Publisher Health

From invisible wafts of diesel exhaust to sun-choking plumes of orange smoke, air pollution is known to damage respiratory well-being. Now, research from Rutgers suggests another reason to hold our breath: Polluted air also may hurt reproductive health.
In a study of air pollution data in relation to markers of reproductive development in infancy, Rutgers researchers found certain pollutants may negatively alter anogenital distance, a measure of prenatal exposure to hormones.
“These findings suggest air pollution may interfere with normal hormone activity during critical periods of prenatal and early infant development, and we suspect that disruption may have long-term consequences for reproductive health,” said Emily Barrett, a professor in the Department of Biostatistics and Epidemiology at the Rutgers School of Public Health and lead author of the study published in the journal Environmental Health Perspectives.
Cross-sectional studies in adult men and women have shown that alterations in anogenital distance — the length between genitals and the anus — may be related to hormone levels as well as semen quality, fertility and reproductive disorders.
In animal studies, anogenital distance is used to determine developmental toxicity of pollutants. One measurable impact is on the reproductive system. When anogenital distance is reduced in male offspring, it’s a sign that a toxic exposure is interfering with fetal testosterone production, Barrett said.
Researchers have speculated that a similar relationship may exist in humans. To test their hypothesis, Barrett and colleagues used data from The Infant Development and Environment Study (TIDES), an ongoing longitudinal study of pregnant women and their children launched in 2010 in four U.S. cities: Minneapolis; Rochester, N.Y.; San Francisco; and Seattle. Anogenital distance at birth in children, and at one year for boys, was measured as part of the TIDES program.
These data were then compared with levels of nitrogen dioxide and fine particulate matter (PM2.5) — particle pollution 2.5 micrometers or smaller released during the burning of gasoline, oil, diesel and wood. An air pollution monitoring system administered by the University of Washington tracked pollution levels in the residential areas of TIDES participants during pregnancy.

By comparing these two measures, the researchers identified a link between exposure to air pollution during key developmental windows and anogenital distance.
For instance, higher PM2.5 exposure during the so-called male programming window at the end of the first trimester, when the male fetus typically receives a surge of hormones, was associated with shorter anogenital length at birth.
The researchers also observed that higher PM2.5 during mini puberty (a period in early infancy when hormone production is high) was associated with shorter anogenital distance in males at age one. These findings suggest there may be multiple points during early development that the reproductive system may be vulnerable to the impacts of air pollutants.
“PM2.5 is like a trojan horse,” said Barrett, adding that particulate matter can carry metals such as cadmium and lead, known endocrine disruptors. “When these disruptors interfere with the body’s hormones, the result could be lifelong impacts on our health, from cancer risks to impaired ability to conceive a child.”

Doctors often prescribe radiation along with surgery to treat a brain tumor called meningioma that originates in the protective membranes surrounding the brain. But side effects from radiation can be serious, including memory loss and cognitive decline, so it’s important to know which patients really need it.
Now, researchers at UC San Francisco and Northwestern Medicine, in collaboration with 10 other medical centers, have found a highly accurate way to predict the best treatment for patients based on patterns of gene expression — which genes are turned on and off — in their tumors.
Screening tumors using this new approach could change the course of treatment for nearly 1 in 3 people with meningioma, the most common form of brain tumor diagnosed in 42,000 Americans each year. Unlike other brain tumors, meningiomas occur most often in female, Black and elderly patients.
In a paper appearing Nov. 9, 2023 in Nature Medicine, the team concluded that just 1 in 5 patients with low-grade tumors (those less likely to regrow) may need radiation, while around 2 in 5 with higher-grade tumors may be better off without radiation, based on the results of the new gene-expression test.
“There’s been a lot of controversy in the field in terms of who should receive radiotherapy and who shouldn’t,” said David Raleigh, MD, PhD, a radiation oncologist in the UCSF Brain Tumor Center and a senior author of the study, along with Stephen Magill, MD, PhD, assistant professor of neurological surgery at Northwestern University Feinberg School of Medicine. “Our biomarker takes the guessing game out of this and shows us which patients are likely to benefit from radiotherapy and which may get toxicity and possibly no benefit from radiation.”
From microscopes to molecules
Because meningiomas grow slowly, a patient may be unaware of their tumor until they start to experience neurological symptoms like numbness, vision loss or personality changes. There are no pharmaceutical treatments, so doctors rely on surgery to remove the tumor and radiation to prevent it from growing back. Doctors treat these tumors based on guidance from the World Health Organization, which stages them according to severity.

