Beneficial gut microbe has surprising metabolic capabilities

To address childhood malnutrition — which affects 200 million children globally — researchers at Washington University School of Medicine in St. Louis developed a therapeutic food that nourishes the collections of beneficial microbes that reside in the gut, and improves children’s growth and other measures of their health. But to understand just how this food therapy works, the research team led by physician-scientist Jeffrey I. Gordon, MD, zeroed in on how the children’s gut microbiomes respond to the therapy.

In their latest study, the researchers discovered potentially far-reaching effects of a particular gut bacterium that was linked to better growth in Bangladeshi children receiving a therapeutic food designed to nurture healthy gut microbes. This microbiota-directed therapeutic food is called MDCF-2. A strain of the bacterium harbored in the children’s gut microbial communities possessed a previously unknown gene capable of producing and metabolizing key molecules involved in regulating many important functions ranging from appetite, immune responses, neuronal function, and the ability of pathogenic bacteria to produce disease.

The results are published Oct. 25 in the journal Science.

“As we apply new therapies to treat childhood malnutrition by repairing their gut microbiomes, we have an opportunity to study the inner workings of our microbial partners,” said Gordon, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology at WashU Medicine. “We are discovering how the gut microbes affect different aspects of our physiology. This study shows that gut microbes are master biochemists that possess metabolic capabilities that we have been unaware of.”

A better understanding of the effects our gut microbes have on our bodies could lead to new strategies to maintain human health and help guide the development of therapeutics for a wide variety of diseases beyond malnutrition, according to the researchers.

In two randomized controlled clinical trials of the therapeutic food in malnourished Bangladeshi children, the researchers identified a collection of microbes whose abundances and expressed functions correlated with the improved growth of study participants. One of these beneficial organisms is a bacterium called Faecalibacterium prausnitzii.

The paper’s co-first authors — Jiye Cheng, PhD, an assistant professor of pathology & immunology at WashU Medicine, and Sid Venkatesh, PhD, a former postdoctoral researcher in Gordon’s lab who is now an assistant professor at the Institute for Systems Biology and an affiliate assistant professor at the University of Washington, both in Seattle — studied mice born under sterile conditions and then colonized with defined communities of microbes cultured from the Bangladeshi children’s microbiomes. They discovered that levels of two molecules called oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were much lower in the guts of animals that had been colonized with microbial communities containing a specific strain of F. prausnitzii, compared with animals lacking this strain. This was notable given that OEA and PEA are naturally occurring lipid signaling molecules known to play important roles in regulating inflammation, metabolism and appetite.

Gordon’s team employed a series of bioinformatics and biochemical tools to identify the enzyme — fatty acid amide hydrolase (FAAH) — that is produced by the bacterial strain and responsible for degrading OEA and PEA. The human version of FAAH is widely known for its ability to break down specific types of neurotransmitters called endocannabinoids, and in so doing, regulate aspects of human physiology throughout the body. In fact, the human version of this enzyme is the target of a number of investigational drugs, because it plays roles in chronic pain, anxiety and mood, among other neurological states.

Cheng and Venkatesh noted that the discovery of the F. prausnitzii FAAH enzyme represents the first example of a microbial enzyme of this type and revealed a role for microbes in regulating levels of important molecules called N-acylethanolamides, including OEA and PEA, in the gut.

Analysis of malnourished children’s fecal samples collected in the clinical trial of the therapeutic food revealed that the food treatment led to decreased levels of OEA while increasing the abundance of F. prausnitzii and expression of its enzyme. These results indicate that this gut bacterial enzyme could reduce intestinal OEA — an appetite-suppressing compound — which is desirable in children with malnutrition.

In addition to providing new insights into the beneficial effects of the therapeutic food, the paper describes how the bacterial enzyme has a dramatically wider range of capabilities than human FAAH does. These include a unique ability to synthesize lipid-modified amino acids, including a number of novel molecules that the team showed to function as modulators of human receptors involved in sensing the external environment of cells, as well as to serve as regulators of immune responses in the gut.

In addition to synthesizing important regulators of cell function, the bacterial enzyme can control levels of other lipid-containing signaling molecules including neurotransmitters involved in communications between neurons, and so-called quorum-sensing molecules that are used by pathogenic bacteria to coordinate infection and disrupt host immune responses.

“The structures of the human and bacterial FAAH enzyme are very distinct; the investigational drugs that inhibit the human enzyme were found to not affect the bacterial enzyme,” Gordon said. “This opens the door to developing new therapeutics to selectively manipulate the activity and products produced by the bacterial enzyme. This is an example of how microbes have evolved functions that aren’t encoded in our own human genomes but are still important for the normal functions of our human bodies. We now know that we have two different versions of this enzyme in two different locations — our human cells and our gut microbiome.”

Gordon and his colleague, Michael Barratt, PhD, a professor of pathology & immunology and a co-author of the paper, highlighted that the identification of this gut bacterial enzyme offers new opportunities to investigate the beneficial effects of the therapeutic food treatment. Barratt also noted that beyond processing components of the normal diet, enzymes like this in the gut could help explain differences in responses seen between individuals to certain orally administered drugs.

“It’s astonishing how much the microbial version of this enzyme can do,” Gordon said. “In our future studies, we’re interested in investigating whether cousins of this enzyme that might be encoded in the genomes of other bacteria could complement FAAH or perform entirely different activities. These organisms are master chemists, and we’re just beginning to explore what they can do.”

