Researchers Dig Deeper Into How Cells Transport Their Waste For Recycling (Biology)

Findings may have important implications for understanding age-related diseases

Scientists at Sanford Burnham Prebys have gained a deeper insight into the intricacies of autophagy, the process in which cells degrade and recycle cellular components. The findings, published in Current Biology, describe how the “trash bags” in a cell–called autophagosomes–are tagged to direct their movement to the cellular “recycling plants” where waste is processed. The research opens new paths to understanding the relationship between autophagy and age-related diseases such as cancer and neurological disorders.

“Our latest study identifies how a chemical modification (phosphate-related tag) of a key autophagosome component, the protein called LCB3, helps direct the transport of autophagosomes within the cell in the right direction,” says Malene Hansen, Ph.D., professor at Sanford Burnham Prebys and senior author of the study. “We previously reported that LCB3, which is found on the surface of autophagosomes, needs to be tagged for autophagy to function effectively. Now we have a better understanding of how tagging happens and how important it is for autophagosome movement.”

In addition to their own laboratory studies, the Hansen lab worked with colleagues in the lab of Sandra Encalada, Ph.D., at the Scripps Research Institute, San Diego, leaders in the field of transport of cellular components in neurons. Those investigations showed that blocking the chemical modification of the LC3B protein disrupted the efficient transport of autophagosomes toward the cellular recycling plants.

“Waste transport in a cell is like moving garbage trucks down a highway,” says Jose Luis Nieto-Torres, Ph.D., a postdoc in the Hansen laboratory and first author of the study. “Together with our collaborators, we studied the process in nerve cells because they are long and flat, which helps us observe the directional aspects of transport, a critical aspect for waste recycling via autophagy.

“We clearly saw that if phosphate tagging of LC3B was hampered, autophagosomes, or the trash bags filled with waste, failed to move in the direction of lysosomes–cell’s recycling plant. This is potentially very harmful to the health of a cell. It’s somewhat analogous to what would happen if a garbage truck didn’t pick up your trash–your waste could accumulate, become scattered in the neighborhood and create a health hazard.”

As a next step, the researchers want to figure out which waste products are selected for recycling and how a cell determines when to start moving the waste.

“My lab’s research efforts are focused on the relationship between aging and autophagy,” concludes Hansen. “Based on this discovery, we have a new, potential entry point to modulate the activity of recycling in a cell, which may prove relevant to understanding the diminished functions of autophagy that are known to occur in aging cells. Such insights could ultimately lead to new drug targets to combat age-related diseases as well as potential diagnostic markers to assess autophagy ‘health,’ an important goal for the future.”

Additional study authors include Sean-Luc Shanahan and Sviatlana Zaretski at Sanford Burnham Prebys; and Romain Chassefeyre, Tai Chaiamarit, Sara Landeras-Bueno, Adriaan Verhelle and Sandra E. Encalada at Scripps Research.

The study, “LC3B phosphorylation regulates FYCO1 binding and directional transport of autophagosomes”, Published in Current Biology, 2021DOI:

Research reported in this press release was supported by funding to Jose L. Nieto-Torres by a Fundacion Ramon Areces Postdoctoral Fellowship and a K99/R00 pathway to independence National Institutes of Health (NIH) grant (K99AG062774); Romain Chassefeyre was supported by the George E. Hewitt Foundation for Medical Research; and Tai Chaiamarit was supported by a Royal Thai Government Scholarship from the Development and Promotion of Science and Technology Talents Project. This work was also funded by grants to Sandra E. Encalada: an NIH R01 AG049483 grant; the Glenn Foundation for Medical Research Glenn Award for Research in Biological Mechanisms of Aging; a New Scholar in Aging Award from the Lawrence Ellison Foundation; the Baxter Family Foundation; and to Malene Hansen, an NIH R01 GM117466 grant.

Featured image: Malene Hansen, Ph.D., and Jose Luis Nieto-Torres, Ph.D. © Sanford Burnham Prebys

Provided by SBP Discovery

Following the Footsteps of Humankind out of Africa (Archaeology)

Researchers returning to Boker Tachtit in Israel’s Negev illuminate an important chapter in modern humans’ origin story

The Boker Tachtit archaeological excavation site, in Israel’s central Negev desert, holds clues to one of the most important events in human history: the spread of modern humans, Homo sapiens, from Africa into Eurasia, and the subsequent demise of Neanderthal populations in the region. Researchers from the Weizmann Institute of Science and the Max Planck Society, led by Prof. Elisabetta Boaretto, together with Dr. Omry Barzilai of the Israel Antiquities Authority, returned to Boker Tachtit nearly forty years after it was first excavated. Using advanced sampling and dating methods, they offer a new chronological framework – in a study published today in PNAS – for this important chapter in our anthropological evolution, which suggests that Homo sapiens and Neanderthals were far from strangers.

