Humans are outsized actors in the world’s wild places where there are struggles to preserve and protect vital natural resources and animals, birds and plants. Yet people and their plus-sized footprint are rarely discussed in models seeking to predict and plan for trajectories of endangered species.
Sustainability scholars at Michigan State University in this week’s journal Nature Ecology and Evolution reveal the decades-long gaps in research and propose a new way of creating accurate visions for endangered species.
To map and predict species geographic distributions around the globe and understand the factors that drive them, ecologists, conservation biologists and others use powerful computational tools called species distribution models (SDMs). These tools are used for conservation, understanding disease spread, food security, policy planning, and many other applications. To inform their predictions, scientists typically include the surrounding environment, such as climate and natural habitat.
But according to PhD candidate Veronica Frans, “we have a new reality that must be recognized if we want SDM predictions to be realistic and most helpful: we live in a human-dominated world.”
Frans and her advisor Jianguo “Jack” Liu, Rachel Carson chair in sustainability and director of MSU’s Center for Systems Integration and Sustainability, reviewed and synthesized 12,854 published studies covering over 58,000 species around the world, modeled across local to global spatial scales. They found that only 11 percent of those studies included human activities — which Frans said doesn’t reflect reality.
“Nearly half the articles projecting to future climates held human predictors constant over time,” Frans said. “That’s risking false optimism about the effects of human activities compared to climate change.”
They also found how scientists have been considering the future: nearly half of the SDM studies predicting species distributions have used different future climate scenarios but left data related to human activities constant over time. This means that modelers trying to understand where species will be distributed in the next 50 to 100 years were assuming human activities, development, infrastructure, and other human pressures will not change in the future.

“In our current era, human influence is pervasive and human-species interactions are diversifying and amplifying, and yet it is not being well accounted for in one of the most popular modeling tools in ecology,” Frans said.
They noted that modelers haven’t had a choice in the matter: geographic data on future human development have been sparse.
“This is an important aspect we must work to improve, since nature and humans are tightly linked, not only locally, but also across long distances” Liu said. “They form metacoupled human and natural systems. We will only be able to make significant and swift progress toward global sustainability when we consider all aspects of our real world.”
The article “Gaps and opportunities in modeling human influence on species distributions in the Anthropocene,” was funded by the National Science Foundation and Michigan AgBioResearch.

The nasal microbiota of intensive care unit (ICU) patients effectively distinguishes sepsis from non-septic cases and outperforms analyzing the gut microbiota to predict sepsis, according to a new study published in Microbiology Spectrum, a journal of the American Society for Microbiology.
“These findings have implications for the development of diagnostic strategies and advancements in critical care medicine,” said corresponding study author Xiaolong He, M.D., Ph.D., a professor at the Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China. “In the past, we have paid more attention to the intestinal microbiota of sepsis patients, and the respiratory microbiota also deserves our attention.”
Sepsis is a severe illness with a high mortality rate between 29.9% to 57.5%. Despite the establishment of the third international consensus definition of sepsis and septic shock (Sepsis-3) in 2016, there are still many aspects of sepsis that warrant further exploration to improve its diagnosis. The evolution of the diagnostic criteria from Sepsis-1 to Sepsis-3 shows the need for continued investigation. Additionally, sepsis diagnostic criteria have shifted from focusing solely on the inflammatory response to also including organ failure caused by infection. While considerable progress has been made in the diagnosis of sepsis, no biological indicators with strong sensitivity and specificity have been identified. Furthermore, the low culture positivity rate and the presence of few culturable microorganisms limit the diagnosis of clinical sepsis. Therefore, the identification of a new, effective and reliable biomarker for sepsis has been a goal of researchers.
In the new study, researchers recruited 157 subjects (89 with sepsis) of both sexes at the affiliated hospital of Southern Medical University. They collected nasal swabs and fecal specimens from septic and non-septic patients in the ICU and Department of Respiratory and Critical Care Medicine. The scientists extracted and sequenced DNA using Illumina technology. Bioinformatics analysis, statistical processing, and machine learning techniques were used to differentiate between septic and non-septic patients.
He and colleagues discovered that nasal microbiota of septic patients exhibited significantly lower community richness (P=0.002) and distinct compositions (P=0.001) compared to non-septic patients. Corynebacterium, Staphylococcus, Acinetobacter and Pseudomonas were identified as enriched genera in the nasal microbiota of septic patients.
“Looking forward, we suggest the potential for further research, possibly through animal models or larger patient cohorts, to deepen our understanding of microbiota’s role in sepsis beyond the antibiotic effect,” He said.

