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Cell Biology

How Old Can We Get? It Might be Written in Stem Cells – Bioscience Technology

If only, wrote an ancient Japanese poet, when one heard that Old Age was coming one could bolt the door.

Science is working on it.

Aging is as much about the physical processes of repair and regeneration and their slow-motion failure as it is the passage of time. And scientists studying stem cell and regenerative biology are making progress understanding those processes, developing treatments for the many diseases whose risks increase as we get older, while at times seeming to draw close to a broader anti-aging breakthrough.

If stem cells offer potential solutions, theyre also part of the problem. Stem cells, which can differentiate into many cell types, are important parts of the bodys repair system, but lose regenerative potency as we age. In addition, their self-renewing ability allows the mutations that affect every cell to accumulate across cellular generations, and some of those mutations lead to disease.

We do think that stem cells are a key player in at least some of the manifestations of age, said Professor of Stem Cell and Regenerative Biology David Scadden, co-director of the Harvard Stem Cell Institute. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.

When it comes to aging, certain tissue types seem to lead the charge, according to Professor of Stem Cell and Regenerative Biology Lee Rubin, who directs the Harvard Stem Cell Institutes Therapeutic Screening Center. Particular tissues nerve cells appear to be one somehow signal to others that its time to age. This raises the prospect, Rubin said, that aging might be reversed by treating these key tissue categories, rather than designing individual treatments for the myriad tissue types that make up the body.

The process of aging involves all tissues in your body and, while different things go wrong in each tissue, they go wrong at basically the same rate, Rubin said. We can think of it as a process that is somehow coordinated, or there are fundamental processes in each tissue that play out.

In addition to key tissues, certain chemical pathways like insulin signaling seem to be able to control aging, said Rubin, whose work has received backing from the National Institute of Neurological Disorders and Stroke, as well as private foundations. The insulin signaling pathway is a chemical chain reaction in which the hormone insulin helps the body metabolize glucose. Reducing it has been shown to greatly extend life span in flies and worms, Rubin said. Also, signaling doesnt have to be reduced in all tissues.

If you just reduce it in neurons, the whole fly or worm lives longer, Rubin said. Certain key tissues in those organisms, if you selectively manipulate those tissues, have a positive effect on a number of processes in other tissues.

Because it circulates throughout the body, blood is an obvious place to look for controlling or signaling molecules that prompt or coordinate aging. A key carrier of oxygen and nutrients, blood is also rich with other compounds, some of which appear to play a role in decline linked to age.

Scadden described recent work done separately by Ben Ebert, a professor of medicine working at Harvard-affiliated Brigham and Womens Hospital, and Steve McCarroll, the Dorothy and Milton Flier Associate Professor of Biomedical Science and Genetics, that identified age-related changes in the blood that can increase the risk of diseases we dont typically think of as blood diseases.

Another tantalizing study, published in 2013, used the blood of a young mouse to rejuvenate the organs of an older one. In these parabiotic experiments, conducted by Professor of Stem Cell and Regenerative Biology Richard Lee and Forst Family Professor of Stem Cell and Regenerative Biology Amy Wagers, the circulatory systems of the two mice were joined, allowing the blood of the young to flow through the older ones body. The older mouse showed improvements in muscle tone and heart function. Later, similar experiments done by Rubin also showed improvements in neuronal health and brain functioning.

The young mouses fate depended on the age of the older mouse, Rubin said. If the latter was middle-aged, the young mouse appeared to be fine. If the older mouse was very old, however, the young mouse did worse.

Rubin said the experiments suggest that blood contains both positive and negative factors that influence aging. It may be, he said, that both are always present, but that positive factors outweigh negative in the young and that negative factors increase as we age.

Researchers have identified but not yet confirmed candidate blood factors for the rejuvenating effects. What seems not in doubt is the overall effect of the young blood on the old mouse. Interest is intense enough that a California company, Alkahest, has begun experiments giving Alzheimers patients plasma from young blood in hopes of improving cognition and brain function.

Even if that approach works, Rubin said, there would be practical hurdles to the widespread administration of young peoples blood plasma to older patients. But with an active compound identified, a drug could be made available to restore at least some cognitive function in Alzheimers patients.

In addition to the overall process of aging, researchers at the Harvard Stem Cell Institute, as well as across the University and its affiliated institutions, are investigating an array of diseases whose incidence increases sometimes dramatically with age.

The list includes several of the countrys top causes of death heart disease, stroke, diabetes, and cancer as well as rarer conditions such as the lethal neurodegenerative disorder amyotrophic lateral sclerosis (ALS).

Two decades ago, when stem cell research hit mainstream consciousness, many thought its greatest promise would be in stem cells ability to grow replacement parts: organs and tissues for damage caused by trauma or disease.

The stem cell revolution is still developing, Scadden said, but so far has taken a different form than many expected. The dream of harnessing stem cells to grow replacement hearts, livers, and kidneys remains, but potentially powerful uses have emerged in modeling disease for drug discovery and in targeting treatment for personalized medicine.

Researchers have taken from the sick easily accessible cells, such as skin or blood, and reprogrammed them into the affected tissue type nerve cells in the case of ALS, which most commonly strikes between 55 and 75, according to the National Institutes of Health (NIH).

These tissues are used as models to study the disease and test interventions. Work on ALS in the lab of Professor of Stem Cell and Regenerative Biology Kevin Eggan has identified a drug approved for epilepsy that might be effective against ALS. This application is now entering clinical trials, in collaboration with Harvard-affiliated Massachusetts General Hospital.

In the end, stem cells might have their greatest impact as a drug-discovery tool, Scadden said.

Much of stem cell medicine is ultimately going to be medicine, he said. Even here, we thought stem cells would provide mostly replacement parts. I think thats clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.

Also evolving is knowledge of stem cell biology. Our previous understanding was that once embryonic stem cells differentiated into stem cells for muscle, blood, skin, and other tissue, those stem cells remained flexible enough to further develop into an array of different cells within the tissue, whenever needed.

Recent work on blood stem cells, however, indicates that this plasticity within a particular tissue type may be more limited than previously thought, Scadden said. Instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.

If thats the case, Scadden said, problems might arise in part from the loss of some of these stem cell subpopulations, a scenario that could explain individual variation in aging. Getting old may be something like the endgame in chess, he said, when players are down to just a few pieces that dictate their ability to defend and attack.

If were graced and happen to have a queen and couple of bishops, were doing OK, said Scadden, whose work is largely funded through the NIH. But if we are left with pawns, we may lose resilience as we age.

Scaddens lab is using fluorescent tags to mark stem cells in different laboratory animals and then following them to see which ones do what work. It might be possible to boost populations of particularly potent players the queens to fight disease.

Were just at the beginning of this, Scadden said. I think that our sense of stem cells as this highly adaptable cell type may or may not be true. What we observe when we look at a population may not be the case with individuals.

The replacement parts scenario for stem cells hasnt gone away. One example is in the work of Harvard Stem Cell Institute co-director and Xander University Professor Douglas Melton, who has made significant progress growing replacement insulin-producing beta cells for treatment of diabetes.

