illustration by the project twins

Single-cell biology is a hot topic these days. And at the cutting edge of the field is single-cell RNA sequencing (scRNA-seq).

Conventional bulk methods of RNA sequencing (RNA-seq) process hundreds of thousands of cells at a time and average out the differences. But no two cells are exactly alike, and scRNA-seq can reveal the subtle changes that make each one unique. It can even reveal entirely new cell types.

For instance, after using scRNA-seq to probe some 2,400 immune-system cells, Aviv Regev of the Broad Institute in Cambridge, Massachusetts, and her colleagues came across some dendritic cells that had potent T-cell-stimulating activity (A.-C. Villani et al. Science 356, eaah4573; 2017). Regev says that a vaccine to stimulate these cells could potentially boost the immune system and protect against cancer.

But such discoveries are hard-won. Its much more difficult to manipulate individual cells than large populations, and because each cell yields only a tiny amount of RNA, theres no room for error. Another problem is analysing the enormous amounts of data that result not least because the tools used can be unintuitive.

Typically, RNA-seq data is analysed by laboriously typing commands into a Unix operating system. Data files are passed from one software package to the next, with each tool tackling one step in the process: genome alignment, quality control, variant calling and so on.

The process is complicated. But for bulk RNA-seq, at least, a consensus has emerged as to which algorithms work best for each step and how they should be run. As a result, pipelines now exist that are, if not exactly plug-and-play, at least tractable for non-experts. To analyse differences in gene expression, says Aaron Lun, a computational biologist at Cancer Research UK in Cambridge, bulk RNA-seq is pretty much a solved problem.

The same cannot be said for scRNA-seq: researchers are still working out what they can do with the data sets and which algorithms are the most useful.

But a range of online resources and tools are beginning to ease the process of scRNA-seq data analysis. One page at GitHub, called Awesome Single Cell (go.nature.com/2rmb1hp), catalogues more than 70 tools and resources, covering every step of the analysis process. The field has spawned a cottage industry of computational-biology tools, says Cole Trapnell, a biologist at the University of Washington in Seattle.

Lana Garmire, a bioinformatician at the University of Hawaii in Honolulu, laid out the basic steps of scRNA-seq data analysis (and some 48 tools to perform them) in a review published last year (O. B. Poirion et al. Front. Genet. 7, 163; 2016). Although each experiment is unique, she says, most analysis pipelines follow the same steps to clean up and filter the sequencing data, work out which transcripts are expressed and correct for differences in amplification efficiency. Researchers then run one or more secondary analyses to detect subpopulations and other functions.

In many cases, says Christina Kendziorski, a biostatistician at the University of WisconsinMadison, the tools used in bulk RNA-seq can be applied to scRNA-seq. But fundamental differences in the data mean that this is not always possible. For one thing, single-cell data are noisier, says Lun. With so little RNA to work with, small changes in amplification and capture efficiencies can produce large differences from cell to cell and day to day that have nothing to do with biology. Researchers must therefore be vigilant for batch effects, in which seemingly identical cells prepared on different days differ for purely technical reasons, and for dropouts genes that are expressed in the cell but not picked up in the sequence data.

Another challenge is the scale, says Joshua Ho, a bioinformatician at the Victor Chang Cardiac Research Institute in Sydney, Australia. A typical bulk RNA-seq experiment involves a handful of samples, but scRNA-seq studies can involve thousands. Tools that can handle a dozen samples often slow to a crawl when confronted with ten or a hundred times as many. (Hos Falco software taps on-demand cloud-computing resources to address that problem.)

Even the seemingly simple question of what constitutes a good cell preparation is complicated in the world of scRNA-seq. Luns workflow assumes that most of the cells have approximately equivalent RNA abundances. But that assumption isnt necessarily true, he says. For instance, he says, naive T cells, which have never been activated by an antigen and are relatively quiescent, tend to have less messenger RNA than other immune cells and could end up being removed during analysis because a program thinks there is insufficient RNA for processing.

Perhaps most significantly, researchers performing scRNA-seq tend to ask different questions from those analysing bulk RNA. Bulk analyses typically investigate how gene expression differs between two or more treatment conditions. But researchers working with single cells are often aiming to identify new cell types or states or reconstruct developmental cellular pathways. Because the aims are different, that necessarily requires a different set of tools to analyse the data, says Lun.

One common type of single-cell analysis, for instance, is dimensionality reduction. This process simplifies data sets to facilitate the identification of similar cells. According to Martin Hemberg, a computational biologist at the Wellcome Trust Sanger Institute in Cambridge, UK, scRNA-seq data represent each cell as a list of 20,000 gene-expression values. Dimensionality-reduction algorithms such as principal component analysis (PCA) and t-distributed stochastic neighbour embedding (t-SNE) effectively project those shapes into two or three dimensions, making clusters of similar cells apparent. Another popular application is pseudo-time analysis. Trapnell developed the first such tool, called Monocle, in 2014. The software uses machine learning to infer from an scRNA-seq experiment the sequence of gene-expression changes that accompany cellular differentiation, much like inferring the path of a foot race by photographing the runners from the air, Trapnell says.

