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Patient defies genetic fate to avoid Alzheimer’s

Remarkably, Doug Whitney, 75, has escaped genetic destiny. Like many members of his family, Whitney inherited a rare genetic mutation that all but guarantees he would develop early-onset Alzheimer’s disease. But Whitney, whose relatives first showed symptoms of cognitive decline in their early 50s, remains mentally sharp with no signs of the devastating disease, and a new study by researchers at Washington University School of Medicine in St. Louis helps explain why.

Their findings, published Feb. 10, 2025, in Nature Medicine, point to potential therapeutic avenues to explore to help protect against the development of Alzheimer’s.

Combing through data on Whitney’s genes, and information gleaned from his brain scans and other biological features, the researchers identified changes in genes and proteins suggestive of resisting neurodegeneration. They also observed a near absence of the buildup in the brain of the key Alzheimer’s protein – tau – that is associated with the onset of disease symptoms such as cognitive decline.

“These extensive studies indicate a remarkable resistance to tau pathology and neurodegeneration,” said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at WashU Medicine and co-senior author of the study.

Man caring for plantMegan Farmer
Doug Whitney, 75, cares for a plant in his home near Seattle, Wash. Despite having inherited a genetic mutation that has led other family members to develop Alzheimer’s disease at about age 50, Whitney remains cognitively healthy. Researchers at WashU Medicine report new insights into what might be protecting Whitney from the devastating disease.

Whitney, who lives near Seattle, Wash., was first identified as an exceptional case in 2011, when he arrived at WashU Medicine to enroll in a groundbreaking Alzheimer’s study: the Dominantly Inherited Alzheimer Network (DIAN) study. The international network focuses on families with inherited forms of Alzheimer’s disease that lead to cognitive decline at an early age, typically in a person’s 30s, 40s or 50s, and is led by WashU Medicine clinicians and researchers in the Charles F. and Joanne Knight Alzheimer Disease Research Center.

“When he came to WashU Medicine for the first time, together with his cousin, he was already 10 years past the age of onset for his family,” said Jorge Llibre-Guerra, MD, an assistant professor of neurology and co-first author of the study. Whitney’s family members with the same genetic variant typically showed signs of the onset of Alzheimer’s around 50 years of age. Because Whitney showed no sign of cognitive decline, WashU Medicine clinicians and researchers initially assumed that he was not a carrier of the genetic variant in the presenilin 2 (PSEN2) gene that had led to early-onset Alzheimer’s for every other member of his family who had inherited the genetic mutation.

“It came as a big surprise to learn that he was actually a mutation carrier,” said Llibre-Guerra. “At that point, he earned the title of the DIAN escapee, because he actually was able to escape the expected course of the disease.”

Whitney is one of three known escapees – more formally called “exceptional resilience mutation carriers” – in the world. The inherited form of Alzheimer’s that they have avoided accounts for fewer than 1% of all cases worldwide, and researchers expect that identifying successful treatments for this rare form of Alzheimer’s will inform prevention and treatment efforts for more common forms of the disease that develop later in life. So, identifying a case so rare and relatively early in a person’s life was an incredible opportunity for the WashU Medicine team: some unknown factor in Whitney’s body or in his genes was preventing the PSEN2 mutation from fully taking hold.

“If we are able uncover the mechanism behind this resilience,” said Llibre-Guerra, “we could try to replicate it with a targeted therapy designed to delay or prevent the onset of Alzheimer’s, leveraging the same protective factors that have kept Mr. Whitney from developing this disease to benefit others.”

Whatever that factor may be, Whitney is grateful to have the opportunity to contribute to the search for an effective treatment for the disease that has haunted his relatives for generations.

“My family has been devastated by this disease since the early 1900s, and probably going back further than that,” said Whitney. “It’s really important to me to figure this out. My mom had 13 brothers and sisters, and 10 died before they were 60 years old. It’s been a plague.”

The PSEN2 mutation Whitney carries is linked to an over-production of amyloid protein, which accumulates in the brain as the first stage in the progression of Alzheimer’s. The second stage, associated with the cognitive decline characteristic of the disease, involves a buildup of tau protein in the brain.

In this study, scans of Whitney’s brain showed a significant accumulation of amyloid but only a localized concentration of tau in his left occipital lobe. Tau usually spreads to multiple regions of the brain in typical inherited Alzheimer’s cases, with symptom onset associated with its presence in the medial temporal lobe, which is an area of the brain closely involved in memory.

“The goal now is to discover the precise reason why Mr. Whitney has escaped genetic fate,” Bateman said. “This discovery could become a powerful prevention for everyone. We call on researchers to help in the search.”

There are few clues as to what underlies Whitney’s resistance to tau accumulation. While the team identified that he carried specific genes that may be linked to staving off Alzheimer’s disease, the researchers do not yet have information on the genes’ functions. They also analyzed Whitney’s cerebrospinal fluid for biomolecules that might indicate unusual cellular activity in his brain and found a significantly higher-than-normal level of what are known as “heat shock” proteins.

Whitney worked as a shipboard mechanic for many years, enduring high temperatures in the engine rooms of naval vessels. That experience may have left him with elevated levels of heat shock proteins, which are created by the body to refold and repair other essential proteins in the body that have been damaged by stresses such as high temperatures.

“We don’t yet understand how or if heat shock proteins may be mediating the effect,” Llibre-Guerra said, acknowledging the established role of misfolded proteins in Alzheimer’s pathology. “However, in this case they may be involved in preventing aggregation and misfolding of tau proteins, but we do not know for sure.”

Couple in living roomMegan Farmer
Doug Whitney (left) and his wife Ione Whitney work on word puzzles in their home near Seattle, Wash. Doug Whitney is the subject of a new study by researchers at WashU Medicine looking into why he has escaped developing Alzheimer’s disease at an early age, despite having inherited a gene mutation that caused other family members to develop Alzheimer’s at about age 50. Most of those family members died before age 60.

Llibre-Guerra said he hopes the insights learned from Whitney will inspire future population studies or animal models to continue investigating this exceptional case.

