Category Archives: Cell Biology

Cell Biology

Priming the immune system to attack cancer | Penn Today – Penn Today

Immunotherapies, such as checkpoint inhibitor drugs, have made worlds of difference for the treatment of cancer. Most clinicians and scientists understand these drugs to act on whats known as the adaptive immune system, the T cells and B cells that respond to specific threats to the body.

New research from an international team co-led by George Hajishengallis of the University of Pennsylvania School of Dental Medicine suggests that the innate immune system, which responds more generally to bodily invaders, may be an important yet overlooked component of immunotherapys success.

Their work, published in the journal Cell, found that training the innate immune system with -glucan, a compound derived from fungus, inspired the production of innate immune cells, specifically neutrophils, that were primed to prevent or attack tumors in an animal model.

The focus in immunotherapy is placed on adaptive immunity, like checkpoint inhibitors inhibit the interaction between cancer cells and T cells, says Hajishengallis, a co-senior author on the work. The innate immune cells, or myeloid cells, have not been considered so important. Yet our work suggests the myeloid cells can play a critical role in regulating tumor behavior.

The current study builds on earlier work published in Cell by Hajishengallis and a multi-institutional team of collaborators, which showed that trained immunity, elicited through exposure to exposure to the fungus-derived compound -glucan, could improve immune recovery after chemotherapy in a mouse model.

In that previous study, the researchers also showed that the memory of the innate immune system was held within the bone marrow, in hematopoetic stem cells that serve as precursors of myeloid cells, such as neutrophils, monocytes, and macrophages.

The team next wanted to get at the details of the mechanism by which this memory was encoded. The fact that -glucan helps you fight tumors doesnt necessarily mean it was through trained immunity, says Hajishengallis.

To confirm that link, the researchers isolated neutrophils from mice that had received the innate immune training via exposure to -glucan and transferred them, along with cells that grow into melanoma tumors, to mice that had not received -glucan. Tumor growth was significantly dampened in animals that received cells from mice that had been trained.

To further support this link between myeloid precurors and the protective quality of trained immunity, the scientists performed bone marrow transplants, transferring bone marrow cells from trained mice to untrained mice that had been irradiated, effectively eliminating their own bone marrow.

When challenged later, the mice that were recipients of bone marrow from trained mice fought tumors much better than those that received bone marrow from untrained mice.

This is innate immune memory at work, said Technical University Dresdens Triantafyllos Chavakis, a long-term collaborator of Hajishengallis and co-senior author of the study.

The experiment relied on the memory of bone marrow precursors of neutrophils of the trained donor mice, which were transferred by transplantation to the recipient mice and gave rise to neutrophils with tumor-killing ability.

The researchers found that the antitumor activity likely resulted from trained neutrophils producing higher levels of reactive oxygen species, or ROS, than did untrained neutrophils. ROS can cause harm in certain contexts but in cancer can be beneficial, as it acts to kill tumor cells.

Looking closely at the myeloid precursors in the bone marrow of trained animals, the team found significant changes in gene expression that biased the cells toward making neutrophils, specifically a type associated with anti-tumor activity, a classification known as tumor-associated neutrophils type I (TAN1).

Further investigation revealed that these changes elicited by innate immune training cause an epigenetic rewiring of bone marrow precursor cells, changes that acted to make certain genes more accessible to being transcribed and also pointed to the Type I interferon signaling pathway as a likely regulator of innate immune training. Indeed, mice lacking a receptor for Type I interferon couldnt generate trained neutrophils.

-glucan is already in clinical trials for cancer immunotherapy, but the researchers say this finding suggests a novel mechanism of action with new treatment approaches.

This is a breakthrough concept that can be therapeutically exploited for cancer immunotherapy in humans, Hajishengallis says, specifically by transferring neutrophils from -glucan-trained donors to cancer patients who would be recipients.

Hajishengalliss coauthors on the study were Penn Dental Medicines Xiaofei Li; Technical University Dresdens Lydia Kalafati, Ioannis Kourtzelis, Tatyana Grinenko, Eman Haga, Anupam Sinha, Canan Has, Marina Nati, Sundary Sormendi, Ales Neuwirth, Antonios Chatzigeorgiou, Athanasios Ziogas, Pallavi Subramanian, Ben Wielockx, Peter Mirtschink, Kyoung-Jin Chung, Mathias Lesche, Andreas Dahl, Panayotis Verginis, Ioannis Mitroulis, and Triantafllos Chavakis; University of Bonns Jonas Schulte-Schrepping, Joachim L. Schultze, and Mihai G. Netea; Biomedical Research Foundation of the Academy of Athens Aikaterini Hatzioannou; DFG-Center for Regenerative Therapies Dresdens Sevina Dietz; Max Planck Institute of Molecular Cell Biology and Genetics Antonio Miguel de Jess Domingues and Ian Henry; and Max Planck Institute of Biochemistrys Peter Murray.

Kalafati and Kourtzelis were co-first authors and Hajishengallis, Verginis, Mitroulis, and Chavakis were co-senior authors.

George Hajishengallis is the Thomas W. Evans Centennial Professor in the Department of Basic and Translational Sciences in the University of Pennsylvania School of Dental Medicine.

The study was funded by the European Research Council and the National Institutes of Health (grants DE024716, DE026152, and DE28561).

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Priming the immune system to attack cancer | Penn Today - Penn Today

Cell Biology

The Microfluidic Devices Market To Line Up With The Technological Up Gradations, Reach USD 5246.4 Million – Eurowire

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According to a new market report published by Persistence Market Research Global Market Study on Microfluidic Devices: Asia to Witness Highest Growth by 2019 the global microfluidic device market was valued at USD 1,531.2 million in 2013 and is expected to grow at a CAGR of 22.8% from 2013 to 2019, to reach an estimated value of USD 5,246.4 million in 2019.

Globally, the microfluidic device market is witnessing significant growth due to increasing R&D investment in pharmaceuticals, life science and rising point of care testing demand. New trends in healthcare, such as health care at home, supports point of care testing (POCT) as the most efficient and effective delivery of healthcare. Miniaturization also reduces the cost for screening compounds in pharmaceutical companies for cell biology problems.

