Bortezomib Prunes Inflammatory T Cells: Hope for Inflammatory Diseases that Make the Young Old and Make the Old Want to Die

Inflammatory diseases such as arthritis, inflammatory bowel disease, multiple sclerosis, lupus, and many more, can strike at any time. Such diseases can create such suffering and disability that they make young people old very quickly, and can make old people wish they were dead.

A fairly new drug in the proteasome inhibitor class, Bortezomib, is used to treat a cancer of the bone marrow cells, multiple myeloma. But now, scientists have discovered a new use for Bortezomib: killing off active and proliferating T cells that cause so much damage in inflammatory diseases -- while leaving the resting T cells alone.

Those looking for a new treatment for a range of inflammatory diseases like arthritis, multiple sclerosis, inflammatory bowel disease, and lupus may need to look no further than a drug already available for treating cancer. In a research report published in the July 2010 print issue of the Journal of Leukocyte Biology (http://www.jleukbio.org), Japanese scientists use mice to show that bortezomib, currently used to treat cancers that affect white blood cells, induces cell death only in harmful (active and proliferating) T cells, leaving the rest unharmed. If the results prove true in humans, it offers hope that this drugs or others similar to it might be used to treat inflammatory diseases without the side effects of current drugs that affect all T cells equally.

"Unfortunately, there are a lot of people who are suffering from autoimmune and inflammatory disease," said Koichi Yanaba, M.D., Ph.D., a scientist from the Department of Dermatology at Nagasaki University Graduate School of Biomedical Sciences who was involved in the research. "We believe that this new-type remedy for autoimmune and inflammatory disease could successfully treat them in the near future."

To make this discovery, scientists used two groups of mice—the first treated with bortezomib and the second with saline. Researchers induced contact hypersensitivity reaction with oxazolone, a chemical allergen used for immunological experiments and found that bortezomib significantly inhibited the contact hypersensitivity responses. Results strongly suggest that bortezomib treatment enhanced T cell death by inhibiting NF-kappa B activation, which plays a key role in regulating the immune response to infection. This in turn led to the suppression of inflammatory responses in immune cells by reducing interferon-gamma production. _Eurekalert

Inflammation complicates many diseases of old age, including Alzheimer's, heart disease, lung and other respiratory diseases, digestive system diseases, and so on. Finding better and more specific treatments for blocking excessive inflammation while allowing normal immune function to continue, would extend life for many and reduce morbidity for many more.

Another Way to Add Years to Your Life

Physorg
Most people spend a third of their lives sleeping. Doing without sleep does not seem to work well, in terms of achieving optimal focus and concentration. The brain seems to need that "down time" for some reason. This may be the reason:

Levels of adenosine triphosphate (ATP), the energy currency of cells, in rats increased in four key brain regions normally active during wakefulness. Shown here is the energy surge measured in the frontal cortex, a brain region associated with higher-level thinking. Credit: Courtesy, with permission: Dworak et al. The Journal of Neuroscience 2010.

In the initial stages of sleep, energy levels increase dramatically in brain regions found to be active during waking hours, according to new research in the June 30 issue of the Journal of Neuroscience. These results suggest that a surge of cellular energy may replenish brain processes needed to function normally while awake.

The authors measured levels of adenosine triphosphate (ATP), the energy currency of cells, in rats. They found that ATP levels in four key brain regions normally active during wakefulness increased when the rats were in non-REM sleep, but were accompanied by an overall decrease in brain activity. When the animals were awake, ATP levels were steady. When the rats were gently nudged to stay awake three or six hours past their normal sleep times, there was no increase in ATP.
The authors conclude that sleep is necessary for this ATP energy surge, as keeping the rats awake prevented the surge. The energy increase may then power restorative processes absent during wakefulness, because brain cells consume large amounts of energy just performing daily waking functions. _Physorg

Now that scientists have a clue as to where to look for sleep's regenerative effects on the brain, they can begin to devise alternative ways of stimulating that regeneration -- other than to consume 1/3 of every 24 hour day for that purpose.

Alternative schedules of sleep / wake cycles, napping strategies, electromagnetic stimulation, nutritional or exercise strategies, etc -- there is likely to be workable ways by which an individual could achieve brain ATP regeneration AND redeem some of those 8 hours of sleep for productive or leisure activity. More living, in other words, without endangering one's health.

It is a mere glimpse behind the curtain of sleep, but it could prove to be a useful one. Two extra hours of productive wakefulness over 30 years can give you two and a half extra years of intentional living. If you are just as rested and just as healthy, then there are few reasons not to have more awake time.

Printing Out New Organs and Other Adventures in New Biology

It may not be long before severely burned persons will be able to lie back and watch while an entirely new skin is printed onto their body -- saving their lives.

The same printer technology that sits on your desk could soon be a common fixture in rebuilding human tissue, treating burns by laying down layers of a patients' own skin or even rebuilding whole organs.

A team at Wake Forest University has built a "bioprinter" that uses cells instead of ink. It even uses an ordinary, off-the-shelf printhead, connected to test tubes full of different cell types instead of wells full of colored inks.

Led by Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in Winston–Salem, N.C., the team is working on treating burns. Such wounds can be hard to treat, because in severe cases there might not be enough healthy skin on the patient to harvest or culture for a graft.Grafting skin to cover burn wounds is also important for preventing infections, which can be a source of complications. Printing out cells grown in culture would eliminate these problems. Another application is repairing scar tissue.

The breakthrough in using bioprinting for tissue regeneration is the gel used to contain the cells: The mixture must hold the cells in place when they are laid down as well as provide a viable medium where they can be kept alive while they are held in the reservoirs. "It took us seven years," he says. "There's lots of trial and error; this isn't trivial chemistry," he adds.

