Purdue University researchers are developing and validating patent-pending poly (lactic-co-glycolic acid), or PLGA, nanoparticles modified with adenosine triphosphate, or ATP, to enhance immunotherapy effects against malignant tumors.
The nanoparticles slowly release drugs that induce immunogenic cell death, or ICD, in tumors. ICD generates tumor antigens and other molecules to bring immune cells to a tumor’s microenvironment. The researchers have attached ATP to the nanoparticles, which also recruits immune cells to the tumor to initiate anti-tumor immune responses.
Yoon Yeo leads a team of researchers from the College of Pharmacy, the Metabolite Profiling Facility in the Bindley Bioscience Center, and the Purdue Institute for Cancer Research to develop the nanoparticles. Yeo is the associate department head and Lillian Barboul Thomas Professor of Industrial and Molecular Pharmaceutics and Biomedical Engineering; she is also a member of the Purdue Institute for Drug Discovery and the Purdue Institute for Cancer Research.
The researchers validated their work using paclitaxel, a chemotherapy drug used to treat several types of cancers. They found that tumors grew slower in mice treated with paclitaxel enclosed within ATP-modified nanoparticles than in mice treated with paclitaxel in non-modified nanoparticles.
“When combined with an existing immunotherapy drug, the ATP-modified, paclitaxel-loaded nanoparticles eliminated tumors in mice and protected them from rechallenge with tumor cells,” Yeo said.
The research has been published in the peer-reviewed journal ACS Nano.
Challenges to systemic immunotherapy delivery
Immunotherapy is a promising approach to fighting cancer, but Yeo said it does not benefit a large population of patients because they do not have the powerful immune cells needed to combat tumors.

“Pharmacological agents to activate immune cells can directly be given to tumors,” Yeo said. “Then the immune system can fight not only the treated tumors but also nontreated tumors in distant locations as the activated immune cells circulate in the bloodstream.”
However, Yeo said most tumors with poor prognoses are not always locatable or accessible. Therefore, they may not be effectively treated by local therapy. She and her team envisioned systemic delivery of immunotherapy, but there are challenges.
“For successful systemic administration, active ingredients that stimulate anti-tumor immune responses need to be simultaneously present in tumors to exert concerted effects on the target,” Yeo said. “The ingredients also must maintain their activity until they reach tumors, but not cause toxic off-target effects. Moreover, the carriers traditionally used in local drug delivery offer limited utility in systemic application because they may not be compatible with blood components.”
Yeo and her colleagues used biocompatible polymeric nanoparticles to deliver immunotherapy compounds and modified them to safely activate the immune system.
“We employed poly (lactic-co-glycolic acid), or PLGA, nanoparticles based on the strong track record of the polymer in FDA-approved products and its routine use in the systemic delivery of poorly water-soluble drugs,” Yeo said.
Tests verified the ATP-modified PLGA nanoparticles were well tolerated in mice upon multiple systemic injections. They were able to recruit dendritic cells, the immune cells that recognize tumor antigens and bring specialized immune cells to fight off tumors.

“Moreover, the nanoparticles were shown to control the release of paclitaxel to minimize its systemic toxicity,” Yeo said.
The next development steps
Yeo and her colleagues will continue their work on the ATP-modified nanoparticles.
“We are currently working on improving the delivery of the nanoparticles to tumors and combining them with other treatments that will circumvent the resistance to the nanoparticle-delivered immunotherapy,” Yeo said. “To finance these efforts, we will apply for continued support from the National Institutes of Health. We are also open to industry partnerships to take this technology to the clinic.” Yeo and the research team received funding from the National Institutes of Health, the National Center for Advancing Translational Sciences, the Indiana Clinical and Translational Sciences Institute, and the Purdue Institute for Cancer Research.

Researchers have identified a protein that, when targeted, enables cisplatin-resistant cancer cells to become responsive to treatment. Cisplatin, and other similar platinum drugs, are incredibly effective at killing rapidly growing cancer cells, which is why they have been used in treating cancers for over 45 years. However, these drugs are non-targeted and can cause debilitating toxic side effects, resulting in a diminished lifestyle, and patients in poor health are deemed ineligible for use.
In a study, published today in Cancer Research, a journal of the American Association for Cancer Research, researchers say they have discovered that the protein puromycin-sensitive aminopeptidase (NPEPPS) plays a role in regulating response to platinum chemotherapy in patients with bladder cancer.
“We found that this protein is a driver in resistance to platinum therapy. If we remove it experimentally or pharmacologically, we can re-sensitize the cancer cells to their pre-resistant level of response,” says James Costello, PhD, co-corresponding author and associate professor at the University of Colorado Anschutz Medical Campus.
Costello and co-authors aimed to understand why most bladder cancer patients do not respond well to platinum-based drug regimens. By identifying the role NPEPPS plays, researchers were then able to genetically disrupt the function of NPEPPS, ultimately making cancer cells more responsive to platinum drugs.
“Our multi-omic assessment, including the use of tiny organoids derived from patients’ bladder cancer samples, yielded findings that could make this effective treatment an option for many more patients,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Foundation Distinguished Chair at Cedars-Sinai and co-corresponding author of the study.
Theodorescu added that the approach is an example of how precision medicine is leading the change in how cancer is treated by defining cancer vulnerabilities such as NPEPPS that can be targeted with small molecules and used in combination with cisplatin. Indeed, the Theodorescu and Costello laboratories are doing just that.
“This novel therapeutic approach could allow the administration of lower platinum drug doses, potentially decreasing debilitating side effects while also making platinum-based therapies more effective,” says Costello, also with the CU Cancer Center. He points to next steps in utilizing this new approach in hopes of expanding its use to other cancers.
“A high percentage of all cancer patients will see a platinum drug in their treatment. Our work opens the door for extending these findings to other cancer types. Our goal is to help platinum-based agents be more effective in many clinical settings.”

