Announcements

Updates on campus events, policies, construction and more.

close  

Information for Our Community

Whether you are part of our community or are interested in joining us, we welcome you to Washington University School of Medicine.

close  


New drug targets for Alzheimer’s identified from cerebrospinal fluid

A multitude of genes have been linked to the development of Alzheimer’s disease. Specifically how those genes might influence the progression of neurodegeneration remains something of a black box though, in part because of the challenges of examining in molecular detail the brain of a living patient.

Using cerebrospinal fluid (CSF) collected from living patients, a team of researchers at Washington University School of Medicine in St. Louis has for the first time linked disease-related proteins and genes to identify specific cellular pathways responsible for Alzheimer’s genesis and progression. Because these proteins were gathered from CSF, they are a good proxy for activity in the brain, and several of them may be potential targets for therapies.

The findings are available in Nature Genetics.

The use of patients’ CSF is a step forward for such studies and may be the best way to acquire relevant samples that help map out the constellation of protein activity, known as the proteome, said Carlos Cruchaga, PhD, the Barbara Burton and Reuben Morriss III professor of psychiatry and director of the NeuroGenomics and Informatics Center at WashU Medicine.

“Our goal is to identify risk-linked and protective genes, and also identify the causal role they play,” Cruchaga said. “To do that, we need to study human-derived data. That is why we decided to do a large proteomic study of cerebrospinal fluid, because we know that CSF is a good representation of the pathology of the disease.”

Cruchaga explained that similar investigations have relied on brain tissues collected postmortem, and therefore only provide information about the later stages of Alzheimer’s. Other studies have looked at blood plasma, which is not specific to the tissues affected by the disease.

In the past decade and a half of researching Alzheimer’s disease, scientists have increased the number of regions of our genome known to be associated with the condition from 10 to nearly 80. However, knowing the gene or region of DNA associated with the disease is only the first step. Linking an individual’s proteomic profile – that is, which proteins are active and to what degree – to their genetic code establishes a holistic view of the cellular activities in the brain. By comparing CSF samples from people with and without Alzheimer’s disease, the researchers could then identify which cellular pathways are dysfunctional.

“Sometimes within a region of DNA known to be associated with Alzheimer’s there are many genes, and we don’t know which of those genes are driving the medical condition,” Cruchaga said. “By adding the proteins to the analysis, we can determine the gene driving the association, determine the molecular pathway that they are part of, as well as to identify novel protein-to-protein interactions that otherwise will not be possible.”

Cruchaga and his collaborators had access to a rich database of information through the Knight-ADRC and the Dominantly Inherited Alzheimer Network (DIAN), which are based at WashU Medicine, as well as other studies through their collaborators. These studies were also able to provide the genetic information and CSF samples of 3,506 individuals, both healthy donors and those with Alzheimer’s disease.

The team cross-referenced proteomic data from the CSF samples with existing studies that had identified areas of the genome correlated with Alzheimer’s. From this process, they narrowed in on 1,883 proteins of the 6,361 in the CSF proteomic atlas. The investigators used three different established statistical analyses that can identify with high confidence genes and proteins that are part of the biological pathways leading to the disease. With this technique, they determined that 38 proteins are likely to have causal effects in Alzheimer’s progression; 15 of these can be targeted by medicines.

“The novelty and the strength of this analysis is that we have defined proteins that modify risk,” Cruchaga said. “So now that we have the causal steps, we can establish where the steps are leading to in the brain.”

The immediate implications for understanding and developing treatments for Alzheimer’s from this study are significant, but Cruchaga said he believes that CSF proteomics may yield a treasure trove of information for many neurological conditions, ranging from Parkinson’s disease to schizophrenia.

“That’s the power of this approach – once you have an atlas of genetic variants, and that of the protein levels, you can apply this to any disease,” he said.

Proteins are not the only key to unlocking these conditions to be found in the CSF. Cruchaga also is investigating the potential of metabolites – substances released by cells when breaking down other compounds as part of their routine processes that are also found in CSF. In a separate paper, also published in Nature Genetics, he and his collaborators demonstrated the promise of this approach and reported associations between specific metabolites and conditions including Parkinson’s disease, diabetes and dementia.