NCI director delivers Korsmeyer lecture

W. Kimryn Rathmell, MD, PhD, the director of the National Cancer Institute (NCI) of the National Institutes of Health (NIH), delivered the 19th annual Stanley J. Korsmeyer Memorial Lectureship at Washington University School of Medicine in St. Louis on Thursday, Oct. 17. Korsmeyer was a former WashU Medicine medical oncologist and researcher whose groundbreaking discoveries opened up new ways of understanding and treating cancer. He died of lung cancer in 2005 at age 54.

Speaking to a large audience of WashU Medicine faculty and trainees at the Eric P. Newman Education Center, Rathmell noted that her own research was inspired by Korsmeyer’s work, and she offered her perspective on the next era of cancer research in the U.S. and what it will take to further accelerate progress in the field.

Rathmell highlighted the country’s National Cancer Plan, which sets the ambitious goal of cutting cancer mortality in half by 2047. Citing progress in her own work on kidney cancer as an example, she called for the next era of cancer research to take a 360-degree view of the field in a way that fosters new types of collaborations and that includes a vision for researchers, patients and community members to contribute. She emphasized the importance of equity in the field, taking into consideration differences in race and gender in cancer research and treatment so that interventions benefit all patients. She also pointed to the central importance of cancer prevention and early detection, especially in light of recent trends showing an increase in cancer diagnoses among younger Americans.

Korsmeyer made groundbreaking discoveries in the understanding of programmed cell death — called apoptosis — and how cancer cells resist it. Prior to this work, scientists thought cancer developed because of too much cell proliferation. He remains one of the most widely cited researchers in the world, with more than 100,000 citations and counting.

In her remarks, Rathmell highlighted the exceptional work of WashU Medicine physicians and researchers at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. Siteman is the only NCI-designated Comprehensive Cancer Center in Missouri and the surrounding region and is a national leader in cancer research and clinical care, pioneering the use of genome sequencing to guide cancer treatment. With three Specialized Programs of Research Excellence (SPORE) grants from the NCI — in blood, endometrial and pancreatic cancers — WashU Medicine researchers are at the cutting edge of the field.

The Korsmeyer lecture is part of Siteman Cancer Center’s Basic Science Seminar Series. Launched in 2006, it has brought six Nobel laureates and many other world-renowned scientists to the Medical Campus.

White Coat Ceremony marks beginning of medical training

Few items of clothing are as tied to a profession as a white coat is to being a doctor. For patients and their families awaiting news of a test result, a diagnosis or a treatment plan, the coat signals expertise, responsibility and even hope. Donning white coats for the first time Friday, Oct. 18, members of the newest class at Washington University School of Medicine felt the full weight of that cotton-polyester coat.

Friends and family of the 124 new medical students filled Graham Chapel on the Danforth Campus to witness them receive their white coats from faculty members involved in their training. They then recited their class oath, which they had crafted as a team.

Graphic of statistics on entering class of WashU Medicine in 2024

Katie Gertler

Click image to view full size.

“It is a powerful symbol of the medical profession’s profound responsibility, unwavering dedication and deep commitment to healing,” said Tammy L. Sonn, MD, associate dean for student affairs and a professor of obstetrics & gynecology, in her welcoming remarks.

This year’s cohort includes members of Gen Z fresh from their undergraduate degrees, to early-vintage Millennials arriving from other careers. The class has 65 women and 59 men. Slightly over a quarter are from socioeconomically disadvantaged backgrounds, and 89% have received a merit- or needs-based scholarship. They were drawn to St. Louis from more than half of the states in the U.S., as well as from Canada and France.

In his address at the ceremony, David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of WashU Medicine, and the Spencer T. and Ann W. Olin Distinguished Professor, said that strangers gathering together to pursue the welfare of other people, as these students had chosen to do, is the heart of medicine.

“This ability to care about a person you don’t even know is the miracle of human civilization,” Perlmutter said. “Human bodies fail and they suffer and they hurt each other, and we are the ones charged with fixing them, comforting them and figuring out ways to get them back on their feet.”

Lauren Everett, president of the new class of medical students at WashU Medicine, receives her white coat at a ceremony at Graham Chapel Oct. 18.

Matt Miller

Lauren Everett (left), president of the new class of medical students at WashU Medicine, receives her white coat from Emily Sotaro, MD, associate professor of otolaryngology, at a ceremony at Graham Chapel Friday, Oct. 18.

That theme of service was echoed by the keynote speaker, Dineo Khabele MD, the Mitchell & Elaine Yanow Professor and head of the Department of Obstetrics & Gynecology, who recalled her early training in New York at the height of both the AIDS and crack cocaine epidemics. Those patient populations were not always treated with the full dignity they deserved from the medical profession, she said.

“The white coat on its own is not enough; you have to earn the trust of the patients that you serve,” she said. “That trustworthiness comes from your credibility, your competence and your compassion.”

Lauren Everett, president of the new class, served as a medic in the U.S. Air Force for several years, during which she was deployed to Afghanistan. On being promoted to a more supervisory role, she realized that emergency medicine was calling her back.

“You have this opportunity to be the calm in someone else’s storm, and I find that very fulfilling,” Everett said. Nevertheless, she added, becoming a doctor “is a little bit intimidating. We’re going to be the ones who people are going to come looking for when things go wrong, so there’s a level of increased responsibility.”

