The research was published online September 28 in the journal Nature Communications.

Deep in a tumor, full of rapidly dividing cells, cancer cells are faced with a lack of oxygen, a condition called hypoxia. Cancer cells that survive these tough environments end up seeking what they missed, slowly making their way to the oxygen-rich bloodstream and often seeding metastasis elsewhere in the body, explains lead study author Daniele Gilkes, Ph.D., an assistant professor of oncology at Johns Hopkins.

The team identified 16 genes responsible for this protection from reactive oxygen species, “which is a stress that occurs when the cells enter the bloodstream,” Gilkes says. “Although the hypoxic cells are localized in what we call the perinecrotic region of a tumor — meaning they’re sitting right next to dead cells — we think that they’re able to migrate into higher [oxygen] levels where they can actually find the bloodstream,” she says. “Cells able to survive super-low oxygen concentrations do a better job of surviving in the bloodstream. This is how, even after a tumor is removed, we sometimes find that cancer cells have set up elsewhere in the body. Lower levels of oxygen in a tumor correlate with worse prognosis.”

The scientists sought to learn what helps these post-hypoxic cells survive in an environment that would kill other cancer cells, and which genes were being turned on to facilitate survival.

In laboratory studies, Gilkes’ team color-coded hypoxic cells green, then applied a technique called spatial transcriptomics to identify which genes were turned on in the perinecrotic region, and that stayed on when the cells migrated to more oxygenated tumor regions. They compared cells in the primary tumors of mice with those that had entered the blood stream or the lungs. A subset of hypoxia-induced genes continued to be expressed long after cancer cells escaped the initial tumor.

“The results suggest the potential for a sort of memory of exposure to hypoxic conditions,” says Gilkes.

The new research showed a disparity between what occurs in laboratory models and what happens in the human body, solving a mystery that was puzzling scientists. When cells in a dish are hypoxic and returned to high levels of oxygen in a short time, they tend to stop expressing the (hypoxia-induced) genes and go back to normal. However, in tumors, hypoxia can be more of a chronic condition, not acute. When Gilkes’ team exposed cells to hypoxia for a longer period — five days was usually enough — they mimicked what was happening in the mouse models.

Results were particularly predictive for triple-negative breast cancer (TNBC), which has a high rate of recurrence. The researchers found that patient biopsies from TNBC that had recurred within three years had higher levels of a protein called MUC1.

As part of their research model, Gilkes and team blocked MUC1 using a compound called GO-203 to see if it would reduce the spread of breast cancer cells to the lung. Their aim was to specifically eliminate aggressive, post-hypoxic metastatic cells.

“If we reduced the level of MUC1 in these hypoxic cells, they were no longer able to survive in the bloodstream or in presence of reactive oxygen species, and they formed fewer metastases in mice,” Gilkes says. However, there are other factors at play, she says, and additional research will be needed to see if this finding is true across cancer types.

A phase I/II clinical trial targeting MUC1 for patients with advanced cancers across a variety of solid tumor types — including those found in breast, ovarian, and colorectal cancer — is ongoing, Gilkes says.

Study co-authors were Inês Godet, Harsh Oza, Yi Shi, Natalie Joe, Alyssa Weinstein, Jeanette Johnson, Michael Considine, Swathi Talluri, Jingyuan Zhang, Reid Xu, Steven Doctorman, Genevieve Stein-O’Brien, Luciane Kagohara, Cesar Santa-Maria and Elana Fertig, from Johns Hopkins, and Delma Mbulaiteye from the NIDDK STEP-UP Program at the National Institutes of Health.

The work was funded by The Jayne Koskinas Ted Giovanis Foundation for Health and Policy, the NCI/ SKCCC Core grant number P50CA006973, NCI grant number 5U01CA253403-03, and the National Cancer Center.

Santa-Maria has received research funds from AstraZeneca, GSK/ Tesaro, Merck, Gilead, Celldex, BMS and Pfizer, and consulting fees from Seattle Genetics. Fertig serves on the scientific advisory board of Resistance Bio, is a consultant for Merck and Mestag Therapeutics, and has received research funding from Abbvie, Inc. and Roche/Genentech. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

A campuswide collaboration is using sewage surveillance as a vital strategy in the fight against diseases that spread through the water such as legionella and shigella. The ones that are most difficult to combat are diseases with antimicrobial resistance, which means they are able to survive against antibiotics that are intended to kill them.

A recent paper in Nature Water offers an encouraging insight: Monitoring sewage for antimicrobial resistance indicators is proving to be more efficient and more comprehensive than testing individuals. This approach not only detects antimicrobial resistance more effectively but also reveals its connection to socioeconomic factors, which are often key drivers of the spread of resistance.

