Reversing Cancer’s Gluttony (Medicine)

Researchers report that pancreatic cancer tumors use multiple mechanisms to avoid starvation, suggesting a new target for treating a very difficult and deadly disease

In new findings published online March 18, 2021 in the journal Cancer Cell, an international team of researchers, led by scientists at University of California San Diego School of Medicine and Moores Cancer Center, describe how pancreatic cancer cells use an alternative method to find necessary nutrients, defying current therapies, to help them grow and spread.

Pancreatic cancer accounts for roughly 3 percent of all cancers in the United States, but it is among the most aggressive and deadly, resulting in 7 percent of all cancer deaths annually. Pancreatic cancer is especially deadly once it metastasizes, with the number of people who are alive five years later declining from 37 percent to just 3 percent.

All cancer cells require a constant supply of nutrients. Some types of cancer achieve this by creating their own vascular networks to pull in nutrients from the host’s blood supply. But other cancers, notably pancreatic ductal adenocarcinoma, are surrounded by a thick layer of connective tissue and extracellular molecules (the so-called tumor stroma) that act not just as a sort of a dividing line between malignant cells and normal host tissues, but also as a hindrance to cancer cells obtaining sufficient resources, including blood supply.

As a result, pancreatic and other nutritionally stressed cancers employ a number of adaptive mechanisms to avoid death by starvation, a risk particularly high in rapidly growing tumors. One such mechanism is autophagy or self-eating. Autophagy allows nutritionally stressed cancers to digest intracellular proteins, especially denatured or damaged proteins, and use the liberated amino acid building blocks as an energy source to fuel their metabolism.

Past research indicating autophagy is elevated in pancreatic cancer gave rise to the idea that inhibiting self-eating might be used to starve tumors. Yet, multiple clinical trials using compounds that inhibit autophagic protein degradation combined with traditional chemotherapy, did not produce any added therapeutic benefit compared to chemotherapy alone, said Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine.

In the new study, Hua Su, PhD, a postdoctoral fellow in Karin’s lab and first author of the study, and collaborators investigated why pancreatic cancers survive autophagy and, in fact, appear to thrive. They found that inhibition of autophagy resulted in rapid upregulation or increased activity of a different nutrient procurement pathway called macropinocytosis, derived from the Greek for “large drinking or gulping.”

Macropinocytosis enables autophagy-compromised and nutritionally stressed cancer cells to take up exogenous proteins (found outside the cell), digest them and use their amino acids for energy generation. “This explains why autophagy inhibitors fail to starve pancreatic cancer and cannot induce its regression,” said Su. “Once autophagy is inhibited, cancer cells simply resort to a different mechanism to feed themselves.”

In experiments using mouse cancer models and human pancreatic cancers grown in mice, Su and colleagues found that a combination of autophagy and macropinocytosis inhibitors resulted in rapid and nearly complete tumor regression.

“These results provide another example of the plastic nature of pancreatic cancer metabolism,” said senior author Karin. “It also shows that combined inhibition of the two major nutrient procurement pathways can result in a successful blockade of energy supply resulting in tumor starvation and consequent shrinkage.”

Study co-author Andrew Lowy, MD, chief of the Division of Surgical Oncology at Moores Cancer Center at UC San Diego Health and a professor of surgery at UC San Diego School of Medicine, said the new data demonstrate the promise of targeting tumor metabolism as a treatment strategy and that success will likely require combining multiple agents for multiple targets.

“I believe that these findings are exciting and support the idea that we will make significant impact against this very difficult disease in the near-future,” Lowy said.

Co-authors include: Fei Yang, Rao Fu, Xiaohong Pu and Beicheng Sun, Nanjing University Medical School; Xin Li and Yinling Hu, National Cancer Institute; Randall French, Evangeline Mose, Brittney Trinh, Junlai Liu, Laura Antonucci, Yuan Liu, Avi Kumar and Christian M. Metallo, UC San Diego; Jelena Todoric, UC San Diego and Medical University of Vienna; Maria Diaz-Meco and Jorge Moscat, Weill Cornell Medicine.

Funding for this research came, in part, from Padres Pedal the Cause/C3 (PPTC2018), the UC Pancreatic Cancer Consortium, the National Institutes of Health (R01CA211794, R37AI043477, P01DK098108, R01CA155630, R03CA223717, R01CA234245, R01CA218254, R01DK108743), the Youth Program of the National Natural Science Foundation of China (81802757, 82002931) and the National Key Research and Development Program of China (2016YFC0905900).

Featured image: Pancreatic cancer cells (blue) growing as a sphere encased in membranes (red). Photo credit: National Cancer Institute


Reference: Hua Su, Rao Fu, Fei Yang et al., “Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis”, Cancer Cell, 2021. DOI: https://doi.org/10.1016/j.ccell.2021.02.016


Provided by UC San Diego

Could Leak in Blood-brain Barrier Cause Poor Memory? (Neuroscience)

Researchers review 150 articles to determine what happens as the blood-brain barrier ages.

Have you forgotten where you laid your keys?  Ever wondered where you had parked your car? Or having trouble remembering the name of the new neighbor? Unfortunately, these things seem to get worse as one gets older. A big question for researchers is where does benign forgetfulness end and true disease begin?