Matt Miller

Larissa Rays Wahba, a student in the Medical Scientist Training Program at WashU Medicine, poses in the white coat she received during a ceremony at Graham Chapel Friday, Oct. 18.

As a student in the Medical Scientist Training Program at WashU, Larissa Rays Wahba is drawn to the lab and the clinic. A native of Brazil, Rays Wahba moved to New York while in middle school. Shortly after, her mother was diagnosed with breast cancer. The family needed to navigate the medical system of a new country in a foreign language.

“There was definitely a lot of fear and confusion,” Rays Wahba said. “But if it hadn’t been for the patience and communications of my mother’s care team to our family, I don’t think she would have had such a successful outcome.”

Rays Wahba’s desire to conduct research was inspired by her mother, who despite the demands of pursuing a law career and raising two daughters, decided to participate in post-treatment medical studies. This introduction to the research component of medical practice is a big part of Rays Wahba’s motivation to study at WashU Medicine. The White Coat Ceremony is a recommitment to those twin desires for service and expanding knowledge.

“Putting it on means that you now have a responsibility to yourself, to your patients, to your community and to society as a whole,” Rays Wahba said.

Implantable device may prevent death from opioid overdose

The opioid epidemic claims more than 70,000 lives each year in the U.S., and lifesaving interventions are urgently needed. Although naloxone, sold as an over-the-counter nasal spray or injectable, saves lives by quickly restoring normal breathing during an overdose, administrating the medication requires a knowledgeable bystander – limiting its lifesaving potential.

A team from Washington University School of Medicine in St. Louis and Northwestern University in Chicago has developed a device that may rescue people from overdose without bystander help. In animal studies, the researchers found that the implantable device detects an overdose, rapidly delivers naloxone to prevent death and can alert emergency first responders.

The findings are available Oct. 23 in Science Advances.

“Naloxone has saved many lives,” said Robert W. Gereau, PhD, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and director of the WashU Medicine Pain Center. “But during an overdose, people are often alone and unable to realize they are overdosing. If someone else is present, they need access to naloxone — also known as Narcan — and need to know how to use it within minutes. We identified an opportunity to save more lives by developing a device that quickly administers naloxone to at-risk individuals without human intervention.”

Prescription opioids – such as oxycodone – have helped people manage the physical and mental challenges of daily debilitating pain. But the addictive properties of painkillers can lead to their misuse and abuse, which are among the driving forces behind the opioid epidemic. In addition, cheap and easy-to-access synthetic drugs – fentanyl, for example – have flooded the illicit market. Such ultrapotent drugs have accelerated the rise in overdose deaths in the U.S. and were responsible for roughly 70% of such deaths in 2023.

The researchers worked with experts in engineering and material sciences led by John A. Rogers, PhD, a professor of materials science and engineering, biomedical engineering and neurological surgery at Northwestern University, to develop a device – the Naloximeter – that uses a drop in oxygen levels as a signal for a potential overdose. Overdosing on opioids leads to slow and shallow breathing. Minutes after the drugs begin to impact respiratory function, breathing stops. Implanted under the skin, the Naloximeter senses oxygen in the surrounding tissues, sending a warning notification to a mobile application if the levels drop below a threshold. If the user doesn’t abort the rescue process within 30 seconds, the device releases stored naloxone.

graphical representation of the function of the naloximeter

Eric Young

Implanted under the skin, the Naloximeter, developed by researchers at WashU Medicine and Northwestern University, senses dropping oxygen in the surrounding tissues and sends a warning notification to a mobile application. If the user doesn’t engage with the warning message within 30 seconds, the device releases stored naloxone and can send an alert to first responders.

The researchers implanted the device in the neck, chest or back of small and large animals. The device detected signs of overdose within a minute of dropping oxygen levels, and all animals fully recovered within five minutes of receiving naloxone from the devices.

Naloxone displaces harmful opioids from receptors on the surface of brain cells, altering the cells’ activity. But the drug doesn’t stick around; when the opioids reoccupy and reactivate the receptors, overdose symptoms can return. To provide additional support, the device relays an emergency alert to first responders.

“An additional benefit of calling first responders is that it helps people re-engage with health-care providers,” said Jose Moron-Concepcion, PhD, the Henry E. Mallinckrodt Professor of Anesthesiology at WashU Medicine and an author on the study. “We want to save people from dying from an overdose and also reduce harm from opioids by helping people access the resources and treatments to prevent future overdoses from occurring.”

The researchers were awarded a patent – with some help from the Office of Technology Management at WashU – to protect the intellectual property of the device.

“The Naloximeter is a proof-of-concept platform that isn’t limited to the opioid crisis,” said Joanna Ciatti, a graduate student in Rogers’ lab. “This technology has far-reaching implications for those threatened by other emergent medical conditions such as anaphylaxis or epilepsy. Our study lays important groundwork for future clinical translation. We hope others in the field can build off of these findings to help make autonomous rescue devices a reality.”

Nancy Spector, MD, speaks to WashU Medicine faculty at the Eric P. Newman Education Center.

ELAM program provides leadership development opportunities for faculty

Nearly 100 faculty members from Washington University School of Medicine in St. Louis attended a daylong session led by the Hedwig van Ameringen Executive Leadership in Academic Medicine (ELAM) program focused on building critical leadership skills, embracing sponsorship and exploring effective ways to communicate as tools to advance their careers and professional impact.