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Some of the major players in the Microfluidic Device market:

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In addition, microfluidic proteomic devices are increasingly being used to quantify and identify proteins and to study interactions of different proteins with reagent in array. Different materials such as glass, silicon, polymer metal and ceramics, are used to manufacture microfluidic devices. The global microfluidic device market was valued at USD 1,531.2 million in 2013. It is likely to grow at a CAGR of 22.8% during 2013 to 2019 to reach USD 5,246.4 million in 2019.

In North America, rising aging population, increasing health awareness, rising chronic and lifestyle diseases, technological developments for various home use applications, and proper insurance coverage are driving the use of microfluidic devices in the market. Usage of microfluidic technology in North America is high compared to other regions of the world due to its early adoption and multiple applications in different industries.

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In Europe, the microfluidic device market is driven by rising diagnostic requirements due to increasing lifestyle associated diseases, aging population and improving healthcare infrastructure. On the other hand, increasing healthcare costs has shifted the focus of healthcare from hospitals to home, which would increase the use of microfluidic devices in the region.

However, Asia is becoming one of the most attractive markets for medical device companies. The growth for microfluidic devices is much faster than developed countries due to widening health insurance penetration and up-gradation of health care systems. Asia is one of the producers of generic drugs, which require microfluidic devices for toxicity testing of drugs.

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The Microfluidic Devices Market To Line Up With The Technological Up Gradations, Reach USD 5246.4 Million - Eurowire

Cell Biology

New Organic Compounds Discovered That Could Have Helped Form the First Cells – Lab Manager Magazine

Drying, followed by rehydration, of a glycolide/glycine mixed monomer solution results in polymers which self-assemble into macromolecular aggregates, as observed by light microscopy.

Jim Cleaves, ELSI

Chemists studying how life started often focus on how modern biopolymers like peptides and nucleic acids contributed, but modern biopolymers don't form easily without help from living organisms. A possible solution to this paradox is that life started using different components, and many non-biological chemicals were likely abundant in the environment. A new survey conducted by an international team of chemists from the Earth-Life Science Institute (ELSI) at Tokyo Institute of Technology and other institutes from Malaysia, the Czech Republic, the US, and India, has found that a diverse set of such compounds easily form polymers under primitive environmental conditions, and some even spontaneously form cell-like structures.

Understanding how life started on Earth is one of the most challenging questions modern science attempts to explain. Scientists presently study modern organisms and try to see what aspects of their biochemistry are universal, and thus were probably present in the organisms from which they descended. The best guess is that life has thrived on Earth for at least 3.5 billion of Earth's 4.5 billion year history since the planet formed, and most scientists would say life likely began before there is good evidence for its existence. Problematically, since Earth's surface is dynamic, the earliest traces of life on Earth have not been preserved in the geological record. However, the earliest evidence for life on Earth tells us little about what the earliest organisms were made of, or what was going on inside their cells. "There is clearly a lot left to learn from prebiotic chemistry about how life may have arisen," says the study's co-author Jim Cleaves.

A hallmark of life is evolution, and the mechanisms of evolution suggest that common traits can suddenly be displaced by rare and novel mutations which allow mutant organisms to survive better and proliferate, often replacing previously common organisms very rapidly. Paleontological, ecological, and laboratory evidence suggests this occurs commonly and quickly. One example is an invasive organism like the dandelion, which was introduced to the Americas from Europe and is now a common weed causing lawn-concerned homeowners to spend countless hours of effort and dollars to eradicate. Another less whimsical example is COVID-19, a virus (technically not living, but technically an organism) which was probably confined to a small population of bats for years, but suddenly spread among humans around the world. Organisms which reproduce faster than their competitors, even only slightly faster, quickly send their competitors to what Leon Trotsky termed the "ash heap of history." As most organisms which have ever existed are extinct, co-author Tony Z. Jia suggests that "to understand how modern biology emerged, it is important to study plausible non-biological chemistries or structures not currently present in modern biology which potentially went extinct as life complexified."

This idea of evolutionary replacement is pushed to an extreme when scientists try to understand the origins of life. All modern organisms have a few core commonalities: all life is cellular, life uses DNA as an information storage molecule, and uses DNA to make ribonucleic RNA as an intermediary way to make proteins. Proteins perform most of the catalysis in modern biochemistry, and they are created using a very nearly universal "code" to make them from RNA. How this code came to be is in itself enigmatic, but these deep questions point to their possibly having been a very murky period in early biological evolution ~ 4 billion years ago during which almost none of the molecular features observed in modern biochemistry were present, and few if any of the ones that were present have been carried forward.

A new study by scholars based at the Earth-Life Science Institute at Tokyo Institute of Technology showed that non-biological chemicals produce polymers and cell-like structures under primitive Earth-like settings.

Kuhan Chandru

Proteins are linear polymers of amino acids. These floppy strings of polymerized amino acids fold into unique three-dimensional shapes, forming extremely efficient catalysts which foster precise chemical reactions. In principle, many types of polymerized molecules could form similar strings and fold to form similar catalytic shapes, and synthetic chemists have already discovered many examples. "The point of this kind of study is finding functional polymers in plausibly prebiotic systems without the assistance of biology, including grad students," says co-author Irena Mamajanov.

Scientists have found many ways to make biological organic compounds without the intervention of biology, and these mechanisms help explain these compounds' presence in samples like carbonaceous meteorites, which are relics of the early solar system, and which scientists don't think ever hosted life. These primordial meteorite samples also contain many other types of molecules which could have formed complex folded polymers like proteins, which could have helped steer primitive chemistry. Proteins, by virtue of their folding and catalysis mediate much of the complex biochemical evolution observed in living systems. The ELSI team reasoned that alternative polymers could have helped this occur before the coding between DNA and protein evolved. "Perhaps we cannot reverse-engineer the origin of life; it may be more productive to try and build it from scratch, and not necessarily using modern biomolecules. There were large reservoirs of non-biological chemicals that existed on the primeval Earth. How they helped in the formation of life-as-we-know-it is what we are interested in," says co-author Kuhan Chandru.

