Cuts in the cranium, which is more than 4,000 years old, hint that people in the ancient civilization attempted to treat a scourge that persists today.Fluctuating disease rates, innovative treatments and talk of “moonshots” in the White House may make cancer seem like a modern scourge. But a new discovery highlights how humans dealt with the illness and hunted for cures as far back as the time of the ancient Egyptians.Scientists led by Edgard Camarós, a paleopathologist at the University of Santiago de Compostela in Spain were studying an approximately 4,600-year-old Egyptian skull when they found signs of brain cancer and its treatment.“There was an uncomfortable silence in the room, because we knew what we had just discovered,” Dr. Camarós said.Using a microscope, he and Tatiana Tondini of the University of Tübingen in Germany and Albert Isidro of the University Hospital Sagrat Cor in Spain, the study’s other authors, found cut marks around the skull’s edges surrounding dozens of lesions that earlier researchers had linked to metastasized brain cancer. The shape of the cuts indicated that they had been made with a metal tool. This discovery, reported in a study published Wednesday in the journal Frontiers in Medicine, suggests that ancient Egyptians studied brain cancer using surgery. If the cuts were made while the person was alive, they may have even attempted to treat it.The new discovery not only expands scientific knowledge of Egyptian medicine, it may also push back the timeline of humanity’s documented attempts to treat cancer by up to 1,000 years.Cancer has bedeviled humans for as long as we have existed, and it even afflicted life on Earth long before.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

A new study by researchers from Arizona State University and their colleagues highlights a dietary strategy for significant health improvement and weight management.
Participants following an intermittent fasting and protein-pacing regimen, which involves evenly spaced protein intake throughout the day, saw better gut health, weight loss and metabolic responses. These benefits were notably greater than those seen with simple calorie restriction.
The findings, reported today in the journal Nature Communications, could advance our understanding of the relationship between the gut microbiome and metabolism and improve strategies for managing obesity.
The researchers compared the effects of two low-calorie dietary interventions: a heart-healthy continuous calorie-restricted diet (based on USDA dietary recommendations), and a calorie-restricted regimen incorporating intermittent fasting and protein pacing.
The trial was conducted with 41 individuals who were overweight or obese over a period of eight weeks. Individuals in the intermittent fasting and protein-pacing group showed a decrease in symptoms of gastrointestinal problems and an increase in diversity of the gut microbiota compared with those in the calorie-restriction group.
The intermittent fasting protocol increased beneficial microbes in the gut that have been linked to a lean body type and improved overall health. Additionally, it increased the levels of certain proteins (cytokines) in the blood associated with weight loss, as well as amino acid byproducts that promote fat burning.
Intermittent fasting is an eating pattern that cycles between periods of fasting and eating. The method has recently gained popularity for its potential health benefits, including weight loss, improved metabolic health and enhanced brain function.

“Given the gut microbiota’s location and its constant interaction with the GI tract, we have been gaining a deeper understanding of its pivotal role in dietary responses these last several years,” says Alex Mohr, lead author of the new study. “While limited in duration and sample size, this comprehensive investigation — which included the analysis of the gut microbiome, cytokines, fecal short-chain fatty acids and blood metabolites — underscores the intricate interplay between diet, host metabolism and microbial communities.”
Mohr led the microbiome and molecular investigations, evaluating gut microbial composition, inflammatory molecules called cytokines, SCFAs (metabolites derived from dietary fiber, important for regulating energy balance) and the metabolome.
Mohr is a researcher with the Biodesign Center for Health Through Microbiomes at ASU. Rosa Krajmalnik-Brown, the center director, and researchers Devin Bowes, Karen Sweazea and Corrie Whisner are also contributors to the study.
Corresponding author Paul Anciero of the Department of Health and Human Physiological Sciences at Skidmore College led the clinical trial, which tracked weight loss and body composition.
The study also included contributions from ASU researchers Paniz Jasbi and Judith Klein-Seetharaman, with the School of Molecular Sciences, and Dorothy Sears and Haiwei Gu, with the College of Health Solutions.
Diet, microbiome and weight loss
The gut microbiome refers to the diverse community of microorganisms residing in the gastrointestinal tract, including bacteria, viruses, fungi and other microbes. Numbering in the many trillions of organisms, this complex ecosystem plays a crucial role in essential bodily functions and overall health.