For building tissue, several printing methods were tried, including three-dimensional CAD and laser printing. But once the group hit on the inkjet method, it turned out to work so well that some of the early work on building tissue was done on modified inkjet printers from a local office supply store.

Other organs have been constructed from cultured cells, but they were built on a scaffolding to give them their three-dimensional shape. Skin doesn't require a matrix because it is relatively flat to begin with.

So far, the system has been tested on mice, which are given wounds similar to burns. Those that were treated with printer-generated cells healed in three weeks, whereas those that were allowed to recover naturally required five weeks. The researchers plan to test the system on bigger animals in the future. The technology is still in the early stages, Atala says. As of yet there is no timetable for human tests or for the publication of the mouse research results.

The Wake Forest group is not just working on skin. Bone tissue and a two-chambered mouse heart have both been successfully printed. The heart was stimulated to beat when the cells were shocked with electricity, and the printed bones have been implanted in mice. _SciAm

Another approach to tissue regeneration is the use of biodegradable polymers as a scaffolding for the growth of replacement cells and tissues.

Here is an idea that is genuinely visionary -- which is exactly the sort of thinking we need to promote if we are ever to get to where we want to go. If we can take our biology to the level that allows us to grow living, breathing, thinking buildings that keep us comfortable and safe, imagine the level of accomplishment that human tissue engineering will have achieved.

A healthy, vibrant, and expansive society requires the best from all of its citizens. We cannot afford to be overly focused upon just one goal. We need to also be developing ideas and processes that may have no immediate use -- but which may indeed be earthshaking and earth saving sometime in the future.

Regenerative Medicine Roadmap

PDFRegen-RoadmapPDF
FightAging presents a look at what it describes as "The Dawn of the Age of Tissue Engineering", and presents a roadmap of regenerative medicine in PDF format. via Brian Wang

Regenerative medicine is one of several different approaches to life extension and improved human longevity.

Cell therapy involves the adding of younger or progenitor cells, the removal of senescent or destructive cells, and the genetic reprogramming of cells in situ. New and reprogrammed cells then grow within the pre-existing matrix.

Tissue engineering involves the growth of tissues or entire organs within artificial scaffolding. This growth may occur outside the body (for later transplant) or inside the body with in situ tissue engineering.

Cell therapy is the easier approach, but may take several decades of development to achieve the regenerative power that tissue engineering promises to provide within one decade.

Hormonal and growth factor regenerative medicine use chemicals to alter the cells from the outside, in a therapeutic sequence. This approach is even easier than cell therapy, but is also more limited.

There are other regenerative therapies which work via the immune system, and via epigenetic systems, and some of these will come into use within the next decade or two.

Other life extension strategies -- such as cryonics, mitochondrial rejuvenation, technological prostheses, and the total redesign of the human body -- will continue to receive varying levels of support. One should also keep an eye on SENS.

Thymosin Beta 4 Helps Regenerate Damaged Brain in Rats

The small protein thymosin beta 4 has multiple functions: it moonlights to repair injured tissues [6], has anti-inflammatory efficacy in monocyte/macrophages [7], promotes wound healing [8] and mediates angiogenesis [9]. Tβ4 has been also shown to play a relevant role during the development of different neural cell types in the rat brain [10]. In particular, Tβ4 plays a neurotrophic and antiapoptotic role during the development of the nervous system [11]. __PLoSONE

New research to be reported June 3 at the Annual Meeting of the Society for Academic Emergency Medicine in Phoenix, showed that in adult rats, thymosin beta-4 assisted in the repair of nerve fibres in the brain and in growing new blood vessels.

A synthetic version of a naturally occurring peptide promoted the creation of new blood vessels and repaired damaged nerve cells in lab animals, according to researchers at Henry Ford Hospital in Detroit.

"This successful experiment holds promise for treating clot-induced strokes in humans," says study lead author Daniel C. Morris, M.D., senior staff physician in the Department of Emergency Medicine at Henry Ford Hospital. "Neurorestorative therapy is the next frontier in the treatment of stroke." _SD

This is a potentially important finding for regenerative medicine, given how common cerebral vascular accident is in humans, and how dismal the prognosis typically is afterward.

Thymosin beta-4 is an immune modulating protein, which demonstrates once again how important the brain and the immune system are to one another. Given that Thymosin beta-4 is not a growth factor, as such, it will be important to generate a picture of the entire mechanism involved, for a complete understanding of potential therapies for brain damage, using this protein.

Neural Stimulators Control Inflammatory Processes

Scientists have known about the connection between the mind-brain and the immune system for many decades. From the "laughter cure" devised by Norman Cousins to mitigate a severe inflammatory disease to the decades old scientific discipline of psychoneuroimmunology, the importance of the connection between the brain and the immune system has been known. A malfunctioning immune system leads to both suffering and an early death, so discovering better ways to dampen an out of control immune response is vital to achieving long and healthy lives.

But finding the best way of controlling immune function by way of the brain has not always been easy. One of the latest attempts at such control comes from a business startup in Boston called Setpoint Medical.

The technology is based on a decade of research elucidating how the brain controls the immune system, particularly inflammation. The treatment has not yet been tested in patients, but based on animal research, scientists hope it will provide an alternative treatment that is more effective and have fewer side effects than existing drugs.

...Over the last decade, Kevin Tracey, an immunologist and neurosurgeon at the Feinstein Institute for Medical Research in Manhasset, NY, has shown that inflammation is controlled in part by the vagus nerve, which carries signals between the brain and a number of visceral organs. Most notably for immune function, it makes direct connections to the spleen, which houses different types of immune cells poised for release at times of infection.

