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Cells Across the Body Talk to Each Other About Aging

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Biologists discovered that mitochondria in different tissues talk to each other to repair injured cells. When their signal fails, the biological clock starts winding down.

Chemical signals released by mitochondria are somehow communicated to mitochondria in other tissues, with consequences for how rapidly organisms age.Kristina Armitage/Quanta Magazine

Introduction

Aging can seem like an unregulated process: As time marches along, our cells and bodies inevitably accumulate dings and dents that cause dysfunctions, failures and ultimately death. However, in 1993 a discovery upended that interpretation of events. Researchers found a mutation in a single gene that doubled a worm’s life span; subsequent work showed that related genes, all involved in the response to insulin, are key regulators of aging in a host of animals, from worms and flies to humans. The discovery suggested that aging is not a random process — indeed, specific genes regulate it — and opened the door to further research into how aging proceeds at a molecular level.

Recently, a set of papers documented a new biochemical pathway that regulates aging, one based on signals passed between mitochondria, the organelles best known as the powerhouse of the cell. Working with worms, the researchers found that damage to mitochondria in brain cells triggered a repair response that was then amplified, setting off similar reactions in mitochondria throughout the worm’s body. The effect of this repair activity was to extend the organism’s life span: The worms with repaired mitochondrial damage lived 50% longer.

What’s more, cells in the germline — the cells that produce eggs and sperm — were central to this anti-aging communication system. It’s a finding that adds new dimensions to the fertility concerns implied when people talk about aging and their “biological clock.” Some of the findings were reported in Science Advances and others were posted on the scientific preprint server biorxiv.org in the fall.

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The research builds on a recent body of work that suggests that mitochondria are social organelles that can talk to one another even when they are in different tissues. In essence, the mitochondria function as cellular walkie-talkies, sending messages throughout the body that influence the survival and life span of the entire organism.

“The important thing here is that in addition to genetic programs, there is also a very important factor to regulate aging, which is the communication between tissues,” said David Vilchez, who studies aging at the University of Cologne and was not involved in the new research.

The cell biologist Andrew Dillin discovered the first hints of this novel pathway that regulates life span about a decade ago. He was hunting for life-extending genes in Caenorhabditis elegans worms when he found that genetically damaging the mitochondria extended the worms’ lives by 50%.

That was unexpected. Dillin had assumed that defective mitochondria would hasten death rather than prolong life — after all, mitochondria are central to cell functioning. Yet for some reason, gumming up the smooth functioning of the mitochondria compelled the worms to live longer.

More intriguing was the fact that damaged mitochondria in the worms’ nervous system seemed to be driving the effect. “It really says that some mitochondria are more important than others,” said Dillin, who is now a professor at the University of California, Berkeley. “The neurons dictate this over the rest of the organism, and that was really surprising.”

Andrew Dillion stands at a podium while giving a talk.
Over the past decade, the cell biologist Andrew Dillin has uncovered the biochemical details of a novel pathway that regulates aging, in which mitochondria in cells across the body communicate about cellular health.Courtesy of Andrew Dillin

Introduction

Now, Dillin and his team have expanded that finding by discovering new details about how mitochondria in the brain communicate with cells across the worm’s body to extend life.

First, he had to understand why damage to the brain’s mitochondria could possibly have a beneficial effect on the organism. A mitochondrion’s process for generating energy requires exceedingly complex molecular machinery with dozens of different protein parts. When things go awry, such as when some components are missing or misfolded, mitochondria activate a stress response, known as the unfolded protein response, which delivers repair enzymes to help the complexes assemble properly and restore mitochondrial function. In this way, the unfolded protein response keeps cells healthy.

Dillin expected this process to unfold only inside the neurons with damaged mitochondria. Yet he observed that cells in other tissues of the worm’s body also turned on repair responses even though their mitochondria were intact.

Like taking a car to a mechanic regularly, the unfolded protein response seemed to keep cells in good running order.

It’s this repair activity that helped the worms live longer. Like taking a car to a mechanic regularly, the unfolded protein response seemed to keep cells in good running order and function as anti-aging detailing. What remained mysterious was how this unfolded protein response was communicated to the rest of the organism.