Obesity is now the most common form of malnutrition in most countries, with the rates rising in all categories of men, women, children and adolescents since 1990. Obesity rates in adult men have nearly tripled since 1990, with obesity rates in woman doubling in that time. The rates of obesity in children and adolescents quadrupled in that time frame, as well. As of 2022, nearly 880 million adults and nearly 160 million children were living with obesity.
The prevalence of malnutrition across the globe was shared by the NCD Risk Factor Collaboration, a network of health scientists from around the world who provide and evaluate data on major risk factors for all countries, in collaboration with the World Health Organization. Dr. Peter Katzmarzyk, Associate Executive Director of the Population and Public Health Sciences department of Pennington Biomedical Research Center in Baton Rouge, was an author contributor to this publication.
The network participants reviewed body mass index data from more than 3,600 studies from 1990 to 2022, determining the rates of malnutrition, either from obesity or underweight, for all countries, and the degree to which the data has changed through the years.
“The current rates of obesity appear overwhelming, but the trend has been moving in this direction for more than three decades,” said Dr. Katzmarzyk. “With more than 1 billion people living with obesity, it is important that we do not talk about obesity in a vacuum. We know that obesity can directly lead to comorbidities, including high blood pressure, heart disease, diabetes, cancer, and obstructive sleep apnea. By better understanding the root causes of obesity, we can identify ways to prevent, treat or even reverse its adverse effects.”
Out of the 190-plus countries represented in this study, the United States ranked 10th highest in the world for the prevalence of obesity in men, with an increase in percentage of men from 16.9 percent in 1990 to 41.6 percent in 2022. For women, the obesity rate in 1990 was 21.2 percent, climbing to 43.8 percent in 2022, with ranking 36th highest in the world. For boys, the rate of obesity increased from 11.5 percent in 1990 to 21.7 percent in 2022, ranking the U.S. 26th highest in the world. The rate of obesity for girls in the U.S. ranked 22nd highest in the world, with the rate climbing from 11.6 percent in 1990 to 19.4 percent in 2022.
The results echo the prevalence of obesity on granular levels, as in 2020, 38 percent of adults in Louisiana are facing obesity, according to County Health Rankings and Roadmaps.
“The results of this study resoundingly affirm the value of Pennington Biomedical’s mission,” said Dr. John Kirwan, Executive Director of Pennington Biomedical. “With the prevalence of obesity growing through the decades, we remain steadfast in our commitment to promote metabolic health, eliminate metabolic disease, discover the triggers of obesity and improve the health of all people. I extend my appreciation and applaud the contribution that Dr. Katzmarzyk made to this important global study.”
Over the same period, the rates of children, adolescents and adults being underweight fell on a global scale, with the rate of underweight of men in some African countries falling steeply. Both obesity and underweight are forms of malnutrition, with obesity rates higher than the rates of underweight for boys and girls in two thirds of the world’s countries.
The Pennington Biomedical-led study “International Study of Childhood Obesity, Lifestyle and the Environment,” is among the thousands of studies to have informed these results. The study involved more than 6,000 children from all inhabited continents.

With two-thirds of children in the U.S. failing to meet national physical activity guidelines, kinesiologists at the University of Massachusetts Amherst have been looking at the impact of the family dog on the exercise habits of kids.
Could having a canine best friend get kids on their feet and help bring them more in line with the minimum recommendation of 60 minutes of moderate to vigorous physical activity every day?
A preliminary UMass Amherst study in 2022, reported in a recent issue of the Journal for the Measurement of Physical Behaviour, tested and validated a new approach for measuring dog-facilitated physical activity among kids.
The study, involving 12 children, found that about 20% of their daily physical activity came from time in close proximity with the family dog. Now a larger study, aimed at including a more diverse population, is underway.
The UMass Behavioral Medicine Lab, directed by exercise scientist Katie Potter, studies ways to help people become more active, with a current focus on children and dogs. An assistant professor of kinesiology in the School of Public Health and Health Sciences, Potter is looking for families with kids and one or more dogs to wear ActiGraph accelerometers, with a Bluetooth feature that measures proximity, as they go about their routine life.
This time, there is an option for participants to complete the weeklong study remotely, allowing families outside of Western Massachusetts to take part.
“There are so many ways we might leverage the human-dog bond to promote physical activity in kids, but first we need to understand how much physical activity dog-owning kids get with their dogs,” Potter says.

