June 13, 2017 Mitochondria are tiny, free-floating organelles inside cells. New Northwestern Medicine research has discovered that they play an important role in hematopoiesis, the bodys process for creating new blood cells. Credit: Northwestern University

New Northwestern Medicine research published in Nature Cell Biology has shown that mitochondria, traditionally known for their role creating energy in cells, also play an important role in hematopoiesis, the body's process for creating new blood cells.

"Historically, mitochondria are viewed as ATPenergyproducing organelles," explained principal investigator Navdeep Chandel, PhD, the David W. Cugell Professor of Medicine in the Division of Pulmonary and Critical Care Medicine. "Previously, my laboratory provided evidence that mitochondria can dictate cell function or fate independent of ATP production. We established the idea that mitochondria are signaling organelles."

In the current study, Chandel's team, including post-doctoral fellow Elena Ans, PhD, and graduate students Sam Weinberg and Lauren Diebold, demonstrated that mitochondria control hematopoietic stem cell fate by preventing the generation of a metabolite called 2-hydroxyglutarate (2HG). The scientists showed that mice with stem cells deficient in mitochondrial function cannot generate blood cells due to elevated levels of 2HG, which causes histone and DNA hyper-methylation.

"This is a great example of two laboratories complementing their expertise to work on a project," said Chandel, also a professor of Cell and Molecular Biology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Paul Schumacker, PhD, professor of Pediatrics, Cell and Molecular Biology and Medicine, was also a co-author on the paper.

Chandel co-authored an accompanying paper in Nature Cell Biology, led by Jian Xu, PhD, at the University of Texas Southwestern Medical Center, which demonstrated that initiation of erythropoiesis, the production of red blood cells specifically, requires functional mitochondria.

"These two studies collectively support the idea that metabolism dictates stem cell fate, which is a rapidly evolving subject matter," said Chandel, who recently wrote a review in Nature Cell Biology highlighting this idea. "An important implication of this work is that diseases linked to mitochondrial dysfunction like neurodegeneration or normal aging process might be due to elevation in metabolites like 2HG."

Explore further: Novel method enables absolute quantification of mitochondrial metabolites

More information: Elena Ans? et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function, Nature Cell Biology (2017). DOI: 10.1038/ncb3529

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Mitochondria behind blood cell formation - Phys.org - Phys.Org

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

Decades of research into characterization, prevention, detection and treatment have substantially expanded our collective understanding of cancer biology. However, these insights elicit a new generation of unanswered questions about the complexity of this group of often-deadly diseases. Historical investigations yielded the key understandings that cancer cells arise from indigenous cells, and most, if not all, tumors are derived from a single parent cell1. In 2000, Hanahan and Weinberg simplified the many aspects of transformation from normal human cells into cancerous ones through six essential cell physiology alterations. These so-called hallmarks of cancer include self-sufficiency in growth signals, insensitivity to anti-growth or inhibitory signals, evasion of apoptosis, unlimited replication capability, sustained angiogenesis, and tissue invasion and metastasis2. They later added deregulating cellular energetics and avoiding immune destruction as emerging hallmarks; genome instability and mutation and tumor-promoting inflammation as enabling characteristics3. The impact of external stimuli, interactions with neighboring cells and the extracellular matrix (ECM), heterogeneity, inherited traits, and other factors further complicate the elucidation of cancer biology.

Along with the expanding scope of research interests, methodologies have evolved to include live cell studies in addition to conventional biochemical and fixed cell assays. Live cell assays allow researchers to dynamically study a cells function in an environment that better represents in vivo conditions. Kinetic imaging of live cells provides a useful framework in which to gather meaningful details of cellular dynamics in real time, however, applications are often constrained by the limited versatility of available instruments. Most imaging systems are not suitable for capturing the widely ranging timelines in which cellular events occur from sub-second responses to events manifesting over days or weeks. Thus, multiple, dedicated instruments or bulky external accessories are often required, taking up precious bench space. Similarly, integrated image processing and data analysis is frequently limited or requires additional software to properly quantify the captured information.

Here, we describe an automated live cell imager designed for a wide range of temporal dynamics in live cell assays. Specifically, we demonstrate its capabilities for short-, medium- and long-term kinetic assays typically used when investigating cancer hallmarks. The integrated design of this system precludes the use of multiple instruments, while the advanced image capture and data analysis features deliver powerful and actionable insights.