“We have made all of the data we have available, as well as the tissue samples,” he said. “If researchers want to request those to do additional analysis, that’s something we would welcome.”

WashU Medicine and Weizmann Institute of Science establish joint research program

Washington University School of Medicine in St. Louis and the Weizmann Institute of Science (WIS) in Israel have launched a collaboration to support joint research projects focused on understanding the role of microbes and the immune and nervous systems in human health and disease.

The new program in Microbial, Immunologic and Neurologic Disorders (MIND) is accepting joint proposals from researchers at WashU and WIS to execute collaborative research projects. The program is planning future academic conferences and opportunities for researchers at WashU Medicine and WIS to travel and conduct research at the other institution.

The program is co-directed by Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology and a BJC Investigator at WashU Medicine; Ido Amit, PhD, a professor of immunology and the Eden and Steven Romick Professorial Chair at WIS; and Ronen Alon, PhD, the Linda Jacobs Professorial Chair in Immune and Stem Cell Research at WIS.

Kipnis

“We want to cultivate collaborations between these two premier scientific institutions, which have so many overlapping areas of expertise and untapped potential to make discoveries that advance knowledge and ultimately improve health,” Kipnis said. “We see an opportunity to address critical questions about causes and potential treatment of human disease — particularly those such as Alzheimer’s and other neurological conditions involving interactions among microbes and the human immune and nervous systems. This program serves as a substantial source of seed funding to help researchers — especially early-career scientists — build new and innovative research programs that can attract larger grants and funding sources.”

Added Amit: “The two institutions share a similar passion for curiosity-driven basic research. Through this unique collaboration, we will combine the excellence of the WashU and WIS communities in medical research, genomics and AI to make significant progress into understanding the diverse mechanisms at play leading to neurological disorders, such as Alzheimer’s disease.”

Representatives from the new joint research program will hold a webinar on Feb. 20 to help scientists learn about one another’s research through five-minute “elevator pitches.” Visit the announcement for more information about the webinar and submission process. The deadline for proposal submissions is March 31.

Each proposal must be co-led by at least one researcher from WashU Medicine and one from the Weizmann Institute of Science. At WashU Medicine, researchers at the tenure-track assistant professor rank and above are eligible. At WIS, researchers at the senior scientist level and higher are eligible. Early-career faculty at both institutions are strongly encouraged to apply.

Each selected joint project will receive up to $100,000 to be divided between the awarded principal investigators from each institution according to their needs. Proposals will be evaluated based on scientific merit and alignment with the selected theme, the strength of the collaboration, innovation and potential for long-term funding.

Proposals will be evaluated by members of an executive committee, including Kipnis, Amit and Alon as well as Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor, and Megan A. Cooper, MD, PhD, the Anthony R. French, MD, PhD, Professor in Pediatrics, both at WashU Medicine; and David Zeevi, PhD, a professor of plant and environmental sciences at WIS.

Nasal COVID-19 vaccine based on WashU technology to enter U.S. clinical trials

A nasal vaccine for COVID-19 – based on technology developed at Washington University in St. Louis – is poised to enter a phase 1 clinical trial in the U.S. after an investigational new drug application from Ocugen, Inc. was approved by the Food and Drug Administration (FDA). Ocugen, a U.S.-based biotechnology company, licensed the innovative technology from WashU in 2022.

The trial will be sponsored and conducted by the National Institute of Allergy and Infectious Diseases (NIAID), of the National Institutes of Health (NIH). The FDA’s action is a critical first step toward initiation of the phase 1 trial, planned for this spring.

While cases of COVID-19 have fallen dramatically since the early years of the pandemic, the virus continues to circulate and still causes significant illnesses and deaths. The nasal vaccine technology is designed to induce strong immunity in the nose and upper respiratory tract, right where the virus enters the body, thereby potentially stopping transmission of the virus in addition to reducing serious illness and death. Most COVID-19 vaccines are injected into the arm or leg, and while they are effective at reducing illness and death, they do not halt transmission. The new trial will evaluate the safety and efficacy of the vaccine administered via two routes: inhaled into the lungs and sprayed into the nose.

“I am delighted to see this nasal vaccination technology, created by scientists right here at WashU Medicine, advance toward clinical trials,” said Doug E. Frantz, PhD, the Vice Chancellor for Innovation and Commercialization at WashU. “This powerful technology has the potential not only to help control COVID-19 but to reduce the burden of respiratory infections worldwide. The technology could be adapted for other common respiratory viruses such as seasonal influenza, avian flu and respiratory syncytial virus (RSV) that cause enormous sickness and death.”

A version of the vaccine has been available in India since 2022 through a licensing agreement between WashU and the Indian biotechnology company Bharat Biotech.

The Phase 1 trial is funded through Project NextGen, a U.S. government agency initiative to develop next-generation COVID-19 vaccines and therapeutics through public-private partnerships.

The trial will enroll 80 adults ages 18 to 64 years. Participants will be randomly assigned to one of four groups: low-dose intranasal, high-dose intranasal, low-dose inhaled and high-dose inhaled. The primary aim of the trial is to determine safety, but researchers will also assess immunogenicity by measuring antibody production and efficacy by determining the number of breakthrough COVID-19 cases.

The investigational nasal vaccine was co-developed by WashU Medicine scientists Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and the co-director of the Center for Vaccines & Immunity to Microbial Pathogens, and David T. Curiel, MD, PhD, the Distinguished Professor of Radiation Oncology, along with members of their laboratories.

Diamond and Curiel inserted a gene from SARS-CoV-2, the virus that causes COVID-19, into a harmless virus known as an adenovirus. The adenovirus carries the SARS-CoV-2 protein into the nose, enabling people to mount an immune defense against the SARS-CoV-2 virus without becoming sick.

“It is gratifying to see the vaccine that we conceived, designed and conducted initial testing on move closer to becoming available here in the U.S.,” said Diamond, also a professor of molecular microbiology and of pathology & immunology.