The event, held Oct. 10 at the Eric P. Newman Education Center, included networking opportunities and two formal workshops, Empowering Excellence: The Art of Being an Effective Sponsor and Sponsee and Graceful Self-Promotion: Strategies to Support Success, Belonging and Inclusion. Led by Nancy Spector, MD, and Kheyandra Lewis, MD, the workshops addressed issues that impact career advancement for faculty from a range of experiences and disciplines. Research shows that faculty who are sponsored and who effectively communicate their impact typically advance further and faster than those who lack these supports.

“Sponsorship and effective communication are key leadership skills,” said Renée Shellhaas, MD, senior associate dean for faculty promotions and career development and the David T. Blasingame Professor of Neurology at WashU Medicine. “This full day of workshops and networking, capped off by an excellent keynote talk, exemplifies the proactive steps we are taking at WashU Medicine to develop and support the careers of our faculty and their leaders.”

Spector, a nationally recognized expert in faculty development and leadership education, concluded the day with a keynote address, “Moving the Needle: Strategies to Support Success, Belonging and Inclusion.”

The address, which drew attention to key areas impacting faculty advancement, from elder care responsibilities to representation, dovetailed with the priorities at the heart of WashU Medicine’s push to be a leader in faculty development, said David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of WashU Medicine and the Spencer T. and Ann W. Olin Distinguished Professor.

“Sponsoring this event is a symbol of our school’s commitment to leadership development, inclusion and belonging,” Perlmutter said in welcoming the ELAM team and introducing Spector’s address. “As our community becomes more diverse, it is important to me — and to all of us — that everyone who works and studies at WashU is supported to reach their full potential. That means we all need to work to build work environments where respect, professionalism, trust, inclusion, and belonging are prioritized.”

Now in its 30th year, ELAM is one of the nation’s most prestigious leadership development programs for women in academic medical and health sciences fields. The program has more than 1,500 alumnae (ELUMs), including several current WashU Medicine faculty. The Office of Faculty Promotions & Career Development sponsors eligible faculty to apply and participate in ELAM programs.

Cardiac tissue from mouse models of heart failure treated with a monoclonal antibody show much less scarring than untreated animals

Immunotherapy blocks scarring, improves heart function in mice with heart failure

A new study from Washington University School of Medicine in St. Louis suggests that a type of immunotherapy — similar to that approved by the Food and Drug Administration (FDA) to treat inflammatory conditions such as arthritis — also may be an effective treatment strategy for heart failure.

The study is published Oct. 23 in the journal Nature.

After a heart attack, viral infection or other injury to the heart, scar tissue often forms in the heart muscle, where it interferes with the heart’s normal contractions and plays a leading role in heart failure, the progressive loss of the heart’s ability to pump sufficient blood to the body. This chronic condition creates a worsening feedback loop that can only be slowed with available medical therapies, but it has no cure.

Studying human tissue samples as part of the new study, the researchers identified a type of fibroblast cell in the heart as the main culprit responsible for the formation of scar tissue in heart failure. To see if they could prevent scar formation, the scientists turned to mouse models of heart failure that have the very same type of fibroblasts. They used a therapeutic protein — called a monoclonal antibody — that blocks the formation of this harmful type of fibroblast, and succeeded in reducing the formation of scar tissue and improving heart function in the mice.

“After scar tissue forms in the heart, its ability to recover is dramatically impaired or impossible,” said cardiologist and senior author Kory Lavine, MD, PhD, a professor of medicine in the Cardiovascular Division at WashU Medicine. “Heart failure is a growing problem in the U.S. and globally, affecting millions of people. Current treatments can help relieve symptoms and slow the progression, but there is a tremendous need for better therapies that actually stop the disease process and prevent the formation of new scar tissue that causes a loss of heart function. We are hopeful our study will lead to clinical trials investigating this immunotherapy strategy in heart failure patients.”

Fibroblasts have many roles in the heart, and parsing out the differences between various populations of these cells has been challenging. Some types of fibroblasts support the heart’s structural integrity and maintain good blood flow through the heart’s blood vessels, while others are responsible for driving inflammation and the development of scar tissue. Only recently, with the wide availability of the most advanced single cell sequencing technologies, could scientists peg which groups of cells are which.

“These various types of fibroblasts highlight newly recognized opportunities to craft treatment strategies that specifically block the type of fibroblasts that promote scarring and protect fibroblasts that maintain the structure of the heart, so the heart doesn’t rupture,” Lavine said. “Our research suggests that the fibroblasts that promote scarring in the injured heart are very similar to fibroblasts associated with cancer and other inflammatory processes. This opens the door to immunotherapies that potentially can stop the inflammation and resulting scar tissue.”

The research team, co-led by Junedh Amrute, a graduate student in Lavine’s lab, used genetic methods to demonstrate that a signaling molecule called IL-1 beta was important in a chain of events driving fibroblasts to create scar tissue in heart failure. With that in mind, they tested a mouse monoclonal antibody that blocks IL-1 beta and found beneficial effects in the mouse hearts. The mouse monoclonal antibody was provided by Amgen, whose scientists were also co-authors of the study. Monoclonal antibodies are proteins manufactured in the lab that modulate the immune system. The treatment reduced the formation of scar tissue and improved the pumping capacity of the mouse hearts, as measured on an echocardiogram.

At least two FDA-approved monoclonal antibodies — canakinumab and rilonacept — can block IL-1 signaling. These immunotherapies are approved to treat inflammatory disorders such as juvenile idiopathic arthritis and recurrent pericarditis, which is inflammation of the sac surrounding the heart.