Numerous animal studies have shown that stimulating the vagus nerve can put a brake on the immune system, stopping the rapid recruitment of immune cells to the site of injury or infection. "Think of it as a thermostat for the immune system," says James Broderick, interim president of the company and a partner at Morgenthaler Ventures, Setpoint's key investor. "This reflex puts a damper on the immune system."

The effect is similar to that of a popular class of drugs, called TNF alpha blockers, used to treat arthritis and other autoimmune diseases. These drugs block the release of an immune signaling molecule that is central to inducing inflammation. While they work effectively in 50 to 70 percent of patients, the drugs can lose their effectiveness over time and have been linked to some serious side effects, such as infection and cancer. Vagus nerve stimulation blocks both the signal molecule and other cytokines involved in inflammation. _TechnologyReview

This novel approach to treating autoimmune diseases and hyper-immune responses may be used instead of drug treatment, or along with drug treatment to allow lower doses of drugs.

Brain Cell Regeneration Using Reprogrammed Astroglia

The brain consists of two major cell types: neurons, which transmit information, and glial cells, which support and protect neurons. Interestingly, evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue. However, in order for the repaired brain areas to function properly, it is important that astroglia be directed into appropriate neuronal subclasses. In this study, we show that non-neurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons. We achieved this result through forced expression of the same transcription factors that instruct the genesis of these distinct neuronal subtypes during embryonic forebrain development. Moreover we demonstrate that reactive astroglia isolated from the adult cortex after local injury can be reprogrammed into synapse-forming excitatory or inhibitory neurons following a similar strategy. Our findings provide evidence that endogenous glial cells may prove a promising strategy for replacing neurons that have degenerated due to trauma or disease. _PLOS

Scientists from the Helmholtz Center and Ludwig-Maximilians University in Munich, have used a virus to reprogram brain helper cells -- astroglia -- into actual neurons. They were able to convert astroglia from early post-natal and adult mouse brains into either excitatory or inhibitory neurons, depending upon the transcription factors which were introduced.

The study adds to growing evidence that certain cell types can be transformed directly into other cell types without first being converted into stem cells. Researchers have previously transformed skin cells into neurons, and one type of pancreatic cell into another. Marius Wernig, a coauthor of the skin cell study and a stem cell biologist at Stanford University, says there's a growing awareness that it may not be necessary to erase a cell's existing identity before giving it a new one.

...this latest study "means that these astroglial cells could be converted in the brain" without the need for a transplant. Berninger says that one of the next challenges is to determine whether these reprogrammed neurons can survive and function in a living brain.

Fortunately, the brain seems to have a ready source of astroglia. When the brain is injured, these cells proliferate, similar to the way the skin repairs itself after a wound. The researchers found they could also derive neurons from injury-induced astroglia taken from the brains of adult mice. _TechnologyReview

More:

we first aimed at a more potent neuronal reprogramming by inducing higher and more persistent expression of neurogenic fate determinants in astroglial cells. This allowed us not only to obtain fully functional neurons that also establish synapses from astroglial cells in vitro but also to demonstrate that distinct neurogenic transcription factors, such as on the one hand Neurog2 and on the other Dlx2 alone or in combination with Mash1, can indeed instruct the selective generation of different neuronal subtypes, such as glutamatergic and GABAergic neurons, respectively. Moreover, we found that the reprogramming efficiency of postnatal cortical astroglia towards GABAergic neurons by Dlx2 could be enhanced by first expanding the astroglial cells under neurosphere conditions prior to forced expression of Dlx2. Given that following brain injury reactive astroglia from the adult cerebral cortex de-differentiate, resume proliferation, and can give rise to self-renewing neurospheres in vitro [16], we finally show that neuronal reprogramming and subtype specification are not restricted to postnatal stages but can also be achieved from adult cortical astroglia responding to injury. _PLOS

The findings are a striking reminder that nature offers us many more possibilities than we can presently conceive of. But perhaps we will grow in our conceptual capacity, over time.

The possibility of regenerating brain tissue in situ -- without the need for inserting new cells from elsewhere -- offers new hope for brain trauma, infection, infarct, atrophy, and senility. But it also offers a distinctly new possibility which most observors are not quite ready to think about -- much less discuss.

I am referring to the possibility of growing entirely new neural networks in situ, from astroglia. The possibility that humans can induce their own brains to create entirely new brain centers and pathways, using more advanced forms of such techniques, should not be overlooked.

There is currently a race between biological methods of repairing and enhancing human organs, and technological methods of compensating for organ damage or loss -- the cyborg approach. A cyborg may utilise nano-technological enhancement, and thus manifest no outward sign of distinction from standard normal humans. The same would be true for most biological enhancements or remediation.

This lack of overt differences between ordinary persons and enhanced persons is quite important to most military uses of enhanced individuals, and to virtually all covert uses by government and other organisations.

But these tools of transformation are not likely to remain limited to deep pocketed groups and individuals. Garage biohackers are not as uncommon as you might think, and are performing a similar service for bio-hacking as the garage techno-hackers performed for microcomputers in the early days. And it is also extremely likely that persons involved in expensive and large scale research into bio-transformation technologies will set off on their own as they discover the ability to profit from their technical knowledge and skills.

Cross-posted at Al Fin

Tricks of Epigenetic Memory

It is common knowledge that a person's memory tends to get a bit foggy as he ages. A young person's memory tends to be crisper and quicker than that of a person in senescence. But it is possible that there is a means within our grasp by which we can turn back the clock in the aging brain -- back to a time of quicker and clearer recall, and a stronger grasp of new knowledge.

A new study published in Science sheds some light on how “memory disturbances” in an aging mouse brain are associated with altered “hippocampal chromatin plasticity” — the combination of DNA, histones, and other proteins that make up the chromosomes associated with the hippocampus. Specifically, the study describes an acetyl genetic switch that produces memory impairment in aging 16-month-old mice. Because the acetyl wasn’t present in young 3-month-old mice, the study concludes that it acts as a switch for a cluster of learning and memory genes.