Dysregulation of cellular signaling is a significant foundation for most of the aforementioned hallmarks of cancer4. Capturing a rapid, short-lived signaling event, such as calcium flux following GPCR activation, requires high temporal resolution. The automated live cell imager provides image capture rates of up to 20 frames per second, while in-line injectors enable reagent addition with continuous monitoring of cellular response. In the provided calcium mobilization example, we characterize the ATP-induced activation of endogenously expressed P2Y receptors in HeLa cells, using the cell membrane permeable calcium indicator dye Fluo-4 AM. Binding of calcium ions to Fluo-4 causes a structural change that results in a significant increase in fluorescence quantum yield and more than a hundred-fold increase in fluorescence relative to the unbound state. Per Figure 1, ATP (10 M final) was injected at t=5 seconds, an increase in intracellular calcium was detected approximately 3 seconds after the addition, and peak calcium mobilization for the entire field of cells was reached 13 seconds post-ATP addition. Image preprocessing and object masking tools reduced background fluorescence and a generated a larger assay window compared to total fluorescence measurements, resulting in a seven-fold increase in relative Fluo-4 fluorescence following ATP addition.

The relationship between wound healing and tumorigenesis is well-established5,6. Additionally, although migration is a function of normal cells, it is considered one of the hallmarks of cancer when dysregulated signals lead to cancer metastasis. Scratch assays are widely used to investigate in vitro cell migration and wound healing, where a monolayer cell culture is manually scratched to generate an area free of cells into which surrounding cells can migrate and proliferate. The imaging chamber of the automated live cell imager maintains cell health through consistent environmental conditions, including temperature, gas and humidity levels, over the entire incubation period, which is cell-dependent, but typically lasts no more than twenty-four hours. Automated phase contrast (label-free) imaging tracks the migratory characteristics of the cell model at pre-determined time points, while advanced software automatically places object masks to track parameters such as object size, area and total signal over the incubation period. In the provided scratch assay example, an approximately 500 m wide wound was created using HT-1080 fibrosarcoma cells and ibidi culture inserts. Per Figure 2A, the wound was treated with different concentrations of the migration inhibitor, cytochalasin D; and kinetic images were captured over twenty-four hours, while the cells were incubated under controlled conditions of 37 C, 5 percent CO2. Percent confluency was calculated (Figure 2B), showing that wound closure inhibition is proportional to cytochalasin D concentration, to the point where cytotoxicity begins to affect the cells neighboring the wound.

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Revealing New Details of Cancer Biology with Automated Kinetic Live Cell Imaging - Bioscience Technology

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

Mitochondria are tiny, free-floating organelles inside cells. New Northwestern Medicine research has discovered that they play an important role in hematopoiesis, the bodys process for creating new blood cells.

New Northwestern Medicine research published in Nature Cell Biology has shown that mitochondria, traditionally known for their role creating energy in cells, also play animportant role in hematopoiesis, the bodys process for creating new blood cells.

Historically, mitochondria are viewed as ATP energy producing organelles, explained principal investigator Navdeep Chandel, PhD,the David W. Cugell Professor ofMedicinein the Division ofPulmonary and Critical Care Medicine. Previously, my laboratory provided evidence that mitochondria can dictate cell function or fate independent of ATP production.We established the idea that mitochondria are signaling organelles.

In the currentstudy, Chandels team, including post-doctoral fellow Elena Ans, PhD, and graduate students Sam Weinberg and Lauren Diebold, demonstrated that mitochondria control hematopoietic stem cell fate by preventing the generation of a metabolite called 2-hydroxyglutarate (2HG). The scientists showed that mice with stem cells deficient in mitochondrial function cannot generate blood cells due to elevated levels of 2HG, which causes histone and DNA hyper-methylation.

This is a great example of two laboratories complementing their expertise to work on a project, said Chandel, also a professor ofCell and Molecular Biologyand a member of theRobert H. Lurie Comprehensive Cancer Center of Northwestern University.

Sam Weinberg, a graduate student in the Medical Scientist Training Program, and Lauren Diebold, a graduate student in the Driskill Graduate Program in Life Sciences, were co-authors on the paper.

Paul Schumacker, PhD, professor of Pediatrics, Cell and Molecular Biology and Medicine, was also a co-author on the paper.