CAR-T cell therapies are transforming the treatment of previously incurable blood cancers. Six approved CAR-T products have been administered to more than 20,000 people, and more than 500 clinical trials are underway. However, according to a recent study out of the Massachusetts General Hospital, among 100 patients suffering from lymphomas, myelomas or B-cell acute lymphoblastic leukemias that were treated with CAR-T cell therapies, 24% only had partial responses, and 20% were not responsive at all — and these are typical success rates for patients treated with CAR-T therapies.
CAR-T cells are created from a patient’s own immune T cells by introducing so-called “chimeric antigen receptors” (CARs) to their molecular repertoires that enable them to seek out and kill specific cancer cells. Following their laborious and costly engineering and amplification outside the body, they are re-administered to the same patient as a living therapeutic.
Oncological researchers suspect that disappointing treatment results can be the result of several circumstances, including poor quality of the CAR-T cell products that are administered to patients, or the CAR-T cells not persisting sufficiently long in patients or becoming exhausted in their tumor-fighting abilities. New therapeutic strategies are urgently needed that can help overcome these shortcomings and further boost the quality and efficacy of CAR-T cells during their manufacturing or even in the patients’ bodies.
Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a simple intervention in the form of a biodegradable scaffold material that can be locally injected under the skin and used to restimulate CAR-T cells after their administration to increase their therapeutic efficacy. In mice that developed an aggressive blood tumor and were treated with a non-curative dose of CAR-T cells, the team’s “T-cell enhancing scaffolds” (TES) significantly curbed tumor growth and prolonged the animals’ survival. The improved therapeutic efficacy of the CAR-T cells was due to TES’ ability to increase the numbers of CAR-T cells in the blood circulation, as well as steer their differentiation into tumor-killing subtypes of T cells. The findings are published in Nature Biomedical Engineering.
“Although our strategy needs to be translated to human needs and settings, it potentially offers a safe, and simple avenue on which to further improve CAR-T cell therapies in patients with poor responses,” said Wyss Founding Core Faculty member David Mooney, Ph.D., who led the study. “It also could have future potential to simplify the extremely arduous and expensive manufacturing of CAR-T cell by transferring part of the process into patients’ bodies.” Mooney is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS.
A number of CAR-T cell-stimulating approaches have been developed that, besides introducing CAR receptors, made other genetic modifications to patients’ T cells to better maintain their therapeutic efficacies (cell-intrinsic) or that, inspired by vaccines, target other parts of the immune system to support CAR-T cells in their tumor cell attack (cell-extrinsic). However, most of them involve new challenges, including even more complex cell manipulations during CAR-T cell manufacturing and control of the resulting cells’ behavior in the case of cell-intrinsic methods, or unintended side-effects in the body in the case of cell-extrinsic methods.
Creating a pseudo-lymph node under the skin
“Previously, our team had designed biomaterial scaffolds that enabled the expansion of T-cells for immunotherapies in a culture dish by mimicking antigen-presenting cells (APCs), which normally reprogram T-cells in lymph nodes by presenting tumor antigens to them. We hypothesized that this basic concept could also be applied to potently stimulate CAR-T cells in the body — TES could essentially function as pseudo-lymph nodes,” said co-first author David Zhang, who obtained his Ph.D. working in Mooney’s group.

TES biomaterial scaffolds consist of tiny biodegradable mesoporous silica rods (MSRs) that self-assemble into a 3D, cell-permeable scaffold structures when injected under the skin, and connect themselves to the blood circulation via small blood vessels. TES are loaded with a soluble molecule known as interleukin-2 (IL-2), which is continuously released and stimulates the multiplication of T cells entering the TES from the blood circulation. In addition, the MSRs are coated with a double layer of lipids that mimics the outer cell membrane of an APC a T-cell would encounter in a lymph node. This lipid layer presents two antibody molecules, anti-CD3 and anti-CD28, to the T-cell receptor on the surface of T cells in a way similar to how APC-presented tumor antigens normally stimulate the receptors. This then induces the CAR-T cells to increase their numbers and differentiate into tumor-killing subtypes of T cells.
First, the researchers determined optimal anti-CD3:anti-CD28 antibody ratios and quantities in TES that helped recruit maximum numbers of cultured CAR-T cells and induce them to become “effector T-cells” with tumor cell-killing potential. When injected under the skin of mice, TES connected themselves with the animals’ vasculature and remained traceable as vascularized nodules for more than three weeks. More than 60% of the cells permeating their porous network were neutrophils, a type of white blood cell that acts as the immune system’s first line of defense, while a much smaller but significant proportion consisted of T cells that usually are part of delayed and much more target-specific tumor cell (or pathogen)-directed immune defenses.
The researchers think that “by causing some minor inflammation, TES scaffolds stimulate their vascularization and help attract certain classes of immune cells, which would add to the immune cells traveling passively through TES,” said co-first Joshua Brockman, Ph.D., who was a Postdoctoral Fellow on Mooney’s team and now is an Assistant Professor at the University of Wisconsin-Madison. “By removing the injected scaffolds again at different time points, culturing them with CAR-T cells, and measuring the cells’ activation level, we were able to conclude that TES could stimulate CAR-T cells for at least seven days following their injection.”
TESting in tumors
To test TES’ potential as therapy boosters, the team used a clinically-relevant mouse model of human Burkitt’s lymphoma, a blood cancer caused by B-cells becoming cancerous and impacting many organs. They first administered human lymphoma cells to the mice and then gave them a curative dose of CAR-T cells developed against this tumor before injecting TES under the skin of the animals. Importantly, TES that contained the full complement of IL-2, anti-CD3 and anti-CD28 factors, increased the numbers of circulating CAR-T cells more than five-fold over blank TES lacking the three factors, and more CAR-T cells had acquired a tumor cell-killing potential. When lower doses of CAR-T cells that were not sufficient to cure the cancer (subcurative doses) were used in otherwise the same settings, CAR-T cells multiplied even more.
“TES took up CAR-T cells into their porous structure, where they boosted their proliferation, activation, and differentiation, and eventually their exit into the blood stream to carry out their tumor-killing functions,” summarized Zhang. “And, importantly, while lymphoma-bearing animals that received subcurative doses of CAR-T cells and blank TES succumbed quickly to the spreading cancer, animals injected with CAR-T cells plus fully functional TES survived for much longer.”
Brockman added that “this aggressive lymphoma mouse model was an ideal tool to provide proof-of-concept. However, it corresponds to a cancer patient at late stages of the disease whose treatment requires a lot of cytotoxic T cell potential. In translating TES further toward human patients, even longer-lasting and more balanced approaches might be called for that also enhance the CAR-T cells’ memory of tumors.”

