Despite last sharing a common ancestor over a billion years ago, animals and fungi are similar in many ways. Both belong to a broader group called ‘eukaryotes’ — organisms whose cells store their genetic material inside a closed compartment called the ‘nucleus’. The two differ, however, in how they carry out many physiological processes, including the most common type of cell division — mitosis.

Most animal cells undergo ‘open’ mitosis, in which the nuclear envelope — the two-layered membrane separating the nucleus from the rest of the cell — breaks down when cell division begins. However, most fungi use a different form of cell division — called ‘closed’ mitosis — in which the nuclear envelope remains intact throughout the division process. However, very little is known about why or how these two distinct modes of cell division evolved and what factors determine which mode would be predominantly followed by a particular species.

This question captured the attention of scientists in the Dey Group at EMBL Heidelberg, who investigate the evolutionary origins of the nucleus and cell division. “By studying diversity across organisms and reconstructing how things evolved, we can begin to ask if there are universal rules that underlie how such fundamental biological processes work,” said Gautam Dey, Group Leader at EMBL Heidelberg.

In 2020, during the COVID-19 lockdown, an unexpected path to answering this question grew out of discussions between Dey’s group and Omaya Dudin’s team at the Swiss Federal Institute of Technology (EPFL), Lausanne. Dudin is an expert in an unusual group of marine protists — Ichthyosporea. Ichthyosporea are closely related to both fungi and animals, with different species lying closer to one or the other group on the evolutionary family tree.

The Dey and Dudin groups, in collaboration with Yannick Schwab’s group at EMBL Heidelberg, decided to probe the origins of open and closed mitosis using Ichthyosporea as a model. Interestingly, the researchers found that certain species of Ichthyosporea undergo closed mitosis while others undergo open mitosis. Therefore, by comparing and contrasting their biology, they could obtain insights into how organisms adapt to and use these two cell division modes.

Hiral Shah, an EIPOD fellow working across the three groups, led the study. “Having recognised very early that Ichthyosporea, with their many nuclei and key evolutionary position between animal and fungi, were well-suited for addressing this question, it was clear that this would require bringing together the cell biological and technical expertise of the Dey, Dudin, and Schwab groups, and this is exactly what the EIPOD fellowship allowed me to do,” said Shah.

Upon closely probing the mechanisms of cell division in two species of Ichthyosporeans, the researchers found that one species, S. arctica, favours closed mitosis, similar to fungi. S. arctica also has a life cycle with a multinucleate stage, where many nuclei exist within the same cell — another feature shared with many fungal species as well as the embryonic stages of certain animals, such as fruit flies. Another species, C. perkinsii, turned out to be much more animal-like, relying on open mitosis. Its life cycle involves primarily mononucleate stages, where each cell has a single nucleus.

“Our findings led to the key inference that the way animal cells do mitosis evolved hundreds of millions of years before animals did. The work therefore has direct implications for our general understanding of how eukaryotic cell division mechanisms evolve and diversify in the context of diverse life cycles, and provides a key piece of the animal origins puzzle,” said Dey.

The study combined expertise in comparative phylogenetics, electron microscopy (from the Schwab Group and the electron microscopy core facility (EMCF) at EMBL Heidelberg), and ultrastructure expansion microscopy, a technique that involves embedding biological samples in a transparent gel and physically expanding it. Additionally, Eelco Tromer, from the University of Groningen in the Netherlands, and Iva Tolic, from the Ru?er Boškovi? Institute in Zagreb, Croatia, provided expertise in comparative genomics and mitotic spindle geometry and biophysics, respectively.

“The first time we saw an expanded S. arctica nucleus, we knew this technique would change the way we study the cell biology of non-model organisms,” said Shah, who brought back the expansion microscopy technique to EMBL Heidelberg after a stint at the Dudin lab. Dey agrees: “A key breakthrough in this study came with our application of ultrastructure expansion microscopy (U-ExM) to the analysis of the ichthyosporean cytoskeleton. Without U-ExM, immunofluorescence and most dye labelling protocols do not work in this understudied group of marine holozoans.”