Pathologists currently classify meningiomas by looking at them under a microscope for features that indicate whether they may grow back, a system that is very good but not perfect. Patients with Grade 1 tumors don’t usually receive radiation treatment if their tumors can be removed completely during surgery. Yet approximately 20% of the time, the tumors recur. Those with Grade 2 and 3 tumors, which are much more aggressive and more likely to grow back after surgery, are often treated with radiation after surgery. It has been unclear how many of these patients, particularly those with Grade 2 tumors, actually need radiation treatment.
Raleigh, along with Magill and lead author William Chen, MD, decided to look at classifying tumors according to which of their genes are turned on and off, thereby offering clues to how aggressive they might be.
“Gene-expression tests like this, that analyze a small number of genes at a time, are widely available for breast, prostate and some other cancers, and they’ve proven to be a very accurate and inexpensive alternative to other types of tests,” said Chen.
How to turn guesses into answers
Raleigh and Chen and their multidisciplinary team suspected that gene expression could more accurately point out the patients who would be helped by radiotherapy. Using samples from 1,856 meningioma patients at 12 medical centers in the U.S., Europe and Hong Kong, Raleigh’s team came up with a set of 34 genes whose gene expression patterns had the potential to predict whether a tumor would return.
One-fifth of the Grade 1 tumors — the same number that grow back after surgery — expressed the patterns that Raleigh’s team found could predict a tumor’s regrowth. This fraction of patients may benefit from radiation. The researchers also found that two-fifths of patients with Grade 2 and 3 tumors did not have a recurrence, and this, too, could be predicted by the tumor’s gene expression.
“When to proceed with additional surgery, radiotherapy or simply to observe a small residual meningioma is not always clear,” said Magill. “This test adds information that can let us tailor our surgical and radiation approach to provide the best outcome for each patient and maximize both quality and quantity of life.”
The team’s next step is to test the approach in two clinical trials currently being developed.
Funding: This study was supported by NIH grants (P50 CA097257, P50 CA221747, U01 CA180868, U10 CA180822, R01 CA262311, F32 CA213944, F30 CA246808, T32 GM007618) and philanthropy. For a full list of funders, please see the study.