Another is in Lees research. With support from the NIH, Lee is working to make heart muscle cells that can be used to repair damaged hearts.

Trials in this area have already begun, though with cells not genetically matched to the patient. In France, researchers are placing partially differentiated embryonic stem cells on the outside of the heart as a temporary aid to healing. Another trial, planned by researchers in Seattle, would inject fully differentiated heart muscle cells into a patient after a heart attack as a kind of very localized heart transplant.

Lees approach will take longer to develop. He wants to exploit the potential of stem cell biology to grow cells that are genetically matched to the patient. Researchers would reprogram cells taken from the patient into heart cells and, as in the Seattle experiment, inject them into damaged parts of the heart. The advantage of Lees approach is that because the cells would be genetically identical to the patient, he or she could avoid antirejection drugs for life.

What were thinking about is longer-term but more ambitious, Lee said. Avoiding immune suppression could change the way we think about things, because it opens the door to many decades of potential benefit.

Change has been a constant in Lees career, and he says theres no reason to think that will slow. Patient populations are older and more complex, disease profiles are changing, and the tools physicians have at their disposal are more powerful and more targeted.

Many of our patients today wouldnt be alive if not for the benefit of research advances, he said. Cardiology has completely changed in the last 25 years. If you think its not going to change even more in the next 25 years, youre probably wrong.

When Lee envisions the full potential of stem cell science, he sees treatments and replacement organs with the power to transform how we develop and grow old.

It may not be there for you and me, but for our children or their children, ultimately, regenerative biology and stem cell biology have that kind of potential, he said. We imagine a world where it doesnt matter what mutations or other things youre born with, because we can give you a good life.

Lees not guessing at future longevity. Hes not even sure extending life span beyond the current record, 122, is possible. Instead, he cites surveys that suggest that most Americans target 90 as their expectation for a long, healthy life.

Thats about a decade more than we get now in America, Lee said. We have work to do.

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How Old Can We Get? It Might be Written in Stem Cells - Bioscience Technology

Anatomy

Grey’s Anatomy: A look back at THAT bomb scene – EW.com

One of the tensest events in the history of Greys Anatomy is the infamous scene from As We Know It, which premiered following Super Bowl XL in 2006, the second half of a two-part episode. After surgically removing a bomb from a mans torso, Meredith Grey (Ellen Pompeo) hands it over to defuser Dylan Young (Kyle Chandler) and it blows up before he even makes it out of the ER.

Executive producer Shonda Rhimes, Pompeo, and episode director Peter Horton recall the details.

SHONDA RHIMES: I remember having to talk it through with [then ABC Entertainment Group president] Stephen McPherson.It was a big deal that we were doing the Super Bowl episode, so I wanted to make sure it was something they wanted to do. He seemed fine with it. PETER HORTON: It was a very ambitious proposition. There were a number of long days because of that. When that explosion scene came up, the only way you get through it is with a tremendous amount of prep. We worked on how we wanted to do it, what walls we wanted to collapse, what lights we wanted to fall. RHIMES: I always knew the [bomb] moment was going to involve Ellen. I dont know if anyone else was jealous. I dont think anyone thought like, Oh, great, I want to have my hand stuck in a body cavity and stand there with all those horrors. ELLEN POMPEO: It was very late at night when we filmed it. I had been working something like 17 hours. I was exhausted, so I was excited that I didnt have to do the stunt. They had this amazing stunt girl who was going to do it for me. They strapped her toa cable so they could pull her back when Kyle blows up. HORTON: The stunt double was fairly young. She wasnt quite prepared for when she got yanked, having landed on her back and getting her head snapped back. And boy, did it. You could hear it. As stunt people do, she immediately sat up and said, Im fine. But clearly she had whacked her head hard, so she had to go through concussion protocol. Wed only had one take of this thing, and I needed to have a couple of things adjusted from that one take, so I had Ellen do it. POMPEO: We had a knock-down, drag-out fight because he insisted I do the stunt. I said, A fing professional stuntwoman just gave herself a concussion doing it. Ive been working 18 hours. I can barely see straight. Now you want me to try it? He was adamant. I was adamant. We were screaming at each other. I even said to him, Why are you even making me do this? Youre going to use that take with her head bouncingoff the floor, because it looked amazing. It was like slow motion. Anyway, I ended up doing it, despite me not wanting to. And of course they used the first take. HORTON: If you look in the episode, you will see the stunt girl hit her head. We left that in. It had been very effective. But we used part of Ellens take, which is the part she never remembers. We never would have put her in jeopardy. We pulled her much slower than we pulledthe stunt double.

POMPEO: I remember thinking Kyle Chandler was amazing.I wasnt surprised his career really took off after that because he was so natural. RHIMES: He would pitch me ideas on how Dylan, his character, could maybe not explode, and I would show him the linein the script that said, Dylan explodes. Thats literally all it said. He was written to explode. But I did not expect to have Kyle Chandler. I didnt want to explode him. HORTON: Whenever you direct anything, some of your best moments are accidents. When we did the blast, all of these bits of debris fill the air and come slowly down like a rainstorm. It added such a fabulous texture to that moment, when Ellen is sitting up and looking at the remains of poor Kyle Chandler. POMPEO: Nothing seemed as monumental back then because we had no idea how long this show would run or how iconic these moments would become. HORTON:It was the highlight of Greys Anatomy in all of its 12 years. It was a special moment when it all came together in just the right way.

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Grey's Anatomy: A look back at THAT bomb scene - EW.com

Genetics

Closer look at brain circuits reveals important role of genetics – Medical Xpress

April 19, 2017 A serial electron microscopy reconstruction of a single synaptic connection. Credit: Anton Maximov

Scientists at The Scripps Research Institute (TSRI) in La Jolla have revealed new clues to the wiring of the brain. A team led by Associate Professor Anton Maximov found that neurons in brain regions that store memory can form networks in the absence of synaptic activity.

"Our results imply that assembly of neural circuits in areas required for cognition is largely controlled by intrinsic genetic programs that operate independently of the external world," Maximov explained.

A similar phenomenon was observed by the group of Professor Nils Brose at the Max Planck Institute for Experimental Medicine in Germany. The two complementary studies were co-published as cover stories in the April 19, 2017, issue of the journal Neuron.

The "Nature vs. Nurture" Question

Experience makes every brain unique by changing the patterns and properties of neuronal connections. Vision, hearing, smell, taste and touch play particularly important roles during early postnatal life when the majority of synapses is formed. New synapses also appear in the adult brain during learning. These activity-dependent changes in neuronal wiring are driven by chemical neurotransmitters that relay signals from one neuron to another. Yet, animals and humans have innate behaviors whose features are consistent across generations, suggesting that some synaptic connections are genetically predetermined.

The notion that neurons do not need to communicate to develop networks has also been supported by earlier discoveries of synapses in mice that lacked transmitter secretion in the entire brain. These studies were performed in the laboratory of Professor Thomas Sdhof, who won the 2013 Nobel Prize in Physiology or Medicine.

"We thought these experiments were quite intriguing," Maximov said, "but they also had a major limitation: mice with completely disabled nervous systems became paralyzed and died shortly after birth, when circuitry in the brain is still rudimental."