Interested families can fill out a screening survey to see if they qualify to participate. The study will include children between 7 and 10 years old, and a dog who has been with the family at least six months.
“Our preliminary study was the first time that this type of research had been done specifically quantifying physical activity with the dog and the kid in proximity together,” says Colleen Chase, lead author of the recent paper and a doctoral student in Potter’s lab. “We’re interested in replicating that study to see whether that 20% value holds at a significant sample size of participants.”
Research has shown that children get more exercise when it is enjoyable, motivational and involves social interaction. “If a child has a dog and is bonded with the dog, that’s going to lead to greater enjoyment of whatever activity they are partaking in. And having a dog is a form of social support,” says Chase, who is leading this research study as part of her doctoral dissertation. “So, we see the way this lines up nicely with what other studies have shown is going to promote kids being more active.”
Chase says if the research continues to show that dogs have a positive impact on the physical activity of children, researchers can look for ways to involve kids who don’t have a family dog. “There’s a financial and time burden associated with pet ownership, and we acknowledge that,” Chase says.
She could envision dog-walking programs in animal shelters or after-school programs involving dog play to expand access to the benefits of hanging out with a dog.
“This is a pretty concerning issue in the United States right now,” Chase says of physical inactivity among kids. “That’s why we’re trying to get creative with methods to address this. It’s a very wholesome line of research. You know, we’re working with kids. We’re working with dogs. But we do have these larger, significant health problems that we are working to address through this research.”

From pacemakers to neurostimulators, implantable medical devices rely on batteries to keep the heart on beat and dampen pain. But batteries eventually run low and require invasive surgeries to replace. To address these challenges, researchers in China devised an implantable battery that runs on oxygen in the body. The study, published March 27 in the journal Chem, shows in rats that the proof-of-concept design can deliver stable power and is compatible with the biological system.
“When you think about it, oxygen is the source of our life,” says corresponding author Xizheng Liu, who specializes in energy materials and devices at Tianjin University of Technology. “If we can leverage the continuous supply of oxygen in the body, battery life won’t be limited by the finite materials within conventional batteries.”
To build a safe and efficient battery, the researchers made its electrodes out of a sodium-based alloy and nanoporous gold, a material with pores thousands of times smaller than a hair’s width. Gold has been known for its compatibility with living systems, and sodium is an essential and ubiquitous element in the human body. The electrodes undergo chemical reactions with oxygen in the body to produce electricity. To protect the battery, the researchers encased it within a porous polymer film that is soft and flexible.
The researchers then implanted the battery under the skin on the backs of rats and measured its electricity output. Two weeks later, they found that the battery can produce stable voltages between 1.3 V and 1.4 V, with a maximum power density of 2.6 µW/cm2. Although the output is insufficient to power medical devices, the design shows that harnessing oxygen in the body for energy is possible.
The team also evaluated inflammatory reactions, metabolic changes, and tissue regeneration around the battery. The rats showed no apparent inflammation. Byproducts from the battery’s chemical reactions, including sodium ions, hydroxide ions, and low levels of hydrogen peroxide, were easily metabolized by the body and did not affect the kidneys and liver. The rats healed well after implantation, with the hair on their back completely regrown after four weeks. To the researchers’ surprise, blood vessels also regenerated around the battery.
“We were puzzled by the unstable electricity output right after implantation,” says Liu. “It turned out we had to give the wound time to heal, for blood vessels to regenerate around the battery and supply oxygen, before the battery could provide stable electricity. This is a surprising and interesting finding because it means that the battery can help monitor wound healing.”
Next, the team plans to up the battery’s energy delivery by exploring more efficient materials for the electrodes and optimizing the battery structure and design. Liu also noted that the battery is easy to scale up in production and choosing cost-effective materials can further lower the price. The team’s battery may also find other purposes beyond powering medical devices.
“Because tumor cells are sensitive to oxygen levels, implanting this oxygen-consuming battery around it may help starve cancers. It’s also possible to convert the battery energy to heat to kill cancer cells,” says Liu. “From a new energy source to potential biotherapies, the prospects for this battery are exciting.”