President Biden will put pressure on Xi Jinping to crack down on the Chinese facilities that make chemical compounds used in potent drugs.President Biden will press the Chinese leader Xi Jinping on Wednesday to crack down on the Chinese firms that are helping to produce fentanyl, a potent drug that has killed hundreds of thousands of Americans.An agreement to curb China’s illicit exports of fentanyl and, particularly, the chemicals that can be combined to make the drug, could be one of the more significant achievements for the United States out of Mr. Biden and Mr. Xi’s meeting, which is taking place as leaders from Pacific nations gather for an international conference in San Francisco.China is home to a thriving chemical industry that pumps out compounds that are made into pharmaceuticals, fragrances, textile dyes and fertilizers. Some of those same compounds can also be combined to create fentanyl, an opioid that can be 100 times as potent as morphine.U.S. officials argue that this vast chemical industry is playing a key role in the American fentanyl crisis by supplying the bulk of materials used in illegal drug labs, including in Mexico, which is now the largest exporter of fentanyl to the United States.The Chinese government denies that its country plays such a pivotal role and instead blames the United States for harboring a culture of drug use.“All-out marketing by pharmaceutical companies, over-prescription by doctors, ineffective government crackdowns and the negative implications of marijuana legalization are among the combination of factors behind an ever-growing market for narcotics,” China’s foreign ministry said in a statement last year.U.S. officials say they have stopped more fentanyl from coming into the United States in the past two years than in the previous five years combined. According to the Centers for Disease Control and Prevention, fentanyl and other synthetic opioids may have resulted in more than 77,000 overdose deaths in the United States between May 2022 and April 2023. The problem with fentanyl overdoses is particularly acute in San Francisco, where Mr. Biden and Mr. Xi are meeting.Ian Johnson, a senior fellow for China studies at the Council on Foreign Relations, said that getting China to agree to do something about fentanyl would resonate more with average Americans than the typical “deliverables” from international meetings.“For Biden, that would be nice to have to show to the heartland of the United States that relations with China are more than just some esoteric matter, but can actually bring something to ordinary people,” Mr. Johnson said in a briefing held by the council last week. Republicans have made fentanyl-related deaths a central piece of their campaign against Mr. Biden and Democrats in the 2024 elections.Red stained pollen grain sample at the U.S. Customs and Border Protection in Chicago, last year.Lyndon French for The New York TimesCollecting pollen samples at a Customs and Border Protection facility. The extent to which an agreement with China would curb the flow of fentanyl into the United States is unclear.Lyndon French for The New York TimesStill, given the difficulties with policing an illicit industry, the extent to which an agreement would curb the flow of fentanyl into the United States is unclear.Roselyn Hsueh, an associate professor of political science at Temple University, said that an agreement between Mr. Biden and Mr. Xi could lead to the Chinese central government providing more oversight and investing more resources into inspection and monitoring. But she said Beijing had run into difficulty in the past clamping down on fentanyl and precursor chemicals.Before 2019, China was the primary source of fentanyl coming into the United States, typically through the mail and other commercial couriers. As a part of trade talks with former President Donald J. Trump, the Chinese government in 2019 agreed to prohibit the production, sale and export of all fentanyl-related drugs except through special licenses.But that resulted in Chinese companies rerouting to Mexico, and India emerging as a new production site, Ms. Hsueh said. The main source of U.S. fentanyl became Mexican criminal organizations, which used Chinese-made components and Chinese money-laundering services.Today, online sales that mask the identities of sellers and buyers further complicate enforcement. The regulation and enforcement of fentanyl and precursor chemicals remains “fragmented and decentralized” among Chinese local governments, industry associations and firms with vested interests in the chemical trade, Ms. Hsueh said.U.S. officials have said that problem is compounded because many of the ingredients used to make fentanyl are legal chemicals that can be used for legitimate purposes in other industries. The United States has sanctioned dozens of people in China and Hong Kong for their role in fentanyl trafficking. In September, Mr. Biden added China to the U.S. list of the world’s major drug-producing countries, a move that the Chinese government denounced as “a malicious smear.”Last month, the U.S. customs department released an updated strategy to combat fentanyl and synthetic drugs, including through the enhanced use of data and counterintelligence operations to track drug manufacturing and distribution networks, and target suspicious locations and recipients that demonstrate patterns of illicit activity. “In my 30 years as a customs official, the trafficking of synthetic illicit drugs like fentanyl is one of the toughest, most daunting challenges I have ever seen,” said Troy Miller, the acting commissioner for Customs and Border Protection.U.S. officials say they have stopped more fentanyl from coming into the United States in the past two years than in the previous five years combined.Mamta Popat/Arizona Daily Star, via Associated PressU.S. officials believe China’s dominance as a chemical producer makes Beijing’s cooperation key for enforcement. Administration officials, including Commerce Secretary Gina Raimondo, have raised the issue with top Chinese officials during recent trips to China.When six lawmakers, including Senator Chuck Schumer, the majority leader, had a chance to talk to Mr. Xi during a visit to China last month, the main issue they brought up was not trade or military coordination or climate change, but the harm that fentanyl had caused in their home states.“Everyone told stories, personal stories about how, you know, friends of ours, family, have died from fentanyl, and how this was a really important issue, and I think that you could tell that made an impression on him, how deeply we felt about it,” said Mr. Schumer, a New York Democrat.Fentanyl precursors from China have become a bipartisan issue in Congress, and the six senators who spoke with Mr. Xi included three Democrats and three Republicans.“China needs to enforce laws that prevent the export of fentanyl precursors to international drug markets,” said Senator Bill Cassidy, Republican of Louisiana.Despite the scale of the problem, there is hope that greater coordination between the United States and China could improve the situation. Cooperation between the countries on preventing shipments of the precursor chemicals stalled several years ago after the United States sanctioned a Chinese government entity for its alleged involvement in human rights abuses in China’s westernmost region, Xinjiang.That sanctioned entity was located at the same address in Beijing as the National Narcotics Laboratory of China, which plays a key role in China’s law enforcement effort on drug-related chemicals.Chinese officials deeply resent American sanctions on their institutions, and U.S. officials have taken the position that because of the risk of confusion among the two institutes at the same address, neither institute can work with the United States.China then broadened its position in August 2022 when it halted any counternarcotics coordination with the United States as one of a series of measures taken in response to a visit to Taiwan by Nancy Pelosi, then the speaker of the House. Beijing claims Taiwan, a self-ruled island democracy, as part of its territory.Eileen Sullivan