Chandel co-authored an accompanying paper in Nature Cell Biology, led by Jian Xu, PhD, at the University of Texas Southwestern Medical Center, which demonstrated that initiation of erythropoiesis, the production of red blood cells specifically, requires functional mitochondria.

These two studies collectively support the idea that metabolism dictates stem cell fate, which is a rapidly evolving subject matter, said Chandel, who recently wrote a review in Nature Cell Biology highlighting this idea. An important implication of this work is that diseases linked to mitochondrial dysfunction like neurodegeneration or normal aging process might be due to elevation in metabolites like 2HG.

This research was supported by National Institutes of Health grants R35CA197532, T32GM008061, T32 T32HL076139, K01DK093543 and R01DK111430, and Cancer Prevention and Research Institute of Texas New Investigator award RR140025.

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Mitochondria Behind Blood Cell Formation - Northwestern University NewsCenter

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.

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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 combined team of researchers from the University of Arkansas and Cornell University has found that a type of fungus kills female goldenrod soldier beetles in a unique wayby causing them to attract males, which assists ...

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Humans are responsible for the movement of an increasing number of species into new territories which they previously never inhabited. The number of established alien species varies according to world region. What was previously ...

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

Theres a famous scene in an Indiana Jones movie where the hero barely makes it under a closing gate descending on him in an underground tunnel. He rolls under the gate in the nick of time, but his signature fedora comes off. With fractions of a second to spare, he reaches his arm under the gate and snatches the hat.

Something like that happens in the cell. Sometimes, when chromosomes are being winched apart by the spindle into the daughter cells, fragments of DNA break off and become entangled in the spindles microtubules. Unless they are rescued and make it into the nuclei of the new cells, disaster could result. The resulting cells will become unstable, resulting in cancer or cell death. Time is of the essence! The cell is following a precisely choreographed screenplay, where thousands of actors must play their roles perfectly at the right time and place. Like the gate descending on Indiana Jones, the cleavage furrow is rapidly constricting the midpoint of the spindle, with those fragments stuck there. Can the cell rescue them in time?

This crisis happens daily in life. Like the city folk above ground, oblivious to Indiana Jones and his frantic brush with death under the streets, we hear and see nothing of the near-catastrophes happening inside our cells. But if it werent for the cells fast-acting hand, all would be lost. The dramatic true story is told in fascinating news from the University of California, Santa Cruz, under the title, Hail Mary mechanism can rescue cells with severely damaged chromosomes. The authors liken what happens to a quarterbacks all-or-nothing long pass in the last seconds of a critical football game. It calls for desperate plays.

William Sullivan calls this a worst case scenario for the cell. The potential consequences include cell death or a cancerous cell growing out of control. But Sullivan, a professor of molecular, cell, and developmental biology at UC Santa Cruz, has found that the cell still has one more trick up its sleeve to rescue the broken chromosome.

The latest findings from Sullivans lab, published in the June 5 issue of Journal of Cell Biology, reveal new aspects of a remarkable mechanism that carries broken chromosomes through the process of cell division so that they can be repaired and function normally in the daughter cells. [Emphasis added.]

Sullivans research team studied a strain of fruit flies that they mutated to increase the incidence of DNA fragmentation. By inserting fluorescent tags, they were able to witness this amazing mechanism, like a Hail Mary pass with time running out. What they saw was not unlike Indiana Joness arm reaching for his hat.

The mechanism involves the creation of a DNA tether which acts as a lifeline to keep the broken fragment connected to the chromosome.

Sullivans research has shown that chromosome fragments dont segregate with the rest of the chromosomes, but get pulled in later just before the newly forming nuclear membrane closes. The DNA tether seems to keep the nuclear envelope from closing, and then the chromosome fragment just glides right in at the last moment, Sullivan said.

Its a good thing this tether works most of the time. When it doesnt, the action-adventure movie turns into a horror flick.

If this mechanism fails, however, and the chromosome fragment gets left outside the nucleus, the consequences are dire. The fragment forms a micronucleus with its own membrane and becomes prone to extensive rearrangements of its genetic material, which can then be reincorporated into chromosomes during the next cell division. Micronuclei and genetic rearrangements are commonly seen in cancer cells.