One of these antibodies also has been evaluated in a clinical trial for atherosclerosis, a buildup of plaque that hardens the arteries. The trial, called CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study), showed a benefit for study participants with atherosclerosis.

“Even though this trial was not designed to test this treatment in heart failure, there are hints in the data that the monoclonal antibody might be beneficial for patients with heart failure,” Lavine said. “Secondary analyses of the data from this trial showed that the treatment was associated with a sizable reduction in heart failure admissions compared with standard care. Our new study may help explain why.”

Even so, the IL-1 antibody used in the CANTOS study had some side effects, such as increased risk of infection, that could perhaps be reduced with a more targeted antibody that specifically blocks IL-1 signaling in cardiac fibroblasts, according to the researchers.

“We are hopeful that the combination of all of this evidence, including our work on the IL-1 beta pathway, will lead to the design of a clinical trial to specifically test the role of targeted immunotherapy in heart failure patients,” Lavine said.

WashU Medicine faculty members gather for the First R01 Celebration.

WashU Medicine celebrates first R01 recipients

Washington University School of Medicine in St. Louis celebrated rising investigators at the First R01 Celebration, marking a significant milestone for scientists embarking on their independent research careers.

The event honored recipients of their first R01 research grants from the National Institutes of Health (NIH). The research grants represent the NIH’s recognition of investigators’ rigorous, innovative proposals and confidence in the impact of the research.

“The path to the first R01 grant is demanding and highly competitive,” said Mark Lowe, MD, PhD, vice chancellor for research and the Harvey R. Colten Professor of Pediatric Science at WashU Medicine, to the honorees gathered on Oct. 8 at Moore Auditorium for a formal celebratory program. “Success requires rigorous planning, a compelling research hypothesis and significant preliminary data. Each of you has met and likely exceeded the expectations of your study sections. Your first R01 is an example of what you can do through dedication, innovation and relentless pursuit of scientific excellence.”

The celebration was organized and sponsored by the Office of Faculty Promotions and Career Development and the Office of the Vice Chancellor for Research.

“These awards demonstrate the high caliber and impact of your research as recognized by your peers and the wider scientific community,” said Renée Shellhaas, MD, senior associate dean for faculty promotions and career development and the David T. Blasingame Professor of Neurology.

David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of WashU Medicine and the Spencer T. and Ann W. Olin Distinguished Professor, congratulated the honorees, and Iris Dickhoff-Peper, PhD, assistant vice chancellor for research, presented on post-award processes to support a growing research portfolio.

The program concluded with a Q&A panel composed of senior and rising investigators, including William G. Powderly, MD, the J. William Campbell Professor of Medicine, co-director of the Division of Infectious Diseases and the Larry J. Shapiro Director of the Institute for Public Health; Melanie Fields, MD, associate professor of pediatrics and of neurology; and Harrison Gabel, PhD, associate professor of neuroscience.

First R01 Celebration honorees:

Tao Che, PhD, Anesthesiology
Abby Ling-Lee Cheng, MD, Orthopaedic Surgery
Jessika Contreras, MD, Radiation Oncology
Nicole Marie Gilbert, PhD, Pediatrics
Gabriel E. Haller, PhD, Neurosurgery
Amjad Horani, MD, Pediatrics
Jing Wang Hughes, MD, PhD, Medicine, Endocrinology, Metabolism and Lipid Research
Alexxai V. Kravitz, PhD, Psychiatry
Vivia V. McCutcheon, PhD, Psychiatry
Naoka Murakami, MD, PhD, Medicine, Nephrology
Stephanie Markovina, MD, PhD, Radiation Oncology
Hysell Viviana Oviedo, PhD, Neuroscience
Russell K. Pachynski, MD, Medicine, Oncology
Cyrus A. Raji, MD, PhD, Radiology
David A. Rosen, MD, PhD, Pediatrics
Dmitri Samovski, PhD, Medicine, Geriatrics and Nutritional Science
Chihiro Sato, PhD, Neurology
Jason D. Ulrich, PhD, Neurology
Diana J. Whalen, PhD, Psychiatry
Elizabeth L. Yanik, PhD, Orthopaedic Surgery
Christian W. Zemlin, PhD, Surgery
Jin Zhang, PhD, Radiation Oncology

Other faculty members who have recently received first R01 or equivalent awards:

Erik R. Dubberke, MD, Medicine, Infectious Diseases
Angela Hirbe, MD, PhD, Medicine, Oncology
Andrew Findlay, MD, Neurology
Carmen Halabi, MD, PhD, Pediatrics
Ashley Steed, MD, PhD, Pediatrics
Michael H. Johnson, MD, Surgery
William C. Chapman, Jr., MD, Surgery
Stephanie Perkins, MD, Radiation Oncology
Kristen Sanfilippo, MD, Medicine, Hematology and Oncology
Aimilia Gastounioti, PhD, Radiology

Adam Kepecs, PhD, the Robert J. Terry Professor of Neuroscience and a professor of psychiatry at WashU Medicine, has been awarded the NIH Director’s Pioneer Award to explore how the brain interprets immune system signals and how they contribute to psychiatric conditions such as depression.

Kepecs awarded NIH Director’s Pioneer Award

Adam Kepecs, PhD, the Robert J. Terry Professor of Neuroscience and a professor of psychiatry at Washington University School of Medicine in St. Louis, has been selected for a National Institutes of Health (NIH) Director’s Pioneer Award, to study how the brain’s neural circuits decode signals from the immune system and orchestrate adjustments in behavior and motivation. The prestigious award, from the NIH, is designed to support high-risk, high-reward research. As part of the honor, the Kepecs lab will receive a total of $3.5 million in funding over five years.