The ELSI team did something simple yet profound: they took a large set of structurally diverse small organic molecules which could plausibly be made by prebiotic processes and tried to see if they could form polymers when evaporated from dilute solution. To their surprise, they found many of the primitive compounds could, though they also found some of them decomposed rapidly. This simple criterion, whether a compound is able to be dried without decomposing, may have been one of the earliest evolutionary selection pressures for primordial molecules.

The team conducted one further simple test. They took these dried reactions, added water, and looked at them under a microscope. To their surprise, some of the products of these reaction formed cell-sized compartments. That simple starting materials containing 10 to 20 atoms can be converted to self-organized cell-like aggregates containing millions of atoms provides startling insight into how simple chemistry may have led to complex chemistry bordering on the kind of complexity associated with living systems, while not using modern biochemicals.

"We didn't test every possible compound, but we tested a lot of possible compounds. The diversity of chemical behaviors we found was surprising, and suggests this kind of small-molecule to functional-aggregate behavior is a common feature of organic chemistry, which may make the origin of life a more common phenomenon than previously thought," concludes co-author Niraja Bapat.

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New Organic Compounds Discovered That Could Have Helped Form the First Cells - Lab Manager Magazine

Cell Biology

Sustainable Bioenergy Production Unlocked by New Protein Nanobioreactor – SciTechDaily

Illustration of a carboxysome and enzymes. Credit: Professor Luning Liu

Researchers at the University of Liverpool have unlocked new possibilities for the future development of sustainable, clean bioenergy. The study, published in Nature Communications, shows how bacterial protein cages can be reprogrammed as nanoscale bioreactors for hydrogen production.

The carboxysome is a specialized bacterial organelle that encapsulates the essential CO2-fixing enzyme Rubisco into a virus-like protein shell. The naturally designed architecture, semi-permeability, and catalytic improvement of carboxysomes have inspired the rational design and engineering of new nanomaterials to incorporate different enzymes into the shell for enhanced catalytic performance.

The first step in the study involved researchers installing specific genetic elements into the industrial bacterium E. coli to produce empty carboxysome shells. They further identified a small linker called an encapsulation peptide capable of directing external proteins into the shell.

The extreme oxygen sensitive character of hydrogenases (enzymes that catalyze the generation and conversion of hydrogen) is a long-standing issue for hydrogen production in bacteria, so the team developed methods to incorporate catalytically active hydrogenases into the empty shell.

Project lead Professor Luning Liu, Professor of Microbial Bioenergetics and Bioengineering at the Institute of Systems, Molecular and Integrative Biology, said: Our newly designed bioreactor is ideal for oxygen-sensitive enzymes, and marks an important step towards being able to develop and produce a bio-factory for hydrogen production.

In collaboration with Professor Andy Cooper in the Materials Innovation Factory (MIF) at the University, the researchers then tested the hydrogen-production activities of the bacterial cells and the biochemically isolated nanobioreactors. The nanobioreactor achieved a ~550% improvement in hydrogen-production efficiency and a greater oxygen tolerance in contrast to the enzymes without shell encapsulation.

The next step for our research is answering how we can further stabilize the encapsulation system and improve yields, said Professor Liu. We are also excited that this technical platform opens the door for us, in future studies, to create a diverse range of synthetic factories to encase various enzymes and molecules for customized functions.

First author, PhD student Tianpei Li, said: Due to climate change, there is a pressing need to reduce the emission of carbon dioxide from burning fossil fuels. Our study paves the way for engineering carboxysome shell-based nanoreactors to recruit specific enzymes and opens the door for new possibilities for developing sustainable, clean bioenergy.

Reference: Reprogramming bacterial protein organelles as a nanoreactor for hydrogen production by Tianpei Li, Qiuyao Jiang, Jiafeng Huang, Catherine M. Aitchison, Fang Huang, Mengru Yang, Gregory F. Dykes, Hai-Lun He, Qiang Wang, Reiner Sebastian Sprick, Andrew I. Cooper and Lu-Ning Liu, 28 October 2020, Nature Communications.DOI: 10.1038/s41467-020-19280-0

The project was funded by Royal Society, Biotechnology and Biological Sciences Research Council (BBSRC), British Council Newton Fund and Leverhulme Trust. The project was also carried out in collaboration with the Centre for Cell Imaging, Centre for Proteome Research and Biomedical Electron Microscopy Unit at the University, and researchers from Henan University and Central South University, China.

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Sustainable Bioenergy Production Unlocked by New Protein Nanobioreactor - SciTechDaily

Cell Biology

‘Relatively simple’ therapy could help cure blindness – Newstalk

A new therapy being developed to help restore vision to people who are blind could be used within years.

The treatment involves a "relatively simple" injection into the eye and is a "relatively straightforward surgery".

That's according to John Flannery, a Professor of Neurobiology in the Department of Molecular and Cell Biology at the University of Berkeley and a member of the Medical and Scientific Advisory Board for Fighting Blindness Ireland.

He told Futureproof with Johnathan McCrea how blindness develops in some people and how his research will attempt to remove the disease from patients.

His startup company has recently been bought by Novartis and they will partner to develop the treatment.

Professor Flannery said "the hope is for some patients, they'll get a significant increase in their vision".

He added that "manufacturing enough of the treatment is not doing to be that difficult".

In explaining how blindness develops in some people, Professor Flannery said "almost all the inherited blindnesses occur over time".

He said: "The gene defect you have when you're born, and depending on what you inherit, it can manifest as a small child or sometimes not until you're a teenager and some conditions, likemacular degeneration, not until you're 50 or 60."

Professor Flannery said technology is been tested to get the eye to see something when there's no biological retina, but that its success is a long time away.

He said: "There have been some attempts to connect a video camera to the patient's brain in patients that are completely blind.

"That's been incredibly challenging because we know quite a bit about how the retina works but we don't know much about it encodes the signal.

"That will be quite a bit off until we have an electronic prosthetic.

"Nobody, in my knowledge, has been able to interpret the signals coming out of the eye and understanding what the picture is."

Professor Flannery said his research on how to develop therapies for blind patients starts out on testing with animals such as mice.

He said that the current treatments available to patients are for those who have recessive conditions, meaning they got the gene from both of their parents, which continues much of his work.

Professor Flannery explained how the therapy aimed to cure blindness would work.

He said: "The progress in the field has been to use the shell of the virus, the outside coat of the virus.