Think about what is required for this trick to work. Genes have to construct the tether, and enzymes have to know where to attach it. This means that all the information to pull off this whole stunt has to be written into the script before the director calls, Action! Could evolution write a script like that? In the neo-Darwinist version, cells that did not have the tether would die or grow cancerous. The cost of selection would be enormous. All the players and their props would have to learn their roles by chance, figuring out by sheer dumb luck where to be and what to do before a cell could succeed at this stunt and survive. We dont think Sullivan or his funding agencies are relying on chance to pull that off.

We want to understand the mechanism that keeps that from happening, Sullivan said. We are currently identifying the genes responsible for generating the DNA tether, which could be promising novel targets for the next generation of cancer therapies.

Sullivan has just received a new four-year, $1.5 million grant from the National Institute of General Medical Sciences to continue this research.

The Hail Mary pass is just one of a whole catalog of strategies the cell can draw on to protect its genome. Heres another strategy announced at Rice University, where researchers determined that Biologys need for speed tolerates a few mistakes.

Biology must be in a hurry. In balancing speed and accuracy to duplicate DNA, produce proteins and carry out other processes, evolution has apparently determined that speed is of higher priority, according to Rice University researchers.

Rice scientists are challenging assumptions that perfectly accurate transcription and translation are critical to the success of biological systems. It turns out a few mistakes here and there arent critical as long as the great majority of the biopolymers produced are correct.

Although the researchers are evolutionists, we can see that what they really found is optimization at work (a form of intelligent design in action).

A new paper shows how nature has optimized two processes, DNA replication and protein translation, that are fundamental to life. By simultaneously analyzing the balance between speed and accuracy, the Rice team determined that naturally selected reaction rates optimize for speed as long as the error level is tolerable.

When you think about what a cell has to do before it divides, theres not much room for evolution in the mistakes. Millions of base pairs must be duplicated in a time crunch, while the molecular machinery is in operation. Its like duplicating a factory while the machinery is running! A smart manager will recognize that the cost of being too precise is not worth the delay if the results are adequate to meet the requirements. They use an analogy we are familiar with:

Kinetic proofreading is the biochemical process that allows enzymes, such as those responsible for protein and DNA production, to achieve better accuracy between chemically similar substrates. Sequences are compared to templates at multiple steps and are either approved or discarded, but each step requires time and energy resources and as a result various tradeoffs occur.

Additional checking processes slow down the system and consume extra energy, Banerjee said. Think of an airport security system that checks passengers. Higher security (accuracy) means a need for more personnel (energy), with longer waiting times for passengers (less speed).

Despite the one evolution reference, these researchers smell design:

That makes just as much sense for biology as it does for engineering, Igoshin said. Once youre accurate enough, you stop optimizing.

We see a similar optimization strategy in news from Brandeis University about double-stranded break (DSB) repair. When one strand of DNA breaks, thats bad. When both strands of DNA become separated, thats really bad. Specialized enzymes can inspect and repair these DSBs, but they also have to sacrifice accuracy for speed. The enzymes look for similar sequences to use as a template for the bandage that will re-join the strands.

But how perfect does the match have to be? Ranjith Anand, the first author on the Nature paper, said this was one of the central questions that the Haber lab wanted to answer.

They found that repair was still possible when every sixth base in a stretch of about 100 bases was different. Previous studies of RAD51 in the test tube had suggested that the protein had a much more stringent requirement for matching.

That one of the six base pairs could be a mismatch surprised the scientists. The process is permissive of mismatches during the repairing, says Anand.

We begin to see a kind of molecular triage going on, as if battlefield medics use whatever is on hand to keep the soldier from dying. Most damage gets accurately repaired, so the cell is unaffected, the article says. For somatic cells, imperfect bandages will probably cause no significant harm. Darwinism would require that the mistakes (1) become incorporated into the germline, and (2) provide functional innovations that are positively selected. And thus a wolf became a whale, and a dinosaur took flight into the skies.

Sensible viewers of these action adventures undoubtedly sense good directing, acting, and optimization behind them. Clifford Tabin expressed his amazement about lifes development in Phys.org back in 2013.

When I teach medical students, theyre more interested in the rare people who are born with birth defects, They want to understand embryology so they understand how things go awry, but Im more interested in the fact that for everyone sitting in my classroomall 200 of those medical students and dental students it went right! And every one of them has a heart on the left side and every one of them has two kidneys, and how the heck do you do that?