A BJC Investigator at WashU Medicine, Kepecs is renowned for his work on brain circuits involved in cognition and decision making, and how these circuits can produce psychiatric symptoms. The Pioneer Award will support his pursuit of an intriguing hypothesis: that immune signals, such as cytokines, are sensed by brain circuits and contribute to mood disorders such as depression.

“We are thrilled Dr. Kepecs has received this impressive honor from the NIH,” said Linda Richards, PhD, the Edison Professor and head of the Department of Neuroscience at WashU Medicine. “Dr. Kepecs is an innovative and creative thinker, and this work in particular has enormous potential to change our understanding of how immune signals may be sensed by specific cells and circuits in the brain to impact cognition and behavior.”

Kepecs’ team will map immunoceptive circuits — the brain pathways that detect immune signals — and translate them into behavioral responses. While immune signals such as inflammatory cytokines can trigger protective behaviors during acute illness, they also may drive long-term changes in mood and motivation in chronic inflammatory conditions.

The genesis of this work is the influence the immune system has on our behavior when we are sick. Fever, nausea, vomiting, and the desire to crawl into bed and never leave are the unpleasant but necessary tools the body uses to cope with and outlast an infection. The physical symptoms of fever and vomiting have known neurological triggers that respond to the presence of infection-fighting molecules, called cytokines, from the immune system. The psychiatric crawl-into-bed symptoms such as apathy and depression also may be triggered by cytokines, according to Kepecs.

By pursuing how the immune system interacts with neural circuits that are involved in psychiatric disorders, Kepecs and his lab are sailing into unfamiliar waters, seeking to discover how conditions such as depression emerge – and perhaps how to alleviate them.

“If we can identify the relevant neural circuits, we can gain insight into how the brain communicates with the immune system,” said Kepecs, “and open immediate opportunities for developing targeted drugs for depression and related conditions.”

The research uses cutting-edge technologies for whole-brain mapping, cellular-resolution activity tracking, and precise manipulations of neural circuits.

In previous research, Kepecs has pioneered the understanding of how the brain calculates confidence in decisions, treating confidence not as a vague feeling but as a measurable process rooted in neural circuits. His team demonstrated that confidence reflects a probability calculation — how likely one is to make the right choice based on evidence. By studying this in humans and rodents, the researchers identified specific brain circuits and cell types that perform these calculations, with implications for psychiatric disorders including anxiety and compulsive behavior.

Building on this foundation, Kepecs has shown how computational analysis of behavior can provide an objective framework to study mental dysfunctions and link human to animal behavior for deeper mechanistic insights. This approach paves the way for more precise diagnoses of psychiatric conditions. In one study, Kepecs’ lab identified brain circuits responsible for hallucination-like perception in rodents, with the goal of translating these findings to better understand psychosis in humans.

Kepecs was named a BJC Investigator in 2019 and has been recognized for excellence in research as a Kavli Frontiers of Science fellow, a John Merck Scholar, a Klingenstein Fellow and an Alfred P. Sloan research fellow. He also has been awarded the McKnight Foundation Memory and Cognitive Disorders Award.

Camacho honored by NIH for research on emotional neurodevelopment

Maria Catalina Camacho, PhD, an assistant professor in the Department of Psychiatry at Washington University School of Medicine in St. Louis, has received the NIH Director’s Early Independence Award, part of the National Institutes of Health (NIH) High-Risk, High-Reward Research program.

This year, the award provides $1.25 million over five years to, according to the NIH, “promising, newly graduated scientists with the intellect, scientific creativity, drive and maturity” to take an accelerated path to an independent research career. Around 10 scholars are selected for this opportunity annually.

Camacho’s research focuses on how the human brain makes sense of a person’s social and emotional worlds, with the goal of better understanding the neurobiological underpinnings that place some children at risk for developing anxiety or depressive symptoms.

The grant will help fund a study that will test a computational model of how early experiences shape emotional neurodevelopment. To build such a model, Camacho’s lab will collect data from 3- and 4-year-old children. “By doing this, we can test hypotheses about how early social experiences shape our brains to learn how to understand emotions,” Camacho said. “We think that early emotional neurodevelopment can set up a child to be more or less vulnerable to developing anxiety or depressive symptoms later in life, so this is an important basic scientific step to understanding how depression and anxiety emerge.”

“I am so excited by this study,” Camacho said. “I’ve always been motivated to study anxiety and depression by, unfortunately, the many loved ones in my life who have struggled with these symptoms, especially the negative social consequences of them. Depression and anxiety commonly co-occur but have distinct features. I and many others think that identifying the developmental and neuroscientific basis will make it easier to identify children at risk and potentially inform intervention and treatment.”

Chad M. Sylvester, MD, PhD, an associate professor of psychiatry at WashU Medicine who has mentored Camacho, said she “is a superstar who is incredibly deserving of this highly competitive early-career award. She is the whole package: Dr. Camacho has groundbreaking ideas; she is a gifted communicator; she is a tireless and highly dedicated mentor; and she is an amazing colleague and collaborator. I cannot wait to see the incredible science that she produces.”