Diamond and Curiel’s early studies at WashU Medicine showed that nasal delivery of this vaccine creates a strong immune response throughout the body, especially in the nose and respiratory tract. In animal studies conducted in 2020 and 2021, the nasal vaccine entirely prevented infection from taking hold in the nose and lungs — suggesting that vaccinated individuals would be able to fend off the virus before it could multiply and cause an infection. Last year, Jacco Boon, PhD, a professor of medicine, of molecular microbiology and of pathology & immunology at WashU Medicine, showed that hamsters vaccinated with the nasal COVID-19 vaccine and subsequently infected did not pass the virus on to others, breaking the cycle of transmission.

“All effective vaccines reduce sickness and death, but COVID-19 vaccination through the nose and mouth also seems to reduce transmission,” said Curiel, also a professor of medicine and of obstetrics & gynecology. “This capability is critical in slowing the spread of respiratory infections such as COVID-19 through a population, and the same vaccine technology can be designed to target other COVID-19 strains as well as influenza and other respiratory viruses.”

Rutledge-Jukes named to Forbes’ 30 under 30

Heath Rutledge-Jukes, 25, a second-year student at Washington University School of Medicine in St. Louis, has earned a spot on Forbes’ “30 Under 30” education list.

Rutledge-Jukes co-founded King of the Curve, a test-prep company for would-be medical students required to take standardized exams such as the Medical College Admission Test, or MCAT. The app aims to boost scores by deterring high-stress, last-minute study sessions and offering personalized content that turns learning into a daily habit. To date, Rutledge-Jukes said, the app has been downloaded more than 400,000 times.

Rutledge-Jukes founded the company in 2020 with his two former classmates from Florida Southern College, in Lakeland, Fla. The trio has raised more than $1 million, largely from Kapor Capital in Oakland, Calif.

International Alzheimer’s prevention trial in young adults begins

The first participants in an international clinical trial aimed at preventing Alzheimer’s disease in young adults at high risk of the disease have been enrolled. The trial, led by Washington University School of Medicine in St. Louis, aims to determine whether stopping the early molecular changes that lead to symptomatic Alzheimer’s disease can prevent the disease from ever taking hold. The study is enrolling people as young as 18 who have few or no detectable Alzheimer’s-related molecular changes in their brains, up to 25 years before the expected onset of dementia symptoms.

While the trial is limited to members of families with genetic mutations that all but guarantee they will develop Alzheimer’s at a young age, typically in their 30s, 40s or 50s, the researchers expect that the study’s results will inform prevention and treatment efforts for all forms of Alzheimer’s disease.

Called the Primary Prevention Trial, the new study investigates whether remternetug — an investigational antibody being developed by Eli Lilly and Company — can remove plaques of a key Alzheimer’s protein called amyloid beta from the brain or block them from accumulating in the first place. Both genetic and nongenetic forms of Alzheimer’s disease start with amyloid slowly collecting in the brain two decades before memory and thinking problems arise. By clearing out low levels of amyloid beta plaques or preventing them from accumulating during the early, asymptomatic phase of the disease, or both, the researchers hope to interrupt the disease process at the earliest stage and spare people from ever developing symptoms.

“We have seen tremendous progress in the treatment of Alzheimer disease in the past few years,” said Eric McDade, DO, a professor of neurology and the trial’s principal investigator. “Two amyloid-targeting drugs were shown to slow symptoms of the disease and have now been approved by the Food and Drug Administration (FDA) as treatments for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. This provides strong support for our hypothesis that intervening when amyloid beta plaques are at the very earliest stage, long before symptoms arise, could prevent symptoms from emerging in the first place.”

The trial is part of the Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (Knight Family DIAN-TU), a clinical trials platform designed to find medicines to prevent or treat Alzheimer’s disease. It is closely associated with DIAN, a National Institutes of Health (NIH)-funded international research network led by WashU Medicine that involves research institutes in North America, Australia, Europe, Asia and South America. DIAN follows families with mutations in any of three genes that cause Alzheimer’s at a young age. A child born into such a family has a 50% chance of inheriting such a mutation, and those who do so typically develop signs of dementia near the same age his or her parent did. All the participants in the Primary Prevention Trial come from such families.

“My grandfather passed away from Alzheimer’s, and so did his mother and all but one of his brothers,” said Hannah Richardson, 24, a participant in the Primary Prevention Trial. “My mom and my uncle have been participating in DIAN trials since I was about 10 years old. My mom was always very open about her diagnosis and how it spurred her advocacy for Alzheimer’s research, and I’ve always known I wanted to follow in her footsteps. I am happy to be involved in the Primary Prevention Trial and be involved in research because I know how important it is.”

A female patient lies in an MRI machineMatt Miller
Hannah Richardson, 24, undergoes a brain scan as part of the Primary Prevention Trial for Alzheimer’s disease. Richardson comes from a family with a history of early-onset Alzheimer’s.

The trial was first announced in 2021. At that time, the researchers planned to use a different investigational drug — gantenerumab, by Roche/Genentech. However, Roche/Genentech discontinued the development of gantenerumab after data from other Alzheimer’s trials were not supportive.

Remternetug was chosen as a replacement because, in early phase trials in symptomatic patients with more common forms of Alzheimer’s, it has been shown to robustly remove amyloid plaques to a comparable extent as donanemab, an FDA-approved Alzheimer’s therapy also produced by Lilly. Importantly, remternetug can be given via injection just under the skin, a faster and less invasive route of administration than IV infusion, which is how the approved treatments are currently delivered. Additionally, participants will receive remternetug or placebo every 3 months, a less frequent dosing schedule than the bi-weekly or monthly dosing schedules required for the two FDA-approved Alzheimer’s medications. The results will help scientists determine the optimal dosing schedule for prevention.

Each participant will be treated for two years. McDade expects to report the results of the trial within the next four to five years, depending on how long it takes to meet enrollment goals.