An analysis of how brains with different forms of autism develop has revealed common underlying mechanisms that may respond to existing medications.
For the study, Rutgers Health researchers used a technique called induced pluripotent stem cells to transform the blood cells of people with both genetic and unexplained (or idiopathic) autism spectrum disorder (ASD) into early brain cells called neural precursor cells. As the precursor cells from both groups matured in the lab, defects in a common signaling pathway that controls structural proteins led them to struggle with an important step in cell differentiation, the growth of neurites, and the cell migration needed for proper brain architecture.
Although some cell lines exhibited too much activity in this mTOR pathway, while others exhibited too little, the researchers could correct both problems and spur better cell differentiation with existing drugs that either stimulate or inhibit the activity of mTOR (mechanistic target of rapamycin).
“Cells in a dish are not fully human cells that have developed in a fetus and functioned in a person, but they are a lot closer than mouse cells,” said Emanuel DiCicco-Bloom, a professor of neuroscience and cell biology/pediatrics at Robert Wood Johnson Medical School and senior author of the study in eLife.
“This finding is particularly interesting because the process of growing new synaptic spines when people learn things is completely analogous to the processes we observed in the cells we used for this experiment: growing axons and migrating during fetal development,” DiCicco-Bloom said. “So even though this experiment mimicked a process you’d see during early to mid-pregnancy, the same process involving structural proteins is happening right now in you and me, which means that if we took cells from people with autism and found this abnormal regulation of mTOR in their cells in a dish, those people might be candidates as adults for mTOR regulating drugs to improve their function.”
The visible symptoms of ASD vary widely but typically feature some repetitive behaviors and some impairment in communication and social interaction. The condition’s incidence has increased from about 1 in 150 children in 2000 to 1 in 36 children in 2020, according to the
Centers for Disease Control and Prevention. Roughly 10 to 15 percent of people with ASD have genes that are known to elevate their risk for ASD. Other cases are idiopathic, meaning they are unexplained.

Rutgers Health researchers began the study with blood from three unrelated people with idiopathic ASD, ages 4 to 14 years, with the expectation of finding person-specific differences in the processes occurring during development in utero. When the researchers used the pluripotent stem cell technique to transform blood cells into the sort of neuron precursors typically found in fetal brains, they unexpectedly found many similarities, including abnormalities in the mTOR pathway, which regulates cell creation, metabolism, neurite growth, remodeling and destruction, among many other functions.
The researchers then gained access to blood cells from another three patients with ASD caused by a particular genetic abnormality associated with about 1 percent of ASD, deletion of genes on chromosome 16, called 16p11.2 deletion. They performed the same experiment and found the same disruptions in neuron development.
Subsequent analysis showed that the mTOR signaling disruptions in some patients stemmed from excessive amounts of a particular molecule, while the disruptions in others stemmed from insufficient amounts. In either case, the researchers could use existing medications approved for use in other conditions to correct the problem and stimulate normal development.
The study team has already begun a follow-up investigation to see if people with ASD stemming from other genetic causes exhibit similar disruptions in mTOR activity during development. If mTOR signaling disruption proves a common feature of ASD, tests of mTOR function could help clinicians diagnose the condition more accurately and differentiate it from other conditions with similar effects.
“A couple of very rare genetic types of autism have already been linked to the mTOR pathway, but this is the first to connect mTOR with genes in the 16p11.2 area, which does not have mTOR on it, and with three presumably different types of idiopathic autism from three unrelated people,” said Smrithi Prem, lead author of the study and a psychiatry resident at Penn Medicine who led the study as an MD/PhD student at Robert Wood Johnson Medical School.
“These findings also echo something that has appeared in studies of other conditions, that not all people with mTOR dysregulation have excessive activation that needs inhibition,” Prem said. “There are two kinds of mTOR dysregulation, but most trials we’ve run on people with mTOR dysregulation have only used inhibitors. Our findings showed that cells from two of the people we studied needed more mTOR, not less, and that may spur trials that give different types of mTOR treatment to different individual patients.”

Penn Engineers have developed a novel method for manufacturing CAR T cells, one that takes just 24 hours and requires only one step, thanks to the use of lipid nanoparticles (LNPs), the potent delivery vehicles that played a critical role in the Moderna and Pfizer-BioNTech COVID-19 vaccines.
For patients with certain types of cancer, CAR T cell therapy has been nothing short of life changing. Developed in part by Carl June, Richard W. Vague Professor at Penn Medicine, and approved by the Food and Drug Administration (FDA) in 2017, CAR T cell therapy mobilizes patients’ own immune systems to fight lymphoma and leukemia, among other cancers.
However, the process for manufacturing CAR T cells themselves is time-consuming and costly, requiring multiple steps across days. The state of the art involves extracting patients’ T cells, then activating them with tiny magnetic beads, before giving the T cells genetic instructions to make chimeric antigen receptors (CARs), the specialized receptors that help T cells eliminate cancer cells.
Now, Penn Engineers have developed a novel method for manufacturing CAR T cells, one that takes just 24 hours and requires only one step, thanks to the use of lipid nanoparticles (LNPs), the potent delivery vehicles that played a critical role in the Moderna and Pfizer-BioNTech COVID-19 vaccines.
In a new paper in Advanced Materials, Michael J. Mitchell, Associate Professor in Bioengineering, describes the creation of “activating lipid nanoparticles” (aLNPs), which can activate T cells and deliver the genetic instructions for CARs in a single step, greatly simplifying the CAR T cell manufacturing process. “We wanted to combine these two extremely promising areas of research,” says Ann Metzloff, a doctoral student and NSF Graduate Research Fellow in the Mitchell lab and the paper’s lead author. “How could we apply lipid nanoparticles to CAR T cell therapy?”
In some ways, T cells function like a military reserve unit: in times of health, they remain inactive, but when they detect pathogens, they mobilize, rapidly expanding their numbers before turning to face the threat. Cancer poses a unique challenge to this defense strategy. Since cancer cells are the body’s own, T cells don’t automatically treat cancer as dangerous, hence the need to first “activate” T cells and deliver cancer-detecting CARs in CAR T cell therapy.
Until now, the most efficient means of activating T cells has been to extract them from a patient’s bloodstream and then mix those cells with magnetic beads attached to specific antibodies — molecules that provoke an immune response. “The beads are expensive,” says Metzloff. “They also need to be removed with a magnet before you can clinically administer the T cells. However, in doing so, you actually lose a lot of the T cells, too.”
Made primarily of lipids, the same water-repellent molecules that constitute household cooking fats like butter and olive oil, lipid nanoparticles have proven tremendously effective at delivering delicate molecular payloads. Their capsule-like shape can enclose and protect mRNA, which provides instructions for cells to manufacture proteins. Due to the widespread use of the COVID-19 vaccines, says Metzloff, “The safety and efficacy of lipid nanoparticles has been shown in billions of people around the world.”