Vaccine shows promise against aggressive breast cancer

A small clinical trial shows promising results for patients with triple-negative breast cancer who received an investigational vaccine designed to prevent recurrence of tumors. Conducted at Washington University School of Medicine in St. Louis with a therapy designed by WashU Medicine researchers, the trial is the first to report results for this type of vaccine — known as a neoantigen DNA vaccine — for breast cancer patients.

The study, which found the vaccine to be well-tolerated and to stimulate the immune system, is available Nov. 14 in the journal Genome Medicine.

The phase I clinical trial — conducted at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine — involved 18 patients diagnosed with triple-negative breast cancer that was not metastatic, meaning it had not spread to other organs. Each patient received the standard of care and three doses of a personalized vaccine tailored to home in on key mutations in their specific tumor and train immune cells to recognize and attack any cells bearing these mutations.

Following treatment, 14 of 18 patients showed immune responses to the vaccine and, after three years, 16 patients remained cancer-free. While the early-stage trial was designed to evaluate safety of the vaccine and did not include a control group to determine efficacy, the researchers analyzed historical data from patients with triple-negative breast cancer treated with the standard of care only. In that group, on average, about half of patients remained cancer-free at three years post-treatment.

“These results were better than we expected,” said senior author William E. Gillanders, MD, the Mary Culver Distinguished Professor of Surgery at WashU Medicine who treats patients at Siteman. “Obviously, it’s not a perfect comparison, and we acknowledge the limitations of this type of analysis, but we are continuing to pursue this vaccine strategy and have ongoing randomized controlled trials that do make a direct comparison between the standard of care plus a vaccine, versus standard of care alone. We are encouraged by what we’re seeing with these patients so far.”

Triple-negative breast cancer is an aggressive tumor type that grows even in the absence of the hormonal fuel that drives growth of other types of breast cancer. To date, triple-negative breast cancer has no targeted therapies and is usually treated with traditional approaches that include surgery, chemotherapy and radiation therapy. For reasons that scientists are still investigating, this tumor tends to be more common among African American patients diagnosed with breast cancer. In this trial, one-third of the participants (six of 18) were African American.

For this trial, patients with triple-negative breast cancer who still had evidence of a tumor remaining after a first round of chemotherapy were eligible to participate. Such patients are at high risk of cancer recurrence even after the remaining tumor is surgically removed. After surgical removal, the research team analyzed and compared the tumor tissue with the same patient’s healthy tissue to find unique genetic mutations in the cancer cells. Such mutations in a patient’s cancer cells alter the proteins only in the tumor, making it possible to train the immune system to go after the altered proteins and leave healthy tissues alone.

Using software they designed, the researchers selected altered proteins — called neoantigens — that were made by the patients’ tumors and that were identified as most likely to trigger a strong immune response. On average, each patient’s vaccine contained 11 neoantigens (ranging from a minimum of four to a maximum of 20) specific to their tumor.

The software development was led by computational biologists Obi Griffith, PhD, a professor of medicine, and Malachi Griffith, PhD, an associate professor of medicine, both in the Division of Oncology at WashU Medicine. A related paper published simultaneously in the same journal describes the software tools they developed. One of their goals is to make these computational resources widely accessible to cancer researchers and clinicians worldwide.

“We hope to promote the use of this software for the design of cancer vaccines,” Malachi Griffith said. “These are complex algorithms, but in general, the software takes in a list of mutations and interprets them in the context of their potential to be good neoantigen candidates. The tools rank the possible neoantigens based on our current knowledge of what matters in stimulating the immune system to attack cancer cells. These software tools were developed with support from the National Cancer Institute, and they have an open license that makes them broadly available for both academic and commercial uses.”

Several studies of cancer vaccines are ongoing at Siteman. Vaccines for all of these trials are made in a WashU Medicine facility that meets the good manufacturing practice (GMP) requirements set by the Food and Drug Administration. In some of the vaccine clinical trials for breast cancer patients, personalized vaccines are being investigated in combination with immunotherapies called checkpoint inhibitors that boost the action of T cells.

“We are excited about the promise of these neoantigen vaccines,” Gillanders said. “We are hopeful that we will be able to bring more and more of this type of vaccine technology to our patients and help improve treatment outcomes in patients with aggressive cancers.”