Other tools address subpopulation detection (for instance, Pagoda, from Peter Kharchenko at Harvard Medical School in Boston, Massachusetts) and spatial positioning, which uses data on the distribution of gene expression in tissues to determine where in a tissue each transcriptome arose. Rahul Satija of the New York Genome Center in New York City, who developed one such tool, Seurat, as a postdoc with Regev, says that the software uses these data to position cells as points in 3D space. Thats why we named the package Seurat, he explains, because the dots reminded us of points on a pointillist painting.

Although targeted to specific tasks, these tools often address multiple functions. Seurat, for instance, powered the cell-subpopulation analysis Regevs team performed to identify new classes of immune cells.

Most scRNA-seq tools exist as Unix programs or packages in the programming language R. But relatively few biologists are comfortable working in those environments, says Gene Yeo, a bioinformatician at the University of California, San Diego. Even if they are, they may lack the time required to download and configure everything to make such tools work.

Some ready-to-use pipelines have been developed. And there are end-to-end graphical tools too, including the commercial GenSeq package from FlowJo, as well as a pair of open-source web tools: Granatum from Garmires group, and ASAP (the Automated Single-cell Analysis Pipeline) from the lab of Bart Deplancke, a bioengineer at the Swiss Federal Institute of Technology in Lausanne.

ASAP and Granatum use a web browser to provide relatively simple, interactive workflows that allow researchers to explore their data graphically. Users upload their data and the software walks them through the steps one by one. For ASAP, that means taking data through preprocessing, visualization, clustering and differential gene-expression analysis; Granatum allows pseudo-time analyses and the integration of protein-interaction data as well.

According to both Garmire and Deplancke, ASAP and Granatum were designed to allow researchers and computational biologists to work together. Researchers used to think of [bioinformaticians] as magical creatures who just get the data and magically generate the result, says Xun Zhu, a PhD student at the University of Hawaii at Manoa, and lead developer on Granatum. Now they can participate a little bit in terms of tuning the parameters. And thats a good thing.

The tools arent perfect for every situation, of course. A pipeline that excels at identifying cell types, for instance, might stumble with pseudo-time analysis. Plus, appropriate methods are very data-set dependent, says Sandrine Dudoit, a biostatistician at the University of California, Berkeley. The methods and tuning parameters may need to be adjusted to account for variables such as sequencing length. But Marioni says its important not to put complete faith in the pipeline. Just because the satellite navigation tells you to drive into the river, you dont drive into the river, he says.

For beginners, caution is warranted. Bioinformatics tools can almost always yield an answer; the question is, does that answer mean anything? Dudoits advice is do some exploratory analysis, and verify that the assumptions underlying your chosen algorithms make sense.

Some analytical tasks still remain challenging, says Satija, including comparing data sets across experimental conditions or organisms and integrating data from different omics. (A planned update to Seurat should address the former issue, he notes.)

But enough tools exist to keep most researchers occupied. Kendziorski suggests that people who are interested just dive in. Each new tool can unveil another facet of biology; just keep your eyes on the science, and be judicious in your choice.

Excerpt from:
Single-cell sequencing made simple - Nature.com

The Salk Institute has hired two new faculty members, bringing expertise in immunology and mitochondrial function.

* Susan Kaech will become director of the Norris Center for Immunobiology and Microbial Pathogenesis.

* Gerald Shadel will join Salks Molecular and Cell Biology Laboratory.

Kaech studies how immune cells called T cells remember previous infections, so they can respond more quickly to the same infection. Shes also studied how cancer suppresses the immune response.

Shadel specializes in the roles of mitochondrial dysfunction in aging and disease. Mitochondria are cellular organelles that contain their own DNA and are best known as the cells energy producers. Unhealthy mitochondria are a factor in Alzheimers and Parkinsons diseases, as well as cardiovascular ailments.

Both currently at Yale University, they are scheduled to arrive in early 2018. While married to each other, Kaech and Shadel conduct their research independently.

Kaechs research has won her awards including the Howard Hughes Medical Institute Early Career Scientist award, the Presidential Early Career Award for Scientists and Engineers, the Edward Mallinckrodt Jr. award and the Burroughs-Wellcome Foundation award.

Kaech and Shadel said they were attracted to the Salk Institute not only because of its reputation as a center of basic research, but by the scientific community in San Diego as a whole.

The scientific community is very welcoming and warm and scientifically interactive, Kaech said.

Moreover, the scientific community participates in the larger San Diego community, taking part in activities such as educational outreach, fundraising and philanthropy.

It seems to be a little bit more vibrant in the San Diego community than what I've experienced before, Kaech said.

Likewise, the nonscientific community is interested in what San Diego scientists are doing.