The TSRI team set out to investigate if neurons can form and maintain connections with appropriate partners in genetically engineered animals that live into adulthood with virtually no synaptic activity in the hippocampus, a brain region that is critical for learning and memory storage. "While the idea may sound crazy at the first glance," Maximov continued, "several observations hinted that this task is technically feasible." Indeed, mammals can survive with injuries and developmental abnormalities that result in a massive loss of brain tissue.

Inspired by these examples, Richard Sando, a graduate student in the Maximov lab, generated mice whose hippocampus permanently lacked secretion of glutamate, a neurotransmitter that activates neurons when a memory is formed. Despite apparent inability to learn and remember, these animals could eat, walk around, groom, and even engage in rudimental social interactions.

Working closely with Professor Mark Ellisman, who directs the National Center for Microscopy and Imaging Research at the University of California, San Diego, Sando and his co-workers then examined the connectivity in permanently inactive areas. Combining contemporary genetic and imaging tools was fruitful: the collaborative team found that several key stages of neural circuit development widely believed to require synaptic activity were remarkably unaffected in their mouse model.

The outcomes of ultra-structural analyses were particularly surprising: it turns out that neurotransmission is unnecessary for assembly of basic building blocks of single synaptic connections, including so-called dendritic spines that recruit signaling complexes that enable neurons to sense glutamate.

Maximov emphasized that the mice could not function normally. In a way, their hippocampus can be compared to a computer that goes though the assembly line, but never gets plugged to a power source and loaded with software. As the next step, the team aims to exploit new chemical-genetic approaches to test if intrinsically-formed networks can support learning.

Explore further: Mice offer a window into sleep's role in memory

More information: "Assembly of excitatory synapses in the absence of glutamatergic neurotransmission," Neuron (2017). DOI: 10.1016/j.neuron.2017.03.047

Sleep provides essential support for learning and memory, but scientists do not fully understand how that process works on a molecular level. What happens to synapses, the connections between neurons, during sleep that helps ...

Scientists at The Scripps Research Institute (TSRI) have identified a new pathway that appears to play a major role in information processing in the brain. Their research also offers insight into how imbalances in this pathway ...

Scientists from the Institut Pasteur and the CNRS were able to make real-time observations over a period of several months that reveal how new adult-born neurons are formed and evolve in the olfactory bulb of mice. They made ...

One goal in neurobiology is to understand how the flow of electrical signals through brain circuits gives rise to perception, action, thought, learning and memories.

A number of psychiatric and neurological disorders may result from abnormal synapses, the neuron-to-neuron connection sites that enable chemical communication between brain cells. The timing, frequency, and intensity of neuronal ...

Research led by SUNY Downstate Medical Center has identified a brain receptor that appears to initiate adolescent synaptic pruning, a process believed necessary for learning, but one that appears to go awry in both autism ...

Scientists at The Scripps Research Institute (TSRI) in La Jolla have revealed new clues to the wiring of the brain. A team led by Associate Professor Anton Maximov found that neurons in brain regions that store memory can ...

For people with severe brain injuries, researchers have found that the rhythm of daily fluctuations in body temperature is related to their level of consciousness, according to a preliminary study published in the April 19, ...

Each time we get feedback, the brain is hard at work updating its knowledge and behavior in response to changes in the environment; yet, if there's uncertainty or volatility in the environment, the entire process must be ...

Most left-handers can rattle off a list of their eminent comrades-in-arms: Oprah Winfrey, Albert Einstein, and Barack Obama, just to name three, but they may want to add on cockatoos, "southpaw" squirrels, and some house ...

When we learn to read, we say one word at a time. But how does the brain actually put words together when we read full sentences?

Johns Hopkins researchers today published new evidence refuting the long-held scientific belief that the gut nerve cells we're born with are the same ones we die with.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

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Closer look at brain circuits reveals important role of genetics - Medical Xpress

Cell Biology

Cell biologists discover crucial ‘traffic regulator’ in neurons – Medical Xpress

April 19, 2017 This is a scanning electron micrograph (false color) of a human induced pluripotent stem cell-derived neuron. Credit: Thomas Deerinck, UC San Diego

Cell biologists from Utrecht University have discovered the protein that may be the crucial traffic regulator for the transport of vital molecules inside nerve cells. When this traffic regulator is removed, the flow of traffic comes to a halt. 'Traffic jams' are reported to play a key role in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The results of their research will be published in the scientific journal Neuron on April 19.

Neurons are the main cells in the nervous system. They process information by sending, receiving, and combining signals from around the brain and the body. All neurons have a cell body where molecules vital for its functioning and maintenance are produced. The axon, a long and slender extension that can reach one metre in length in humans, sends information from the nerve cell to other nerve cells. Neuronal survival is highly dependent on the transport of vital molecules within this axon. Research has shown that defects in the transport function in the axons play a key role in degenerative brain diseases such as Alzheimer.

First comprehensive map

"Previous research examined transport processes in small areas of the axon, such as the very beginning or the very end. This left it unclear how the movement of molecules through the axon was regulated over long distances. In our study, we provide the first comprehensive map of transport in mammalian axons", says Casper Hoogenraad, Professor of Cell Biology at Utrecht University, explaining the relevance of this study.

Stumped

In most neurons, an area between the cell body and the axon called the 'axon initial segment' serves as a checkpoint: only some molecules can pass through it. This area has stumped scientists for more than a decade. Why should one type of molecule be able to pass through this area, while others cannot? The answer is to be found in the traffic regulator, a protein called MAP2. "With this discovery, we have answered a fundamental question about the unique functioning of nerve cells that has occupied scientists for a long time", lead author of the study Dr Laura Gumy says.

Driving force

The cell biologists from Utrecht first discovered that larger quantities of MAP2 accumulate between the cell body and the axon. When they removed MAP2 from the neuron, the normal pattern of molecule movement changed. Certain molecules suddenly ceased to enter the axon, whereas others accumulated in the axon instead of passing through to the cell body. This abnormal transport indicates that MAP2 is the driving force behind transport within the axon.

Car key

The cell biologists from Utrecht University went on to make another very important discovery. Since axons are so long, transport in the neurons is carried out by sets of proteins - known as 'motor proteins' - that carry packages of other proteins on their back. As it turns out, MAP2 is able to switch a specific 'motor protein' on or off, like a car key. This means that MAP2 actually controls which packages of molecules may enter the axon and which may not. Targeting the activity of the transport engine allowed the researchers to make another interesting discovery: MAP2 is also able to control the delivery of molecules at specific points along the axon.

New targets for therapies

"Transport within axons has been shown to fail in Alzheimer, Parkinson's disease and Huntington's disease, as well as in many other diseases. When the neuron is no longer able to control where molecules go, or is unable to get molecules to where they need to be, it cannot do its job. By understanding how transport works, we have laid the foundation for considering new targets and potential therapies for various neurodegenerative disorders", Casper Hoogenraad concludes.