Camacho earned a bachelor’s degree with honors in psychology in 2014 from Stanford University in Palo Alto, Calif., and her doctorate in neuroscience in 2022 from WashU Medicine’s Division of Biology & Biomedical Sciences under Deanna M. Barch, PhD, vice dean of research and a professor of psychological & brain sciences in Arts & Sciences, and the Gregory B. Couch Professor of Psychiatry. Camacho is continuing her research at WashU Medicine.

A fluorescent green and red image of the airways of a mouse lung.

Viruses found hiding in lungs’ immune cells long after initial illness

Doctors have long known that children who become seriously ill with certain respiratory viruses such as respiratory syncytial virus (RSV) are at elevated risk of developing asthma later in life. What they haven’t known is why.

A new study by researchers at Washington University School of Medicine in St. Louis may have solved the mystery. The study, in mice, shows that respiratory viruses can hide out in immune cells in the lungs long after the initial symptoms of an infection have resolved, creating a persistently inflammatory environment that promotes the development of lung disease. Further, they showed that eliminating the infected cells reduces signs of chronic lung damage before they progress to a full-blown chronic respiratory illness.

The findings, published Oct. 2 in Nature Microbiology, point to a potential new approach to preventing asthma, chronic obstructive pulmonary disease (COPD) and other chronic lung diseases by eradicating the persistent respiratory viruses that fuel these conditions.

“Right now, children who have been hospitalized for a respiratory infection such as RSV are sent home once their symptoms resolve,” said senior author Carolina B. López, PhD, a professor of molecular microbiology and a BJC Investigator at WashU Medicine. “To reduce the risk that these children will go on to develop asthma, maybe in the future we will be able to check if all of the virus is truly gone from the lung, and eliminate all lingering virus, before we send them home.”

About 27 million people in the U.S. are living with asthma. Many factors influence a person’s likelihood of developing the chronic breathing illness, including living in a neighborhood with poor air quality, having exposure to cigarette smoke and being hospitalized for viral pneumonia or bronchitis while young. Some researchers — López included — suspected that the link between serious lung infection and subsequent asthma diagnosis was due to lingering virus in the lungs that causes ongoing damage, but a direct link between the ongoing presence of virus and chronic lung disease has not been previously shown.

López and first author Ítalo Araújo Castro, PhD, a postdoctoral researcher in her lab, developed a unique system involving a natural mouse virus known as Sendai virus, and fluorescent markers of infection. Sendai is related to human parainfluenza virus, a common respiratory virus that, like RSV, has been linked to asthma in children. Sendai behaves in mice in very much the same way that human parainfluenza virus behaves in people, making it an excellent model of the kinds of infections that could lead to chronic lung disease.

Using the fluorescent trackers, the researchers could observe signs of the virus throughout infection. After about two weeks, the mice recovered, but viral RNA and protein were still detectable several weeks later in their lungs, hidden away in immune cells.

“Finding persistent virus in immune cells was unexpected,” López said. “I think that’s why it had been missed before. Everyone had been looking for viral products in the epithelial cells that line the surface of the respiratory system, because that’s where these viruses primarily replicate. But they were in the immune cells.”

Moreover, the presence of the virus changed the behavior of the infected immune cells, causing them to become more inflammatory than the uninfected immune cells. Persistent inflammation sets the stage for chronic lung disease to arise, the researchers said. Indeed, seven weeks after infection, the mice’s lungs exhibited inflammation of air sacs and blood vessels, abnormal development of lung cells and excess immune tissue — all signs of chronic inflammatory lung damage, even though the mice appeared outwardly to have recovered. Once the infected immune cells were eliminated, the signs of damage diminished.

“We use a perfectly matched virus-host pairing to prove that a common respiratory virus can be maintained in immunocompetent hosts for way longer than the acute phase of the infection, and that this viral persistence can result in chronic lung conditions,” Castro said. “Probably the long-term health effects we see in people who are supposed to be recovered from an acute infection are actually due to persistence of virus in their lungs.”

The findings point to new ways to think about preventing chronic lung diseases, the researchers said.

“Pretty much every single child gets infected with these viruses before the age of 3, and maybe 5% get serious enough disease that they could potentially develop persistent infection,” López said. “We’re not going to be able to prevent children from getting infected in the first place. But if we understand how these viruses persist and the effects that persistence has on the lungs, we may be able to reduce the risk of serious long-term problems.”

image of a medical professional using a needle to inject vaccine into patient's arm

$12 million grant aimed at probing how vaccines induce lasting immunity

Researchers at Washington University School of Medicine in St. Louis have received a $12 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) to study how vaccines trigger long-lasting immune responses. The work may inform the design of new, more protective vaccines for respiratory viruses, including SARS-CoV-2 and influenza.

“During the COVID-19 pandemic, we witnessed the development of effective vaccines against SARS-CoV-2 in record time,” said Ali Ellebedy, PhD, the Leo Loeb Professor of Pathology & Immunology at WashU Medicine. “But we also watched their effectiveness wane in a matter of months. Our work aims to understand how to design vaccines that trigger enduring immunity against rapidly mutating respiratory viruses.”

Waning immunity is not unique to COVID-19 vaccines. For five decades, the flu vaccine has required an annual update. Antibodies that help clear the influenza virus are almost gone within six months to a year after infection or vaccination, Ellebedy explained, and the virus is adept at rapidly changing to escape immune protection, rendering the previous year’s vaccine ineffective.