So that's another kind of attraction, (the interest) seems a little bit more communitywide, Kaech said. Science is clearly on the minds of people in San Diego.

The Salk Institute itself exemplifies this collaborative spirit, Kaech said.

Great minds are there, all interacting together, she said. How they cross-fertilize each other's research is very exciting, for me to be a part of that.

Shadels honors include an Amgen Outstanding Investigator award, the Glenn Foundations Glenn Award for Research in Biological Mechanisms of Aging and the Glenn/AFAR Breakthroughs in Gerontology Award.

Shadel said being located at the Salk Institute will put him in a better position to study the multiple functions of mitochondria, in part by interdisciplinary research with other experts.

I think my lab has been instrumental, along with others, to show that mitochondria are integrated into cells for other reasons in addition to the energetic functions, Shadel said.

What really excited me about the Salk was this chance to interact with really great experts in other fields and bring my research to the interface with other disciplines and really answer questions in bold new ways.

I also knew several of the people who were professors there already who are involved in the aging research realm mostly, but also others are involved in metabolism as well.

What this leads to is the power of fundamental science to help solve some of societys most pressing problems, Shadel said.

In my opinion, the most transformative types of discoveries are born out of pure basic research endeavors, and the Salk Institute has a really rich history of groundbreaking basic science, he said.

bradley.fikes@sduniontribune.com

(619) 293-1020

UPDATES:

The Salk Institute has hired two new faculty members, bringing expertise in immunology and mitochondrial function. Both from Yale University, they are scheduled to arrive in early 2018 with the rank of full professor.

-- Susan Kaech will become director of the Norris Center for Immunobiology and Microbial Pathogenesis. She studies how immune cells called T cells remember previous infections, enabling them to mobilize more rapidly to subsequent exposure.

-- Gerald Shadel will join the Salks Molecular and Cell Biology Laboratory. He is noted for research on the role of mitochondrial dysfunction in aging and disease. Mitochondria are organelles that contain their own DNA.

View original post here:
Salk Institute hires two noted researchers - The San Diego Union-Tribune

Leukemia researchers led by Dr. John Dick have traced the origins of relapse in acute myeloid leukemia (AML) to rare therapy-resistant leukemia stem cells that are already present at diagnosis and before chemotherapy begins.

They have also identified two distinct stem-cell like populations from which relapse can arise in different patients in this aggressive cancer that they previously showed starts in blood stem cells in the bone marrow.

The findings provide significant insights into cell types fated to relapse and can help accelerate the quest for new, upfront therapies, says Dr. Dick, a Senior Scientist at Princess Margaret Cancer Centre, University Health Network, and Professor in the Department of Molecular Genetics, University of Toronto. He holds the Canada Research Chair in Stem Cell Biology and is Co-leader of the Acute Leukemia Translational Research Initiative at the Ontario Institute for Cancer Research. This study was primarily undertaken by post-doctoral fellow Dr. Liran Shlush and Scientific Associate Dr. Amanda Mitchell.

"For the first time, we have married together knowledge of stem cell biology and genetics areas that historically have often been operating as separate camps to identify mutations stem cells carry and how they are related to one another in AML," says Dr. Dick, who pioneered the cancer stem cell field by identifying leukemia stem cells in 1994.

A decade ago, he replicated the entire human leukemia disease process by introducing oncogenes into normal human blood cells, transplanting them into xenografts (special immune-deficient mice that accept human grafts) and watching leukemia develop a motherlode discovery that has guided leukemia research ever since.

The researchers set out to solve the mystery of AML relapse by analysing paired patient samples of blood taken at the initial clinic visit and blood taken post-treatment when disease recurred.

"First, we asked what are the similarities and differences between these samples. We carried out detailed genetic studies and used whole genome sequencing to look at every part of the DNA at diagnosis, and every part of the DNA at relapse," says Dr. Dick. "Next, we asked in which cells are genetic changes occurring."

The two-part approach netted a set of mutations seen only at relapse that enabled the team to sift and sort leukemic and normal stem cells using tools developed in the Dick lab a few years ago to zero in on specific cell types fated to relapse.

"This is a story that couldn't have happened five years ago, but with the evolution of deep sequencing, we were able to use the technology at just the right time and harness it with what we've been working on for decades," he says.

Today's findings augment recent research also published in Nature (Dec.7, 2016) detailing the team's development of a "stemness biomarker" a 17-gene signature derived from leukemia stem cells that can predict at diagnosis which AML patients will respond to standard treatment.

Dr. Dick says: "Our new findings add to that knowledge and we hope that we will soon have a new biomarker that will tell whether a patient will respond to standard chemotherapy, and then another to track patients in remission to identify those where treatment failed and the rare leukemia stem cells are coming back.

"These new kinds of biomarkers will lead to new kinds of clinical trials with targeted chemotherapy. Right now, everybody gets one size fits all because in AML we've never had any opportunity to identify patients upfront, only after they relapse. Now we have the first step to identify these patients at the outset and during remission."