“This study by Dave Mooney’s group demonstrates the power of using engineering to mimic multicellular interactions that are central to our immune system’s ability to fight off cancers. This technology could go a long way in changing the lives of many cancer patients receiving CAR-T therapies who are not yet benefitting from them,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.
Other authors on the study are Kwasi Adu-Berchie, Yutong Liu, Yoav Binenbaum, Irene de Lázaro, Miguel Sobral, and Rea Tresa. The study was funded by the Wyss Institute at Harvard University, Food and Drug Administration (under award# 5F01FD006589), and National Institutes of Health (under award# 1R01EB015498, #R01 CA276459, and U01CA214369).

Scientists at the University of Southern California have developed an artificial intelligence (AI)-powered system to track tiny devices that monitor markers of disease in the gut. Devices using the novel system may help at-risk individuals monitor their gastrointestinal (GI) tract health at home, without the need for invasive tests in hospital settings. This work appears June 12 in the journal Cell Reports Physical Science.
“Ingestibles are like Fitbits for the gut,” says author Yasser Khan, assistant professor of electrical and computer engineering at the University of Southern California. “But tracking them once swallowed has been a significant challenge.”
Gas that is formed in the intestines when bacteria break down food can offer insights into a person’s health. Currently, to measure GI tract gases, physicians either use direct methods such as flatus collection and intestinal tube collection, or indirect methods such as breath testing and stool analysis. Ingestible capsules — devices that a user swallows — offer a promising alternative, but no such technologies have been developed for precise gas sensing.
To tackle this problem, Khan and colleagues developed a system that includes a wearable coil, which the user can conceal under a t-shirt or other clothing. The coil creates a magnetic field, which interacts with sensors embedded in an ingestible pill after it has been swallowed. AI analyzes the signals the pill receives, pinpointing where the device is located in the gut within less than a few millimeters. In addition, the system monitors 3D real-time concentrations of ammonia, a proxy for a bacteria linked with ulcers and gastric cancer, via the device’s optical gas-sensing membranes.
While previous attempts to track ingestibles as they journey through the gut have relied on bulky desktop coils, the wearable coil can be used anywhere, says Khan. The technology may also have other applications beyond measuring GI tract gases, such as identifying inflammation in the gut caused by Crohn’s disease and delivering drugs to precisely these regions.
The researchers tested the system’s performance in a variety of mediums that mimic the GI tract, including a simulated cow intestine and liquids designed to replicate stomach and intestinal fluids.
“During these tests, the device demonstrated its ability to pinpoint its location and measure levels of oxygen and ammonia gases,” says Khan. “Any ingestible device can utilize the technology we’ve developed.”
However, there are still improvements to be made to the device, says Khan, such as designing it to be smaller and to use less power. Next, as they continue to hone the device, Khan and colleagues plan to test it in pigs in order to study its safety and effectiveness in an organism with human-like biology.
“Successful outcomes from these trials will bring the device nearer to readiness for human clinical trials,” says Khan. “We are optimistic about the practicality of the system and believe it will soon be applicable for use in humans.”

A mother’s contribution to the makeup of a newborn baby’s microbiota has been well documented. Now a new paper published June 12 in Cell Host & Microbe shows the important contributions that fathers make to the composition of microorganisms colonizing a baby’s gut as well. Furthermore, the study confirmed that maternal fecal microbiota transfer (FMT) in babies born by caesarean section can help to correct the microbiota disturbances often observed in babies who are not born vaginally.
Fetuses have sterile gastrointestinal tracts, and babies’ bodies are colonized during and shortly after birth. About half of the strains found in infants’ bodies can be traced to the maternal gut. This led the researchers to hypothesize that other people who have close contact with the infant could contribute to the rest, providing a stable source of microbial strains associated with good health.
“This study provides significant insight into how a newborn is colonized,” says lead author Willem M. de Vos, of Wageningen University and the University of Helsinki. “The role of the father may be small, but it is not to be neglected. It is likely that the same holds for others who have close contact with the newborn.”
“We are very happy to have found this connection,” says co-author Nicola Segata of the University of Trento in Italy. “This highlights the importance of studying other microbial contributions as well, such as those from siblings and from daycare peers.” Segata’s group provided computational analysis, while de Vos’s group designed the study.
Inspired by his own experiences as a parent, for many years de Vos has studied the microbiota of infants and how babies’ gastrointestinal tracts become colonized after birth. In October 2020, he and colleagues published a proof-of-concept study in Cellthat confirmed exposing caesarian-born newborns to their mother’s microbiota just after birth was both safe and effective at giving the babies a microbial makeup that looks more similar to babies born vaginally. The babies were fed a small amount of their mothers’ fecal microbiota shortly after birth.
This new paper provides follow-up data on that study as well as new research looking at the contributions of fathers to infants’ microbial makeups. The authors say that because caesarian births now account for about one-quarter of births worldwide, there should be an increased focus on creating a healthy balance of gut microbiota in these infants.
The investigators performed metagenomic analysis of fecal samples from newborns and their parents. They looked for the presence of a wide range of bacterial strains over time. For the babies who were part of the earlier study, they confirmed through follow-up analysis that maternal FMT reduced the levels of potential pathogenetic bacterial strains significantly for up to a year.