After some investigation, Dillin’s team discovered that the mitochondria in stressed neurons were using vesicles — bubblelike containers that move materials around the cell or between cells — to carry a signal called Wnt beyond the nerve cells to other cells in the body. Biologists already knew that Wnt plays a role in setting up the body pattern during early embryonic development, during which it also triggers repair processes like the unfolded protein response. Still, how could Wnt signaling, when turned on in an adult, avoid activating the embryonic program?

Dillin suspected that there had to be another signal that Wnt interacted with. After further work, the researchers discovered that a gene expressed in the mitochondria of the germline — and in no other mitochondria — can interrupt Wnt’s developmental processes. That result suggested to him that germline cells play critical roles in relaying the Wnt signal between the nervous system and tissues throughout the rest of the body.

“The germline is absolutely essential for this,” Dillin said. It isn’t clear, however, whether the germline mitochondria act as amplifiers, receiving the signal from the brain’s mitochondria and transmitting it to other tissues, or if the receiving tissues are “listening” for signals from both sources.

Either way, the strength of the germline signal regulates the organism’s life span, Dillin said. As a worm ages, the quality of its eggs or sperm declines — what we refer to as the ticking of a biological clock. The decline is also reflected in the germ cells’ changing ability to transmit signals from the brain’s mitochondria, he suggested. As the worm grows older, its germline transmits the repair signal less effectively, and so its body declines, too

Scientists don’t yet know whether these findings apply to humans and how we age. Still, the hypothesis makes sense from a broader evolutionary standpoint, Dillin said. As long as the germ cells are healthy, they send pro-survival signals to ensure that their host organism survives to reproduce. But as the quality of the germ cells declines, there is no evolutionary reason to keep extending life span further; from evolution’s perspective, life exists to reproduce itself.

The fact that mitochondria can talk among themselves might seem somewhat alarming, but there is an explanation. Long ago, mitochondria were free-living bacteria that joined forces with another type of primitive cell to work together in what became our modern complex cells. So, their ability to communicate is probably a relic from the free-living bacterial ancestor of mitochondria.

“This little thing that’s been ticking inside of cells for billions of years still retains its bacterial origins,” Dillin said. And if his research in worms holds up in more complex organisms like humans, it’s possible that your mitochondria are talking right now about your age.

New discovery about “killer torpedoes” may be the next breakthrough in cancer treatment

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In our body, we have both an innate immune system and an immune system that is developed throughout life. Part of the innate immune system consists of so-called NK cells. This is a type of immune cell that specializes in killing cancer cells. These cells may be of great importance for cancer treatment in the future.

The NK cells kill cancer cells with the help of small “killer torpedoes” that the NK cells secrete. In biology, they are called vesicles.

Vesicles are small bubbles with a fatty wall of lipids and a space filled with toxic proteins. These are the torpedoes’ “weapons”.

Researchers at the Institute of Clinical Medicine have recently discovered new things about these killer torpedoes.

We have discovered that we can separate the killer torpedoes from other types of vesicles so that they form a kind of arsenal of weapons. Our research also shows that this type of vesicle is probably stored in a separate room inside the NK cell.”

Miriam Aarsund Larsen

She is a doctoral research fellow from the research group of Professor Marit Inngjerdingen at the Department of Pharmacology at the Institute of Clinical Medicine.

The goal is to develop a completely new type of immunotherapy against cancer

“We intend to investigate this further. Our goal is to develop a new type of cancer treatment based on the killer vesicles in the NK cells,” Aarsund Larsen says.

Marit Inngjerdingen and her research group are the only ones in Norway studying the vesicles in NK cells as a possible new type of treatment against cancer.

“Many people have heard of cell therapy, which is a form of immunotherapy where immune cells are used to fight cancer. But there are several challenges associated with this type of treatment. Among other things, the cancer cells prevent the body’s immune cells from attacking them,” Aarsund Larsen explains.

