics — a highly unusual path for a medical trainee — he developed statistical methods to understand neuroscience data. He didn’t know it then, but that expertise would come in handy once those nagging questions about the neuroscience of anesthesia finally felt too big to ignore. After publishing his critiques of anesthesiology in a 2010 article in the New England Journal of Medicine and receiving an NIH Pioneer Award to conduct what the agency calls “high-risk, high-reward research,” he started using electroencephalography, or EEG, to record and analyze brain wave patterns of patients under general anesthesia. Brown went on to demonstrate that anesthesia is nothing like natural sleep; instead, it’s more like a coma, with large, slow oscillations in neural activity that prevent different parts of the brain from communicating. He has shown that different classes of anesthetic drugs create unique EEG patterns and that those patterns differ depending on dosage and a patient’s age and health status. His research has moved the field toward a more rigorous, brain-centered understanding of anesthesia and of unconsciousness itself. Brown is the first anesthesiologist, the first statistician, and the first African American to be elected to all three of the National Academies of Sciences, Engineering, and Medicine. He also received the 2024 National Medal of Science. In addition to his role at HMS, Brown is the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at the Massachusetts Institute of Technology. Harvard Medicine associate editor Molly McDonough spoke with Brown to learn more about what we now know — and still don’t — about anesthesia and the brain. The interview has been edited for length and clarity.

There was a long-standing idea that anesthesiologists could use anesthesia without really understanding how it worked. Why didn’t that sit right with you?

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I think anesthesiologists enjoyed being able to say, “We do it, but we don’t know how it works.” It was like having a secret handshake, and only those who knew the handshake could administer anesthesia. But there’s no way you can improve it if you have no idea how it works. There were some obvious phenomena that I could see were occurring based on neuroscience. For example, when a neurologist is evaluating a patient in coma, they often check the patient’s oculocephalic reflex — how the eyes move — not because they’re interested in the eyes, but because that gives them a window into the part of the brainstem where the circuits controlling arousal are located. And if you check that reflex in someone under general anesthesia, you see that the reflex is lost. Also, a patient would need to lose physical sensation in order to tolerate a surgical procedure. It seemed reasonable to begin thinking of general anesthesia as a pharmacologically mediated, reversible coma. You’ve pointed out that anesthesiologists tend to use the word “sleep” in the context of general anesthesia, which doesn’t really make sense. Anesthesiologists tell patients, “You’re going to go to sleep.” And then they say to each other, “Well, I don’t really mean that.” But what do they mean? They say sleep because, understandably, they don’t want to frighten patients by telling them they will be in a pharmacologically mediated, reversible coma. I realized that anesthesiologists didn’t have a clear definition of general anesthesia. So, I stated one. There are four components: You’re unconscious, you don’t feel pain, you don’t form memories, and you’re not moving around. The key point is to create these states while keeping the patient physiologically stable and bringing them out once the surgery is finished. That started to clarify my thinking; it allowed me to think about the various components and how we were generating each of them. It also changed how I spoke to patients. I won’t say, “I’m going to put you in a pharmacologically mediated, reversible coma, but don’t worry, I can wake you up.” But I can say, “Look, you’re going to be unconscious. You won’t realize anything that’s going on or perceive any pain. You won’t form any memories of what’s happening. I’ll probably give you some medications to relax your muscles to make it easier for the surgeons to operate. I’ll be with you the whole time, watching your heart rate, blood pressure, blood oxygen levels, carbon dioxide levels, and temperature to make sure they are stable. When all is done, the muscle relaxant has been reversed, and the effects of the other anesthetics have worn off, I’ll wake you up.” So, I just give them the definition of general anesthesia in lay terms. Do we understand now how anesthesia works? I think we now understand the principal mechanisms through which it works, particularly for widely used agents like propofol and the ether

Anesthesia

“ It was like having a secret handshake, and only those who knew the handshake could administer anesthesia.”

anesthetics — sevoflurane, isoflurane, and desflurane. In 2011, I started using the EEG to monitor all my patients during general anesthesia. It’s very impressive to watch: As you administer the medications, you see the patients’ brain wave oscillations start to change. During the normal eyes open, awake state, EEG oscillations have frequencies of around 40 cycles per second with small amplitudes. As the anesthetic quickly reaches various parts of the brain, the oscillations become larger in amplitude and decrease in frequency — dropping to about 8 to 14 cycles per second (called alpha oscillations) and 0.3 to 4 cycles per second (called slow-delta oscillations). At the same time, individual neurons fire far less often, slowing from about 10 to 12 times per second to roughly once every one to two seconds. Hence, one of the things that propofol and the ether anesthetics are doing is dramatically altering dynamics so that normal communication among brain regions can’t continue. Because these oscillations are not natural and are sustained sometimes for several hours, they explain why postoperative brain dysfunction can be common, particularly in the elderly. Another thing we’ve learned is that high doses of these anesthetics alter the brain’s ability to produce ATP, the primary energy source for cells. This manifests in a specific pattern on the EEG called “burst suppression,” a warning sign that the brain’s metabolism is being altered. We see this commonly in older patients, 60 years and over. They enter this state very readily with small doses of these anesthetics. If we are not monitoring, burst suppression is not detected, and patients are overdosed. But that continuous EEG monitoring is not standard, right? Unfortunately, that’s right. EEG monitoring is used much more regularly in Europe, South America, and perhaps in Asia, but not here in the United States. I think this is a fundamental shortcoming. There are monitors that take EEG brain wave data and simplify it into a single number or index displayed on a screen. Anesthesiologists are basically told, “Don’t worry about the unprocessed EEG signal, just use the index. As long as it’s within a certain range, the patient is fine.” It’s a total black box. And there are well-known situations in which the indices are frequently incorrect, such as with children, and with certain anesthetics like ketamine and dexmedetomidine. Within weeks of when I first started reading EEG patterns directly, I could see unique signatures depending on which class of drugs we were using and that those signatures also changed depending on how old the patients were and their state of health. It was obvious, but no one had sat down and looked at it.

awake under anesthesia is a horrible occurrence. However, it is very uncommon. What’s more common is that patients wake up with delirium or brain dysfunction because they had too much anesthesia. Is that the issue you’re trying to address in your research now? Two things. One is teaching anesthesiologists to read real-time EEG, making use of what we already know. The second is to build a closedloop system to deliver anesthesia. It’s like putting a plane on autopilot, reading the EEG in real time and using it to dose the anesthetic to maintain a certain level of unconsciousness. We have good reasons to believe this works based on animal studies we’ve recently completed. By thinking of anesthesia as a measurable form of unconsciousness, does that tell us anything about what consciousness actually is? When people ask me what I study, I say that I study unconsciousness, because that’s what I want to create in the most sound way for the purpose of anesthesia care. But we know that a person can be in a coma because of a stroke that affects the cortex, the brainstem, or the thalamus. There are all sorts of ways of turning the system off. That suggests the conscious process depends on these brain areas being well integrated and communicating in such a way that you’re awake and you’re aware. To the extent that I can map how different approaches to anesthesia diminish awareness, alter perception, or produce unconsciousness, I can provide information to investigators who study the harder problem: How does the brain integrate information to create consciousness? We don’t need to wait until that problem is solved, though, to improve anesthesia care. I think that well before we figure out all the details of consciousness, we can develop more sound, neurophysiology-based approaches to anesthesia. If you could travel back in time and explain the modern science of anesthesia to William Morton and John Collins Warren, what do you think would surprise them most?