In a new systematic review, Melissa J. Perry, Sc.D., MHS, dean of the George Mason University College of Public Health, and Lauren Ellis, MPH, doctoral student at Northeastern University, foundthat there is a strong association between insecticide exposure and lower sperm concentration in adult men globally.
“Understanding how insecticides affect sperm concentration in humans is critical given their ubiquity in the environment and documented reproductive hazards. Insecticides are a concern for public health and all men, who are exposed primarily through the consumption of contaminated food and water,” says Ellis.
The team reviewed decades of human evidence regarding the health impacts of exposure to two widely used insecticide classes, organophosphates and N-methyl carbamates, and found consistent associations with lower sperm concentration, which warrants concern, particularly in light ofobserved downward trends in semen quality demonstrated by other studies.
“This review is the most comprehensive evidence sizing up more than 25 years of research on male fertility and reproductive health. The evidence available has reached a point that we must take regulatory action to reduce insecticide exposure,” says Dr. Perry, the senior author on the paper.
The research team systematically reviewed 25 human studies of occupational and environmental insecticide exposure conducted over the course of25 years.To the reviewers’ knowledge, this is the most comprehensive systematic review on this topic to date, and the first to use these methods to quantitatively synthesize decades of epidemiological literature.
“Adult Organophosphate and Carbamate Insecticide Exposure and Sperm Concentration: A Systematic Review and Meta-Analysis of the Epidemiological Evidence” was published online in Environmental Health Perspectives in November 2023 (DOI is 10.1289/EHP12678). Karen Molina, C. Rebecca Robbins, and Marlaina Freisthler from George Washington University; Daria Sgargi from the Cesare Maltoni Cancer Research Center, Ramazzini Institute; and Daniele Mandrioli from the University of Bologna are additional authors on the paper.
Most of the research was conducted while Perry and Ellis were at George Washington University. There was no outside funding for this research.

Pancreatic cancer is one of the deadliest types of cancers in humans. It is the fourth leading cause of cancer-related deaths in the western world. The early stages of the disease often progress without symptoms, so diagnosis is usually very late. Another problem: Advanced tumors — and their metastases — cannot be completely removed. Chemotherapies, in turn, attack not only the tumor cells but also healthy cells throughout the body. Innovative nanoparticles could be a new approach to treat cancer more precisely. The approach was developed by a research team from the Max Planck Institute (MPI) for Multidisciplinary Sciences, the University Medical Center Göttingen (UMG), and the Karlsruhe Institute of Technology (KIT). The therapy is now to be optimized for clinical application as quickly as possible.
The method promises to treat pancreatic carcinomas with more accuracy and with fewer side effects than current cancer therapies. Using so-called nanoparticles, they transported the active substance Gemcitabine in large quantities directly into the tumor.
“Targeting the drug in high concentrations into the tumor cells with the help of the nanoparticles increases the efficacy and spares healthy cells. This can reduce the severe side effects that occur with Gemcitabine,” explains Myrto Ischyropoulou, lead author of the study recently published in the journal Advanced Materials. “Currently, patients are given the free drug. This is distributed throughout the body and can lead to toxic effects in all parts of the body. The nanoparticles, on the other hand, release the drug mainly in the tumor.” Joanna Napp, scientist at the UMG and the MPI, adds: “Using imaging methods, we have already been able to demonstrate in mouse models that the nanoparticles accumulate in the tumors.”
The administration of nanoparticles also allows resistance mechanisms in the tumor to be circumvented. “Free Gemcitabine is often no longer taken up by the tumor very early on and is thus largely ineffective there. However, it still leads to considerable side effects, for example in the liver and kidneys,” explains Claus Feldmann from KIT. “By using a different uptake mechanism in tumor cells, our nanoparticles could be a very effective new therapeutic approach here.”
The research success is an excellent example of successful interdisciplinary cooperation, says Frauke Alves, group leader at the MPI and the UMG. “From the idea to the development of the new nanoparticles to preclinical testing, chemists, biologists, pharmacists, and physicians have worked hand in hand.” With a spin-off, the scientists are now working to bring their new nanoparticles out of the test phase and into clinical use as quickly as possible.