But other vaccines maintain immunity long-term or indefinitely. The smallpox vaccine offered strong protection that helped eradicate the virus, rendering routine immunization unnecessary. Vaccines against polio, chickenpox, measles, mumps and rubella, among others, confer lifelong immunity. Some vaccines require a periodic booster that reeducates the immune system how to respond to a threat.

“Lifelong protection is the gold standard in vaccine development,” Ellebedy said. “We have an opportunity to learn from successful vaccine events, which have stopped the spread of pathogens or even eliminated them. We need to understand what such vaccines are doing to the immune system that the flu and COVID-19 vaccines are not able to do.”

Ellebedy is leading the newly funded study with co-principal investigator Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine, and clinical lead Rachel M. Presti, MD, PhD, a professor of medicine. As co-directors of the Center for Vaccines & Immunity to Microbial Pathogens at WashU Medicine, funded in part by Andrew M. and Jane M. Bursky, the trio has built the infrastructure that will help them define the factors that enable enduring immunity after vaccination.

The researchers will immunize study participants against influenza viruses and SARS-CoV-2 and examine B and T cells – subsets of immune cells involved in fighting pathogens – in the blood, draining lymph nodes and bone marrow. Induced immune responses after a flu or COVID-19 vaccine will be compared with responses after systemic vaccines that trigger effective, lifelong immune responses.

Respiratory viruses infect the mucus-secreting membranes of the respiratory tract, including the nose, sinuses, throat, airways and lungs. The researchers also will study the durability of the immune response at the infection site of study participants who recover from COVID-19 or the flu, compared with the systemic immune responses in the blood of the same participants. Such knowledge may help guide the design of nasal vaccines for respiratory viruses.

Their work adds to other major pandemic preparedness research projects at WashU Medicine. Recently, Diamond and Sean Whelan, PhD, the Marvin A. Brennecke Distinguished Professor and head of the Department of Molecular Microbiology, were awarded two grants totaling more than $90 million over the next three years from NIAID to design rapid responses to pathogens such as chikungunya, dengue and parainfluenza viruses.

“Respiratory viruses threaten world health,” said Diamond, also a professor of molecular microbiology and of pathology & immunology. “To prevent viral outbreaks, we need more effective vaccines. Studying human immune responses after vaccination or infection will help untangle the immunological shortcomings of current vaccines and identify the factors that are responsible for comprehensive and long-lasting immunity against disease.”

Thomas Nickolas, director of the Division of Bone and Mineral Diseases starting January, 2025

Nickolas to lead Division of Bone and Mineral Diseases

Thomas Nickolas, MD, a respected clinical nephrologist and researcher focused on kidney disease and bone health, has been named the next director of the Division of Bone and Mineral Diseases in the Department of Medicine at Washington University School of Medicine in St. Louis. He comes to WashU Medicine from Columbia University in New York and will begin his new role in January.

“It is a great pleasure to welcome Dr. Nickolas to WashU Medicine,” said Victoria J. Fraser, MD, the Adolphus Busch Professor of Medicine and head of the Department of Medicine. “He has a well-earned reputation as a creative and dedicated physician-scientist, and we are excited to have him further advance the division’s mission to combine research and exceptional patient care. His efforts to understand the links between kidney health and bone health have led to clinical trials for treatments that will improve the quality of life and overall health of people with kidney diseases.”

Nickolas investigates the effects of kidney function on skeletal health across the life span. He also has studied the impact of HIV and metabolic disorders such as diabetes on skeletal health. All of these contribute to bone impairments, in which the normal accumulation and retention of key minerals in the skeletal system are dysregulated, resulting in bone weakness, deformities and fractures.

Insights from his research have led his team to develop novel approaches to understand and treat bone disorders and prevent fractures in patients with kidney diseases.

A graduate of Rutgers University in New Brunswick, N.J., Nickolas earned his medical degree from the University of Pittsburgh School of Medicine in Pennsylvania. He completed his residency at the University of Pennsylvania and his nephrology fellowship at Columbia University, a training program he went on to direct. He earned a master’s degree in biostatistics and epidemiology from the Columbia University Mailman School of Public Health.

Nickolas is an active leader in the American Society of Nephrology, the American Society for Bone and Mineral Research, the Kidney Disease Improving Global Outcomes Guidelines Group, the International Osteoporosis Foundation, and is co-organizing the 2025 and 2027 Gordon Research Conferences on Physiology, Biology and Pathology of Phosphate. His contributions to the field were recognized this year with the American Society of Nephrology’s Jack Coburn Endowed Lectureship on Bone and Mineral Disorders in chronic kidney disease.

“It is both humbling and an honor to assume the role of director of the bone and mineral diseases division,” said Nickolas. “This is a storied division that has made unprecedented contributions to the whole gamut of bone and mineral diseases. The expertise here, from epigenetics to endocrinology and beyond, makes WashU Medicine one of the most exciting and rewarding places in the country to work in bone and mineral disorders. I am excited for the future of this group and how it will continue to advance our shared mission of improving musculoskeletal health for all.”

Nickolas is stepping into a role held for the past 14 years by Roberto Civitelli, MD, the Sydney M. and Stella H. Shoenberg Professor of Medicine. During Civitelli’s tenure, the division has developed innovative training initiatives, such as the Skeletal Disorders Training Program and the Metabolic Bone Disorders fellowship, while also expanding its research footprint.

Civitelli will continue his work in the clinic and lab as a faculty member in the Department of Medicine and as a professor of orthopedic surgery and of cell biology & physiology.

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