“We are pleased to partner with the DIAN-TU team to evaluate whether remternetug can help slow or prevent the accumulation of amyloid plaque, a defining event in the early cascade of Alzheimer’s disease onset,” said Mark Mintun, MD, Group Vice President-Neuroscience R&D at Lilly.

The Primary Prevention Trial will enroll about 240 participants from families that carry mutations in one of the three key genes that cause early-onset Alzheimer’s. Both those who have and have not inherited the mutation are eligible, with noncarriers serving as a comparison group for their relatives. Participants must be 11 to 25 years younger than the expected age of symptom onset based on their family history, and have no signs of cognitive impairment and no or very few amyloid deposits in their brains. At the end of the experimental period, participants who carry a mutation will be eligible to receive the drug for an additional four years as part of an open-label extension of the study.

McDade and colleagues are primarily looking to see whether remternetug prevents amyloid plaques from building up in the brain. They will also be measuring the effects of the drug on molecular signs of Alzheimer’s disease in the blood and cerebrospinal fluid. Because the participants are so young, the researchers do not expect to see any changes to cognitive function during the time period of the trial. WashU Medicine will continue following participants long-term beyond the clinical trial to assess for the potential effects on cognition.

More than $130 million has been earmarked for the trial, including grants totaling an estimated $98.3 million from the NIH’s National Institute on Aging (NIA) and $14 million from the Alzheimer’s Association and the GHR Foundation. The NIA has been a major supporter of DIAN and its clinical trials unit since the network was established in 2008.

“The Alzheimer’s Association is proud to be a longstanding part of this strong collaboration between academic researchers, government, industry, philanthropy and the DIAN families,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead. “This innovative study in this special Alzheimer’s patient population has the potential to significantly impact how we prevent Alzheimer’s disease, saving individuals and families from the anguish of this fatal disease.”

In addition, WashU has pledged to raise an additional $6.5 million, and longtime WashU benefactor and Alzheimer’s research supporters Joanne Knight of St. Louis and family have committed up to $11.5 million in support of the trial.

“Alzheimer’s disease has impacted our family for decades across multiple generations,” said Joanne Knight. “We are so thrilled to have the opportunity to support this trial aimed at preventing the devastating effects of the disease.”

Already, the Knight Alzheimer’s Primary Prevention Challenge has garnered contributions from more than 150 donors. The trial is being conducted in close partnership with Lilly, which also is providing significant funding.

“This a groundbreaking approach,” said GHR Foundation’s Chief Operating Officer Fred Miller. “For the first time, we’re working to prevent the buildup of Alzheimer’s pathology before it starts. The research will provide insight on how we prevent Alzheimer’s disease for these families, as well as the nearly 13 million Americans projected to have Alzheimer’s disease by 2050 and countless others around the world.”

Along with the Knight Family DIAN-TU Primary Prevention Trial, WashU Medicine also runs the international Knight Family DIAN-TU Tau NexGen Trial, which is aimed at identifying drugs to prevent or slow Alzheimer’s. Like the Primary Prevention Trial, the Tau NexGen Trial involves members of families that carry dominant Alzheimer’s mutations, but those in Tau NexGen are at or near the age of symptom onset and have already accumulated significant brain changes. Tau NexGen evaluates whether a combination of the FDA-approved drug lecanemab, which targets amyloid, and another drug that targets an Alzheimer’s-related protein called tau can reverse, halt or slow the progression of disease.

Mobilizing the best to start the fight earlier

NIH awards $10 million to study human virome

Genomics researchers at Washington University School of Medicine in St. Louis will play pivotal roles in the Human Virome Program, a new National Institutes of Health (NIH) initiative to better understand the vast and varied collection of viruses that live in and on our bodies, known as the human virome, and how they affect our overall health.

The NIH has announced a new round of funding in the program, with two of the five research grants under a specific initiative of the program — which is the characterization of functional interactions between viruses and the human microbial hosts — awarded to WashU Medicine researchers. This success reflects a strong interdisciplinary research network and laboratory infrastructure at WashU Medicine based on its leadership roles in other massive genome research efforts, including the Human Genome Project.

Gautam Dantas, PhD, the Conan Professor of Laboratory and Genomic Medicine in the Department of Pathology & Immunology at WashU Medicine, and Megan Baldridge, MD, PhD, an associate professor of medicine, have received a $5.2 million, 5-year grant for research on bacteriophages, viruses also known as phages, which specifically infect bacteria.

MATT MILLER/WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
Dantas

They will study the roles bacteriophages play when the gut microbiome in healthy individuals is thrown off balance by exposure to antibiotics or other intestinal disturbances, such as infections in preterm infants and inflammatory bowel disease in adults.

“What is particularly troubling about these inflammatory diseases is that we still don’t know what causes them,” Dantas said. “Our study is a first step toward determining whether phages are part of a mechanism that could explain why people get these diseases. We’ll be using machine learning, artificial intelligence and other analytical tools to identify viruses that may influence disease progression.”

Baldridge

A team of multiple principal investigators, including Kristine Wylie, PhD, associate professor of pediatrics at WashU Medicine; Molly Stout, MD, associate professor of obstetrics and gynecology at University of Michigan; and Linda Ernst, MD, professor of pathology at the University of Chicago Pritzker School of Medicine and vice chair for pathology research at Endeavor Health in suburban Chicago, has received a $5.7 million, 5-year NIH grant to study how pregnancy-related immune system changes are influenced by viruses that infect human cells.

Their study focuses on examining viral communities and immune responses during pregnancy and postpartum. Body sites will include vagina, placenta, blood and nasal passages.

Wylie

Research has indicated that disruptions in these host-virus dynamics may contribute to infectious diseases and preterm births.

“The viruses in and on our bodies are kept in check by our immune systems,” Wylie said. “During pregnancy and the postpartum period there are huge, developmentally programmed changes in the function of the maternal-fetal immune systems, and those changes give us an opportunity to study how immune system changes affect the virome.”

Exploring the human virome’s dark matter

By some estimates, the human microbiome hosts more than 380 trillion viruses. This would make commensal viral particles far more prevalent than bacterial cells in the human microbiome and the cells that make up the human body combined.