The research was funded by the Ontario Institute for Cancer Research, the Cancer Stem Cell Consortium via Genome Canada and the Ontario Genomics Institute, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Terry Fox Foundation, a Canada Research Chair and The Princess Margaret Cancer Foundation.

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

Reference:

Shlush, L. I., Mitchell, A., Heisler, L., Abelson, S., Ng, S. W., Trotman-Grant, A., . . . Dick, J. E. (2017). Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. doi:10.1038/nature22993

Go here to see the original:
Stem Cells Play a Role in Acute Myeloid Leukemia Relapse - Technology Networks

Scientists canstudy only the things that we can observe. We are limited to studying natural, detectable phenomena.

In the history of biology, bursts of discoveries often follow breakthroughs in technology.

The first microscopes in the 1590s permitted discovery of cells and microbes in the 1600s. Biologists described the tenets of modern cell theory by the 1850s. All organisms are made of cells. Cells are the basic unit of living things. Cells are produced by other cells.

After World War II, the 1946 Atomic Energy Act permitted the U.S. government to sell radioactive isotopes, produced in nuclear reactors, for research and medical treatments. Using these atomic energy byproducts, biologists identified DNA as the genetic material in 1952. They described the structure of DNA in 1953, and explained how DNA replicates in 1958.

Those dominoes of DNA discovery that began falling in the middle of the last century led to the release of the complete human genome sequence at the start of this century. Along the way, we invented technologies to automate gene sequencing. And what started as a slow, laborious, expensive process has become a rapid, easy, inexpensive way to map every gene of any organism thata biologist studies.

At the start of the DNA age, biologists identified a species of interest and acquired a specimen. They then extracted, sequenced and compared its genes with other species.

Modern, automated gene sequencing reverses this process.

With high-throughput DNA sequencers, biologists identify all of the genes in a sample of ocean water or human gut contents. They use computer programs to assemble the most likely community of microorganisms in the sample. They use gene sequences to identify species present in a microbiome, all of the microbes in the sample.

Invention of microscopes led to the discovery of cells and microorganisms. Invention of high-throughput gene sequencing techniques has led to the discovery of microbiomes around us, on us and in us.

Biologists have just begun to discover the extent and impact of microbiomes. Consider these microbiome discoveries published in the past two months:

Pregnant mothers with decreased vaginal microbiome diversity experience more preterm births.

Characterizing the gut microbiome of patients with inflammatory bowel disease can advise effective therapies to treat the condition.

Patients with an imbalanced gut microbiome are more likely to have scleroderma, an autoimmune disease that hardens and scars connective tissue.

Composition of a persons microbiome might influence his or her risk for obesity and nonalcoholic fatty liver disease. Characterization of the gut microbiome might provide early warning of the disease.

Composition of the microbiome in hair follicles might influence the development of acne in patients.

What you dont see, you cant understand. As individual organisms, we are living ecological communities with healthy and diverse or not microbiomes on us and in us. We interact with and depend on individuals of other species to feed us and provide us other ecological services. Each of those individuals has a microbiome.

You cant tell the players without a program. Were in the earliest stages of writing programs to identify players in microbiomes on which we depend.

Steve Rissing is a biology professor at Ohio State University.

steverissing@hotmail.com

See the original post:
Biology: Technological advances help us understand the world in and around us - The Columbus Dispatch

June 30, 2017 Researchers have found a way to tweak cells' movement patterns to resemble those of other cell types. Credit: Tim Phelps/Johns Hopkins University

Johns Hopkins researchers report they have uncovered a mechanism in amoebae that rapidly changes the way cells migrate by resetting their sensitivity to the naturally occurring internal signaling events that drive such movement. The finding, described in a report published online March 28 in Nature Cell Biology, demonstrates that the migratory behavior of cells may be less "hard-wired" than previously thought, the researchers say, and advances the future possibility of finding ways to manipulate and control some deadly forms of cell migration, including cancer metastasis.

"In different tissues inside the body, cells adopt different ways to migrate, based on their genetic profile and environment," says Yuchuan Miao, a graduate student at the Johns Hopkins University School of Medicine and lead author of the study. "This gives them better efficiency to perform specific tasks." For example, white blood cells rhythmically extend small protrusions that allow them to squeeze through blood vessels, whereas skin cells glide, like moving "fans," to close wounds.

On the other hand, Miao notes, uncontrolled cell migration contributes to diseases, including cancer and atherosclerosis, the two leading causes of death in the United States. The migration of tumor cells to distant sites in the body, or metastasis, is what kills most cancer patients, and defective white blood cell migration causes atherosclerosis and inflammatory diseases, such as arthritis, which affects 54 million Americans and costs more than $125 billion annually in medical expenditures and lost earnings.

Because cells migrate in different ways, many drugs already designed to prevent migration work only narrowly and are rarely more than mildly effective, fueling the search for new strategies to control migratory switches and treat migration-related diseases, according to senior author Peter Devreotes, Ph.D., a professor and director of the Department of Cell Biology at the Johns Hopkins University School of Medicine's Institute for Basic Biomedical Research.