Actually, the more common scenario is that if you’re anesthetizing someone and you’re worried about them being awake, your natural action is to give them more anesthesia. So you tend to overdose patients because you do not completely trust the index. People being

I think they’d be surprised to know that a large fraction, maybe 70 percent, of the way anesthesia is practiced today is essentially the way they did it back then. We still widely use ethers that patients breathe while they’re having surgery. It’s really interesting: Before the use of ether for anesthesia was discovered, do you know what the primary area of research was in surgery? It was coming up with better ways to strap patients down. The discovery of ether changed surgery overnight: from butchery and intolerable pain to more humane therapeutic procedures. It has to be acknowledged as one of medicine’s greatest innovations. So I’d say, “Dr. Morton, you made a truly transformative discovery that we’re still using today, almost the same way. The world is grateful for this. It inspires us to use our deeper understanding of neuroscience and the brain to create the next-generation solution.”

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So if you’re just looking at a number and not the actual EEG signatures, the risk is that you might assume someone is unconscious when they actually have awareness?

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Mind

Maps A ONE-OF-A-KIND MRI SCANNER CAPTURES THE BRAIN’S WIRING IN UNPRECEDENTED DETAIL

COURTESY OF BORIS KEIL

BY AMOS ESTY

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CONNECTOME 2.0

The average human brain is only about the size of a cantaloupe. But packed within it is a dense network of billions of neurons and tens of thousands of miles of axons, the fibers that connect neurons to one another. This network, called the connectome, is thought to play an essential role in shaping both our personalities and, in some cases, pathologies, but its complexity has made it difficult to map in detail. That’s changing, thanks in part to a one-of-a-kind MRI scanner — called the Connectome 2.0 — that is allowing researchers to create some of the highest resolution maps yet of the human connectome. The machine was installed at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in 2023, and researchers are now using it to better understand the relationship between the structure of the brain and how it functions. A typical MRI machine used in a hospital can identify abnormalities such as a blood clot or tumor. But many neurological and psychiatric conditions, such as severe depression or schizophrenia, are thought to result at least in part from abnormalities in the connectome. Those won’t show up on a standard MRI scan, “yet there is something wrong that we can’t see,” says Susie Huang, MD ’10, an HMS associate professor of radiology at Mass General and associate director of the Martinos Center. Anastasia Yendiki, an HMS associate professor of radiology at Mass General, uses the Connectome 2.0 in her work as one of three principal investigators of the Center for Large-Scale Imaging of Neural Circuits (LINC), a long-term project funded by the NIH BRAIN Initiative. She is using the Connectome 2.0 to create the most detailed map to date of the human connectome. This understanding of a typical connectome could be used to identify variation in a specific patient. Researchers use the Connectome 2.0 to collect images with a technique called diffusion MRI, which can determine the location and direction of axons. Diffusion MRI tracks the movement of water molecules through the brain. Water travels more easily along bundles of axons than across them, just as it’s easier to walk along a sidewalk than to cross a busy road. Researchers then use various algorithms to piece together the data and create visualizations of the connectome. A better understanding of the connectome and how it varies from person to person could help researchers identify indicators of neurodegeneration and personalize treatments for conditions such as multiple sclerosis and obsessive-compulsive disorder. But beyond the clinical applications, Huang and Yendiki share an appreciation for the awe-inspiring images that the Connectome 2.0 makes possible. “The whole reason I got interested in science was being able to see something for the first time that no one else has ever seen, and then to be able to understand it better,” Huang says. Yendiki remembers being “just blown away” when she first saw images produced by diffusion MRI and learned how it works. “I thought it was the most science fiction thing I had ever heard,” she says. The samples to the right offer a glimpse of the work they and their colleagues are doing to create a new view of the human brain.

FIGURE 1

FIGURE 4

AMOS ESTY IS THE EDITOR OF HARVARD MEDICINE MAGAZINE.

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CONNECTOME 1.0

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Connectome

AXON DIAMETER INDEX 3.8

MICRONS

1.8

FIGURE 2

FIGURE 3

TAKING A DEEP LOOK INSIDE THE BRAIN Figure 1: The Connectome 2.0 is the successor to the original Connectome scanner, which was installed at Mass General in 2011. The Connectome 2.0 improves significantly on the design and performance of the original, enabling researchers to produce more detailed maps of the fiber pathways. In the image produced using the Connectome 2.0 (left), small pathways in the brainstem are much more visible than in the image from the Connectome 1.0 (right). Figure 2: In addition to studying the paths axons take across the brain, researchers are also interested in the fibers’ diameter. Knowing the size of axons across different brain regions can indicate how quickly information passes through neural circuits. In some conditions, such as multiple sclerosis, axon diameter may serve as an early biomarker. Although individual axons are too small to see directly even with the Connectome 2.0, researchers can approximate their diameter. This heatmap displays the average estimated axon diameter (in microns) in cross sections of the brains of 10 healthy adults. “We’re actively exploring what these structural biomarkers can provide in terms of signs of early neurodegeneration,” says Huang. Figure 3: Yendiki is leading a project that is using the Connectome 2.0 to produce high-resolution images of postmortem human brains. Since they can stay in the scanner for long periods, the postmortem brains allow researchers to “push the limits of what the technology can do when time is not an issue,” Yendiki says. Figure 4: Ultimately, Yendiki thinks that for any condition associated with an abnormal brain network, not just a single location, clinicians will benefit from detailed maps of the connectome. “We would like to have something like a Google Maps of the brain,” she says. Images courtesy of Susie Huang (figs. 1 & 2), Anastasia Yendiki, Ting Gong, and Chiara Maffei (figs. 3 & 4).

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Updates & Observations from the HMS Community

The power of this institution is that you can dream up any idea and you tell someone about it and all of a sudden all these world-class experts will be coming to you with ideas that build on yours and allow you to make it a reality.