But the vast majority of the diverse assemblage of viruses that reside in healthy humans remains unidentified and poorly understood. Unlocking the secrets of the human virome’s “dark matter” could help researchers construct refined models that may untangle the complexities of human disease onset, better understand their causes and suggest new and more-effective treatments.

The NIH launched the Human Virome Program in 2022 to overcome specific obstacles to human virome research, such as the need for new sequencing techniques that focus on virus identification and the lack of centralized databases where new virus discoveries can be shared and compared.

Each study funded by the program is expected to contribute to the initiative’s primary goal of establishing a comprehensive inventory of every virus in the human microbiome, including information on their interactions with gut bacteria and human cells.

WashU Medicine’s success in landing two of the five research grants under a specific initiative of the program — which is the characterization of functional interactions between viruses and the human microbial hosts — reflects a strong interdisciplinary research network and laboratory infrastructure in place based on its leadership roles in other massive genome research efforts, including the Human Genome Project and the Human Microbiome Project.

A common focus of the Dantas, Baldridge and Wylie virome studies will be exploring biological factors driving dramatic shifts in the composition of the human microbiome. Previous work by their teams has shown that perturbations in microbial populations can signal whether a microbiome is stable and healthy or shifting in ways that make it vulnerable to disease-causing pathogens, including viruses.

Dantas, Baldridge and their collaborators will be analyzing fecal samples from healthy participants and individuals receiving treatment for intestinal illnesses.

“The big deliverable here is functional discovery relevant to human health,” Dantas said. “As we go through the genomic sequencing of these samples, we are going to be capturing and discovering pieces of DNA for which there is little information about what they do. We’ll try to figure out which of those pieces of DNA are viruses, and we’ll try to associate particular functions and features to them, to understand how they influence the balance between healthy and diseased states in the human gut.”

Wylie’s project similarly aims to generate fundamental discoveries on the composition and function of viral communities. Her team leverages ViroCap, a patented technique that she and WashU colleagues developed nine years ago to improve the sensitivity of genomic sequencing for virus analysis. The process, which can detect viruses that occur in very low abundance, allows researchers to identify and compare characteristics of viruses that have never been documented – a key goal of the Human Virome Program.

Wylie’s team has a history of collaboration and of examining the viral communities in pregnancy. Ernst studies placental biology and its relationship to maternal, fetal and neonatal disease and Stout focuses on maternal heart disease and preterm birth prevention.

$14 million supports work to diversify human genome research

Washington University School of Medicine in St. Louis has received two large grants renewing funding for the Human Pangenome Reference Sequencing Project. This ambitious program began in 2019 with the goal of increasing the diversity of human genome sequences that are pooled into the widely used reference genome. A thorough representation of human genetic diversity can help researchers discover how genetic variation contributes to disease and perhaps offer new routes to innovative treatments.

Funded by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH), the project aims to accurately reflect the full range of human diversity worldwide, make the reference genome more useful to researchers and ensure that all people — regardless of their genetic ancestry — can benefit from the promise of precision medicine.

WashU Medicine serves as the national coordinating center for the entire project and houses one of the data production centers performing genomic sequencing. Nationally, the two grants total $29 million, and, of that, WashU Medicine will receive about $14 million to fund its coordinating and sequencing centers.

“We are excited to continue this work expanding and diversifying the pangenome reference sequence, as well as building and disseminating the new tools and resources,” said principal investigator Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and head of the Department of Genetics at WashU Medicine. “Human genomics is a cornerstone of personalized medicine. This project will help ensure that the human genomes we study accurately reflect human diversity so that newly developed precision treatments have the potential to benefit everyone.”

Human Genome Project’s origins at WashU

The original human genome reference sequence, completed in 2002, was based on the genomes of a small number of volunteers. And in most portions of that first reference genome, the sequence was from a single person.

WashU Medicine’s McDonnell Genome Institute played a major role in the original Human Genome Project that produced the first reference sequence. The institute contributed 25% of the genetic data to identify all 3.1 billion base pairs of DNA that make up the human genome. While a massive milestone in the history of human genome research, the original reference genome reflected a tiny fraction of the scope of human diversity.

To widen this view, the first phase of the pangenome reference project added genomes from 350 people of different racial and ethnic backgrounds to the reference data. Now, the second phase will add genomes from an additional 200 individuals, increasing the total number to 550 individuals of diverse backgrounds. All the data and tools developed by the researchers are made available as resources to the broader scientific community.

The investigators emphasize the importance of considering the ethical, legal and social implications of genomic research. The project includes a team of researchers dedicated to addressing these issues, including attention to informed consent for participating in research, understanding how the data are used and protected and ensuring that these resources are equitably accessible.

For the national coordinating center, WashU Medicine leads a collaboration with UC Santa Cruz and the European Molecular Biology Laboratory’s European Bioinformatics Institute to form the Human Pangenome Reference Consortium Coordination Center. The second center, focused on sequencing — the Center for Human Genome Reference Diversity— is led by UC Santa Cruz and comprises the McDonnell Genome Institute at WashU and the University of Washington.

Study identifies benefits, risks linked to popular weight-loss drugs

Demand for weight-loss medications sold under brand names such as Ozempic and Wegovy continues to surge, with a recent study reporting one in eight Americans has taken or is currently using the drugs to treat diabetes, heart disease or obesity.

Formally, these drugs are known as glucagon-like peptide-1 receptor agonists (GLP-1RA) and include Mounjaro and Zepbound. Informally, media, patients and even some physicians have dubbed GLP-1 medications as “miracle drugs” because of the profound weight loss among users. While these health benefits are well established, information is sparse on the drugs’ effects across the body’s organ systems.

Now, scientists at Washington University School of Medicine in St. Louis and the Veterans Affairs (VA) St. Louis Health Care System have systematically evaluated health outcomes among more than 2 million people with diabetes taking the popular weight-loss drugs. They found widespread associations with benefits to cognitive and behavioral health, while also revealing increased risks for pancreatitis and kidney conditions, among others.