For the newer study, they compared the fecal microbiomes of 73 infants; 21 were born by caesarian section and 52 were born vaginally. They longitudinally collected samples for over a year and compared the microbiota of the babies to those of both their mothers and fathers. The researchers discovered that many of the strains found in the babies at 3 weeks, 3 months, and 12 months originated in the father, not in the mother. These include Bifidobacterium longum strains, which are known to utilize mother’s milk oligosaccharides but counterintuitively may originate from the father rather than the mother.
“Knowing that the father substantially contributes to a baby’s developing microbiome underlies the important role of physical and social interactions between the newborn and their father, as well as with other family members,” Segata says. “We hope this study will help to create awareness of those important contributions.”
The investigators in Helsinki have completed another maternal FMT trial, this one a double-blind placebo-controlled trial in babies born by caesarian (trial NCT04173208). They are now conducting long-term follow-up with those infants, studying not only the microbiome but many other health and immune functions.
Another study also published June 12 in Cell Host & Microbe by some of the same authors shows that where an infant is born — whether at home or at a hospital — affects transmission of gut microbiota as well. Birth location affects the timing of transmission, except for Bifidobacterium longum, which are transmitted consistently regardless of the setting.
This work was supported by the Netherlands Organization for Scientific Research, Business Finland, the Academy of Finland, the European Research Council, EMBO, the European H2020 programme, the National Cancer Institute of the National Institutes of Health, and the Premio Internazionale Lombardia e Ricerca 2019.

Researchers at North Carolina State University have demonstrated a new method that leverages artificial intelligence (AI) and computer simulations to train robotic exoskeletons to autonomously help users save energy while walking, running and climbing stairs.
“This work proposes and demonstrates a new machine-learning framework that bridges the gap between simulation and reality to autonomously control wearable robots to improve mobility and health of humans,” says Hao Su, corresponding author of a paper on the work which will be published June 12 in the journal Nature.
“Exoskeletons have enormous potential to improve human locomotive performance,” says Su, who is an associate professor of mechanical and aerospace engineering at North Carolina State University. “However, their development and broad dissemination are limited by the requirement for lengthy human tests and handcrafted control laws.
“The key idea here is that the embodied AI in a portable exoskeleton is learning how to help people walk, run or climb in a computer simulation, without requiring any experiments,” says Su.
Specifically, the researchers focused on improving autonomous control of embodied AI systems — which are systems where an AI program is integrated into a physical robot technology. This work focused on teaching robotic exoskeletons how to assist able-bodied people with various movements. Normally, users have to spend hours “training” an exoskeleton so that the technology knows how much force is needed — and when to apply that force — to help users walk, run or climb stairs. The new method allows users to utilize the exoskeletons immediately.
“This work is essentially making science fiction reality — allowing people to burn less energy while conducting a variety of tasks,” says Su.
“We have developed a way to train and control wearable robots to directly benefit humans,” says Shuzhen Luo, first author of the paper and a former postdoctoral researcher at NC State. Luo is now an assistant professor at Embry-Riddle Aeronautical University.

For example, in testing with human subjects, the researchers found that study participants used 24.3% less metabolic energy when walking in the robotic exoskeleton than without the exoskeleton. Participants used 13.1% less energy when running in the exoskeleton, and 15.4% less energy when climbing stairs.
“It’s important to note that these energy reductions are comparing the performance of the robotic exoskeleton to that of a user who is not wearing an exoskeleton,” Su says. “That means it’s a true measure of how much energy the exoskeleton saves.”
While this study focused on the researchers’ work with able-bodied people, the new method also applies to robotic exoskeleton applications aimed at helping people with mobility impairments.
“Our framework may offer a generalizable and scalable strategy for the rapid development and widespread adoption of a variety of assistive robots for both able-bodied and mobility-impaired individuals,” Su says.
“We are in the early stages of testing the new method’s performance in robotic exoskeletons being used by older adults and people with neurological conditions, such as cerebral palsy. And we are also interested in exploring how the method could improve the performance of robotic prosthetic devices for amputee populations.”
This research was done with support from the National Science Foundation under awards 1944655 and 2026622; the National Institute on Disability, Independent Living, and Rehabilitation Research, under award 90DPGE0019 and Switzer Research Fellowship SFGE22000372; and the National Institutes of Health, under award 1R01EB035404.
Shuzhen Luo and Hao Su are co-inventors on intellectual property related to the controller discussed in this work. Su is also a co-founder of, and has a financial interest in, Picasso Intelligence, LLC, which develops exoskeletons.