Wadi Zin basin in the Ein Avdat National Park. Star indicating the location of Boker Tachtit © Weizmann Institute of Science

According to the “recent African origin” theory, Homo sapiens originated in Africa as early as 270,000 years ago and at different times took either the northern route to Eurasia, passing through the Levant, or several possible southern routes to remote corners of Asia and even Oceania – reaching as far as Australia by land. Boker Tachtit, located in the Wadi Zin basin, in what today is the Ein Avdat National Park, is considered a key site for tracing this migration. It is a major site in the Levant for documenting an important period in humankind’s prehistory: the transition from Middle to Upper Paleolithic – from a predominantly Neanderthal prehistorical culture to the beginning of modern humans’ reign. This transition was marked by technological innovations such as blade production and the introduction of standardized tools made from bones and antlers.

Prof. Boaretto: “The Middle-to-Upper Paleolithic transition was a rather fast-evolving event that began at Boker Tachtit approximately 50-49,000 years ago and ended about 44,000 years ago”

American archaeologist Anthony Marks, who first excavated and published his analysis of Boker Tachtit in the early 1980s, defines the site as a transitional industry from the Middle to the Upper Paleolithic and, based on a single radiocarbon date, concluded that it dates to 47,000 years ago. The problem was, however, that additional dates obtained from the site, some reaching as late as 34,000 years ago, made the timing of the transition very problematic.

“If we are to follow this timeline, then the transitional period could have lasted more than 10,000 years, and yet artifacts excavated from northern sites in Israel, Lebanon and even Turkey suggest that the transition occurred much faster,” says Boaretto, who heads D-REAMS – The Dangoor Research Accelerator Mass Spectrometry – Laboratory at the Weizmann Institute, which specializes in advanced archaeological dating methods. “Marks managed to date only a few specimens from Boker Tachtit, owing to the limitations of radiocarbon dating then, and the range of his proposed dates is not consistent with evidence gathered from other – old and new – excavation sites in the region,” Boaretto says. “Radiocarbon dating, the method that he used in his study, has evolved tremendously since his time.”

Neanderthals and Homo sapiens in the Negev coexisted and most likely interacted with one another resulting in both genetic interbreeding and cultural exchange

To resolve these questions, Boaretto, Barzilai and their multidisciplinary team performed advanced dating methods on specimens obtained from Boker Tachtit during the new excavations that they performed in 2013–2015. These included the latest techniques, such as high-resolution radiocarbon dating of single charcoal pieces found at the site and optically stimulated luminescence dating of quartz sand grains, performed at the Weizmann Institute and at the Max Planck Institute, respectively. The researchers also integrated detailed studies of the sediments, using microarchaeological methods to understand how the site was formed physically, contributing necessary data for the construction of its chronological framework.

(l-r) View of the Boker Tachtit excavation site. Circled: a group of unearthed flint stone artifacts; Flint point representative of the Upper Paleolithic in Boker Tachtit. Photo: Clara Amit, Israel Antiquities Authority

“We are now able to conclude with greater confidence that the Middle-to-Upper Paleolithic transition was a rather fast-evolving event that began at Boker Tachtit approximately 50-49,000 years ago and ended about 44,000 years ago,” says Boaretto. This dating allows for a certain overlap between the material transition that occurred at Boker Tachtit and that of the Mediterranean woodland region (Lebanon, Turkey) between 49,000 and 46,000 years ago. Still, it shows that Boker Tachtit was the earliest site for this transition in the Levant, and that, based on the materials found, is a testimony to the last dispersal event of modern humans from Africa.

According to the new dating scheme, the early phase at Boker Tachtit also overlaps with the locally previous, Middle Paleolithic culture in the region – that of the Neanderthals. “This goes to show that Neanderthals and Homo sapiens in the Negev coexisted and most likely interacted with one another, resulting in not only genetic interbreeding, as is postulated by the ‘recent African origin’ theory, but also in cultural exchange,” Boaretto and Barzilai conclude.