...Dr. Fischer’s research shows that when young mice are learning, an acetyl group binds to a particular point on the histone protein. The cluster of learning and memory genes on the surrounding DNA ends up close to the acetyl group. This acetyl group was missing in the older mice that had been given the same tasks. By injecting an enzyme known to encourage acetyl groups to bind to any kind of histone molecule, Fischer’s team flipped the acetyl genetic switch to the “on” position in the older mice and their learning and memory performance became similar to that of 3-month-old mice. _hplus

More:

Dr Fischer, of the European Neuroscience Institute in Goettingen, Germany, pinpointed a tiny protein called H4K12 that controls genes key to memory and learning in the mouse brain.

...In an accompanying article, Professor David Sweatt , a U.S. neurobiologist, said that turning on H4K12 was likely to help with both Alzheimer's and age-related memory loss.
He said the German results 'provide important proof of principle that this might be a viable approach to therapeutic interventions in ageing'.
'These studies will hopefully lead to more effective prevention strategies to improve quality of life in the aged, as well as contribute to a better understanding of memory function,' he added.
The treatment of other brain conditions, such as schizophrenia and Parkinson's disease, could be improved by finding other switches that act in a similar way.
Dr Marie Janson, of the Alzheimer's Research Trust, said: 'Although in mice, this research gives us clues about how memories are formed and function in the brain.
'We now need to find out if the same processes happen in the human brain.
'This understanding is vital if we are to develop ways to protect the ageing brain from cognitive decline.
'Alzheimer's and other dementias are complex, with many things happening in the brain, so it's likely that we'll need several drugs to treat them effectively._DailyMail

Brain function is inextricably tied to genetic function. The relationship is certainly of a circular nature. If we are to learn to live long and fulfilling lives, we will need to undertand ourselves better, at a much deeper level than we once thought possible.

Stem Cells to Restore Your Hearing, Your Heart, Your Teeth

Stanford University researchers have developed a way to grow replacement "hair cells" for the inner ear, in mice. The hair cells are responsible for hearing, and the cumulative loss of hair cells over a lifetime result in permanent hearing loss. If humans could learn to regenerate the hair cells in the inner ear, hearing loss could be reversed without the need for electronic devices such as cochlear implants or hearing aids. Source via Brian Wang

Geron scientists have demonstrated the safety of GRNCM1 (cardiomyocites or stem cells) for replacing damaged heart tissue. This treatment, once approved, is likely to be used to treat chronic heart failure -- a significant cause of death and disability worldwide.
Source 1 (via Brian Wang), Source 2

Columbia University researchers are developing a method for growing replacement teeth "in place", inside the actual socket of the lost tooth. The method utilises stem cells to re-grow the tooth along with accompanying soft tissue support. This approach will do away with the need to use hardware implants, or to grow teeth outside the body in culture media.
Source via Brian Wang

The re-growth of body organs in place -- using the original tissue matrix as a scaffolding -- is a safer approach than re-growing organs outside the body, then surgically implanting them. Both approaches will probably become common, but in circumstances where in situ stem cell replacement is effective, most persons will likely opt for that approach.

Stem Cells from Endometrial Tissue Reverse Parkinson's?

Scientists at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), have injected endometrial stem cells into the brains of mice with an induced form of Parkinson's Disease. The injected stem cells began producing dopamine -- the neurotransmitter that is deficient in Parkinson's.

The finding raises the possibility that women with Parkinson's disease could serve as their own stem cell donors. Similarly, because endometrial stem cells are readily available and easy to collect, banks of endometrial stem cells could be stored for men and women with Parkinson's disease.

"These early results are encouraging," said Alan E. Guttmacher, M.D., acting director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH Institute that funded the study. "Endometrial stem cells are widely available, easy to access and appear to take on the characteristics of nervous system tissue readily."

Parkinson's disease results from a loss of brain cells that produce the chemical messenger dopamine, which aids the transmission of brain signals that coordinate movement. This is the first time that researchers have successfully transplanted stem cells derived from the endometrium, or the lining of the uterus, into another kind of tissue (the brain) and shown that these cells can develop into cells with the properties of that tissue. The findings appear online in the Journal of Cellular and Molecular Medicine. _SD

An optimal form of brain regeneration would likely combine the use of exogenous growth factors and stem cells, along with the stimulation of endogenous stem cell and growth factor production. There is a lot to be learned about how the brain works normally, and what goes wrong in degenerative conditions, trauma, ischemia, and aging.

Even an Old Hippocampus Continues Making New Neurons

The brain maintains neuronal stem cells throughout life, according to scientists at Max Planck Institute who studied the phenomenon of lifelong neurogenesis in mouse brains.

The precise factors that influence the reactivation of dormant stem cells are not yet clear. The cells can, however, be stimulated to divide again. The scientists observed more newborn hippocampal neurons in physically active mice than in their inactive counterparts. "Consequently, running promotes the formation of new neurons," says Verdon Taylor. Pathological brain activity, for example that which occurs during epileptic seizures, also triggers the division of the neuronal stem cells.

...The presence of neurons that are formed over the course of life has also been demonstrated in the human hippocamus. Therefore, scientists suspect that different types of active and inactive stem cells also arise in the human brain. It is possible that inactive stem cells in humans can also be activated in a similar way to inactive stem cells in mice. _Physorg

If increased physical activity can stimulate new nerve cell generation, a strong argument could be made for encouraging a more active physical regimen throughout a person's lifetime. Such a finding argues for the importance of physical rehabilitation as a treatment for neurodegenerative diseases, and after a stroke or other necrotising brain injury.