To incorporate LNPs into the production of CAR T cells, Metzloff and Mitchell wondered if it might be possible to attach the activating antibodies used on the magnetic beads directly to the surface of the LNPs. Employing LNPs this way, they thought, might make it possible to eliminate the need for activating beads in the production process altogether. “This is novel,” says Metzloff, “because we’re using lipid nanoparticles not just to deliver mRNA encoding CARs, but also to initiate an advantageous activation state.”
Over the course of two years, Metzloff carefully optimized the design of the aLNPs. One of the primary challenges was to find the right ratio of one antibody to another. “There were a lot of choices to make,” Metzloff recalls, “since this hadn’t been done before.”
By attaching the antibodies directly to LNPs, the researchers were able to reduce the number of steps involved in the process of manufacturing CAR T cells from three to one, and to halve the time required, from 48 hours to just 24 hours. “This will hopefully have a transformative effect on the process for manufacturing CAR T cells,” says Mitchell. “It currently takes so much time to make them, and thus they are not accessible to many patients around the world who need them.”
CAR T cells manufactured using aLNPs have yet to be tested in humans, but in mouse models, CAR T cells created using the process described in the paper had a significant effect on leukemia, reducing the size of tumors, thereby demonstrating the feasibility of the technology.
Metzloff also sees additional potential for aLNPs. “I think aLNPs could be explored more broadly as a platform to deliver other cargoes to T cells,” she says. “We demonstrated in this paper one specific clinical application, but lipid nanoparticles can be used to encapsulate lots of different things: proteins, different types of mRNA. The aLNPs have broad potential utility for T cell cancer therapy as a whole, beyond this one mRNA CAR T cell application that we’ve shown here.”
This study was conducted at the University of Pennsylvania School of Engineering and Applied Science and is supported by the U.S. National Institutes of Health Director’s New Innovator Award (DP2 TR002776), a U.S. National Science Foundation CAREER Award (CBET-2145491), an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET), and a Burroughs Wellcome Fund Career Award at the Scientific Interface. Further support for this paper and the researchers involved came from the Emerson Collective, U.S. National Science Foundation Graduate Research Fellowships, a U.S. National Institutes of Health Ruth L. Kirschstein National Research Service Award (F31CA260922), the National Institute of Dental and Craniofacial Research of the US National Institutes of Health (T90DE030854), the University of Pennsylvania Fontaine Fellowship, the Norman and Selma Kron Research Fellowship, and the Robert Wood Johnson Foundation Health Policy Research Scholars Program. The researchers thank the Human Immunology Core at the University of Pennsylvania (RRID: SCR_022380) for assistance with primary human T cell procurement. The HIC is supported in part by NIH P30 AI045008 and P30 CA016520.