WashU Medicine, BJC Health System launch Center for Health AI

Washington University School of Medicine and BJC Health System, both located in St. Louis, have launched the joint Center for Health AI to harness the power of cutting-edge artificial intelligence (AI) and fundamentally change the way health care is provided. The center will focus on making care more personalized and effective for patients and more efficient and manageable for physicians, nurses and all those striving to ensure patients receive the very best care.

The center is the first major initiative to evolve from the new, long-term affiliation between WashU Medicine and BJC that was finalized earlier this year and helps establish both organizations as leaders in developing and leveraging AI technologies to transform health care. With a joint leadership structure and a focus on shared goals, the center embodies the close collaboration envisioned by the WashU-BJC partnership.

“WashU Medicine and BJC are committed to pushing the boundaries of health care innovation to ensure that our caregivers, our patients and the communities we serve benefit from AI technologies,” 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. “The center brings together leaders and experts from across the organizations to generate new AI-based solutions and leverage emerging AI technologies in ways that will profoundly change how we work together and care for patients. It will become a magnet for recruiting health care professionals who want to shape the future of medicine.”

A major focus of the center will be using AI to streamline workflows and administrative tasks, making health care more efficient.

“Clinicians at BJC and WashU Medicine have piloted a new AI tool to help with documentation during patient visits so they can focus more fully on their patients,” said Nick Barto, president of BJC Health System. “Saving time in this way helps reduce health care workers’ burnout, and more focused attention from clinicians helps improve the experience for patients. We hope to broaden the use of this tool – and others like it – to help alleviate administrative burdens and enhance patient care. The result is a win-win.”

At a time when the demand for health care has never been greater, AI also can streamline the scheduling of patient appointments and predict the demand for equipment and other resources. Such technologies can help health care operations run more smoothly and prevent staff and supply chain shortages that can limit the ability to provide timely care.

The new center will be led by WashU Medicine’s Philip R.O. Payne, PhD, who will serve as the inaugural chief health AI officer, and Deborah O’Dell, chief data & analytics officer at BJC Health System. In addition to O’Dell, the center’s operating team includes Paul Scheel, MD, CEO of Washington University Physicians; Chris Miller, MD, chief clinical officer of BJC; Jessie Minton, WashU’s Chief Information Officer; and Jerry Fox, Chief Information & Digital Officer of BJC.

“AI is not a substitute for clinicians, but when used appropriately, it can enhance their capabilities, guide decision making and improve the quality, safety and outcomes of the care we provide to our patients,” said Payne, also the Janet and Bernard Becker Professor and the director of the Institute for Informatics, Data Science & Biostatistics at WashU Medicine. “With advances in AI, we’ve finally reached the point where the massive amounts of data captured about patients can be used to improve the efficiency and accessibility of care, the accuracy of diagnosis and treatment, and ultimately the health of the people in the communities we serve.”

To date, much of the attention on AI’s potential to improve patient care has focused on tools that improve diagnostic accuracy, enhance precision medicine and predict individual patients’ disease risks so physicians can better manage their care. WashU Medicine and BJC already have contributed to advances in this area, and such work will be supported by and expanded upon by the center. For example, our clinicians already have developed and implemented AI tools that can flag patients at high risk of sepsis or chemotherapy complications; analyze mammograms or other types of medical images to reliably detect microscopic tumors; help identify which treatments may be most effective for individual patients with complex or rare diseases; and predict excessive blood loss during surgery so blood products can be deployed efficiently to the operating room, which helps to reduce waste.

Because training the next generation of health care leaders is an important part of WashU Medicine’s and BJC’s missions, the center also will provide a unique opportunity for medical residents and students to develop the skills and experience they will need to thrive as AI becomes an ever-more-important aspect of patient care.

“Medical students and residents will benefit from immersive, practical training in AI-driven care delivery,” Payne said. “The unique environment we are creating will enable the next generation of physicians to harness AI to deliver exceptional patient care.”

The center also is designed to help clinicians and business leaders from WashU Medicine and BJC develop innovative AI tools by fostering cross-organizational collaboration, providing technical expertise and guidance, and assisting with evaluating AI technologies for safety and accuracy. Successful initiatives will be scaled up and implemented across the integrated health system so innovative ideas and tools can be translated into meaningful improvements in care and operations.