The killer torpedoes penetrate the cancer cells and kill them

The vesicles, which we here call killer torpedoes, have a built-in ability to attach themselves to cancer cells, and to penetrate and kill them.

“The killer torpedoes are good at getting into cancer tumors. They then use their weapons and skills to kill the cancer cells from the inside,” the doctoral research fellow explains.

This is a major advantage compared to other forms of cancer treatment, according to the researchers. They explain that another challenge with cell therapy is that the immune cells are not very good at getting into cancer tumors. Then it also becomes more difficult to attack them.

Inngjerdingen and Aarsund Larsen’s research shows that this is precisely what the killer torpedoes do so well.

“We can even imagine that we can fill them up with chemotherapy to provide more targeted treatment, with fewer side effects,” Aarsund Larsen says.

The research field is still in its early stages

The researchers emphasise that research on vesicles in NK cells as a possible new form of treatment against cancer is still in its early stages.

“This line of research has just begun, and we need to conduct many more studies before we can say with certainty that this is better than the therapy that is already on the market,” Aarsund Larsen says.

She points out that some studies have shown that vesicles have an effect in mice with cancer.”Our plan is to manipulate our unique killer vesicles to become even better at attacking cancer tumors,” she explains.

Clinical studies on vesicles from stem cells

Clinical studies on vesicles from other types of cells already exist, especially on stem cells. These show that the vesicles have the ability to reduce corneal inflammation, according to the researchers.

“We believe that we can use vesicles from NK cells to kill various types of unwanted cells. This is not limited to cancer. It is also conceivable that we can direct them against over activated T cells, which are seen in various autoimmune conditions,” Inngjerdingen says.

Studied the killer torpedoes in NK cells in the lab

Inngjerdingen and Aarsund Larsen examined the killer vesicles in NK cells from humans that they cultured in the laboratory. They tested them on cancer cell lines, which are immortalized cancer cells from patients. They have used these to make small lumps of cancer, in order to be able to model a real tumor.

“Then we measured how many cancer cells died after treatment with the killer vesicles,” Aarsund Larsen says.

Scientists identify brain molecule that triggers schizophrenia-like behaviors, brain changes

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Scientists at The Scripps Research Institute (TSRI) have identified a molecule in the brain that triggers schizophrenia-like behaviors, brain changes and global gene expression in an animal model. The research gives scientists new tools for someday preventing or treating psychiatric disorders such as schizophrenia, bipolar disorder and autism.

“This new model speaks to how schizophrenia could arise before birth and identifies possible novel drug targets,” said Jerold Chun, a professor and member of the Dorris Neuroscience Center at TSRI who was senior author of the new study.

The findings were published April 7, 2014, in the journal Translational Psychiatry.

What Causes Schizophrenia?

According to the World Health Organization, more than 21 million people worldwide suffer from schizophrenia, a severe psychiatric disorder that can cause delusions and hallucinations and lead to increased risk of suicide.

Although psychiatric disorders have a genetic component, it is known that environmental factors also contribute to disease risk. There is an especially strong link between psychiatric disorders and complications during gestation or birth, such as prenatal bleeding, low oxygen or malnutrition of the mother during pregnancy.

In the new study, the researchers studied one particular known risk factor: bleeding in the brain, called fetal cerebral hemorrhage, which can occur in utero and in premature babies and can be detected via ultrasound.

In particular, the researchers wanted to examine the role of a lipid called lysophosphatidic acid (LPA), which is produced during hemorrhaging. Previous studies had linked increased LPA signaling to alterations in architecture of the fetal brain and the initiation of hydrocephalus (an accumulation of brain fluid that distorts the brain). Both types of events can also increase the risk of psychiatric disorders.

“LPA may be the common factor,” said Beth Thomas, an associate professor at TSRI and co-author of the new study.

Mouse Models Show Symptoms

To test this theory, the research team designed an experiment to see if increased LPA signaling led to schizophrenia-like symptoms in animal models.