The team is collaborating across Virginia Tech with experts such as Leigh-Anne Krometis in biological systems engineering and Alasdair Cohen and Julia Gohlke in population health sciences to focus on serving rural communities where the issues are most acute.

Globally, low-to middle-income communities bear the brunt of infectious diseases and the challenges of antimicrobial resistance. Sewage surveillance could be a game changer in addressing these disparities. This method not only captures a snapshot of antimicrobial resistance at the community level, but also reveals how socioeconomic factors drive the issue.

The National Science Foundation Research Traineeship focuses on advancing sewage surveillance to combat antimicrobial resistance. The work is integral to broader efforts led by Vikesland and the Fralin Life Sciences Institute program for technology enabled environmental surveillance and control to sense and monitor waterborne health threats.

The study analyzed data from 275 human fecal samples across 23 countries and 234 urban sewage samples from 62 countries to investigate antibiotic resistance gene levels. Socio-economic data, including health and governance indicators from World Bank databases, were incorporated to explore links between antibiotic resistance genes and socio-economic factors. The group utilized machine learning to assess antibiotic resistance gene abundance in relation to socio-economic factors, revealing significant correlations. Statistical methods supported the finding that within country antibiotic resistance gene variation was lower than between countries.

Big picture, the team’s findings show sewage surveillance is emerging as a powerful tool in the fight against antimicrobial resistance. It even has the potential to protect vulnerable communities more effectively.

The study led by Xuehua Zhong, a professor of biology in Arts & Sciences, was published Nov. 6 in Science Advances.

Zhong’s new research focuses on DNA methylation, a normal biological process in living cells wherein small chemical groups called methyl groups are added to DNA. This activity controls which genes are turned on and off, which in turn affects different traits — including how organisms respond to their environments.

Part of this job involves silencing, or turning off, certain snippets of DNA that move around within an organism’s genome. These so-called jumping genes, or transposons, can cause damage if not controlled. The entire process is regulated by enzymes, but mammals and plants have developed different enzymes to add methyl groups.

“Mammals only have two major enzymes that add methyl groups in one DNA context, but plants actually have multiple enzymes that do that in three DNA contexts,” said Zhong, who is the Dean’s Distinguished Professorial Scholar and program director for plant and microbial biosciences at WashU. “This is the focus of our study. The question is — why do plants need extra methylation enzymes?”

Looking forward, Zhong’s research could pave the way for innovations in agriculture by improving crop resilience. “Certain genes or combinations of genes are contributing to certain features or traits,” Zhong explained. “If we find precisely how they are regulated, then we can find a way to innovate our technology for crop improvement.”

Evolving differernt functions

The new study is centered around two enzymes specifically found in plants: CMT3 and CMT2. Both enzymes are responsible for adding methyl groups to DNA, but CMT3 specializes in the parts of DNA called the CHG sequences, while CMT2 specializes in different parts called CHH sequences. Despite their functional differences, both enzymes are a part of the same chromomethylase (CMT) family, which evolved through duplication events that provide plants with additional copies of genetic information.

Using a common model plant called Arabidopsis thaliana, or thale cress, Zhong and her team investigated how these duplicated enzymes evolved different functions over time. They discovered that somewhere along the evolutionary timeline, CMT2 lost its ability to methylate CHG sequences. This is because it’s missing an important amino acid called arginine.

“Arginine is special because it has charge,” said Jia Gwee, a graduate student in biology and co-first author of the study. “In a cell, it’s positively charged and thus can form hydrogen bonds or other chemical interactions with, for example, the negatively charged DNA.”

However, CMT2 has a different amino acid — valine. “Valine is not charged, so it is unable to recognize the CHG context like CMT3. That’s what we think contributes to the differences between the two enzymes,” said Gwee, winner of the Dean’s Award for Graduate Research Excellence in Arts & Sciences.

To confirm this evolutionary change, the Zhong lab used a mutation to switch arginine back into CMT2. As they expected, CMT2 was able to perform both CHG and CHH methylation. This suggests that CMT2 was originally a duplicate of CMT3, a backup system to help lighten the load as DNA became more complex: “But instead of simply copying the original function, it developed something new,” Zhong explained.

This research also provided insights about CMT2’s unique structure. The enzyme has a long, flexible N-terminal that controls its own protein stability. “This is one of the ways plants evolved for genome stability and to fight environmental stresses,” Zhong said. This feature may explain why CMT2 evolved in plants growing in such a wide variety of conditions worldwide.

Much of the data for this study came from the 1001 Genomes Project, which aims to discover whole-genome sequence variation in A. thaliana strains from around the globe.