Prof. Elisabetta Boaretto is the incumbent of the Dangoor Chair of Archaeological Sciences; the Head of the Dangoor Research Accelerator Mass Spectrometry Laboratory (D-REAMS); and the Head of the Helen and Martin Kimmel Center for Archaeological Science.

Prof. Boaretto’s research is supported by the Instituto Serrapilheira; and Dana and Yossie Hollander.

Featured image: Depiction of the different routes that Homo sapiens migrated by according to the “recent African origin” theory. Adapted from Wikimedia Commons

Provided by Weizmann Institute of Science

Energy Production in the Mitochondria Regulated by Microbes (Biology)

Energy production in the mitochondria was found to be regulated by microbes residing in the depths of the bowels

The last decade has witnessed a revolution in the study of the symbiotic relations between gut bacteria and their animal hosts, including humans, wherein these microbes were found to affect both health and disease. Yet, despite the immense progress that has been made, the mechanisms by which bowel-dwelling microbes engage with our bodily functions are not well understood. A recently published study conducted by scientists at the Weizmann Institute of Science has exposed a fundamental regulatory mechanism based on a tight relationship between gut bacteria and host energy production in a fruit fly model. These findings offer a unifying explanation for the diverse mechanistic impacts of gut bacteria and also account for the well-known trade-off between survival and reproduction.

Dr. Yulia Gnainsky. A semblance of cooperation between gut bacteria and their “primordial mothers” © Weizmann Institute of Science

Previous work by the group of Prof. Yoav Soen of the Biomolecular Sciences Department revealed a surprising connection between gut bacteria and oogenesis – the production or development of ova (egg cells) – in the ovaries. In the current study – led by Dr. Yulia Gnainsky in collaboration with Dr. Sergey Malitsky and Dr. Maxim Itkin from the Life Sciences Core Facilities Department – the researchers sought to understand exactly how gut bacteria wield their remote influence over the reproductive system. Recruiting the fruit fly to their cause, they found that this influence is mediated by bacterial-derived factors that regulate both the production of energy in the host body and the energy expenditure on various host functions. This includes regulation of the development and function of the reproductive system by circulating bacterial metabolites that are required for cellular respiration in the mitochondria.

Prof. Yoav Soen: “We uncovered a fundamental mechanism of bacterial regulation over mitochondrial activity throughout the host body”

The mitochondrion, popularly referred to as the cell’s “powerhouse,” is the eukaryotic organelle mediating the process of cellular respiration. Often found in hundreds or even thousands of copies in most of the body’s cells, mitochondria are our main source for the production of ATP – the primary energy currency of all organisms. ATP production in the mitochondria relies on key coenzymes, such as FAD. Coenzymes are commonly synthesized from vitamins that serve as precursor molecules. The precursor for the biosynthesis of FAD, for example, is vitamin B2 (riboflavin). However, much like humans and other animals, the fly cannot produce B-type vitamins on its own, so the provision of vitamins such as riboflavin has to be “outsourced” – to the diet or the gut microbiota (or both). B vitamins and other metabolic products of gut bacteria are absorbed in the intestine and subsequently distributed to numerous destinations throughout the body.

While the significance of bacterial vitamins is expected to increase when the host is malnourished, the researchers hypothesized that the bacterial supply of B vitamins can regulate the mitochondrial function in host cells under a range of standard nutritional conditions as well. To test their hypothesis, they removed all gut bacteria from female fruit flies – leaving them germ free – and noted a shortage of FAD, which led to reduced mitochondrial activity, lower ATP production and mild weight loss. Substantial attenuation of mitochondrial activity was observed in the ovaries, particularly in follicle cells of the developing egg chamber. To determine if the repressed oogenesis is caused by the attenuation of ovarian mitochondrial activity, the researchers inhibited the expression of certain mitochondrial genes in ovarian follicle cells, this time without eliminating the gut microbiota. They found that disrupting the mitochondrial function of these cells is enough to significantly impair oogenesis; in fact, this effect was similar to the one that was observed in germ-free flies. Moreover, recolonization of germ-free female flies with gut bacteria (or alternatively, supplementing their diets with riboflavin), restored the mitochondrial function in the follicle cells, elevated the ATP levels in the ovaries and the entire body and increased ova production. The causal relation between gut bacterial metabolism and host energy production was further supported by measurements of ATP levels and overall weight of male flies.