Hope Mirendil, an alumna of the TSRI graduate program and first author of the new study, spearheaded the effort to develop the first-ever animal model of fetal cerebral hemorrhage. In a clever experimental paradigm, fetal mice received an injection of a non-reactive saline solution, blood serum (which naturally contains LPA in addition to other molecules) or pure LPA.

  • Ten weeks after the mice were born, they were tested for schizophrenia-like symptoms. The researchers found that female mice given LPA-containing serum or LPA alone displayed hyperactivity upon stimulation, showed anxiety and had increased numbers of dopamine-producing neurons—all which are characteristic of schizophrenia and other psychiatric disorders.

The real litmus test to show if these symptoms were specific to psychiatric disorders, according to Mirendil, was “prepulse inhibition test,” which measures the “startle” response to loud noises. Most mice—and humans—startle when they hear a loud noise. However, if a softer noise (known as a prepulse) is played before the loud tone, mice and humans are “primed” and startle less at the second, louder noise. Yet mice and humans with symptoms of schizophrenia startle just as much at loud noises even with a prepulse, perhaps because they lack the ability to filter sensory information.

Indeed, the female mice injected with serum or LPA alone startled regardless of whether a prepulse was placed before the loud tone.

Next, the researchers analyzed brain changes, revealing schizophrenia-like changes in neurotransmitter-expressing cells. Global gene expression studies found that the LPA-treated mice shared many similar molecular markers as those found in humans with schizophrenia. To further test the role of LPA, the researchers used a molecule to block only LPA signaling in the brain.

This treatment prevented schizophrenia-like symptoms.

Implications for Human Health

This research provides new insights, but also new questions, into the developmental origins of psychiatric disorders.

For example, the researchers only saw symptoms in female mice. Could schizophrenia be triggered by different factors in men and women as well?

“Hopefully this animal model can be further explored to tease out potential differences in the pathological triggers that lead to disease symptoms in males versus females,” said Thomas.

In addition to Chun, Thomas and Mirendil, authors of the study, “LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage,” were Candy De Loera of TSRI; and Kinya Okada and Yuji Inomata of the Mitsubishi Tanabe Pharma Corporation.

Scientists manipulate molecules inside living cells with temperature gradients

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The ability to make measurements of the biomolecular interactions that occur inside living cells is essential for understanding complex biological processes. But probing the inside of living cells without damaging them is a challenge. The cell membrane shields electrical fields, prohibiting the use of electrophoresis, a technique that is commonly used to analyze biological samples in a variety of areas outside living cells.
molecules 1

Now in a new paper, researchers have demonstrated for the first time that thermophoresis—the movement of molecules due to a rather than an electric field—can be used to measure the movement of DNA and other molecules inside living cells. The paper, by Maren R. Reichl and Dieter Braun at the Ludwig Maximilian University of Munich, is published in a recent issue of The Journal of the American Chemical Society.

“Our work shows that the measurement of thermophoresis in living cells is possible—moreover, in parallel across the cell and not at one single point,” Braun told Phys.org.

In the new technique, a temperature gradient is applied across a cell by an infrared laser. Fluorescently marked molecules inside the cell move along this temperature gradient from hotter to colder regions. A camera can record this thermophoretic movement, with every camera pixel measuring thermophoresis simultaneously and independently. The technique can be performed in the natural environment of cells in vivo.

The researchers demonstrated the use of thermophoresis measurements of DNA in the cytoplasm of living cells. Interestingly, the results revealed that DNA movement in the cytoplasm is slowed down, probably due to molecular crowding. In addition to measuring the movement of DNA, the thermophoresis technique could also measure the movement of proteins, pharmaceutical components, and other molecules in cells as long as they can move through the cytoplasm. Ribosomes, for example, are so large and bound to the endoplasmic reticulum that they cannot easily diffuse through the cytoplasm, making them poor candidates for thermophoresis.

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Thermophoresis measurements of DNA and the dye molecule BCECF in the cytoplasm of living cells. Credit: Reichl and Braun. ©2014 American Chemical Society

One way that thermophoresis inside living cells can be used is to measure the binding affinities of molecules. As the scientists explain, the binding of a fluorescently marked molecule such as DNA or a protein leads to a change in the thermophoretic depletion strength. Binding affinities can reveal more detailed information about the interactions of these molecules.