"People have thought that cells are typed by the way they look and migrate; our work shows that we can change the cell's migrating mode within minutes," adds Devreotes.

For the new study, Devreotes and his team focused on how chemical signaling molecules activate the motility machinery to generate protrusions, cellular "feet" that are a first step in migration. To do this, they engineered a strain of Dictyostelium discoideum, an amoeba that can move itself around in a manner similar to white blood cells. The engineered amoebae responded to the chemical rapamycin by rapidly moving the enzyme Inp54p to the cell surface, where it disrupted the signaling network. The cells also contained fluorescent proteins, or "markers," that lit up and showed researchers when and where signaling molecules were at work.

Experiments showed that the engineered cells changed their migration behavior within minutes of Inp54p recruitment. Some cells, which the researchers termed "oscillators," first extended protrusions all around the cell margins and then suddenly pulled them back again, moving in short spurts before repeating the cycle. Fluorescent markers showed that these cycles corresponded to alternating periods of total activation and inactivation, in contrast to the small bursts of activity seen in normal cells.

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Other cells began to glide as "fans," with a broad zone of protrusions marked by persistent signaling activity.

Devreotes describes the signaling behavior at the cell surface as a series of waves of activated signaling molecules that switch on the cellular motility machinery as they spread. In their normal state, cells spontaneously initiated signaling events to form short-lived waves that made small protrusions.

In contrast, oscillators had faster signaling waves that reached the entire cell boundary to generate protrusions before dying out. Fans also showed expanded waves that continually activated the cell front without ever reaching the cell rear, resulting in wide, persistent protrusions.

The scientists say their experiments show that the cell movement changes they saw resulted from lowering the threshold level of signaling activity required to form a wave. That is, cells with a lower threshold are more likely to generate waves and, once initiated, the activation signals spread farther with each step.

Devreotes says the team's experimental results offer what appears to be the first direct evidence that waves of signaling molecules drive migratory behavior. Previously, his laboratory showed a link between signaling and migration, but had not specifically examined waves.

In further experiments, Devreotes and his team found that they could recruit different proteins to shift cell motility, suggesting, he says, that altering threshold is a general cell property that can change behaviorno matter how cells migrate. His team was also able to restore normal motility to fans and oscillators by blocking various signaling activities, suggesting new targets for drugs that could be designed to control migration.

Devreotes cautions that what happens in an amoeba may not have an exact counterpart in a human cell, but studies in his lab suggest that something like the wave-signaling mechanism they uncovered operates in human cells as well.

The bottom line, says Miao, is that "we now know we can change signaling wave behavior to control the types of protrusions cells make. When cells have different protrusions, they have different migratory modes. When we come to understand the essential differences between cells' migratory modes, we should have better ways to control them during disease conditions."

Explore further: How cells communicate to move together as a group

More information: Yuchuan Miao et al. Altering the threshold of an excitable signal transduction network changes cell migratory modes, Nature Cell Biology (2017). DOI: 10.1038/ncb3495

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Read this article:
Scientists manipulate 'signaling' molecules to control cell migration - Phys.Org

Johns Hopkins researchers report they have uncovered a mechanism in amoebae that rapidly changes the way cells migrate by resetting their sensitivity to the naturally occurring internal signaling events that drive such movement. The finding, described in a report published online March 28 in Nature Cell Biology, demonstrates that the migratory behavior of cells may be less hard-wired than previously thought, the researchers say, and advances the future possibility of finding ways to manipulate and control some deadly forms of cell migration, including cancer metastasis.

"In different tissues inside the body, cells adopt different ways to migrate, based on their genetic profile and environment," says Yuchuan Miao, a graduate student at the Johns Hopkins University School of Medicine and lead author of the study. "This gives them better efficiency to perform specific tasks." For example, white blood cells rhythmically extend small protrusions that allow them to squeeze through blood vessels, whereas skin cells glide, like moving fans, to close wounds.

On the other hand, Miao notes, uncontrolled cell migration contributes to diseases, including cancer and atherosclerosis, the two leading causes of death in the United States. The migration of tumor cells to distant sites in the body, or metastasis, is what kills most cancer patients, and defective white blood cell migration causes atherosclerosis and inflammatory diseases, such as arthritis, which affects 54 million Americans and costs more than $125 billion annually in medical expenditures and lost earnings.

Because cells migrate in different ways, many drugs already designed to prevent migration work only narrowly and are rarely more than mildly effective, fueling the search for new strategies to control migratory switches and treat migration-related diseases, according to senior author Peter Devreotes, Ph.D., a professor and director of the Department of Cell Biology at the Johns Hopkins University School of Medicines Institute for Basic Biomedical Research.

People have thought that cells are typed by the way they look and migrate; our work shows that we can change the cell's migrating mode within minutes, adds Devreotes.