You are not just a ball of cells, he says; you are the result of mechanical principles that guide the growth of structures through many stages, subject to physical forces, that usually work. And that is indeed astonishing.

Photo: Hat from Indiana Jones movie, for sale at auction, by Deidre Willard (Indys hat) [CC BY 2.0], via Wikimedia Commons.

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Hat Grab: Cells Take Extreme Measures to Rescue Their DNA - Discovery Institute

Some bodily activities, sleeping, for instance, mostly occur once every 24 hours; they follow a circadian rhythm. Other bodily functions, such as body temperature, cognitive performance and blood pressure, present an additional 12-hour cycle, but little is known about the biological basis of their rhythm. A team of scientists from various institutions, including Baylor College of Medicine, has revealed that, in addition to 24-hour clocks, mammals and other organisms have 12-hour clocks that are autonomous, work independently from 24-hour clocks and can be modified by external factors. Studying 12-hour clocks is important because altered 12-hour cycles have been linked to human disease. The study appears in Cell Metabolism.

Our lab has been working on how the 24-hour cycles are regulated, and we and others have shown that disturbing these clocks may lead to diseases of metabolism, said senior author Dr. Bert OMalley, chair and professor of molecular and cellular biology and Thomas C. Thompson Chair in Cell Biology at Baylor College of Medicine. For instance, experimental evidence shows that night-shift workers who periodically change their night and day shifts or people who travel overseas often alter their sleep cycles, and this seems to make them prone to gain weight and develop diabetes and other alterations of metabolism that may lead to disease. Its not a good idea to disturb the circadian rhythm on a regular basis.

In addition to physiological activities that cycle every 24 hours, mammals and other organisms have activities that repeat every 12 hours. For example, it has been reported that blood pressure, body temperature, hormone levels and response to therapy fluctuate in 12-hour cycles. In addition, altered 12-hour cycles have been associated with human diseases. Other researchers had identified about 200 genes that are activated in 12-hour cycles. In this study, OMalley and his colleagues set out to determine whether there was a larger number of 12-hour genes and whether their cycles followed the definition of a biological clock, that is whether they worked autonomously and their oscillation could be adjusted by the environment.

Math meets biology to indentify the bodys internal clocks

Dr. Bokai Zhu, first author of this study and a postdoctoral fellow in the OMalley lab, carried out biological analyses to determine the activity of thousands of mice genes in time. Then, co-author Dr. Clifford Dacso, professor of molecular and cellular biology at Baylor College of Medicine, and co-author and mathematician Dr. Athanasios Antoulas, professor of electrical and computer engineering at Rice University, applied mathematical analyses to these biological data.

We were surprised to identify more than 3,000 genes that were expressed following 12-hour rhythms. A large portion of these genes was superimposed on the already known 24-hour gene activities, Zhu said.

The 12-hour clock is autonomous and can be synchronized by external cues

Further work showed that the 12-hour rhythms of genetic activity work as biological clocks. They occur regularly and autonomously in the cells, and their oscillation can be synchronized by certain external stimuli. OMalley and colleagues discovered that 12-hour clocks are independent from 24-hour clocks. When they experimentally eliminated a 24-hour clock, 12-hour clocks continued ticking. Furthermore, the external cues that can synchronize 24-hour clocks, such as sunlight, do not affect 12-hour clocks.

Of all the genes we analyzed, two sets with 12-hour cycles stood out; those involved with protein quality control and processing, which mainly occur in a cellular structure called endoplasmic reticulum, and those related to the energy supply of the cell, which involves the mitochondria, Zhu said. The activities of the endoplasmic reticulum and mitochondria depend on each other, and we have shown here that the 12-hour genes in the endoplasmic reticulum are synchronized with the 12-hour genes in the mitochondria, which provide the energy needed for protein processing.

In addition, we found that certain liver conditions are associated with disturbed 12-hour gene expression in mice. We anticipate that further study of 12-hour cycles might lead to opportunities to improve prevention of or treatments for diseases of the liver and other organs in the future, OMalley said.

Other contributors to this work include Qiang Zhang, Yinghong Pan, Emily M. Mace and Brian York. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Rice University, the University of Houston and the Max Planck Institute.