Explore further: New technique can help understand neurodegenerative diseases

More information: Neuron (2017). DOI: 10.1016/j.neuron.2017.03.046

Journal reference: Neuron

Provided by: Utrecht University

Cell biologists at Utrecht University have successfully moved selected parts of a neuron to another specific location within the cell. This allows them to accurately study which role the position of a cell component performs ...

A major contributor to most neurological diseases is the degeneration of a wire-like part of nerve cells called an axon, which electrically transmits information from one neuron to another. The molecular programs underlying ...

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As tiny embryos in the womb, we start out with a lot more neuronal material than we actually need. During development, the body drastically prunes back the excesscutting the branches from nerve cell bodies, known as axons, ...

Scientists at The Scripps Research Institute (TSRI) in La Jolla have revealed new clues to the wiring of the brain. A team led by Associate Professor Anton Maximov found that neurons in brain regions that store memory can ...

For people with severe brain injuries, researchers have found that the rhythm of daily fluctuations in body temperature is related to their level of consciousness, according to a preliminary study published in the April 19, ...

Each time we get feedback, the brain is hard at work updating its knowledge and behavior in response to changes in the environment; yet, if there's uncertainty or volatility in the environment, the entire process must be ...

Most left-handers can rattle off a list of their eminent comrades-in-arms: Oprah Winfrey, Albert Einstein, and Barack Obama, just to name three, but they may want to add on cockatoos, "southpaw" squirrels, and some house ...

When we learn to read, we say one word at a time. But how does the brain actually put words together when we read full sentences?

Johns Hopkins researchers today published new evidence refuting the long-held scientific belief that the gut nerve cells we're born with are the same ones we die with.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Follow this link:
Cell biologists discover crucial 'traffic regulator' in neurons - Medical Xpress

Cell Biology

Researchers study secrets of aging via stem cells – Harvard Gazette

Third in an occasional series on how Harvard researchers are tackling the problematic issues of aging.

If only, wrote an ancient Japanese poet, when one heard that Old Age was coming one could bolt the door.

Science is working on it.

Aging is as much about the physical processes of repair and regeneration and their slow-motion failure as it is the passage of time. And scientists studying stem cell and regenerative biology are making progress understanding those processes, developing treatments for the many diseases whose risks increase as we get older, while at times seeming to draw close to a broader anti-aging breakthrough.

If stem cells offer potential solutions, theyre also part of the problem. Stem cells, which can differentiate into many cell types, are important parts of the bodys repair system, but lose regenerative potency as we age. In addition, their self-renewing ability allows the mutations that affect every cell to accumulate across cellular generations, and some of those mutations lead to disease.

We do think that stem cells are a key player in at least some of the manifestations of age, said Professor of Stem Cell and Regenerative Biology David Scadden, co-director of the Harvard Stem Cell Institute. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.

When it comes to aging, certain tissue types seem to lead the charge, according to Professor of Stem Cell and Regenerative Biology Lee Rubin, who directs the Harvard Stem Cell Institutes Therapeutic Screening Center. Particular tissues nerve cells appear to be one somehow signal to others that its time to age. This raises the prospect, Rubin said, that aging might be reversed by treating these key tissue categories, rather than designing individual treatments for the myriad tissue types that make up the body.

The process of aging involves all tissues in your body and, while different things go wrong in each tissue, they go wrong at basically the same rate, Rubin said. We can think of it as a process that is somehow coordinated, or there are fundamental processes in each tissue that play out.

In addition to key tissues, certain chemical pathways like insulin signaling seem to be able to control aging, said Rubin, whose work has received backing from the National Institute of Neurological Disorders and Stroke, as well as private foundations. The insulin signaling pathway is a chemical chain reaction in which the hormone insulin helps the body metabolize glucose. Reducing it has been shown to greatly extend life span in flies and worms, Rubin said. Also, signaling doesnt have to be reduced in all tissues.

If you just reduce it in neurons, the whole fly or worm lives longer, Rubin said. Certain key tissues in those organisms, if you selectively manipulate those tissues, have a positive effect on a number of processes in other tissues.

Because it circulates throughout the body, blood is an obvious place to look for controlling or signaling molecules that prompt or coordinate aging. A key carrier of oxygen and nutrients, blood is also rich with other compounds, some of which appear to play a role in decline linked to age.

Scadden described recent work done separately by Ben Ebert, a professor of medicine working at Harvard-affiliated Brigham and Womens Hospital, and Steve McCarroll, the Dorothy and Milton Flier Associate Professor of Biomedical Science and Genetics, that identified age-related changes in the blood that can increase the risk of diseases we dont typically think of as blood diseases.

Another tantalizing study, published in 2013, used the blood of a young mouse to rejuvenate the organs of an older one. In these parabiotic experiments, conducted by Professor of Stem Cell and Regenerative Biology Richard Lee and Forst Family Professor of Stem Cell and Regenerative Biology Amy Wagers, the circulatory systems of the two mice were joined, allowing the blood of the young to flow through the older ones body. The older mouse showed improvements in muscle tone and heart function. Later, similar experiments done by Rubin also showed improvements in neuronal health and brain functioning.

The young mouses fate depended on the age of the older mouse, Rubin said. If the latter was middle-aged, the young mouse appeared to be fine. If the older mouse was very old, however, the young mouse did worse.

Rubin said the experiments suggest that blood contains both positive and negative factors that influence aging. It may be, he said, that both are always present, but that positive factors outweigh negative in the young and that negative factors increase as we age.

Researchers have identified but not yet confirmed candidate blood factors for the rejuvenating effects. What seems not in doubt is the overall effect of the young blood on the old mouse. Interest is intense enough that a California company, Alkahest, has begun experiments giving Alzheimers patients plasma from young blood in hopes of improving cognition and brain function.

Even if that approach works, Rubin said, there would be practical hurdles to the widespread administration of young peoples blood plasma to older patients. But with an active compound identified, a drug could be made available to restore at least some cognitive function in Alzheimers patients.

In addition to the overall process of aging, researchers at the Harvard Stem Cell Institute, as well as across the University and its affiliated institutions, are investigating an array of diseases whose incidence increases sometimes dramatically with age.

The list includes several of the countrys top causes of death heart disease, stroke, diabetes, and cancer as well as rarer conditions such as the lethal neurodegenerative disorder amyotrophic lateral sclerosis (ALS).

Two decades ago, when stem cell research hit mainstream consciousness, many thought its greatest promise would be in stem cells ability to grow replacement parts: organs and tissues for damage caused by trauma or disease.

The stem cell revolution is still developing, Scadden said, but so far has taken a different form than many expected. The dream of harnessing stem cells to grow replacement hearts, livers, and kidneys remains, but potentially powerful uses have emerged in modeling disease for drug discovery and in targeting treatment for personalized medicine.

We thought stem cells would provide mostly replacement parts. I think thats clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.

David Scadden

Researchers have taken from the sick easily accessible cells, such as skin or blood, and reprogrammed them into the affected tissue type nerve cells in the case of ALS, which most commonly strikes between 55 and 75, according to the National Institutes of Health (NIH).