For the new study, Devreotes and his team focused on how chemical signaling molecules activate the motility machinery to generate protrusions, cellular feet that are a first step in migration. To do this, they engineered a strain of Dictyostelium discoideum, an amoeba that can move itself around in a manner similar to white blood cells. The engineered amoebae responded to the chemical rapamycin by rapidly moving the enzyme Inp54p to the cell surface, where it disrupted the signaling network. The cells also contained fluorescent proteins, or markers, that lit up and showed researchers when and where signaling molecules were at work.

Experiments showed that the engineered cells changed their migration behavior within minutes of Inp54p recruitment. Some cells, which the researchers termed oscillators, first extended protrusions all around the cell margins and then suddenly pulled them back again, moving in short spurts before repeating the cycle. Fluorescent markers showed that these cycles corresponded to alternating periods of total activation and inactivation, in contrast to the small bursts of activity seen in normal cells.

Other cells began to glide as fans, with a broad zone of protrusions marked by persistent signaling activity.

Devreotes describes the signaling behavior at the cell surface as a series of waves of activated signaling molecules that switch on the cellular motility machinery as they spread. In their normal state, cells spontaneously initiated signaling events to form short-lived waves that made small protrusions.

In contrast, oscillators had faster signaling waves that reached the entire cell boundary to generate protrusions before dying out. Fans also showed expanded waves that continually activated the cell front without ever reaching the cell rear, resulting in wide, persistent protrusions.

The scientists say their experiments show that the cell movement changes they saw resulted from lowering the threshold level of signaling activity required to form a wave. That is, cells with a lower threshold are more likely to generate waves and, once initiated, the activation signals spread farther with each step.

Devreotes says the teams experimental results offer what appears to be the first direct evidence that waves of signaling molecules drive migratory behavior. Previously, his laboratory showed a link between signaling and migration, but had not specifically examined waves.

In further experiments, Devreotes and his team found that they could recruit different proteins to shift cell motility, suggesting, he says, that altering threshold is a general cell property that can change behaviorno matter how cells migrate. His team was also able to restore normal motility to fans and oscillators by blocking various signaling activities, suggesting new targets for drugs that could be designed to control migration.

Devreotes cautions that what happens in an amoeba may not have an exact counterpart in a human cell, but studies in his lab suggest that something like the wave-signaling mechanism they uncovered operates in human cells as well.

The bottom line, says Miao, is that we now know we can change signaling wave behavior to control the types of protrusions cells make. When cells have different protrusions, they have different migratory modes. When we come to understand the essential differences between cells migratory modes, we should have better ways to control them during disease conditions.

Read more:
Scientists Manipulate 'Signaling' Molecules to Control Cell Migration - Bioscience Technology

Lebanon Dartmouth-Hitchcock and Geisel School of Medicine at Dartmouth announced the hiring of a new leader for Norris Cotton Cancer Center in a release on Thursday.

Dr. Steven Leach, 57, a surgical oncologist, comes to Norris Cotton from the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York.

His new position will include overseeing cancer research at Dartmouth and the Geisel School of Medicine, as well as the cancer care that is provided throughout Dartmouth-Hitchcocks health system.

Both D-H and Dartmouth officials welcomed Leach in Thursdays release.

Dr. Leach is a world renowned pancreatic cancer specialist with significant interest in the biology, models, and mechanisms of cancer development and in genomic research to perform sequencing and analysis of the cell types involved in human pancreatic cancer, said Dr. James Weinstein, D-Hs outgoing chief executive.

He will lead Dartmouth-Hitchcock and the Cancer Center into a new era of research and discovery at the molecular level that will benefit patients for generations to come.

At Geisel, where Leach will hold the title of Preston T. and Virginia R. Kelsey Distinguished Chair in Cancer, the schools dean Dr. Duane Compton said, I look forward to working with (Leach) to grow our cancer-related research programs across Dartmouth and build on our outstanding cancer clinical care through Dartmouth-Hitchcock.

Leach will be the first permanent director of the center since former director Mark Israel left the post last fall. Chris Amos, the chairman of Geisels biomedical data science department, has served as interim director since October.

Leach was drawn to the position at Norris Cotton because of the opportunity to work throughout the region in with a multidisciplinary focus in collaboration with researchers at Geisel, D-H and Dartmouth College to push scientific envelopes, he said, in a phone interview on Thursday afternoon.

While hes in the midst of transitioning to the center, Leach said hes deeply involved in a crash course in all things Dartmouth ... issues and opportunities.

Leach comes to the job amid controversy about how funds raised for cancer research were spent. In October, Israel filed a lawsuit against Dartmouth-Hitchcock, alleging that he was ousted in an act of illegal retaliation after he objected to the diversion of $6 million raised for cancer research, including $1.6 million raised from The Prouty, Norris Cottons signature fundraising event.

D-H subsequently asked Grafton County Superior Court Judge Lawrence A. MacLeod Jr. to move the case to arbitration and, in April, MacLeod agreed. MacLeod has not yet ruled on a motion Israel filed last month seeking permission to file an amended suit.