One of the keys to having a healthy brain at any age is having a healthy blood-brain barrier, a complex interface of blood vessels that run through the brain. Researchers reviewed more than 150 articles to look at what happens to the blood-brain barrier as we age. Their findings were published March 15 in Nature Aging.

Whether the changes to the blood-brain barrier alters brain function, however, is still up for debate. But research shows the blood-brain barrier leaks as we age, and we lose cells called pericytes. 

“It turns out very little is known how the blood-brain barrier ages,” said lead author William Banks, a gerontology researcher at the University of Washington School of Medicine and at the Veterans Affairs Puget Sound Health Care System. “It’s often hard to tell normal aging from early disease.”

The blood-brain barrier, discovered in the late 1800s, prevents the unregulated leakage of substances from blood into the brain. The brain is an especially sensitive organ and cannot tolerate direct exposure to many of the substances in the blood. Increasingly, scientists have realized that the blood-brain barrier also allows many substances into the brain in a regulated way to serve the nutritional needs of the brain. It also transports informational molecules from the blood to the brain and pumps toxins out of the brain. A malfunctioning blood-brain barrier can contribute to diseases such as multiple sclerosis, diabetes, and Alzheimer’s. 

Before scientists can understand how such malfunctioning can contribute to the diseases of aging, they need to understand how a healthy blood-brain barrier normally ages. 

Research shows that healthy aging individuals have a very small leak in their blood-brain barrier. This leakage is associated with some measures of the benign forgetfulness of aging, considered by most scientists to be normal. But could this leak and the difficulties in recall be the early stages of Alzheimer’s disease?

When a person carries the ApoE4 allele, the strongest genetic risk of Alzheimer’s risk, researchers said there is an acceleration of most of the blood-brain barrier age-related changes.

People with ApoE4 have a hard time getting rid of amyloid beta peptide in their brains, which causes an accumulation of plaque. With healthy aging, the pumps in the blood-brain barrier work less efficiently in getting rid of the amyloid beta peptide. The pumps work even less well in people with Alzheimer’s disease.

Another key finding in the review is that as we age, two cells begin to change in the blood-brain barrier: pericytes and astrocytes.

Recent work suggests that the leak in the blood-brain barrier that occurs with Alzheimer’s may be due to an age-related loss of pericytes. Astrocytes, by contrast, seem to be overactive. Recent work suggests that preserving pericyte function by giving the factors that they secrete or even transplanting them could lead to a healthier blood-brain barrier.

Some research suggests that pericyte health can be preserved by some of the same interventions that extend lifespan, such as regular exercise, caloric restriction, and rapamycin.

Other findings raise the question of whether the brain’s source of nutrition and its grip on control of the immune and endocrine systems could deteriorate with aging. Another finding raises the possibility that the rate at which many drugs are taken up by the brain may explain why older folks sometimes have different sensitivities to drugs than their children or grandchildren.

The research was supported by the Department of Veterans Affairs and National Institutes of Aging R01AG059088. Other researchers include May Reed, Aric Logsdon, Elizabeth Rhea, Michelle Erickson, all gerontology researchers with the UW School of Medicine and with the Geriatrics Research Education and Clinical Center at the Veterans Affairs Puget Sound Health Care System.

Featured image: Research shows that leakage in the blood-brain barrier is associated with forgetfulness in aging. © Gettyimages


Reference: Banks, W.A., Reed, M.J., Logsdon, A.F. et al. Healthy aging and the blood–brain barrier. Nat Aging 1, 243–254 (2021). https://doi.org/10.1038/s43587-021-00043-5


Provided by UW Medicine

Light It Up: uOttawa Researchers Demonstrate Practical Metal Nanostructures (Engineering)

Researchers at the University of Ottawa have debunked the decade-old myth of metals being useless in photonics – the science and technology of light – with their findings, recently published in Nature Communications, expected to lead to many applications in the field of nanophotonics.

“We broke the record for the resonance quality factor (Q-factor) of a periodic array of metal nanoparticles by one order of magnitude compared to previous reports,” said senior author Dr. Ksenia Dolgaleva, Canada Research Chair in Integrated Photonics (Tier 2) and Associate Professor in the School of Electrical Engineering and Computer Science (EECS) at the University of Ottawa.

“It is a well-known fact that metals are very lossy when they interact with light, which means they cause the dissipation of electrical energy. The high losses compromise their use in optics and photonics. We demonstrated ultra-high-Q resonances in a metasurface (an artificially structured surface) comprised of an array of metal nanoparticles embedded inside a flat glass substrate. These resonances can be used for efficient light manipulating and enhanced light-matter interaction, showing metals are useful in photonics.”

“In previous works, researchers attempted to mitigate the adverse effect of losses to access favorable properties of metal nanoparticle arrays,” observed the co-lead author of the study Md Saad Bin-Alam, a uOttawa doctoral student in EECS.

“However, their attempts did not provide a significant improvement in the quality factors of the resonances of the arrays. We implemented a combination of techniques rather than a single approach and obtained an order-of-magnitude improvement demonstrating a metal nanoparticle array (metasurface) with a record-high quality factor.”

According to the researchers, structured surfaces – also called metasurfaces – have very promising prospects in a variety of nanophotonic applications that can never be explored using traditional natural bulk materials. Sensors, nanolasers, light beam shaping and steering are just a few examples of the many applications.