These tissues are used as models to study the disease and test interventions. Work on ALS in the lab of Professor of Stem Cell and Regenerative Biology Kevin Eggan has identified a drug approved for epilepsy that might be effective against ALS. This application is now entering clinical trials, in collaboration with Harvard-affiliated Massachusetts General Hospital.

In the end, stem cells might have their greatest impact as a drug-discovery tool, Scadden said.

Much of stem cell medicine is ultimately going to be medicine, he said. Even here, we thought stem cells would provide mostly replacement parts. I think thats clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.

Also evolving is knowledge of stem cell biology. Our previous understanding was that once embryonic stem cells differentiated into stem cells for muscle, blood, skin, and other tissue, those stem cells remained flexible enough to further develop into an array of different cells within the tissue, whenever needed.

Recent work on blood stem cells, however, indicates that this plasticity within a particular tissue type may be more limited than previously thought, Scadden said. Instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.

If thats the case, Scadden said, problems might arise in part from the loss of some of these stem cell subpopulations, a scenario that could explain individual variation in aging. Getting old may be something like the endgame in chess, he said, when players are down to just a few pieces that dictate their ability to defend and attack.

If were graced and happen to have a queen and couple of bishops, were doing OK, said Scadden, whose work is largely funded through the NIH. But if we are left with pawns, we may lose resilience as we age.

Scaddens lab is using fluorescent tags to mark stem cells in different laboratory animals and then following them to see which ones do what work. It might be possible to boost populations of particularly potent players the queens to fight disease.

Were just at the beginning of this, Scadden said. I think that our sense of stem cells as this highly adaptable cell type may or may not be true. What we observe when we look at a population may not be the case with individuals.

The replacement parts scenario for stem cells hasnt gone away. One example is in the work of Harvard Stem Cell Institute co-director and Xander University Professor Douglas Melton, who has made significant progress growing replacement insulin-producing beta cells for treatment of diabetes.

Another is in Lees research. With support from the NIH, Lee is working to make heart muscle cells that can be used to repair damaged hearts.

Trials in this area have already begun, though with cells not genetically matched to the patient. In France, researchers are placing partially differentiated embryonic stem cells on the outside of the heart as a temporary aid to healing. Another trial, planned by researchers in Seattle, would inject fully differentiated heart muscle cells into a patient after a heart attack as a kind of very localized heart transplant.

Lees approach will take longer to develop. He wants to exploit the potential of stem cell biology to grow cells that are genetically matched to the patient. Researchers would reprogram cells taken from the patient into heart cells and, as in the Seattle experiment, inject them into damaged parts of the heart. The advantage of Lees approach is that because the cells would be genetically identical to the patient, he or she could avoid antirejection drugs for life.

What were thinking about is longer-term but more ambitious, Lee said. Avoiding immune suppression could change the way we think about things, because it opens the door to many decades of potential benefit.

Change has been a constant in Lees career, and he says theres no reason to think that will slow. Patient populations are older and more complex, disease profiles are changing, and the tools physicians have at their disposal are more powerful and more targeted.

Many of our patients today wouldnt be alive if not for the benefit of research advances, he said. Cardiology has completely changed in the last 25 years. If you think its not going to change even more in the next 25 years, youre probably wrong.

When Lee envisions the full potential of stem cell science, he sees treatments and replacement organs with the power to transform how we develop and grow old.

It may not be there for you and me, but for our children or their children, ultimately, regenerative biology and stem cell biology have that kind of potential, he said. We imagine a world where it doesnt matter what mutations or other things youre born with, because we can give you a good life.

Lees not guessing at future longevity. Hes not even sure extending life span beyond the current record, 122, is possible. Instead, he cites surveys that suggest that most Americans target 90 as their expectation for a long, healthy life.

Thats about a decade more than we get now in America, Lee said. We have work to do.

Read more:
Researchers study secrets of aging via stem cells - Harvard Gazette

Anatomy

Anatomy of a winning streak: How the Yankees have become MLB’s hottest team – CBSSports.com

The New York Yankees are the hottest team in baseball. Monday night they beat the Chicago White Sox (NYY 7, CWS 4) for their eighth consecutive win, which is the longest winning streak by any team in baseball this season -- no other club has won more than five games in a row -- and New York's longest winning streak since a 10-gamer in June 2012.

Thanks to this winning streak, the Yankees currently boast a plus-23 run differential, the best in baseball. They rank second among all teams in runs scored per game (5.15) and fourth in runs allowed per game (3.38), so they're playing well in both phases. This eight-game winning streak has had a real impact on their postseason chances. From FanGraphs:

Coming into the season the Yankees had a 15.9 percent chance to make the postseason, according to the projections and depth charts at FanGraphs. Two weeks in, they are up to 39.9 percent, fourth highest in the American League. Improving your odds 24 percentage points in two weeks is pretty great. No, the Yankees won't keep winning forever, but these eight wins are in the bank. They can't be taken away.

What, exactly, has propelled the Yankees to this eight-game winning streak? Well, as I mentioned earlier, they're both creating runs and preventing runs well, and yes, there's a little luck involved too. The Yankees aren't being carried by one or two players. It's a team effort. Here are the biggest reasons the Yankees are now the hottest team in MLB.

It always starts with pitching, doesn't it? Five games into the season the Yankees were 1-4 and their starters had a 7.59 ERA and 1.88 WHIP in 21 1/3 innings. Not once in those five games did a starter record an out after the fifth inning. The Yankees were getting low quality innings from the starters and they were taxing the bullpen. That's a bad combination.

The eight-game winning streak started in New York's sixth game of the season, and since then their starters have pitched to a 2.77 ERA and 1.00 WHIP in 52 innings. Only once in those eight games did the starter fail to complete six full innings -- rookie lefty Jordan Montgomery went 4 2/3 innings in his MLB debut Wednesday because he was on a pitch limit. Now the rotation is providing quality innings and bulk innings.

Oddly enough, staff ace Masahiro Tanaka has been the Yankees'worst starter in the early going. He was one of the AL's top hurlers last year, but control issues have hampered him early. Erstwhile ace CC Sabathia reinvented himself as a cutter pitcher last year and has a 1.47 ERA in 18 1/3 innings and three starts so far. He has been the club's most reliable starting pitcher.

Their most electric starter has been Michael Pineda , at least during this eight-game winning streak. He retired the first 20 batters he faced in the home opener April 10, then Sunday night he chucked seven innings of two-run ball. Pineda is both talented and unpredictable. He'll dominate one start and blow up the next -- he allowed four runs in 3 2/3 innings in his first start of the season, so yeah -- though these last two times out, the good version of the man they call Big Mike showed up.

We all know about Dellin Betances and Aroldis Chapman , who form arguably the top setup man-closer combination in baseball. Having those two at the end of the game sure makes life easy for manager Joe Girardi. The rest of the bullpen has been very good too, however. Tyler Clippard picked up a save Saturday when Chapman and Betances were unavailable due to their recent workloads, and rookie righty Jonathan Holder has yet to allow a run in five appearances.

Adam Warren , who never quite fit in with the Chicago Cubs last year before being traded back to the Yankees, and Bryan Mitchell competed for rotation spots in spring training and opened the regular season as multi-inning relievers. Mitchell allowed his first run of the season Sunday. Warren allowed his first run Monday after retiring the first 22 batters he faced this season. Those two have combined to allow two runs and six base runners in 13 1/3 innings spread across nine appearances.