Planes, trains, boats, automobiles and even feet. During the past decades and centuries, global travel and human migration have made all of us more worldly — from our broadening awareness of the world beyond our birthplaces, to our more sophisticated palates, to our immune systems that are increasingly challenged by unfamiliar bacteria and viruses.
In the elderly, these newly imported pathogens can gain the upper hand frighteningly quickly. Unfortunately, however, vaccination in this age group isn’t as effective as it is in younger people.
Now a study conducted in mice by Stanford Medicine and the National Institute of Health’s Rocky Mountain Laboratories provides tantalizing evidence that it may one day be possible to rev up an elderly immune system with a one-time treatment that modulates the composition of a type of immune cell.
The treatment significantly improved the ability of geriatric animals’ immune systems to tackle a new virus head on, as well as to respond vigorously to vaccination — enabling them to fight off a new threat months later.
“This is a real paradigm shift — researchers and clinicians should think in a new way about the immune system and aging,” said postdoctoral scholar Jason Ross, MD, PhD. “The idea that it’s possible to tune the entire immune system of millions of cells simply by affecting the function of such a rare population is surprising and exciting.”
Ross and Lara Myers, PhD, a research fellow at Rocky Mountain Laboratories, are the lead authors of the study, which will be published March 27 in Nature. Irving Weissman, MD, professor of pathology and of developmental biology, and Kim Hasenkrug, PhD, the chief of Rocky Mountain Laboratories’ Retroviral Immunology Section, are the senior authors of the research.
A shift in the immune system
The targeted cells are a subset of what’s known as hematopoietic stem cells, or HSCs. HSCs are the granddaddies of the immune system, giving rise to all the other types of blood and immune cells including B and T cells, which are collectively known as lymphocytes. As we age, our HSCs begin to favor the production of other immune cells called myeloid cells over lymphocytes. This shift hampers our ability to fully react to new viral or bacterial threats and makes our response to vaccination much less robust than that of younger people.

“Older people just don’t make many new B and T cell lymphocytes,” said Weissman, who is the Virginia and D.K. Ludwig Professor in Clinical Investigation in Cancer Research. “During the start of the COVID-19 pandemic it quickly became clear that older people were dying in larger numbers than younger people. This trend continued even after vaccinations became available. If we can revitalize the aging human immune system like we did in mice, it could be lifesaving when the next global pathogen arises.”
Weissman was the first to isolate HSCs in mice and humans in the late 1980s. In the years since, he and his colleagues have investigated the molecular minutiae of these cells, painstakingly tracing the complicated relationships among the scores of cell types that arise in their wake.
Some of these descendants make up what’s known as the adaptive immune system: highly specialized B and T lymphocytes that each recognize just one particular three-dimensional structure — perhaps a pointy bit here or a telltale knobby clump there — that betrays an invading virus or bacteria. Like trained assassins once they spot their mark, B lymphocytes churn out antibodies that latch onto the telltale structures and target infected or foreign cells for destruction, while various subtypes of T lymphocytes either demolish infected cells or raise a hue and cry to summon other immune cells to finish off the enemy.
The specificity of the B and T lymphocytes allows the immune system to have memory; once you’ve been exposed to a specific invader, the body reacts swiftly and decisively if that same pathogen is seen again. This is the basic concept behind vaccination — trigger an initial response to a harmless mimic of a dangerous bacteria or virus. In response, the lymphocytes that recognize the invader not only give rise to cells that eliminate the infection but also generate long-lived memory B and T cells that, in some cases, can last a lifetime. Thus, the system is primed when the threat becomes real.
Another key part of our immune system is called innate immunity, and it’s much less discriminating. In the blood, it’s run by a class of cells called myeloid cells. Like school janitors, these cells scour the body, gobbling up any unfamiliar cells or bits of detritus. They also trigger inflammatory responses, which recruit other cells and chemicals to infected sites. Inflammation helps the body protect itself against invaders, but it can be a major problem when triggered inappropriately or overenthusiastically, and aging has been linked to chronic inflammation in humans.
An evolutionary disadvantage
Ross and Weissman knew from previous research that during aging, the number of HSCs that make balanced proportions of lymphocytes and myeloid cells decline, while those that are myeloid-biased increase their numbers. This favors the production of myeloid cells. Early in human history, when people rarely left their birthplace and lived shorter lives, this gradual change probably had no consequences (it may even have been favorable) because people were likely to encounter all their surrounding pathogens by young adulthood and be protected by their memory lymphocytes. But now it’s distinctly disadvantageous.