Mutations are changes in the molecular “letters” that make up the DNA code, the blueprint for all living cells. Some of these changes can have little effect, but others can lead to diseases, including cancer. Now, a new study introduces an original technique, called HiDEF-seq, that can accurately detect the early molecular changes in DNA code that precede mutations.
The study authors say their technique — HiDEF-seq, short for Hairpin Duplex Enhanced Fidelity Sequencing — could advance our understanding of the basic causes of mutations, in both healthy cells and in cancer, and how genetic changes naturally accumulate in human cells as people age.
Led by a team of researchers at NYU Langone Health, with collaborators across North America and in Denmark, the work helps to resolve the earliest steps in how mutations occur in DNA.
The new study is based on the understanding that DNA is made up of two strands of molecular letters, or bases. Each strand is composed of four types of letters: adenine (A), thymine (T), guanine (G), and cytosine (C). The bases of each strand pair with bases in the other strand in a specific pattern, with As pairing with Ts and Gs pairing with Cs. This allows the DNA code to be replicated and passed down accurately from one generation of cells to the next. Importantly, mutations are changes in the DNA code that are present in both strands of DNA. For example, a base pair of G and C, with a G on one strand paired with a C on the other strand, can mutate to an A and T base pair.
However, researchers say, most mutations have their origins in DNA changes that are present in only one of the two DNA strands, and these single-strand changes, such as a mismatched G and T base pair, cannot be accurately identified using previous testing techniques. These changes can occur when a DNA strand is not copied correctly during replication, as a cell divides into two cells, or when one of the two DNA strands is damaged by heat or by other chemicals in the body. If these single-strand DNA changes are not repaired by the cell, then the changes are at risk of becoming permanent double-strand mutations.
Publishing in the journal Nature online June 12, the HiDEF-seq technique was shown to detect double-strand mutations with extremely high accuracy, with an estimate of one recording error per 100 trillion base pairs analyzed. Moreover, HiDEF-seq detected changes in the DNA letter code while they were present on just one of the two strands of DNA, before they become permanent double-strand mutations.
“Our new HiDEF-seq sequencing technique allows us to see the earliest fingerprints of molecular changes in DNA when the changes are only in single strands of DNA,” said senior study author Gilad Evrony, MD, PhD, a core member of the Center for Human Genetics & Genomics at NYU Grossman School of Medicine.

Because people with genetic syndromes linked to cancer are known to have higher rates of mutations in their cells than cells in people with no cancer predisposition, researchers began their experiments by describing the DNA changes in healthy cells from people with these syndromes. Specifically, investigators worked with healthy cells from people with polymerase proofreading-associated polyposis (PPAP), a hereditary condition linked to an increased risk for colorectal cancer, and congenital mismatch repair deficiency (CMMRD), another hereditary condition that increases the likelihood of several cancers in children.
Using HiDEF-seq, researchers found a higher number of single-strand DNA changes in their cells, such as a T paired with a C in place of the original G paired with a C, than in the cells from people who did not have either syndrome. Moreover, the pattern of these single-strand changes was similar to the pattern observed in the double-strand DNA mutations for people with either syndrome.
Subsequent experiments were performed in human sperm, which are known to have among the lowest double-strand mutation rates of any human cell type. Researchers found that the pattern of chemical damage, called cytosine deamination, observed by HiDEF-seq in single stands of DNA in sperm, closely matched the damage observed in blood DNA intentionally damaged by heat. This, the researchers say, suggests that the two patterns of chemical damage to DNA, one natural and the other induced, occur through a similar process.
“Our study lays the foundation for using the HiDEF-seq technique in future experiments to transform our understanding of how DNA damage and mutations arise,” said Evrony, who is also an assistant professor in the Department of Pediatrics and the Department of Neuroscience and Physiology at NYU Grossman School of Medicine. Single-strand changes in DNA occur continually as cells divide and multiply, and while layers of repair mechanisms fix most changes, some get through and become mutations.
“Our long-term goal is to use HiDEF-seq to create a comprehensive catalogue of single-strand DNA mismatch and damage patterns that will help explain the known double-strand mutation patterns,” said Evrony. “In the future, we hope to combine profiling of single-strand DNA lesions, as obtained from HiDEF-seq, with the lesions’ resulting double-strand mutations to better understand and monitor the everyday effects on DNA from environmental exposures.”
Geneticists estimate that there are approximately 12 billion bases or individual DNA letters that can be damaged or mismatched in each human cell, as there are two copies of the genetic code, with one copy inherited from each parent. Each of these copies comprisea double-stranded DNA spanning 3 billion base pairs. Evrony says that every base position in the genetic code is likely damaged or mutated at some point during an individual’s lifetime in at least some cells.