GRETCHEN ERTL

SEE PAGE 52

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ALU M NI P ROF ILE

Rethinking the Roots of Schizophrenia W HO

ROBERT FR EED M A N , M D ’72 A F F I L IAT IO N

VIS I T I N G CLI N I CA L PROF ESSOR OF P S YCH I AT RY, UN I V E RSI TY OF COLORA D O

TIMOTHY ARCHIBALD

ANSCH UTZ SCH O O L OF M E D I C I N E

Robert Freedman was standing in front of his psychiatry class, and he was floundering. The assignment was to present a case study of his patient with schizophrenia, who was sitting just a few feet away, to his HMS classmates and professor. The professor pressed Freedman for details about the patient’s parents — this was the early 1970s, after all, when schizophrenia was largely understood as the legacy of insensitive or even cruel parenting. But Freedman didn’t know the answers, and he was mortified. Afterward, Freedman asked the patient how he’d felt during the ordeal. The man’s response came as a surprise: “The air conditioner was very interesting.” While the professor was probing his family history, Freedman’s patient was focusing on voices he heard in the drone of the unit overhead. “I realized for the first time that we had overlooked an interesting sensory problem,” recalls Freedman. It was a moment that foreshadowed the arc of his career: a shift away from searching for answers in family narratives and toward uncovering the brain circuitry that shapes how people with schizophrenia filter the world. Freedman originally wanted to be a lawyer. But a social science requirement at Harvard College landed him in the classroom of cognitive psychologist George Miller, who fascinated Freedman by framing schizophrenia as some kind of psychedelic mind experiment. “I decided then and there to go into medical school instead,” he says. At HMS, working under psychiatrist John Allan Hobson, MD ’59, and neurophysiologist Stephen Kuffler, Freedman was introduced to electrophysiology, the study of the brain’s electrical signals. After a research stint at the NIH and a psychiatric residency at the University of Chicago, he joined the

faculty at the University of Colorado and began applying skills he’d honed at HMS to clinical research on schizophrenia. As he got to know more patients, the romantic view that first captivated him gave way to an understanding that the delusions of schizophrenia are more terrifying than mind-expanding, but his interest only increased. “People with schizophrenia have enormous creative abilities,” Freedman says. “I admire them for what they struggle against when the world around them is threatening and they just keep plugging away.” Early on, Freedman figured out a way to measure the sensory issues he’d suspected: a test consisting of two clicking sounds. In a neurotypical brain, the first click evokes a slew of electrical activity as the person directs attention to the sound — but subsequent clicks evoke less. The brain, constantly exposed to more information than it can process, must weed things out. But people with schizophrenia tend to show as much electrical activity in response to the second click as the first, indicating possible deficiencies in that weeding process. Freedman traced this phenomenon to the hippocampus, where a neurotransmitter called acetylcholine activates receptors that help dampen repeat signals. If that circuitry was malfunctioning, he wondered, could the issue be genetic? To find out, he hopped in a van and crisscrossed Utah and Colorado searching for large families with multiple cases of schizophrenia. He traced the faulty click response through those family trees, making it a genetic clue: By comparing the DNA of relatives who failed the test with those who didn’t, he zeroed in on a gene called CHRNA7, which encodes the receptor that acetylcholine triggers in the brain’s filtering process. Freedman tried using different drugs to manipulate that receptor in patients, but results were modest. Then, one day in the shower, he had a realization: Babies of parents with schizophrenia are more likely to fail click tests within weeks of birth. Perhaps by the time a person is born, the hardware is wired, and intervening in adults is too late. In the fetal hippocampus, receptors for acetylcholine are abundant, but the neuro transmitter itself doesn’t surge until just before birth. Until then, the fetus relies on

choline, a nutrient from the mother’s diet, to activate the receptors. But many women are choline deficient, and some fetuses have impaired CHRNA7 function. If mothers don’t get enough choline to activate the fetus’s receptors at the right time, could the circuitry fail to form properly? In clinical trials, Freedman and colleagues found that newborns whose mothers received extra choline — including newborns with impaired CHRNA7 function — had improved results on the click test compared to those whose mothers did not. As they grew into toddlers, they demonstrated improved attention and social engagement. The work suggests that supporting the brain at the right moment could reduce biological risks for traits linked to schizophrenia, as well as for related conditions like autism and ADHD. While more trials are ongoing, demonstrating that choline prevents schizophrenia would take decades, as the illness is usually diagnosed in young adulthood. But choline has many benefits for developing fetuses, is relatively safe, and doesn’t require a prescription. It’s a departure from the traditional pharmacology of schizophrenia, which relies on dopamine-blocking drugs with severe side effects. “I’ve kind of been out in the wilderness looking at acetylcholine and this strange receptor,” Freedman says. “The idea we could prevent schizophrenia is far out there, but it essentially just fell out of the science.” Despite focusing on just one of many genes that could raise the risk of schizophrenia, Freedman has played a central role in linking the condition to biology. That contribution made him a main character in the 2020 book Hidden Valley Road, which follows the Galvins, a family he met on his Colorado van trips. Six of 12 Galvin children developed schizophrenia, offering an extraordinary opportunity to study the genetics of the disease. Freedman says he’s grateful for the attention the book brought, if only because it helped him spread the word about prenatal choline. These days, another role competes for his time. He recently moved to San Francisco to be closer to his four grandchildren. After decades studying how brains are built early in life, the subject now feels personal. His greatest pleasure has been “the really great kids in our studies and in our families,” he says. “That’s what it’s all about.” Molly McDonough

The idea we could prevent schizophrenia is far out there, but it essentially just fell out of the science. ROBERT FREEDMAN

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BO O KS HE LF IN T E RVIEW

Your Gut Is a Brain TR ISHA PAS R IC H A TAL KS A BOU T HER NEW BO O K AN D H E R L I F E LO NG OBS ESS ION W IT H T H E GU T

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Rounds In 2005, when she was still in high school, Trisha Pasricha made national news for a science fair project in which she tracked electrical signals in the gut to improve on standard lie-detector tests. It turned out to be a sign of things to come. More than 20 years later, now an HMS assistant professor of medicine and a neurogastroenterologist at Beth Israel Deaconess Medical Center, Pasricha remains both deeply fascinated by the gut and a regular presence in the media. In addition to writing the “Ask a Doctor” column for The Washington Post, she has a devoted following on social media and is often quoted about popular health topics in the news. And now she is the author of a new book, You’ve Been Pooping All Wrong: How to Make Your Bowel Movements a Joy. “Forty percent of Americans’ daily lives are disrupted by their bowels, and 15 percent have irritable bowel syndrome,” she writes. The book offers both advice on a wide range of poop-related ailments and anxieties and a deep discussion of the science of the gut, drawing from the latest research, including her own, to explain what we know about the gut-brain connection. In her clinical work, for example, Pasricha noticed that many of her patients with Parkinson’s disease mentioned having ulcers when they were younger. Intrigued, she pored over thousands of patient records and found that ulcers and other gastrointestinal injuries were associated with a 76 percent increased risk of the disease. It’s one of many findings Pasricha discusses in her book that call for a rethinking of the gut-brain relationship. “What we’re learning about Parkinson’s disease is shedding light on other diseases,” she writes. “Perhaps put more simply, the gut is telling us something about the human body that we never realized before.”