The study is published Jan. 20 in the journal Nature Medicine.

“Given the drugs’ newness and skyrocketing popularity, it is important to systematically examine their effects on all body systems — leaving no stone unturned — to understand what they do and what they don’t do,” said the study’s senior author, Ziyad Al-Aly, MD, a clinical epidemiologist and nephrologist who treats patients at the WashU Medicine-affiliated John J. Cochran Veterans Hospital in St. Louis.

“Our approach has allowed us to build a comprehensive atlas mapping the associations of GLP-1RA spanning all organ systems,” he said. “The study’s results provide insights into some known and previously unrecognized benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas.”

The drugs, taken once a week by injection, simulate naturally produced hormones that curb appetite and slow digestion, creating longer-lasting satiety. A healthy diet and exercise also assist with weight loss.

For the study, WashU Medicine researchers analyzed de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs. They compared 175 health outcomes between veterans who took GLP-1RA drugs to treat their diabetes and those who took more traditional medications sold under brand names such as Jardiance, Glipizide and Januvia.

Altogether, the dataset examined more than 2 million veterans who were treated for diabetes from Oct. 1, 2017, to Dec. 31, 2023. Patients included people of diverse ages, races and sexes.

GLP-1RA drugs were associated with significant benefits to neurological and behavioral health, with reduced risks of seizures and addiction to substances such as alcohol, cannabis, stimulants and opioids. People taking the weight-loss drugs also experienced decreased risks of suicidal ideation, self-harm, bulimia and psychotic disorders such as schizophrenia.

WashU Medicine’s findings also showed a decreased risk of neurocognitive disorders such as Alzheimer’s and dementia.

“Interestingly, GLP-1RA drugs act on receptors that are expressed in brain areas involved in impulse control, reward and addiction — potentially explaining their effectiveness in curbing appetite and addiction disorders,” said Al-Aly, the director of the Clinical Epidemiology Center at the VA St. Louis Health Care System, where he is head of the research and development service. “These drugs also reduce inflammation in the brain and result in weight loss; both these factors may improve brain health and explain the reduced risk of conditions like Alzheimer’s disease and dementia.”

While GLP-1RA drugs display effectiveness against a wide array of health problems, the magnitude of associated benefits is modest — about a 10 percent to 20 percent reduction for most outcomes. “However, the modest effect does not negate the potential value of these drugs, especially for conditions where few effective treatment options exist, for example, dementia,” Al-Aly said. “This may also imply that these drugs are most beneficial when used in conjunction with other interventions, such as lifestyle changes or other medications.”

The study also confirmed past research findings detailing the drugs’ potential to lower the risk of heart attack, stroke and other cardiovascular concerns.

Matt Miller
“Our approach has allowed us to build a comprehensive atlas mapping the associations of GLP-1RA spanning all organ systems,” said the study’s senior author, Ziyad Al-Aly, MD, a clinical epidemiologist and nephrologist at WashU Medicine. “The study’s results provide insights into some known and previously unrecognized benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas.”

Al-Aly emphasized that his study also highlighted potential downsides to the medications, including an increased risk of gastrointestinal problems such as nausea, vomiting, diarrhea, and in rare cases paralysis of the stomach. “These have been well documented in the research and anecdotally,” Al-Aly said. “Our study confirmed such findings.”

But what is novel is the potential ways GLP-1RA drugs can negatively affect the pancreas and kidneys. While these adverse effects are uncommon, they can be very serious; physicians must be vigilant for signs of pancreatitis and monitor kidney function among people taking GLP-1RA medications. Kidney problems can occur without symptoms until the condition is at an advanced stage with limited treatment options.

“GLP-1RA drugs can have broad health benefits,” Al-Aly said. “However, they are not without risks. Our findings underscore the possibility for wider applications for these medications but also highlight important risks that should be carefully monitored in people taking these drugs.”

Brains of people with sickle cell disease appear older

Individuals with sickle cell disease – a chronic illness where misshapen, sticky blood cells clump together, reducing oxygen delivery to organs – are at a higher risk for stroke and resulting cognitive disability. But even in the absence of stroke, many such patients struggle with remembering, focusing, learning and problem solving, among other cognitive problems, with many facing challenges in school and in the workplace.

Now a multidisciplinary team of researchers and physicians at Washington University School of Medicine in St. Louis has published a study that helps explain how the illness might affect cognitive performance in sickle cell patients without a history of stroke. The researchers found such participants had brains that appeared older than expected for their age. Individuals experiencing economic deprivation, who struggle to meet basic needs, even in the absence of sickle cell disease, had more-aged appearing brains, the team also found.

The study was published January 17 in JAMA Network Open.

“Our study explains how a chronic illness and low socioeconomic status can cause cognitive problems,” said Andria Ford, MD, a professor of neurology and chief of the section of stroke and cerebrovascular diseases at WashU Medicine and corresponding author on the study. “We found that such factors could impact brain development and/or aging, which ultimately affects the mental processes involved in thinking, remembering and problem solving, among others. Understanding the influence that sickle cell disease and economic deprivation have on brain structure may lead to treatments and preventive measures that potentially could preserve cognitive function.”

More than 200 young, Black adults with and without sickle cell disease, living in St. Louis and the surrounding region in eastern Missouri and southwestern Illinois, participated in brain MRI scans and cognitive tests. The researchers – including Yasheng Chen, DSc, an associate professor of neurology at WashU Medicine and senior author on the study – calculated each person’s brain age using a brain-age prediction tool that was developed using MRI brain scans from a diverse group of more than 14,000 healthy people of known ages. The estimated brain age was compared with the individual’s actual age.

The researchers found that participants with sickle cell disease had brains that appeared an average of 14 years older than their actual age. Sickle cell participants with older-looking brains also scored lower on cognitive tests.

The study also found that socioeconomic status correlates with brain age. On average, a seven-year gap was found between the brain age and the participants’ actual age in healthy individuals experiencing poverty. The more severe the economic deprivation, the older the brains of such study subjects appeared.