Funding for the study was provided by National Institutes of Health grants UG3NS132024, R21HD105910, DP5OD028158, T32AG052909, F32AG076287, and P30CA016087. Additional funding support was provided by the Sontag Foundation, the Pew Foundation, and the Jacob Goldfield Foundation.
Evrony and NYU have a patent application pending on the HiDEF-seq method.
Evrony owns equity in DNA-sequencing companies Illumina, Pacific Biosciences, and Oxford Nanopore Technologies, some of whose products were adapted for use in this study. All of these arrangements are being managed in accordance with the policies and practices of NYU Langone Health.
Besides Evrony, other NYU Langone researchers involved in this study are co-lead authors Mei-Hong Liu and Benjamin Costa, and co-authors Emilia Bianchini, Una Choi, Rachel Bandler, Marta Gronska-Peski, Adam Schwing, Zachary Murphy, Caitlin Loh, and Tina Truong. Other study co-investigators include Emilie Lassen, Daniel Rosenkjaer, Anne-Bine Skytte, at the Cryos International Sperm and Egg Bank in Copenhagen, Denmark; Shany Picciotto and Jonathan Shoag, at Case Western Reserve University in Cleveland, Ohio; Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Nuno Miguel Nunes, and Uri Tabori, at The Hospital for Sick Children in Toronto, Canada; Randall Brand, at the University of Pittsburgh in Pennsylvania; Tomi Pastinen, at Children’s Mercy Kansas City in Missouri; and Richard Wagner, at the Universite de Sherbrooke in Canada.

Malaria, one of the world’s deadliest infectious diseases, is caused by several species of single-celled parasites that are transmitted via the bite of infected Anopheles mosquitoes. Despite major control and eradication efforts, nearly half of the world’s population still lives in regions where they are at risk of contracting malaria, and the World Health Organization estimates that malaria causes nearly 250 million infections and more than 600,000 deaths each year.
Beyond this massive modern impact, malaria has strongly shaped our human evolutionary history. “Although largely a tropical disease today, only a century ago the pathogen’s range covered half the world’s land surface, including parts of the northern USA, southern Canada, Scandinavia, and Siberia,” says lead author Megan Michel, a doctoral researcher at the Max Planck-Harvard Research Center for the a research collaboration between the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) and the Initiative for the Science of the Human Past at Harvard University. “Malaria’s legacy is written in our very genomes: genetic variants responsible for devastating blood disorders such as sickle cell disease are thought to persist in human populations because they confer partial resistance to malaria infection.”
Despite this evolutionary impact, the origins and spread of the two deadliest species of malaria parasites, Plasmodium falciparum and Plasmodium vivax, remain shrouded in mystery. Malaria infections leave no clear visible traces in human skeletal remains, and scant references in historical texts can be difficult to decipher. However, recent advances in the ancient DNA field have revealed that human teeth can preserve traces of pathogens present in a person’s blood at the time of death, providing an opportunity to study illnesses that are normally invisible in the archaeological record.
To explore malaria’s enigmatic history, an international team of researchers representing 80 institutions and 21 countries reconstructed ancient Plasmodium genome-wide data from 36 malaria-infected individuals spanning 5,500 years of human history on five continents. These ancient malaria cases provide an unprecedented opportunity to reconstruct the worldwide spread of malaria and its historical impact at global, regional, and even individual scales.
Following biomolecular breadcrumbs in the Americas
Malaria is endemic in tropical regions of the Americas today, and scientists have long debated whether P. vivax, a malaria species adapted to survive in temperate climates, may have arrived via the Bering Strait with the peopling of the continent or traveled in the wake of European colonization. To track the parasites’ journey into the Americas, the team analyzed ancientDNA from a malaria-infected individual from Laguna de los Cóndores, a high-altitude site situated in the remote cloud forests of the eastern Peruvian Andes. Genomic analysis revealed remarkable similarity between the Laguna de los Cóndores P. vivax strain and ancient European P. vivax, strongly suggesting that European colonizers spread this species to the Americas within the first century or so after contact. “Amplified by the effects of warfare, enslavement, and population displacement, infectious diseases, including malaria, devastated Indigenous peoples of the Americas during the colonial period, with mortality rates as high as 90 percent in some places,” says coauthor Evelyn Guevara, a postdoctoral researcher at the University of Helsinki and the MPI-EVA.
Remarkably, the team also uncovered genetic links between the Laguna de los Cóndores strain and modern Peruvian P. vivax populations 400 to 500 years later. “In addition to showing that malaria spread rapidly into what is a relatively remote region today, our data suggest that the pathogen thrived there, establishing an endemic focus and giving rise to parasites that are still infecting people in Peru today,” says co-author Eirini Skourtanioti, postdoctoral researcher at MPI-EVA and MHAAM.