The gut microbiome helps break down food, produce vitamins and promote the absorption of nutrients. It plays a role in the development and function of the immune system by protecting the body against harmful pathogens. Finally, the gut microbiome keenly regulates metabolism, impacting body weight, fat storage and insulin sensitivity.
Caloric restriction, intermittent fasting (limiting food consumption to certain windows on some days) and protein pacing (controlled protein intake at specific meals) have been shown to affect body weight and composition, but the effect of these dietary modifications on the gut microbiome has been unclear until now.
“A healthy gut microbiome is essential for overall health, particularly in managing obesity and metabolic diseases,” says Sweazea, the ASU principal investigator of this Isagenix-funded study. “The gut bacteria influence how we store fat, balance glucose levels and respond to hormones that make us feel hungry or full. Disruptions in the gut microbiota can lead to increased inflammation, insulin resistance and weight gain, underscoring the critical role of gut health in preventing and managing metabolic disorders.”
Study and findings
The clinical trial involved 27 female and 14 male participants who were overweight or obese. Participants were divided into two groups: one following the intermittent fasting and protein pacing regimen, and the other adhering to a heart-healthy, calorie-restricted diet. Both groups were monitored over eight weeks for changes in weight, body composition, gut microbiome composition and plasma metabolomic signatures.
Participants following the intermittent fasting and protein pacing regimen experienced a significant reduction in gut symptoms and an increase in beneficial gut bacteria, particularly from the Christensenellaceae family. The study also found these microbes are associated with improved fat oxidation and metabolic health. In contrast, the calorie-restricted group showed an increase in metabolites linked to longevity-related pathways.
Despite both groups having similar average weekly energy intake, the intermittent fasting and protein pacing group achieved greater weight loss and fat reduction with an average loss of 8.81% of their initial body weights during the study. In comparison, those on a calorie-restricted diet lost an average of 5.4% body weight.
Participants who followed the intermittent fasting and protein-pacing diet experienced reductions in overall body fat, including belly fat and deep abdominal fat, and saw an increase in the percentage of lean body mass.
The study underscores the potential of intermittent fasting and protein-pacing diets in improving gut health and weight management. While further research is necessary, these findings offer a promising avenue for creating effective dietary interventions for obesity and related metabolic disorders.
“By identifying shifts in specific microbes, functional pathways and associated metabolites, this line of work holds promise for personalized health strategies as we can better tailor nutritional regimens to enhance gut function and metabolic outcomes,” Mohr says.
Additional institutions contributing to the study: Systems Precision Engineering and Advanced Research (SPEAR); Center of Translational Science, Florida International University; Isagenix International LLC; and the School of Health and Rehabilitation Sciences, Department of Sports Medicine and Nutrition, University of Pittsburgh.

Changing how often a popular cancer therapy is delivered would reduce greenhouse gas emissions and improve environmental impact without decreasing cancer survival, according to a new analysis from researchers at the University of Michigan Health Rogel Cancer Center.
The team looked at 7,813 veterans receiving the immunotherapy treatment pembrolizumab through the Veterans Health Administration. Pembrolizumab is an intravenous treatment that is often given every three weeks at a standard, one-size-fits-all dose of 200 milligrams. Researchers estimated the environmental impact of patients coming in for this care every three weeks: carbon dioxide emissions from patients’ transportation to and from the clinic, manufacturing of the drug, and medical waste like needles, tubing and bags used during the compounding and infusing process.
Then they considered alternative scenarios. What if patients received 400 milligrams of pembrolizumab every six weeks, a dose approved by the U.S. Food and Drug Administration? What if they received a dose proportionate to their weight instead of the standard dose, as pembrolizumab was originally approved by FDA? Data suggests these approaches achieve cancer outcomes equivalent to the standard three-week flat dosing and likely reduce the burdens of cancer treatment that patients face.
They found that for this cohort of patients, extending treatments to every six weeks instead of every three weeks would have required 15,000 fewer infusions. That means 15,000 fewer trips to the clinic and 15,000 fewer incidents of compounding and infusing treatments. In total, this change would reduce greenhouse gas emissions in just the VHA by 200 tons per year. Results are published in The Lancet Oncology.
“As providers, every time we’re with a patient we’re faced with this litany of decisions that both we and the patient have to make. Those decisions — every three week dosing or every six week dosing — seem small but they really add up,” said study author Garth W. Strohbehn, M.D., M.Phil., assistant professor of internal medicine at Michigan Medicine.
Next, researchers looked at the impact that the reduced carbon emissions could have on climate change and human health — not just for the person with cancer, but for all of us, due to rising global temperatures. The model indicates that by continuing the current trends in pembrolizumab dosing instead of changing to less-frequent dosing, about three more people will die per year between now and 2100 because of the extra greenhouse gas emissions.
“There will more than likely be folks completely uninvolved in cancer care who are harmed by choosing to dose this medicine the way that we do. It doesn’t need to happen,” said Strohbehn, who is also a member of the U-M Institute for Healthcare Policy and Innovation and early career research scientist at the VA Ann Arbor Center for Clinical Management Research.