“Metasurfaces made of noble metal nanoparticles – gold or silver for instance – possess some unique benefits over non-metallic nanoparticles. They can confine and control light in a nanoscale volume that is less than one quarter of the wavelength of light (less than 100 nm, while the width of a hair is over 10 000 nm),” explained Md Saad Bin-Alam.

“Interestingly, unlike in non-metallic nanoparticles, the light is not confined or trapped inside the metal nanoparticles but is concentrated close to their surface. This phenomenon is scientifically called ‘localized surface plasmon resonances (LSPRs)’. This feature gives a great superiority to metal nanoparticles compared to their dielectric counterparts, because one could exploit such surface resonances to detect bio-organisms or molecules in medicine or chemistry. Also, such surface resonances could be used as the feedback mechanism necessary for laser gain. In such a way, one can realize a nanoscale tiny laser that can be adopted in many future nanophotonic applications, like light detection and ranging (LiDAR) for the far-field object detection.”

According to the researchers, the efficiency of these applications depends on the resonant Q-factors.

“Unfortunately, due to the high ‘absorptive’ and ‘radiative’ loss in metal nanoparticles, the LSPRs Q-factors are very low,” said co-lead author Dr. Orad Reshef, a postdoctoral fellow in the Department of Physics at the University of Ottawa.

“More than a decade ago, researchers found a way to mitigate the dissipative loss by carefully arranging the nanoparticles in a lattice. From such ‘surface lattice’ manipulation, a new ‘surface lattice resonance (SLR)’ emerges with suppressed losses. Until our work, the maximum Q-factors reported in SLRs was around a few hundred. Although such early reported SLRs were better than the low-Q LSPRs, they were still not very impressive for efficient applications. It led to the myth that metals are not useful for practical applications.”

A myth that the group was able to deconstruct during its work at the University of Ottawa’s Advanced Research Complex between 2017 and 2020.

“At first, we performed numerical modelling of a gold nanoparticle metasurface and were surprised to obtain quality factors of several thousand,” said Md Saad Bin-Alam, who primarily designed the metasurface structure.

“This value has never been reported experimentally, and we decided to analyze why and to attempt an experimental demonstration of such a high Q. We observed a very high-Q SLR of value nearly 2400, that is at least 10 times larger than the largest SLRs Q reported earlier.”

A discovery that made them realize that there’s still a lot to learn about metals.

“Our research proved that we are still far from knowing all the hidden mysteries of metal (plasmonic) nanostructures,” concluded Dr. Orad Reshef, who fabricated the metasurface sample. “Our work has debunked a decade-long myth that such structures are not suitable for real-life optical applications due to the high losses. We demonstrated that, by properly engineering the nanostructure and carefully conducting an experiment, one can improve the result significantly.”

From left to right: Dr. Orad Reshef, Md Saad Bin-Alam and Yaryna Mamchur. © University of Ottawa

The paper “Ultra-high-Q resonances in plasmonic metasurfaces” is published in Nature Communications. Md Saad Bin-Alam and Dr. Orad Reshef primarily conducted the research. They were supported by Yaryna Mamchur and Dr. Mikko Huttunen in the experiment and the numerical modelling, respectively. Professors Ksenia Dolgaleva and Robert W. Boyd jointly supervised the research in collaboration with Professor Jean-Michel Ménard and Iridian Spectral Inc. The other co-authors, Dr. Zahirul Alam and Dr. Jeremy Upham, took part in preparing the manuscript. Dr. Alam also helped with the experimental setup.

Featured image: An artist’s view of a metasurface consisting of a rectangular array of rectangular gold nanostructures generating plasmonic surface lattice resonances. Illustration: Yaryna Mamchur, co-author and Mitacs Summer Student from the National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute,” who worked in Professor Ksenia Dolgaleva’s lab in the summer of 2019 at uOttawa. © University of Ottawa


Provided by University of Ottawa

Identifying Rare Genetic Variants That Increase Risk For Lung Cancer (Medicine)

Lung cancer is the leading cause of cancer death in the U.S. for both men and women. While risk for this disease can be influenced by environmental and lifestyle factors like smoking, studies estimate that 18% of lung cancer cases are due to inherited genetic variants. New research led by Baylor College of Medicine investigates how genetic variants contribute to increased risk of lung cancer.

The researchers performed whole exome sequencing on germline (inherited) DNA from eight large-scale datasets, including 1,045 patients with a family history of lung cancer or early-onset cancer. Those groups are more likely to harbor genetic risk variants. The analysis also included 885 control cases.

Dr. Chris Amos © BCM

“We were looking for variants that have a relatively high impact on risk but occur at relatively low frequency,” said Dr. Chris Amos, corresponding author of the study, professor of medicine – epidemiology and population sciences and director of the Institute for Clinical and Translational Research (ICTR) at Baylor. “If a variant occurs at low frequency, you have to look at many different large data sources to validate the variant. These results can be replicated in many different European populations.”

The researchers identified 25 new rare pathogenic variants associated with lung cancer susceptibility and validated five of those variants.

Of those five, two variants involved genes with known connections to lung cancer risk, ATM and MPZL2. Three variants involved novel lung cancer susceptibility genes, POMCSTAU2 and MLNR. According to co-first author of the study, Dr. Yanhong Liu, exome sequencing allowed the researchers to identify more variants that impact proteins and cell function.