Making new neurons is not the same thing as being sure the neurons are healthy and optimally functioning. Scientists are learning more about the micro-differences between healthy neurons and those that are not so healthy. The delicate micro-structures called dentritic trees or arbours, are important to good communication within the neuronal networks. And the health of these dendritic trees depends upon optimal quantities of certain cell proteins -- which are under genetic control.

And that genetic control is of course under the control of transcription factors which are influenced by a number of other things -- some under genetic control, and some influenced by the evironment.

Finding more ways that a person can optimise the generation of healthy new neurons -- and to maintain the health of those in existence -- will be worth all the time it will take.

A Second Level of Gene Transcription Control

Controlling gene expression is an important key to controlling ageing, cancer, diseases of degeneration and autoimmunity, and virtually any other mechanism of human health and pathology. As scientist learn more about the mechanisms of gene expression, they also discover new ways of intervening to prevent or treat disease. The following article discusses the ongoing clarification of an important added complexity of gene expression that will certainly be exploited for good effect before long.

A new study published online today (April 29) in Cell helps drive home just how widespread this second level of gene control is, and implicates a cancer-causing transcription factor as a major player in the process.

"This is another piece in the puzzle that demonstrates controlling the elongation phase of transcription" -- the production of messenger RNA as the transcriptional apparatus propagates down the gene -- "is one of the more important control mechanisms," said biochemist David Price of the University of Iowa, who was not involved in the study. "[This] paper is going to help convince the field that this is just the way it is."

Scientists once believed that transcription factors promoted gene expression simply by recruiting RNA polymerase II (Pol II) machinery to the promoter region of their target genes, and letting the Pol II take over from there. But over the last 20 years, several lines of evidence indicated that once bound to the promoter, Pol II pauses, or stalls, just a little ways down the transcript, and needs another signal (such as a transcription factor) to continue transcribing the gene. Recent evidence suggests that this pause is a widespread phenomenon in the genome, but "there's been some reluctance in the transcription community to accept that there are these polymerases poised [just past the start site] all throughout the human genome," Price said.

Exploring the role of this mechanism of gene control in mouse embryonic stem cells (ESCs), molecular biologist Richard Young of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology and his colleagues have all but eliminated that doubt. They found evidence of paused polymerases on the vast majority of genes -- both those actively being transcribed and those that remained silent.

"We're thinking now that at all genes where RNA polymerase II initiates transcription, there is a pause step," Young said. "So even genes that are being currently and actively transcribed, polymerase initiates [transcription], but must go through this pause checkpoint before it's allowed to proceed to elongation."

The team further showed that the well-studied transcription factor c-Myc, which is involved in cell self-renewal and proliferation and has been implicated in 15-30 percent of human cancers, is an example of the additional factor needed to push Pol II past the pause. Instead of promoting gene expression by recruiting Pol II to the genes, c-Myc appears to release already-initiated polymerases from this paused stage. It does so by recruiting a protein known as positive transcription elongation factor b (P-TEPb) to release the Pol II to finish what it started.

Understanding the details of this mechanism of gene control could thus have important implications for the treatment of a variety of ailments, said molecular biologist and clinician B. Matija Peterlin of the University of California, San Francisco, who also did not participate in the research. "I think it brings a whole new aspect to not just cancer [research] but" other diseases as well, Peterlin said. "If you attenuate the activity of P-TEFb, you might be able to [develop] a non-gene-modifying way treat a lot of human diseases."

P.B. Rahl, et al., "c-Myc regulates transcriptional pause release," Cell:141,1-14,2010.

Read more: More support for transcription trick - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57384/#ixzz0malxMCbC _the-scientist

Nano-Magnets Lead Stem Cells to Damaged Heart

A promising way of healing damaged heart tissue involves combining stem cells with nano-magnets.  The magnetised stem cells are then steered to the site of damage, using magnetic fields.

"Stem cell therapies show great promise as a treatment for heart injuries, but 24 hours after infusion, we found that less than 10 percent of the stem cells remain in the injured area," said Eduardo Marbán, M.D., director of the Cedars-Sinai Heart Institute. "Once injected into a patient's artery, many stem cells are lost due to the combination of tissue blood flow, which can wash out stem cells, and cardiac contraction, which can squeeze out stem cells. We needed to find a way to guide more of the cells directly to the area of the heart that we want to heal."
Marbán's team, including Ke Cheng, Ph.D. and other researchers, then began a new animal investigation, loading cardiac stem cells with micro-size iron particles. The iron-loaded cells were then injected into rats with a heart attack. When a toy magnet was placed externally above the heart and close to the damaged heart muscle, the stem cells clustered at the site of injury, retention of cells in the heart tripled, and the injected cells went on to heal the heart more effectively.
"Tissue viability is enhanced and heart function is greater with magnetic targeting," said Marbán, who holds the Mark Siegel Family Foundation Chair at the Cedars-Sinai Heart Institute and directs Cedars-Sinai's Board of Governors Heart Stem Cell Center. "This remarkably simple method could easily be coupled with current stem cell treatments to enhance their effectiveness." _Physorg

Image Source

The combination of stem cells with nanotechnology provides another synergistic surprise, loaded with hope for future cures and life extension potential.

Tomorrow's medical treatments will be more individualised, more targeted to specific systems and tissues. As a result, the collateral damage will be lessened, interventional dosing and exposure can be moderated, and a desired outcome can be made more likely.

Switching Off Cancer Using Nanoparticles

Cuanas
Scientists at Cal Tech in Pasadena have used targeted nanoparticles to alter the gene expression of cancer cells in human cancer patients. Their phase 1 clinical trial established the efficacy of their targeting approach and was published in the 21 March advanced online Nature.