“The dream would be to record binding affinities in living , i.e., translating the award-winning microscale thermophoresis (MST) technique of our startup company Nanotemper into ,” Braun said. “However, the measurement protocol is not yet robust against the shape of the cell, so some more tricks to make it work will be necessary. But we are optimistic—experimental tricks are our specialty.”

Gene Used In Embryogenesis Can Repair Adult Tissue.

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There are some amazing genes and cellular processes active during embryonic development that are never seen again later in life. Though some insects and amphibians are able to carry those traits into adulthood, mammals have a dramatic decrease in the ability to regenerate tissue after birth. A new study has shown that one embryonic protein can be used to help regenerate adult tissue in a living organism, not just in a dish.

The protein Lin28a typically only contributes to processes during embryogenesis, affecting things like metabolism and the pluripotency of stem cells. A study published Nov. 7 in Cell has shown that these proteins can actually be used in adult tissue and help in the regeneration of cartilage, hair follicles, bone, and mesenchyme, a type of undifferentiated connective tissue. It works by binding microRNA in the cell’s nucleus to inhibit let7. Let7 encourages cells to mature and lose the regenerative abilities.

Mice that had been genetically altered to produce Lin28a throughout life had outstanding regenerative power. Though regular mice typically stop producing new hair at around 10 weeks, those with a continued presence of Lin28a kept growing fur throughout their lives. Lin28a also boosted regeneration of limbs. During development, Lin28a is commonly found in the limb buds, but is hardly expressed in those regions after birth. For the mice over expressing Lin28a, some digits that were amputated early in life grew back nearly completely. This ability was diminished as the mouse approached adulthood. Because cardiac tissue also wasn’t regenerated by the presence of Lin28a, there could be other unknown proteins that regulate body aging.

Lin28a was also shown to promote prompt healing of damaged ears, increase metabolism, and contribute to cell proliferation and migration, which are necessary for tissue repair. Unfortunately, some of these attributes can also lead to tumorigenesis, which has been the focus of a great deal of recent cancer research.

This discovery is a long way off from having clinical significance as a miracle “fountain of youth” treatment. Because Lin28a binds to RNA, not the surface of the cell, current drug delivery systems would be very ineffective. Also, because the protein affects so many different tissues in the body, it would be incredibly difficult to target only the desired area. In the future, however, this could be used as a treatment for diseases like alopecia and for tissues that have been injured or are degenerating.

Fountain of youth? Scientists discover why wounds heal quicker for young people

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Fountain of youth? Scientists discover why wounds heal quicker for young people .

The mystery of why wounds heal more quickly in the young compared to the elderly may soon be solved following the discovery of two of the genes involved in tissue regeneration.

Scientists believe that the findings will help to develop new drugs and treatments for faster wound-healing as well as shedding light on the ageing process itself, and what could amount to a genetic “fountain of youth”.

Two teams of researchers found separate genes that accelerate tissue regeneration in laboratory mice. Both genes, which are also present in the human genome, are more active in young mice compared to older mice.

The scientists believe that the genes, called Lin28a and IMP1, are designed to be especially active during the foetal stages of development and are gradually turned off as an animal ages – which could explain why wounds take longer to heal in the elderly and how ageing occurs.

One of the teams, led by George Daley of the Boston Children’s Hospital and Harvard Medical School, activated the Lin28a gene in adult mice and found that shaved fur on their backs grew back much faster than in ordinary adult mice where the gene had not be artificially boosted.

“It sounds like science fiction, but Lin28a could be part of a healing cocktail that gives adults the superior tissue repair seen in juvenile animals,” said Dr Daley, whose study is published in the journal Cell.

Asked what the implications are for human health, Dr Daley said: “My strongest conclusion is that Lin28a, or drug manipulations that mimic the metabolic effects of Lin28a, enhances wound healing and tissue repair, and thus in the future might translate into improved healing of wounds after surgery or trauma in patients.”