"We use a very different virus for the eye that's never been shown to cause disease, we put in a copy of the gene that the patient has a defect in.

"We use the virus shell to carry the DNA and protect it and that virus will carry the DNA into the retinal shells and that's a one time only repair."

He said that the virus contains a "zip-code" which controls which cells have the therapeutic gene.

Professor Flannery added: "It's a question of scale, a normal human has 150 million photoreceptors, which are the ones that are affected in these conditions.

"You can inject with a very small volume many hundreds of million virus particles."

Professor Flannery said that an experiment showed that blind mice were able to move around and explore as much as other mice.

He said: "In a couple of the therapies that are currently in the clinic, the patients have to be treated as quickly as possible because their photoreceptor cells are dying and if you get to the stage where theirphotoreceptors have died, the gene in the cell is gone.

"The therapy that we're trying to develop, which is called optogenetics, is for patients at the very late stages of blindness.

"What we're doing is capitalising on the knowledge that the photoreceptors talk to other cells in the retina that aren't light-sensitive

"Our gene therapy is designed to add light sensitively to the third cell in this chain between the damaged photo and the brain.

"Since it's in the middle, if you can make that cell light-sensitive, that's a new opportunity for restoring vision in the blind.

Professor Flannery said this treatment is "particularly appealing because you could treat someone at any age or any stage".

He said: "Because unlike the other therapies where you have to identify the exact genetic defect in the patient and put that exact gene back, this is putting a light-sensitive function in a different cell.

"It doesn't require you to know what the defect is in the patients."

partnering with Novartis to bring the therapy to the clinic

Professor Flannery said they would begin to start testing the therapy in small groups of patients shortly after successful trials in dogs.

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'Relatively simple' therapy could help cure blindness - Newstalk

Cell Biology

Angelika Amon, cell biologist who pioneered research on chromosome imbalance, dies at 53 – MIT News

Angelika Amon, professor of biology and a member of the Koch Institute for Integrative Cancer Research, died on Oct. 29 at age 53, following a two-and-a-half-year battle with ovarian cancer.

"Known for her piercing scientific insight and infectious enthusiasm for the deepest questions of science, Professor Amon built an extraordinary career and in the process, a devoted community of colleagues, students and friends," MIT President L. Rafael Reif wrote in a letter to the MIT community.

Angelika was a force of nature and a highly valued member of our community, reflects Tyler Jacks, the David H. Koch Professor of Biology at MIT and director of the Koch Institute. Her intellect and wit were equally sharp, and she brought unmatched passion to everything she did. Through her groundbreaking research, her mentorship of so many, her teaching, and a host of other contributions, Angelika has made an incredible impact on the world one that will last long into the future.

A pioneer in cell biology

From the earliest stages of her career, Amon made profound contributions to our understanding of the fundamental biology of the cell, deciphering the regulatory networks that govern cell division and proliferation in yeast, mice, and mammalian organoids, and shedding light on the causes of chromosome mis-segregation and its consequences for human diseases.

Human cells have 23 pairs of chromosomes, but as they divide they can make errors that lead to too many or too few chromosomes, resulting in aneuploidy. Amons meticulous and rigorous experiments, first in yeast and then in mammalian cells, helped to uncover the biological consequences of having too many chromosomes. Her studies determined that extra chromosomes significantly impact the composition of the cell, causing stress in important processes such as protein folding and metabolism, and leading to additional mistakes that could drive cancer. Although stress resulting from aneuploidy affects cells ability to survive and proliferate, cancer cells which are nearly universally aneuploid can grow uncontrollably. Amon showed that aneuploidy disrupts cells usual error-repair systems, allowing genetic mutations to quickly accumulate.

Aneuploidy is usually fatal, but in some instances extra copies of specific chromosomes can lead to conditions such as Down syndrome and developmental disorders including those known as Patau and Edwards syndromes. This led Amon to work to understand how these negative effects result in some of the health problems associated specifically with Down syndrome, such as acute lymphoblastic leukemia. Her expertise in this area led her to be named co-director of the recently established Alana Down Syndrome Center at MIT.

Angelikas intellect and research were as astonishing as her bravery and her spirit. Her labs fundamental work on aneuploidy was integral to our establishment of the center, say Li-Huei Tsai, the Picower Professor of Neuroscience and co-director of the Alana Down Syndrome Center. Her exploration of the myriad consequences of aneuploidy for human health was vitally important and will continue to guide scientific and medical research.

Another major focus of research in the Amon lab has been on the relationship between how cells grow, divide, and age. Among other insights, this work has revealed that once cells reach a certain large size, they lose the ability to proliferate and are unable to reenter the cell cycle. Further, this growth contributes to senescence, an irreversible cell cycle arrest, and tissue aging. In related work, Amon has investigated the relationships between stem cell size, stem cell function, and tissue age. Her labs studies have found that in hematopoetic stem cells, small size is important to cells ability to function and proliferate in fact, she posted recent findings on bioRxiv earlier this week and have been examining the same questions in epithelial cells as well.

Amon lab experiments delved deep into the mechanics of the biology, trying to understand the mechanisms behind their observations. To support this work, she established research collaborations to leverage approaches and technologies developed by her colleagues at the Koch Institute, including sophisticated intestinal organoid and mouse models developed by the Yilmaz Laboratory, and a microfluidic device developed by the Manalis Laboratory for measuring physical characteristics of single cells.

The thrill of discovery

Born in 1967, Amon grew up in Vienna, Austria, in a family of six. Playing outside all day with her three younger siblings, she developed an early love of biology and animals. She could not remember a time when she was not interested in biology, initially wanting to become a zoologist. But in high school, she saw an old black-and-white film from the 1950s about chromosome segregation, and found the moment that the sister chromatids split apart breathtaking. She knew then that she wanted to study the inner workings of the cell and decided to focus on genetics at the University of Vienna in Austria.

After receiving her BS, Amon continued her doctoral work there under Professor Kim Nasmyth at the Research Institute of Molecular Pathology, earning her PhD in 1993. From the outset, she made important contributions to the field of cell cycle dynamics. Her work on yeast genetics in the Nasmyth laboratory led to major discoveries about how one stage of the cell cycle sets up for the next, revealing that cyclins, proteins that accumulate within cells as they enter mitosis, must be broken down before cells pass from mitosis to G1, a period of cell growth.