Malaria on the march in Europe
While the role of colonialism in the spread of malaria is evident in the Americas, the team uncovered military activities that shaped the regional spread of malaria on the other side of the Atlantic. The cemetery at the Gothic cathedral of St. Rombout’s in Mechelen, Belgium was located adjacent to the first permanent military hospital (1567-1715 CE) in early modern Europe. Ancient human and pathogen DNA identified local cases of P. vivax among the general population buried before the construction of the military hospital, while individuals buried after its construction included cases of the more virulent P. falciparum malaria. “Most interestingly, we observe more cases of malaria in non-local male individuals from the military hospital period,” explains co-author Federica Pierini, postdoctoral researcher at the MPI-EVA. “We also identified several individuals infected with P. falciparum, a species that thrived in Mediterranean climates before eradication but was not thought to be endemic north of the Alps during this period.”
These virulent cases were found in non-local male individuals of diverse Mediterranean origins, who were likely soldiers recruited from northern Italy, Spain, and other Mediterranean regions to fight in the Hapsburg Army of Flanders during the 80 Years’ War. “We find that the large-scale troop movements played an important role in the spread of malaria during this period, similar to cases of so-called airport malaria in temperate Europe today,” explains Alexander Herbig, Group Leader of Computational Pathogenomics at the MPI-EVA. “In our globalized world, infected travelers carry Plasmodium parasites back to regions where malaria is now eradicated, and mosquitoes capable of transmitting these parasites can even lead to cases of ongoing local transmission. Although the landscape of malaria infection in Europe is radically different today than it was 500 years ago, we see parallels in the ways in which human mobility shapes malaria risk.”
Himalayan trade and a surprising high-altitude infection
On the other side of the world, the team unexpectedly identified the earliest known case of P. falciparum malaria at the high Himalayan site of Chokhopani (ca. 800 BCE), located along the Kali Gandaki River Valley in the Mustang District of Nepal. At 2800 meters above sea level, the site lies far outside the habitat range for both the malaria parasite and the Anopheles mosquito. “The region surrounding Chokhopani is cold and quite dry,” said co-author Christina Warinner, Associate Professor of Anthropology at Harvard University and Group Leader at the MPI-EVA. “Neither the parasite nor the mosquitoes capable of transmitting malaria can survive at this altitude. For us this raised a key question: how did the Chokhopani individual acquire the malaria infection that may have ultimately led to his death?”
Human genetic analysis revealed that the infected individual was a local male with genetic adaptations for life at high altitude. However, archaeological evidence at Chokhopani and other nearby sites suggests that these Himalayan populations were actively engaged in long-distance trade. “We think of these regions today as remote and inaccessible, but in fact the Kali Gandaki River Valley served as a kind of trans-Himalayan highway connecting people on the Tibetan Plateau with the Indian subcontinent,” says co-author Mark Aldenderfer, Distinguished Professor Emeritus at the University of California, Merced, whose excavations in the region have revealed its long-distance trade connections. “Copper artifacts recovered from Chokhopani’s burial chambers prove that the ancient inhabitants of Mustang were part of larger exchange networks that included northern India, and you don’t have to travel very far to reach the low-lying, poorly drained regions of the Nepalese and Indian Terai where malaria is endemic today.” The team believes that the man likely traveled to a lower-altitude malaria-endemic region, possibly for trade or other purposes, before returning or being brought back to Chokhopani, where he was later buried. The intimate details revealed by ancient DNA give clues to the myriad ways that infectious diseases like malaria spread in the past, giving rise to our current disease landscape.
Past and future of a dynamic disease
Today, the human experience of malaria is at a crossroads. Thanks to advances in mosquito control and concerted public health campaigns, malaria deaths reached an all-time low in the 2010s. However, the emergence of antimalarial drug-resistant parasites and insecticide-resistant vectors threatens to reverse decades of progress, while climate change and environmental destruction are making new regions vulnerable to malaria vector species. The team hopes that ancient DNA may provide an additional tool for understanding and even combating this public health threat.
“For the first time, we are able to explore the ancient diversity of parasites from regions like Europe, where malaria is now eradicated,” says senior author Johannes Krause, Director of Archaeogenetics at the Max Planck Institute for Evolutionary Anthropology. “We see how mobility and population displacement spread malaria in the past, just as modern globalization makes malaria-free countries and regions vulnerable to reintroduction today. We hope that studying ancient diseases like malaria will provide a new window into understanding these organisms that continue to shape the world we live in today.”

Immune system cells called macrophages play an unexpected role in the complicated connection between obesity and cancer, a Vanderbilt University Medical Center-led research team has discovered.
Obesity increases the frequency of macrophages in tumors and induces their expression of the immune checkpoint protein PD-1 — a target of cancer immunotherapies. The findings, published June 12 in the journal Nature, provide a mechanistic explanation for how obesity can contribute to both increased cancer risk and enhanced responses to immunotherapy. They may also suggest strategies for improving immunotherapy and for identifying patients who will respond best to such treatments.
“Obesity is the second leading modifiable risk factor for cancer, behind only smoking, and obese individuals have a greater risk for worse outcomes. But they also can respond better to immunotherapy,” said Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology and director of the Vanderbilt Center for Immunobiology. “How is it that there can be this worse outcome on one hand, but better outcome on another? That’s an interesting question.”
Postdoctoral fellow Jackie Bader, PhD, led the studies to examine the influence of obesity on cancer and to explore this “obesity paradox” — that obesity can contribute to cancer progression but also improve response to immunotherapy.
In a mouse model, the researchers found striking differences between the macrophages isolated from tumors in obese versus lean mice. While the protein PD-1 is an immunotherapy target normally thought to act on T cells, they discovered that the macrophages in tumors from obese mice expressed higher levels of PD-1, and that PD-1 acted directly on the macrophages to suppress their function.
In tumor samples from patients with kidney cancer, the researchers also found PD-1-expressing macrophages, and in human endometrial tumor biopsies from patients before and after 10% weight loss, they showed that PD-1 expression on tumor-associated macrophages decreased following weight loss.
“We were very fortunate to have collaborators that provided us with samples from the same patients before and after weight loss that reinforced the findings from our mouse models,” Bader said.