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You conducted that science fair experiment when you were in high school. Your father is a prominent neurogastroenterologist. And, as you point out in the book, there’s the matter of your initials. Do you feel like you’ve been preparing your whole life to write this book? I did feel that way. I’ve had this book in me for a long time. I’ve wanted to address and normalize and destigmatize the conversation since I became a gastroenterologist. But the part about the science of the gut-brain connection, that’s been brewing for years, even since childhood. I wanted to share all of that cool science. People sometimes say, “Why did you go into GI? It’s a gross field. You must love poop.” Actually, I’m not obsessed with poop per se, but I am obsessed with the gut. I think that if you grew up the way I did, which was hearing about how our bodies work and how the enteric nervous system interacts with our central nervous system — that’s so cool. I think it’s the most exciting field, I would say in medicine,

but at the very least in GI. We know a lot about how the gut and the brain communicate with each other, but we also don’t know so much. You’ve been doing a lot of interviews lately, and it seems like you’ve struck a nerve. People are really excited to talk about the logistics of pooping. It’s surprising in a way, and then also absolutely not surprising to me. It’s why I knew I could write this book and should write this book. It’s something that is treated as so shameful, as something we should never talk about in public. But I discovered both as a clinician and in my writing for The Washington Post that whenever you offer people a window of opportunity to talk about their guts, you open the floodgates. People want that information. Do you think the role of the gut has been underappreciated in overall health and well-being? Yes. I think most people still believe that the gut is just plumbing. It’s just this tube that transports food from point A to point B. People don’t treat the gut like a brain, which is the way I think of my gut and treat my gut. I think every neurogastroenterologist thinks of the gut as this brain. It is this remarkably sophisticated organ that you have to protect at all costs. We know some foods are good or bad for our health, but we’re not thinking like, “What I’m putting into my body is going to have immediate consequences on this very delicate, sensitive brain.” That’s a frame shift that I hope the book gives people. Your gut is so much more than plumbing. Everything you do, whether it’s your thoughts, your mood, what you eat — all of those things will have a big impact on your gut. And then in turn, that is going to influence all those other aspects of your health. Do you think that’s changing? Fiber seems to be having its day. Fiber has come back. Protein was really big and then everyone got into “fibermaxxing” lately, which is a trend I’m totally here for. But what I fear is that at the end of the day, we’re still going to find that most people are not meeting their fiber goals. The latest data is that 95 percent of Americans are not meeting their fiber goals. You’ve been involved in medical journalism for a long time. What have you learned about communicating about complex scientific topics?

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It’s hard. What I love about the Post column is that I have about 800 to 1,000 words to really dig deep into a topic, and then I can link to multiple sources that back up even more in detail what I’m saying. When it comes to social media, you have three seconds to hook somebody to want to watch. You have 60 seconds to get one message across, and you have to find some way to pack in all that nuance that you would’ve had a lot more time for in a column. I have a love-hate relationship with social media. I only got on it two years ago, and the only reason was because I read this really disturbing statistic about how the majority of Gen Z is getting their health information from TikTok. So I got on social media so that I could ask the questions that people want to ask and to be, I hope, a voice that is bringing in the science. But even for myself, I try not to spend too much time on social media because it’ll really suck you in. When you see patients, are they coming to you with bad information about gut health? Yes. Having done this, I tell my other colleagues that they should look at what patients are looking at. They should type in “gut health” or “IBS” on TikTok, because you’d be surprised how many times a patient will come in and they are trying some of the latest trends, like supplements and juice cleanses. And they don’t necessarily engage with you unless you indicate that you know what they’re talking about, you’re familiar with it, you’re not judging it. So usually I say, “What have you tried that you might’ve seen on social media for your symptoms?” And it’s almost never nothing. But if you don’t ask, they won’t tell you because they assume you’re a traditional doctor who will dismiss this kind of stuff. You write about the relationship between the gut and risk of developing Parkinson’s disease. What’s currently understood about that link? The part that’s more strongly established is that there is a subset of patients with Parkinson’s for whom the disease originates outside the brain, and the gut is one of those places. The olfactory bulb has been discussed as another possible pathway. The hypothesis that Parkinson’s disease can originate in the gut was first proposed in the early 2000s. Then it was shown in a series of experiments to be the case that indeed the alpha-synuclein protein can misfold and propagate in this very reproducible staged fashion through the vagus nerve up to the brain. So that part is known.

BOOKS IN B RI EF R ECE NT BOO KS F ROM THE H M S COM M UNITY

I think most people still believe that the gut is just plumbing. It’s just this tube that transports food from point A to point B. TRISHA PASRICHA

What’s an even bigger black box, one my lab is trying to study right now, is how dopamine signals in the gut influence dopamine signals in the brain. We already know so much about dopamine in the brain, but its role in the gut is so different. It acts more like a hormone and is involved in protecting the lining of the gut. It can actually be involved in suppressing tumor formation. It doesn’t cross the blood-brain barrier, but dopamine in the gut could indirectly upregulate or downregulate dopamine in the brain. We just don’t understand well enough how these systems are communicating. I have this hypothesis that maybe some early changes in dopamine in the gut could be what indirectly causes changes in the brain, almost as a kind of compensatory mechanism to these injuries. That, ultimately, might be what leads to Parkinson’s. My five-to-10-year plan in my lab is to understand those questions. Beyond Parkinson’s, what would you most like to know about the connection between the gut and the brain?

The part that we’re all trying to figure out is what triggers the alpha-synuclein protein to misfold. I think most of us are starting to appreciate that even though the hallmark of Parkinson’s disease is misfolded alpha- synuclein protein, we don’t know that that’s the end of the story. There are probably other triggers that have nothing to do with alpha- synuclein that are contributing to the disease. We don’t fully know what those triggers are yet. There are hypotheses. People have talked a lot about pesticides on the foods we ingest. I studied ulcers because of this interesting pattern I recognized with patients who were saying, “Yeah, I did have these ulcers back in the day.” It was just a question I started asking them, and it felt to me like more of my Parkinson’s patients were saying that they had them than the non-Parkinson’s patients. And then I found this old paper that noted a link, so we decided to do a big study. What we found is that people who had these older gastrointestinal injuries were later at a higher risk of Parkinson’s. I don’t know if that’s the trigger that caused the Parkinson’s or whether people who are destined to get Parkinson’s are more likely to be susceptible to injuries earlier on.