“We’re going beyond laboratory conditions,” Zhong said. “We’re looking at all of the wild accessions in plants using this larger data set.” She believes part of the reason A. thaliana has evolved to thrive despite environmental stresses is because of the diversification that happens during the methylation process, including those jumping transposons: “One jump might help species deal with harsh environmental conditions.”

Results from a Virginia Tech-led study provide the first direct geochemical evidence of the slushy planet — otherwise known as the “plumeworld ocean” era — when sky-high carbon dioxide levels forced the frozen Earth into a massive, rapid melting period.

“Our results have important implications for understanding how Earth’s climate and ocean chemistry changed after the extreme conditions of the last global ice age,” said lead author Tian Gan, a former Virginia Tech postdoctoral researcher. Gan worked with geologist Shuhai Xiao on the study, which was released Nov. 5 in the Proceedings of the National Academy of Sciences journal.

Deep-frozen Earth

The last global ice age took place about 635 million to 650 million years ago, when scientists believe global temperatures dropped and the polar ice caps began to creep around the hemispheres. The growing ice reflected more sunlight away from the Earth, setting off a spiral of plunging temperatures.

“A quarter of the ocean was frozen due to extremely low carbon-dioxide levels,” said Xiao, who recently was inducted into the National Academy of Sciences.

When the surface ocean sealed, a chain of reactions stuttered to a stop:

• The water cycle locked up. No evaporation and very little rain or snow.
• Without water, there was a massive slowdown in a carbon-dioxide consuming process called chemical weathering, where rocks erode and disintegrate.
• Without weathering and erosion, carbon dioxide began to amass in the atmosphere and trap heat.

“It was just a matter of time until the carbon-dioxide levels were high enough to break the pattern of ice,” Xiao said. “When it ended, it probably ended catastrophically.”

Plume world

Suddenly, heat started to build. The ice caps began to recede, and Earth’s climate backpedaled furiously toward the drippy and soupy. Over a mere 10 million years, average global temperatures swung from minus 50 to 120 degrees Fahrenheit (minus 45 to 48 degrees Celsius).

But the ice didn’t melt and remix with seawater at the same time. The research findings paint a very different world than what we can imagine: vast rivers of glacial water rushing like a reverse tsunami from the land into the sea, then pooling on top of extra salty, extra dense ocean water.

The researchers tested this version of the prehistoric world by looking at a set of carbonate rocks that formed as the global ice age was ending.

They analyzed a certain geochemical signature, the relative abundance of lithium isotopes, recorded within the carbonate rocks. According to plumeworld ocean theory, the geochemical signatures of freshwater would be stronger in rocks formed under nearshore meltwater than in the rocks formed offshore, beneath the deep, salty sea — and that’s exactly what the researchers observed.

The findings bring the limit of environmental change into better focus, said Xiao, but they also give researchers additional insight into the frontiers of biology and the resiliency of life under extreme conditions — hot, cold, and slushy.

Study collaborators include:

• Ben Gill, Virginia Tech associate professor of sedimentary geochemistry
• Morrison Nolan, former graduate student, now at Denison University
• Collaborators from the Chinese Academy of Sciences, University of Maryland at College Park, University of Munich in Germany, University of North Carolina at Chapel Hill, and University of Nevada at Las Vegas

In a pair of recent papers, scientists in the lab of molecular biologist John Petrini, PhD, showed that innate immune signaling plays a key role in maintaining genome stability during DNA replication. Furthermore, the researchers showed that chronic activation of these immune pathways can contribute to tumor development in a mouse model of breast cancer.

Not only do the findings add vital insights to our understanding of fundamental human biology, says Dr. Petrini, they may also shed new light on tumor initiation and present potential opportunities for new therapies.

“Living organisms have evolved complex pathways to sense, signal, and repair damaged DNA,” he says. “Here we’re learning new things about the role of the innate immune system in responding to that damage — both in the context of cancer and also in human health more generally.”

How Chronic Activation of the Innate Immune System Can Lead to Cancer

The newest paper, led by first author Hexiao Wang, PhD, a postdoctoral fellow in the Petrini Lab, and published in Genes & Development, reveals a connection between innate immune signaling and tumor development in breast tissue. And, Dr. Petrini says, the data suggest that when instability arises in the genome, chronic activation of the innate immune system can greatly increase the chances of developing cancer.

The study focused on a protein complex called the Mre11 complex, which plays a pivotal role in maintaining the stability of the genome by sensing and repairing double-strand breaks in DNA.

To study how problems with the Mre11 complex can lead to cancer, the team manipulated copies of the protein in mammary tissue organoids (miniature lab-grown model organs) and then implanted them into laboratory animals.