Towards the end of her doctorate, Amon became interested in fruitfly genetics and read the work of Ruth Lehmann, then a faculty member at MIT and a member of the Whitehead Institute. Impressed by the elegance of Lehmanns genetic approach, she applied and was accepted to her lab. In 1994, Amon arrived in the United States, not knowing that it would become her permanent home or that she would eventually become a professor.

While Amons love affair with fruitfly genetics would prove short, her promise was immediately apparent to Lehmann, now director of the Whitehead Institute. I will never forget picking Angelika up from the airport when she was flying in from Vienna to join my lab. Despite the long trip, she was just so full of energy, ready to talk science, says Lehmann. She had read all the papers in the new field and cut through the results to hit equally on the main points.

But as Amon frequently was fond of saying, yeast will spoil you. Lehmann explains that because they grow so fast and there are so many tools, your brain is the only limitation. I tried to convince her of the beauty and advantages of my slower-growing favorite organism. But in the end, yeast won and Angelika went on to establish a remarkable body of work, starting with her many contributions to how cells divide and more recently to discover a cellular aneuploidy program.

In 1996, after Lehmann had left for New York Universitys Skirball Institute, Amon was invited to become a Whitehead Fellow, a prestigious program that offers recent PhDs resources and mentorship to undertake their own investigations. Her work on the question of how yeast cells progress through the cell cycle and partition their chromosomes would be instrumental in establishing her as one of the worlds leading geneticists. While at Whitehead, her lab made key findings centered around the role of an enzyme called Cdc14 in prompting cells to exit mitosis, including that the enzyme is sequestered in a cellular compartment called the nucleolus and must be released before the cell can exit.

I was one of those blessed to share with her a eureka moment, as she would call it, says Rosella Visintin, a postdoc in Amons lab at the time of the discovery and now an assistant professor at the European School of Molecular Medicine in Milan. She had so many. Most of us are lucky to get just one, and I was one of the lucky ones. Ill never forget her smile and scream neither will the entire Whitehead Institute when she saw for the first time Cdc14 localization: You did it, you did it, you figured it out! Passion, excitement, joy everything was in that scream.

In 1999, Amons work as a Whitehead Fellow earned her a faculty position in the MIT Department of Biology and the MIT Center for Cancer Research, the predecessor to the Koch Institute. A full professor since 2007, she also became the Kathleen and Curtis Marble Professor in Cancer Research, associate director of the Paul F. Glenn Center for Biology of Aging Research at MIT, a member of the Ludwig Center for Molecular Oncology at MIT, and an investigator of the Howard Hughes Medical Institute.

Her pathbreaking research was recognized by several awards and honors, including the 2003 National Science Foundation Alan T. Waterman Award, the 2007 Paul Marks Prize for Cancer Research, the 2008 National Academy of Sciences (NAS) Award in Molecular Biology, and the 2013 Ernst Jung Prize for Medicine. In 2019, she won the Breakthrough Prize in Life Sciences and the Vilcek Prize in Biomedical Science, and was named to the Carnegie Corporation of New Yorks annual list of Great Immigrants, Great Americans. This year, she was given the Human Frontier Science Program Nakasone Award. She was also a member of the NAS and the American Academy of Arts and Sciences.

Lighting the way forward

Amons perseverance, deep curiosity, and enthusiasm for discovery served her well in her roles as teacher, mentor, and colleague. She has worked with many labs across the world and developed a deep network of scientific collaboration and friendships. She was a sought-after speaker for seminars and the many conferences she attended. In over 20 years as a professor at MIT, she has mentored more than 80 postdocs, graduate students, and undergraduates, and received the School of Sciences undergraduate teaching prize.

Angelika was an amazing, energetic, passionate, and creative scientist, an outstanding mentor to many, and an excellent teacher, says Alan Grossman, the Praecis Professor of Biology and head of MITs Department of Biology. Her impact and legacy will live on and be perpetuated by all those she touched.

Angelika existed in a league of her own, explains Kristin Knouse, one of Amons former graduate students and a current Whitehead Fellow. She had the energy and excitement of someone who picked up a pipette for the first time, but the brilliance and wisdom of someone who had been doing it for decades. Her infectious energy and brilliant mind were matched by a boundless heart and tenacious grit. She could glance at any data and immediately deliver a sharp insight that would never have crossed any other mind. Her positive attributes were infectious, and any interaction with her, no matter how transient, assuredly left you feeling better about yourself and your science.

Taking great delight in helping young scientists find their own eureka moments, Amon was a fearless advocate for science and the rights of women and minorities and inspired others to fight as well. She was not afraid to speak out in support of the research and causes she believed strongly in. She was a role model for young female scientists and spent countless hours mentoring and guiding them in a male-dominated field. While she graciously accepted awards for women in science, including the Vanderbilt Prize and the Women in Cell Biology Senior Award, she questioned the value of prizes focused on women as women, rather than on their scientific contributions.

Angelika Amon was an inspiring leader, notes Lehmann, not only by her trailblazing science but also by her fearlessness to call out sexism and other -isms in our community. Her captivating laugh and unwavering mentorship and guidance will be missed by students and faculty alike. MIT and the science community have lost an exemplary leader, mentor, friend, and mensch.

Amons wide-ranging curiosity led her to consider new ideas beyond her own field. In recent years, she has developed a love for dinosaurs and fossils, and often mentioned that she would like to study terraforming, which she considered essential for a human success to life on other planets.

It was always amazing to talk with Angelika about science, because her interests were so deep and so broad, her intellect so sharp, and her enthusiasm so infectious, remembers Vivian Siegel, a lecturer in the Department of Biology and friend since Amons postdoctoral days. Beyond her own work in the lab, she was fascinated by so many things, including dinosaurs dreaming of taking her daughters on a dig lichen, and even life on Mars.

Angelika was brilliant; she illuminated science and scientists, says Frank Solomon, professor of biology and member of the Koch Institute. And she was intense; she warmed the people around her, and expanded what it means to be a friend.

Amon is survived by her husband Johannes Weis, and her daughters Theresa and Clara Weis, and her three siblings and their families.