The bacterial-mitochondrial axis of regulation will most likely be found across different animal species 

“In our effort to elucidate the ‘remote’ influence of gut bacteria over the reproductive system, we uncovered a fundamental mechanism of bacterial regulation over mitochondrial activity throughout the host body,” Prof. Soen explains. “As previously observed time and again, the relative simplicity of the fruit fly model makes it particularly effective for discovering elementary processes that characterize all living beings, including humans. Since the basic mechanisms of energy production are highly evolutionarily conserved, we expect that this bacterial-mitochondrial axis of regulation will be found to apply to many other species as well.”

The findings of this study also offer a mechanistic explanation for the known trade-off between survival and reproduction. Various conditions of stress (including malnutrition) require reduced investment in the highly energy-consuming process of reproduction, so as to enable the body to cope with the stressor(s). The causal link between a shortage of type-B vitamins (and their derived coenzymes) and the predominant repression of mitochondrial activity in the ovary prioritizes the expenditure of energy on processes that ensure personal survival over reproduction. “Although we have only demonstrated this mechanistic reallocation of energy in germ-free flies, we expect it to apply in a broad range of scenarios,” says Dr. Gnainsky.

Taken together, these findings uncover an important bacterial-mitochondrial axis of influence, linking gut bacteria with systemic regulation of host energy and reproduction. The fact that the mitochondrion is a genetically distinct organelle that is thought to be derived from ancient bacteria forms an intriguing image of cooperation between gut bacteria and their “primordial mothers” – the mitochondria.

Science Numbers

The mitochondrion is a descendent of bacteria that merged through endosymbiosis with other unicellular microorganisms nearly 1.5 billion years ago.

Featured image: Ova in the early stages of their development in a segment of a fruit fly’s ovary. Green – inactive mitochondria; Yellow-red – active mitochondria © Weizmann Institute of Science

Provided by Weizmann Institute of Science

Carcinogen-exposed Cells Provide Clues in Fighting Treatment-resistant Cancers (Medicine)

Key Takeaways

  • This study explores for the first time how the mutation-independent effect of environmental carcinogens leads to the recruitment of CD8+ T cells, the dominant antitumor cell type.
  • Research raises the possibility of an injection of a chemokine known as CCL21 into a tumor to induce an antitumor response through CD8+ T cells.

“We showed how cells exposed to certain carcinogens become immunogenic, that is, become targets for the immune attack, and how that exposure might be exploited to treat such major forms of cancer as breast and other epithelial cancers.”

— Shadmehr (Shawn) Demehri, MD, PhD
Center for Cancer Immunology and Cutaneous Biology Research Center, Massachusetts General Hospital

Researchers from Massachusetts General Hospital (MGH) have discovered a biological mechanism that transforms cells exposed to carcinogens from environmental factors like smoking and ultraviolet light into immunogenic cells that can be harnessed therapeutically to fight treatment-resistant cancers. As reported in Science Advances, that mechanism involves spurring the release  of small proteins known as chemokines which, in turn, recruit antitumor immune cells (CD8+ T cells) to the tumor site to block metastasis, potentially enhancing the effectiveness of a new generation of immunotherapies.

“Immunotherapeutics have shown tremendous promise in recent years, but the fact is their response rate for many types of cancers is very low,” says senior author Shadmehr (Shawn) Demehri, MD, PhD, an investigator in the Center for Cancer Immunology and the Cutaneous Biology Research Center at MGH. “We showed how cells exposed to certain carcinogens become immunogenic, that is, become targets for the immune attack, and how that exposure might be exploited to treat such major forms of cancer as breast and other epithelial cancers.”

CD8+ T cells are known to effectively attack the cells exposed to environmental carcinogens. But in the past, science has focused mainly on the mutations caused by these exposures in a patient’s heritable DNA as the reason for the immune attack. In their laboratory work with mice, the MGH team demonstrated for the first time another consequence of carcinogen exposure that can have significant immunologic implications, namely, the nongenetic alteration of cells through such harmful environmental factors as smoking, ultraviolet light and pollution.

“This finding is particularly important because it could open the door to therapeutic interventions that aren’t practical with a DNA approach, since no clinician wants to introduce even more genetic mutations into cancer cells just to make them more immunogenic,” explains Demehri. “We learned if there was another immunogenic element associated with carcinogen exposure independent of or even complementary to the presence of the mutation, then you could deliver that factor into a ‘cold’ tumor to make it ‘hot,’ meaning it would become immunogenic and responsive to immunotherapies.”