“That’s the point we’re trying to make here: There are likely to be health costs that non-patients in a society can expect to bear when we choose to practice cancer care the way we do. Do we have a moral obligation to change the way we’re doing things if the patient in front of us is not harmed by it?”
Patient transportation to and from appointments was the biggest driver of carbon emissions, researchers found, which suggests that less-frequent infusion treatments would not only help the environment but also potentially improve patient quality of life due to fewer trips to the hospital. Researchers also estimated significant cost savings for VHA from the alternative dosing regimens since the total amount of drug used with the weight-based doses is lower than the one-size-fits-all approach, echoing earlier findings from Strohbehn’s team.
The study authors suggest that multiple policy actions would need to be aligned to facility this change. They suggest payers could develop targeted incentives around environmentally conscious care. Professional societies could alter guidelines with environmental sustainability in mind, where patient outcomes are not expected to be impacted by the adoption of more sustainable care. Requiring environmental report cards for individual drugs at the time of approval could also increase awareness.
“I think there’s value in holding a mirror up to the conventional system and encouraging self-reflection,” Strohbehn said.

N.I.H. officials suggested federal record keepers helped them hide emails. If so, “that’s really damaging to trust in all of government,” one expert said.House Republicans on Tuesday accused officials at the National Institutes of Health of orchestrating “a conspiracy at the highest levels” of the agency to hide public records related to the origins of the Covid pandemic. And the lawmakers promised to expand an investigation that has turned up emails in which senior health officials talked openly about trying to evade federal records laws.The latest accusations — coming days before a House panel publicly questions Dr. Anthony S. Fauci, a former top N.I.H. official — represent one front of an intensifying push by lawmakers to link American research groups and the country’s premier medical research agency with the beginnings of the Covid pandemic.That push has so far yielded no evidence that American scientists or health officials had anything to do with the coronavirus outbreak. But the House panel, the Select Subcommittee on the Coronavirus Pandemic, has released a series of private emails that suggest at least some N.I.H. officials deleted messages and tried to skirt public records laws in the face of scrutiny over the pandemic.Even those N.I.H. officials whose job it was to produce records under the Freedom of Information Act may have helped their colleagues avoid their obligations under that law, several emails suggest. The law, known as FOIA, gives people the right to obtain copies of federal records.“I learned from our foia lady here how to make emails disappear after i am foia’d but before the search starts, so i think we are all safe,” Dr. David Morens, a former senior adviser to Dr. Fauci, wrote in February 2021. That email chain included Dr. Gerald Keusch, a scientist and former N.I.H. official, and Peter Daszak, the president of EcoHealth Alliance, a virus-hunting nonprofit group whose work with Chinese scientists has drawn scrutiny from lawmakers.“Plus i deleted most of those earlier emails after sending them to gmail,” Dr. Morens added, referring to his personal Gmail account.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