This research was supported by grants from the NationaI Institutes of Health (U24 DK097748 and R01 HD07857), the Brockman Foundation, the Center for Advancement of Science in Space, Peter J. Fluor Family Fund, Philip J. Carroll, Jr. Professorship, Joyce Family Foundation, the National Science Foundation Grant CCF-1320866 and the German Science Foundation Grant AN-693/1-1.

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12-hour biological clock coordinates essential bodily functions - Baylor College of Medicine News (press release)

June 6, 2017 First author Angela Arensdorf, Ph.D., and corresponding author Stacey Ogden, Ph.D., an associate member of the St. Jude Department of Cell and Molecular Biology. Credit: Peter Barta / St. Jude Children's Research Hospital

St. Jude Children's Research Hospital molecular biologists have identified an enzyme that activates and "supercharges" cellular machinery that controls how cells become specialized cells in the body.

Malfunction of that machinery, dubbed the Sonic Hedgehog pathway, causes a variety of developmental disorders and cancers, including childhood medulloblastoma and basal cell carcinoma. Researchers believe their basic discovery opens a new research pathway that could lead to drugs to treat such disorders.

Led by Stacey Ogden, Ph.D., an associate member of the St. Jude Department of Cell and Molecular Biology, the research was published June 6 in the journal Cell Reports.

The scientific puzzle the researchers sought to understand was how a major activator of the Sonic Hedgehog pathway, called Smoothened, manages to make its way into an antenna-like cell structure called a "primary cilium," where it communicates with its downstream signaling partners.

Every cell in the body sprouts a primary cilium, which harbors a whole factory of cellular machinery that the cell uses to translate external stimuli into cell responses. Such stimuli include mechanical movement and chemical signals such as hormones. Normally, Smoothened is barred from the primary cilium, keeping the Sonic Hedgehog pathway safely controlled.

In their experiments with cell cultures, the researchers discovered that an enzyme called Phospholipase A2 triggers a mechanism that opens the way for Smoothened movement into the cilium. What's more, the phospholipase triggers an amplification that "supercharges" Smoothened signaling.

"We've basically revealed a new layer of regulation of Smoothened trafficking," Ogden said. "This is a very hot area of research now, because Smoothened trafficking appears to be a very crucial control point for signaling activity. So, if you can change Smoothened trafficking, you can very easily adjust the amplitude of Sonic Hedgehog signaling."

The basic finding has potential clinical importance, Ogden said, because reduced activity in the Sonic Hedgehog pathway is commonly found in genetic disorders of primary cilia function. These disorders include Joubert syndrome, Bardet-Biedl syndrome, Ellis van Creveld syndrome and polycystic kidney diseaseone of the most common genetic diseases in the U.S., affecting more than 600,000 people. Better understanding of the control machinery for the Sonic Hedgehog pathway could lead to more effective therapies for the disorders, Ogden said.

Conversely, hyperactivity of the Sonic Hedgehog pathway is the cause of about 30 percent of childhood medulloblastomas. Medulloblastoma is the most common malignant brain tumor of childhood, accounting for about 20 percent of all childhood brain tumors. Current treatments using surgery, radiation and chemotherapy cause severe side effects, so more precise drug treatments are urgently needed.

"One of the drugs now being used to treat medulloblastoma is a Smoothened inhibitor," Ogden said. "But tumor cells frequently become resistant to this drug and begin to grow again because of mutations in Smoothened that enable it to overcome the drug's inhibition. We want to determine whether drugs to inhibit Phospholipase A2 could reduce Sonic Hedgehog activity in cases where Smoothened becomes insensitive to targeted inhibition."

In adults, Hedgehog pathway hyperactivation also causes basal cell carcinoma, the most common skin cancer and one of the most common cancers. Hedgehog pathway activation also may accelerate other types of tumors by affecting the tissue surrounding the tumor, called the stroma, to create an environment more conducive to growth, Ogden said.

"So Hedgehog pathway inhibitors may be useful in combination therapies with other traditional chemotherapies for other types of solid tumors," she said.

In further research, Ogden and her colleagues are continuing to examine Smoothened regulation and exploring drugs that affect its activity.

Explore further: Blocking a protein in a critical signaling pathway could offer a new way to combat tumors

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St. Jude Children's Research Hospital molecular biologists have identified an enzyme that activates and "supercharges" cellular machinery that controls how cells become specialized cells in the body.

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Researchers identify a key controller of biological machinery in cell's ... - Phys.Org