Aldehydes are toxic compounds that are produced in the body by metabolic processes, especially upon alcohol consumption. They are dangerous because they bind to cellular macromolecules such as DNA, RNA, and proteins, and crosslink them.
Crosslinking damage to DNA must be repaired by the cell to prevent premature aging and cancer. However, it was previously unknown whether and how cells sense and resolve crosslinking damage to single-stranded RNA. A team led by Professor Julian Stingele from the Gene Center Munich has now shown that RNA crosslinking damage is toxic because it impairs protein synthesis.
“It was previously difficult to study specifically RNA crosslinking damage, as most chemicals also damage DNA,” says lead author Jacqueline Cordes. “We therefore utilized a new approach to induce and study RNA damage in the absence of DNA damage,” adds Dr. Shubo Zhao, also lead author of the study. Using this novel experimental system, the researchers uncovered a previously unknown mechanism by which the ribosome can act as a sensor for crosslinking damage. Ribosomes run along the messenger molecule mRNA to translate the information stored in the mRNA into proteins. As the researchers demonstrate, the ribosome gets stuck as soon as it encounters a lesion. This leads to collisions with subsequent ribosomes, triggering removal of the damage.
“Our new findings indicate that compounds commonly considered solely as DNA-damaging agents challenge cellular homeostasis on a much broader level. Given that such agents are often used for chemotherapy, our work has imminent implications for the mechanisms of action of frequently-used anti-cancer drugs,” says Stingele.
Aldehydes are toxic compounds that are produced in the body by metabolic processes, especially upon alcohol consumption. They are dangerous because they bind to cellular macromolecules such as DNA, RNA, and proteins, and crosslink them.
Crosslinking damage to DNA must be repaired by the cell to prevent premature aging and cancer. However, it was previously unknown whether and how cells sense and resolve crosslinking damage to single-stranded RNA. A team led by Professor Julian Stingele from the Gene Center Munich has now shown that RNA crosslinking damage is toxic because it impairs protein synthesis.
“It was previously difficult to study specifically RNA crosslinking damage, as most chemicals also damage DNA,” says lead author Jacqueline Cordes. “We therefore utilized a new approach to induce and study RNA damage in the absence of DNA damage,” adds Dr. Shubo Zhao, also lead author of the study. Using this novel experimental system, the researchers uncovered a previously unknown mechanism by which the ribosome can act as a sensor for crosslinking damage. Ribosomes run along the messenger molecule mRNA to translate the information stored in the mRNA into proteins. As the researchers demonstrate, the ribosome gets stuck as soon as it encounters a lesion. This leads to collisions with subsequent ribosomes, triggering removal of the damage.
“Our new findings indicate that compounds commonly considered solely as DNA-damaging agents challenge cellular homeostasis on a much broader level. Given that such agents are often used for chemotherapy, our work has imminent implications for the mechanisms of action of frequently-used anti-cancer drugs,” says Stingele.