I wish we knew more about how and why the gut ages and how the aging gut influences the aging brain, because these two systems are obviously very closely connected. People have invested a lot of time studying dementia and cognition as we age, but very few have studied the role of the gut in that process. And my work in Parkinson’s is kind of a small piece of that much bigger puzzle. You cover a lot of ground in the book, but one thing you do not mention is that you have an asteroid named after you. How did that come about? Thanks for bringing up my asteroid. Basically that was the result of the story I tell in the book about studying in high school how the act of lying can create these changes in the electrical rhythm of your stomach that are measurable and are real. I got second place at the Intel International Science and Engineering Fair. The top three winners would all get asteroids named after them. It was the coolest prize as a high schooler. Every now and then, when there’s an asteroid that’s headed towards Earth, I think, “Please don’t let this be my asteroid.”

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Wellness Versus Living Well “We’re all going to die,” writes Ezekiel Emanuel, MD ’88. “You can waste your time trying to extend your life for a few minutes, obsessing over scores of adjustments to your diet or exercise routines, or you can follow six straightforward, smart wellness behaviors and make the time you have healthier and more meaningful.” Emanuel acknowledges that Eat Your Ice Cream: Six Simple Rules for a Long and Healthy Life joins a long list of guides to good health. But he argues that too much advice treats health as a grueling full-time job rather than a foundation for living. “Wellness ought to be in the background,” he writes, “an unconscious part of your lifestyle, not an obsession.” While the behaviors Emanuel identifies — such as good nutrition and getting enough sleep — are familiar, he distinguishes his approach by prioritizing socializing. Family, friends, and social interaction, he says, are “probably the most essential elements of wellness, longevity, and happiness.”

Rounds

The Presidential Politics of Health Care

Updating an Instant Classic

Taking the Long View

A Prescription for Innovation

In 2009, as the battle over the Affordable Care Act heated up, David Blumenthal, MD ’75, and James Morone published The Heart of Power, a history of the presidential politics of health care from Franklin D. Roosevelt through George W. Bush. In their new book, Whiplash: From the Battle for Obamacare to the War on Science, they pick up the story where they left off, describing how health care took center stage during a tumultuous time. “Three presidents, as different from each other as they could be, led the country to very different places so fast it has whipped our heads around,” they write. Blumenthal and Morone discuss how debates over the Affordable Care Act and COVID-19 turned health care into a divisive issue, to the point that opinions on masks and childhood vaccinations became indicators of party affiliation. “The long partisan war over insuring Americans had morphed into a completely different clash between two combustible images,” they write. “Public health, science, even expertise itself — cracked along the political divide.”

Siddhartha Mukherjee, MD ’00, was a fledgling oncologist when he first turned to writing to make sense of the “bewildering, shape-shifting disease” of cancer. Journal entries penned between fellowship shifts at Dana-Farber Cancer Institute helped the young physician process the emotional tumult of caring for patients and the scientific complexities of the disease they faced. Those notes later coalesced into The Emperor of All Maladies: A Biography of Cancer, published in 2010. That Pulitzer Prize-winning book traced the story of cancer back thousands of years. But in the 15 years since its release, says Mukherjee, “so much has changed in the landscape of cancer prevention, detection, and treatment that it felt as if the book needed to be refreshed.” In an updated edition, Mukherjee includes four new chapters that he says are “essential to understanding” what has changed and what might be coming. “The book is a journey, after all,” he writes.

Daniel Sodickson, MD ’96, has been hooked on imaging ever since spending a month in a cardiac imaging lab while a student at HMS. In The Future of Seeing: How Imaging Is Changing Our World, he makes a convincing case for sharing his obsession. Sodickson recounts the history of imaging from the evolution of light-sensing cells all the way to the invention of modern instruments that enable us to see at both cosmic and subatomic scales. These technologies, he says, have been an engine of progress. “From the earliest dawn of human history, we humans have sought to extend our vision,” he writes. “Imaging permeates the history of scientific revolutions, and societal revolutions are frequently tied to the way we see.” Imaging technologies — such as smartphones and surveillance cameras — are already almost ubiquitous, and Sodickson imagines a future where they are even more so. Although he discusses some of the concerns this raises, Sodickson remains optimistic: “Whenever one extends one’s vision, one invariably expands one’s mind.”

As an intern at Apple, in 2010, Halle Tecco realized how little attention the tech industry was paying to health care. Inspired to fill that gap, she founded a venture capital firm focused on digital health and dedicated her career to the field. In M assively Better Healthcare, Tecco — a course director for the Master of Science in Clinical Service Operations program at HMS, adjunct professor at Columbia Business School, and graduate of Harvard Business School — shares what she’s learned along the way. Tecco describes a health care system filled with entrenched incumbents, regulation, and misaligned incentives, all of which conspire to make innovation in health care particularly difficult. She distills her advice into four rules, including the injunction to “work from the inside out” — to learn to operate within the constraints of the system rather than to ignore them. And, despite the many challenges, Tecco urges innovators to take on health care: “You don’t need venture capital to get started,” she says. “All you really need is passion, a burning problem to solve, and the courage to take that first step.”

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Why a global disease became a personal mission

U.S. medical licensing exams and completed her clinical fellowship.

Assel Talaspayeva

Nearly 600 million adults worldwide have diabetes, including about 842,000 in Talaspayeva’s home country of Kazakhstan, where an estimated half of cases go undiagnosed. “Diabetes is very common in my country, and I saw a lot of impacts of this disease,” she says.

How she learned to run clinical trials

M ASTE R OF M E DICAL SC I E N CE IN CLINICAL R ESEA RCH P RO G RAM

Where her path took a turn After medical school and an ophthalmology residency in Almaty, Kazakhstan, Talaspayeva knew she’d need to leave the country to meaningfully advance care for diabetic retinopathy. She wanted to train with leaders in her field at the Beetham Eye Institute at Joslin Diabetes Center. The transition was daunting — she had to relearn medicine in English, her third language — but the effort paid off when she passed the 50 HARVARD MEDICINE

Talaspayeva enrolled in the new master of medical science in clinical research program to strengthen her trial-running skills. “This training allowed me to deepen my understanding in study design, biostatistics, and evidence generation,” she says. She is already applying what she learned as a certified investigator with the Diabetic Retinopathy Clinical Research Retina Network, enrolling patients in a phase 3 trial of an oral medication for non-proliferative diabetic retinopathy. What her capstone project focuses on Her research examines anti- VEGF treatment, a standardof-care injection that restores

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or preserves vision in about one-third of patients with diabetic retinopathy. She is working to identify factors that cause the other two-thirds to respond weakly. Who mentored her along the way She credits her supervisor, Lloyd P. Aiello, and Jennifer Sun, chair of the DRCR Retina Network, with helping her develop her interest in clinical trials: “One of the most valuable aspects of the program is learning alongside people from diverse professional and research backgrounds.” What’s next Talaspayeva will continue treating patients and running clinical trials, with the long-term goal of helping to modernize diagnostics and care for diabetic retinopathy in Kazakhstan. Bobbie Collins

GRETCHEN ERTL

ST U D E NT LIFE | C L ASS O F 2026

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ST U DE NT LIFE | C L ASS O F 2026

How he overcame doubts to co-lead a national nonprofit

Leonard Nettey

Nettey nearly turned down the chance to co-lead what would become the MV3 Foundation — a nonprofit dedicated to empowering Black students to pursue careers in health care and biomedical science. “I was worried about stretching myself too thin and about not being able to give the idea the attention it needed,” he says. But when classmate Ashley Kyalwazi asked a second time, he said yes. The organization has now helped more than 175 undergraduates nationwide through peer community and mentorship.