“Our goal with AI is to use data to improve the patient experience in ways that truly matter,” O’Dell said. “There are things we can do behind the scenes to get patients the care they need more quickly and smoothly, while reducing provider burnout. We have very capable leaders in administrative and clinical functions across the system who are already thinking about how they can use AI technology to improve efficiency. The center is here to support them in that journey.”

‘What’s your pain right now?’ Sickle cell, loss, and survival in America

Researchers make glioblastoma cells visible to attacking immune cells

Even treated with the most advanced therapies, patients with glioblastoma — an aggressive brain cancer — typically survive less than two years after diagnosis. Efforts to treat this cancer with the latest immunotherapies have been unsuccessful, likely because glioblastoma cells have few, if any, natural targets for the immune system to attack.

In a cell-based study, scientists at Washington University School of Medicine in St. Louis have forced glioblastoma cells to display immune system targets, potentially making them visible to immune cells and newly vulnerable to immunotherapies. The strategy involves a combination of two drugs, each already FDA-approved to treat different cancers.

The study is online in the journal Nature Genetics.

“For patients whose tumors do not naturally produce targets for immunotherapy, we showed there is a way to induce their generation,” said co-senior author Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and head of the Department of Genetics at WashU Medicine. “In other words, when there is no target, we can create one. This is a very new way of designing targeted and precision therapies for cancer. We are hopeful that in the near future we will be able to move into clinical trials, where immunotherapy can be combined with this strategy to provide new therapeutic approaches for patients with very hard-to-treat cancers.”

To create immune targets on cancer cells, Wang has focused on stretches of DNA in the genome known as transposable elements. In recent years, transposable elements have emerged as a double-edged sword in cancer, according to Wang. His work has shown that transposable elements play a role in causing tumors to develop even as they present vulnerabilities that could be exploited to create new cancer treatment strategies.

For this study, Wang’s team took advantage of the fact that transposable elements naturally can cause a tumor to churn out random proteins that are unique to the tumor and not present in normal cells. Called tumor antigens or neoantigens, these unusual proteins could be the targets for immunotherapies, such as checkpoint inhibitors, antibodies, vaccines and genetically engineered T cell therapies.

Even so, some tumors, including glioblastoma, have few immune targets produced naturally by transposable elements. To address this, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD, the August A. Busch Jr. Professor of Neurological Surgery, have demonstrated how to purposely force transposable elements to produce immune system targets on glioblastoma cells that normally lack them.

The researchers used a combination of two drugs that influence the so-called epigenome, which controls which genes are turned on in a cell and to what degree. When treated with the two epigenetic therapy drugs, the tightly packed DNA molecules of the glioblastoma cells unfurled, triggering transposable elements to begin making the unusual proteins that could be used to target the cancer cells. The two drugs were decitabine, which is approved to treat myelodysplastic syndromes, a group of blood cancers; and panobinostat, which is approved for multiple myeloma, a cancer of white blood cells.

Before investigating this strategy in people, the researchers are seeking ways to target the epigenetic therapy so that only the tumor cells are induced to make neoantigens. In the new study, the researchers cautioned that normal cells also produced targets when exposed to the two drugs. Even though normal cells didn’t produce as many neoantigens as the glioblastoma cells did, Wang and Kim said there is a risk of unwanted side effects if normal cells create these targets as well.

In ongoing work, Wang and Kim are investigating how to use CRISPR molecular editing technology to induce specific parts of the genome in cancer cells to produce the same neoantigens from transposable elements that are common across the human population. Such a strategy could give many patients’ tumors — even different cancer types — the same targets that could respond to the same immunotherapy, while sparing healthy cells. There are then multiple possible ways to go after such a shared target, including checkpoint inhibitors, vaccines, engineered antibodies and engineered T cells.

“Immunotherapy has revolutionized the treatment of some specific cancers, such as melanoma,” said Kim, who treats patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and is also the director of the Brain Tumor Center there. “Progress in glioblastoma has been slow by comparison because of how resistant this tumor is to the latest therapeutic strategies. But with recent advancements in immunotherapies and epigenetic therapies that could be used in combination, I’m hopeful that we are on the right path for a similar transformative change in the treatment of glioblastoma.”

My social media is helpful and positive. Here is how yours can be, too

Researchers solve medical mystery of neurological symptoms in kids

Most people who visit a doctor when they feel unwell seek a diagnosis and a treatment plan. But for some 30 million Americans with rare diseases, their symptoms don’t match well-known disease patterns, sending families on diagnostic odysseys that can last years or even lifetimes.