Dr. Yanhong Liu © BCM

Investigating the contribution of insertions or deletions

“Mutations of DNA where sections are either inserted or deleted have been understudied compared to single nucleotide variants, but they are also very important because they can result in truncated proteins,” said Liu, assistant professor of medicine – epidemiology and population sciences and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Of the 25 candidate variants we identified, two-thirds of them are insertions or deletions.”

In order to further understand the effect of these candidate variants on cellular functions, the Baylor researchers applied endogenous DNA damage assays, which test for replications of certain types of mutations in DNA.

The researchers hypothesized that lung cancer risk genes drive an increased level of endogenous DNA damage in cells, leading to genomic instability and ultimately causing cancer.”

Dr. Jun Xia © BCM

“Many studies have looked at lung cancer risk genes, but the function of those genes has not been well understood. In our study, we found that dysregulation or mutations in these candidate genes showed increased DNA damage, suggesting that their potential cancer-causing role might be due to genome instability at the DNA level,” said Dr. Jun Xia, co-first author of the study and postdoctoral associate in the Department of Molecular and Human Genetics and ICTR at Baylor.

The analysis showed that POMCMLNR and ATM variants led to increased levels of DNA damage. ATM is known to be a critical first responder to DNA damage, and several ATM variants are linked to increased susceptibility for multiple cancers. According to Amos, understanding which variants cause increased DNA damage could be key to unlocking treatments for these cancers.

“We know from breast cancer that PARP inhibitors, drugs that prevent DNA repair, work in people with inherited BRCA1 and BRCA2 mutations because those cells already have some DNA damage due to the inherited mutation. If you disable PARP, the cancer cells can’t repair DNA damage and won’t survive,” said Amos, member of the Dan L Duncan Comprehensive Cancer Center at Baylor and CPRIT Scholar.

It’s possible that people with inherited ATM mutations causing them to develop lung cancer may respond to those PARP inhibitors as well, and that is something that needs to be studied further.”

The results are published in the journal, NPJ Precision Oncology.

Other authors from Baylor include Spiridon Tsavachidis, Xiangjun Xiao, Margaret R. Spitz, Chao Cheng, Jinyoung Byun, Wei Hong, Yafang Li, Dakai Zhu, Zhuoyi Song, Susan M. Rosenberg, Michael E. Scheurer and Farrah Kheradmand.

This work was supported by grants from the National Institutes of Health, Intramural Research Program of the National Human Genome Research Institute, and Herrick Foundation. For a full list of authors, affiliations and funding, see the publication.

Featured image: Illustration of the DNA double helix. The newly discovered genetic variants are involved in mechanisms of DNA repair/Peggy&Marco


Reference: Liu, Y., Xia, J., McKay, J. et al. Rare deleterious germline variants and risk of lung cancer. npj Precis. Onc. 5, 12 (2021). https://doi.org/10.1038/s41698-021-00146-7


Provided by BCM

Researchers Discover Inflammatory Mechanism Responsible for Bone Erosion in Rheumatoid Arthritis (Medicine)

In a study aimed at investigating the mechanism responsible for exacerbating rheumatoid arthritis in smokers, researchers at the Center for Research on Inflammatory Diseases (CRID), linked to the University of São Paulo (USP) in Brazil, discovered a novel path in the inflammatory process associated with the bone damage caused by rheumatoid arthritis. The discovery opens up opportunities for new therapeutic interventions to mitigate the effects of the disease, for which there is no specific treatment at this time.

An article on the study is published in Proceedings of the National Academy of Sciences (PNAS). The researchers identified the action of a molecular mechanism involved in the inflammatory process: release by T-lymphocytes of extracellular vesicles loaded with genetic material (microRNAs). The vesicles reach cells in bone tissue, increasing the formation of osteoclasts, cells that break down bone matrix in joints (a critical function in bone maintenance, repair, and remodeling).

“The study set out to extend our understanding of how cigarette smoke exacerbates the inflammatory process in rheumatoid arthritis. We discovered a path associated with bone damage. This is an important finding since pain and inflammation have been treated with medications, but the bone damage that is a debilitating complication of this disease is practically irreversible,” said Fernando de Queiroz Cunha, principal investigator of CRID, one of the Research, Innovation and Dissemination Centers (RIDCs) supported by FAPESP.

Rheumatoid arthritis is an autoimmune disease in which for an unknown reason the immune system mistakes parts of the patient’s body for an invading pathogen and attacks them. The inflammation triggered by the immune system’s overreaction is known to involve Th17 cells, a T-cell subtype, and to create cascading effects such as the release of cytokines (signaling proteins), including IL-17, as well as other molecules that participate in the disease’s progression.

Smoking is known to be an aggravating factor for rheumatoid arthritis. Previous research by the same CRID group showed that cigarette smoke exacerbates the inflammatory process in arthritis mainly by activating the aryl hydrocarbon receptor (AhR) on Th17 cells. 