M D - PHD P ROG RAM HE ALT H SCIE N C ES AND T EC HNOLOGY T RAC K

GRETCHEN ERTL

Why mentorship matters so much to him “I’m here because I’ve had so many valuable mentors in my life,” Nettey says. Born in Canada to Ghanaian immigrants

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and raised first outside Toronto and then outside Atlanta, Nettey grew up in a close-knit community. “We always had people who helped us get started and get to the next step. I credit this community upbringing with the idea that it’s good to look after people.” He hopes MV3 will launch the careers of more Black medical professionals and create more mentors for future generations. When school stopped coming easily Nettey sailed through school until he enrolled in a demanding molecular life sciences program as an undergraduate at the University of Pennsylvania. “The other students clearly knew so much more,” he says. He developed new study strategies to catch up but says the most important lesson from that year wasn’t academic. “I focused on being a good person and giving back to the people

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around me. Then, no matter how poorly any test goes, I always have my friends, my family.” What questions drive his research After working on vaccine research at the National Institutes of Health, Nettey joined Alex Shalek’s lab at MIT for his PhD. His research examined T cells in pediatric inflammatory bowel disease. Where he’s headed next Nettey will complete his residency in internal medicine at Brigham and Women’s Hospital. “I don’t see a future for myself that doesn’t incorporate being with patients, contributing to research and the advancement of academic medicine, and supporting the next generation,” he says. Christina Hernandez Sherwood

When she first became curious about brain surgery

Nikki Pérez

When Pérez was in high school, a biology teacher arranged for her to shadow a neurosurgeon. “I fell in love with it from the second I walked into the OR,” she says. “I liked the pace. I liked the way the team communicated. There was almost a choreography to it.”

M D P RO G RAM PATHWAYS T RACK

Why dance helped draw her to medicine Pérez majored in both dance and biology at Williams College, drawn to the way dance connects the mind and body. She volunteered at nursing homes, developing choreography tailored to residents’ conditions and abilities — work that became the foundation of her undergraduate thesis. “The brain has a remarkable capacity for plasticity, and I saw that very clearly in working with residents,” she says. 52 HARVARD MEDICINE

What caring for her father taught her about being a doctor While living in New York after college, Pérez’s father was diagnosed with pancreatic and colorectal cancers. The experience shaped the kind of doctor she has become. “It’s very different to care for someone with the perspective of a daughter than with the perspective of a provider,” she says. “I think being able to hold those two perspectives together allows me to connect with patients and their families more meaningfully.” Who encouraged her interest in global neurosurgery At HMS, Pérez worked with Mission: BRAIN, a nonprofit working to increase global access to neurosurgical care. In her third year, she was invited by Kee Park, director of the Program in Global

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Surgery and Social Change, to lead the Boston Declaration, a five-year effort to mobilize coordinated action against disparities in access to neurosurgical care. How HMS made it possible “The power of this institution is that you can dream up any idea and you tell someone about it and all of a sudden all these world-class experts will be coming to you with ideas that build on yours and allow you to make it a reality,” Pérez says. She credits her mentors not only for their knowledge but for the humility and excitement they bring to collaboration. Where she’s headed next Pérez will complete her residency in neurosurgery at the Barrow Neurological Institute in Phoenix, Arizona. Mike Campbell

GRETCHEN ERTL

ST U D E NT LIFE | C L ASS O F 2026

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ST U DE NT LIFE | C L ASS O F 2026

How an anatomy lesson sparked a medical career

Anusha Nathan

“Part of why I came to medical school is because I feel like you’re invited into some of the most intimate moments of an individual’s story,” Nathan says. This empathy has driven her since a sixth-grade biology class first sparked a desire to create prosthetics. Though she shifted from engineering to medicine as an undergraduate, her focus on making people better stayed strong. The HST program became her dream because of its emphasis on the mechanistic underpinnings of medicine and “doing good research that is going to fundamentally change the field of medicine.”

GRETCHEN ERTL

M D - PHD P ROG RAM HE ALT H SCIE N C ES AND T EC HNOLOGY T RAC K

When the pandemic redirected her research Nathan started researching HIV vaccines for her HST thesis in

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February 2020. Less than two months later, her path changed when her research adviser, Gaurav Gaiha, an HMS associate professor of medicine at Massachusetts General Hospital, asked if she wanted to work on developing a vaccine for COVID-19. Nathan said yes immediately: “It was the most whirlwind experience of my entire life to be able to do science at the pace that we did it in an atmosphere full of individuals who just wanted to make a difference.” Why she’s developing a different kind of vaccine In the Gaiha Lab, Nathan helped develop vaccines that trigger T cells rather than antibodies, targeting parts of viral particles that are unlikely to mutate from year to year or across related viruses. “Our goal is to augment the responses from the current vaccines to prevent us from

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eeding boosters every single n year,” she says. Where her research has taken her Nathan was invited to present her research to the World Health Organization in February 2022 and the United Nations Science, Technology, and Innovation panel in May 2022. She also worked at the Ragon Institute to develop HIV vaccines that are now in clinical trials in sub-Saharan Africa. “I’ve had all these wonderful opportunities,” she says. What’s next Nathan will complete her residency in internal medicine at Mass General’s Stanbury Physician-Scientist Pathway, which supports doctors interested in conducting rigorous bench research alongside a clinical practice. Stephanie McPherson

P O P QUIZ

What advice do you wish you had received at HMS?

MD ’20

Medical training is an ultramarathon made possible by incredible sacrifices — by our family, friends, and our own prime years. The inertia of sacrifice often leads to a slippery slope of sacrifices. It’s important to make these decisions actively and in consultation with those that make the journey possible for you. Remember that a life without anything good is bad, and that there is compound interest on earlier life experiences, too! Ann Durbin

Cheryl Warner

Stephanie Pincus

MD ’93

MD ’79

MD ’68

Don’t stress about your future. You will definitely have success if you were talented enough to get into HMS. Focus on yourself and enjoy the learning process. Be kind to yourself and to others.