Separately, Thomas Donovan, the director of the Charitable Trusts Unit in the New Hampshire Attorney Generals Office, concluded in January that D-H had not violated the law in 2015 when it spent money from donors on salary, equipment and occupancy costs associated with research.

And in February, cancer center officials announced in a Valley News op-ed a pledge that supporters donations will be used only for activities related to research and patient care, as well as governance guidelines written into a new agreement between D-H and Dartmouth College that clarify the authority of the centers director, who is a joint employee of both organizations.

For his part, Leach said he is aware of the issues relating to the way these funds were spent, but he has full confidence in the leadership of the two organizations moving forward.

Im confident in the leadership there that weve got everything in place, he said.

Leach himself is an enthusiastic fundraiser and he looks forward to connecting with people to tell the story of the wonderful science thats being done at Dartmouth.

(Its) something I really enjoy, he said.

Leach brings experiences as a researcher, teacher and clinician to the position.

He has served as the director for Sloan Ketterings pancreatic research center since it opened in 2014. He is also a professor of surgery at Weill Cornell Medical College of Cornell University.

Prior to coming to New York, Leach worked at Johns Hopkins University where he was a professor of pancreatic cancer research, surgery, oncology and cell biology, and chief of the division of surgical oncology.

At heart, Leach said he is a physician scientist, who began as a surgeon operating on all kinds of cancer patients and moved into research, teaching and administrative roles.

Leach holds a bachelors degree in biology from Princeton University and a medical degree from Emory University. He did a residency in general surgery and a post-doctoral research fellowship at Yale University, and a surgical oncology fellowship at the University of Texas MD Anderson Cancer Center.

He recently completed a term on Princetons board of trustees and serves as chairman of the Pancreatic Cancer Action Networks Scientific and Medical Advisory Board.

He expects to start the new position in September, but will be in the Upper Valley biking 50 miles in The Prouty on July 8.

Im looking forward to coming up and experiencing The Prouty, Leach said.

Nora Doyle-Burr can be reached at ndoyleburr@vnews.com or 603-727-3213.

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Norris Cotton Cancer Center Announces New Chief From NY - Valley News

News By Nathan Luzum | Thursday, June 29 Courtesy of Wikimedia Commons

Zebrafish are model organisms to study because they have similargenetic structure to humans.

Zebrafish, a model organism already renowned for its regenerative abilities, has shown promise in yet another area of the fieldspinal regeneration.

Duke researchers discovered that when massive cushioning cells in the zebrafish notochorda precursor to the spine in vertebratesare damaged, another type of cell can find and replace the damaged ones. Because these cushioningor vacuolatedcells are similar betweenfish and humans, the discovery could yield clues with the potential tohelp victims of back or neck pain.

We saw that a cell type surrounding the giant cells moved in to the region of disruption and [was] actually able to replace the giant cells that had been compromised, restoring the notochord structure, wrote Jamie Garcia, graduate student in the School of Medicineand co-first author of the paper.

Michel Bagnat, senior author of the paper and associate professor of cell biology, likened the notochord to a tube. The outside of the notochord, orcasing of the tube, is composed of sheath cells, while the interior houses immense, egg-shaped vacuolated cells. These vacuolated cells account for the notochords ability to cushion and stretch.

However, Bagnat explained, the initial purpose of the research was not to identify a spinal repair mechanism, but rather to explain how the notochord can withstand such heavymechanical stress.

What you have is a very large cell, which is presumably fragile, that is subject to a lot of stress, he said. And then we ask, How is it keeping together?

They first concentrated on caveolaeminuscule pockets of the cell membraneas one possible explanation for the notochord's durability, and discovered that vacuolated cells lacking caveolae collapsed under heavy stress, ceasingto function properly.

We made mutants to basically disrupt [caveolae], and we were expecting that there would be some sort of disruption in these cells, which we found, Bagnat said.

The role of caveolae in the notochord matched the original hypothesis, but the research took an unexpected turnwhen the mutant zebrafish lacking proper caveolae ended up developing a fully formed spine.Bagnat explained that this was because the surrounding sheath cells differentiatedor transformedinto vacuolated cells. Somehow, the released contents of the damaged cell induced nearby sheath cells to replace the damaged structure.

The study is relevant to spinal degeneration in humans, as humans also possessvacuolated cells as shock-absorbing intervertebral discs. These discs can degenerate or become herniated, causing neck or back pain. However, according to the Mayfield Brain and Spine Clinic,nearly 30 percent of people without such pain also have some form of degeneration in intervertebral discs.

The disappearance of the giant vacuolated cells (which are conserved from fish to human) is often associated with degenerative disc disease, Garcia wrote. If we can understand how this basic regeneration process works in fish, we can better understand and possibly implement disc regeneration in humans who experience this condition.