The researchers wondered if they could tilt the balance back toward a younger immune system by depleting myeloid-leaning HSCs and allowing the more balanced HSCs to replace them. Their hunch was correct. Mice between 18 and 24 months old (doddering in the mouse world) that were treated with an antibody targeting the myeloid-leaning HSCs for destruction had more of the balanced HSCs — and more new, naïve B and T lymphocytes — than their untreated peers even several weeks later.
“These new, naïve lymphocytes provide better immune coverage for novel infections like those humans increasingly encounter as our world becomes more global,” Weissman said. “Without this renewal, these new infectious agents would not be recognized by the existing pool of memory lymphocytes.”
The treatment also reduced some negative outcomes like inflammation that can arise when an elderly immune system grapples with a new pathogen.
“Not only did we see a shift toward cells involved in adaptive immunity, but we also observed a dampening in the levels of inflammatory proteins in the treated animals,” Ross said. “We were surprised that a single course of treatment had such a long-lasting effect. The difference between the treated and untreated animals remained dramatic even two months later.”
When the treated animals were vaccinated eight weeks later against a virus they hadn’t encountered before, their immune systems responded more vigorously than untreated animals’, and they were significantly better able to resist infection by that virus. (In contrast, young mice used as controls passed all the challenges with flying colors.)
“Every feature of an aging immune system — functional markers on the cells, the prevalence of inflammatory proteins, the response to vaccination and the ability to resist a lethal infection — was impacted by this single course of treatment targeting just one cell type,” Ross said.
Finally, the researchers showed that mouse and human myeloid-biased HSCs are similar enough that it may one day be possible to use a similar technique to revitalize aging human immune systems, perhaps making a person less vulnerable to novel infections and improving their response to vaccination.
“We believe that this study represents the first steps in applying this strategy in humans,” Ross said.
The study also has interesting implications for stem cell biology and the way HSCs rely on biological niches, or specific neighborhoods of cells, for their longevity and function throughout our lives.
“Most people in immunology have believed that you lose these kinds of tissue-specific stem cells as you grow older,” Weissman said. “But that is completely wrong. The problems arise when you start to favor one type of HSC over another. And we’ve shown in mice that this can be reversed. This finding changes how we think about stem cells during every stage of aging.”
The study was funded by the National Institutes of Health (grants R35CA220434, R01DK115600 and R01AI143889), the Virginia and D.K. Ludwig Fund for Cancer Research, the RSNA Resident/Fellow Research Grant, a Stanford Cancer Institute Fellowship grant, and the Ellie Guardino Research Fund.

To treat cancer, you have to inhibit cancer cells. Right? Researchers at the Netherlands Cancer Institute did just the opposite. They achieved surprising results by overstimulating cancer cells in the lab and then hitting them at their weak spot: stress. “This goes against the prevailing view.”
Many new drugs inhibit the processes that cancer cells need to divide rapidly. So as to inhibit the cancer as a whole. But cancer cells have all sorts of workarounds to get around that effect. As a result, the tumor becomes unresponsive to treatment.
That’s why researcher Matheus dos Santos Dias is taking a completely different approach. He had to convince some colleagues before he could start working on this quite surprising idea. After all, you’re not going to give cancer cells a boost, are you? “We’re going against the prevailing view that you can only fight cancer cells by inhibiting them,” he knows. “But we had strong evidence that it also works if you overstimulate and exhaust them.”
Everyone makes inhibitors
And so he set out to find a drug that stimulates cancer cells, as well as a perfectly suited partner drug that can then finish the job. By doing so, he wants to upset the balance in cancer cells to the point where they can no longer save themselves. “Compare it to the engine of a racing car: if you crank up the RPM and then turn off the cooling, it’s bound to crash. This is exactly what we are trying to do with the drugs.”
Tricky though: “Activating drugs are not that common, almost everyone makes inhibitors. But we did find one we could work with,” he says. That drug acts on the protein PP2A. In a large-scale experiment with all kinds of drug combinations, he and his colleagues then found a WEE1 inhibitor to be the best partner in crime. That inhibitor targets overactive, stressed cells and keeps them from functioning properly.
Higher gear
Cancer cells and mice with patient tumors respond well to the drug combo. And, not insignificantly, the side effects seem manageable. Dos Santos Dias: “This obviously does not mean it will not have side effects in humans. But we suspect that normal cells can defend themselves against this activation much better than cancer cells, which of themselves are already in a higher gear.”

Resistant & less malignant
“Resistance is a huge problem with existing treatments: cells no longer respond and usually become even more aggressive than they already were. So we also looked at what happens when cells stop responding to our treatment. Surprisingly, resistant cells actually seemed less malignant: they grew less quickly, or not at all.”
“This research makes you think about cancer very differently,” says internist-oncologist Neeltje Steeghs. She heads the Clinical Research Unit at the Netherlands Cancer Institute, where the very first patients receive new treatments within clinical studies.
Paradoxical approach
“I don’t know whether this new combination will work in patients. The reality is that many of these kinds of early studies are not successful. But the current treatments doctors have access to did start there as well. And when you’ve done all you can in the lab, the only step you can and must take is: testing in patients.” The researchers hope to have started the first study in patients by the end of this year.
“In the beginning, doctors and researchers still had questions about this concept, but now the support is incredible,” says Dos Santos Dias. “Scientifically, the concept is hard to refute. I hope that other labs will now also start testing this paradoxical approach, including other drugs as well.”
Matheus dos Santos Dias works at the Netherlands Cancer Institute in the research group of Rene Bernards, who is investigator at Oncode Institute and also a director of Lixte Biotechnology, producer of the PP2A inhibitor used in this study. Both researchers are shareholder of Lixte.
This research was financially supported by KWF Dutch Cancer Society and Oncode Institute.