My era, the late 1970s, was a time of optimism. There was new federal funding for internal medicine residencies that were primary care focused. The dean of HMS, Robert Ebert, together with two young academic internists, helped design and launch a new practice model called Harvard Community Health Plan (HCHP). Positions were highly desired and I, together with eight of my classmates, took jobs there after residency. What we didn’t know was HCHP’s frailty in a rapidly changing economy — a gap at HMS.

Take full advantage of everything around you and don’t be limited by medical school life.

Charles Maletz MD ’82

I wish we had received some minimal information about the economics of the health care industry and how this would affect our careers. Mary McCarthy-Tiella MSc ’21

Your contribution always matters, so speak up in whichever way you can. HMS is rich in diversity, and you are part of that cultural tapestry. Be confident!

MD ’63

In retrospect, I could have selected my future subspecialty in endocrinology and metabolism at an earlier stage, perhaps during our fourth year. This potentially would have given me the opportunity to acquire more pertinent background knowledge prior to graduation. Peter Dean MD ’71

PhD ’16

Take advantage of the extracurricular groups to learn about career paths outside of academia. There is a whole world out there!

Stephen Smith

John Bullock MD ’68

I had great mentors at HMS, and I always received great advice.

THANK YOU TO THOSE READERS WHO WROTE IN TO SHARE THEIR ADVICE. WE HOPE YOU WILL SHARE YOUR THOUGHTS ON OUR NEXT QUESTION: WHAT HAS BEEN THE MOST SIGNIFICANT CHANGE TO THE PRACTICE OF MEDICINE SO FAR IN THE 21ST CENTURY? WE WELCOME RESPONSES AT ALUMNI.HMS.HARVARD.EDU/ROUNDS OR VIA EMAIL TO HARVARDMEDICINE@HMS.HARVARD.EDU. SUBMISSIONS WILL APPEAR IN PRINT, ONLINE, OR BOTH IN A FUTURE ISSUE OF HARVARD MEDICINE.

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As the only one in my class with a degree in engineering, and despite having majored in chemical engineering, I failed the biochemistry course. I had not realized that biochemistry exams did not test our understanding of biochemistry but instead involved rote memorization. The advice I had needed came in time to help me pass the makeup exam the following summer. It was from my classmate John Raaf, MD ’70, who explained, “That’s how they examine.” So, I memorized.

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Kenneth Bridges MD ’76

Medical school students network far less than those in business school, for instance. The emphasis is on solo accomplishment. Life after medical school, however, is about networking and mentors. I wish I had understood that 50 years ago. Anthony Chen MD ’00

Learn from everyone you have the good fortune to meet — whether they are at their most desperate or at the height of their success. And then learn how other people learn, realizing that everyone is different. These things will help as we serve as physicians, as teachers, as mentors, as scientists, as administrators, as innovators — and even as patients ourselves.

NADIA HAFID

Bliss Chang

Kathy Glatter

Rounds

In Memoriam

1940s 1946

Kenneth A. Tollackson, MD NOVEMBER 30, 2025

JULY 7, 2025

SEPTEMBER 16, 2025

1959

Sol Rockenmacher, MD

John A. Benson Jr., MD

Frederic C. Chang Jr., MD

1950s

JANUARY 16, 2026

1951

Bruce H. Hudson, MD

1963

John E. Remmers, MD NOVEMBER 8, 2025

Richard J. Sampson, MD FEBRUARY 6, 2025

William S. Tihen, MD

OCTOBER 19, 2025

1960s

1953

1960

1964

JANUARY 16, 2026

JANUARY 26, 2025

S. James Adelstein, MD

Diana V. Farnsworth, MD

Michael L. Nieland, MD

DECEMBER 12, 2025

JANUARY 21, 2026

Robert G. Hoskins, MD

William F. Gallagher Jr., MD

Matthew C. Riddle, MD

Donald B. Halverstadt, MD

SEPTEMBER 20, 2025

APRIL 4, 2025

NOVEMBER 5, 2025

1954

Oscar E. Starobin, MD JANUARY 27, 2026

SEPTEMBER 9, 2025

1955

Georgiana S. Boyer, MD DECEMBER 3, 2025

Robert A. Brooks, MD FEBRUARY 26, 2026

Richard Polson McClintock, MD

SEPTEMBER 19, 2025

Firmon E. Hardenbergh, MD Melvin Shafron, MD DECEMBER 11, 2025

Paul H. Altrocchi, MD JANUARY 28, 2026

Thomas E. Farrell, MD OCTOBER 15, 2025

MARCH 20, 2026

Donald L. Rife, MD

Daniel J. O’Connor Jr., MD

OCTOBER 10, 2025

DECEMBER 30, 2025 OCTOBER 9, 2024 1967

Stanton P. Goldstein, MD OCTOBER 22, 2025

Eugene J. Mark, MD

MARCH 20, 2026

MARCH 30, 2026

John M. Bishop, MD Frederick R. Deane, MD

Frederick H. Sillman, MD

Jane S. Perrin, MD (Jane Carol Schutter)

DECEMBER 14, 2025

JUNE 24, 2025

DECEMBER 23, 2025

FEBRUARY 18, 2026

Lyle J. Micheli, MD

1962

Charles R. Jorgensen, MD

APRIL 22, 2026

FEBRUARY 7, 2026

Andrew S. Sun, MD

DECEMBER 5, 2025

George J. Hill, MD

Richard J. Hannah, MD

1961

SEPTEMBER 15, 2024

1957

1966

Mark E. Oren, MD

Thomas H. Covey Jr., MD

NOVEMBER 2, 2025

Phil G. Zimmerman, MD

William B. Stason, MD MARCH 24, 2026

1956

JULY 30, 2025

JANUARY 14, 2026

George E. Strobel Jr., MD

John R. Reigart II, MD

1970

Thomas E. Clarke, MD NOVEMBER 9, 2025

Philip Cohen, MD NOVEMBER 13, 2024

Walter T. Rymzo, MD AUGUST 16, 2025 1973

Bruce Donoff, MD DECEMBER 25, 2025 1975

Ellen A. Fleischnick, MD SEPTEMBER 28, 2025 1979

Stanley D. Reed, MD AUGUST 19, 2025

1980s 1981

Christopher Robert Jones, MD SEPTEMBER 27, 2025 1982

Andy Plisko, MD MARCH 10, 2026 1986

David A. Benaron, MD JULY 19, 2025 1987

Paul Y. Liu, MD

JANUARY 26, 2026

1968

Robert A. Lobis, MD OCTOBER 26, 2025 1969

Arthur W. Boylston II, MD OCTOBER 15, 2025

Mark Hallett, MD NOVEMBER 2, 2025

OCTOBER 21, 2025

1958

1970s

1990s 1992

Nathan S. Trookman, MD OCTOBER 27, 2025

2000s 2009

Julia T. Chu, MD

William L. Elkins, MD

SEPTEMBER 29, 2017

NOVEMBER 11, 2025

Myron A. Hofer, MD

2020s

MARCH 29, 2026

2022

Allan Kliman, MD

Justin Slater Reynolds, MD

DECEMBER 7, 2025

JANUARY 2, 2025 THIS LISTING OF DECEASED ALUMNI INCLUDES THOSE WHOSE NOTICES OF DEATH WERE RECEIVED BETWEEN OCTOBER 22, 2025, AND APRIL 22, 2026.