She believed the bond between adults was as sustaining as that between parent and child, and developed a therapy to strengthen and repair broken relationships.Sue Johnson, a British-born Canadian clinical psychologist and best-selling author who developed a novel method of couples therapy based on emotional attachment, challenging what had been the dominant behavioral approach — the idea that behaviors are learned and thus can be changed — died on April 23 in Victoria, British Columbia. She was 76.Her death, in a hospital, was caused by a rare form of melanoma, said her husband, John Douglas.When divorce rates rose in the 1970s, couples therapy blossomed. Drawing from traditional psychotherapy practices, therapists focused mostly on helping distressed couples communicate more effectively, delve into their upbringings and “negotiate and bargain,” as Dr. Johnson put it, over divisive issues like parenting, sex and household chores.In her own practice, however, she became frustrated at how her couples seemed to be stalling out.“My couples didn’t care about insight into their childhood relationships,” she wrote in her book “Hold Me Tight: Seven Conversations for a Lifetime of Love” (2008), which has sold more than a million copies and been translated into 30 languages. “They didn’t want to be reasonable and learn to negotiate. They certainly didn’t want to be taught rules for fighting effectively. Love, it seemed, was all about nonnegotiables. You can’t bargain for compassion, for connection. These are not intellectual reactions; they are emotional responses.”In conventional therapy that sought to modify behavior, emotions had long been dismissed as problematic in dealing with marital issues — something to be tamed — and dependence on a loved one was seen as a sign of dysfunction.Dr. Johnson thought otherwise. She knew of the attachment studies of John Bowlby, the British psychiatrist who studied children who had been traumatized by being orphaned or separated from their parents during World War II. Later researchers began to focus on adult attachments and noted how secure connections among couples helped them weather the inevitable storms of relationships.Dr. Johnson’s 2008 book has sold more than million copies and been translated into 30 languages. Little, Brown SparkWe are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

A team of cancer researchers, led by the University of Houston, has discovered a new subset of T cells that may improve the outcome for patients treated with T-cell therapies.
T cell-based immunotherapy has tremendous value to fight, and often eliminate, cancer. The strategy activates a patient’s immune system and engineers a patient’s own T cells to recognize, attack and kill cancer cells. In this way, the body’s own T cells become living drugs.
While T-cell immunotherapy has revolutionized cancer treatment, there is still much to learn. Unfortunately, not all patients respond to these therapies, so a better understanding of the properties of engineered T cells is necessary to improve clinical responses.
One such study, supported by a grant from the National Institutes of Health, is reported in Nature Cancer by the laboratory of Navin Varadarajan, M.D. Anderson Professor in the William A. Brookshire Department of Chemical and Biomolecular Engineering. The study uses the patented TIMING (Timelapse Imaging Microscopy in Nanowell Grids) approach which applies visual AI to evaluate cell behavior, movement and ability to kill.
“Our results showed that a subset of T cells, labeled as CD8-fit T cells, are capable of high motility and serial killing, found uniquely in patients with clinical response,” reports first author and recent UH graduate Ali Rezvan in Nature Cancer. In addition to the UH team, collaborators include Sattva Neelapu and Harjeet Singh, The University of Texas MD Anderson Cancer Center, Houston; Mike Mattie, Kite Pharma; Nabil Ahmed, Texas Children’s Hospital, Baylor College of Medicine, Houston; and Mohsen Fathi, CellChorus.
To discover the CD8-fit cells, the team used TIMING to track interactions between individual T cells and tumor cells across thousands of cells and integrated the results with single-cell RNA sequencing data.
“Chimeric antigen receptors (CAR) T cells used for the treatment of B cell malignancies can identify T-cell subsets with superior clinical activity. Using infusion products of patients with large B cell lymphoma, we integrated functional profiling using TIMING with subcellular profiling and scRNA-seq to identify a signature of multifunctional CD8 T cells (CD8-fit),” said Rezvan. “We profiled these cells using single-cell RNA sequencing to identify the CD8-fit molecular signature that could be used to predict durable patient outcomes to T-cell therapies and validated our findings with independent datasets.”
The team also found that the CD8-fit signature is present in pre-manufactured T cells, longitudinally persists in patients post-infusion, and most importantly, is associated with long-term positive clinical responses. According to the researchers, it is likely that these T cells can drive clinical benefit in other tumors.
“This work illustrates the excellence of graduate students Ali Rezvan and Melisa Montalvo; and post-doctoral researchers Melisa Martinez-Paniagua and Irfan Bandey among others,” said Varadarajan.
CellChorus, a spinoff from Varadarajan’s Single Cell Lab at UH, is developing the AI-powered TIMING platform. The company recently announced a $2.5 million Small Business Innovation Research grant from the National Center for Advancing Translational Sciences of the National Institutes of Health to advance TIMING for cell therapy applications.