Chapman and Betances get all the headlines and deservedly so. They've combined to allow one run with 17 strikeouts in 10 2/3 innings. Bullpens are not a two-man show, however. Not these days. Bullpen depth is crucial and the Yankees have gotten strong work from supporting cast members like Clippard, Holder, Warren and Mitchell. The Yankees are second in bullpen ERA (1.36), third in bullpen WHIP (0.96) and fifth in bullpen strikeout rate (10.7 K/9) in all of baseball thanks to their relief depth.

This spring MLB.com ranked 24-year-old Aaron Judge as the 42nd-best prospect in baseball, though his MLB debut did not go too well last season. The Yankees called him up after trading Carlos Beltran to the Texas Rangers and installed him as their starting right fielder. Judge hit .179/.263/.345 (61 OPS+) in 27 games before suffering an oblique injury. He's a massive human listed at 6-feet-7 and 275 pounds, and pitchers took advantage of that big strike zone -- Judge struck out 42 times in 95 plate appearances (44.2 percent) in 2016.

All throughout the minors Judge's history has been get promoted to a new level, struggle initially, then adjust and rake. He spent the offseason working with the Yankees' hitting instructors and the result is a .275/.356/.650 (175 OPS+) batting line with four very long home runs. Statcast says Judge is responsible for five of the 12 hardest-hit balls in MLB this season. The man is as strong as that 6-7 frame would lead you to believe.

Judge has gone 9 for 25 (.360) with four home runs during the eight-game winning streak, and he also became the first Yankee to be intentionally walked using the automatic intentional walk rule. Pitchers are aware of the damage he can do at the plate and his at-bats have become must-see television for other players around the league.

Judge is always going to strike out a bunch because he's so darn big, though he has been able to cut his strikeout rate down to 28.9 percent. That is still higher than the 21.7 percent league average, but Judge's strikeout rate is no longer untenable like it was last season. The Yankees are in the middle of a youth movement and Judge is one of their most prized young players. He has lived up to the hype this year.

The Yankees know a thing or two about veteran players not living up to their big-money contracts. They released Alex Rodriguez last year and ran out the final season of Mark Teixeira 's contract. There have been countless others over the years.

Last season the Yankees ranked 22nd among the 30 teams in runs per game (4.20) largely because their veterans disappointed. A-Rod and Teixeira dragged down the offense, and others like Starlin Castro , Chase Headley and Jacoby Ellsbury did not give the Yankees nearly as much as expected. They were OK at best.

Castro, Headley and Ellsbury have given the Yankees what they've paid for this season, and that's big production. Check out their performances:

2016 Stats

2017 Stats

During 8-Game Win Streak

2017 Salary

Castro

.270/.300/.433 (93 OPS+)

.365/.389/.538 (157 OPS+)

12 for 32 (.375), 3 2B, 2 HR

$9.9M

Ellsbury

.263/.330/.374 (88 OPS+)

.326/.367/.435 (124 OPS+)

8 for 27 (.296), 4 SB

$21.1M

Headley

.253/.331/.385 (91 OPS+)

.395/.509/.605 (212 OPS+)

10 for 27 (.385), 2 2B, 1 HR

$13M

Ellsbury in particular has helped the Yankees with his lineup versatility. He has started games not only at his customary leadoff spot, but also in the cleanup spot and the No. 5 spot. Ellsbury doesn't fit the traditional middle-of-the-order run-producer mold, but the Yankees have bounced him around and he has produced everywhere he has been in the lineup.

Obviously these three won't play this well all season -- I suppose Castro, who is still only 27, could be figuring things out as he enters what should be the prime of his career -- but they're crushing the ball right now and helping the Yankees win games. They didn't do that much last season.

Perhaps the most impressive thing about this eight-game winning streak is that the Yankees have done it without Gary Sanchez and Didi Gregorius , their starting catcher and starting shortstop. Sanchez injured his biceps taking a swing and landed on the 10-day disabled list the day before the winning streak started. Gregorius has not played at all this season due to a shoulder injury suffered during the World Baseball Classic.

Backup catcher Austin Romine has taken over behind the plate and gone 7 for 21 (.333) with two doubles, one homer, four walks and three strikeouts during Sanchez's absence. Ronald Torreyes has taken over for Gregorius at short, and while his .250/.250/.425 (85 OPS+) batting line is underwhelming, he has come up with some clutch hits. In fact, his two-run triple last Sunday could easily be considered a turning point for the Yankees.

That triple drove in New York's first two runs of the game. They would eventually complete the comeback and win that game to kick off this eight-game winning streak. Torreyes might be hitting .250, but his 10 RBI are second on the team behind Judge, who has 11.

Furthermore, fourth outfielder Aaron Hicks has already swatted three home runs in his limited time, including two in one game last Thursday. His two home runs accounted for all three runs the Yankees scored in their win that night. Hicks his contributed off the bench in a big way already.

Losing Sanchez and Gregorius, arguably the Yankees' two best position players, could have been devastating. Instead, their replacements have played well and helped not only keep the team afloat, but also thrive. The Yankees are getting some nice production from unexpected sources in Romine, Torreyes and Hicks.

Is it better to be lucky or good? It doesn't matter, because the Yankees have been both during this streak. At one point last week they went 1 for 30 (.033) with runners in scoring position during a three-game span, yet they won all three games because A) They've been hitting home runs; and B) The other team kept making mistakes. Carlos Martinez gift-wrapped the Yankees two runs Saturday with a wild pitch and an error, for example.

The Yankees haven't played the best competition during this winning streak -- they've played their past seven games against the struggling Tampa Bay Rays , St. Louis Cardinals and Chicago White Sox -- but you can only play who is on the schedule. Besides, one of the reasons the Yankees have played only onepostseason game the past four years has been their inability to beat the teams they're "supposed" to beat. The Yankees have played well during this winning streak and they deserve a lot of credit. They've also benefited from some sloppy play by their opponents. No doubt about it.

Coming into this season I thought the Yankees had the widest range of possible outcomes among all 30 teams in baseball. If the kids like Judge and Sanchez and Greg Bird perform well and the pitching holds together, they could absolutely be in the mix for a postseason spot. But if the kids stumble and the pitching falls apart, a win total in the 70s is not out of the question.

Early on, the Yankees have gotten great work from their pitching staff and Judge, as well as several key veterans and bench players, and it has helped them put together this winning streak. There are still 149 games to play, so this is far from over. If nothing else, the 2017 Yankees sure seem to be a heck of a lot more interesting and exciting than the 2013-16 versions. Those teams were mediocre and boring.

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Anatomy of a winning streak: How the Yankees have become MLB's hottest team - CBSSports.com

Anatomy

The unmistakable anatomy of a President Trump flip-flop – Chicago Tribune

President Donald Trump took to Fox News on Tuesday morning to defend his flip-flop on labeling China a currency manipulator. And what we got was a perfect little illustration of a president who believes his campaign-trail promises mean basically nothing.