The study revealed that the Lin28a gene is responsible for a protein that binds to the key molecules of RNA involved in the metabolism of energy within the mitochondria, the “power packs” of the cells. The result is that when the gene is active, the cells are better and more efficient at repairing themselves – the activated genes also accelerated the repair of injuries.

Tissue regeneration is important in early foetal development and when damaged tissues need to be healed. A gradual loss of tissue regeneration and repair is one of the hallmarks of ageing so anything that could improve it could lead to anti-ageing treatments

“We were surprised that what was previously believed to be a mundane cellular ‘housekeeping’ function would be so important for tissue repair,” said Shyh-Chang Ng of Harvard Medical School, the lead author of the Cell study.

“One of our experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing, suggesting that it could be possible to use drugs to promote tissue repair in humans.”

The second gene, IMP1, also produces a protein that binds to the RNA molecules, but this time it promotes the self-renewal of key stem cells during foetal development, and also during tissue repair in later life, said Hao Zhu of the University of Texas in Dallas.

“This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration,” Dr Zhu said.

Scientists believe that the findings will help to develop new drugs and treatments for faster wound-healing as well as shedding light on the ageing process itself, and what could amount to a genetic “fountain of youth”.

Two teams of researchers found separate genes that accelerate tissue regeneration in laboratory mice. Both genes, which are also present in the human genome, are more active in young mice compared to older mice.

The scientists believe that the genes, called Lin28a and IMP1, are designed to be especially active during the foetal stages of development and are gradually turned off as an animal ages – which could explain why wounds take longer to heal in the elderly and how ageing occurs.

One of the teams, led by George Daley of the Boston Children’s Hospital and Harvard Medical School, activated the Lin28a gene in adult mice and found that shaved fur on their backs grew back much faster than in ordinary adult mice where the gene had not be artificially boosted.

“It sounds like science fiction, but Lin28a could be part of a healing cocktail that gives adults the superior tissue repair seen in juvenile animals,” said Dr Daley, whose study is published in the journal Cell.

Asked what the implications are for human health, Dr Daley said: “My strongest conclusion is that Lin28a, or drug manipulations that mimic the metabolic effects of Lin28a, enhances wound healing and tissue repair, and thus in the future might translate into improved healing of wounds after surgery or trauma in patients.”

The study revealed that the Lin28a gene is responsible for a protein that binds to the key molecules of RNA involved in the metabolism of energy within the mitochondria, the “power packs” of the cells. The result is that when the gene is active, the cells are better and more efficient at repairing themselves – the activated genes also accelerated the repair of injuries.

Tissue regeneration is important in early foetal development and when damaged tissues need to be healed. A gradual loss of tissue regeneration and repair is one of the hallmarks of ageing so anything that could improve it could lead to anti-ageing treatments

“We were surprised that what was previously believed to be a mundane cellular ‘housekeeping’ function would be so important for tissue repair,” said Shyh-Chang Ng of Harvard Medical School, the lead author of the Cell study.

“One of our experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing, suggesting that it could be possible to use drugs to promote tissue repair in humans.”

The second gene, IMP1, also produces a protein that binds to the RNA molecules, but this time it promotes the self-renewal of key stem cells during foetal development, and also during tissue repair in later life, said Hao Zhu of the University of Texas in Dallas.

“This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration,” Dr Zhu said.

Scientists believe that the findings will help to develop new drugs and treatments for faster wound-healing as well as shedding light on the ageing process itself, and what could amount to a genetic “fountain of youth”.

Two teams of researchers found separate genes that accelerate tissue regeneration in laboratory mice. Both genes, which are also present in the human genome, are more active in young mice compared to older mice.

The scientists believe that the genes, called Lin28a and IMP1, are designed to be especially active during the foetal stages of development and are gradually turned off as an animal ages – which could explain why wounds take longer to heal in the elderly and how ageing occurs.

One of the teams, led by George Daley of the Boston Children’s Hospital and Harvard Medical School, activated the Lin28a gene in adult mice and found that shaved fur on their backs grew back much faster than in ordinary adult mice where the gene had not be artificially boosted.