But a cross-disciplinary team of researchers and physicians from Washington University School of Medicine in St. Louis and colleagues from around the world has solved the mystery of a child with a rare genetic illness that did not fit any known disease. The team found a link between the child’s neurological symptoms and a genetic change that affects how proteins are properly folded within cells, providing the parents with a molecular diagnosis and identifying an entirely new type of genetic disorder.

The results, published Oct. 31 in the journal Science, have potential to help find new therapies for rare brain malformations.

“Many patients with severe, rare genetic disease remain undiagnosed despite extensive medical evaluation,” said Stephen Pak, PhD, a professor of pediatrics and a co-corresponding author on the study. “Our study has helped a family better understand their child’s illness, preventing further unnecessary clinical evaluations and tests. The findings also have made it possible to identify 22 additional patients with the same or overlapping neurological symptoms and genetic changes that affect protein folding, paving the way for even more diagnoses and, ultimately, potential treatments.”

According to Pak, about 10% of patients with suspected genetic disorders have a variant in a gene that has not yet been linked to a disease. His career has been focused on solving such medical mysteries.

Pak and author Tim Schedl, PhD, a professor of genetics and a co-director of the model organisms screening center at WashU Medicine, use tiny roundworms called C. elegans to assess whether specific genetic changes found in undiagnosed patients are responsible for their symptoms. With funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH), they and a team of researchers at WashU Medicine have committed to solving more such cases.

For this study, they teamed up with researchers and doctors from more than a dozen institutions across North America, Europe, India and China to identify the cause of a cluster of clinical findings in a boy from Germany, and other similar cases. The German patient had an intellectual disability, low muscle tone and a small brain with abnormal structures. Doctors also found changes to the CCT3 gene, so Pak’s team set out to determine if it could be the cause of the patient’s condition.

C. elegans has counterparts to about 50% of human genes, including the CCT3 gene, which is known as cct-3 in roundworms. Weimin Yuan, PhD, a staff scientist in pediatrics and co-first author, found that C. elegans with the patient’s genetic variant moved slower than roundworms with a healthy copy of the gene did, revealing that the genetic change can affect mobility and the nervous system.

The affected CCT3 protein is part of the large TRIC/CCT molecular complex whose job is to fold other proteins into their proper shape so they function as they should within cells. The study found that the protein-folding machinery cannot perform without a specific amount of healthy CCT3.

“We knew the child has one good and one bad variant gene copy,” Schedl said. “Our studies in C. elegans revealed that the genetic change reduces the activity of the normal protein, decreasing the capacity of the protein-folding machinery, and that for both C. elegans cct-3 and human CCT3, having 50% of activity was insufficient for normal biological function.”

The outcome of having reduced protein-folding machinery, they found, was that actin proteins – which help to maintain cell shape and movement –were incorrectly folded and abnormally distributed throughout the cells of C. elegans that carried the patient’s variant.

“An understanding of the impact of the genetic change informs the treatment modality,” Schedl added, “because the treatment needed to increase the amount of a normal protein differs from the treatment needed when the protein is poisonous or overactive.”

photo of roundwormsMatt Miller
Researchers at WashU Medicine modeled the effects of a patient’s genetic change in the tiny roundworm, C. elegans. Their findings, published in Science, contributed to the identification of a new type of rare disorder involving intellectual disability and brain malformations.

Collaborators from RWTH Aachen University in Germany and Stanford University performed complementary investigations into cct3 variants in zebrafish – which illuminated the effects of the gene on brain development – and in yeast, which clarified its role in protein folding, respectively.

To see if there are other patients out there with this same disorder, researchers mined a freely accessible global database of individuals with intellectual and developmental disabilities. They identified 22 individuals with genetic changes in seven of the eight CCT proteins that form the protein-folding machine. Abnormalities in mobility and actin folding were again seen in roundworms with variants affecting CCT1 and CCT7 proteins, just as the WashU Medicine team observed with dysfunctional CCT3. Together, these patients represent a new type of rare genetic disease involving the protein folding machinery.

“This work underscores the importance of using simpler model organisms, like C. elegans, to provide novel insights into human pathobiology,” said co-author Gary Silverman, MD, PhD, the Harriet B. Spoehrer Professor of Pediatrics and head of the Department of Pediatrics.