This study also demonstrates the importance of going beyond traditional model organism research when trying to answer broad biological questions, and the potential insights further research on Ichthyosporean systems might reveal. “Ichthyosporean development displays remarkable diversity,” said Dudin. “On one hand, several species exhibit developmental patterns similar to those of early insect embryos, featuring multinucleated stages and synchronised cellularisation. On the other hand, C. perkinsii undergoes cleavage division, symmetry breaking, and forms multicellular colonies with distinct cell types, similar to the ‘canonical view’ of early animal embryos. This diversity not only helps in understanding the path to animals but also offers a fascinating opportunity for comparative embryology outside of animals, which is, in itself, very exciting.”

The project’s inherent interdisciplinarity served not only as a good testbed for this type of collaborative research but also for the unique postdoctoral training afforded at EMBL. “Hiral’s project nicely illustrates the virtue of the EIPOD programme: a truly interdisciplinary project, bundling innovative biology with advanced methods, all contributing to a truly spectacular personal development,” said Schwab. “We (as mentors) witnessed the birth of a strong scientist, and this is really rewarding!”

The Dey, Dudin, and Schwab groups are currently also collaborating on the PlanExM project, part of the TREC expedition — an EMBL-led initiative to explore and sample the biodiversity along European coasts. PlanExM aims to apply expansion microscopy to study the ultrastructural diversity of marine protists directly in environmental samples. “The project grew out of the realisation that U-ExM is going to be a game-changer for protistology and marine microbiology,” said Dey. With this project, as well as others currently underway, the research team hopes to shed further light on the diversity of life on Earth and the evolution of the fundamental biological processes.

A new study conducted by Western University biology professor Liana Zanette, in collaboration with Calum Cunningham and Chris Johnson from the University of Tasmania, demonstrates kangaroos, wallabies and other Australian marsupials fear humans far more than any other predator. Findings of the study, were published May 21 in the journal Proceedings of the Royal Society B.

These results greatly strengthen findings from similar studies by Zanette and her collaborators, and others, conducted in North America, Europe, Africa and Asia, which show wildlife worldwide fear the human ‘super predator’ far more than lions, leopards, cougars, bears, wolves or dogs.

For this new study, Zanette and her colleagues worked in the eucalypt forest in Tasmania and experimentally demonstrated that kangaroos, wallabies and other marsupials were 2.4 times more likely to flee in response to hearing human voices compared to hearing dogs, Tasmanian devils or wolves. Every species in the marsupial community, moreover, demonstrated the same pattern, being roughly twice as likely to flee from humans as the next most frightening predator, which in each case was dogs, and all were most vigilant to humans.

“These results greatly expand the growing experimental evidence that wildlife worldwide perceive humans as the planet’s most frightening predator,” said Zanette, a renowned wildlife ecologist. “The very substantial fear of humans demonstrated here, and in comparable recent experiments, can be expected to have dramatic ecological consequences, because other new research has established that fear itself can reduce wildlife numbers, and fear of humans can cause cascading impacts on multiple species throughout entire landscapes.”

To conduct their experiment, the team deployed hidden automated camera-speaker systems that, when triggered by an animal passing within a short distance (approximately 10 meters, or 30 feet), filmed the response to humans speaking calmly, dogs barking, Tasmanian devils snarling, wolves howling or non-threatening controls, such as sheep bleating.

“Global surveys show humans kill prey at much higher rates than other predators, making humans a ‘super predator,’ and the profound fear of humans being revealed in wildlife everywhere is wholly consistent with humanity’s unique lethality,” said Zanette. “Humans are ‘the invisible killer’ insofar as we do not often think of ourselves as a major predator, let alone the most dangerous, but wildlife clearly think differently — and recognize us for what we are.”

In aggressive cases of leukemia, the only chance for a cure is to replace the diseased blood system with a healthy one. Although the transplantation of donor blood stem cells is a well-established form of treatment, it is an onerous process for patients. First, chemotherapy is used to remove the body’s own blood stem cells as well as most of the blood cells. Only then do the attending physicians intravenously administer the stem cells from a suitable donor to the patient. This procedure is associated with side effects and potential complications.

The team led by Professor Lukas Jeker from the Department of Biomedicine at the University of Basel has taken a different approach. Writing in the journal Nature, the team describes how all blood cells can be removed from a leukemia sufferer in a targeted manner while a new blood system is built up at the same time. The results represent the successful completion of a project funded by the European Research Council with a Consolidator Grant of EUR 2.4 million.