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HARVARD MEDICINE

ALU M N I RE P ORT

A Challenge to the HMS Community Louise Aronson Alumni Council President

Almost 40 years ago, I stood at a pay phone in Grand Central Station speaking to the surgeon who had interviewed me earlier that day for admission to HMS. I had left Boston enchanted by the school, and its allure disturbed me. I worried Harvard people were arrogant and snobbish, traits I hoped not to develop during my medical training. My interviewer reassured me that I had it all wrong, that what made HMS great was the people. If my four years as Alumni Council president have taught me anything, it’s that he was right. The students, alumni, staff, and leadership I have interacted with are smart, kind, generous, and moral. So it’s because of my deep admiration for this community that, in my final commentary as Council president, I’d like to issue a challenge to all of us with relationships to HMS, the nation’s flagship medical school, to consider how we can do more to improve our health care system and the health of Americans. Physicians are trained to treat disease and injury and to develop new therapeutics. By contrast, health is often the purview of other professions, our equally essential but far less well remunerated colleagues in public health and health policy, social work, and physical therapy. As part of this larger whole, I wonder whether our focus as physicians, scientists, and physician-leaders is where it should be when, decade after decade, American health outcomes continue to fall far short of those in peer countries while costing considerably more. Are we making the best use of our education and voices at a moment when so many in this country lack access at every level of care, when the less fortunate among us are also less likely to receive standard-ofcare treatments, and when medical costs are the leading cause of bankruptcy? With apologies for the crude metaphor: Isn’t it a problem that we pride ourselves on our skills in cleaning the bathroom, fixing the oven, and designing a cutting-edge alarm system while the house crumbles around the family that lives there?

Many at HMS are already doing this important work. Among the characteristically outstanding initiatives led by its faculty are the innovative educational programs of the Office for Community Centered Medical Education, the research of health policy experts such as Zirui Song, MD ’14, on private equity in health care, and the investigative work of cardiologist Lisa Rosenbaum for her New England Journal of Medicine podcast Not Otherwise Specified. But while such efforts are mentioned in official newsletters and speeches, almost without exception, health systems and the media tout scientific discoveries, real estate acquisitions, and cutting-edge therapeutics more fervently and frequently. Too often, the deeply significant work of connecting care with patients is lost in a sea of notably more enthusiastic reportage about surgeries and organ-focused

I wonder whether our focus as physicians, scientists, and physicianleaders is where it should be.

centers, discoveries, and commercial ventures. Enthusiasm, it seems to me, reflects values, and values direct priorities. In my four years leading the Council, I have worked with alumni from diverse specialties, backgrounds, locations, and HMS generations. Their intelligence and integrity, as well as our largely shared ambitions for HMS and medicine, make me wonder what more we might do as individuals and as alumni to heal the many ails of American health care. At Harvard, thousands of alumni, faculty, and students proudly supported the institution as it stood up to federal efforts to interfere with its core functions. But many of us have remained fairly quiet in the face of steadily worsening medical injustices or the “businessification” of health care, a nationwide trend

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that has suspiciously coincided with declines in access and outcomes for patients and record dissatisfaction among clinicians. It is clear that we cannot rely on insurance companies and corporate health groups, whether for-profit or nonprofit, to create systems that support patients and clinicians — indeed, all trends point in the opposite direction. Given our outstanding education and outsized reach in health care, I wonder what would happen if more of us, whether in practice or academia, industry or administration, decided to more highly prioritize and valorize improving health and access to good medical care for Americans and human beings worldwide. If in our specialties and societies, institutions and health systems, we consistently advocated both for fundamental reform of our health care system — even if we have benefited personally from its current priorities — and for ways to get the multitude of proven behaviors and treatments to the hundreds of millions of people who need them. If, in other words, we prioritized health and health equity even as we continue to work in science and medicine. Of course, it’s easy to talk about change and much more difficult to make it happen, especially in this fraught moment for health care and our nation. Following money is not just understandable but necessary. People need jobs. Prestige matters. Budgets are finite. But it’s also true that making a difference requires ambitious goals and taking risks. Our current systems are failing most of us. Surely it’s time to better align our priorities as physicians and health scientists with our nation’s greatest needs. Challenging times offer opportunities for change. Given the remarkable talents and reach of the people I have had the pleasure of working with these last four years as Alumni Council president, I would love to see HMS and HMS alumni at the vanguard of these efforts. Together, we can move the U.S. toward better health care for all by advancing policies, training students, and filling hallways, clinics, hospitals, laboratories, and leadership with physicians determined to steer our nation to a more equitable and cost-effective health system, one that produces the sorts of outcomes worthy of an HMS education.

WHAT WILL BE YOUR LEGACY? When you include Harvard Medical School in your estate plan, you create a legacy of

Did You Know? 1

helping to secure a healthier tomorrow. By following these tips, you can make a

A retirement account can be the most highly-taxed asset that people pass to heirs. TIP: Leave other types of assets to your heirs and gift retirement assets to a charitable organization such as HMS.

larger gift to the School while maintaining control of your assets in your lifetime.

Designating HMS as a beneficiary of your individual retirement account, investment account, savings account, or donor-advised fund is as easy as filling out a form.

Benefits Shared by both gift options:

• Fulfill your financial, tax, and estate planning goals

• Reduce or eliminate estate tax • Improve health and well-being for all

Without a will, the laws of your state will decide how your estate is divided. TIP: Work with an attorney to create a will or living trust that accomplishes your personal and philanthropic goals.

• Create enduring impact at Harvard Including HMS in your will or living trust is a simple way to make a gift—it costs nothing now but provides future support for the causes most important to you.

Learn more at hms.harvard.edu/future-gifts

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“The whole reason I got interested in science was being able to see something for the first time that no one else has ever seen and then to be able to understand it better.” S U S I E H U A N G , M D ’ 1 0 ( T U R N T O PA G E 3 8 F O R M O R E )