Blocking PD-1 with an immunotherapy drug in the mouse models increased tumor-associated macrophage activity, including their ability to stimulate T cells.
Cancer immunotherapy studies have largely focused on T cells, because they are the immune cells that can kill cancer cells, Bader and Rathmell said. But macrophages play important roles in influencing what T cells do.
“I’ve always been ‘team macrophage,'” Bader said. “Macrophages are thought of as being like a garbage truck: They clean up the mess. But they have a huge spectrum of activity to enhance the immune response, and they’re more plastic and manipulatable than other immune cells, which makes them really interesting.”
The presence of more macrophages expressing PD-1 in tumors in an obese setting provides a mechanistic explanation for the obesity paradox, Bader and Rathmell said. Increased PD-1 expression suppresses immune surveillance by macrophages — and subsequently suppresses the killer T cells — allowing tumors to grow (the increased cancer risk of obesity). PD-1 blockade with immunotherapy allows the increased number of PD-1-expressing macrophages to act (the enhanced response to immunotherapy).
Currently, immune checkpoint inhibitors work in only 20%-30% of patients.
“We clearly want to find ways to make immunotherapies work better, and in the obese setting, they naturally work better,” Rathmell said. “Understanding how these processes are working biologically may give us clues about how to improve immunotherapy in general.”
The findings also suggest that examining levels of PD-1-expressing tumor macrophages may help identify patients who will respond better to immunotherapy.
“It could be that the greater the proportion of PD-1-expressing macrophages a tumor has, the better the response to immunotherapy will be,” Rathmell said.
The research was supported by the National Institutes of Health (grants K00CA234920, F31CA261049, F30CA239367, F30CA247202, K00CA253718, F99CA274695, T32DK007314, R01CA217987, T32GM007753, K08CA241351, R01CA238263, R01DK105550, T32GM007347, K12 CA090625, T32DK101003), American Association for Cancer Research and Vanderbilt-Incyte Alliance.

Ubiquitous wearable technologies, like smartwatches, could help researchers better understand progressive neurological disorders like Parkinson’s disease and speed up the approval of new therapies, a critical need given that no drugs exist to slow progression of the world’s fastest growing brain disease.
New research appearing today in the journal njp Parkinson’s Disease adds to growing evidence that widely used and user-friendly consumer devices, in this instance an Apple Watch paired with an iPhone, can detect changes in Parkinson’s symptoms over time in individuals in the early stages of the disease.
“Digital measures hold the promise to provide objective, sensitive, real-world measures of disease progression in Parkinson’s disease,” said Jamie Adams, MD, an associate professor of Neurology at the University of Rochester Medical Center, the Center for Health + Technology, and lead author of the study. “This study shows that data generated by smartwatches and smartphones can remotely monitor and detect changes in multiple domains of the disease. These digital assessments could help evaluate the efficacy of future therapies.”
“On behalf of Critical Path Institute, we are delighted to see the astounding progress of this unique project,” said Diane Stephenson, PhD, executive director of Critical Path for Parkinson’s consortium and co-author of the study. “The early and often feedback from regulators have shaped this study in ways that now can link the clinical meaningfulness of symptoms measured by digital health technologies to the voice of people with lived experience. By partnering with patients, regulators, industry, and academic experts this project is serving as a precedent for other disease areas to follow.”
Parkinson’s is a complex disease, and the onset and severity of symptoms and progression varies widely from patient to patient. Traditional tools employed to track the disease are often subjective and collect information episodically during clinic visits. As a result, these tools do not adequately portray the day-to-day experience of individuals with Parkinson’s, limitations that have contributed to the slow pace of new therapies.
In contrast, smartwatches and smartphones can passively monitor many of the symptoms of the disease, such as gait and tremor. Additional information can be collected through tasks such as finger tapping and voice recording to measure speech-related symptoms. Adams and her colleagues recently demonstrated the devices could detect differences between individuals with early, untreated Parkson’s and age-matched controls.
In the new study, called WATCH-PD, the researchers followed participants with early-stage Parkinson’s for 12 months. Over the course of the year, the data collected by the devices showed that participants with early Parkinson’s experienced significant declines in measures of gait, an increase in tremor, and modest changes in speech. The smartwatch was able to detect decreases in arm swing, a common clinical feature of the disease, and activity in the form of the number of daily steps. The progression of symptoms in individuals in the study was consistent with other long-term studies of the disease.
The study was designed to replicate a multi-center clinical trial in individuals with early and untreated Parkinson’s disease and involved the participation and input from the pharmaceutical industry, regulators, investigators, and individuals with disease. The WATCH-PD study has recently been extended with support from the Michael J. Fox Foundation and will follow participants for an additional 18 months.
“This study brings us closer to having meaningful digital measures for future use in Parkinson’s clinical trials, which may speed up therapeutic development and get treatments to our patients faster.” said Adams.
Additional authors include Ray Dorsey, Melissa Kostrzebski, Peggy Auinger, Peter Wilmot, Yvonne Pohlson, and Stella Jensen-Roberts with URMC; Tairmae Kangarloo, Yishu Gong, Vahe Khachadourian, Brian Tracey, Dmitri Volfson, and Robert Latzman with Takeda Pharmaceuticals; Martijn Müller with the Critical Path Institute; Joshua Cosman with AbbVie Pharmaceuticals; Jeremy Edgerton with Biogen; David Anderson and Allen Best with Clinical Ink; and the Parkinson Study Group Watch-PD Study investigators and collaborators including Christopher Tarolli from URMC. The research was supported with funding from Biogen, Takeda, and the members of the Critical Path for Parkinson’s Consortium.