When oncogenes (genes known to drive cancer) were activated in these mice, tumors arose about 40% of the time, compared with about 5% in their normal counterparts. And the tumors in the mice with mutant Mre11 organoids were highly aggressive.

The research further showed that the mutant Mre11 led to higher activation of interferon-stimulated genes (ISGs). Interferons are signaling molecules that are released by cells in response to viral infections, immune responses, and other cellular stressors.

They also found that the normally tightly controlled packaging of DNA was improperly accessible in these organoids — making it more likely that genes will get expressed, when they otherwise would be inaccessible for transcription.

“We actually saw differences in the expression of more than 5,600 genes between the two different groups of mice,” Dr. Petrini says.

And strikingly, these profound effects depended on an immune sensor called IFI205.

When the organoids were further manipulated so they would lack IFI205, the packaging of DNA returned almost to normal, and the mice developed cancer at essentially the same rate as normal mice.

“So what we learned is that problems with Mre11 — which can be inherited or develop during life like other mutations — can create an environment where the activation of an oncogene is much more likely to lead to cancer,” Dr. Petrini says. “And that the real lynch pin of this cascade is this innate immune sensor, IFI205, which detects that there’s a problem and starts sending out alarm signals. In other words, when problems with Mre11 occur, chronic activation of this innate immune signaling can significantly contribute to the development of cancer.”

New Understandings Could Pave the Way for Future Treatments

The work builds on a previous study, led by Christopher Wardlaw, PhD, a former senior scientist in the Petrini Lab, that appeared in Nature Communications.

That study focused on the role of the Mre11 complex in maintaining genomic integrity. It found that when the Mre11 complex is inactive or deficient, it results in the accumulation of DNA in the cytoplasm of cells and in the activation of innate immune signaling. This research primarily looked at the involvement of ISG15, a protein made by an interferon-stimulating gene, in protecting against replication stress and promoting genomic stability.

“Together, these studies shed new light on how the Mre11 complex works to protect the genome when cells replicate, and how, when it’s not working properly, it can trigger the innate immune system in ways that can promote cancer,” Dr. Petrini says.

By shedding light on the interrelationships between these complex systems and processes, the researchers hope to identify new strategies to prevent or treat cancer, he adds, such as finding ways to short-circuit the increased DNA accessibility when Mre11 isn’t working properly.

It is well-known that education has many positive effects. People who spend more time in school are generally healthier, smarter, and have better jobs and higher incomes than those with less education. However, whether prolonged education actually causes changes in brain structure over the long term and protects against brain aging, was still unknown.

It is challenging to study this, because alongside education, many other factors influence brain structure, such as the conditions under which someone grows up, DNA traits, and environmental pollution. Nonetheless, researchers Rogier Kievit (PI of the Lifespan Cognitive Dynamics lab) and Nicholas Judd from Radboudumc and the Donders Institute found a unique opportunity to very precisely examine the effects of an extra year of education.

Aging

In 1972, a change in the law in the United Kingdom raised the number of mandatory school years from fifteen to sixteen, while all other circumstances remained constant. This created an interesting ‘natural experiment’, an event not under the control of researchers which divides people into an exposed and unexposed group. Data from approximately 30,000 people who attended school around that time, including MRI scans taken much later (46 years after), is available. This dataset is the world’s largest collection of brain imaging data.

The researchers examined the MRI scans for the structure of various brain regions, but they found no differences between those who attended school longer and those who did not. ‘This surprised us’, says Judd. ‘We know that education is beneficial, and we had expected education to provide protection against brain aging. Aging shows up in all of our MRI measures, for instance we see a decline in total volume, surface area, cortical thickness, and worse water diffusion in the brain. However, the extra year of education appears to have no effect here.’

Brain structure

It’s possible that the brain looked different immediately after the extra year of education, but that wasn’t measured. ‘Maybe education temporarily increases brain size, but it returns to normal later. After all, it has to fit in your head’, explains Kievit. ‘It could be like sports: if you train hard for a year at sixteen, you’ll see a positive effect on your muscles, but fifty years later, that effect is gone.’ It’s also possible that extra education only produces microscopic changes in the brain, which are not visible with MRI.

Both in this study and in other, smaller studies, links have been found between more education and brain benefits. For example, people who receive more education have stronger cognitive abilities, better health, and a higher likelihood of employment. However, this is not visible in brain structure via MRI. Kievit notes: ‘Our study shows that one should be cautious about assigning causation when only a correlation is observed. Although we also see correlations between education and the brain, we see no evidence of this in brain structure.’