“It sounds like science fiction, but Lin28a could be part of a healing cocktail that gives adults the superior tissue repair seen in juvenile animals,” said Dr Daley, whose study is published in the journal Cell.

Asked what the implications are for human health, Dr Daley said: “My strongest conclusion is that Lin28a, or drug manipulations that mimic the metabolic effects of Lin28a, enhances wound healing and tissue repair, and thus in the future might translate into improved healing of wounds after surgery or trauma in patients.”

The study revealed that the Lin28a gene is responsible for a protein that binds to the key molecules of RNA involved in the metabolism of energy within the mitochondria, the “power packs” of the cells. The result is that when the gene is active, the cells are better and more efficient at repairing themselves – the activated genes also accelerated the repair of injuries.

Tissue regeneration is important in early foetal development and when damaged tissues need to be healed. A gradual loss of tissue regeneration and repair is one of the hallmarks of ageing so anything that could improve it could lead to anti-ageing treatments

“We were surprised that what was previously believed to be a mundane cellular ‘housekeeping’ function would be so important for tissue repair,” said Shyh-Chang Ng of Harvard Medical School, the lead author of the Cell study.

“One of our experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing, suggesting that it could be possible to use drugs to promote tissue repair in humans.”

The second gene, IMP1, also produces a protein that binds to the RNA molecules, but this time it promotes the self-renewal of key stem cells during foetal development, and also during tissue repair in later life, said Hao Zhu of the University of Texas in Dallas.

“This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration,” Dr Zhu said.

The 2013 Nobel Prize in Physiology or Medicine.

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The 2013 Nobel Prize honours three scientists who have solved the mystery of how the cell organizes its transport system. Each cell is a factory that produces and exports molecules. For instance, insulin is manufactured and released into the blood and chemical signals called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. The three Nobel Laureates have discovered the molecular principles that govern how this cargo is delivered to the right place at the right time in the cell.

Randy Schekman discovered a set of genes that were required for vesicle traffic. James Rothman  unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Thomas Südhof revealed how signals instruct vesicles to release their cargo with precision.

Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.

How cargo is transported in the cell

In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are everything. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. How do these vesicles know where and when to deliver their cargo?

Traffic congestion reveals genetic controllers

Randy Schekman was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman identified three classes of genes that control different facets of the cell´s transport system, thereby providing new insights into the tightly regulated machinery that mediates vesicle transport in the cell.

Docking with precision

James Rothman was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents.

It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery.

Timing is everything

Thomas Südhof was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium ions were known to be involved in this process and in the 1990s, Südhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. The zipper opens up and signal substances are released. Südhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command.

Vesicle transport gives insight into disease processes

The three Nobel Laureates have discovered a fundamental process in cell physiology. These discoveries have had a major impact on our understanding of how cargo is delivered with timing and precision within and outside the cell.  Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Defective vesicle transport occurs in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. Without this wonderfully precise organization, the cell would lapse into chaos.

James E. Rothman was born 1950 in Haverhill, Massachusetts, USA. He received his PhD from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University in California, where he started his research on the vesicles of the cell. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University. In 2008, he joined the faculty of Yale University in New Haven, Connecticut, USA, where he is currently Professor and Chairman in the Department of Cell Biology.

Randy W. Schekman was born 1948 in St Paul, Minnesota, USA, studied at the University of California in Los Angeles and at Stanford University, where he obtained his PhD in 1974 under the supervision of Arthur Kornberg (Nobel Prize 1959) and in the same department that Rothman joined a few years later. In 1976, Schekman joined the faculty of the University of California at Berkeley, where he is currently Professor in the Department of Molecular and Cell biology. Schekman is also an investigator of Howard Hughes Medical Institute.

Thomas C. Südhof was born in 1955 in Göttingen, Germany. He studied at the Georg-August-Universität in Göttingen, where he received an MD in 1982 and a Doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas, Texas, USA, as a postdoctoral fellow with Michael Brown and Joseph Goldstein (who shared the 1985 Nobel Prize in Physiology or Medicine). Südhof became an investigator of Howard Hughes Medical Institute in 1991 and was appointed Professor of Molecular and Cellular Physiology at Stanford University in 2008.

