June 13, 2017 Credit: The Scripps Research Institute

Scientists at The Scripps Research Institute (TSRI) have solved a cellular mystery that may have important implications for fundamental biology and diseases like ALS. Their new research suggests that RNA may be the secret ingredient that helps cells to assemble, organize internal architecture, and ultimately dissolve dynamic droplet-like compartments.

These droplet-like structures are commonly known as membraneless organelles, and they are key to how cells compartmentalize their biochemistry and regulate processes such as gene expression and response to stress.

For 200 years, scientists have known of the existence of membraneless organelles in cells and wondered how they are regulated. Recent studies suggested that increasing the fraction of RNA can lead to the formation of protein-RNA droplets by a process called liquid-liquid phase separation.

"It is basically the same type of immiscibility phenomenon that drives oil to form droplets in water," said TSRI Associate Professor Ashok Deniz, who co-led the study published recently in the journal Angewandte Chemie as a Very Important Paper (VIP). "While several weak biomolecular forces collectively result in protein-RNA droplet formation, we focused on one particular type in this study: electrostatic interactions driven by oppositely charged biomolecules. A major discovery was that further increase in RNA concentration can dissolve these droplets, bringing back a homogeneous liquid phase."

The speed at which these droplets form and dissolve may be key to cellular survival. "Droplets can form and dissolve as they are needed, which allows cells to adapt very quickly to cellular stress," said Research Associate Priya Banerjee, who co-led the study and served as co-first author with graduate students Anthony N. Milin and Mahdi Muhammad Moosa of TSRI.

The new study suggests that the negative charge of RNA molecules is a key to both creating and dissolving droplets. "RNA is like a double agent," said Banerjee.

How Droplets Form and Disappear

RNA has an overall negative charge. When it initially comes in contact with positively-charged proteins, the oppositely charged molecules attract each other. Together, they create a molecular assembly and form liquid droplets. These droplets allow cells to carry out important functions.

The researchers also found that droplets will quickly dissolve when one increases RNA in the system.

"Adding more RNA to this system disrupts the fine balance between negative and positive charges, leading to the formation of negatively-charged assemblies that now repel each other, thus dissolving the droplet," said study co-author Paulo L. Onuchic, a graduate student in the Deniz Lab.

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This unique finding sheds light on an unexpected regulatory pathway. The research also challenges the previous conception that biomolecular forces that create droplets should be reversed to dissolve them. Instead of reversing the processthrough either removal of RNA or posttranslational modification of the protein to destroy its positive chargethe researchers found that the system can simply add more RNA to dissolve a droplet.

"The window-like behavior of droplet formation as a function of RNA concentration observed here exhibits a unidirectional route that can be exploited by cells using processes such as transcription," said Banerjee.

In further experiments, the team demonstrated that RNA synthesis by cellular machineries indeed forms and dissolves these droplets.

Creating "Hollow" Droplets

The fact that RNA can dissolve droplets gave the researchers a unique chance to control RNA addition and watch the dissolution process. "To our surprise, instead of a simple process of droplet dissolution, we observed hollow spheres forming inside droplets. Taking a step back, you see that by adding more RNA, we are creating low-density droplets inside high-density droplets," said Deniz.

Deniz compared this phenomenon to an ice cube melting from the inside. Interestingly, these internal droplets, called vacuoles, resemble the complex internal substructures that are typically observed in a number of cellular droplet-like organelles.

"The key to creating vacuoles is this unidirectional transition from an initial homogeneous liquid to two immiscible liquid phases and back to a homogeneous phase just by increasing the fraction of RNA," added Banerjee.

The team went on to test whether these findings would apply to a key protein found in stress-granules, important "droplet" organelles that protect cells during stress. They investigated an RNA-binding protein called FUS, which has been implicated in ALS.

"With FUS, we found that RNA can both form and dissolve droplets in the same fashion as the simpler model system. Remarkably, FUS droplets also exhibited complex internal substructures, which paves the way for ascertaining the biological role of these vacuoles," said Milin.

While this research is still in its early stages, the researchers believe mutations in FUS may interfere in the normal droplet dynamics in some patients with ALS, possibly stopping their cells from coping properly with cellular stress.

The work opens a number of avenues for future research in cell biology and disease, including quantitative studies of this specific type of phase transition in other biological systems, understanding the molecular determinants in proteins and RNA that control the droplet dynamics, and further studies of complex patterning of droplets.