Bagnat noted that a spinal repair mechanism is likely to exist in humans, but whether the process is the same as in zebrafish is unknown at this point.

If there was no repair mechanism, we would probably lose these vacuolated cells out of the center of the intervertebral disc very rapidly, Bagnat said. [However], in fact, we keep them for quite a long time.

Both Bagnat and Garcia explained that one of the labs interests is understanding how the sheath cells receive the necessary instructions to differentiate into a vacuolated cell. Bagnat suspected that the answer may lie in the contents released by a damaged vacuolated cell, sostudying this fluid could answer some major questions concerning disc repair.

If you understand the biology, perhaps you can keep the disc in better shape for a longer time, he said.

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New research on spinal cord repair mechanism in fish can pave way for human spinal cord regeneration - Duke Chronicle

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Posted 6/27/17 (Tue)

By Neal A. Shipman Farmer Editor

After serving as McKenzie Countys deputy auditor for the past three and a half years, Erica Johnsrud is confident that she can now successfully do the duties of being the countys auditor/treasurer. Its a big step forward from being the deputy to the department head, stated Johnsrud, who officially began duties on June 25. Im confident that I can do the job and Linda Svihovec has trained me well. And the McKenzie County Board of County Commissioners believe that Johnsrud is the right person for the job as they appointed her to fill out the remainder of Svihovecs term on May 16. The experience that Ive had as the deputy auditor provides a continuity going forward, stated Johnsrud, who is a 1996 graduate of Watford City High School and a 1999 graduate of Jamestown College with a major in biology and minor in chemistry, as well as a Ph.D. in cell biology and anatomy from the University of Kansas Medical Center.

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Latest News - McKenzie County Farmer

June 27, 2017 Just a few days old embryonic cell clusters: with functional Pramel7 (left), without the protein (right) the development of the stem cells remains stuck and the embyos die. Credit: Paolo Cinelli, USZ

Researchers from the University of Zurich and the University Hospital Zurich have discovered the protein that enables natural embryonic stem cells to form all body cells. In the case of embryonic stem cells maintained in cell cultures, this allrounder potential is limited. Scientists want to use this knowledge to treat large bone fractures with stem cells.

Stem cells are considered biological allrounders because they have the potential to develop into the various body cell types. For the majority of stem cells, however, this designation is too far-reaching. Adult stem cells, for example, can replace cells in their own tissue in case of injury, but a fat stem cell will never generate a nerve or liver cell. Scientists therefore distinguish between multipotent adult stem cells and the actual allrounders - the pluripotent embryonic stem cells.

Epigenetic marks determine potential for development

Differences exist even among the true allrounders, however. Embryonic stem cells that grow in laboratory cell cultures are in a different state than the pluripotent cells found inside the embryos in the first days of development. In a study in the journal Nature Cell Biology, researchers led by Paolo Cinelli of the University Hospital Zurich and Raffaella Santoro of the University of Zurich have now demonstrated the mechanism by which natural allrounders differ from embryonic stem cells in cultures.

At the center of their discovery is a protein called Pramel7 (for "preferentially expressed antigen in melanoma"-like 7) found in the cells of embryonic cell clusters that are just a few days old. This protein guarantees that the genetic material is freed from epigenetic marks consisting of chemical DNA tags in the form of methyl groups. "The more methyl groups are removed, the more open the Book of Life becomes," Cinelli says. Since any cell of the human body can develop from an embryonic stem cell, all genes have to be freely accessible at the beginning. The more a cell develops or differentiates, the stronger its genetic material is methylated and "sealed closed" again. In a bone cell, for example, only those genes are active that the cell requires for its function, the biochemist explains.

Protein is responsible for perfect pluripotency

Despite its short action period of just a few days, Pramel7 seems to play a vital role: When the researchers headed up by Cinelli and Santoro switched off the gene for this protein using genetic tricks, development remained stuck in the embryonic cell cluster stage. In the cultivated stem cells, on the other hand, Pramel7 is rarely found. This circumstance could also explain why the genetic material of these cells contains more methyl groups than that of natural embryonic cells - the perfect allrounders, as Cinelli calls them.

Using the stem cell function to regenerate bone tissue

His interest in stem cells lies in the hope of one day being able to help people with complex bone fractures. "Bones are great at regenerating and they are the only tissue that does not build scars," Paolo Cinelli says. The bone stumps must be touching, however, in order to grow together. When a bone breaks in multiple places and even through the skin, for example, in a motorcycle accident, the sections of bone in between are often no longer usable. For such cases, a bone replacement is required. His team is studying carrier materials that they want to populate with the body's own stem cells in the future. "For this reason, we have to know how stem cells work," Cinelli adds.

Explore further: New tools to study the origin of embryonic stem cells

More information: Urs Graf et al, Pramel7 mediates ground-state pluripotency through proteasomalepigenetic combined pathways, Nature Cell Biology (2017). DOI: 10.1038/ncb3554

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What makes stem cells into perfect allrounders - Phys.Org