“AhR is a pollutant-detecting intracellular sensor that participates in the inflammatory process. When AhR is activated on T-cells by certain ligands, they differentiate to Th17 even more. The increase in Th17 cells exacerbates the inflammatory process. Although smoking doesn’t cause rheumatoid arthritis, it makes the disease worse,” said Paula Donate, a CRID researcher whose postdoctoral research was supported by FAPESP

Donate explained that AhR acts mainly as a transcription factor. “If this receptor is activated by an external agent such as cigarette smoke, it enters the cell nucleus together with other proteins and promotes the transcription of various genes, including microRNAs, which are small regulatory RNAs inside the cell,” she said.

Extracellular component

In the study, the researchers wanted to find out which microRNAs in Th17 cells were more expressed owing to AhR activation. Their analysis pointed to miR-132. They analyzed the full set of microRNAs expressed by Th17 cells and correlated the findings with data from a laboratory trial involving mice and human patient samples.

“To our surprise, however, when we treated T-cells with antagonists of the microRNAs, they continued to differentiate normally into Th17 cells, releasing the cytokines characteristic of the inflammatory process in rheumatoid arthritis. If it had no influence on the intracellular process, it was a sign that miR-132 could be released into the extracellular medium,” Donate said.

When the researchers isolated extracellular vesicles released by Th17 and studied them in vitro, they found that the large amounts of miR-132 packaged in extracellular vesicles acted as inflammatory mediators, inducing differentiation of osteoclasts via inhibition of the enzyme cyclooxygenase 2 (COX-2).

“Extracellular vesicles are a key cellular communication mechanism. They’re released by practically all cell types and found in all kinds of body fluid. In the case of Th17 cells, the vesicles released in joints can transport microRNAs to bone tissue, augmenting the quantity of osteoclasts and bone erosion. In sum, this is a previously unknown mechanism that we succeeded in elucidating and that in future could be a basis for novel therapies for joint injury,” Donate said.

The article “Cigarette smoke induces miR-132 in Th17 cells that enhance osteoclastogenesis in inflammatory arthritis” (doi: 10.1073/pnas.2017120118) by Paula B. Donate, Kalil Alves de Lima, Raphael S. Peres, Fausto Almeida, Sandra Y. Fukada, Tarcilia A. Silva, Daniele C. Nascimento, Nerry T. Cecilio, Jhimmy Talbot, Rene D. Oliveira, Geraldo A. Passos, José Carlos Alves-Filho, Thiago M. Cunha, Paulo Louzada-Junior, Foo Y. Liew and Fernando Q. Cunha can be retrieved from: www.pnas.org/content/118/1/e2017120118

Featured image: In a study of the effects of cigarette smoking on exacerbation of the disease, scientists at a FAPESP-supported research center identified a novel pathway in the inflammatory process relating to bone damage (image: Wikimedia Commons)


Provided by FAPESP

New Method Targets Disease-causing Proteins for Destruction (Medicine)

Scientists at the University of Wisconsin–Madison have developed a way to use a cell’s own recycling machinery to destroy disease-causing proteins, a technology that could produce entirely new kinds of drugs.

Some cancers, for instance, are associated with abnormal proteins or an excess of normally harmless proteins. By eliminating them, researchers believe they can treat the underlying cause of disease and restore a healthy balance in cells.

The new technique builds on an earlier strategy by researchers and pharmaceutical companies to remove proteins residing inside of a cell, and expands on this system to include proteins outside or on the surface of liver cells.

“In the past, to develop a new drug, we often needed to find a molecule that bound to the protein of interest and also changed the function of the protein. But there are many potential proteins associated with diseases whose function you cannot block easily,” says Weiping Tang, a professor of pharmacy and chemistry at the University of Wisconsin–Madison who led the new research. “With the targeted protein degradation strategy, we can go after many of those proteins.”

Tang, with colleagues in the UW–Madison School of Pharmacy, demonstrated the new method in proof-of-concept experiments on lab-grown liver cells. They were able to neutralize multiple extracellular proteins, including EGFR, a cancer-associated protein. The scientists published their findings March 4 in the journal ACS Central Science.

The technology works much like a city’s trash-collection system. Antibodies attach tags for destruction to specific proteins, marking them as unwanted. A shuttle protein on the liver cell, serving as a kind of garbage truck, recognizes these markers, engulfs the protein, and ferries it to the protein-digesting compartment of the cell, which breaks down the protein into reusable parts.

Many researchers over the past several years, including the Tang group, have developed tools to selectively target for destruction certain cellular proteins found on the inside of cells, named PROTACs. Multiple PROTAC-based drugs are now in clinical trials to treat several cancers.

The Tang lab is now expanding the scope of targets to additional proteins found outside of or on the surface of the liver cell. They have turned to the lysosome, a compartment of the cell that digests and destroys all kinds of materials, including what the cell engulfs from outside. Since the liver is the primary organ that breaks down proteins in the body, it is an ideal tissue to selectively degrade undesired proteins.

“I believe there’s a great future ahead of us, but we need to invest our resources and time to investigate the protein degradation strategy further”

— says Tang

To gain access to the lysosome, the researchers relied on a lysosome shuttle named ASGPR. The shuttle is primarily found on the surface of liver cells. It recognizes certain sugars on proteins and delivers the proteins to the lysosome for digestion.

To help encourage ASGPR to recognize and help destroy disease-causing proteins, researchers in earlier studies learned they could attach three specific sugars to the proteins. But first they had to figure out how to go about attaching them to the proteins they wanted to eliminate.