An unexpected genetic discovery in wheat has led to opportunities for metabolic engineering of versatile compounds with potential to improve its nutritional qualities and resilience to disease.
Researchers in the Osbourn group at the John Innes Centre have been investigating biosynthetic gene clusters in wheat — groups of genes that are co-localized on the genome and work together to produce specific molecules.
In a study which appears in Nature Communications, they identified a gene cluster activated by pathogen infection, which was found to produce a compound they named triticein.
Experiments to determine the structure of triticein surprisingly identified this compound as an isoflavone rather than a flavone, as the team had expected.
Isoflavones are a class of phytoestrogen compounds well studied for their benefits to human health, which include prevention of cardiovascular disease and some cancers. They are mostly found in the legume family of which soybeans are the main source in the human diet.
The discovery of an alternative route to isoflavonoid biosynthesis, this time in wheat, and the elucidation of the triticein biosynthetic pathway in this study, provides exciting opportunities for future research and paves the way for metabolic engineering efforts. Increasing triticein production in wheat, for example, may aid in developing cultivars with higher disease tolerance.
Another possibility is that wheat triticein-forming genes can be expressed in other plants or microbes, from which the molecule can be produced, and its antimicrobial properties further investigated.
And because triticein is an isoflavone there is a possibility that it may have health benefits like others in this class, although there is much further research to be done on this prospect.
Dr. Rajesh Chandra Misra, a post-doctoral scientist at the John Innes Centre and one of the lead authors explained: “We do not know anything specifically about potential health benefits of triticein, only about other isoflavones. Also, the concentrations of triticein (and other isoflavones) that we found in wheat grains were very low, so wheat cannot be currently considered as a source of dietary isoflavones.”
Joint lead author Dr Guy Polturak previously at the John Innes Centre and now at The Hebrew University of Jerusalem reflected: “This study is a nice example of how scientific research sometimes takes scientists down unintended paths, eventually leading to unexpected discoveries. The main aim of this research was to learn about wheat chemical defence mechanisms, but it led to interesting new findings on plant biochemistry, in this case the discovery of a unique isoflavone synthase.”

A team led by scientists at Rensselaer Polytechnic Institute has 3D-printed hair follicles in human skin tissue cultured in the lab. This marks the first time researchers have used the technology to generate hair follicles, which play an important role in skin healing and function.
The finding, published in the journal Science Advances, has potential applications in regenerative medicine and drug testing, though engineering skin grafts that grow hair are still several years away.
“Our work is a proof-of-concept that hair follicle structures can be created in a highly precise, reproducible way using 3D-bioprinting. This kind of automated process is needed to make future biomanufacturing of skin possible,” said Pankaj Karande, Ph.D., an associate professor of chemical and biological engineering and a member of Rensselaer’s Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies, who led the study.
“The reconstruction of hair follicles using human-derived cells has historically been a challenge. Some studies have shown that if these cells are cultured in a three-dimensional environment, they can potentially originate new hair follicles or hair shafts, and our study builds on this work,” Karande said.
When it comes to engineering human skin, hair may at first seem superfluous. However, hair follicles are quite important: They produce sweat, helping regulate body temperature, and they contain stem cells that help skin heal.
Hair follicles are also an entry point for topical drugs and cosmetics, making them an important part of dermatological testing. But today, initial safety testing is done on engineered skin tissues that lack hair follicles.
“Right now, contemporary skin models — the engineered structures that mimic human skin — are quite simple. Increasing their complexity by adding hair follicles would give us even more information about how skin interacts with topical products,” said Carolina Catarino, Ph.D., first author of the study, who earned her doctorate at Rensselaer and is now a researcher developing new skin testing methods at Grupo Boticário, a cosmetics company in her home country of Brazil.