Mixing console for blood systems

The system established by the researchers in Jeker’s team can be imagined as a mixing console, where a DJ gradually fades down the level of the first song while raising the volume of the second until the first track dies away completely and only the second is audible.

The fading-down process works as follows: Specific antibodies coupled to a cytotoxic drug recognize all blood cells in the patient’s body based on a surface structure. This marker is common to all the different types of blood cell (both healthy and diseased) but does not appear on other cells of the body. Bit by bit, the antibody-drug conjugate therefore recognizes and destroys all cells of the diseased blood system.

While this is taking place, the second song also starts — that is, the patient receives a transplant of new, healthy blood cells from a suitable donor. To prevent the antibody-drug conjugates from also attacking the new blood stem cells, or the blood cells they produce, the researchers use genetic engineering techniques to modify the donor stem cells in a targeted manner. Specifically, they introduce a small change in the surface molecule so that the antibodies don’t recognize the new blood cells. The researchers refer to this targeted modification of the donor stem cells as “shielding,” because it acts like a protective shield against the cancer treatment.

Elaborate search for suitable regulators

The two first authors of the study, Simon Garaudé and Dr. Romina Matter-Marone, worked with an interdisciplinary team of bioinformaticians, biochemists, genetic engineering specialists, and clinicians from academia and industry to select the best-suited target structure — and the best protective modification for the fading-down process — from the multitude of surface molecules on blood cells. The chosen molecule, known as CD45, proved extremely promising in trials on mice and human cells in the laboratory.

“We needed a surface molecule that appeared with approximately the same frequency on all blood cells if possible, including the leukemia cells, but that wasn’t present on other cells in the body,” explains Jeker. CD45 met this requirement and, at the same time, was also suitable for “shielding” — in other words, it could be modified on the donor blood stem cells in such a way that these cells were protected from the cancer treatment but the function of CD45 remained completely normal.

Applications beyond cancer

“The new approach could pave the way for new treatment options for patients whose state of health is incompatible with the chemotherapy needed for stem cell transplantation,” says joint first author Romina Matter-Marone. Although further tests and optimization are needed, the aim is for initial clinical trials to begin in just a few years’ time.

The “mixing console for blood systems” also opens up further possibilities, as joint first author Simon Garaudé explains: “We show how cells that are ‘invisible’ to a blood cell remover can be used to swap out the entire blood system.” This, he says, is an important step toward a programmable blood system that could also assume functions on demand — for example, to correct a serious genetic defect or to impart resistance to specific viruses such as HIV.

“Timely identification of infants at highest risk of RSV-related morbidity is key to prevention,” said lead author Brittney M. Snyder, PhD, assistant professor, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center. “Our personalized risk prediction tool may have applications in allocating expensive and/or limited immunoprophylaxis (immunization with nirsevimab or palivizumab) to achieve the greatest benefit and in promoting RSV prevention among families with high-risk infants.”

More than half of RSV LRTIs are among healthy, term infants who are generally considered low risk. These infants are, in fact, at risk for requiring intensive care unit -level care, and some may die from their illness. Early immunization with nirsevimab is recommended for all infants by the Centers for Disease Control & Prevention, yet in October 2023 nirsevimab was in short supply and the CDC recommended giving it only to high-risk infants who weren’t eligible for immunization with palivizumab.Both products, which prevent RSV LRTI in newborns and young children, are monoclonal antibodies (nirsevimab is long-acting and only requires one dose, while palivizumab is short-acting and requires monthly injections during RSV season).

In the population-based study by Dr. Snyder and colleagues including children insured by the Tennessee Medicaid Program, the researchers assessed infants who did not receive RSV immunoprophylaxis in the first year of life. They gathered demographic and clinical data from administrative health care encounters and linked birth certificates. “To predict whether these infants developed severe RSV LRTI requiring ICU admission during the first year of life, we developed a multivariable logistic regression model. The model includes demographic and clinical variables collected at or shortly after birth-19 variables in all, such as prenatal smoking, delivery method, maternal age and assisted breathing (ventilation) during birth hospitalization,” said lead biostatistician Tebeb Gebretsadik, MPH, Department of Biostatistics, Vanderbilt University Medical Center.