Explore further: Acetone experiences Leidenfrost effect, no hotplate needed

More information: Priya R. Banerjee et al. Reentrant phase transition drives dynamic substructure formation in ribonucleoprotein droplets, Angewandte Chemie International Edition (2017). DOI: 10.1002/anie.201703191

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Scientists solve a mystery in cellular 'droplet' organelles - Phys.org - Phys.Org

A medical school in Chicago is launching a new center to study tissue regeneration and stem cell biology.

The College of Medicine at the University of Illinois at Chicago says there will be a symposium to commemorate the opening of the center, which will be housed at the medical school.

Officials say researchers will study molecular signals that drive stem cells to mature into different types of cells, among other topics. They'll also investigate issues such as the best ways to transplant engineered cells.

Several different professors will be involved, including the head of the university's pharmacology department.

University officials say there's a search underway to find a director and additional faculty.

See the article here:
Chicago Medical School Launches Stem Cell Biology Center - Peoria Public Radio

Celgene has landed an option on four natural killer (NK) cell-based blood cancer therapeutics in a deal with Dragonfly Therapeutics. The agreement sees Celgene hand over $33 million and commit to more in milestones to access next-generation immuno-oncology candidates aimed at some of its core therapeutic areas.

Cambridge, Massachusetts-based Dragonfly has given Celgene the exclusive option to license up to four assets designed to treat acute myeloid leukemia, multiple myeloma and other hematological cancers. The candidates will emerge from a platform that Dragonfly sees establishing NK cell alongside T cells as a critical component of the push to weaponize the immune system to defeat cancers. Celyad and Innate Pharma have landed deals on the strength of their own attempts to use NK cells.

Dragonflys platform generates bridges designed to bind to proteins found on the surface of tumor cells and NK cells. The aim is to stimulate NK cells. Once activated and aware of the presence of the cancer cells, NK cells attack tumors directly while also enlisting the support of T and B cells. T cells, the cornerstone of current immuno-oncology approaches, then join the direct attack on the tumor, while B cells produce antibodies to help the fight against the cancer.

The potential of the approach has attracted the attention of Celgene.

NK-cell biology and immunotherapy are increasingly critical areas of hematologic research and we are looking forward to working with Dragonflys team of world-leading experts, Rupert Vessey, D.Phil., Celgenes president of research and early development, said in a statement. This collaboration will leverage the strengths of each company as we work together to bring innovative therapies to patients.

The discovery-stage biotech is a long way from showing its biological linker molecules can trigger the desired immune responses. But Celgene, in keeping with its willingness to make early bets on promising biotechs, has seen enough potential in Dragonfly to follow up last months equity investment with the R&D pact.

At this early stage, the perception of potential rests partly on the identities of the people involved with Dragonfly. Tyler Jacks, Ph.D., who heads up the Koch Institute for Integrative Cancer Research at MIT and co-chairs the White Houses Cancer Moonshot, is one cofounder. UC Berkeley NK cell specialist David Raulet, Ph.D., is another. Jacks and Raulet are joined by serial environmental entrepreneur Bill Haney, who brings his experience of building startups, albeit outside of life sciences, to the role of CEO of Dragonfly.

The trio have put together a scientific advisory board that features Nobel Prize winner Harold Varmus, M.D.a former director of the National Cancer Instituteand other researchers from MIT, Stanford University and MD Anderson Cancer Center.

Dragonfly has used these credentials to raise an undisclosed amount of cash from an unusual mix of investors. Celgene sits alongside members of the Disney family and the Duke of Bedford on the list of people and organizations to put money into Dragonfly to date.

The involvement of Celgene in a discovery-stage company that has largely eschewed traditional sources of investment in favor of cash from family offices is in line with its history of spotting and backing biotechs earlier than its peers. Celgene, under the management of George Golumbeski, Ph.D., andTom Daniel, M.D., got in on the ground floor at companies including Agios Pharmaceuticals, Bluebird Bio and Foundation Medicine. And it has had the confidence to put up eye-watering sums of money, such as the $1 billion it gave Juno Therapeutics in return for equity and an option on its immuno-oncology programs.