Tang’s group focused on antibodies, which are ideal candidates since they recognize and bind to specific proteins. The team attached the sugary tag that would activate ASGPR to an antibody that would track down the specific proteins they hoped to destroy. In this way, the scientists could shuttle the protein to the lysosome of liver cells with this highly targeted trash-collection system.

They tested their technology against several proteins, including EGFR, which tumors produce in excess. By attaching the sugary tag to an EGFR antibody, the scientists were able to deplete a significant amount of the protein that otherwise accumulated outside of cancerous liver cells grown in the lab.

Tang’s lab is now working to refine the ASGPR method by making it more effective, and to expand the strategy to destroy proteins on the surface of other types of cells. They are also interested in collaborating with other researchers to help them test the removal of a wider array of disease-associated proteins.

“I believe there’s a great future ahead of us, but we need to invest our resources and time to investigate the protein degradation strategy further,” says Tang.

Featured image: Weiping Tang, a professor of pharmacy and chemistry at the University of Wisconsin–Madison. PHOTO BY SALLY GRIFFITH-OH


Reference: Yaxian Zhou, Peng Teng, Nathan T. Montgomery, Xiaolei Li, and Weiping Tang, “Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins”, ACS Cent. Sci. 2021.
https://doi.org/10.1021/acscentsci.1c00146


Provided by Wisconsin-Madison

Australian-led International Research Team Generates The First Model of Early Human Embryos from Skin Cells (Biology)

In a discovery that will revolutionise research into the causes of early miscarriage, infertility and the study of early human development – an international team of scientists led by Monash University in Melbourne, Australia has generated a model of a human embryo from skin cells.

The team, led by Professor Jose Polo, has successfully reprogrammed these fibroblasts or skin cells into a 3-dimensional cellular structure that is morphologically and molecularly similar to human blastocysts. Called iBlastoids, these can be used to model the biology of early human embryos in the laboratory.

The research, published today in Nature, was led by Professor Polo, from Monash University’s Biomedicine Discovery Institute and the Australian Regenerative Medicine Institute, and includes first authors Dr Xiaodong (Ethan) Liu and PhD student Jia Ping Tan, as well as the groups of Australian collaborators Dr Jennifer Zenker, from Monash University and Professor Ryan Lister from the University of Western Australia and international collaborators, Associate Professor Owen Rackham from Duke-National University of Singapore and Professor Amander Clark from UCLA in the United States.

The achievement is a significant breakthrough for the future study of early human development and infertility. To date, the only way to study these first days has been through the use of difficult to obtain, and scarce, blastocysts obtained from IVF procedures.

“iBlastoids will allow scientists to study the very early steps in human development and some of the causes of infertility, congenital diseases and the impact of toxins and viruses on early embryos – without the use of human blastocysts and, importantly, at an unprecedented scale, accelerating our understanding and the development of new therapies,” Professor Polo said.

The Polo Lab succeeded in generating the iBlastoids using a technique called “nuclear reprogramming” which allowed them to change the cellular identity of human skin cells that – when placed in a 3D ‘jelly’ scaffold known as an extracellular matrix – organised into blastocyst-like structures which they named iBlastoids.

iBlastoids model the overall genetics and architecture of human blastocysts, including an inner cell mass-like structure made up of epiblast-like cells, surrounded by an outer layer of trophectoderm-like cells and a cavity resembling the blastocoel.

In human embryos the epiblast goes on to develop into the embryo proper, while the trophectoderm becomes the placenta. However, “iBlastoids are not completely identical to a blastocyst. For example, early blastocysts are enclosed within the zone pellucida, a membrane derived from the egg that interacts with sperm during the fertilisation process and later disappears. As iBlastoids are derived from adult fibroblasts, they do not possess a zona pellucida” he said.

An iBlastoid is not generated using an egg or sperm, and has limited ability to develop beyond the first few days.

The lead author on the Nature paper, Dr Xiaodong (Ethan) Liu, a post-doctoral researcher in the Polo Lab, said: “Only when all the data came together and pointed to the same place, could we believe that we had made such a discovery.

Co-first author and PhD student in the Polo Lab, Jia Ping Tan, added: “We are really amazed to discover skin cells can be reprogrammed into these 3D cellular structures resembling the blastocyst.”

The research is published as the International Society for Stem Cell Research is about to release guidelines for research on modelling human embryos in vitro following 2017 and 2018 reports on the generation of mouse “blastoids” in vitro by the UK and Netherland scientists as well as advances in the generation of human stem cells that replicate aspects of early embryonic development. These guidelines are expected in the first half of this year.

It is not known whether the new guidelines will reference the study published today in Nature, which is the first to produce an integrated stem cell model that closely mimics key fate and spatio-temporal decisions made by the early human embryo. However, in a paper published in Stem Cell Reports last February (2020), the Society states that: “if such models could be developed for the early human embryo, they would have great potential benefits for understanding early human development, for biomedical science, and for reducing the use of animals and human embryos in research. However, guidelines for the ethical conduct of this line of work are at present not well defined.”

Although there is no legislative precedent with respect to working with human integrated stem cell models of blastocysts, such as iBlastoids, all experiments had Monash University Human Ethics approval in compliance with Australian law and international guidelines referencing the “primitive streak rule” that states that human blastocysts cannot be cultured beyond the development of the primitive streak, a transient structure that appears at Day 14 in embryonic development.