“Dr. Karande’s lab is at the forefront of skin tissue engineering. This team has already successfully printed skin with working blood vessels, and this latest research is an exciting next step in developing and testing better treatments for burns and other skin conditions,” said Deepak Vashishth, Ph.D., director of the Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies.
“Dr. Karande’s work is a great example of advances being made by RPI researchers at the interface of engineering and life sciences with impact on human health,” said Shekhar Garde, Ph.D., dean of Rensselaer’s School of Engineering. “Bringing multichannel 3-D printing to biological realm is opening exciting opportunities that would have been hard to imagine in the past.”
The researchers created their follicle-bearing skin with 3D-printing techniques adapted for printing at the cellular level.
The scientists begin by allowing samples of skin and follicle cells to divide and multiply in the lab until there are enough printable cells. Next, the researchers mix each type of cell with proteins and other materials to create the “bio-ink” used by the printer. Using an extremely thin needle to deposit the bio-ink, the printer builds the skin layer by layer, while also creating channels for depositing the hair cells. Over time, the skin cells migrate to these channels surrounding the hair cells, mirroring the follicle structures present in real skin.
Right now, these tissues have a lifespan of two to three weeks, which is not enough time for hair shafts to develop. The research team’s future work aims to extend that period, allowing the hair follicle to mature further and paving the way for their use in drug testing and skin grafts.

Iron storage “spheres” inside the bacterium C. diff — the leading cause of hospital-acquired infections — could offer new targets for antibacterial drugs to combat the pathogen.
A team of Vanderbilt researchers discovered that C. diff (Clostridioides difficile) produces the spheres, called ferrosomes, and that these structures are important for infection in an animal model. The findings, reported Nov. 15 in the journal Nature, are also a rare demonstration of a membrane-bound structure inside a pathogenic bacterium.
Bacteria have long been thought not to contain organelles (such as a nucleus, mitochondria and other specialized structures) like eukaryotic cells, but that biological dogma appears to be incorrect.
“The emerging idea that bacteria do compartmentalize biochemical processes in a way similar to eukaryotic cells really flips the field of microbiology on its head,” said Eric Skaar, PhD, MPH, the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology, and Inflammation.
Skaar, co-corresponding author Qiangjun Zhou, PhD, assistant professor of Cell and Developmental Biology, and their colleagues were intrigued by findings reported several years ago that some environmental bacteria produce iron-containing ferrosomes.
They knew that the genes in these bacteria were conserved in C. diff and other anaerobic bacteria (bacteria that die in the presence of oxygen), and they set out to determine if C. diff produces ferrosomes to manage its need for iron. Like all living organisms, C. diff requires iron to survive and grow. Skaar and his team have focused on how pathogens like C. diff acquire iron and other metals, with a goal of finding new pathways that could be exploited to “starve” pathogens of essential nutrients.
C. diff causes about 500,000 infections and more than 29,000 deaths in the United States each year, according to the Centers for Disease Control and Prevention, and treatment options are limited. People taking antibiotics that disrupt the healthy microbes in the gut are at increased risk for C. diff infection, which causes diarrhea and colitis. New strategies for treating this urgent public health threat are needed, Skaar said.

To look for iron inside C. diff, the researchers first drew on expertise and resources in the Vanderbilt Institute of Nanoscale Science and Engineering (VINSE).
“The best way to look for the accumulation of elements in a small space like a cell is with a method called STEM-EDS, which has not commonly been used for biological samples,” Skaar said. “We were fortunate to have access to a STEM-EDS instrument and collaborators at VINSE, and we quickly proved that there was an accumulation of iron ‘dots’ within the bacterium.”
Co-first authors Hualiang Pi, PhD, and Rong Sun, PhD, led studies to show that those iron dots represented organelles that were important to C. diff infection.
Pi and Skaar’s team found that two genes (fezA and fezB), which are similar to those in environmental bacteria, were required for ferrosome formation. Using C. diff bacteria missing these genes, they showed that ferrosomes are required for C. diff to fully colonize and cause disease in an animal model. They found that ferrosomes were even more important for C. diff infection in a model of inflammatory bowel disease, demonstrating that these iron-containing structures help the bacterium combat “nutritional immunity” — the host response of producing proteins to bind iron and attempt to starve the pathogen.
Sun and Zhou’s team used cryogenic electron microscopy (cryo-EM) and cryo-tomography to show that the ferrosome structures were encased in a membrane, classifying them as organelles.
Skaar noted that “Vanderbilt’s unique geography” — the proximity of experts in engineering, cell biology and the Medical Center — and specialized tools for STEM-EDS and cryo-EM made the research possible.