Silicon chips detect intracellular pressure changes in living cells.

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The ability to measure pressure changes inside different components of a living cell is important, because it offers an alternative way to study fundamental processes that involve cell deformation1. Most current techniques such as pipette aspiration2, optical interferometry3 or external pressure probes4 use either indirect measurement methods or approaches that can damage the cell membrane.chip

Here we show that a silicon chip small enough to be internalized into a living cell can be used to detect pressure changes inside the cell. The chip, which consists of two membranes separated by a vacuum gap to form a Fabry–Pérot resonator, detects pressure changes that can be quantified from the intensity of the reflected light. Using this chip, we show that extracellular hydrostatic pressure is transmitted into HeLa cells and that these cells can endure hypo-osmotic stress without significantly increasing their intracellular hydrostatic pressure.

Scientists create replacement organs using body’s own cells.

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One of the problems of organ transplants is the potential for the body to reject the foreign organ. For this reason, organ donor recipients have to take drugs that suppress the immune system.

Scientists are having preliminary success with a new way to get patients new organs that they may need: bioartificial organs made of plastic and the patient’s own cells.

So far, only a few such organs have been created and transplanted, and the they aren’t complex organs — just simples one like bladders and a windpipe. But, the New York Times reports, scientists are working on creating more complex organs such as kidneys and livers with these techniques.

A windpipe made to order

The Times article features the case of Andemariam Beyene, whose doctors discovered a golf ball-sized tumor growing in his windpipe two-and-a-half years ago. When he was nearly out of options for treatment, he went to see Dr. Paolo Macchiarini, at the Karolinska Institute in Stockholm, who suggested making Mr. Beyene a windpipe out of plastic and his own cells.

In order to make it, Dr. Macchiarini began by using a porous, fibrous plastic to make a copy of Mr. Beyene’s windpipe. He then seeded it with stem cells from Mr. Beyene’s bone marrow and placed the windpipe in an incubator that spun the windpipe “rotisserie-style,” says the Times, in a nutrient solution.

Then, he substituted that in for Mr. Beyene’s cancerous windpipe.

Fifteen months after surgery, Mr. Beyene is cancer-free.

The blueprint

Scientists are looking to nature to guidance on how to create these bioartificial organs.

In Dr. Macchiarini’s lab, a researcher named Philipp Jungebluth took a heart and lungs from a rat and put them in a glass jar. A detergent-like liquid connected via tube dripped into the jar and out, slowly stripping the organs of their living cells. After all the cells were gone (in three days), what was left of the organs was the scaffold, the basic shape of the organ, composed of a matrix of proteins and other compounds that keep the right cells in the right places.

Human scaffolds could be better for building new organs than synthetic scaffolds that just try to imitate nature. For example, donor lungs could be stripped of cells and re-seeded with a patient’s own cells before implantation.

Dr. Macchiarini has used scaffolds to successfully replace windpipes from cadavers in about a dozen patients who don’t have the major problem facing other organ donor recipients: the risk of organ rejection.

But scaffolds still have some problems of traditional organ transplants: They require donor organs, for which there is a long waiting list, and the patient has to wait for the organ to be stripped of cells. Also, when it comes to windpipes, a donated windpipe may not be the right size. For that reason, Mr. Beyene’s windpipe, made of the plastic replica of his own windpipe, fit perfectly.

Dr. Macchiarini is looking at future improvements on this still preliminary work: The Times reports that someday, re-seeding the cells of a new organ may not take place outside the body:

“Instead, he envisions developing even better scaffolds and implanting them without cells, relying on drugs to stimulate the body to send cells to the site. His ultimate dream is to eliminate even the synthetic scaffold. Instead, drugs would enable the body to rebuild its own scaffold.”

“Don’t touch the patient,” Dr. Macchiarini told The Times. “Just use his body to recreate his own organ. It would be fantastic.”

Source: The New York Times /Smart planet