Continue reading here:
Celgene bags option on NK cell-based blood cancer assets - FierceBiotech

June 12, 2017 Dynamic remodeling in ESCRT-III polymers. Vps4 mediates turnover of ESCRT-III subunits within growing and constricting polymers - analogous to Lego figures exchanging the building blocks within a large spiral assembly. Credit: Beata Edyta Mierzwa, BeataScienceArt.com

Cells multiply by duplicating themselves: they grow, replicate their components, and finally split into two. Many diseases are related to defective cell division; cancer is one of them. Understanding mechanisms conducting this division is therefore essential in the search for cancer treatments. Researchers at the University of Geneva (UNIGE), Switzerland, in collaboration with the IMBA- Institute of Molecular Biotechnology at the Vienna BioCenter (VBC) and the Weill Cornell Medical College in New York, have turned their attention in particular to the role of ESCRT proteins, which are responsible for severing cell membranes. These proteins assemble in spirals that gradually bring about cleavage of the membrane, spirals that are constantly renewing themselves with the help of the Vps4 molecule. Without this molecule the renewal stops, eventually preventing the membrane from being severed. This research, reported in the journal Nature Cell Biology, sheds new light on the fight against cancer and HIV, both of which depend on cell division.

In a previous research, the team led by Professor Aurlien Roux of the Department of Biochemistry at the Faculty of Sciences of the UNIGE, discovered that ESCRT proteins assemble in the form of spirals, a structure that is unique amongst the many forms created by the organism's filamentous proteins. Why this unique form? During cell division, the cell contracts at its centre to separate the two daughter cells. At the end of this stage, called cytokinesis, a very thin link remains between the cells, a tube of plasma membrane - the cell's skin - called the "cytoplasmic bridge". The spirals formed by ESCRT proteins coil around the inner surface of this tube and constrict it in order to sever it, a stage called abscission. Professor Roux's team showed that these spirals behaved like the springs of a watch, suggesting a scenario wherein the more the ESCRT proteins assembled, the more tightly they were compressed.

Research conducted simultaneously in vitro and in vivo

After discovering why these molecules assembled in spirals, the UNIGE researchers examined the dynamics of the assembly. Until now scientists have thought that they assembled like Lego blocks, the proteins being added progressively to the structure without ever leaving it. In this new study, biochemists were able to invalidate this hypothesis. To do so they joined forces with the Gerlich group at IMBA, Vienna Biocenter, to conduct the experiment simultaneously in vivo (the Viennese scientists' part) and in vitro (the Genevan scientists' part).

"On our side, we observed the dynamics of the ESCRT proteins by isolating them on a flat artificial membrane that we created using lipids, onto which we placed the ESCRT protein complexes," explains Nicolas Chiaruttini, a research scientist at UNIGE. "And contrary to what we thought, the proteins do not form a rigidly fixed spiral that is compressed; instead there is a constant renewal of proteins, creating supple, mobile spirals in constant motion." Using a new imaging technique, the team led by Simon Scheuring in New York, working in collaboration with the UNIGE team, was able to directly visualize the dynamics and flexibility of these spirals. Conducting further research, the biochemists noted that this renewal cannot occur without the Vps4 molecule, which is an integral part of ESCRT protein complexes. "Vps4 is known for disassembling molecules in polymeric structures," says Aurlien Roux. "So it is the indispensable ingredient for the severing of membranes insofar as it enables the renewal of spirals."

It is worthwhile noting that the Viennese researchers reached exactly the same conclusions. "During our observations in the cell in motion, Vps4 was revealed to be necessary for the renewal of spirals," explains Beata Mierzwa, a researcher at IMBA-VBC. More importantly, the team observed that the absence or inactivation of Vps4 inhibited cell division in 50% of cases and delayed it significantly in the other 50%. Vps4 and the constant renewal of ESCRTs appear, therefore, to be essential for abscission. "It is rare to be able to conduct experiments in vivo and in vitro simultaneously, and the fact that the results coincide firmly establishes our study."

Another way to approach cancer and HIV

Cancer is characterized by excessive multiplication of diseased cells. By elucidating the role of the Vps4 molecule in cell division, researchers have decipher mechanisms that could be targeted as new treatments that would, for instance, block ESCRT protein renewal directly, thereby preventing the proliferation of the disease. Similarly, when a cell is infected by the Human Immunodeficiency Virus, virus particles bud from the membrane, then eventually break off from it to infect other cells. The virus must also sever the cell membrane in order to be released and spread the diseasea stage that is also carried out by ESCRT proteins. Here again, targeting the Vps4 molecule could prevent the virus from leaving the infected cell.

The primary role of fundamental research is not to find new drugs for cancer or AIDS traitements, but rather, by understanding how ESCRT and Vps4 participate in cell division and virus replication, "to provide knowledge essential to treat those diseases, and clues about potential interactions between treatments", concludes Aurlien Roux.

Explore further: Researchers discover a new mechanism that deforms cell membranes

More information: "Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodelling during cytokinesis," Nature Cell Biology (2017). DOI: 10.1038/ncb3559

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A single molecule is missing and the cell world is empty - Phys.Org