“Our findings can inform clinicians, the scientific community, and patients and families all around the world that changes to the genetic message that are needed to make the eight-protein complex cause disease,” added Pak, who together with Schedl and a team of NIH-funded researchers at WashU Medicine, aim to solve challenging medical mysteries using advanced technologies. “If next week a patient with brain malformations and neurological symptoms is found to have a variant that affects the protein-folding machine, the patient will receive a diagnosis.”

Complexity of tumors revealed in 3D

A new analysis led by researchers at Washington University School of Medicine in St. Louis has revealed detailed 3D maps of the internal structures of multiple tumor types. These cancer atlases reveal how different tumor cells — and the cells of a tumor’s surrounding environment — are organized, in 3D, and how that organization changes when a tumor spreads to other organs.

The detailed findings offer scientists valuable blueprints of tumors that could lead to new approaches to therapy and spark a new era in the field of cancer biology, according to the researchers.

The study is part of a group of 12 papers published Oct. 30 in the Nature suite of journals by members of the Human Tumor Atlas Network, a research consortium funded by the National Cancer Institute (NCI) of the National Institutes of Health (NIH). The 3D analysis — published in Nature — includes detailed data about breast, colorectal, pancreas, kidney, uterine and bile duct cancers.

The last decade of cancer research has been defined by tremendous advances in understanding the activities of cells in a tumor’s environment — both the cancer itself and its support cells, including on a single-cell level. The new study begins to reveal not just what each cell is up to, but also where each cell is located in the intact tumor and how each interacts with its neighboring cells, whether those cells are next door, down the street or in a completely different neighborhood.

This new information could help scientists understand how tumors spread or develop treatment resistance, to name a few intensive areas of ongoing study.

“These 3D maps of tumors are important because they finally let us see what, until now, we have only been able to infer about tumor structures and their complexity,” said co-senior author Li Ding, PhD, the David English Smith Professor of Medicine. “We understood that cancer cells, immune cells and structural cells were all present in the tumor, sometimes protecting the cancer from chemotherapy and immune system attack, but now we can actually see those battle lines. We now have the ability to see how regions of the tumor differ in 3D space and how the behavior changes in response to therapy or when the tumor spreads to other organs. These studies have opened a new era in cancer research with the potential to transform the way we understand and treat cancer in the future.”

The study is led by Ding, also a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine; and her fellow co-senior authors Feng Chen, PhD, a professor of medicine; Ryan C. Fields, MD, the Kim and Tim Eberlein Distinguished Professor; William E. Gillanders, MD, a professor of surgery, all of WashU Medicine; and Benjamin J. Raphael, PhD, of Princeton University.

3D organization of tumor neighborhoods

In general, the researchers found that tumors had higher metabolic activity — that is, they burned more fuel — in their cores and more immune system activity on their edges. They also found that a tumor can contain multiple neighborhoods with different genetic mutations driving the tumor’s growth. These neighborhoods are being appreciated for how they lead to treatment response and resistance in various cancer types. This suggests different targeted treatments may be needed to address key mutations in different neighborhoods.

“This understanding of 3D cancer metabolism will affect how our current treatments work, and sometimes don’t work, and will lead to development of novel treatments in cancer,” said Fields, who treats patients at Siteman. “It really is transformative.”

In addition, some tumor neighborhoods can have high immune cell activity — known as hot regions. The same tumor also can have so-called cold regions that do not have much, if any, immune activity. Hot regions typically respond well to immunotherapies, but cold regions do not, possibly helping to explain why some tumors appear responsive to immunotherapies at first and then develop resistance. If various mutation profiles as well as cold and hot neighborhoods can be identified, it presents the possibility of designing treatment strategies that could be effective against all neighborhoods within the same tumor.

The researchers — including co-first authors, Chia-Kuei (Simon) Mo and Jingxian (Clara) Liu, both graduate students in Ding’s lab — also found large variation in how deeply immune cells had infiltrated the various tumors and where different immune cell types, such as T cells or macrophages, assembled. Some metastatic tumor samples showed the cancer breaking through immune cell boundaries to continue the invasion of healthy tissue, perhaps illustrating a phenomenon called immune cell exhaustion, in which the immune system is overwhelmed by an aggressive cancer and can no longer contain its growth.