Dedicated memory tests on smartphones enable the detection of “mild cognitive impairment,” a condition that may indicate Alzheimer’s disease, with high accuracy. Researchers from DZNE, the Otto-von-Guericke University Magdeburg and the University of Wisconsin-Madison in the United States who collaborated with the Magdeburg-based company “neotiv” report these findings in the scientific journal npj Digital Medicine. Their study is based on data from 199 older adults. The results underline the potential of mobile apps for Alzheimer’s disease research, clinical trials and routine medical care. The app that has been evaluated is now being offered to medical doctors to support the early detection of memory problems.
Memory problems are a key symptom of Alzheimer’s disease. Not surprisingly, their severity and progression play a central role in the diagnosis of Alzheimer’s disease and also in Alzheimer’s research. In current clinical practice, memory assessment is performed under the guidance of a medical professional. The individuals being tested have to complete standardized tasks in writing or in conversation: for example, remembering and repeating words, spontaneously naming as many terms as possible on a certain topic or drawing geometric figures according to instructions. All these tests necessarily require professional supervision, otherwise the results are not conclusive. Thus, these tests cannot be completed alone, for example at home.
Prof. Emrah Düzel, a senior neuroscientist at DZNE’s Magdeburg site and at University Magdeburg as well as entrepreneur in medical technology, advocates a new approach: “It has advantages if you can carry out such tests on your own and only have to visit the doctor’s office to evaluate the results. Just as we know it from a long-term ECG, for example. Unsupervised testing would help to detect clinically relevant memory impairment at an earlier stage and track disease progression more closely than is currently possible. In view of recent developments in Alzheimer’s therapy and new treatment options, early diagnosis is becoming increasingly important.”
Comparison between remote at-home and supervised in-clinic testing
In addition to his involvement in dementia research, Düzel is also “Chief Medical Officer” of “neotiv,” a Magdeburg-based start-up with which the DZNE has been cooperating for several years. The company has developed an app with which memory tests can be carried out autonomously with no need for professional supervision. The software runs on smartphones and tablets, and has been scientifically validated; it is used in Alzheimer’s disease research and is now also offered as a digital tool for medical doctors to support the detection of mild cognitive impairment (MCI). Although MCI has little impact on the affected individuals daily living, they have nevertheless an increased risk of developing Alzheimer’s dementia within a few years.
Dr. David Berron, research group leader at DZNE and also co-founder of neotiv explains: “As part of the validation process, we applied these novel remote and unsupervised assessments as well as an established in-clinic neuropsychological test battery. We found that the novel method is comparable to in-clinic assessments and detects mild cognitive impairment, also known as MCI, with high accuracy. This technology has enormous potential to provide clinicians with information that they cannot obtain during a patient vist to the clinic.” These findings have now been published in the scientific journal npj Digital Medicine.
Participants from Germany and the USA
A total of 199 women and men over the age of 60 participated in the current study. They were located either in Germany or the USA and were each involved in one of two long-term observational studies, both of which address Alzheimer’s — the most common dementia: DZNE’s DELCODE study (Longitudinal Cognitive Impairment and Dementia Study) and the WRAP (Wisconsin Registry for Alzheimer’s Prevention) study of the University of Wisconsin-Madison. The study sample reflected varying cognitive conditions as they occur in a real world situation: It included individuals who were cognitively healthy, patients with MCI and others with subjectively perceived but not measurable memory problems. The diagnosis was based on established assessments that included e. g. memory and language tasks. In addition, all participants completed multiple memory assessments with the neotiv app over a period of at least six weeks, using their own smartphones or tablets — and wherever it was convenient for them. “We found that a majority of our WRAP participants were able to complete the unsupervised digital tasks remotely and they were satisfied with the tasks and the digital platform,” says Lindsay Clark, PhD, neuropsychologist and lead investigator of the Assessing Memory with Mobile Devices study at the University of Wisconsin-Madison.

Remembering images and detecting differences
“Assessments with the neotiv app are interactive and comprise three types of memory tasks. These address different areas of the brain that can be affected by Alzheimer’s disease in different disease stages. Many years of research have gone into this,” Düzel explains. Essentially, these tests involve remembering images or recognizing differences between images that are presented by the app. Using a specially developed score, the German-US research team was able to compare the results of the app with the findings of the established in-clinic assessments. “Our study shows that memory complaints can be meaningfully assessed using this digital, remote and unsupervised approach,” says Düzel. “If the results from the digital assessment indicate that there is memory impairment typical of MCI, this paves the way for further clinical examinations. If test results indicate that memory is within the age-specific normal range, individuals can be given an all-clear signal for the time being. And for Alzheimer’s disease research, this approach provides a digital cognitive assessment tool that can be used in clinical studies — as is already being done in Germany, the USA, Sweden and other countries.”
Outlook
Further studies are in preparation or already underway. The novel memory assessment is to be tested on even larger study groups, and the researchers also intend to investigate whether it can be used to track the progression of Alzheimer’s disease over a longer period of time. Berron: “Information about how quickly memory declines over time is important for medical doctors and patients. It is also important for clinical trials as new treatments aim to slow the rate of cognitive decline.” The cognitive neuroscientist describes the challenges: “To advance such self-tests, a patient’s clinical data must be linked to self-tests outside the clinic, in the real-world. This is no easy task, but as our current study shows, we are making progress as a field.”