Here's the exchange with "Fox and Friends" host Ainsley Earhardt:

TRUMP: Somebody said "Currency manipulation." What am I going to do? In the middle of him talking with North Korea, I'm going to hit them with currency manipulation? This is the fake media that just does a number. Think of it: He's working so nicely, many coal ships have been sent back, fuel has been sent back, they're not dealing the same way. Nobody's ever seen it like that. Nobody's ever seen such a positive response on our behalf from China, and then the fake media goes, "Donald Trump has changed his stance on China." I haven't changed my stance. China's trying to help us. I don't know if they are going to be able to or not, but do I want to start heavy, heavy trade or currency manipulation statements against someone who's out there trying to stop what could be a very bad situation? You understand that.

EARHARDT: I understand that.

Yes, we all understand that.

Except that the "fake media" didn't invent anything here. Trump has said repeatedly that he would label China a currency manipulator as many as a dozen times as a 2016 candidate and three times on Twitter back in 2012, according to the Donald Trump database. This is the definition of him changing his stance; Trump's contention that it isn't is complete nonsense.

Trump's "Contract with the American Voter," which is still on his campaign website and is labeled a "contract" (!), pledges to do this within 100 days: "THIRD, I will direct the Secretary of the Treasury to label China a currency manipulator." And here's what Trump said in late October in Florida: "I blame our politicians for letting this take place. So easy to stop. So easy to stop."

Except that it's apparently not so easy to stop, which is really the point here. As Trump has acknowledged to his credit, perhaps China plays a significant role in containing North Korea and is otherwise a world power to be reckoned with. Against that backdrop, labeling it a currency manipulator is a dicey move.

But that backdrop was very much the same when Trump made this promise, over and over. And he still made it, over and over.

This is a nice little microcosm of Trump's repeated flip-flops and contortions. It goes a little something like this:

1. Amateur politician makes big statement (in this case, that China is a currency manipulator)

2. Amateur politician promises to take swift and controversial action (to label China a currency manipulator as president)

3. Crowd cheers

4. Amateur politician repeats promise over and over, to more cheers

5. Amateur politician actually becomes president

6. Amateur politician-president realizes his stance was completely impractical (given China's role in containing North Korea, among other things)

7. Amateur politician-president can't understand why people would have taken him at his word in the first place

The arc is completely similar on any number of Trump campaign-trail promises and applause lines: prosecuting Hillary Clinton, repealing Obamacare, attacking Barack Obama for golfing as president, renegotiating the Iran deal, calling NATO obsolete, etc. Trump made big promises and statements on each that proved impractical once he was actually in position to make good on them. So he didn't even try. And on each one, he simply wants us to grant him a mulligan.

The only conclusions from there are: a) He makes big promises about hugely consequential issues without doing his homework confirming the belief that he's in way over his head or b) He says these things without ever planning to do them lying to his supporters. It's the old "Stupid or Liar" theory.

It's one thing to come across new information as president; it's another to have been completely unaware of things like China's role in North Korea while making huge promises as a candidate. That's Foreign Policy 101 stuff.

And this casual approach to facts and the political and foreign policy realities of the day has cost Trump dearly when it comes to his credibility.

Aaron Blake is senior political reporter for Washington Post's The Fix.

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The unmistakable anatomy of a President Trump flip-flop - Chicago Tribune

Anatomy

‘Filled with hate, filled with anger’: Anatomy of a shooting allegedly fueled by hatred of white people – Los Angeles Times

Fresno police said they believe a shooting rampage downtown Tuesday that left three white men dead was racially motivated.

Fresno Police Chief Jerry Dyer said the suspect, Kori Ali Muhammad, gave very specific, detailed information to police that led officers to believe this was a hate-motivated crime, but did not elaborate on what those statements were.

If in fact hes lashing out at white people white males in this case that would constitute a hate crime, Dyer said. We believe it is a hate crime, definitely a hate crime.

The chief said investigators dont believe Muhammad worked with anyone else in the attack, calling him an individual that is filled with hate, filled with anger.

Family members said Muhammad had spoken of a war going on between blacks and whites in America.

Heres a rundown of what happened:

Police believe Muhammad killed a Motel 6 security guard, Carl Williams. The unarmed 25-year-old was shot outside the motel on North Blackstone Avenue.

Muhammad cut off his braids and shaved his face, significantly changing his appearance, after Fresno police put out a news release about that killing.

After being aware of that media release, Muhammad made a decision to himself that he was not going to go to jail for shooting a security guard that he was going to kill as many people as he could today and thats what he set out to do, Dyer said.

Grandmother Glenestene Taylor said Muhammad was acting strangely when he visited her Sunday. He was crying, but she believed he was simply going out of town.

I thought thats why hes upset, because he thinks of me as a mother, said Taylor, 81. Hes always telling me, Ill take care of it. Ill protect you. Dont you worry about it. He really didnt want to go but he was going.

The shootings began around 10:30 a.m. in downtown Fresno.

Dyer said that Muhammad fired sixteen rounds in less than two minutes, but immediately surrendered when approached by Fresno Police Officer Frank Borrego, and made spontaneous statements.

Those statements were I did it. I shot them, Dyer said, adding that Muhammad identified himself and said, You guys are looking for me.

He yelled Allahu akbar from the back seat of the patrol car. Muhammad later said he made that statement in order to pledge allegiance to God in case anything happened to him, Dyer said.

The victims of Tuesdays shootings were a 34-year-old white man who was a passenger in a PG&E vehicle, a 37-year-old white man killed on the sidewalk and a 58-year-old man shot in the Catholic Charities parking lot. Another 59-year-old white man was shot at but not struck.

The gunman also approached two Latina women, a mother and daughter, in a vehicle. He pointed the gun directly at them but did not fire. They drove away from the location, hearing gunfire as they left.

Dyer said Muhammad gave very specific, detailed information to police which led officer to believe this was a hate-motivated crime, but did not elaborate on what those statements were.

Muhammad was in the area because of several abandoned houses in the vicinity; according to Dyer, Muhammad was living on the streets and was hoping to stay at one such house. Muhammads grandmother said she didnt believe he was homeless.

Mason and Marcum reported from Fresno, and Branson-Potts and Serna from Los Angeles. Times staff writers Richard Winton and Veronica Rocha contributed to this report.

ALSO

'Dreamer,' 23, sues after he is deported by Trump administration

Fewer shootings by police that's the goal of new rules adopted by the L.A. Police Commission

Woman shot to death in West Hollywood residential area

Here is the original post:
'Filled with hate, filled with anger': Anatomy of a shooting allegedly fueled by hatred of white people - Los Angeles Times

Anatomy

How ‘Grey’s Anatomy’ Brings Dream Weddings to the Small Screen (PHOTOS) – Wetpaint

The production team at Greys Anatomy including set decorator Nicole Cramer, former set decorator Karen Bruck, and costume designer Mimi Melgaard knows how to put on a helluva wedding, especially 13 seasons into the ABC drama.

I'm not a wedding planner, but we always joke that I could be after how many weddings weve done, Nicole tells Cosmopolitan.