A multidisciplinary research team at the University of California, Irvine has revealed that the circadian clock — the biological pacemaker that governs daily rhythms in physiological processes, including immune functions — can be leveraged to enhance the efficacy of checkpoint inhibitor cancer therapy. Checkpoint inhibitors block different proteins from binding to tumor cells, allowing the immune system’s T cells to kill the tumor.
The study, published online today in the journal Nature Immunology, provides deeper insights into the intricate relationship among the circadian clock, immune regulation and tumor development and found that a therapeutic approach optimizing time-of-day delivery based on an individual’s unique circadian patterns offers new avenues for prevention and treatment.
“Disruption of the internal biological pacemaker is an inherent aspect of modern society that may contribute to the rising incidence of many cancer types. We found that proper regulation of circadian rhythms is necessary to suppress inflammation and support peak immune function,” said corresponding author Selma Masri, UC Irvine associate professor of biological chemistry. “Understanding precisely how circadian disruption promotes disease progression could lead to behavior modification to reduce cancer risk.”
Team members used an advanced single-cell RNA sequencing technique in a genetic model of colorectal cancer and identified clock-dependent changes controlling the number of myeloid-derived cells that suppress T cell activation. They discovered that disruption of the internal clock in the epithelial cells lining the intestine alters secretion of cytokine proteins, leading to heightened inflammation, increased numbers of immunosuppressive myeloid cells and cancer progression. These findings were leveraged to demonstrate that providing immunotherapy at the time of day when these immunosuppressive myeloid cells are most abundant significantly enhanced the efficacy of immune checkpoint blockades in solid tumors.
“As we enhance our understanding of the fundamental mechanism of circadian regulation of immunity, we will be able to harness the power of the body’s natural rhythms to fight cancer and develop more personalized and effective treatment strategies,” said lead author Bridget Fortin, a UC Irvine doctoral student in the Department of Biological Chemistry.
While this study represents a significant step forward in defining circadian control of anti-tumor immunity, the team believes future research should focus on exploring additional factors and cell types influencing time-of-day response to checkpoint inhibitor therapy.
Other team members included UC Irvine School of Medicine graduate students and faculty from the departments of biological chemistry, physiology and biophysics, surgery, and medicine.
This work was supported by the National Cancer Institute, the V Foundation and Johnson & Johnson, among others.

Scientists have designed an intersectional technique for precisely targeting subpopulations of cells and parsing out specific functions.
As gene sequencing technologies become more powerful, our understanding of cellular diversity has grown in parallel. This led scientists at St. Jude Children’s Research Hospital to create a tool to improve the ease and accuracy with which investigators can study specific subpopulations of cells. The tool, named Conditional Viral Expression by Ribozyme Guided Degradation (ConVERGD), allows researchers to specifically access these subgroups of cells and precisely manipulate them based on multiple features of the cell.
ConVERGD offers numerous advantages over existing intersectional expression platforms by accommodating more complex genetic payloads and increased adaptability. The researchers demonstrated the utility of ConVERGD by studying a previously unidentified subpopulation of norepinephrine neurons. The work demonstrates the substantial impact that investigations into cellular subpopulations could have on fundamental research and health care. The findings were published today in Nature Neuroscience.
Same type of cells, different functions
For Lindsay Schwarz, PhD, St. Jude Department of Developmental Neurobiology, necessity drove invention as she explored the neuronal cell landscape, and in particular, neuronal cells that produce norepinephrine. “Norepinephrine neurons have been thought to be just one type of neuron. But when they’re activated in the brain, they can cause a lot of different types of behavior, such as enhancing attention and memory formation or eliciting a stress response or fight-or-flight response,” Schwarz said. “But if it’s only one type of neuron releasing this one molecule, then how does it make you do different things?”
To explore such questions requires the ability to selectively interrogate cellular subpopulations with extreme prejudice. To this end, Schwarz found all attempts using current practices were coming up short. “We didn’t go into this project thinking we would build a new tool, but it seemed like a need in the community.”
Improving on current cellular subpopulation targeting technology
Targeting subpopulations of cells requires passing them through several genetic filters. These intersectional filters interrogate what genes the cells express and what pathways and connections they make, parsing out the different subpopulations so that researchers can focus on a select group of isolated cells.