Among 429,365 infants in the study, 713 had severe RSV LRTI requiring ICU admission. The tool had good predictive accuracy and internal validation that indicated a good fit.

“Our objective was to develop a personalized tool for use in all newborns using readily available birth and postnatal data to predict risk of RSV LRTI requiring ICU admission, useful for prioritizing RSV prevention products with limited availability,” said Principal Investigator Tina V. Hartert, MD, MPH, professor of medicine and pediatrics at Vanderbilt University Medical Center. Even though the recent nirsevimab shortage has, fortunately, eased up, it is not known whether shortages will occur in the future. “This tool may be particularly helpful in prioritizing which infants should be immunized during times of limited availability of RSV prevention medicines. Using the tool to identify if their infant is at high risk for RSV infection requiring ICU care may also persuade vaccine-hesitant families to accept RSV immunoprophylaxis, by showing them their newborn is at high risk,” she added.

“To ensure compatibility with nirsevimab and maternal vaccination, our tool was developed for use in all infants,” concluded co-author Niek Achten, MD, postdoctoral fellow in pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands, who imagined the need for such a tool. “In addition to use in the United States during times of limited availability, our tool may prove useful in countries with budgetary constraints needing to prioritize administration to the highest risk infants.”

The authors note that next steps to ensure optimal usefulness include validation of the tool in external populations, further cost-effectiveness analyses and decision curve analyses.

For the first time, a team of researchers from the National Park Service, U.S. Geological Survey, the University of California, Davis, and other institutions have documented and sampled some of the impaired waters, pinpointing 75 locations across a Texas-sized area of northern Alaska’s Brooks Range.

These degraded rivers and streams could have significant implications for drinking water and fisheries in Arctic watersheds as the climate changes, the researchers said.

“The more we flew around, we started noticing more and more orange rivers and streams,” said lead author Jon O’Donnell, an ecologist for the NPS’ Arctic Inventory and Monitoring Network. “There are certain sites that look almost like a milky orange juice.

Those orange streams can be problematic both in terms of being toxic but might also prevent migration of fish to spawning areas.”

Visible from space

O’Donnell first noticed an issue when he visited a river in 2018 that appeared rusty despite having been clear the year prior. He began asking around and compiling locations while grabbing water samples when possible in the remote region, where helicopters are generally the only way to access the rivers and streams.

“The stained rivers are so big we can see them from space,” said Brett Poulin, an assistant professor of environmental toxicology at UC Davis who was a principal investigator in the research. “These have to be stained a lot to pick them up from space.”

Poulin, whose expertise is in water chemistry, thought the staining looked similar to what happens with acid mine drainage, except no mines are near any of the impaired rivers, including along the famed Salmon River and other federally protected waters.

One hypothesis is that the permafrost, which is essentially frozen ground, stores minerals and as the climate warmed, the metal ores that were once locked up were exposed to water and oxygen, resulting in the release of acid and metals.

“Chemistry tells us minerals are weathering,” Poulin said. “Understanding what’s in the water is a fingerprint as to what occurred.”

The impacted rivers are on federal lands managed by Bureau of Land Management, Fish and Wildlife Service and NPS, including Gates of the Arctic and Kobuk Valley national parks.

Poulin and Ph.D. candidate Taylor Evinger analyzed initial samples, then collected their own on a trip last August, while others took samples in June and July. This year, they will take three trips during the summer to collect additional samples.

Acidic water releasing metals

Some samples from the impaired waters have a pH of 2.3 compared to the average pH of 8 for these rivers. This means the sulfide minerals are weathering, resulting in highly acidic and corrosive conditions that release additional metals. Elevated or high levels of iron, zinc, nickel, copper and cadmium have been measured.

“We see a lot of different types of metals in these waters,” Evinger said. “One of the most dominant metals is iron. That’s what is causing the color change.”

While O’Donnell first noticed a change in 2018, satellite images have turned up stained waters dating back to 2008.

“The issue is slowly propagating from small headwaters into bigger rivers over time,” he said. “When emergent issues or threats come about, we need to be able to understand them.”