Lead author Dr Mark E Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, told the press that in principle:

"Every protein now is druggable because its inhibition is accomplished by destroying the mRNA."

"And we can go after mRNAs in a very designed way, given all the genomic data that are and will become available," he added.

However, as is often the case, what looks straightforward in theory is fraught with obstacles when you try and apply it in practice. One such difficulty, when trying to apply RNAi technology to humans is, how do you deliver such tiny, fragile molecules, the small interfering RNAs (siRNAs), to the tumors?

Senior author Dr Antoni Ribas, an associate professor of medicine and surgery and a researcher at UCLA's Jonsson Comprehensive Cancer Center, said:

"There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive."

Davis and colleagues had a solution: they had already been working on ways to deliver nucleic acids into cells before RNAi was discovered. They eventually came up with a method featuring four components, one of which is a unique polymer that can assemble itself into a targeted nanoparticle that carries siRNA.

Davis explained that their nanoparticles can take the siRNAs into the targeted site within the body, and when they reach their target, the cancer cells inside the tumor, the nanoparticles enter the cells and release the siRNAs.

The researchers used a new method developed at Caltech to find and image the nanoparticles inside cells biopsied from the tumors of several patients taking part in the trial.

They also found that the more nanoparticles a patient was given, the more were present in the tumor cells: thus establishing there was a dose-dependent response.

But what was even better, said Davis, was they found evidence the siRNAs had done their job: in the cells they analyzed, which had been targeted to prevent production of the cell-growth protein ribonucleotide reductase, they found the corresponding mRNA had been degraded. Thus effectively the siRNAs had silenced the gene that was fuelling cancer growth.

Davis explained that this was the first time that anyone has found an RNA fragment from patient cells showing that the RNAi mechanism had severed the mRNA at exactly the correct base:

"It proves that the RNA interference mechanism can happen using siRNA in a human," said Davis.

Ribas said:

"This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles."

"We can start thinking about targeting the untargetable," he added. _MedicalNews

As the authors say, this is just the beginning. Silencing gene expression by targeting the mRNA is only a temporary approach. If such treatment kills all of the cancer cells -- and leaves normal cells alone -- then being only temporary will not be an impediment.

But in many types of cancer -- and other disease -- it will not be enough merely to block the offensive mRNA. You will want to alter the DNA itself to put a permanent stop to the flow of a particular unwanted mRNA. That will require a different approach altogether.

The challenge is vast and seemingly unending. But it is worthwhile.

H/T Cuanas

New Hope for Treating Autoimmune Diseases

Cell
The autoimmune diseases cause untold pain, misery, and hardship -- not to mention expense -- throughout the human lifespan. When the person's immune system attacks other cells in his own body, treatment options are generally limited and sub-optimal. But now, researchers at the University of Alberta, Calgary, have devised a treatment (and prevention) for Type 1 diabetes which may lead to a revolution in the treatment and prevention of autoimmune diseases -- such as multiple sclerosis, rheumatoid arthritis, lupus, and many more.

Researchers from the University of Calgary in Alberta, led by Dr. Pere Santamaria, were looking to halt the autoimmune response that causes type 1 diabetes, but do so without damaging the immune cells that control and regulate the immune system or that protect against infections. So the team focused on developing a highly targeted antigen-specific immunotherapy - one, they explained, that could address the "internal tug-of-war between aggressive T cells that want to cause the disease and weaker T cells that want to stop it from occurring."

The researchers produced a unique vaccine comprising nanoparticles, which are thousands of times smaller than the size of a cell. They coated the particles with type 1 diabetes-relevant peptides, or protein fragments, that were bound to certain molecules that play a critical role in immune cell communication (called MHC molecules).

In the mice, the nanoparticle treatment expanded a type of regulatory T cell -- these cells ultimately suppressed the aggressive immune attack that destroys the insulin-producing beta cells of the pancreas. The researchers noted that the expanded cells shut down the immune attack by preventing autoreactive immune cells from being stimulated, either by the peptide contained in the vaccine or by any other diabetes autoantigen presented simultaneously by antigen-presenting cells. With the immune response that causes diabetes blocked, mice with type 1 diabetes regained normal blood sugars. And those that would have contracted the disease didn't.

The study also provides important - and promising - insight into the ability to translate these findings into therapeutics for people: Nanoparticles that were coated with molecules specific to human type 1 diabetes were able to restore normal blood sugar levels in a humanized mouse model of diabetes (that is, a mouse that has been genetically altered to biologically simulate type 1 diabetes in people). _ jdrf

Article abstract from Cell

H/T Brian Wang

Science is slowly but surely decoding the complex signaling involved in life, disease, and ageing. With the better tools being provided by advanced genetics, nanotechnology, immunology, and information technology, it is easy to feel that there are no secrets of life that will not be unwrapped and decoded sooner or later.

Human Cell Aging Reversed by Biotime

Biotime researchers report the successful resetting of the "age clock" of mature human cells back to the embryonic age. This was apparently accomplished using telomeric technology similar to what Geron has been working on.

In the article, BioTime and its collaborators demonstrate the successful reversal of the developmental aging of normal human cells. Using precise genetic modifications, normal human cells were induced to reverse both the "clock" of differentiation (the process by which an embryonic stem cell becomes the many specialized differentiated cell types of the body), and the "clock" of cellular aging (telomere length). As a result, aged differentiated cells became young stem cells capable of regeneration.
_NextBigFuture

More links, videos, and information from Brian Wang and at the BioTime website.

Hydrogen Sulfide Suspended Animation Video

Roth's technique replaces inhaled oxygen with hydrogen sulfide. Normally toxic, hydrogen sulfide has the curious ability to alter the mammalian metabolism when applied in a cold environment. Using this technique, Roth has already managed to place lab animals into suspended animation, and safely bring them back. When in a suspended state, the body can better cope with the deadly oxygen deprivation that results from shock, massive blood loss, and heart attacks.
Source

The 1000 Year Old Brain? Can They Last?