The use of adeno-associated virus (AAV)-based reporter tools which can deliver genetic material into specific cells with high precision is an ideal approach for applying these intersectional filters. These reporter tools are used to label or monitor gene expression and protein localization within specific cells or regions. However, they can be complex to design and offer a limited amount of space within them.
“One of our main goals was to design a tool where your gene of interest only got expressed when conveyed with multiple features but is really easy for end users to modify and put in whatever genes they want,” explained Schwarz.
Robust ribozymes offer next-generation specificity
Schwarz and first author Alex Hughes, PhD, a graduate of the St. Jude Graduate School of Biomedical Sciences, currently of the Allen Institute for Brain Science, leveraged two separate technologies in the design of ConVERGD, namely AAV-based reporter technology and inspiration from the world of ribozymes, strands of RNA that can behave like enzymes by catalyzing biochemical reactions.
Importantly, ribozymes can be engineered to control the on/off switch for gene expression with extreme precision. “We initially heard about ribozymes from a journal club that was thinking more therapeutically about how to use AAVs,” Schwarz said. “Alex came back and figured that he could come up with a way to utilize these in neuroscience tools.”
Exciting for the neuroscience community and beyond
As a proof-of-concept, Schwarz and Hughes used ConVERGD to interrogate a subpopulation of norepinephrine neurons. “Collectively, norepinephrine neurons do a lot of different things,” Schwarz explained. “The subset we were targeting makes norepinephrine, but they also make this other opioid peptide called dynorphin, which hasn’t been characterized in these neurons before. With ConVERGD, we found that activating just these dynorphin-expressing neurons was enough to elicit an anxiety response.”

By parsing out the functions and assigning them to a subpopulation of cells, Schwarz is hopeful that targeted therapy is a possibility. “We treat anxiety and depression with drugs that target norepinephrine signaling, but they target it globally,” Schwarz said. “You’re also going to see a detriment to other important functions for norepinephrine that you don’t want to see. Targeting these neurons more specifically could help to ameliorate that.”
The work will have ripple effects outside of St. Jude. “We’re really excited about this for the community,” Schwarz said. “ConVERGD should be amenable to any tissue. It could be useful beyond neuroscience.”