Healthy brains shrink as people age, while premature shrinking is characteristic of neurological illnesses such as Alzheimer’s disease. But a smaller brain that appears older can also result from stunted growth early in life. Sickle cell disease is congenital, chronically depriving the developing brain of oxygen and possibly affecting its growth from birth. Also, children exposed to long-term economic deprivation and poverty experience cognitive challenges that affect their academic performance, Ford explained.

As a part of the same study, the researchers are again performing cognitive tests and scanning the brains of the same healthy and sickle cell participants three years after their first scan to investigate if the older-looking brains aged prematurely, or if their development was stunted.

“A single brain scan helps measure the participants’ brain age only in that moment,” said Ford, who treats patients at Barnes-Jewish Hospital. “But multiple time points can help us understand if the brain is stable, initially capturing differences that were present since childhood, or prematurely aging and able to predict the trajectory of someone’s cognitive decline. Identifying who is at greatest risk for future cognitive disability with a single MRI scan can be a powerful tool for helping patients with neurological conditions.”

Drug in clinical trials for breast cancer could also treat some blood cancers

Two new studies led by researchers at Washington University School of Medicine in St. Louis have identified a possible way to block the progression of several forms of blood cancer using a drug already in clinical trials against breast cancer.

The studies — both conducted in patient samples and animal models — found that inhibiting a protein called RSK1 reduces inflammation and stops the progression of blood cancers called myeloproliferative neoplasms (MPNs) as well as an aggressive form of acute myeloid leukemia (AML). With the RSK1 inhibitor already in clinical testing, the path to expanded use as a treatment for blood cancers likely is accelerated.

One study appears Jan. 16 in Nature Communications. The second is available online in Blood Cancer Journal.

In humans, MPNs can be slow-growing blood cancers that simmer for years. Doctors can monitor the disease and treat symptoms, but there is no reliable way to cure it or slow progression. Patients with MPNs are at high risk of developing a secondary AML that is very aggressive with no effective treatment options.

“Patients with chronic MPNs can live with the disease sometimes for decades, but they’re at increased risk of developing secondary AML, which has a poor prognosis,” said senior author Stephen T. Oh, MD, PhD, an associate professor of medicine and co-director of the Division of Hematology at WashU Medicine. “These patients have no effective medical therapies, so we hope this new drug will help fill that gap in clinical care. At minimum, we’re hopeful this drug can stop the chronic disease from progressing to AML. But the goal is to eliminate the disease and get patients into remission.”

According to Oh, researchers have long been seeking an inhibitor to block MPN progression because current therapies only reduce symptoms caused by the disease, including severe fatigue, night sweats, poor appetite, weight loss, and an enlarged spleen, but do not slow progression of the disease or reduce the risk of it evolving into acute leukemia.

In theory, using RSK1 inhibitors to treat patients with chronic MPNs may improve their health to a point where they could become eligible for a stem cell transplant, which is the preferred therapy for many blood cancers because it can potentially lead to long-term remission. Oh treats patients with MPNs and related blood cancers at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

In the Nature Communications study, inhibiting RSK1 helped reverse the progression of MPNs in mice, reducing fibrosis, or scar formation, in the bone marrow. Inhibiting RSK1 eliminated up to 96% of cancer in mice after four weeks. It also showed evidence of preventing the chronic disease from transforming into secondary AML.

In the Blood Cancer Journal study, blocking this protein treats a specific form of AML called FLT3-ITD AML that develops directly — without an MPN developing first. This type of AML can be treated with established drugs called FLT3 inhibitors, but the cancer often develops resistance to this treatment over time. Because the RSK1 inhibitor blocks a different pathway, Oh and his co-authors suggested, it could help address this resistance.

The specific RSK1 inhibitor used in both studies, called PMD-026, is given as a pill and is currently in clinical trials as a treatment for breast cancer. Those ongoing studies seek to determine efficacy, and early testing showed trial subjects with metastatic breast cancer have tolerated the drug well with low-grade side effects.

Tracking the path to MPN development – and stopping it

An earlier study by Oh’s group identified a signaling molecule called DUSP6 as an important protein driving the progression of MPNs. Further work identified the downstream signals triggered by DUSP6, and RSK1 stood out as the one they could potentially block with the RSK1 inhibitor already in clinical trials for breast cancer.

The investigational drug PMD-026 is a pan-RSK inhibitor in that it blocks all four versions of the protein — RSK1, RSK2, RSK3 and RSK4. In breast cancer, the evidence suggests that PMD-026 may work by blocking RSK2. If approved by the Food and Drug Administration to treat breast cancer, it would be the first drug on the market to inhibit the RSK family of proteins.

Oh and his team, including Tim Kong, first author of both studies and an MD-PhD student in Oh’s lab, became interested in working with the company that makes the drug — a biotech firm called Phoenix Molecular Designs — when they identified RSK1 as a key driver of several blood cancers and hypothesized that this drug potentially could block its activity as well. The company provided the drug for these studies.

“We are excited about these studies because they highlight RSK1 as a novel therapeutic target for MPNs and AML with a viable strategy for moving an investigational drug into clinical trials in the near future,” Oh said. “There are a few scenarios that we’re considering in designing a future clinical trial. It will most likely be for patients who are beyond the standard therapies that we use for the chronic phase of this disease but are not eligible for stem cell transplantation due to age or overall health.”

Fatal neurodegenerative disease in kids also affects the bowel

As a leading researcher of rare diseases that affect children’s brains, Jonathan D. Cooper, PhD, thought little about the gastrointestinal (GI) system. That is, until the parents of children with a condition that Cooper studies urged him to investigate why debilitating digestive issues troubled their kids, who suffer from an incurable and fatal neurodegenerative brain condition called Batten disease.

Doctors had informed the parents that their children could succumb to blindness, seizures, dementia, an inability to walk, and would die in childhood. But the parents told Cooper they felt unprepared for the severe constipation and intestinal problems their kids also experienced.