“If we can see exhausted T cells inside a tumor, we could potentially activate those T cells with a checkpoint inhibitor or other immunotherapies,” Ding said. “But if we don’t see them, we will know certain immunotherapies won’t work. These tumor maps can help us predict treatment resistance. We have never been able to talk this way about tumors before — being able to see that immune cells are present in the tumor, suggesting opportunities to exploit them for treatments.”

WashU Medicine researchers led two more studies as part of this package of publications. One, appearing in Nature Cancer and co-led by Ding and Gillanders, provides a detailed analysis of breast cancer, identifying how different types of breast tumors originate from different cell types. The research team also found that T cell exhaustion was common in an aggressive tumor known as triple-negative breast cancer. Knowledge of the “cell of origin” and the immune landscape in breast cancer could help guide future treatment strategies.

The other paper, appearing in Nature Methods and co-led by Ding, of WashU Medicine, and Raphael, of Princeton, describes new methods for 3D analyses of tumors, including those used in the study of the six tumor types that appeared in Nature.

Healthy brains suppress inappropriate immune responses

The brain constantly engages in dialogue with the body’s immune system. Such communication appears aimed at ensuring a delicate balance between defending against injury and infection and guarding healthy tissue.

Now, scientists at Washington University School of Medicine in St. Louis have revealed how the two strike a healthy balance. The study, in mice, found that fragments of immune-stimulating proteins – dubbed guardian peptides – are produced by the brain and spinal cord of the central nervous system to maintain the brain’s immune balance and permit a healthy interchange of information with the immune system.

The study, published Oct. 30 in the journal Nature, has the potential to improve treatments for diseases, such as multiple sclerosis (MS) and Alzheimer’s disease, among others.

“We have found guardian brain peptides that actively engage with the immune system to keep it in check, possibly preventing destructive immune responses,” said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “We think such peptides help the immune system to maintain a state of ‘immune privilege.’ We are intrigued by the possibility of developing such proteins from healthy brains into a therapy to suppress inappropriate immune responses and develop better disease-modifying therapies for neuroinflammatory diseases.”

Immune surveillance involves a subset of T cells that can initiate an immune response when alerted to a threat. That alert comes in the form of a tiny protein fragment – a sample of the potential threat – displayed on the surface of another group of presenting immune cells. If T cells deem the protein fragment threatening, they mount an attack.

The researchers found that guardian peptides were presented by immune cells at the interface of the brain’s borders, where they attracted and activated a subset of immune T cells whose function is regulatory, such that these cells dampen abnormal immune reactions.

Min Woo Kim, a graduate student in WashU Medicine’s Medical Scientist Training Program and a researcher in the Kipnis lab, examined presenting immune cells from the brain and its associated immune tissues in healthy mice. He found an abundance of brain proteins presented by such cells, with the dominant protein being a component of myelin sheath, the protective cover on neurons that becomes damaged in MS.

The researchers found that in mice with MS, such proteins were drastically depleted. By adding the missing brain-derived peptides through injection of vesicles – membrane-bound compartments – into the cerebrospinal fluid of mice with MS, the scientists found that the therapy activated and expanded a subset of suppressor T cells. Motor function improved, and disease progression slowed in the treated mice compared with mice that received control vesicles.

“We have identified a novel process in the brain where the organ actively engages with the immune system to present a healthy image of itself,” Kim said. “That image looks different in mice with multiple sclerosis. We think that other neuroinflammatory and even neurodegenerative diseases may have unique protein signatures presented to the immune system, opening the exciting possibility of using such signatures as a diagnostic tool for early diagnosis.”

WashU Medicine collaborators on the study include Cheryl Lichti, PhD, an associate professor of pathology & immunology; Clair Crewe, PhD, an assistant professor of cell biology & physiology; Maxim N. Artyomov, PhD, the Alumni Endowed Professor of Pathology & Immunology; and the late Emil R. Unanue, PhD, who died before seeing the study’s completion. Unanue, a 1995 Albert Lasker Basic Medical Research Award winner, was a pioneer in describing the interactions between T cells and presenting cells that make it possible for the former to recognize and respond to foreign invaders.

What People With Chronic Illness Need to Know About the ‘October Slide’

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.