Aubrey de Grey claims that the first person to live 1,000 years is alive right now. Perhaps. But would anyone alive right now wish to live 1,000 years with a senile brain? Probably not. That is why it is so important to learn all we can about our brains, so that we can make the necessary improvements that will allow us to stay sharp, clear, and responsive to the many changes that the next 1,000 years will bring.

A World of Manics, Where No One is Depressed?

University of Maryland researchers have taken mice and knocked out PKCI/HINT1 genes -- resulting in mice that do not get depressed or anxious.

Wang said, "Although we don't yet know why the deletion of the gene altered the mood status of the mice, what we have learned about the importance of this gene in mood function and its involvement in human mental disorders is interesting. The protein encoded by this gene could be a potential drug target for development of diagnostic or therapeutic agents that one day might be used for depression, bipolar or schizophrenia disorders. In addition, the knockout mice might be useful as a model to study mania, as there is no other animal model available yet. __MNT

When thrown in the deep end of the pool, these PKCI/HINT1 knockout mice never gave up in despair, when all other mice simply rolled over and drowned. They were literally "never say die" mice. Imagine a world of such people.

Excitable Nerves, They All Said

Sometimes nerves can "excite themselves to death." This over-excitation of NMDA glutamate receptors may lead to Alzheimer's, Parkinson's, and multiple sclerosis -- among other neurodegenerative diseases.

....the N-methyl-D-aspartate receptor belongs to a family of cellular receptors that mediate excitatory nerve transmission in the brain.


Excitatory signals represent the majority of nerve signals in most regions of the human brain. One theory of causation in Alzheimer's, Parkinson's and multiple sclerosis posits that excessive amounts of the excitatory neurotransmitter, glutamate, can cause an overstimulation of glutamate receptors, including the NMDA receptor. Such excitotoxicity, the theory holds, can cause nerve-cell death and subsequent neurological dysfunction.


...The search is well under way for molecules that can shut down the NMDA receptor with much greater specificity. _MNT

Memories to Last 1000 Years?

Humans have short term memories (STMs) and long term memories (LTMs). Short term memory is necessary for maintaining a train of thought, or for remembering why you tied that string around your finger an hour or two ago. Long term memory is for remembering things that happened to you more than a day or so ago. These memories are formed and farmed out by the hippocampus, and the system usually works well for a lifespan of 70 or 80 years. But what happens when we live 1,000 years, and desperately need to remember something that happened 899 years ago?

Scientists have known that memories first form in the hippocampus and are later transferred to long-term storage in other parts of the brain. For some amount of time the memory resides both in the hippocampus and elsewhere in the brain. What’s not been known is how, after a few months or years, the memory is gradually cleared from the hippocampus.


Researchers have also debated the role of neurogenesis in learning and memory. The hippocampus is one of only two places in the adult brain where scientists know that new neurons form. On the basis of previous studies, many researchers think new neurons stabilize memory circuits or are somehow otherwise necessary to form new memories.


The new study suggests the opposite: Newborn neurons weaken or disrupt connections that encode old memories in the hippocampus.


Kaoru Inokuchi, a neuroscientist at the University of Toyama in Japan, and his colleagues used radiation and some genetic tricks to block neurogenesis in rats and mice that had been trained to fear getting a mild electric shock when placed in a particular cage. Control animals, with normal neurogenesis, eventually were able to bypass their hippocampi and retrieve the fear memory directly from long-term storage. But animals in which neurogenesis had been blocked still depended on the hippocampus to recall the fear memory, the researchers found.


Running on an exercise wheel, which boosts neurogenesis, also sped the rate at which old memories were cleared from the hippocampus. __Wired

Surviving the Addiction Bottleneck

The human brain has to survive through the treacherous years of childhood, adolescence, and early adulthood in order to gain the wisdom and experience to know how to live, and what to avoid like the plague. Children, adolescents, and young adults are prone to experimenting with drugs, alcohol, and high-risk / low reward behaviours. If the child becomes a crack whore or even an adolescent drunk or pothead like the US president, the 1,000 year prognosis can be very grim.

We need good ways of reversing the brain warp induced by early and habitual drug use.

Medical researchers led by Stephen Dewey at The Feinstein Institute for Medical Research and Dr. Jonathan Brodie of New York University School of Medicine recruited parolees who were cocaine dependent, each using an average of two grams of cocaine daily for nine years.


While half the participants in the study received a placebo powder mixed into their juice each day, half got a powder containing vigabatrin. After three months, 14 of the 50 study participants who got vigabatrin each day were able to abstain from cocaine use during the final three weeks of the study, compared with only 4 of the 53 who received the placebo. _MoneyTimes

It's a start. And in animals, the same drug reduces drug use for most every addictive substance. Of course, it will be harder to make up for the psychological neotenisation caused by poor childraising, abominable educational practises, and a horrifically dumbed down popular culture.

Does Evolution's Arrow Point to Smaller Human Brains?

Human populations that evolved nearer the equator ended up with generally smaller brains, and typically with lower IQ, than human populations that evolved farther from the equator. Anthropologist John Hawks says that the future may be bringing yet smaller brains to the entire global population.

“We know the brain has been evolving in human populations quite recently,” University of Wisconsin-Madison (UWM) paleoanthropologist John Hawks explains, quoted by LiveScience.