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Angelika Amon, cell biologist who pioneered research on chromosome imbalance, dies at 53 - MIT News

Cell Biology

Touch and taste? Its all in the suckers – ScienceBlog.com

We think because the molecules do not solubilize well, they could, for instance, be found on the surface of octopuses prey and [whatever the animals touch], saidNicholas Bellono, an assistant professor of molecular and cellular biology and the studys senior author. So, when the octopus touches a rock versus a crab, now its arm knows, OK, Im touching a crab [because] I know theres not only touch but theres also this sort of taste.

In addition, scientists found diversity in what the receptors responded to and the signals they then transmitted to the cell and nervous systems.

We think that this is important because it could facilitate complexity in what the octopus senses and also how it can process a range of signals using its semi-autonomous arm nervous system to produce complex behaviors, Bellono said.

The scientists believe this research can help uncover similar receptor systems in other cephalopods, the invertebrate family that also includes squids and cuttlefish. The hope is to determine how these systems work on a molecular level and answer some relatively unexplored questions about how these creatures capabilities evolved to suit their environment.

Not much is known about marine chemotactile behavior and with this receptor family as a model system, we can now study which signals are important for the animal and how they can be encoded, saidLena van Giesen, a postdoctoral fellow in theBellono Laband lead author of the paper. These insights into protein evolution and signal coding go far beyond just cephalopods.

Along with Giesen, other co-authors from the lab includePeter B. Kilian, an animal technician, andCorey A.H. Allard, a postdoctoral fellow.

The strategies they have evolved in order to solve problems in their environment are unique to them and that inspires a great deal of interest from both scientists and non-scientists alike, Kilian said. People are drawn to octopuses and other cephalopods because they are wildly different from most other animals.

The team set out to uncover how the receptors are able to sense chemicals and detect signals in what they touch, like an arm around a snail, to help them make choices.

Octopus arms are distinct and complex. About two-thirds of an octopuss neurons are located in their arms. Because the arms operate partially independently from the brain, if one is severed it can still reach for, identify, and grasp items.

People are drawn to octopuses and other cephalopods because they are wildly different from most other animals.

Peter B. Kilian

The team started by identifying which cells in the suckers actually do the detecting. After isolating and cloning the touch and chemical receptors, they inserted them in frog eggs and in human cell lines to study their function in isolation. Nothing like these receptors exists in frog or human cells, so the cells act essentially like closed vessels for the study of these receptors.

The researchers then exposed those cells to molecules such as extracts from octopus prey and others items to which these receptors are known to react. Some test subjects were water-soluble, like salts, sugars, amino acids; others do not dissolve well and are not typically considered of interest by aquatic animals. Surprisingly, only the poorly soluble molecules activated the receptors.

Researchers then went back to the octopuses in their lab to see whether they too responded to those molecules by putting those same extracts on the floors of their tanks. They found the only odorants the octopuses receptors responded to were a non-dissolving class of naturally occurring chemicals known as terpenoid molecules.

[The octopus] was highly responsive to only the part of the floor that had the molecule infused, Bellono said. This led the researchers to believe that the receptors they identified pick up on these types of molecules and help the octopus distinguish what its touching. With the semi-autonomous nervous system, it can quickly make this decision: Do I contract and grab this crab or keep searching?

While the study provides a molecular explanation for this aquatic touch-taste sensation in octopuses through their chemotactile receptors, the researchers suggest further study is needed, given that a great number of unknown natural compounds could also stimulate these receptors to mediate complex behaviors.

Were now trying to look at other natural molecules that these animals might detect, Bellono said.

This research was supported by the New York Stem Cell Foundation, the Searle Scholars Program, the Sloan Foundation, the Klingenstein-Simons Fellowship, the National Institutes of Health, and the Swiss National Science Foundation.

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Touch and taste? Its all in the suckers - ScienceBlog.com

Cell Biology

Foundational research shows early gene therapy prevents Angelman syndrome – BioWorld Online

Scientists working at the University of North Carolina, Chapel Hill reported in the Oct. 21, 2020, issue of Nature on the successful development of a one-time specific sequence-directed gene therapy approach using the combination of AAV with CRISPR technology that successfully prevented the presentation of Angelman syndrome throughout the lifetime of a mouse model.

Lifelong gene therapy has held promise for decades now as one of the only approaches that could possibly address many neurodevelopmental genetic disorders. But even after decades of research, gene therapy still possesses significant risks due to untoward random genomic insertions of vectors that could ultimately cause other genetic disorders.

Meanwhile, it has been known for decades now that adeno-associated virus (AAV) is a particularly powerful potential gene therapy vector because AAV integrates into the genome so well. However, the integration of AAV has always been random and so it inherently comes with significant risk.

This is the first time that a treatment for Angelman syndrome has been shown to correct this neurodevelopmental disorder.

Principal investigator, Mark Zylka, professor of Cell Biology and Physiology in the Neuroscience Center, University of North Carolina, Chapel Hill, told BioWorld Science, "The key really from what we can tell is going early in treatment. So for the animals that have the disorder we can identify them with genotyping. If you catch it early, you can treat them one time and it lasts forever as far as we can tell.

That longevity, he said, "contrasts with treatments that are in development using antisense technologies that usually have to be injected every 4 months or so, which is not ideal for a pediatric disorder that will last a lifetime."

Angelman syndrome is caused by loss of function of the maternal Ube3a allele, while the paternal allele is normally silenced by a very long antisense noncoding RNA known as Ube3a-ATS. Previously in a 2011 Nature publication Zylka and collaborators demonstrated that a class of drugs called topoisomerase inhibitors could reactivate the paternal allele by interfering with Ube3a-ATS. So Zylka knew that if the paternal copy of Ube3a can be turned on, this will provide the possibility of treating the condition.

Topoisomerase inhibitors, which include chemotherapy agents such as irinotecan and doxorubicin, are not a therapeutic option for Angelman syndrome due to their broad-spectrum nature and toxicity. But with the development of CRISPR combined with AAV, the researchers have now developed a tool to precisely hone in on specific regions of the genome.