Under these legislative recommendations, although iBlastoids are different from blastocysts, the Polo Lab did not culture their iBlastoids beyond Day 11 in vitro and they were monitored closely for the appearance of primitive streak-associated genes.

Infertility and miscarriage can be caused by early-stage human embryos failing to implant or failing to progress at the time of implantation. This takes place in the first two weeks after conception when women do not even know they are pregnant. These ‘silent’ miscarriages are likely to represent a significant proportion of the total number of miscarriages that occur and, according to Professor Polo, the generation of iBlastoids provides a model system that will enable insights into this early stage of pregnancy.

Professor Ross Coppel, the Deputy Dean Research of the Faculty of Medicine at Monash University, noted that this discovery will allow the development of improved methods for IVF, the development of protocols for gene therapy of embryos and better and more informative screening methods for new drugs.

“With further research and the right resources, this discovery could open up entirely new industries for Australia and internationally,” he said.

Additional materials:

Professor Jose Polo discusses iBlastoid research

Caption: Monash University’s Professor Jose Polo answers the following questions: What is an iBlastoid? Why is this research important? Does this mean that human embryos can now be grown in the lab? © Monash Biomedicine Discovery Institute

Laboratory video of iBlastoids

Caption: Laboratory video of iBlastoids, with trophectoderm-like structure in blue and inner cell mass-like structure in yellow. © Monash Biomedicine Discovery Institute

Animation explaining iBlastoid research

Caption: Human skin cells are being reprogrammed by a cocktail of reprogramming factors (RF). During reprogramming, these are then placed into V-shaped microwells, where they gradually develop into a blastocyst-like 3D cellular structure called an iBlastoid. © Monash Biomedicine Discovery Institute

Professor Helen Abud discusses organoids and the importance of iBlastoids

Caption: Professor Helen Abud, President of the Australian Society for Stem Cell Research (ASCCR), and also Head, Department of Anatomy and Developmental Biology; Co-Head, Development and Stem Cells Discovery Program; and Scientific Director, Organoid Program at the Biomedicine Discovery Institute at Monash University answers the following questions: The iBlastoid that has been generated by Professor Polo and his team is an organoid, what is that? How important is the generation of this model of a human blastocyst, the iBlastoid? © Monash Biomedicine Discovery Institute

Featured image: Pictured (L-R): PhD student in the Polo Lab Jia Ping Tan, Professor Jose Polo, Dr Xiaodong (Ethan) Liu © Monash University


Reference:


Provided by Monash University

Scientists Take Step Towards Quantum Supremacy (Quantum)

A Russian-German research team has created a quantum sensor that grants access to measurement and manipulation of individual two-level defects in qubits. The study by NUST MISIS, Russian Quantum Center and the Karlsruhe Institute of Technology, published in npj Quantum Information, may pave the way for quantum computing.

In quantum computing the information is encoded in qubits. Qubits (or quantum bits), the quantum mechanical analogue of a classical bit, are coherent two-level systems. A leading qubit modality today superconducting qubits based on the Josephson junction. That is the kind of qubit IBM and Google used in their quantum processors. However, scientists are still searching for the perfect qubit — the one that can be precisely measured and controlled, while remaining unaffected by its environment.

The key element of a superconducting qubit is the nanoscale superconductor—insulator—superconductor Josephson junction. A Josephson junction is a tunnel junction made of two pieces of superconducting metal separated by a very thin insulating barrier. The most commonly used insulator is aluminum oxide.

Modern techniques do not allow to build a qubit with 100% precision, resulting in so-called tunneling two-level defects that limit the performance of superconducting quantum devices and cause computational errors. Those defects contribute to a qubit’s extremely short life span, or decoherence.

Tunneling defects in aluminum oxide and at surfaces of superconductors are an important source of fluctuations and energy losses in superconducting qubits, ultimately limiting the computer run-time. The more material defects occur, the more they affect the cubit’s performance, causing more computational errors, the researchers noted.

The new quantum sensor grants access to measurement and manipulation of individual two-level defects in quantum systems. According to Prof. Alexey Ustinov, Head of the Laboratory for Superconducting Metamaterials at NUST MISIS and Group Head at Russian Quantum Center, who co-authored the study, the sensor itself is a superconducting qubit, and it allows the detection and manipulation of individual defects. Traditional techniques for studying material structure, such as small-angle X-ray scattering (SAXS), are not sensitive enough to spot small individual defects, therefore using those techniques won’t help to build the best qubit. The study may open avenues for quantum material spectroscopy to investigate the structure of tunneling defects and to develop low-loss dielectrics that are urgently required for the advancement of superconducting quantum computers, the researchers believe.

All images credit: MISIS


Reference: Bilmes, A., Volosheniuk, S., Brehm, J.D. et al. Quantum sensors for microscopic tunneling systems. npj Quantum Inf 7, 27 (2021). https://www.nature.com/articles/s41534-020-00359-x https://doi.org/10.1038/s41534-020-00359-x


Provided by MISIS

Palaeodentistry Lessons: Scientists Examine More Than 60 Teeth of Stegosaurs From Yakutia (Paleontology)

An international team of palaeontologists has examined 63 teeth of polar stegosaurs that inhabited the territory of present-day Yakutia. The team was led by Pavel Skutchas, Associate Professor in the Department of Vertebrate Zoology, St Petersburg University, Doctor of Biology. The finds made it possible to understand that these herbivorous dinosaurs were sedentary, ate very solid food, changed teeth quite often, did not suffer from caries, and also had more complex jaw movements than previously thought. The research findings are published in the journal PLOS ONE.