The results “establish ferrosome formation and all the factors involved in ferrosome formation as potential targets for new antibacterial drugs against an important infectious disease,” Skaar said. “Anytime we find new factors involved in host-pathogen interactions and show that they’re important for infection, that opens entirely new opportunities to make classes of antibacterial drugs that have not existed before. That is especially important in the face of rising antimicrobial resistance that we’re seeing globally.”
In future studies, the researchers plan to explore how ferrosomes are formed, whether other gut pathogens produce ferrosomes, and whether these structures might be shared in the gut as a source of iron. Skaar is also particularly interested in pursuing the emerging area of bacterial organelles.
“We think our study is a rare demonstration of an organelle in a pathogenic bacterium,” he said. “Now we want to know if there are other subcellular compartments in bacteria that we’re interested in that could teach us about how these cells perform various physiologic processes.”
Pi, a former postdoctoral fellow at Vanderbilt, is now an assistant professor of Microbial Pathogenesis at Yale School of Medicine. Sun is a postdoctoral fellow in Cell and Developmental Biology. Other authors of the Nature paper include James McBride, PhD, Angela Kruse, PhD, Katherine Gibson-Corley, DVM, PhD, Evan Krystofiak, PhD, Maribeth Nicholson, MD, MPH, and Jeffrey Spraggins, PhD. The research was supported by grants from the National Institutes of Health (R01AI073843, R01AI164587, U19AI174999, R01AI13858, R00MH113764, F32AI161860, K99AI168483 and K23AI156132).

A nationwide programme to reduce the risk of developing diabetes in the UK is proven beyond reasonable doubt to work, a new study reveals.
The positive effects observed in the NHS Diabetes Prevention Programme — the largest such project in the world helping people across the UK to lose weight and control their blood sugar levels — may have relevance globally for tackling the diabetes epidemic.
The Diabetes Prevention Programme (NHS DPP) in England referred adults with high risk of developing diabetes to lifestyle counselling for losing weight, encouraging physical activity, and other lifestyle improvements. The program started in 2016, but doubts have remained about whether it worked or not.
Now, an international team of researchers from the UK, Germany, USA, and South Africa analysed English health data from over two million patients- finding strong evidence that referral to the programme improved the factors which can lead to people developing Type 2 diabetes.
Publishing their findings today (Wednesday 15 November) in Nature, the research team used state-of-the-art statistical methods that reveal being referred to the that the programme has resulted in improved glycemic control, as well as reductions in Body Mass Index (BMI), weight, high-density lipoprotein (HDL) cholesterol, and triglycerides.
Co-author Professor Justine Davies, from the University of Birmingham, commented: “Our findings clearly demonstrate the huge benefits of intensive lifestyle counselling for improving the health of patients with prediabetes. The evidence also suggests a promising route for improving population health more broadly.
“The positive effects observed in the programme may also extend to other non-communicable diseases such as cancer, which is increasingly thought to be connected to unhealthy lifestyle habits and environments.”
The researchers note that doctors’ scepticism about the effectiveness of lifestyle counselling for successful behaviour change may stem from GPs’ experience that brief counselling — often the only feasible approach in time-constrained consultations — may be of limited benefit.

Lead author Julia Lemp from the University of Heidelberg, in Germany, commented: “There is an urgent need to implement population-based measures that prevent diabetes, enhance its early detection, and address cardiovascular risk factors to prevent or delay its progression to complications.
“Investment in structured, intensive behaviour change programmes may help prevent development of Type 2 diabetes whilst reducing the risk of complications from diabetes and cardiovascular events.
“Our results show beyond reasonable doubt that investments in programs such as this should continue. At the same time, there are many people at risk for diabetes who remain underserved by existing care pathways and for whom targeted prevention strategies should be further explored.”
Diabetes prevalence and related deaths continue to rise in most parts of the world. By 2030, the global number of adults with diabetes is expected to reach 578 million — 10% of the world’s adult population.