First, the team screened 250 different RNA guided CRISPR/Cas9 constructs in cell culture until they identified the best one (Spjw33) reactivating the Ube3a-ATS allele. These clones had the good fortune to target Snord115 genes within the large Ube3a-ATS locus. The Snord genes are functionally redundant, with over 100 of them present in both mice and humans.

Ultimately the CRISPR/Cas9 with the cloned RNA guide was used to a specific region of the DNA, where DNA was inserted into the Snord115 gene of the Ube3a-ATS locus. The inserted DNA possessed a polyadenylation signal that caused the premature termination of the Ube3a-ATS noncoding RNA such that it no longer silenced the paternal expression of Ube3a.

With the Ube3a now made in the mouse, it fully developed and no longer presented with any phenotypes resembling Angelman syndrome throughout the life of the animal.

In short, instead of deleting the gene, this approach disrupted the Ube3a-ATS gene by stopping its full production prematurely. Only a small nonfunctioning part of the noncoding RNA was still produced in treated animals.

Earlier is better

The broad implications are that the study proves that Angelman syndrome can be treated and possibly prevented, if it is done early enough.

Previous studies showed that if turning on the paternal copy later, even within just a few days after birth in a mouse, this approach does not prevent Angelman syndrome.

Zylka said, "It is like with a building. You want to make sure the foundation is done correctly. Tons of time is put into the foundation. If there is a problem with the foundation, then when building on top of it, it is very hard and next to impossible to go back and fix the foundation. When the brain is developing, it is the initial foundation upon which the brain is built that is critical and you cannot really go back and fix it. So this study now shows that you can fix the problem if you catch it early enough by administering just a single treatment."

One encouraging result was the lack of gene therapy occurring in the mother. The team injected the vector into the fetus, but no gene therapy was detectable in the mother's liver and brain. Instead, the gene therapy was restricted to only the fetus. This was remarkable and very important since AAV is well known to particularly target the liver.

The technology to identify fetuses with the mutation that causes Angelman syndrome is already available and currently used in hospitals around the world. Techniques like amniocentesis, chorionic villus sampling, and even newer noninvasive technologies involving taking extra blood from the mom can now detect fetal DNA and cells to find out if there are any Angelman syndrome mutations.

However, there has not been a strong incentive to look for Angelman syndrome given that there are no therapeutic options at this point.

Zylka hopes to ultimately test the approach in the clinic. But first-time gene therapy technologies are often only given one shot in clinical trials and safety is of primary concern. So, extensive further research will be necessary to not throw away his shot (Wolter, J.M. et al. Nature 2020, Advanced publication).

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Foundational research shows early gene therapy prevents Angelman syndrome - BioWorld Online

Cell Biology

Touch and Taste? It’s All in The Octopus Tentacles – Technology Networks

Octopuses have captured the human imagination for centuries, inspiring sagas of sea monsters from Scandinavian kraken legends to TV's "Voyage to the Bottom of the Sea" and, most recently, Netflix's less-threatening "My Octopus Teacher." With their eight suction-cup covered tentacles, their very appearance is unique, and their ability to use those appendages to touch and taste while foraging further sets them apart.

In fact, scientists have wondered for decades how those arms, or more specifically the suction cups on them, do their work, prompting a number of experiments into the biomechanics. But very few have studied what is happening on a molecular level. In a new report, Harvard researchers got a glimpse into how the nervous system in the octopus' arms (which operate largely independently from its centralized brain) manage this feat.

The work published Thursday in Cell.

The scientists identified a novel family of sensors in the first layer of cells inside the suction cups that have adapted to react and detect molecules that don't dissolve well in water. The research suggests these sensors, called chemotactile receptors, use these molecules to help the animal figure out what it's touching and whether that object is prey.

"We think because the molecules do not solubilize well, they could, for instance, be found on the surface of octopuses' prey and [whatever the animals touch]," said Nicholas Bellono, an assistant professor of molecular and cellular biology and the study's senior author. "So, when the octopus touches a rock versus a crab, now its arm knows, 'OK, I'm touching a crab [because] I know there's not only touch but there's also this sort of taste.'"

In addition, scientists found diversity in what the receptors responded to and the signals they then transmitted to the cell and nervous systems.

"We think that this is important because it could facilitate complexity in what the octopus senses and also how it can process a range of signals using its semi-autonomous arm nervous system to produce complex behaviors," Bellono said.

The scientists believe this research can help uncover similar receptor systems in other cephalopods, the invertebrate family that also includes squids and cuttlefish. The hope is to determine how these systems work on a molecular level and answer some relatively unexplored questions about how these creatures' capabilities evolved to suit their environment.

"Not much is known about marine chemotactile behavior and with this receptor family as a model system, we can now study which signals are important for the animal and how they can be encoded," said Lena van Giesen, a postdoctoral fellow in the Bellono Lab and lead author of the paper. "These insights into protein evolution and signal coding go far beyond just cephalopods."

Along with Giesen, other co-authors from the lab include Peter B. Kilian, an animal technician, and Corey A.H. Allard, a postdoctoral fellow.

"The strategies they have evolved in order to solve problems in their environment are unique to them and that inspires a great deal of interest from both scientists and non-scientists alike," Kilian said. "People are drawn to octopuses and other cephalopods because they are wildly different from most other animals."

The team set out to uncover how the receptors are able to sense chemicals and detect signals in what they touch, like a tentacle around a snail, to help them make choices.

Octopus arms are distinct and complex. About two-thirds of an octopus's neurons are located in their arms. Because the arms operate partially independently from the brain, if one is severed it can still reach for, identify, and grasp items.

The team started by identifying which cells in the suckers actually do the detecting. After isolating and cloning the touch and chemical receptors, they inserted them in frog eggs and in human cell lines to study their function in isolation. Nothing like these receptors exists in frog or human cells, so the cells act essentially like closed vessels for the study of these receptors.

The researchers then exposed those cells to molecules such as extracts from octopus prey and others items to which these receptors are known to react. Some test subjects were water-soluble, like salts, sugars, amino acids; others do not dissolve well and are not typically considered of interest by aquatic animals. Surprisingly, only the poorly soluble molecules activated the receptors.

Researchers then went back to the octopuses in their lab to see whether they too responded to those molecules by putting those same extracts on the floors of their tanks. They found the only odorants the octopuses receptors responded to were a non-dissolving class of naturally occurring chemicals known as terpenoid molecules.