Understanding risk

The researchers are in the second year of a three-year grant aimed at understanding what is happening in the water, modeling what other areas may be at risk and assessing implications for drinking water and fishing stocks.

The problem is growing and affecting habitat, water quality and other ecological systems, turning healthy areas into degraded habitats with fewer fish and invertebrates. If rural communities rely on these rivers for drinking water, they could require treatment eventually, and the fishing stocks that feed local residents could be affected.

“There’s a lot of implications,” O’Donnell said. “As the climate continues to warm, we would expect permafrost to continue to thaw and so wherever there are these types of minerals, there’s potential for streams to be turning orange and becoming degraded in terms of water quality.”

More work is needed to better understand the problem and whether rivers and streams can rebound, perhaps after cold weather promotes permafrost recovery.

“I think there will be a lot more detailed work to follow up to address some of the uncertainties that we currently have,” O’Donnell said.

Scientists from Alaska Pacific University, Colorado State University, University of Alaska Anchorage and UC Riverside also contributed to the research.

The research was funded by U.S. Geological Survey-NPS Water Quality Partnership program, the U.S. Geological Survey Changing Arctic Ecosystem Initiative and the NPS Arctic Inventory and Monitoring Program.

The research, published today in Clinical Cancer Research by a team from King’s College London and funded by Breast Cancer Now, marks a new method in cancer treatment.

The discovery is particular to triple negative breast cancer, which makes up 15% of all diagnosed breast cancer. This type of breast cancer is typically aggressive, resistant to chemotherapy, has a lower survival rate and is more common in women under 40.

Usual treatment involves surgery, chemotherapy and radiotherapy, however this type of cancer can evade the drugs and return to spread again.

The scientists conducted data analysis using over 6000 breast cancer samples to investigate the properties of breast cancer cells that are associated with aggressive and chemotherapy-resistant cancers.

They studied the cancer’s biology, what is expressed in the tumour and the cell surface, and the cell’s insides to understand how the cancer cells escape from cancer drugs. They established the presence of the cancer cell surface marker EGFR along with oncogenic molecules cyclin-dependent kinases (CDK), which are responsible for cell division and proliferation.

They used this knowledge against the cancer cells to link cetuximab, a tumour-selective antibody that targets the EGFR protein expressed in this type of cancer, with a CDK-blocking drug to create a tailored drug for breast cancer. Because the antibody drug conjugate specifically targets the cancer cell, it may be possible to administer a lower inhibitor dose than usual which means it’s less toxic for the patient.

Lead author Professor Sophia Karagiannis, from King’s College London, said: “We were on the hunt for cancer’s vulnerabilities and now we’ve found out how we can guide our therapies to one of these. We combined these two drugs to create a tailored antibody drug conjugate for patients with this aggressive cancer. The antibody guides the toxic drug directly to the cancer cell which offers the possibility for a lower dose and less adverse side effects to be experienced.

“More work needs to be done before this therapy can reach the clinic, but we expect that this can offer new treatment options for cancers with unfavourable prognosis. Beyond this antibody drug conjugate, we hope that our concept will lead the way for new antibody drug conjugates of this type to be tailored to patient groups likely to benefit.”

Lead research scientist Dr Anthony Cheung from King’s College London said: ”Triple negative breast cancer represents a molecularly and clinically diverse disease. By exploiting EGFR overexpression and dysregulated cell cycle molecules in selected patient groups, the antibody drug conjugate, but not the antibody alone, could stop the cancer cell from dividing and engender cytotoxic functions specifically against the cancer cells.”

Dr Simon Vincent, director of services, support and influencing at Breast Cancer Now, which funded this research, said: “Each year, around 8,000 women in the UK are diagnosed with triple negative breast cancer, which is typically more aggressive than other breast cancers and more likely to return or spread following treatment.

“This exciting research has not only improved our understanding of the properties of aggressive breast cancer cells that are resistant to chemotherapy but has also brought us closer to developing a targeted therapy that destroys these cancer cells while minimising side effects for patients.

“While further research is needed before this treatment can be used in people, this is an exciting step forward in developing targeted therapies for triple negative breast cancer, and we look forward to seeing how these findings could lead to new and effective ways of tackling this devastating disease.”