“When it comes to recent evolutionary changes, we currently maybe have the least specific details with regard [to] the brain, but we do know from archaeological data that pretty much everywhere we can measure – Europe, China, South Africa, Australia – that brains have shrunk about 150 cubic centimeters, off a mean of about 1,350. That's roughly 10 percent. As to why is it shrinking, perhaps in big societies, as opposed to hunter-gatherer lifestyles, we can rely on other people for more things, can specialize our behavior to a greater extent, and maybe not need our brains as much,” the expert adds. _Softpedia

Modern cultures of hyper-specialisation may lead to even greater shrinking of the human brain. That could be bad for that 1,000 year lifespan.

Smaller brains are typically less intelligent, and will probably be less able to adapt to the lightspeed changes that will hit human populations like truckloads of bricks, every few years to every few dozen years.

Cross-posted at Al Fin

Stem Cell Advances

Any adult cell can become a stem cell. This is a striking finding from the Cambridge, Mass. researchers.

“Essentially, all cells have the potential to become pluripotent. It is something that seems to happen to the cells under these conditions stochastically — that is, in a continuous, but probabilistic fashion,” Jaenisch explains. _Softpedia

Stem cell treatment restores limb function in rats with cervical spine injuries. The UCI team used human embryonic stem cells (pre-oligodendrocytes) that "rebuilt myelin, stopped tissue death and triggered nerve fiber regrowth".

Patients with advanced leukemia successfully treated with stem cells. Of the 58 patients, 35% survived 3 years -- an exceptionally good result for patients at such an advanced stage.

New technique developed to separate "safe" from "unsafe" stem cells before therapy. Stem cells vary in their likelihood to grow out of control and cause malignancies. "Undifferentiated" stem cells are more likely to lose control of growth.

Scientists from Invitrogen and the Buck Institute for Age Research, located in Novato, California, collaborated in developing this innovative solution that depletes greater than 99% of undifferentiated human embryonic stem cells from differentiated populations. They are presenting data on this new technology at the International Society for Cellular Therapy Meeting in San Diego. __LabmateOnline

Stem cells provide the bricks and mortar for constructing human tissues and organs. We are just beginning to learn how to create them, and to use them safely and efficaciously. In ten years -- if the US biomedical system has not been completely destroyed by government intervention -- we will look back to the present, amazed that human medicine was ever so primitive and hopelessly ineffective.

SENS4 Conference in Cambridge England Underway

Kristen Fortney from Ouroborus blog is covering the 4th Strategies for Engineered Negligible Senescence conference, presently underway in Cambridge, England. Below are some excerpts of Kristen's coverage, courtesy of Fight Aging:

SENS4, Session 1: Combating oxidation

Cathy Clarke tested an original and interesting approach to avoiding free radical damage to poly-unsaturated fatty acids, or PUFAs: isotope reinforcement. ... The basic idea here, explained in an earlier paper, is very simple: heavier isotopes make stronger bonds, so isotope-reinforced PUFAs will be more resistant to free radical attack. Will these results transfer to higher organisms? Is there any chance that the deuterium could get incorporated into other molecules, stabilizing proteins that we want to degrade? The authors plan to follow up this study in worms and mice.

SENS4, Session 3: Optimising metabolism against aging

Stephen Spindler described his (ongoing) project to screen a large number of potential lifespan-affecting compounds in mice - so far, several candidates look promising. Interestingly, he also argued that the majority of previous studies measuring the effects of various compounds on rodent life expectancy suffer from serious flaws. In particular, he argued that many of them were confounded by a possible calorie restriction effect: mice are picky eaters, and if you change their diet by adding some compound to it, they will often eat less of it.

SENS4, Session 4: Adult regenerative capacity

Brandon Reines presented a counterintuitive result on regeneration: sometimes old animals have a higher regenerative capacity than young animals. In particular, if you punch a hole in the ear of a young mouse, then it won’t heal; but in a middle-aged mouse it will heal completely. He argued that this happens because mouse ear connective tissues never fully differentiate, and suggested that other neural-crest-derived connective tissues might show similar properties.

SENS4, Session 5: Eliminating recalcitrant intracellular molecules: the lysosome

John Schloendorn discussed ongoing work at the SENS Foundation Research Center to develop new enzymes that can degrade harmful intracellular junk that accumulates with age. So far, they have discovered enzymes that can degrade A2E and 7-ketocholesterol, which are implicated in macular degeneration and osteoporosis, respectively. Their next step will be to construct a drug delivery system to get these enzymes to lysozomes ... On the lighter side, Schloendorn also described some of the Center’s methods for building functional lab equipment on the cheap, all good examples for aspiring DIY biologists.

SENS4, Session 6: Eliminating recalcitrant intracellular molecules: other

Claude Wischik spoke about preventing aggregation of tau protein, which is implicated in Alzheimer’s disease. Clinical trials of their aggregation-inhibiting drug Rember are promising: it seems to slow the down the rate of cognitive decline in patients with mild to moderate Alzheimer’s disease.

SENS4, Sessions 9 and 10: Rejuvenating extracellular material

Kendall Houk gave a very interesting talk on computationally designing enzymes from scratch. They plan to apply their recently published protocol to develop enzymes that can reverse the formation of Advanced Glycation End-products (AGEs) - sugar-modified proteins that accumulate with age and are implicated in several age-related diseases. _links to more information

Ouroborus is updating Kristen's coverage as it comes in.

Twitter updates

Aubrey de Grey's SENS initiative has achieved prominence in scientific gerontology, thanks to financing from the Methuselah Foundation. Under most government health care and pension systems, long life is a bad thing, since the longer you live, the longer the government has to support your existence. That may be why so little progress was made under government financed gerontology research.

With private funding via SENS, expect much more progress. The same applies to private financing of space launch, and other crucial innovations. The private sector is all about getting results. The government is all about soaking up as many resources as possible, growing as large as possible, and employing as many public sector union members as possible.

Cross posted at Al Fin