The Wistar Institute’s Paul M. Lieberman, Ph.D., and lab team led by senior staff scientist and first author, Samantha Soldan, Ph.D., have demonstrated how B cells infected with the Epstein-Barr virus (EBV) can contribute to a pathogenic, inflammatory phenotype that contributes to multiple sclerosis (MS); the group has also shown how these problematic B cells can be selectively targeted in a way that reduces the damaging autoimmune response of multiple sclerosis. The lab’s findings were published in Nature Microbiology in the paper, “Multiple sclerosis patient derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease.”
EBV — a usually inactive, or latent, herpesvirus — affects most of the human population; more than 90% of people carry the virus as a passive, typically symptomless infection. However, EBV infection has been linked to several diseases, including MS: an incurable, chronic autoimmune disease that causes the body’s immune system to attack the myelin sheath of neurons in the brain and nervous system. Because myelin sheathing facilitates fast nervous system signaling (the fatty insulation of myelin along a neuron’s axon allows electrical impulses to travel through neuronal networks faster), its degradation can cause a wide variety of symptoms in both type and severity that may include motor control disruption, sensory issues, and speech difficulties.
Though researchers know that EBV can contribute to the development of MS, the exact mechanisms by which it does so aren’t completely understood. The Lieberman lab, in seeking to understand how EBV contributes to the development of MS, collaborated with Steven Jacobson, Ph.D., of the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke, who contributed cell line samples from patients. The research team analyzed spontaneous lymphoblastoid cell line (SLCL) cell samples from a healthy control group; a group of patients with active MS (as opposed to so-called stable MS; the disease is characterized by unpredictable periods of flare-ups and eased symptoms); and a group of patients with stable MS.
B cells are crucial cells of the immune system that help regulate the body’s immune responses; they have also been implicated in autoimmune conditions due to their role as mediators of which biological signals warrant immune response. And B cells, when infected with EBV, become immortalized — that is, the cells are no longer constrained by senescence, so they can continue to divide an indefinite number of times — as “lymphoblastoid cell lines,” or LCLs. This immortalized B cell state can occur spontaneously within the body as a result of EBV infection, which is how the Lieberman lab was able to extract immortalized SLCL samples for study from the different patient groups.
Having obtained the matched samples, Dr. Lieberman and his team conducted genetic analyses of the SLCLs and confirmed that the MS-positive sample groups showed greater expression of genes associated with lytic EBV (“lytic” describes when latent viruses like EBV become active); they also saw increased inflammatory signaling and expression of the FOXP1 protein, the latter of which was shown to promote lytic EBV gene expression. As a whole, the group’s findings suggested a mechanism of lytic EBV in MS that promoted inflammation and disease.
Diving further, Lieberman’s group tested several antiviral compounds on all SLCL groups and found that one, TAF, reduced lytic EBV gene expression without killing the cells. TAF also significantly reduced the expression of inflammatory cytokines like IL-6 in the SLCLs from the patients with active MS. Finally, when cultured SLCLs from active MS, stable MS, and controls were administered TAF in the presence of antiviral T cells, the T cell response (a major factor in the autoimmune dysfunction of MS) was reduced in SLCLs from patients with MS but not reduced in the control SLCLs — an indication that TAF treatment has potential as a selectively cytotoxic anti-lytic treatment for MS.
“Our work with these SLCLs shows that the problematic inflammation signaling from lytic EBV can be selectively targeted in a way that demonstrably reduces damaging immune responses,” said Dr. Lieberman. “We’re excited about expanding this concept further; we have the potential to see whether TAF or other inhibitors of EBV might be a viable treatment for multiple sclerosis that can stop the autoimmune damage without causing wide-ranging and dangerous cell death.”

Cornell University scientists have designed a way to “cloak” proteins in a generalized technique that could lead to repurposing things like antibodies for biological research and therapeutic applications.
The “cloaked” proteins can be captured by lipid nanoparticles, which are akin to tiny bubbles of fat. These bubbles are small enough to sneak their hidden cargo into living cells, where the proteins uncloak and exert their therapeutic effect.
The group’s paper published in ACS Central Science. The lead author is doctoral student Azmain Alamgir, who works in the labs of the paper’s co-senior authors, Chris Alabi, associate professor of chemical and biomolecular engineering, and Matt DeLisa, professor of engineering.
For some drugs to impact a cell’s biology, and ultimately treat disease, they need to get inside the cell and reach a specific space. Protein-based therapeutics have many virtues — they can have more specific effects, with lower toxicity and diminished immune response — but ease of delivery is not one of them. Proteins are large and cumbersome and don’t freely diffuse into cells as easily as small molecules do.
“We had been looking for a clever way to efficiently get our engineered proteins inside of cells, especially in a translational context that would not only work in lab-cultured cells, but that would also be effective and safe in animal models and eventually in humans,” DeLisa said.
The researchers had the broad idea of using a bioconjugation approach that would allow the proteins to be loaded into lipid nanoparticles, which form around nucleic acids. A major advantage of this approach was that lipid nanoparticles were a key component in the successful COVID-19 vaccines developed by Pfizer-BioNTech and Moderna.
Those vaccines worked by delivering a payload in the form of messenger RNA, which are nucleic acids. The researchers now would use the same lipid nanoparticle delivery concept — the same materials even — but with a protein payload. The trick would be to make proteins look more like nucleic acids.
The researchers found they could accomplish this by “cloaking” the proteins with a negatively charged ion, so they would join with the positively charged lipids electrostatically.
“The crux of our strategy is conceptually very simple,” Alamgir said. “We’re taking proteins and specifically remodeling their surfaces with negative charges, so they look like nucleic acids and can similarly assemble into nanoparticles when formulated with the characteristic lipids.”
The team successfully demonstrated the cloaking method with lysine-reactive sulfonated compounds, killing cancer cells with ribonuclease A and inhibiting tumor signaling with monoclonal immunoglobulin G (IgG) antibodies.