"[The octopus] was highly responsive to only the part of the floor that had the molecule infused," Bellono said. This led the researchers to believe that the receptors they identified pick up on these types of molecules and help the octopus distinguish what it's touching. "With the semi-autonomous nervous system, it can quickly make this decision: 'Do I contract and grab this crab or keep searching?'"

While the study provides a molecular explanation for this aquatic touch-taste sensation in octopuses through their chemotactile receptors, the researchers suggest further study is needed, given that a great number of unknown natural compounds could also stimulate these receptors to mediate complex behaviors.

"We're now trying to look at other natural molecules that these animals might detect," Bellono said.

This research was supported by the New York Stem Cell Foundation, the Searle Scholars Program, the Sloan Foundation, the Klingenstein-Simons Fellowship, the National Institutes of Health, and the Swiss National Science Foundation.

Reference:

Lena van Giesen. Corey A.H. Allard Nicholas W. et al. Molecular basis of chemotactile sensation in octopus. Cell, 2020 DOI: 10.1016/j.cell.2020.09.008

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Touch and Taste? It's All in The Octopus Tentacles - Technology Networks

Cell Biology

University of Michigan’s Yukiko Yamashita discusses the mechanisms of long-term genomic maintenance – The Brown Daily Herald

Elementary schoolers learn that DNA is the instruction manual for life the immutable blueprints that cells follow to build proteins and stay alive.

But DNA is a physical molecule which can change over time. So how do cells, especially the ones which produce offspring, ensure that these blueprints stay safe and functional?

In a virtual seminar hosted Wednesday by the Graduate Program in Molecular Biology, Cell Biology and Biochemistry, titled Asymmetric Stem Cell Division and Germ-line Immortality, Yukiko Yamashita, a professor of life sciences at the University of Michigan, explained how her research resulted in a serendipitous connection between two fields of cell biology.

Yamashita typically studies asymmetric cell division, the process by which a daughter cell will split off from the original cell to specialize for a certain function, while the original cell will remain a stem cell capable of any function.

But a series of deductions and experiments on this process led Yamashita to an insight on the mechanisms of germline immortality.

Germline immortality refers to the fact that certain cells act as vessels for storing and passing down genetic information. Since these cells will carry similar genomes across generations, they can be thought of as immortal, Yamashita said. However, the mechanisms that protect this immortality are currently poorly understood. Yamashita hopes to change that through her research.

Yamashita started by working to answer a simple question: When a stem cell divides, how is the fate of the divided cells determined?

Using fruit flies testes as a model to examine stem cells and differentiated cells, which will specialize into different functions like sperm or other tissue, Yamashitas lab began by examining the latter.

They first determined that a common feature of asymmetric stem cell division was the presence of a mother centrosome, a cellular component which regulates the destination of genetic material during division.

Swathi Yadlapalli, who is currently an assistant professor at Michigans Department of Cell and Developmental Biology but worked in Yamashitas lab at the time, then determined that chromosomes, which would typically assort randomly between the divided cells, were in this case dividing non-randomly.

Specific chromosomes, the X and Y sex chromosomes, would regularly assort toward the mother cell, thereby breaking a fundamental rule of cell division: chromosomes assort randomly. Investigation of these oddly assorted chromosomes found a specific region vital to this activity.

Surprisingly, this region was composed of ribosomal DNA, the coding regions for parts of ribosomes, which are responsible for synthesis of proteins.

If you look at any of your cells, any transcriptionally active cell, 60 percent or more of the entire transcription activity is from ribosomal DNA, Yamashita said. You cant do that high demand of transcription off just a single copy of the gene. For that reason, ribosomal DNA genes are repeated hundreds of hundreds of times in our genome.

rDNA is inherently unstable. As cells age, the rDNA will decay, decreasing the availability of ribosome production sites and ultimately impacting the cells function.

For germ cells, which must preserve genetic information to pass on through generations, this erosion poses a threat to long-term reproductive viability. But organisms have demonstrated the capacity to somehow recover from this loss and produce offspring with more rDNA sites than the previous generation.

Yamashitas lab proposed a mechanism by which the odd non-random assortment observed earlier could replenish rDNA sites, ultimately increasing the cells ability to pass on their genes.

Typically, chromatids, pairs of identical chromosomes, align equally during division. An event called crossing over results in the random swapping of material on two parallel chromatids.

Yamashita realized that chromatids were purposely misaligning and crossing over.

That was a thunderstrike moment for us, Yamashita remembered. This is the asymmetry we have been looking (at) for quite some time. Probably, when we say non-random chromatid segregation, this copy-number asymmetry might be what can explain this.

While Yamashitas lab has yet to prove this mechanism, they can detect an unequal crossing over of these regions, as well as hypothesize as to the origins of the signal which leads to the intentional misalignments.

Yamashita related that her labs advances were due to a willingness to listen to the data, as she puts it.

Yamashita added that, oftentimes, scientists will run experiments repeatedly, each time encountering the same, implausible data. If you keep getting that data, multiple times, that is the moment that data is screaming at you, Yamashita told The Herald. You are wrong! You are on the wrong track. You really have to face this puzzling data.

Germline immortality was not the typical work of the Yamashita Lab, but after following the breadcrumbs left by investigation of asymmetric cell division, she found herself on the path toward new conclusions.

Thats the way I do my science, she said. If theres data thats puzzling (and) controversial but you cannot ignore it, you have to tackle it.

Over 60 audience members virtually attended the hour-long seminar. Questions bubbled in the chat throughout the talk.

Although Yamashita reflected that a virtual environment can lead to difficulties for newcomers to assimilate into the scientific community, she pointed to cost and time benefits making virtual scientific events much more accessible.

Mark Johnson, director of the Graduate Program in Molecular Biology, Cell Biology and Biochemistry, also pointed to the benefits of a virtual seminar. We find that some students and participants feel more comfortable asking questions by chat than they would in person, Johnson said. Virtual events can also bring in a much more diverse and interesting audience, without having the expense of time and travel.

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University of Michigan's Yukiko Yamashita discusses the mechanisms of long-term genomic maintenance - The Brown Daily Herald