“We are all miserable when we can’t poop,” said Cooper, a professor of pediatrics, of genetics and of neurology at Washington University School of Medicine in St. Louis. “It can be painful and a serious quality of life issue for the child and their families.”

The parent perspective led Cooper on a scientific quest that began four years ago — and continues today — to study the half-billion nerve cells in the bowel wall that are part of the enteric nervous system and how Batten disease affects their function. His new work shows enteric neurons in two mouse models of Batten disease degenerate in the bowel, paralleling neurodegeneration long known to occur in brain and spinal cord.

Cooper’s prior research also showed that supplying the missing enzyme to the brain in mouse or sheep Batten disease models via enzyme replacement therapy slowed cellular degeneration. Now his latest study has found that gene therapy in mice produced the same protective effect in the bowel. This genetic treatment reduced bowel symptoms and extended the lifespan of the mice by preventing enteric neuron degeneration.

The findings, published Jan. 15 in Science Translational Medicine, may one day lead to new treatments for Batten disease as well as for other neurodegenerative disorders with gastrointestinal symptoms.

“We believe our studies in mice have demonstrated a novel and highly promising way to successfully treat GI conditions with gene therapy,” said Cooper, the study’s co-senior author. “Importantly, we also established that the GI issues were not secondary to the neurological changes in the brain or spinal cord caused by the disease, but happen in the bowel itself.”

Patient-driven research

VanHoutan familyAmy Goray Photography
Tracy VanHoutan, left, became an advocate for research on Batten disease after his son Noah, fourth from left, was diagnosed. Noah and his younger sister Laine, third from left, died from Batten disease. VanHoutan’s efforts have resulted in valuable collaborations between families and WashU Medicine researchers, which have driven advances into understanding and potentially treating the devastating rare disease.

Batten disease refers to a group of inherited nervous system disorders in which a child lacks a crucial enzyme that breaks down and recycles cellular waste. Also known as neuronal ceroid lipofuscinosis, the disease is named after the accumulated material inside the cells. Not having these enzymes causes progressive brain damage that leads to death. Cooper and his colleagues are exploring exactly how this happens.

The exact number of kids with Batten disease remains unknown; however, some researchers have estimated it affects around three out of every 100,000 children in the U.S.

Two of Tracy VanHoutan’s children had the disease. The father met Cooper in 2009 at a rare disease conference in Hamburg, Germany, after his son, Noah, was diagnosed with a form of Batten disease. VanHoutan had traveled more than 4,000 miles from his home in Chicago to find scientists who might help his 5-year-old-boy, suffering from this extremely rare and understudied disease.

The two clicked immediately. They began speaking regularly. Together, they grieved when Noah died in 2016, just before his 12th birthday. And again, less than two years later, in December 2018, when VanHoutan’s daughter, Laine, died from the disease at age 12.

VanHoutan, who has become an accomplished advocate for rare disease research, invited Cooper to speak at patient-advocacy meetings, some of which were organized through Noah’s Hope-Hope4Bridget Foundation, the nonprofit he founded after his son’s diagnosis. During one of those meetings, Cooper asked parents about the day-to-day issues their children experienced.

Severe constipation, they told him. You might want to investigate it, they suggested.

“And Dr. Cooper listened,” VanHoutan said. “Dr. Cooper is a special scientist because he seeks out patients and their families. It doesn’t matter how old the patient is, he will get on their level and ask and answer questions in a relatable manner. He’ll talk to the parents but also the siblings and grandparents. He wants to know all perspectives.”

Motivated by what he learned from the families, Cooper turned his attention to the nervous system in the gut. Collaborating with Cooper is Robert O. Heuckeroth, MD, PhD, a pediatric gastroenterologist at Children’s Hospital of Philadelphia and a professor of pediatrics and of cell and developmental biology at the University of Pennsylvania. Heuckeroth completed his graduate and medical training at WashU Medicine where he first became interested in the nervous system of the bowel.

Together, the scientists discovered that while Batten disease ravages nerve cells in the brain and spinal cord, it also kills neurons that are part of the GI tract’s enteric nervous system.

Their research on Batten disease in mouse models and in colon tissue from children who died of Batten disease showed that nerve cell degeneration in the bowel occurs in parallel with events in the brain, following a similar pattern and timeline. About half of the nerve cells normally present die in Batten mice as the disease progresses, causing problems with bowel motility.

The basis for treating these diseases is to introduce a working copy the defective gene. This is supplied by a gene therapy virus that instructs cells to make this missing enzyme, secreting it to treat nearby cells. Giving gene therapy to newborn mice with Batten disease prevented the loss of many nerve cells in the bowel and prevented related problems with bowel function. The mice treated by gene therapy also lived significantly longer than untreated Batten disease mice.

The researchers have begun to apply their findings to other forms of Batten disease and similar neurodegenerative conditions in children such as the mucopolysaccharidoses, another group of rare inherited diseases caused by enzyme deficiencies that thwart a cell’s ability to break down material. Symptoms include GI distress, cognitive and developmental decline, skeletal and joint issues, vision impairment and physical deformities, among others.

“Our reasoning is that if nerve cells in the brain die because they’re missing a key enzyme, then there’s a high probability nerve cells in other organ systems could also die,” Cooper explained. “And given that a person has half a billion nerve cells in their bowels, about as many as in the spinal cord, it was important to determine if this occurs, opening up a whole new perspective on these diseases.”

Heuckeroth, a leading expert in the enteric nervous system whom Cooper fondly calls his “co-pilot” in research, added that damage to the enteric nervous system can profoundly impair bowel function, causing debilitating symptoms such as vomiting, distension, constipation, abdominal pain, malnutrition and a predisposition to bowel inflammation, sepsis and death.

“The enteric nervous system controls most aspects of bowel function,” said Heuckeroth. “We believe this work shows for the first time that a serious disease of the enteric nervous system can be treated by gene therapy, at least in mice.”

Cooper and Heuckeroth noted that future studies will focus on providing simultaneous gene therapy to both the brain and bowel, which they think is necessary for optimal outcomes.