Everyones always shocked when they find out weve put a wedding together in 10 days, Mimi adds. Were kind of used to it.

Read on for the behind-the-scenes secrets the women shared, and tune in as Greys Anatomy Season 13 airs on Thursdays at 8 p.m ET on ABC.

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Karen says she got the instruction that this would be Shondas dream wedding That kinda freaked me out. I said, Oh my god, how am I going to live up to that? but notes it wasnt Cristinas dream wedding.

We had to make it a little over the top so it was definitely not Cristinas personality. Nothing about it was her personality, she says.

Im sure that there are brides who can relate to that in real life being dressed up and propped up and having to walk through and have a wedding with 200 people, and you only want to talk to four.

The dress got its own stunt double for the scene in which Meredith rips it off her.

We took the zipper out and inserted a piece of silk fabric that was attached by Velcro and she cut into that, and that piece of silk was easily replaceable for each take we needed to shoot, Mimi says.

Izzie ended up with the nuptials of her dreams after Meredith donated her wedding to her, a wedding Izzie had planned herself amid her cancer treatment.

Her wedding was the fairytale wedding over the top, with candles, romantic, Nicole says.

That was Shondas notes: that Izzie was living vicariously through Meredith by planning the best, most beautiful wedding she could.

Shonda and I wanted her to feel like a princess you know, its a princess wedding, she could be dying, Mimi says of the Kenneth Pool for Amsale dress.

So its a big, beautiful dress with sparkles.

After the Burke fiasco, Cristina had more say over her second wedding, opting for a home wedding, sweet and sophisticated, as Nicole describes it.

She already had a wedding that was so unlike her, so I wanted this one to feel like her, Mimi says. Shonda and Sandra Oh both loved it.

The team wanted to make sure Calzona wore different styles so it doesnt look like two big, white dresses, Mimi says.

They chose a traditional wedding dress for Callie because shes from a more traditional family, her familys Catholic and an off-white dress of torn chiffon for Arizona because Callie was in white, and that color with Jessicas skin just worked perfectly.

Though Calzona ultimately broke up long after the wedding which was filmed at Descanso Gardens they live on in matrimonial bliss in Shondaland headquarters.

We found somebody local in Los Angeles to make the little cake topper to match Callie and Arizona and their dresses, Nicole reveals.

Shonda actually has that cake topper in her office now.

Bailey is that perfect mix of a soft, feminine person who has a strong job So I wanted a really feminine dress for her, Mimi says of this wedding, filmed at Calamigos Ranch with a budget of around $40,000.

We started with a dress and altered it a lot I added the bling around the sweetheart neckline. I added the belt Chandra [Wilson] looks so good in things that hug her figure, which is amazing, that I just went for it.

But Baileys wedding dress wasnt the only one Mimi needed to find.

That was an interesting episode because it went into Richard dancing with his wife, Adele, whod just died, she says.

We had to get a dress for her, too. We tried to get something that felt vintage-y since their wedding was supposed to be decades ago.

Shonda & Co. wanted a barn wedding to reflect Aprils upbringing on a farm, so the team settled on Windy Hill Ranch at El Campeon Farms and decked it out with huge chandeliers, twinkle lights, and cutesy signs. (We were like, April would do this, for sure.)

All told, the wedding cost $20k, even without a reception. Still, it was a breeze, Nicole says.

Of all the weddings, this one was probably the least stressful because the venue was pretty already, she explains. Of course, what youre seeing out the barn doors, the mountain and the lake, are a green screen.

While searching the web for inspiration, Mimi found a dress with which she fell in love, one designed by Peter Langner in Rome.

We sent [Sarah Drews] measurements, and Peter made it with very few changes. The process is usually four or five months for real brides, and he did it lickety-split.

Mimi reveals she and the shows wonderful full-time seamstress created Catherines dress in-house.

Hopefully that seamstress was one of the crew members who ate the three-tier wedding cake by Cake and Art in Los Angeles after filming finished Nicole cant remember if it even made it into the episode!

Nicole reveals this wedding has special significance for the team: The reception took place at Meredith and Dereks house, which we called the The Dream House. It was the last time we ever filmed on that set.

[Caterina Scorsone] was secretly pregnant, so I had to choose a loose silhouette, because nobody [from the show] knew she was pregnant besides Shonda and me, Mimi reveals.

Amelia is so strong, but she has broken parts, so we tried on a lot of dresses to find something that wasnt too girly, wasnt too precious, but that was also beautiful and honored the day for her.

Mimi also says she had to make two other versions of the same dresses one for the rainy scenes of the Season 12 finale and one for the Season 13 premiere when Caterinas pregnancy was much further along.

The production team at Greys Anatomy including set decorator Nicole Cramer, former set decorator Karen Bruck, and costume designer Mimi Melgaard knows how to put on a helluva wedding, especially 13 seasons into the ABC drama.

I'm not a wedding planner, but we always joke that I could be after how many weddings weve done, Nicole tells Cosmopolitan.

Everyones always shocked when they find out weve put a wedding together in 10 days, Mimi adds. Were kind of used to it.

Read on for the behind-the-scenes secrets the women shared, and tune in as Greys Anatomy Season 13 airs on Thursdays at 8 p.m ET on ABC.

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How 'Grey's Anatomy' Brings Dream Weddings to the Small Screen (PHOTOS) - Wetpaint

Immunology

Runners gearing up for marathons to support Southampton Centre for Cancer Immunology campaign – Daily Echo

MORE than 200 people will be taking part in ABP Southampton marathon runs to support a campaign to build a 25million state-of-the-art centre for cancer immunology.

As previously reported by the Echo, the project was launched by the University of Southampton to offer the chance for Hampshire cancer patients to undergo trials using revolutionary new medicines.

Just 4.5million is needed to finish the build of the trailblazing facility at Southampton General Hospital.

Now, 223 runners are hoping to reduce that total by lacing up their shoes and taking part in the ABP Southampton Marathon, Half Marathon and 10k this Sunday.

Professor Tim Elliott, director for the Centre for Cancer Immunology, said: It is wonderful to see such support for the campaign from both staff and students all around the university.

The construction of the centre is well underway but we still need another 4.5m towards our fundraising target to make it a reality.

All contributions make a real difference and we are so grateful to all those running for the campaign.

At last years event, 30 runners collectively raised more than 9,500 towards the centre.

The four-storey building will be home to world-class research facilities, a clinical trials unit, and a suite of molecular biology laboratories, where genetic engineering will be used to develop new vaccine and antibody constructs.

It will also house a pre-clinical immunology lab investigating the complex interaction of cancer and the immune system

The state-of-the-art centre will be the first of its kind in the UK - and bring 50 new jobs to the city.

The flagship purpose-built centre will also bring together world-leading specialists who will use world-class research facilities and laboratories to work on a new cure the disease.

University bosses also hope it could transform the city into a hub for world leading biomedicine research and attract pharmaceutical manufacturers to the region.

The ABP Southampton Marathon, half marathon and 10k will be held this Sunday.

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Runners gearing up for marathons to support Southampton Centre for Cancer Immunology campaign - Daily Echo