That factor is a chemokine known as CCL21, which MGH researchers found to be expressed in breast cancer cells in mice that were exposed to DMBA, a carcinogen similar to that found in cigarette smoke. “Through its signaling, CCL21 recruits CD8+ T cells which infiltrate the tumor, as previous work has shown, and are associated with a significant reduction in relative risk of distant metastasis,” says lead author Kaiwen Li, MD, an investigator in MGH’s Center for Cancer Immunology, MGH’s Cutaneous Biology Research Center and the Department of Urology at Sun Yat-sen Memorial Hospital at China’s Sun Yat-sen University. “Not only does CCL21 induce an antitumor immune response to prevent metastasis, but it overcomes other immune cells known as Tregs (immunosuppressive regulatory T cells) present in tumors from inhibiting the work of the CD8+ T cells.”

As an example of how this unique mechanism could be used therapeutically, the MGH team reported that an injection of CCL21 into the tumor might be able to transform cold breast cancers into hot tumors responsive to current immunotherapies.

“We hope that researchers will use these findings to open a much wider field of investigation into cancer immunology,” emphasizes Demehri. “Specifically, studies are needed to identify the full array of cytokines and chemokines that are induced by environmental carcinogens in various types of cancers with the goal of harnessing the most potent mediators of antitumor immunity.”

Demehri is an associate professor in the Department of Dermatology at Harvard Medical School and director of the High Risk Skin Cancer Clinic at MGH. Li is an associate professor in the Department of Urology at Sun Yat-sen Memorial Hospital. Other co-authors include Tiancheng Li, MD, Zhaoyi Feng, MD, and Mei Huang, PhD, with the Center for Cancer Immunology and the Cutaneous Biology Research Center at MGH.

The research was supported by the Breast Cancer Research Foundation, the Burroughs Wellcome Fund, the Breast Cancer Alliance, the Sidney Kimmel Foundation, the Cancer Research Institute and the National Institutes of Health.

The study, “CD8+ T cell immunity blocks the metastasis of carcinogen-exposed breast cancer”, Published in Science Advances  18 Jun 2021: Vol. 7, no. 25, eabd8936 DOI: 10.1126/sciadv.abd8936

Featured image: New research explores how the mutation-independent effect of environmental carcinogens leads to the recruitment of CD8+ T cells, the dominant antitumor cell type. Here, T cells (red and green) attack carcinogen-exposed breast cancer cells (light blue). Credit: Mei Huang, PhD

Provided by Massachusetts General Hospital

Leptoquarks, the Higgs Boson And the Muon’s Magnetism (Physics)

A new study shows that a class of new unknown particles that could account for the muon’s magnetism, known as leptoquarks, also affects the Higgs boson’s transformation into muons

Zoom into an online particle physics conference, and the chances are you’ll hear the term muon anomaly. This is a longstanding tension with the Standard Model of particle physics, seen in the magnetism of a heavier cousin of the electron called a muon, that has recently been strengthened by measurements made at Fermilab in the US.

In a paper accepted for publication in Physical Review Letters, a trio of theorists including Andreas Crivellin of CERN shows that a class of new unknown particles that could account for the muon anomaly, known as leptoquarks, also affects the transformation, or “decay”, of the Higgs boson into muons.

Leptoquarks are hypothetical particles that connect quarks and leptons, the two types of particles that make up matter at the most fundamental level. They are a popular explanation for the muon anomaly and other anomalies seen in certain decays of particles called B mesons.

In their new study, Crivellin and his colleagues explored how two kinds of leptoquarks that could explain the muon anomaly would affect the rare decay of the Higgs boson into muons, of which the ATLAS and CMS experiments recently obtained the first indications.

They found that one of the two kinds of leptoquarks increases the rate at which this Higgs decay takes place, while the other one decreases it.

“The current measurements of the Higgs decay to muons are not sufficient to see this increase or decrease, and the muon anomaly has yet to be confirmed,” says Crivellin. “But if future measurements, at the LHC or future colliders, display such a change, and the muon anomaly is confirmed, it will be possible to pick out which of the two kinds of leptoquarks would be more likely to explain the muon anomaly.”

Featured image: Displays of candidate events for a Higgs boson decaying into two muons, as recorded by CMS (left) and ATLAS (right). (Image: CERN)

Provided by CERN