Powerful and squat stegosaurs are now one of the most recognisable dinosaurs: they are easily identified by the spines on the tail and the bony plates on the back — osteoderms. The representatives of this group lived about 165–125 million years ago, during the Jurassic and early Cretaceous periods. They were five to seven metres long and had a disproportionately small head. Their teeth were therefore quite small — about a centimetre in height and about the same in width.

Reconstruction of the pulp cavity inside the stegosaurus tooth © SPBU

Palaeontologists from St Petersburg University worked together with colleagues from: the Zoological Institute of the Russian Academy of Sciences; the Borissiak Paleontological Institute of the Russian Academy of Sciences; the University of Bonn; and the Diamond and Precious Metal Geology Institute of the Siberian Branch of the Russian Academy of Sciences. The research materials were collected during a series of expeditions to the Republic of Sakha in 2012 and 2017–2019. On the banks of the Teete stream, not far from the Yakut rural locality of Suntar, there is a large, but not yet fully examined location of dinosaurs.

Excavation site at the Teete stream (the Republic of Sakha) © SPBU

In the Cretaceous, these territories were located close to the North Pole, which means that they can shed light on the life of polar dinosaurs. Was the local fauna different from that of the southern regions? What was the climate here? How were animals affected by the polar day and polar night? The scientists are trying to find answers to these questions, including by studying the teeth of ancient lizards.

‘We have found teeth of animals of different ages — both adults and cubs,’ said Pavel Skutchas. ‘This suggests that the polar stegosaurs are most likely to have been sedentary: they multiplied and raised offspring on the same territory all year round. Additionally, almost all of the finds are extremely eaten away: many of them have two or three facets — worn edges from contact with adjacent teeth.’

Video: Three-dimensional reconstruction of a stegosaurus tooth found at the excavation site near the Teete stream (the Republic of Sakha) © SPBU

This feature prompted the researchers to believe that second dentition in polar stegosaurs could occur sufficiently quickly. The scientists therefore investigated ‘temporary rings’ — the so-called von Ebner lines, which can be used to calculate the number of days required for odontogenesis.

Von Ebner lines showing how long it took a stegosaurus to form a tooth © SPBU

It took stegosaurs only about 95 days to complete this task, although in other dinosaur species the process usually lasted 200 days or longer. These Yakut inhabitants are most likely not to have suffered from caries since it takes much more time for it to appear.

‘The fact that teeth formed quickly, grinded quickly and changed quickly is highly likely to indicate that the stegosaurs from Yakutia ate some kind of tough food. We cannot yet say with 100% certainty that we have found polar adaptation, since there is, in principle, very little information about the teeth of stegosaurs. However, their teeth, found in more southern areas, usually have only one wear surface. In a word, this is a new question for palaeobotanists — what was the hard plant growing in the polar regions that the Yakut stegosaurs ate?’ noted Pavel Skutchas.

The paleontologists are searching for isolated fragments of teeth and bones of ancient animals by washing bone-bearing deposits with special sieves © SPBU

Another remarkable thing made it possible to take a different view on the structure of the jaws of these animals: on the surface of the teeth abrasion, the scientists were able to spot curved micro-furrows. Palaeontologists used to assume that very simple jaw movements were characteristic of stegosaurs — up and down, like scissors. However, now, thanks to the patterns on the facets, it became clear that jaw movements were more complex and included a longitudinal phase.

Another conclusion turned out to be associated with the wavy structure of the enamel. It used to be thought that it was unique to the younger Late Cretaceous dinosaurs, which had a complex dentition, such as the platypus. However, the palaeontologists saw this feature in stegosaurs from Yakutia and decided to examine the teeth of another Early Cretaceous dinosaur, a primitive relative of Triceratops — psittacosaurus. This unique feature turned out to have been prevalent among dinosaurs in general.

‘Stegosaurs are one of the most recognisable and popular dinosaurs that are often seen on T-shirts and various pictures. However, we still know little about them. This research has raised many new questions that can be solved without setting out on an expedition, but by studying materials that have been stored in museums for hundreds of years. We have managed to show what features the polar stegosaurs had. But what is an «ordinary», «benchmark» stegosaurus? This has yet to be investigated,’ stressed Pavel Skutchas.

Video: Three-dimensional reconstruction of the pulp cavity inside the stegosaurus tooth © SPBU

Featured image: Stegosaurus teeth found at the Teete stream (the Republic of Sakha), in different planes. © SPBU


Reference: Skutschas PP, Gvozdkova VA, Averianov AO, Lopatin AV, Martin T, Schellhorn R, et al. (2021) Wear patterns and dental functioning in an Early Cretaceous stegosaur from Yakutia, Eastern Russia. PLoS ONE 16(3): e0248163. doi: 10.1371/journal.pone.0248163


Provided by St. Petersburg State University